Cleveland Clinic Journal of Medicine

Clinical biofeedback therapy is one of the many new approaches in health care aimed at helping individuals take responsibility for their well-being, including responsibility for the cognitive, emotional, and behavioral changes needed to effect healthy physiologic change. This article provides a brief survey of biofeedback therapy by defining what biofeedback involves, reviewing the various modalities that it can serve to monitor, discussing major models of biofeedback therapy, and outlining criteria for evaluating the efficacy of biofeedback interventions.

BIOFEEDBACK: BOTH PROCESS AND INSTRUMENTATION

Biofeedback refers to both a process and the instrumentation used in that process.

The process is one of learning to use physiologic information that is monitored and “fed back” through biofeedback instruments. The term dates from 1969, when it was coined to describe laboratory procedures that had been developed in the 1940s in which research subjects learned to modify heart rate, blood flow, and other physiologic functions that were not normally thought of as being subject to conscious control. Feedback itself has been present through much of human history, particularly through the use of mirrored surfaces to practice the expression of emotion.¹

Biofeedback instruments monitor one or more physiologic processes, measure what is monitored and transform that measurement into auditory and/or visual signals, and present what is monitored and measured in a simple, direct, and immediate way. Biofeedback equipment typically is noninvasive. The instruments provide continuous monitoring and transformation of physiologic data into understandable feedback for the patient being monitored. Current computerized instruments can provide simultaneous displays and recording of multiple channels of physiologic information. The goal is to enable the individual being monitored to change some physiologic process, guided by the information provided by the biofeedback equipment. How many training sessions are necessary varies with the individual and the disorder, ranging from a few to 50 or more. Our experience is that the great majority of patients obtain benefit in 8 to 12 sessions.

MULTIPLE MODALITIES FOR MONITORING

Multiple modalities can be monitored via biofeedback. Surface electromyography is perhaps the most commonly used instrumentation. Other commonly used measures in a psychophysiologic/biofeedback assessment are respiration rate and depth, skin surface temperature (particularly at the fingertips), cardiovascular reactivity (particularly heart rate and blood pressure), and electrodermal response.²

Feedback of real-time physiologic data is limited only by one’s creativity and technological capabilities. Most of the early noncomputerized equipment provided feedback through the onset and offset of sounds, the changing of tones and volume, the turning on and off of lights, and digital numeric displays indicating both the direction of change and absolute values (such as digital peripheral temperature). Current computerized equipment uses such feedback features as computer games, which the patient “wins” by reaching a goal (such as a systolic blood pressure level below 130 mm Hg), mandalas that can be filled in with colors of the patient’s choosing as he or she progresses in the desired direction, and complex computer-generated figures and graphs.

Electroencephalographic biofeedback (neurofeedback) has become a separate area of study and application, with particular use in the treatment of attention deficit disorder. A baseline electroencephalogram is used in neurofeedback assessment to identify abnormal patterns, and follow-up training is provided to teach the patient to change these patterns in a healthy direction.³

More recently, heart rate variability has come into use as a measure of adaptability or autonomic balance. Soviet scientists were the first to study heart rate variability biofeedback, working with cosmonauts in measuring autonomic function. They found that the low-frequency (0.1-Hz) bands produced the highest frequency-specific oscillations in heart rate variability, and training typically proceeds in increasing amplitude of the low-frequency band (also called the baroreceptor band). Because diminished heart rate variability is a predictor of increased risk for cardiac mortality, teaching patients to increase heart rate variability made sense. The training involves instruction in breathing at an identified resonant frequency that is related to optimal low-frequency band power.⁴

Accurate feedback facilitates the learning of any skill, whether it be sinking a golf putt, solving an algebra problem, or controlling physiologic behavior. A man playing darts blindfolded is unlikely to achieve as good a score as he would with the blindfold off, because feedback makes a difference.⁵

Four conditions are important for effective learning;⁵ the learner must:

• Have the capacity to respond
• Be motivated to learn
• Be positively reinforced for learning
• Be given accurate information about the results of the learning effort.

Direct feedback learning model

The direct feedback learning model assumes that adding feedback to the other important conditions of learning will result in a patient gaining control of the relevant physiology being targeted. This model has been used in treating many disorders, including Raynaud phenomenon and urinary and fecal incontinence.

Biofeedback training in this model may involve a coach/instructor/therapist only to the extent of explaining the equipment and its use. In other words, the coach “teaches the patient how to use the mirror.” More commonly.particularly for training in lowered arousal for patients in whom stress reactivity is a significant factor in the development and maintenance of excessive (sympathetic nervous system) arousal that leads to symptoms.a skilled therapist is present. The therapist not only teaches the patient how to use information from biofeedback instruments but also guides the patient in identifying and changing cognitive, emotional, and behavioral patterns that contribute to excessive reactivity. The relationship of physiologic reactivity to the subject matter under discussion also helps diagnostically in identifying stressful areas of life, particularly in psychophysiologic responders who are repressive and denying and who are not good at identifying the stressors in their lives. The equipment becomes a mirror that lets the patient see a problem that he or she had not identified as such.⁵

Therapeutic/stress-management/biofeedback model

When treating patients with disordered physiology (including autonomic imbalance) in the therapeutic/stress-management/biofeedback model, it is essential to understand each patient as an individual. In this model, stress management and psychotherapeutic interventions address particular vulnerabilities that lead to excessive arousal. This approach starts with a psychophysiologic assessment in which resting levels of relevant physiologic dimensions are measured; this is followed by imposition of stressors to measure reactivity and then by a recovery period in which rate and extent of recovery are measured. An interview and psychological test help determine which cognitive, emotional and behavioral patterns contribute to vulnerability. Patients typically respond well to this approach. It is common for patients to use such descriptions as, “I break out in a cold sweat when I’m stressed,” or “I feel heartsick when I’m stressed,” which suggests that the notion of mind-body interaction resonates with patients.⁶

CRITERIA FOR EVALUATING EFFICACY OF BIOFEEDBACK INTERVENTIONS

Several years ago a task force of the Association for Applied Psychophysiology and Biofeedback and the Society for Neuronal Regulation published criteria for evaluating the clinical efficacy of biofeedback/psychophysiologic interventions.⁷ These criteria are detailed below.^3,7

Level 1: Not empirically supported

This designation applies to interventions supported only by anecdotal reports and/or case studies in non–peer-reviewed venues (ie, not empirically supported).

Level 2: Possibly efficacious

This applies to interventions supported by at least one study of sufficient statistical power with well-identified outcome measures but which lacked randomized assignment to a control condition internal to the study.

Level 3: Probably efficacious

This applies to interventions supported by multiple observational studies, clinical studies, wait-list–controlled studies, and within-subject and intrasubject replication studies that demonstrate efficacy.

Level 4: Efficacious

a. In a comparison with a no-treatment control group, alternative treatment group, or sham (placebo) control using randomized assignment, the intervention is shown to be statistically significantly superior to the control condition, or the intervention is equivalent to a treatment of established efficacy in a study with sufficient power to detect moderate differences, and

b. The studies have been conducted with a population treated for a specific problem, for whom inclusion criteria are delineated in a reliable, operationally defined manner, and

c. The study used valid and clearly specified outcome measures related to the problem being treated, and

d. The data were subjected to appropriate data analysis, and

e. The diagnostic and treatment variables and procedures were clearly defined in a manner that permits replication of the study by independent researchers, and

f. The superiority or equivalence of the intervention has been shown in at least two independent research settings.

Level 5: Efficacious and specific

This designation applies when the intervention has been shown to be superior to credible sham therapy, pill therapy, or alternative bona fide treatment in at least two independent research settings.

Efficacy ratings for specific disorders

Despite high standards, biofeedback thrives

The above criteria represent high standards. Since biofeedback training is often more like physical therapy or learning a language, double-blind protocols usually are not feasible, nor is sham training. Moreover, the effectiveness of training is perhaps even more difficult to assess in daily practice, with the inevitable multiplicity of confounding variables. Nevertheless, biofeedback training for many disorders is standing the test of both time and outcomes research, and it is increasingly embraced by the public and recognized by health care insurers and professionals alike.

Clinical biofeedback therapy is one of the many new approaches in health care aimed at helping individuals take responsibility for their well-being, including responsibility for the cognitive, emotional, and behavioral changes needed to effect healthy physiologic change. This article provides a brief survey of biofeedback therapy by defining what biofeedback involves, reviewing the various modalities that it can serve to monitor, discussing major models of biofeedback therapy, and outlining criteria for evaluating the efficacy of biofeedback interventions.

BIOFEEDBACK: BOTH PROCESS AND INSTRUMENTATION

Biofeedback refers to both a process and the instrumentation used in that process.

The process is one of learning to use physiologic information that is monitored and “fed back” through biofeedback instruments. The term dates from 1969, when it was coined to describe laboratory procedures that had been developed in the 1940s in which research subjects learned to modify heart rate, blood flow, and other physiologic functions that were not normally thought of as being subject to conscious control. Feedback itself has been present through much of human history, particularly through the use of mirrored surfaces to practice the expression of emotion.¹

Biofeedback instruments monitor one or more physiologic processes, measure what is monitored and transform that measurement into auditory and/or visual signals, and present what is monitored and measured in a simple, direct, and immediate way. Biofeedback equipment typically is noninvasive. The instruments provide continuous monitoring and transformation of physiologic data into understandable feedback for the patient being monitored. Current computerized instruments can provide simultaneous displays and recording of multiple channels of physiologic information. The goal is to enable the individual being monitored to change some physiologic process, guided by the information provided by the biofeedback equipment. How many training sessions are necessary varies with the individual and the disorder, ranging from a few to 50 or more. Our experience is that the great majority of patients obtain benefit in 8 to 12 sessions.

MULTIPLE MODALITIES FOR MONITORING

Multiple modalities can be monitored via biofeedback. Surface electromyography is perhaps the most commonly used instrumentation. Other commonly used measures in a psychophysiologic/biofeedback assessment are respiration rate and depth, skin surface temperature (particularly at the fingertips), cardiovascular reactivity (particularly heart rate and blood pressure), and electrodermal response.²

Feedback of real-time physiologic data is limited only by one’s creativity and technological capabilities. Most of the early noncomputerized equipment provided feedback through the onset and offset of sounds, the changing of tones and volume, the turning on and off of lights, and digital numeric displays indicating both the direction of change and absolute values (such as digital peripheral temperature). Current computerized equipment uses such feedback features as computer games, which the patient “wins” by reaching a goal (such as a systolic blood pressure level below 130 mm Hg), mandalas that can be filled in with colors of the patient’s choosing as he or she progresses in the desired direction, and complex computer-generated figures and graphs.

Electroencephalographic biofeedback (neurofeedback) has become a separate area of study and application, with particular use in the treatment of attention deficit disorder. A baseline electroencephalogram is used in neurofeedback assessment to identify abnormal patterns, and follow-up training is provided to teach the patient to change these patterns in a healthy direction.³

More recently, heart rate variability has come into use as a measure of adaptability or autonomic balance. Soviet scientists were the first to study heart rate variability biofeedback, working with cosmonauts in measuring autonomic function. They found that the low-frequency (0.1-Hz) bands produced the highest frequency-specific oscillations in heart rate variability, and training typically proceeds in increasing amplitude of the low-frequency band (also called the baroreceptor band). Because diminished heart rate variability is a predictor of increased risk for cardiac mortality, teaching patients to increase heart rate variability made sense. The training involves instruction in breathing at an identified resonant frequency that is related to optimal low-frequency band power.⁴

Accurate feedback facilitates the learning of any skill, whether it be sinking a golf putt, solving an algebra problem, or controlling physiologic behavior. A man playing darts blindfolded is unlikely to achieve as good a score as he would with the blindfold off, because feedback makes a difference.⁵

Four conditions are important for effective learning;⁵ the learner must:

• Have the capacity to respond
• Be motivated to learn
• Be positively reinforced for learning
• Be given accurate information about the results of the learning effort.

Direct feedback learning model

The direct feedback learning model assumes that adding feedback to the other important conditions of learning will result in a patient gaining control of the relevant physiology being targeted. This model has been used in treating many disorders, including Raynaud phenomenon and urinary and fecal incontinence.

Biofeedback training in this model may involve a coach/instructor/therapist only to the extent of explaining the equipment and its use. In other words, the coach “teaches the patient how to use the mirror.” More commonly.particularly for training in lowered arousal for patients in whom stress reactivity is a significant factor in the development and maintenance of excessive (sympathetic nervous system) arousal that leads to symptoms.a skilled therapist is present. The therapist not only teaches the patient how to use information from biofeedback instruments but also guides the patient in identifying and changing cognitive, emotional, and behavioral patterns that contribute to excessive reactivity. The relationship of physiologic reactivity to the subject matter under discussion also helps diagnostically in identifying stressful areas of life, particularly in psychophysiologic responders who are repressive and denying and who are not good at identifying the stressors in their lives. The equipment becomes a mirror that lets the patient see a problem that he or she had not identified as such.⁵

Therapeutic/stress-management/biofeedback model

When treating patients with disordered physiology (including autonomic imbalance) in the therapeutic/stress-management/biofeedback model, it is essential to understand each patient as an individual. In this model, stress management and psychotherapeutic interventions address particular vulnerabilities that lead to excessive arousal. This approach starts with a psychophysiologic assessment in which resting levels of relevant physiologic dimensions are measured; this is followed by imposition of stressors to measure reactivity and then by a recovery period in which rate and extent of recovery are measured. An interview and psychological test help determine which cognitive, emotional and behavioral patterns contribute to vulnerability. Patients typically respond well to this approach. It is common for patients to use such descriptions as, “I break out in a cold sweat when I’m stressed,” or “I feel heartsick when I’m stressed,” which suggests that the notion of mind-body interaction resonates with patients.⁶

CRITERIA FOR EVALUATING EFFICACY OF BIOFEEDBACK INTERVENTIONS

Several years ago a task force of the Association for Applied Psychophysiology and Biofeedback and the Society for Neuronal Regulation published criteria for evaluating the clinical efficacy of biofeedback/psychophysiologic interventions.⁷ These criteria are detailed below.^3,7

Level 1: Not empirically supported

This designation applies to interventions supported only by anecdotal reports and/or case studies in non–peer-reviewed venues (ie, not empirically supported).

Level 2: Possibly efficacious

This applies to interventions supported by at least one study of sufficient statistical power with well-identified outcome measures but which lacked randomized assignment to a control condition internal to the study.

Level 3: Probably efficacious

This applies to interventions supported by multiple observational studies, clinical studies, wait-list–controlled studies, and within-subject and intrasubject replication studies that demonstrate efficacy.

Level 4: Efficacious

a. In a comparison with a no-treatment control group, alternative treatment group, or sham (placebo) control using randomized assignment, the intervention is shown to be statistically significantly superior to the control condition, or the intervention is equivalent to a treatment of established efficacy in a study with sufficient power to detect moderate differences, and

b. The studies have been conducted with a population treated for a specific problem, for whom inclusion criteria are delineated in a reliable, operationally defined manner, and

c. The study used valid and clearly specified outcome measures related to the problem being treated, and

d. The data were subjected to appropriate data analysis, and

e. The diagnostic and treatment variables and procedures were clearly defined in a manner that permits replication of the study by independent researchers, and

f. The superiority or equivalence of the intervention has been shown in at least two independent research settings.

Level 5: Efficacious and specific

This designation applies when the intervention has been shown to be superior to credible sham therapy, pill therapy, or alternative bona fide treatment in at least two independent research settings.

Efficacy ratings for specific disorders

Despite high standards, biofeedback thrives

The above criteria represent high standards. Since biofeedback training is often more like physical therapy or learning a language, double-blind protocols usually are not feasible, nor is sham training. Moreover, the effectiveness of training is perhaps even more difficult to assess in daily practice, with the inevitable multiplicity of confounding variables. Nevertheless, biofeedback training for many disorders is standing the test of both time and outcomes research, and it is increasingly embraced by the public and recognized by health care insurers and professionals alike.

Clinical biofeedback therapy is one of the many new approaches in health care aimed at helping individuals take responsibility for their well-being, including responsibility for the cognitive, emotional, and behavioral changes needed to effect healthy physiologic change. This article provides a brief survey of biofeedback therapy by defining what biofeedback involves, reviewing the various modalities that it can serve to monitor, discussing major models of biofeedback therapy, and outlining criteria for evaluating the efficacy of biofeedback interventions.

BIOFEEDBACK: BOTH PROCESS AND INSTRUMENTATION

Biofeedback refers to both a process and the instrumentation used in that process.

The process is one of learning to use physiologic information that is monitored and “fed back” through biofeedback instruments. The term dates from 1969, when it was coined to describe laboratory procedures that had been developed in the 1940s in which research subjects learned to modify heart rate, blood flow, and other physiologic functions that were not normally thought of as being subject to conscious control. Feedback itself has been present through much of human history, particularly through the use of mirrored surfaces to practice the expression of emotion.¹

Biofeedback instruments monitor one or more physiologic processes, measure what is monitored and transform that measurement into auditory and/or visual signals, and present what is monitored and measured in a simple, direct, and immediate way. Biofeedback equipment typically is noninvasive. The instruments provide continuous monitoring and transformation of physiologic data into understandable feedback for the patient being monitored. Current computerized instruments can provide simultaneous displays and recording of multiple channels of physiologic information. The goal is to enable the individual being monitored to change some physiologic process, guided by the information provided by the biofeedback equipment. How many training sessions are necessary varies with the individual and the disorder, ranging from a few to 50 or more. Our experience is that the great majority of patients obtain benefit in 8 to 12 sessions.

MULTIPLE MODALITIES FOR MONITORING

Multiple modalities can be monitored via biofeedback. Surface electromyography is perhaps the most commonly used instrumentation. Other commonly used measures in a psychophysiologic/biofeedback assessment are respiration rate and depth, skin surface temperature (particularly at the fingertips), cardiovascular reactivity (particularly heart rate and blood pressure), and electrodermal response.²

Feedback of real-time physiologic data is limited only by one’s creativity and technological capabilities. Most of the early noncomputerized equipment provided feedback through the onset and offset of sounds, the changing of tones and volume, the turning on and off of lights, and digital numeric displays indicating both the direction of change and absolute values (such as digital peripheral temperature). Current computerized equipment uses such feedback features as computer games, which the patient “wins” by reaching a goal (such as a systolic blood pressure level below 130 mm Hg), mandalas that can be filled in with colors of the patient’s choosing as he or she progresses in the desired direction, and complex computer-generated figures and graphs.

Electroencephalographic biofeedback (neurofeedback) has become a separate area of study and application, with particular use in the treatment of attention deficit disorder. A baseline electroencephalogram is used in neurofeedback assessment to identify abnormal patterns, and follow-up training is provided to teach the patient to change these patterns in a healthy direction.³

More recently, heart rate variability has come into use as a measure of adaptability or autonomic balance. Soviet scientists were the first to study heart rate variability biofeedback, working with cosmonauts in measuring autonomic function. They found that the low-frequency (0.1-Hz) bands produced the highest frequency-specific oscillations in heart rate variability, and training typically proceeds in increasing amplitude of the low-frequency band (also called the baroreceptor band). Because diminished heart rate variability is a predictor of increased risk for cardiac mortality, teaching patients to increase heart rate variability made sense. The training involves instruction in breathing at an identified resonant frequency that is related to optimal low-frequency band power.⁴

Accurate feedback facilitates the learning of any skill, whether it be sinking a golf putt, solving an algebra problem, or controlling physiologic behavior. A man playing darts blindfolded is unlikely to achieve as good a score as he would with the blindfold off, because feedback makes a difference.⁵

Four conditions are important for effective learning;⁵ the learner must:

• Have the capacity to respond
• Be motivated to learn
• Be positively reinforced for learning
• Be given accurate information about the results of the learning effort.

Direct feedback learning model

The direct feedback learning model assumes that adding feedback to the other important conditions of learning will result in a patient gaining control of the relevant physiology being targeted. This model has been used in treating many disorders, including Raynaud phenomenon and urinary and fecal incontinence.

Biofeedback training in this model may involve a coach/instructor/therapist only to the extent of explaining the equipment and its use. In other words, the coach “teaches the patient how to use the mirror.” More commonly.particularly for training in lowered arousal for patients in whom stress reactivity is a significant factor in the development and maintenance of excessive (sympathetic nervous system) arousal that leads to symptoms.a skilled therapist is present. The therapist not only teaches the patient how to use information from biofeedback instruments but also guides the patient in identifying and changing cognitive, emotional, and behavioral patterns that contribute to excessive reactivity. The relationship of physiologic reactivity to the subject matter under discussion also helps diagnostically in identifying stressful areas of life, particularly in psychophysiologic responders who are repressive and denying and who are not good at identifying the stressors in their lives. The equipment becomes a mirror that lets the patient see a problem that he or she had not identified as such.⁵

Therapeutic/stress-management/biofeedback model

When treating patients with disordered physiology (including autonomic imbalance) in the therapeutic/stress-management/biofeedback model, it is essential to understand each patient as an individual. In this model, stress management and psychotherapeutic interventions address particular vulnerabilities that lead to excessive arousal. This approach starts with a psychophysiologic assessment in which resting levels of relevant physiologic dimensions are measured; this is followed by imposition of stressors to measure reactivity and then by a recovery period in which rate and extent of recovery are measured. An interview and psychological test help determine which cognitive, emotional and behavioral patterns contribute to vulnerability. Patients typically respond well to this approach. It is common for patients to use such descriptions as, “I break out in a cold sweat when I’m stressed,” or “I feel heartsick when I’m stressed,” which suggests that the notion of mind-body interaction resonates with patients.⁶

CRITERIA FOR EVALUATING EFFICACY OF BIOFEEDBACK INTERVENTIONS

Several years ago a task force of the Association for Applied Psychophysiology and Biofeedback and the Society for Neuronal Regulation published criteria for evaluating the clinical efficacy of biofeedback/psychophysiologic interventions.⁷ These criteria are detailed below.^3,7

Level 1: Not empirically supported

This designation applies to interventions supported only by anecdotal reports and/or case studies in non–peer-reviewed venues (ie, not empirically supported).

Level 2: Possibly efficacious

This applies to interventions supported by at least one study of sufficient statistical power with well-identified outcome measures but which lacked randomized assignment to a control condition internal to the study.

Level 3: Probably efficacious

This applies to interventions supported by multiple observational studies, clinical studies, wait-list–controlled studies, and within-subject and intrasubject replication studies that demonstrate efficacy.

Level 4: Efficacious

a. In a comparison with a no-treatment control group, alternative treatment group, or sham (placebo) control using randomized assignment, the intervention is shown to be statistically significantly superior to the control condition, or the intervention is equivalent to a treatment of established efficacy in a study with sufficient power to detect moderate differences, and

b. The studies have been conducted with a population treated for a specific problem, for whom inclusion criteria are delineated in a reliable, operationally defined manner, and

c. The study used valid and clearly specified outcome measures related to the problem being treated, and

d. The data were subjected to appropriate data analysis, and

e. The diagnostic and treatment variables and procedures were clearly defined in a manner that permits replication of the study by independent researchers, and

f. The superiority or equivalence of the intervention has been shown in at least two independent research settings.

Level 5: Efficacious and specific

This designation applies when the intervention has been shown to be superior to credible sham therapy, pill therapy, or alternative bona fide treatment in at least two independent research settings.

Efficacy ratings for specific disorders

Despite high standards, biofeedback thrives

The above criteria represent high standards. Since biofeedback training is often more like physical therapy or learning a language, double-blind protocols usually are not feasible, nor is sham training. Moreover, the effectiveness of training is perhaps even more difficult to assess in daily practice, with the inevitable multiplicity of confounding variables. Nevertheless, biofeedback training for many disorders is standing the test of both time and outcomes research, and it is increasingly embraced by the public and recognized by health care insurers and professionals alike.

The potential of biofeedback therapies in cardiovascular disease is only recently beginning to be explored in a systematic way. This article reviews the rationale for the use of biofeedback therapy in cardiovascular disease and briefly surveys research on the usefulness of biofeedback for several specific cardiovascular parameters and conditions.

RECOGNIZING THE POTENTIAL OF BIOFEEDBACK IN CARDIOVASCULAR DISEASE

Biofeedback is part of a group of modalities known as “self-regulation therapies,” in which a subject is taught to control the activities of his or her autonomic nervous system. The autonomic nervous system has also been called the “visceral,” “involuntary,” and “automatic” nervous system, which suggests that the physiologic processes governed by this branch of the nervous system are largely beyond conscious control. Until the 1950s, this was largely believed to be true. Physicians and scientists had been convinced that the functions regulated by the sympathetic and parasympathetic branches of the autonomic nervous system, such as digestion, blood pressure, and body temperature, were not amenable to self-regulation.

During the 1950s, however, it became clear that functions of the autonomic nervous system could be controlled by conscious thought and training. Subjects could be taught to correctly perceive and also to control heart rate, blood pressure, skin temperature, and other seemingly involuntary functions. The field of biofeedback and applied psychophysiology became possible with these discoveries and with the advent of technologies capable of measuring physiologic variables with enough sensitivity to detect small changes.

Key role of sympathetic/parasympathetic balance

In cardiovascular medicine, biofeedback has a great deal of therapeutic potential because many diseases of the heart and vasculature involve inappropriate regulation of the autonomic nervous system.

Under normal conditions, the sympathetic branch of the autonomic nervous system serves to augment cardiac function in times of stress, increasing heart rate, contractility, and blood pressure, as well as favoring clotting processes that would be mainly adaptive during the “fight or flight” response. The parasympathetic branch of the autonomic nervous system plays the opposite role during health, exerting a calming influence on cardiovascular function.

Normal cardiovascular function is regulated by a balance between sympathetic and parasympathetic inputs to the heart and blood vessels. Heart rate, for example, is governed by the parasympathetic nervous system under resting conditions, when the intrinsic firing rate of the sinus node is decreased by vagal input. Under stressful conditions, this inhibition is released and sympathetic excitation can increase the heart rate even further. In many pathological cardiac conditions, such as arrhythmias, an imbalance between the two branches of the autonomic nervous system causes at least some of the disease manifestations and often contributes to progression.

Biofeedback as a ‘physiologic beta-blocker’

Another good example is heart failure, where over-activation of the sympathetic nervous system results in many of the phenotypic changes in the myocardium and contributes to the downward spiral from compensatory cardiac hypertrophy to end-stage decompensated failure. The role of sympathetic overactivation in heart failure is clearly evident by the success of beta-adrenergic blocking agents in ameliorating symptoms and delaying disease progression. Given the role of autonomic nervous system dysregulation in cardiovascular diseases, biofeedback therapy has the potential to teach patients a skill that may allow them to decrease activation of their autonomic nervous system, theoretically acting as a “physiologic beta-blocker.”

An adjunct to stress management

The potential of biofeedback to have an impact in the arena of cardiovascular disease has not been well explored. Clinically, biofeedback is often used in the context of stress management programs, but biofeedback is not synonymous with stress management. Stress management programs most commonly involve some type of relaxation training and perhaps cognitive behavioral therapy. Biofeedback can be used to augment relaxation, helping the subject to be more aware of physiologic responses and thus be better able to elicit the relaxation response. Biofeedback can also be used to train subjects to control particular physiologic responses that contribute to symptoms or to disease progression. In cardiovascular disease, although stress management is frequently a component of cardiac rehabilitation programs, the question of whether stress management is more effective with or without biofeedback has not been systematically investigated.

PIONEERING STUDIES OF BIOFEEDBACK IN CARDIOVASCULAR DISEASE

Some of the earliest studies of physiologic regulation using biofeedback were attempted in patients with cardiovascular abnormalities. In 1971, Weiss and Engel reported success in using operant conditioning of heart rate in eight patients with premature ventricular contractions.¹ All eight patients were able to achieve some degree of control, and five of the patients were able to decrease the frequency of premature beats, demonstrating increased success over a 21-month follow-up period. Interestingly, use of pharmacologic agents to understand the mechanisms of control suggested that one patient was able to decrease sympathetic control of his heart rate while another increased the parasympathetic influence.

Several years later, Pickering and Gorham reported their work with a single subject, a 31-year-old woman who had a ventricular parasystolic rhythm.² Using a biofeedback technique, they were able to teach the woman to voluntarily control her heart rate, demonstrating that she could both increase and decrease the rate, avoiding the ranges in which the arrhythmia occurred. In the same year, Benson et al demonstrated that they could teach patients the relaxation response and decrease the incidence of premature ventricular contractions.³ Using Holter monitors for validation, these investigators showed that 4 weeks of relaxation training resulted in 8 of 11 patients being able to control their heart rates sufficiently to have therapeutic impact.

These pioneering studies were very early in the development of the field of biofeedback, but they showed what has been clearly established since—that the input of the autonomic nervous system to the heart can be regulated by biofeedback techniques.

A host of parameters for assessment

Many cardiovascular parameters can be used for biofeedback. Commonly these include heart rate, blood pressure, skin temperature, and, more recently, heart rate variability. In each case, the parameter is measured and displayed for the subject, and the subject is taught to make it change in a positive direction through relaxation, thought patterns, imagery, or some combination of techniques. Many times the display of the physiologic parameter and the demonstration that it can be controlled are quite surprising to the subject and lead to an enhanced desire to participate in the therapy.

Heart rate variability: A focus of recent interest

The newest parameter in use, and one that has gained considerable interest in the field of cardiovascular biofeedback, is heart rate variability.⁴ Heart rate variability refers to the variation within the R-R interval of the electrocardiogram during a fixed cycle. It is associated with adaptiveness of the cardiovascular system, and high variability is believed to be a sign of health. Low variability is associated with a number of disease states. Heart rate variability reflects the balance between sympathetic and parasympathetic input to the heart, and many cardiac disease states have been shown to be associated with low variability. Therapies that increase heart rate variability have been shown to improve prognosis.

On the basis of these observations, heart rate variability biofeedback is used to train patients to increase the variability in their heart rate, using feedback from equipment that records the R-R interval from the electrocardiogram or from blood pulse volume sensors. Patients learn to make the variability greater, primarily by breathing at a resonant frequency, as described by Lehrer et al.⁵

Several preliminary studies have been conducted with heart rate variability in cardiac patients, but much remains to be understood about its use. In 63 patients with established coronary artery disease, Del Pozo et al showed that six biofeedback sessions coupled with daily practice resulted in significantly increased heart rate variability.⁶ Similarly, Nolan and colleagues found that five sessions of biofeedback improved symptoms and quality of life in 46 patients with coronary artery disease.⁷ In 14 patients with heart failure, Luskin et al demonstrated that eight sessions of heart rate variability biofeedback produced reductions in perceived stress and improved function on the 6-minute walk test.⁸

It remains unclear whether heart rate variability biofeedback has more or less potential than other types of biofeedback in patients with cardiovascular disease, but these preliminary observations suggest that it may be useful in improving symptoms and quality of life.

Biofeedback in hypertension: Despite decades of study, conclusions elusive

Among diseases of the cardiovascular system, biofeedback has been used most frequently in hypertension, where it has been under investigation for more than 30 years, since the early days of biofeedback study.⁹ The field of biofeedback in hypertension is fraught with difficulties, rendering conclusions about its efficacy difficult.

Biofeedback has been assessed in many different types of hypertension, often within the same study. Essential hypertension and “white coat” hypertension, now known as excessive cardiovascular reactivity, have been most commonly investigated, but with no apparent consensus. The biofeedback techniques used in these studies have ranged from blood pressure biofeedback to electromyography, finger temperature, and skin conductance. More recently, heart rate variability biofeedback has also been used in this population.

In general, biofeedback has been more successful in the treatment of hypertension when respiratory training has been a component of the biofeedback. McGrady has established that certain types of patients with hypertension fare better with biofeedback than others.¹⁰ These include patients with higher baseline blood pressure, higher heart rate, cool hands, high electromyographic response, and high plasma renin activity.in short, patients who can be seen to have a high degree of sympathetic arousal.

Blood pressure can be lowered by 6 to 10 mm Hg when biofeedback is effective, which is less of an effect than that observed with most drug therapy for hypertension. Biofeedback does have the advantage, however, of improving overall cardiovascular reactivity and giving the patient a greater sense of control over his or her physical well-being, which may prove valuable in the setting of hypertension. Typically, the most effective interventions for hypertension (and perhaps for cardiovascular disease in general) are individualized for the patient and not protocol-driven. Thus, although biofeedback has potential in hypertension, its efficacy is not proven and systematic trials are lacking.

Biofeedback in heart failure: Targeting sympathetic overactivation

In patients with heart failure, the sympathetic nervous system is overactivated, as noted previously. High levels of plasma norepinephrine correlate with worse prognosis. Decreasing activation of the sympathetic nervous system improves both symptoms and prognosis, as demonstrated in patients taking beta-adrenergic blocking agents or those treated with a left ventricular assist device.

Several studies have suggested that biofeedback may be able to provide a similar reduction in sympathetic nervous system activation in patients with heart failure. Moser and colleagues showed that a single session of skin temperature biofeedback plus relaxation training increased cardiac output in patients with heart failure,¹¹ while studies by Weiner et al,¹² Bernardi et al,¹³ and Mangin et al¹⁴ showed that training heart failure patients to breathe more slowly increased their exercise tolerance. Although these studies are preliminary, they support the speculation that if biofeedback can decrease activation of the sympathetic nervous system in patients with heart failure, it may actually cause some degree of remodeling of the failing heart, such as that observed with beta-blockers or left ventricular assist device therapy.  

As mentioned earlier, biofeedback can serve as a component of stress management programs. Biofeedback is often a very effective adjunct to stress management because it teaches the subject to control physiologic reactions that are part of the stress response and gives the subject feedback to suggest that he or she is adequately practicing relaxation. Biofeedback-mediated stress management may actually be the most practical use of biofeedback in the setting of cardiovascular disease because it is easy to practice and can have an effect on large numbers of patients.

Mental stress has been well documented as a significant risk factor for many forms of cardiovascular disease, and stress management programs have been shown to have an impact on disease progression and symptoms. Many studies, including those reported by Sheps et al for the Psychophysiological Investigations of Myocardial Ischemia (PIMI) study,¹⁵ have shown that patients who exhibit ischemia in response to a mental stress test have increased mortality from cardiovascular disease. Jiang and colleagues,¹⁶ among others, have shown that mental stress predicts cardiac events in patients with lower ejection fractions, and Blumenthal et al¹⁷ have repeatedly demonstrated that stress management training reduces the incidence of wall motion abnormalities in patients with cardiovascular disease. Stress management is included in many cardiac rehabilitation programs, and it is likely that routine use of biofeedback as a component of stress management programs would benefit patients with cardiovascular disease, in whom reproducibly decreasing activation of the autonomic nervous system should be helpful.

According to a recent article in the Heart Advisor, 84% of physicians believe that stress is a risk for cardiovascular disease but only 35% say they feel knowledgeable about stress and a mere 5% feel that they succeed in helping stressed patients.¹⁸ Anything that could improve these numbers would be beneficial.

CONCLUSIONS

Cardiovascular conditions in which biofeedback has been shown to be helpful include arrhythmias, hypertension, Raynaud phenomenon, ischemia, infarction, and heart failure, but we have barely begun to explore the potential of biofeedback therapy. Given that many cardiovascular diseases involve inappropriate regulation of the autonomic nervous system, instruction in the use of biofeedback to control activation of the sympathetic and parasympathetic nervous systems is likely to be useful in cardiac patients. Systematic trials are needed.

The potential of biofeedback therapies in cardiovascular disease is only recently beginning to be explored in a systematic way. This article reviews the rationale for the use of biofeedback therapy in cardiovascular disease and briefly surveys research on the usefulness of biofeedback for several specific cardiovascular parameters and conditions.

RECOGNIZING THE POTENTIAL OF BIOFEEDBACK IN CARDIOVASCULAR DISEASE

Biofeedback is part of a group of modalities known as “self-regulation therapies,” in which a subject is taught to control the activities of his or her autonomic nervous system. The autonomic nervous system has also been called the “visceral,” “involuntary,” and “automatic” nervous system, which suggests that the physiologic processes governed by this branch of the nervous system are largely beyond conscious control. Until the 1950s, this was largely believed to be true. Physicians and scientists had been convinced that the functions regulated by the sympathetic and parasympathetic branches of the autonomic nervous system, such as digestion, blood pressure, and body temperature, were not amenable to self-regulation.

During the 1950s, however, it became clear that functions of the autonomic nervous system could be controlled by conscious thought and training. Subjects could be taught to correctly perceive and also to control heart rate, blood pressure, skin temperature, and other seemingly involuntary functions. The field of biofeedback and applied psychophysiology became possible with these discoveries and with the advent of technologies capable of measuring physiologic variables with enough sensitivity to detect small changes.

Key role of sympathetic/parasympathetic balance

In cardiovascular medicine, biofeedback has a great deal of therapeutic potential because many diseases of the heart and vasculature involve inappropriate regulation of the autonomic nervous system.

Under normal conditions, the sympathetic branch of the autonomic nervous system serves to augment cardiac function in times of stress, increasing heart rate, contractility, and blood pressure, as well as favoring clotting processes that would be mainly adaptive during the “fight or flight” response. The parasympathetic branch of the autonomic nervous system plays the opposite role during health, exerting a calming influence on cardiovascular function.

Normal cardiovascular function is regulated by a balance between sympathetic and parasympathetic inputs to the heart and blood vessels. Heart rate, for example, is governed by the parasympathetic nervous system under resting conditions, when the intrinsic firing rate of the sinus node is decreased by vagal input. Under stressful conditions, this inhibition is released and sympathetic excitation can increase the heart rate even further. In many pathological cardiac conditions, such as arrhythmias, an imbalance between the two branches of the autonomic nervous system causes at least some of the disease manifestations and often contributes to progression.

Biofeedback as a ‘physiologic beta-blocker’

Another good example is heart failure, where over-activation of the sympathetic nervous system results in many of the phenotypic changes in the myocardium and contributes to the downward spiral from compensatory cardiac hypertrophy to end-stage decompensated failure. The role of sympathetic overactivation in heart failure is clearly evident by the success of beta-adrenergic blocking agents in ameliorating symptoms and delaying disease progression. Given the role of autonomic nervous system dysregulation in cardiovascular diseases, biofeedback therapy has the potential to teach patients a skill that may allow them to decrease activation of their autonomic nervous system, theoretically acting as a “physiologic beta-blocker.”

An adjunct to stress management

The potential of biofeedback to have an impact in the arena of cardiovascular disease has not been well explored. Clinically, biofeedback is often used in the context of stress management programs, but biofeedback is not synonymous with stress management. Stress management programs most commonly involve some type of relaxation training and perhaps cognitive behavioral therapy. Biofeedback can be used to augment relaxation, helping the subject to be more aware of physiologic responses and thus be better able to elicit the relaxation response. Biofeedback can also be used to train subjects to control particular physiologic responses that contribute to symptoms or to disease progression. In cardiovascular disease, although stress management is frequently a component of cardiac rehabilitation programs, the question of whether stress management is more effective with or without biofeedback has not been systematically investigated.

PIONEERING STUDIES OF BIOFEEDBACK IN CARDIOVASCULAR DISEASE

Some of the earliest studies of physiologic regulation using biofeedback were attempted in patients with cardiovascular abnormalities. In 1971, Weiss and Engel reported success in using operant conditioning of heart rate in eight patients with premature ventricular contractions.¹ All eight patients were able to achieve some degree of control, and five of the patients were able to decrease the frequency of premature beats, demonstrating increased success over a 21-month follow-up period. Interestingly, use of pharmacologic agents to understand the mechanisms of control suggested that one patient was able to decrease sympathetic control of his heart rate while another increased the parasympathetic influence.

Several years later, Pickering and Gorham reported their work with a single subject, a 31-year-old woman who had a ventricular parasystolic rhythm.² Using a biofeedback technique, they were able to teach the woman to voluntarily control her heart rate, demonstrating that she could both increase and decrease the rate, avoiding the ranges in which the arrhythmia occurred. In the same year, Benson et al demonstrated that they could teach patients the relaxation response and decrease the incidence of premature ventricular contractions.³ Using Holter monitors for validation, these investigators showed that 4 weeks of relaxation training resulted in 8 of 11 patients being able to control their heart rates sufficiently to have therapeutic impact.

These pioneering studies were very early in the development of the field of biofeedback, but they showed what has been clearly established since—that the input of the autonomic nervous system to the heart can be regulated by biofeedback techniques.

A host of parameters for assessment

Many cardiovascular parameters can be used for biofeedback. Commonly these include heart rate, blood pressure, skin temperature, and, more recently, heart rate variability. In each case, the parameter is measured and displayed for the subject, and the subject is taught to make it change in a positive direction through relaxation, thought patterns, imagery, or some combination of techniques. Many times the display of the physiologic parameter and the demonstration that it can be controlled are quite surprising to the subject and lead to an enhanced desire to participate in the therapy.

Heart rate variability: A focus of recent interest

The newest parameter in use, and one that has gained considerable interest in the field of cardiovascular biofeedback, is heart rate variability.⁴ Heart rate variability refers to the variation within the R-R interval of the electrocardiogram during a fixed cycle. It is associated with adaptiveness of the cardiovascular system, and high variability is believed to be a sign of health. Low variability is associated with a number of disease states. Heart rate variability reflects the balance between sympathetic and parasympathetic input to the heart, and many cardiac disease states have been shown to be associated with low variability. Therapies that increase heart rate variability have been shown to improve prognosis.

On the basis of these observations, heart rate variability biofeedback is used to train patients to increase the variability in their heart rate, using feedback from equipment that records the R-R interval from the electrocardiogram or from blood pulse volume sensors. Patients learn to make the variability greater, primarily by breathing at a resonant frequency, as described by Lehrer et al.⁵

Several preliminary studies have been conducted with heart rate variability in cardiac patients, but much remains to be understood about its use. In 63 patients with established coronary artery disease, Del Pozo et al showed that six biofeedback sessions coupled with daily practice resulted in significantly increased heart rate variability.⁶ Similarly, Nolan and colleagues found that five sessions of biofeedback improved symptoms and quality of life in 46 patients with coronary artery disease.⁷ In 14 patients with heart failure, Luskin et al demonstrated that eight sessions of heart rate variability biofeedback produced reductions in perceived stress and improved function on the 6-minute walk test.⁸

It remains unclear whether heart rate variability biofeedback has more or less potential than other types of biofeedback in patients with cardiovascular disease, but these preliminary observations suggest that it may be useful in improving symptoms and quality of life.

Biofeedback in hypertension: Despite decades of study, conclusions elusive

Among diseases of the cardiovascular system, biofeedback has been used most frequently in hypertension, where it has been under investigation for more than 30 years, since the early days of biofeedback study.⁹ The field of biofeedback in hypertension is fraught with difficulties, rendering conclusions about its efficacy difficult.

Biofeedback has been assessed in many different types of hypertension, often within the same study. Essential hypertension and “white coat” hypertension, now known as excessive cardiovascular reactivity, have been most commonly investigated, but with no apparent consensus. The biofeedback techniques used in these studies have ranged from blood pressure biofeedback to electromyography, finger temperature, and skin conductance. More recently, heart rate variability biofeedback has also been used in this population.

In general, biofeedback has been more successful in the treatment of hypertension when respiratory training has been a component of the biofeedback. McGrady has established that certain types of patients with hypertension fare better with biofeedback than others.¹⁰ These include patients with higher baseline blood pressure, higher heart rate, cool hands, high electromyographic response, and high plasma renin activity.in short, patients who can be seen to have a high degree of sympathetic arousal.

Blood pressure can be lowered by 6 to 10 mm Hg when biofeedback is effective, which is less of an effect than that observed with most drug therapy for hypertension. Biofeedback does have the advantage, however, of improving overall cardiovascular reactivity and giving the patient a greater sense of control over his or her physical well-being, which may prove valuable in the setting of hypertension. Typically, the most effective interventions for hypertension (and perhaps for cardiovascular disease in general) are individualized for the patient and not protocol-driven. Thus, although biofeedback has potential in hypertension, its efficacy is not proven and systematic trials are lacking.

Biofeedback in heart failure: Targeting sympathetic overactivation

In patients with heart failure, the sympathetic nervous system is overactivated, as noted previously. High levels of plasma norepinephrine correlate with worse prognosis. Decreasing activation of the sympathetic nervous system improves both symptoms and prognosis, as demonstrated in patients taking beta-adrenergic blocking agents or those treated with a left ventricular assist device.

Several studies have suggested that biofeedback may be able to provide a similar reduction in sympathetic nervous system activation in patients with heart failure. Moser and colleagues showed that a single session of skin temperature biofeedback plus relaxation training increased cardiac output in patients with heart failure,¹¹ while studies by Weiner et al,¹² Bernardi et al,¹³ and Mangin et al¹⁴ showed that training heart failure patients to breathe more slowly increased their exercise tolerance. Although these studies are preliminary, they support the speculation that if biofeedback can decrease activation of the sympathetic nervous system in patients with heart failure, it may actually cause some degree of remodeling of the failing heart, such as that observed with beta-blockers or left ventricular assist device therapy.  

As mentioned earlier, biofeedback can serve as a component of stress management programs. Biofeedback is often a very effective adjunct to stress management because it teaches the subject to control physiologic reactions that are part of the stress response and gives the subject feedback to suggest that he or she is adequately practicing relaxation. Biofeedback-mediated stress management may actually be the most practical use of biofeedback in the setting of cardiovascular disease because it is easy to practice and can have an effect on large numbers of patients.

Mental stress has been well documented as a significant risk factor for many forms of cardiovascular disease, and stress management programs have been shown to have an impact on disease progression and symptoms. Many studies, including those reported by Sheps et al for the Psychophysiological Investigations of Myocardial Ischemia (PIMI) study,¹⁵ have shown that patients who exhibit ischemia in response to a mental stress test have increased mortality from cardiovascular disease. Jiang and colleagues,¹⁶ among others, have shown that mental stress predicts cardiac events in patients with lower ejection fractions, and Blumenthal et al¹⁷ have repeatedly demonstrated that stress management training reduces the incidence of wall motion abnormalities in patients with cardiovascular disease. Stress management is included in many cardiac rehabilitation programs, and it is likely that routine use of biofeedback as a component of stress management programs would benefit patients with cardiovascular disease, in whom reproducibly decreasing activation of the autonomic nervous system should be helpful.

According to a recent article in the Heart Advisor, 84% of physicians believe that stress is a risk for cardiovascular disease but only 35% say they feel knowledgeable about stress and a mere 5% feel that they succeed in helping stressed patients.¹⁸ Anything that could improve these numbers would be beneficial.

CONCLUSIONS

Cardiovascular conditions in which biofeedback has been shown to be helpful include arrhythmias, hypertension, Raynaud phenomenon, ischemia, infarction, and heart failure, but we have barely begun to explore the potential of biofeedback therapy. Given that many cardiovascular diseases involve inappropriate regulation of the autonomic nervous system, instruction in the use of biofeedback to control activation of the sympathetic and parasympathetic nervous systems is likely to be useful in cardiac patients. Systematic trials are needed.

The potential of biofeedback therapies in cardiovascular disease is only recently beginning to be explored in a systematic way. This article reviews the rationale for the use of biofeedback therapy in cardiovascular disease and briefly surveys research on the usefulness of biofeedback for several specific cardiovascular parameters and conditions.

RECOGNIZING THE POTENTIAL OF BIOFEEDBACK IN CARDIOVASCULAR DISEASE

Biofeedback is part of a group of modalities known as “self-regulation therapies,” in which a subject is taught to control the activities of his or her autonomic nervous system. The autonomic nervous system has also been called the “visceral,” “involuntary,” and “automatic” nervous system, which suggests that the physiologic processes governed by this branch of the nervous system are largely beyond conscious control. Until the 1950s, this was largely believed to be true. Physicians and scientists had been convinced that the functions regulated by the sympathetic and parasympathetic branches of the autonomic nervous system, such as digestion, blood pressure, and body temperature, were not amenable to self-regulation.

During the 1950s, however, it became clear that functions of the autonomic nervous system could be controlled by conscious thought and training. Subjects could be taught to correctly perceive and also to control heart rate, blood pressure, skin temperature, and other seemingly involuntary functions. The field of biofeedback and applied psychophysiology became possible with these discoveries and with the advent of technologies capable of measuring physiologic variables with enough sensitivity to detect small changes.

Key role of sympathetic/parasympathetic balance

In cardiovascular medicine, biofeedback has a great deal of therapeutic potential because many diseases of the heart and vasculature involve inappropriate regulation of the autonomic nervous system.

Under normal conditions, the sympathetic branch of the autonomic nervous system serves to augment cardiac function in times of stress, increasing heart rate, contractility, and blood pressure, as well as favoring clotting processes that would be mainly adaptive during the “fight or flight” response. The parasympathetic branch of the autonomic nervous system plays the opposite role during health, exerting a calming influence on cardiovascular function.

Normal cardiovascular function is regulated by a balance between sympathetic and parasympathetic inputs to the heart and blood vessels. Heart rate, for example, is governed by the parasympathetic nervous system under resting conditions, when the intrinsic firing rate of the sinus node is decreased by vagal input. Under stressful conditions, this inhibition is released and sympathetic excitation can increase the heart rate even further. In many pathological cardiac conditions, such as arrhythmias, an imbalance between the two branches of the autonomic nervous system causes at least some of the disease manifestations and often contributes to progression.

Biofeedback as a ‘physiologic beta-blocker’

Another good example is heart failure, where over-activation of the sympathetic nervous system results in many of the phenotypic changes in the myocardium and contributes to the downward spiral from compensatory cardiac hypertrophy to end-stage decompensated failure. The role of sympathetic overactivation in heart failure is clearly evident by the success of beta-adrenergic blocking agents in ameliorating symptoms and delaying disease progression. Given the role of autonomic nervous system dysregulation in cardiovascular diseases, biofeedback therapy has the potential to teach patients a skill that may allow them to decrease activation of their autonomic nervous system, theoretically acting as a “physiologic beta-blocker.”

An adjunct to stress management

The potential of biofeedback to have an impact in the arena of cardiovascular disease has not been well explored. Clinically, biofeedback is often used in the context of stress management programs, but biofeedback is not synonymous with stress management. Stress management programs most commonly involve some type of relaxation training and perhaps cognitive behavioral therapy. Biofeedback can be used to augment relaxation, helping the subject to be more aware of physiologic responses and thus be better able to elicit the relaxation response. Biofeedback can also be used to train subjects to control particular physiologic responses that contribute to symptoms or to disease progression. In cardiovascular disease, although stress management is frequently a component of cardiac rehabilitation programs, the question of whether stress management is more effective with or without biofeedback has not been systematically investigated.

PIONEERING STUDIES OF BIOFEEDBACK IN CARDIOVASCULAR DISEASE

Some of the earliest studies of physiologic regulation using biofeedback were attempted in patients with cardiovascular abnormalities. In 1971, Weiss and Engel reported success in using operant conditioning of heart rate in eight patients with premature ventricular contractions.¹ All eight patients were able to achieve some degree of control, and five of the patients were able to decrease the frequency of premature beats, demonstrating increased success over a 21-month follow-up period. Interestingly, use of pharmacologic agents to understand the mechanisms of control suggested that one patient was able to decrease sympathetic control of his heart rate while another increased the parasympathetic influence.

Several years later, Pickering and Gorham reported their work with a single subject, a 31-year-old woman who had a ventricular parasystolic rhythm.² Using a biofeedback technique, they were able to teach the woman to voluntarily control her heart rate, demonstrating that she could both increase and decrease the rate, avoiding the ranges in which the arrhythmia occurred. In the same year, Benson et al demonstrated that they could teach patients the relaxation response and decrease the incidence of premature ventricular contractions.³ Using Holter monitors for validation, these investigators showed that 4 weeks of relaxation training resulted in 8 of 11 patients being able to control their heart rates sufficiently to have therapeutic impact.

These pioneering studies were very early in the development of the field of biofeedback, but they showed what has been clearly established since—that the input of the autonomic nervous system to the heart can be regulated by biofeedback techniques.

A host of parameters for assessment

Many cardiovascular parameters can be used for biofeedback. Commonly these include heart rate, blood pressure, skin temperature, and, more recently, heart rate variability. In each case, the parameter is measured and displayed for the subject, and the subject is taught to make it change in a positive direction through relaxation, thought patterns, imagery, or some combination of techniques. Many times the display of the physiologic parameter and the demonstration that it can be controlled are quite surprising to the subject and lead to an enhanced desire to participate in the therapy.

Heart rate variability: A focus of recent interest

The newest parameter in use, and one that has gained considerable interest in the field of cardiovascular biofeedback, is heart rate variability.⁴ Heart rate variability refers to the variation within the R-R interval of the electrocardiogram during a fixed cycle. It is associated with adaptiveness of the cardiovascular system, and high variability is believed to be a sign of health. Low variability is associated with a number of disease states. Heart rate variability reflects the balance between sympathetic and parasympathetic input to the heart, and many cardiac disease states have been shown to be associated with low variability. Therapies that increase heart rate variability have been shown to improve prognosis.

On the basis of these observations, heart rate variability biofeedback is used to train patients to increase the variability in their heart rate, using feedback from equipment that records the R-R interval from the electrocardiogram or from blood pulse volume sensors. Patients learn to make the variability greater, primarily by breathing at a resonant frequency, as described by Lehrer et al.⁵

Several preliminary studies have been conducted with heart rate variability in cardiac patients, but much remains to be understood about its use. In 63 patients with established coronary artery disease, Del Pozo et al showed that six biofeedback sessions coupled with daily practice resulted in significantly increased heart rate variability.⁶ Similarly, Nolan and colleagues found that five sessions of biofeedback improved symptoms and quality of life in 46 patients with coronary artery disease.⁷ In 14 patients with heart failure, Luskin et al demonstrated that eight sessions of heart rate variability biofeedback produced reductions in perceived stress and improved function on the 6-minute walk test.⁸

It remains unclear whether heart rate variability biofeedback has more or less potential than other types of biofeedback in patients with cardiovascular disease, but these preliminary observations suggest that it may be useful in improving symptoms and quality of life.

Biofeedback in hypertension: Despite decades of study, conclusions elusive

Among diseases of the cardiovascular system, biofeedback has been used most frequently in hypertension, where it has been under investigation for more than 30 years, since the early days of biofeedback study.⁹ The field of biofeedback in hypertension is fraught with difficulties, rendering conclusions about its efficacy difficult.

Biofeedback has been assessed in many different types of hypertension, often within the same study. Essential hypertension and “white coat” hypertension, now known as excessive cardiovascular reactivity, have been most commonly investigated, but with no apparent consensus. The biofeedback techniques used in these studies have ranged from blood pressure biofeedback to electromyography, finger temperature, and skin conductance. More recently, heart rate variability biofeedback has also been used in this population.

In general, biofeedback has been more successful in the treatment of hypertension when respiratory training has been a component of the biofeedback. McGrady has established that certain types of patients with hypertension fare better with biofeedback than others.¹⁰ These include patients with higher baseline blood pressure, higher heart rate, cool hands, high electromyographic response, and high plasma renin activity.in short, patients who can be seen to have a high degree of sympathetic arousal.

Blood pressure can be lowered by 6 to 10 mm Hg when biofeedback is effective, which is less of an effect than that observed with most drug therapy for hypertension. Biofeedback does have the advantage, however, of improving overall cardiovascular reactivity and giving the patient a greater sense of control over his or her physical well-being, which may prove valuable in the setting of hypertension. Typically, the most effective interventions for hypertension (and perhaps for cardiovascular disease in general) are individualized for the patient and not protocol-driven. Thus, although biofeedback has potential in hypertension, its efficacy is not proven and systematic trials are lacking.

Biofeedback in heart failure: Targeting sympathetic overactivation

In patients with heart failure, the sympathetic nervous system is overactivated, as noted previously. High levels of plasma norepinephrine correlate with worse prognosis. Decreasing activation of the sympathetic nervous system improves both symptoms and prognosis, as demonstrated in patients taking beta-adrenergic blocking agents or those treated with a left ventricular assist device.

Several studies have suggested that biofeedback may be able to provide a similar reduction in sympathetic nervous system activation in patients with heart failure. Moser and colleagues showed that a single session of skin temperature biofeedback plus relaxation training increased cardiac output in patients with heart failure,¹¹ while studies by Weiner et al,¹² Bernardi et al,¹³ and Mangin et al¹⁴ showed that training heart failure patients to breathe more slowly increased their exercise tolerance. Although these studies are preliminary, they support the speculation that if biofeedback can decrease activation of the sympathetic nervous system in patients with heart failure, it may actually cause some degree of remodeling of the failing heart, such as that observed with beta-blockers or left ventricular assist device therapy.  

As mentioned earlier, biofeedback can serve as a component of stress management programs. Biofeedback is often a very effective adjunct to stress management because it teaches the subject to control physiologic reactions that are part of the stress response and gives the subject feedback to suggest that he or she is adequately practicing relaxation. Biofeedback-mediated stress management may actually be the most practical use of biofeedback in the setting of cardiovascular disease because it is easy to practice and can have an effect on large numbers of patients.

Mental stress has been well documented as a significant risk factor for many forms of cardiovascular disease, and stress management programs have been shown to have an impact on disease progression and symptoms. Many studies, including those reported by Sheps et al for the Psychophysiological Investigations of Myocardial Ischemia (PIMI) study,¹⁵ have shown that patients who exhibit ischemia in response to a mental stress test have increased mortality from cardiovascular disease. Jiang and colleagues,¹⁶ among others, have shown that mental stress predicts cardiac events in patients with lower ejection fractions, and Blumenthal et al¹⁷ have repeatedly demonstrated that stress management training reduces the incidence of wall motion abnormalities in patients with cardiovascular disease. Stress management is included in many cardiac rehabilitation programs, and it is likely that routine use of biofeedback as a component of stress management programs would benefit patients with cardiovascular disease, in whom reproducibly decreasing activation of the autonomic nervous system should be helpful.

According to a recent article in the Heart Advisor, 84% of physicians believe that stress is a risk for cardiovascular disease but only 35% say they feel knowledgeable about stress and a mere 5% feel that they succeed in helping stressed patients.¹⁸ Anything that could improve these numbers would be beneficial.

CONCLUSIONS

Cardiovascular conditions in which biofeedback has been shown to be helpful include arrhythmias, hypertension, Raynaud phenomenon, ischemia, infarction, and heart failure, but we have barely begun to explore the potential of biofeedback therapy. Given that many cardiovascular diseases involve inappropriate regulation of the autonomic nervous system, instruction in the use of biofeedback to control activation of the sympathetic and parasympathetic nervous systems is likely to be useful in cardiac patients. Systematic trials are needed.

Training in self-hypnosis, with or without biofeedback, is a valuable adjunct for children and adults with chronic illnesses or behavioral problems. After defining terms and briefly reviewing the evolution of medical hypnosis, this article provides an overview of the clinical utility and applications of self-hypnosis and various issues in its use, including patient assessment, concurrent use with biofeedback, and how health care providers can become trained in self-hypnosis instruction. Because my experience is primarily with medical hypnosis in children and adolescents, portions of this discussion will devote particular attention to the use of hypnosis in children.

DEFINITIONS

Hypnosis is a state of awareness, often but not always associated with relaxation, during which the participant can give him- or herself suggestions for desired changes to which he or she is more likely to respond than when in the usual state of awareness. Spontaneous self-hypnosis may happen while reading, listening to music, watching television, jogging, dancing, playing a musical instrument, doing tai chi, doing yoga, or performing similar activities. Terms often used to describe mind-body training include relaxation imagery, guided imagery, or visual imagery. These include the same training strategies as those used in hypnosis.

Biofeedback is a term coined in 1969 to describe procedures (developed in 1940s) for training subjects to alter physiologic responses such as brain activity, blood pressure, muscle tension, or heart rate. With biofeedback, participants are trained to improve their health and performance by using signals from their own bodies. In so doing, they strengthen awareness of the connections between their mind and body.

Cyberphysiology was defined by Dr. Earl E. Bakken at the first Archaeus Congress, held in Santa Fe, New Mexico, in 1986. “Cyber” derives from the Greek kybernan, meaning steersman or helmsman. From kybernan came the Latinate term govern, meaning “to control.” Thus, cyberphysiology means to control a physiologic response. In scientific terms, cyberphysiology is the study of how neurally mediated autonomic responses—usually viewed as automatic, reactive reflexes—can be modified by a learning process that appears to be significantly dependent on modification of mental images. Both hypnosis and biofeedback are cyberphysiologic strategies that enable the user to develop voluntary control of certain physiologic processes.

HISTORICAL BEGINNINGS OF HYPNOSIS

Franz Mesmer developed a training system that he called animal magnetism. Mesmer believed that normal body processes were disrupted when there was improper distribution of magnetism, a kind of fluid that could penetrate all matter. He described his ability to direct this magnetic fluid through his presence with the waving of a metallic rod and contact with a large wooden tub called a baquet. Mesmer was convinced that the successful therapeutic effects he observed depended on the magnetic rods he used.

When jealous and hostile colleagues challenged Mesmer’s clinical successes, King Louis XVI of France called for an investigative commission chaired by Benjamin Franklin, who was then the American ambassador to France. Other commission members included Dr. Antoine Lavoisier, the first to isolate the element of oxygen, and Dr. Antoine Guillotine, well known for developing a machine for beheading.¹ After the commission conducted some clever experiments, they concluded that Mesmer’s success was related to application of the imagination. In fact, we are not far beyond that concept today, although we now have brain imaging documentation of changes in the brain associated with the practice of hypnosis.^2–5

CORRECTING MISCONCEPTIONS ABOUT HYPNOSIS

Hypnosis is not sleep

Modern hypnosis is considered to have begun with Mesmer, although the term hypnosis was first used by James Braid, a Scottish ophthalmologist, in 1843. His decision to derive the word from hypnos, the Greek word for sleep, was unfortunate. Hypnosis is not sleep, but the name confuses people.

All hypnosis is self-hypnosis

Another major misconception about hypnosis is that someone—ie, the hypnotist—is in control of a person. In fact, the hypnotist is a coach or teacher who helps the patient to increase his or her self-regulation abilities.⁶ All hypnosis is self-hypnosis; after the initial training, the learner must reinforce the training with daily practice. Adult learners should anticipate practicing approximately 10 minutes twice daily for about 2 months in order to condition the desirable physiologic change or outcome. Children learn more easily and often can achieve desired changes over a period of a few weeks.

IMPORTANCE OF PATIENT ASSESSMENT BEFORE TEACHING SELF-HYPNOSIS

Every candidate for self-hypnosis therapy deserves a thoughtful, careful diagnostic assessment that includes appropriate laboratory procedures, radiologic procedures, or both prior to decisions about treatment. Patients are sometimes referred for specific cyberphysiologic interventions, such as hypnosis, without adequate diagnostic assessments.⁷ When a patient is referred for hypnosis training, the health professional who will provide the training should evaluate the extent of the previous diagnostic assessment and do more if indicated. It is also important that the health professional be knowledgeable and competent with respect to the patient’s specific problem. For example, a dentist who is board-certified in dental hypnosis should not be teaching hypnosis to children with migraine, just as a pediatrician who is board-certified in medical hypnosis should not be extracting teeth using hypnosis.

Mental imagery varies from individual to individual. Many children have visual, auditory, kinesthetic, and olfactory/taste imagery abilities and can use these easily in the process of self-hypnosis. In contrast, many adults do not generate multiple types of mental imagery, and many lack clear visual imagery. It is important that the therapist identify which types of mental imagery the patient prefers before embarking on a therapeutic approach.

Much common ground exists between hypnosis and biofeedback. Both have the potential to provide a powerful validation of mind–body links, contribute to a lowered state of sympathetic arousal, heighten awareness of internal events and sensations, facilitate imagery abilities, narrow the focus of attention, and enhance the internal locus of control.

Adding biofeedback games to self-hypnosis training can make the experience much more interesting for children. Children see evidence on the screen that, by changing their thinking, they have control over a body response such as skin temperature, electrodermal activity, or pulse rate variability. Adults also benefit from the addition of biofeedback to self-hypnosis training. A patient cannot effect a change in a biofeedback response without a change in his or her mental imagery.

A WIDE RANGE OF THERAPEUTIC APPLICATIONS

Hypnosis training is valuable as a primary intervention for prevention of juvenile migraine^8,9 as well as for many performance problems (eg, fear of public speaking or playing tennis), insomnia, and many habit problems (eg, nail-biting, tics, hair-pulling). For treatment of juvenile warts, hypnosis is at least as effective as topical treatment and associated with fewer relapses.¹⁰

Hypnosis is valuable as an adjunctive intervention during painful procedures,^11–13 and many adults and children use self-hypnosis to teach themselves to be comfortable through procedures without any pharmacologic treatment.¹⁴

Training in self-hypnosis is a valuable adjunct for both children and adults with chronic illnesses such as cancer, cardiac failure, asthma, hemophilia, sickle cell disease, and arthritis. Self-hypnosis helps to reduce anxiety and increase comfort, and it provides a therapeutic tool over which the patient has control. Several recent studies have demonstrated the efficacy of hypnosis in the treatment of irritable bowel syndrome.¹⁵

Hypnosis and cardiac disease

With respect to cardiac disease, training in hypnosis can help to reduce symptoms both preoperatively and postoperatively, to enhance the success of rehabilitation following myocardial infarction, and to reduce anxiety associated with chronic heart disease.¹⁶

Hypnosis also is helpful for motivating behaviors associated with prevention of cardiac disease, such as regular exercise, eating a low-fat diet, and smoking cessation. Several studies have found hypnosis to be a helpful adjunct to cognitive behavioral therapy for treatment of obesity.¹⁷ Additionally, a number of studies have demonstrated that hypnosis is useful as an initial intervention for smoking cessation,¹⁸ although only about 45% of persons who stop smoking with hypnosis continue to abstain 6 months later. In the case of both obesity and smoking cessation, hypnosis has modestly better efficacy compared with other treatments for these conditions.

TEACHING SELF-HYPNOSIS: SPECIAL CONSIDERATIONS WITH CHILDREN

Self-hypnosis has great potential in children, as children delight in recognizing their own control over problems such as bed-wetting or wheezing or test anxiety.

As noted above, success with hypnosis requires that the patient practice self-hypnosis daily. In the case of children, it is essential that the coach or teacher emphasize that the child is in control and can decide when and where to use self-hypnosis. The message should be that self-hypnosis belongs to the child and that he or she needs to practice to become more skilled (as with learning soccer or some other sport), but that no one can force him or her to practice.

The choice of strategies for teaching self-hypnosis varies depending on the child’s age and developmental stage. As children mature, their cognitive abilities change. Preschool children are concrete in their thinking, so therapists working with children of this age must select words carefully. Children between ages 2 and 5 years spend a great deal of their time in various types of behavior based on imagination and fantasy. They enjoy stories and may enter a hypnotic state as a parent or teacher reads a story to them. Unlike adults, they often prefer to practice their self-hypnosis with their eyes open. Although adolescents may enjoy learning self-hypnosis methods that are similar to those preferred by adults, immature adolescents may prefer methods that also appeal to younger children. A child with cognitive impairment can learn self-hypnosis if the therapist selects a teaching approach appropriate for the child’s actual developmental stage. Because of developmental changes, a child of 9 years is unlikely to enjoy a method he or she was taught at age 4. Therapists who work with children should be familiar with a variety of hypnosis induction strategies and be capable of creative modification to accommodate a child’s changing developmental circumstances.^19,20

HYPNOSIS RESEARCH WITH CHILDREN

Most subsequent research has consisted of clinical studies documenting the efficacy of hypnosis with children in areas such as pain management, habit problems, wart reduction, and performance anxiety. A recent study completed in Cleveland, Ohio, taught stress-reduction methods, including self-hypnosis, to 8-year-old schoolchildren.³⁰ This study concluded that a short daily stress-management intervention delivered in the classroom setting in elementary school can decrease feelings of anxiety and improve a child’s ability to relax. Many of the children in the study continued to use self-hypnosis in their daily lives after the study was completed.

A host of variables complicate research design

The variability in preferences, learning styles, and developmental stages among children complicates the design of research protocols for studying hypnosis in children. These protocols are often written to describe identical hypnotic inductions, often tape-recorded, to be used at prescribed times. Measured variables do not include whether or not a child likes the induction, listens to the tape, or focuses on entirely different mental imagery of his or her own choosing. Learning disabilities, such as auditory processing handicaps, may interfere with children’s ability to learn and remember self-hypnosis training. Furthermore, learning disabilities are often subtle and may not be recognized without detailed testing.

Each of these variables complicates efforts to perform meta-analyses of hypnosis and related interventions. Analyses of studies on the efficacy of hypnosis in children should include all strategies that induce hypnosis in children—eg, visual imagery, guided imagery, and/or progressive relaxation. Some research studies that are defined as controlled nevertheless mix different therapeutic interventions. An example would be a comparison of hypnosis with guided imagery.

The International Society of Hypnosis is currently sponsoring Cochrane reviews of hypnotherapeutic interventions, including those with children.

Health professionals who wish to teach self-hypnosis should take workshops sponsored by the American Society of Clinical Hypnosis or its component sections, or by the Society for Clinical and Experimental Hypnosis. The Society for Developmental and Behavioral Pediatrics also provides annual workshops to prepare health professionals for teaching self-hypnosis to children. Contact information for these organizations is provided in the sidebar on this page.

The basic workshops should include at least 22 hours of supervised practice of hypnosis techniques and didactic information. After completing such basic training, the professional should seek a mentor who, by phone or e-mail, can provide guidance and support. The professional who is developing skills in self-hypnosis instruction should also attend follow-up workshops, watch videotapes of other teachers, and read basic textbooks and hypnosis journals recommended by professional hypnosis societies.

Hypnosis board examinations are given in four areas: medicine, dentistry, psychology, and social work. The American Society of Clinical Hypnosis has developed a hypnosis certification program for professionals who use hypnosis in their practice and teaching.

Importantly, the professional who is developing skills in self-hypnosis instruction should learn self-hypnosis for him- or herself. Learning self-hypnosis is a valuable lifelong skill that provides many benefits.

THE FUTURE

We anticipate that appropriate and early training in self-hypnosis and biofeedback can enable children to learn to control autonomic responses relating to cardiovascular function. Preventive work by pediatric health professionals may include monitoring of autonomic responses early in life, identification of children most at risk because of autonomic lability, and interventions to reduce that risk via hypnosis and biofeedback training. We anticipate that laboratory and brain imaging studies will provide increasing documentation of the impacts of hypnotic suggestions on neural processing, and that Cochrane reviews will demonstrate increasing evidence for the clinical value of hypnosis.

Training in self-hypnosis, with or without biofeedback, is a valuable adjunct for children and adults with chronic illnesses or behavioral problems. After defining terms and briefly reviewing the evolution of medical hypnosis, this article provides an overview of the clinical utility and applications of self-hypnosis and various issues in its use, including patient assessment, concurrent use with biofeedback, and how health care providers can become trained in self-hypnosis instruction. Because my experience is primarily with medical hypnosis in children and adolescents, portions of this discussion will devote particular attention to the use of hypnosis in children.

DEFINITIONS

Hypnosis is a state of awareness, often but not always associated with relaxation, during which the participant can give him- or herself suggestions for desired changes to which he or she is more likely to respond than when in the usual state of awareness. Spontaneous self-hypnosis may happen while reading, listening to music, watching television, jogging, dancing, playing a musical instrument, doing tai chi, doing yoga, or performing similar activities. Terms often used to describe mind-body training include relaxation imagery, guided imagery, or visual imagery. These include the same training strategies as those used in hypnosis.

Biofeedback is a term coined in 1969 to describe procedures (developed in 1940s) for training subjects to alter physiologic responses such as brain activity, blood pressure, muscle tension, or heart rate. With biofeedback, participants are trained to improve their health and performance by using signals from their own bodies. In so doing, they strengthen awareness of the connections between their mind and body.

Cyberphysiology was defined by Dr. Earl E. Bakken at the first Archaeus Congress, held in Santa Fe, New Mexico, in 1986. “Cyber” derives from the Greek kybernan, meaning steersman or helmsman. From kybernan came the Latinate term govern, meaning “to control.” Thus, cyberphysiology means to control a physiologic response. In scientific terms, cyberphysiology is the study of how neurally mediated autonomic responses—usually viewed as automatic, reactive reflexes—can be modified by a learning process that appears to be significantly dependent on modification of mental images. Both hypnosis and biofeedback are cyberphysiologic strategies that enable the user to develop voluntary control of certain physiologic processes.

HISTORICAL BEGINNINGS OF HYPNOSIS

Franz Mesmer developed a training system that he called animal magnetism. Mesmer believed that normal body processes were disrupted when there was improper distribution of magnetism, a kind of fluid that could penetrate all matter. He described his ability to direct this magnetic fluid through his presence with the waving of a metallic rod and contact with a large wooden tub called a baquet. Mesmer was convinced that the successful therapeutic effects he observed depended on the magnetic rods he used.

When jealous and hostile colleagues challenged Mesmer’s clinical successes, King Louis XVI of France called for an investigative commission chaired by Benjamin Franklin, who was then the American ambassador to France. Other commission members included Dr. Antoine Lavoisier, the first to isolate the element of oxygen, and Dr. Antoine Guillotine, well known for developing a machine for beheading.¹ After the commission conducted some clever experiments, they concluded that Mesmer’s success was related to application of the imagination. In fact, we are not far beyond that concept today, although we now have brain imaging documentation of changes in the brain associated with the practice of hypnosis.^2–5

CORRECTING MISCONCEPTIONS ABOUT HYPNOSIS

Hypnosis is not sleep

Modern hypnosis is considered to have begun with Mesmer, although the term hypnosis was first used by James Braid, a Scottish ophthalmologist, in 1843. His decision to derive the word from hypnos, the Greek word for sleep, was unfortunate. Hypnosis is not sleep, but the name confuses people.

All hypnosis is self-hypnosis

Another major misconception about hypnosis is that someone—ie, the hypnotist—is in control of a person. In fact, the hypnotist is a coach or teacher who helps the patient to increase his or her self-regulation abilities.⁶ All hypnosis is self-hypnosis; after the initial training, the learner must reinforce the training with daily practice. Adult learners should anticipate practicing approximately 10 minutes twice daily for about 2 months in order to condition the desirable physiologic change or outcome. Children learn more easily and often can achieve desired changes over a period of a few weeks.

IMPORTANCE OF PATIENT ASSESSMENT BEFORE TEACHING SELF-HYPNOSIS

Every candidate for self-hypnosis therapy deserves a thoughtful, careful diagnostic assessment that includes appropriate laboratory procedures, radiologic procedures, or both prior to decisions about treatment. Patients are sometimes referred for specific cyberphysiologic interventions, such as hypnosis, without adequate diagnostic assessments.⁷ When a patient is referred for hypnosis training, the health professional who will provide the training should evaluate the extent of the previous diagnostic assessment and do more if indicated. It is also important that the health professional be knowledgeable and competent with respect to the patient’s specific problem. For example, a dentist who is board-certified in dental hypnosis should not be teaching hypnosis to children with migraine, just as a pediatrician who is board-certified in medical hypnosis should not be extracting teeth using hypnosis.

Mental imagery varies from individual to individual. Many children have visual, auditory, kinesthetic, and olfactory/taste imagery abilities and can use these easily in the process of self-hypnosis. In contrast, many adults do not generate multiple types of mental imagery, and many lack clear visual imagery. It is important that the therapist identify which types of mental imagery the patient prefers before embarking on a therapeutic approach.

Much common ground exists between hypnosis and biofeedback. Both have the potential to provide a powerful validation of mind–body links, contribute to a lowered state of sympathetic arousal, heighten awareness of internal events and sensations, facilitate imagery abilities, narrow the focus of attention, and enhance the internal locus of control.

Adding biofeedback games to self-hypnosis training can make the experience much more interesting for children. Children see evidence on the screen that, by changing their thinking, they have control over a body response such as skin temperature, electrodermal activity, or pulse rate variability. Adults also benefit from the addition of biofeedback to self-hypnosis training. A patient cannot effect a change in a biofeedback response without a change in his or her mental imagery.

A WIDE RANGE OF THERAPEUTIC APPLICATIONS

Hypnosis training is valuable as a primary intervention for prevention of juvenile migraine^8,9 as well as for many performance problems (eg, fear of public speaking or playing tennis), insomnia, and many habit problems (eg, nail-biting, tics, hair-pulling). For treatment of juvenile warts, hypnosis is at least as effective as topical treatment and associated with fewer relapses.¹⁰

Hypnosis is valuable as an adjunctive intervention during painful procedures,^11–13 and many adults and children use self-hypnosis to teach themselves to be comfortable through procedures without any pharmacologic treatment.¹⁴

Training in self-hypnosis is a valuable adjunct for both children and adults with chronic illnesses such as cancer, cardiac failure, asthma, hemophilia, sickle cell disease, and arthritis. Self-hypnosis helps to reduce anxiety and increase comfort, and it provides a therapeutic tool over which the patient has control. Several recent studies have demonstrated the efficacy of hypnosis in the treatment of irritable bowel syndrome.¹⁵

Hypnosis and cardiac disease

With respect to cardiac disease, training in hypnosis can help to reduce symptoms both preoperatively and postoperatively, to enhance the success of rehabilitation following myocardial infarction, and to reduce anxiety associated with chronic heart disease.¹⁶

Hypnosis also is helpful for motivating behaviors associated with prevention of cardiac disease, such as regular exercise, eating a low-fat diet, and smoking cessation. Several studies have found hypnosis to be a helpful adjunct to cognitive behavioral therapy for treatment of obesity.¹⁷ Additionally, a number of studies have demonstrated that hypnosis is useful as an initial intervention for smoking cessation,¹⁸ although only about 45% of persons who stop smoking with hypnosis continue to abstain 6 months later. In the case of both obesity and smoking cessation, hypnosis has modestly better efficacy compared with other treatments for these conditions.

TEACHING SELF-HYPNOSIS: SPECIAL CONSIDERATIONS WITH CHILDREN

Self-hypnosis has great potential in children, as children delight in recognizing their own control over problems such as bed-wetting or wheezing or test anxiety.

As noted above, success with hypnosis requires that the patient practice self-hypnosis daily. In the case of children, it is essential that the coach or teacher emphasize that the child is in control and can decide when and where to use self-hypnosis. The message should be that self-hypnosis belongs to the child and that he or she needs to practice to become more skilled (as with learning soccer or some other sport), but that no one can force him or her to practice.

The choice of strategies for teaching self-hypnosis varies depending on the child’s age and developmental stage. As children mature, their cognitive abilities change. Preschool children are concrete in their thinking, so therapists working with children of this age must select words carefully. Children between ages 2 and 5 years spend a great deal of their time in various types of behavior based on imagination and fantasy. They enjoy stories and may enter a hypnotic state as a parent or teacher reads a story to them. Unlike adults, they often prefer to practice their self-hypnosis with their eyes open. Although adolescents may enjoy learning self-hypnosis methods that are similar to those preferred by adults, immature adolescents may prefer methods that also appeal to younger children. A child with cognitive impairment can learn self-hypnosis if the therapist selects a teaching approach appropriate for the child’s actual developmental stage. Because of developmental changes, a child of 9 years is unlikely to enjoy a method he or she was taught at age 4. Therapists who work with children should be familiar with a variety of hypnosis induction strategies and be capable of creative modification to accommodate a child’s changing developmental circumstances.^19,20

HYPNOSIS RESEARCH WITH CHILDREN

Most subsequent research has consisted of clinical studies documenting the efficacy of hypnosis with children in areas such as pain management, habit problems, wart reduction, and performance anxiety. A recent study completed in Cleveland, Ohio, taught stress-reduction methods, including self-hypnosis, to 8-year-old schoolchildren.³⁰ This study concluded that a short daily stress-management intervention delivered in the classroom setting in elementary school can decrease feelings of anxiety and improve a child’s ability to relax. Many of the children in the study continued to use self-hypnosis in their daily lives after the study was completed.

A host of variables complicate research design

The variability in preferences, learning styles, and developmental stages among children complicates the design of research protocols for studying hypnosis in children. These protocols are often written to describe identical hypnotic inductions, often tape-recorded, to be used at prescribed times. Measured variables do not include whether or not a child likes the induction, listens to the tape, or focuses on entirely different mental imagery of his or her own choosing. Learning disabilities, such as auditory processing handicaps, may interfere with children’s ability to learn and remember self-hypnosis training. Furthermore, learning disabilities are often subtle and may not be recognized without detailed testing.

Each of these variables complicates efforts to perform meta-analyses of hypnosis and related interventions. Analyses of studies on the efficacy of hypnosis in children should include all strategies that induce hypnosis in children—eg, visual imagery, guided imagery, and/or progressive relaxation. Some research studies that are defined as controlled nevertheless mix different therapeutic interventions. An example would be a comparison of hypnosis with guided imagery.

The International Society of Hypnosis is currently sponsoring Cochrane reviews of hypnotherapeutic interventions, including those with children.

Health professionals who wish to teach self-hypnosis should take workshops sponsored by the American Society of Clinical Hypnosis or its component sections, or by the Society for Clinical and Experimental Hypnosis. The Society for Developmental and Behavioral Pediatrics also provides annual workshops to prepare health professionals for teaching self-hypnosis to children. Contact information for these organizations is provided in the sidebar on this page.

The basic workshops should include at least 22 hours of supervised practice of hypnosis techniques and didactic information. After completing such basic training, the professional should seek a mentor who, by phone or e-mail, can provide guidance and support. The professional who is developing skills in self-hypnosis instruction should also attend follow-up workshops, watch videotapes of other teachers, and read basic textbooks and hypnosis journals recommended by professional hypnosis societies.

Hypnosis board examinations are given in four areas: medicine, dentistry, psychology, and social work. The American Society of Clinical Hypnosis has developed a hypnosis certification program for professionals who use hypnosis in their practice and teaching.

Importantly, the professional who is developing skills in self-hypnosis instruction should learn self-hypnosis for him- or herself. Learning self-hypnosis is a valuable lifelong skill that provides many benefits.

THE FUTURE

We anticipate that appropriate and early training in self-hypnosis and biofeedback can enable children to learn to control autonomic responses relating to cardiovascular function. Preventive work by pediatric health professionals may include monitoring of autonomic responses early in life, identification of children most at risk because of autonomic lability, and interventions to reduce that risk via hypnosis and biofeedback training. We anticipate that laboratory and brain imaging studies will provide increasing documentation of the impacts of hypnotic suggestions on neural processing, and that Cochrane reviews will demonstrate increasing evidence for the clinical value of hypnosis.

Training in self-hypnosis, with or without biofeedback, is a valuable adjunct for children and adults with chronic illnesses or behavioral problems. After defining terms and briefly reviewing the evolution of medical hypnosis, this article provides an overview of the clinical utility and applications of self-hypnosis and various issues in its use, including patient assessment, concurrent use with biofeedback, and how health care providers can become trained in self-hypnosis instruction. Because my experience is primarily with medical hypnosis in children and adolescents, portions of this discussion will devote particular attention to the use of hypnosis in children.

DEFINITIONS

Hypnosis is a state of awareness, often but not always associated with relaxation, during which the participant can give him- or herself suggestions for desired changes to which he or she is more likely to respond than when in the usual state of awareness. Spontaneous self-hypnosis may happen while reading, listening to music, watching television, jogging, dancing, playing a musical instrument, doing tai chi, doing yoga, or performing similar activities. Terms often used to describe mind-body training include relaxation imagery, guided imagery, or visual imagery. These include the same training strategies as those used in hypnosis.

Biofeedback is a term coined in 1969 to describe procedures (developed in 1940s) for training subjects to alter physiologic responses such as brain activity, blood pressure, muscle tension, or heart rate. With biofeedback, participants are trained to improve their health and performance by using signals from their own bodies. In so doing, they strengthen awareness of the connections between their mind and body.

Cyberphysiology was defined by Dr. Earl E. Bakken at the first Archaeus Congress, held in Santa Fe, New Mexico, in 1986. “Cyber” derives from the Greek kybernan, meaning steersman or helmsman. From kybernan came the Latinate term govern, meaning “to control.” Thus, cyberphysiology means to control a physiologic response. In scientific terms, cyberphysiology is the study of how neurally mediated autonomic responses—usually viewed as automatic, reactive reflexes—can be modified by a learning process that appears to be significantly dependent on modification of mental images. Both hypnosis and biofeedback are cyberphysiologic strategies that enable the user to develop voluntary control of certain physiologic processes.

HISTORICAL BEGINNINGS OF HYPNOSIS

Franz Mesmer developed a training system that he called animal magnetism. Mesmer believed that normal body processes were disrupted when there was improper distribution of magnetism, a kind of fluid that could penetrate all matter. He described his ability to direct this magnetic fluid through his presence with the waving of a metallic rod and contact with a large wooden tub called a baquet. Mesmer was convinced that the successful therapeutic effects he observed depended on the magnetic rods he used.

When jealous and hostile colleagues challenged Mesmer’s clinical successes, King Louis XVI of France called for an investigative commission chaired by Benjamin Franklin, who was then the American ambassador to France. Other commission members included Dr. Antoine Lavoisier, the first to isolate the element of oxygen, and Dr. Antoine Guillotine, well known for developing a machine for beheading.¹ After the commission conducted some clever experiments, they concluded that Mesmer’s success was related to application of the imagination. In fact, we are not far beyond that concept today, although we now have brain imaging documentation of changes in the brain associated with the practice of hypnosis.^2–5

CORRECTING MISCONCEPTIONS ABOUT HYPNOSIS

Hypnosis is not sleep

Modern hypnosis is considered to have begun with Mesmer, although the term hypnosis was first used by James Braid, a Scottish ophthalmologist, in 1843. His decision to derive the word from hypnos, the Greek word for sleep, was unfortunate. Hypnosis is not sleep, but the name confuses people.

All hypnosis is self-hypnosis

Another major misconception about hypnosis is that someone—ie, the hypnotist—is in control of a person. In fact, the hypnotist is a coach or teacher who helps the patient to increase his or her self-regulation abilities.⁶ All hypnosis is self-hypnosis; after the initial training, the learner must reinforce the training with daily practice. Adult learners should anticipate practicing approximately 10 minutes twice daily for about 2 months in order to condition the desirable physiologic change or outcome. Children learn more easily and often can achieve desired changes over a period of a few weeks.

IMPORTANCE OF PATIENT ASSESSMENT BEFORE TEACHING SELF-HYPNOSIS

Every candidate for self-hypnosis therapy deserves a thoughtful, careful diagnostic assessment that includes appropriate laboratory procedures, radiologic procedures, or both prior to decisions about treatment. Patients are sometimes referred for specific cyberphysiologic interventions, such as hypnosis, without adequate diagnostic assessments.⁷ When a patient is referred for hypnosis training, the health professional who will provide the training should evaluate the extent of the previous diagnostic assessment and do more if indicated. It is also important that the health professional be knowledgeable and competent with respect to the patient’s specific problem. For example, a dentist who is board-certified in dental hypnosis should not be teaching hypnosis to children with migraine, just as a pediatrician who is board-certified in medical hypnosis should not be extracting teeth using hypnosis.

Mental imagery varies from individual to individual. Many children have visual, auditory, kinesthetic, and olfactory/taste imagery abilities and can use these easily in the process of self-hypnosis. In contrast, many adults do not generate multiple types of mental imagery, and many lack clear visual imagery. It is important that the therapist identify which types of mental imagery the patient prefers before embarking on a therapeutic approach.

Much common ground exists between hypnosis and biofeedback. Both have the potential to provide a powerful validation of mind–body links, contribute to a lowered state of sympathetic arousal, heighten awareness of internal events and sensations, facilitate imagery abilities, narrow the focus of attention, and enhance the internal locus of control.

Adding biofeedback games to self-hypnosis training can make the experience much more interesting for children. Children see evidence on the screen that, by changing their thinking, they have control over a body response such as skin temperature, electrodermal activity, or pulse rate variability. Adults also benefit from the addition of biofeedback to self-hypnosis training. A patient cannot effect a change in a biofeedback response without a change in his or her mental imagery.

A WIDE RANGE OF THERAPEUTIC APPLICATIONS

Hypnosis training is valuable as a primary intervention for prevention of juvenile migraine^8,9 as well as for many performance problems (eg, fear of public speaking or playing tennis), insomnia, and many habit problems (eg, nail-biting, tics, hair-pulling). For treatment of juvenile warts, hypnosis is at least as effective as topical treatment and associated with fewer relapses.¹⁰

Hypnosis is valuable as an adjunctive intervention during painful procedures,^11–13 and many adults and children use self-hypnosis to teach themselves to be comfortable through procedures without any pharmacologic treatment.¹⁴

Training in self-hypnosis is a valuable adjunct for both children and adults with chronic illnesses such as cancer, cardiac failure, asthma, hemophilia, sickle cell disease, and arthritis. Self-hypnosis helps to reduce anxiety and increase comfort, and it provides a therapeutic tool over which the patient has control. Several recent studies have demonstrated the efficacy of hypnosis in the treatment of irritable bowel syndrome.¹⁵

Hypnosis and cardiac disease

With respect to cardiac disease, training in hypnosis can help to reduce symptoms both preoperatively and postoperatively, to enhance the success of rehabilitation following myocardial infarction, and to reduce anxiety associated with chronic heart disease.¹⁶

Hypnosis also is helpful for motivating behaviors associated with prevention of cardiac disease, such as regular exercise, eating a low-fat diet, and smoking cessation. Several studies have found hypnosis to be a helpful adjunct to cognitive behavioral therapy for treatment of obesity.¹⁷ Additionally, a number of studies have demonstrated that hypnosis is useful as an initial intervention for smoking cessation,¹⁸ although only about 45% of persons who stop smoking with hypnosis continue to abstain 6 months later. In the case of both obesity and smoking cessation, hypnosis has modestly better efficacy compared with other treatments for these conditions.

TEACHING SELF-HYPNOSIS: SPECIAL CONSIDERATIONS WITH CHILDREN

Self-hypnosis has great potential in children, as children delight in recognizing their own control over problems such as bed-wetting or wheezing or test anxiety.

As noted above, success with hypnosis requires that the patient practice self-hypnosis daily. In the case of children, it is essential that the coach or teacher emphasize that the child is in control and can decide when and where to use self-hypnosis. The message should be that self-hypnosis belongs to the child and that he or she needs to practice to become more skilled (as with learning soccer or some other sport), but that no one can force him or her to practice.

The choice of strategies for teaching self-hypnosis varies depending on the child’s age and developmental stage. As children mature, their cognitive abilities change. Preschool children are concrete in their thinking, so therapists working with children of this age must select words carefully. Children between ages 2 and 5 years spend a great deal of their time in various types of behavior based on imagination and fantasy. They enjoy stories and may enter a hypnotic state as a parent or teacher reads a story to them. Unlike adults, they often prefer to practice their self-hypnosis with their eyes open. Although adolescents may enjoy learning self-hypnosis methods that are similar to those preferred by adults, immature adolescents may prefer methods that also appeal to younger children. A child with cognitive impairment can learn self-hypnosis if the therapist selects a teaching approach appropriate for the child’s actual developmental stage. Because of developmental changes, a child of 9 years is unlikely to enjoy a method he or she was taught at age 4. Therapists who work with children should be familiar with a variety of hypnosis induction strategies and be capable of creative modification to accommodate a child’s changing developmental circumstances.^19,20

HYPNOSIS RESEARCH WITH CHILDREN

Most subsequent research has consisted of clinical studies documenting the efficacy of hypnosis with children in areas such as pain management, habit problems, wart reduction, and performance anxiety. A recent study completed in Cleveland, Ohio, taught stress-reduction methods, including self-hypnosis, to 8-year-old schoolchildren.³⁰ This study concluded that a short daily stress-management intervention delivered in the classroom setting in elementary school can decrease feelings of anxiety and improve a child’s ability to relax. Many of the children in the study continued to use self-hypnosis in their daily lives after the study was completed.

A host of variables complicate research design

The variability in preferences, learning styles, and developmental stages among children complicates the design of research protocols for studying hypnosis in children. These protocols are often written to describe identical hypnotic inductions, often tape-recorded, to be used at prescribed times. Measured variables do not include whether or not a child likes the induction, listens to the tape, or focuses on entirely different mental imagery of his or her own choosing. Learning disabilities, such as auditory processing handicaps, may interfere with children’s ability to learn and remember self-hypnosis training. Furthermore, learning disabilities are often subtle and may not be recognized without detailed testing.

Each of these variables complicates efforts to perform meta-analyses of hypnosis and related interventions. Analyses of studies on the efficacy of hypnosis in children should include all strategies that induce hypnosis in children—eg, visual imagery, guided imagery, and/or progressive relaxation. Some research studies that are defined as controlled nevertheless mix different therapeutic interventions. An example would be a comparison of hypnosis with guided imagery.

The International Society of Hypnosis is currently sponsoring Cochrane reviews of hypnotherapeutic interventions, including those with children.

Health professionals who wish to teach self-hypnosis should take workshops sponsored by the American Society of Clinical Hypnosis or its component sections, or by the Society for Clinical and Experimental Hypnosis. The Society for Developmental and Behavioral Pediatrics also provides annual workshops to prepare health professionals for teaching self-hypnosis to children. Contact information for these organizations is provided in the sidebar on this page.

The basic workshops should include at least 22 hours of supervised practice of hypnosis techniques and didactic information. After completing such basic training, the professional should seek a mentor who, by phone or e-mail, can provide guidance and support. The professional who is developing skills in self-hypnosis instruction should also attend follow-up workshops, watch videotapes of other teachers, and read basic textbooks and hypnosis journals recommended by professional hypnosis societies.

Hypnosis board examinations are given in four areas: medicine, dentistry, psychology, and social work. The American Society of Clinical Hypnosis has developed a hypnosis certification program for professionals who use hypnosis in their practice and teaching.

Importantly, the professional who is developing skills in self-hypnosis instruction should learn self-hypnosis for him- or herself. Learning self-hypnosis is a valuable lifelong skill that provides many benefits.

THE FUTURE

We anticipate that appropriate and early training in self-hypnosis and biofeedback can enable children to learn to control autonomic responses relating to cardiovascular function. Preventive work by pediatric health professionals may include monitoring of autonomic responses early in life, identification of children most at risk because of autonomic lability, and interventions to reduce that risk via hypnosis and biofeedback training. We anticipate that laboratory and brain imaging studies will provide increasing documentation of the impacts of hypnotic suggestions on neural processing, and that Cochrane reviews will demonstrate increasing evidence for the clinical value of hypnosis.

Postoperative atrial fibrillation (PAF) is the most common complication of coronary artery bypass graft surgery (CABG), affecting approximately 20% to 40% of patients undergoing this procedure.¹ Occurrence of PAF has been associated with prolonged hospital and intensive care unit (ICU) stays, a decline in neurocognitive ability, an increased risk of stroke and transient ischemic attacks, increased surgical mortality, and increased resource utilization and cost.²

The role of the autonomic nervous system in atrial fibrillation (AF) has been studied extensively, but the impact of the autonomic nervous system on PAF has received little attention. Research on the mechanisms of AF has shown imbalance in the autonomic nervous system when measured using heart rate variability. These studies have demonstrated an increase in sympathetic activity approximately 20 minutes prior to the onset of AF, with a shift to parasympathetic activity directly prior to onset. A correlation between mental stress and changes in the autonomic nervous system, as assessed by heart rate variability, has also been shown.^3–7

Pharmacologic interventions, including beta-blockers and amiodarone, have been proposed as preventive measures for PAF, but the incidence of PAF remains high.¹ Beta-blockade may not be tolerated by patients postoperatively, and there is no consensus on dosing parameters. A meta-analysis on the use of amiodarone in the prevention of PAF was inconclusive,⁸ and the optimal dosing regimen and incidence of adverse events with amiodarone have not been determined.

There are a small number of studies linking clinical hypnosis to changes in the autonomic nervous system.⁹ Clinical hypnosis also has been associated with reductions in anxiety and depression before and after surgical procedures.^10,11 If PAF is a result of transient autonomic dysfunction, then interventions that alter autonomic tone should influence the incidence and duration of PAF. We report here a retrospective analysis of the impact of clinical hypnosis on the occurrence of PAF in patients undergoing CABG.

METHODOLOGY

Fifty consecutive patients undergoing first-time CABG between October 2004 and May 2005 received preoperative hypnoidal explanation of the surgical procedure as part of their preparation for surgery. A group of 50 case-matched patients who had undergone CABG at the same center between October 2003 and May 2004 were chosen as historical controls.

The treatment group (hypnosis group) and the control group were case-matched for presence of diabetes mellitus, use of beta-adrenergic blocking agents, and use of antiarrhythmic medications. The groups were also matched for various predictors of postoperative PAF, such as age, gender, and coronary artery disease. The patients were all treated by the same surgeon (R.N.), with no significant alterations to surgical or pharmacologic protocols.

The surgeon used indirect Ericksonian techniques during the preoperative explanation of the surgery. Milton Erickson, one of the most prominent hypnotherapists in recent times, used an indirect approach to weave suggestions into the dialogue rather than giving direct commands. This approach encourages active participation and gives the patient a sense of greater control in the hospital environment. The surgeon also instructed patients in self-hypnosis using respiration and imagery.

RESULTS

Table 2 presents outcomes in the two study groups. Patients who were treated with clinical hypnosis were less likely to experience PAF: the percentage of patients with one or more episodes of PAF was 6.0% in the treat­ment group versus 24.0% in the control group (P = .003). Likewise, the percentage of patients who were discharged on amiodarone was 14.0% in the treatment group versus 28.0% in the control group (P = .03).

Clinical characteristics were tabulated and compared between the subjects who experienced new-onset PAF and those who did not experience PAF to determine whether there was a covariate responsible for the results observed. With the exception of age, the difference in clinical characteristics between these groups of patients was not statistically significant (using P > .10 as the threshold for significance) (Table 3).

Adverse effects of PAF are well established

The onset of PAF following CABG is a common complication that has been linked to increases in morbidity and mortality, length of stay in the ICU and hospital, and total hospital charges. Villareal et al found that the odds ratio for early mortality (within 30 days) for patients who experienced PAF after CABG was 1.4 (95% confidence interval, 1.12 to 1.68; P = .002).¹² In addition, patients with PAF had significantly higher rates of postoperative infections, renal failure, shock, failure of multiple organ systems, and cardiac arrest compared with those who did not have PAF.¹² A literature analysis by Maisel et al found that PAF increases the likelihood that cardiac surgery patients will need to return to the operating room, be readmitted to the ICU, and require prolonged ventilation or reintubation.¹³ Nickerson et al showed that PAF following cardiac surgery corresponded with an increase in length of stay in both the ICU and hospital.¹⁴

Our study showed statistically significant increases in postoperative hospital charges, postoperative hospital stay, and ICU stay among patients who experi­enced PAF following CABG. These findings are consistent with the current literature. In a study of 720 subjects undergoing CABG, Hravnak et al reported a 1.4-day increase in length of hospital stay and a 0.3­day increase in length of ICU stay among patients who had PAF compared with those who did not.¹⁵ A significant increase in postoperative hospital charges was also observed.¹⁵ Similarly, in a multicenter study of 2,417 patients undergoing isolated CABG procedures, Mathew et al observed increases in ICU stay and hospital stay among those patients who experienced PAF.² These findings indicate that the onset of PAF after CABG is a serious complication and that further study is warranted.

Hypnosis to prevent PAF: Suggestive evidence and mechanisms

Clinical hypnosis has been shown to reduce stress and anxiety in surgical patients and can be highly individualized to address the patient’s needs during the stress­ful preoperative period. Saadat et al found that hypnosis administered directly before ambulatory surgery using Ericksonian techniques reduced patients’ levels of anxiety by 56% from baseline.¹¹ In a South African study specifically in men undergoing CABG, de Klerk et al found that preoperative hypnotherapy led to reductions in both anxiety and depression at discharge that were maintained through 6-week follow-up.¹⁰

These findings, taken together with research linking clinical hypnosis to changes in the autonomic nervous system⁹ and the belief that PAF may result from transient autonomic dysfunction, suggest that hypnosis may reduce the incidence of PAF.

In a study of R-R interval dynamics prior to PAF in patients who had undergone CABG, Hogue et al showed that patients who experienced PAF had higher heart rates directly before PAF onset.¹⁶ Higher heart rates are associated with increased activity of the sympathetic nervous system and/or decreased activity of the parasympathetic nervous system. This finding supports our hypothesis of a relationship between PAF following CABG and excessive adrenergic activation. Chen et al have noted that catecholamine-mediated AF usually occurs in the presence of heart disease and that these types of attacks often happen during the day­time in association with physical or emotional stress.⁴

Bettoni and Zimmermann found that the onset of AF is preceded by a primary increase in adrenergic drive, which changes to increased vagal activity immediately before the occurrence.³ Tomita et al reported that sympathetic tone increases immediately before an occurrence of daytime AF.⁷ These results were supported by Lombardi et al, who detected signs of predominant sympathetic modulation and reduced vagal modulation of sinus node in AF episodes that started during the daytime.⁶ These episodes were characterized by atrial ectopic beats prior to onset.⁶

Modulations in baroreceptor reflex activity may provide further evidence of the importance of the sympathetic/parasympathetic balance in the initiation of AF. Suboptimal functioning of the baroreceptor reflex has been associated with arrhythmias and adverse cardiac events in patients and animal models. Loss of the protective effects of vagal activation has been postulated to increase vulnerability to sympathetically driven ischemia and malignant arrhythmias.¹⁷

Multiple studies have shown that the only conclusive predictor of PAF is age. Notably, heart rate variability is reduced with increased age.¹⁸ By measuring heart rate variability, Taggart et al showed that autonomic balance was improved in patients under induced stress when they were in a hypnotic state.¹⁹ Although no attempts were made to determine heart rate variability in our patient set, other studies have demonstrated an increase in heart rate variability during hypnosis. The results of our study suggest that clinical hypnosis using a personalized Ericksonian approach may have a beneficial effect on the incidence of PAF.

CONCLUSIONS

Clinical hypnosis appears to lower the incidence of PAF in patients undergoing CABG as well as to yield favorable trends toward reduced ICU and postoperative hospital stays, reduced hospital charges, and reduced use of narcotics. Although our study had a small sample size and lacked randomization, its positive results and the absence of side effects suggest that prospective randomized trials should be conducted to further delineate the role of hypnosis in the prevention of PAF. A better understanding of AF, and of the autonomic nervous system’s role in triggering and maintaining PAF, will allow more appropriate treatment of this condition.

Postoperative atrial fibrillation (PAF) is the most common complication of coronary artery bypass graft surgery (CABG), affecting approximately 20% to 40% of patients undergoing this procedure.¹ Occurrence of PAF has been associated with prolonged hospital and intensive care unit (ICU) stays, a decline in neurocognitive ability, an increased risk of stroke and transient ischemic attacks, increased surgical mortality, and increased resource utilization and cost.²

The role of the autonomic nervous system in atrial fibrillation (AF) has been studied extensively, but the impact of the autonomic nervous system on PAF has received little attention. Research on the mechanisms of AF has shown imbalance in the autonomic nervous system when measured using heart rate variability. These studies have demonstrated an increase in sympathetic activity approximately 20 minutes prior to the onset of AF, with a shift to parasympathetic activity directly prior to onset. A correlation between mental stress and changes in the autonomic nervous system, as assessed by heart rate variability, has also been shown.^3–7

Pharmacologic interventions, including beta-blockers and amiodarone, have been proposed as preventive measures for PAF, but the incidence of PAF remains high.¹ Beta-blockade may not be tolerated by patients postoperatively, and there is no consensus on dosing parameters. A meta-analysis on the use of amiodarone in the prevention of PAF was inconclusive,⁸ and the optimal dosing regimen and incidence of adverse events with amiodarone have not been determined.

There are a small number of studies linking clinical hypnosis to changes in the autonomic nervous system.⁹ Clinical hypnosis also has been associated with reductions in anxiety and depression before and after surgical procedures.^10,11 If PAF is a result of transient autonomic dysfunction, then interventions that alter autonomic tone should influence the incidence and duration of PAF. We report here a retrospective analysis of the impact of clinical hypnosis on the occurrence of PAF in patients undergoing CABG.

METHODOLOGY

Fifty consecutive patients undergoing first-time CABG between October 2004 and May 2005 received preoperative hypnoidal explanation of the surgical procedure as part of their preparation for surgery. A group of 50 case-matched patients who had undergone CABG at the same center between October 2003 and May 2004 were chosen as historical controls.

The treatment group (hypnosis group) and the control group were case-matched for presence of diabetes mellitus, use of beta-adrenergic blocking agents, and use of antiarrhythmic medications. The groups were also matched for various predictors of postoperative PAF, such as age, gender, and coronary artery disease. The patients were all treated by the same surgeon (R.N.), with no significant alterations to surgical or pharmacologic protocols.

The surgeon used indirect Ericksonian techniques during the preoperative explanation of the surgery. Milton Erickson, one of the most prominent hypnotherapists in recent times, used an indirect approach to weave suggestions into the dialogue rather than giving direct commands. This approach encourages active participation and gives the patient a sense of greater control in the hospital environment. The surgeon also instructed patients in self-hypnosis using respiration and imagery.

RESULTS

Table 2 presents outcomes in the two study groups. Patients who were treated with clinical hypnosis were less likely to experience PAF: the percentage of patients with one or more episodes of PAF was 6.0% in the treat­ment group versus 24.0% in the control group (P = .003). Likewise, the percentage of patients who were discharged on amiodarone was 14.0% in the treatment group versus 28.0% in the control group (P = .03).

Clinical characteristics were tabulated and compared between the subjects who experienced new-onset PAF and those who did not experience PAF to determine whether there was a covariate responsible for the results observed. With the exception of age, the difference in clinical characteristics between these groups of patients was not statistically significant (using P > .10 as the threshold for significance) (Table 3).

Adverse effects of PAF are well established

The onset of PAF following CABG is a common complication that has been linked to increases in morbidity and mortality, length of stay in the ICU and hospital, and total hospital charges. Villareal et al found that the odds ratio for early mortality (within 30 days) for patients who experienced PAF after CABG was 1.4 (95% confidence interval, 1.12 to 1.68; P = .002).¹² In addition, patients with PAF had significantly higher rates of postoperative infections, renal failure, shock, failure of multiple organ systems, and cardiac arrest compared with those who did not have PAF.¹² A literature analysis by Maisel et al found that PAF increases the likelihood that cardiac surgery patients will need to return to the operating room, be readmitted to the ICU, and require prolonged ventilation or reintubation.¹³ Nickerson et al showed that PAF following cardiac surgery corresponded with an increase in length of stay in both the ICU and hospital.¹⁴

Our study showed statistically significant increases in postoperative hospital charges, postoperative hospital stay, and ICU stay among patients who experi­enced PAF following CABG. These findings are consistent with the current literature. In a study of 720 subjects undergoing CABG, Hravnak et al reported a 1.4-day increase in length of hospital stay and a 0.3­day increase in length of ICU stay among patients who had PAF compared with those who did not.¹⁵ A significant increase in postoperative hospital charges was also observed.¹⁵ Similarly, in a multicenter study of 2,417 patients undergoing isolated CABG procedures, Mathew et al observed increases in ICU stay and hospital stay among those patients who experienced PAF.² These findings indicate that the onset of PAF after CABG is a serious complication and that further study is warranted.

Hypnosis to prevent PAF: Suggestive evidence and mechanisms

Clinical hypnosis has been shown to reduce stress and anxiety in surgical patients and can be highly individualized to address the patient’s needs during the stress­ful preoperative period. Saadat et al found that hypnosis administered directly before ambulatory surgery using Ericksonian techniques reduced patients’ levels of anxiety by 56% from baseline.¹¹ In a South African study specifically in men undergoing CABG, de Klerk et al found that preoperative hypnotherapy led to reductions in both anxiety and depression at discharge that were maintained through 6-week follow-up.¹⁰

These findings, taken together with research linking clinical hypnosis to changes in the autonomic nervous system⁹ and the belief that PAF may result from transient autonomic dysfunction, suggest that hypnosis may reduce the incidence of PAF.

In a study of R-R interval dynamics prior to PAF in patients who had undergone CABG, Hogue et al showed that patients who experienced PAF had higher heart rates directly before PAF onset.¹⁶ Higher heart rates are associated with increased activity of the sympathetic nervous system and/or decreased activity of the parasympathetic nervous system. This finding supports our hypothesis of a relationship between PAF following CABG and excessive adrenergic activation. Chen et al have noted that catecholamine-mediated AF usually occurs in the presence of heart disease and that these types of attacks often happen during the day­time in association with physical or emotional stress.⁴

Bettoni and Zimmermann found that the onset of AF is preceded by a primary increase in adrenergic drive, which changes to increased vagal activity immediately before the occurrence.³ Tomita et al reported that sympathetic tone increases immediately before an occurrence of daytime AF.⁷ These results were supported by Lombardi et al, who detected signs of predominant sympathetic modulation and reduced vagal modulation of sinus node in AF episodes that started during the daytime.⁶ These episodes were characterized by atrial ectopic beats prior to onset.⁶

Modulations in baroreceptor reflex activity may provide further evidence of the importance of the sympathetic/parasympathetic balance in the initiation of AF. Suboptimal functioning of the baroreceptor reflex has been associated with arrhythmias and adverse cardiac events in patients and animal models. Loss of the protective effects of vagal activation has been postulated to increase vulnerability to sympathetically driven ischemia and malignant arrhythmias.¹⁷

Multiple studies have shown that the only conclusive predictor of PAF is age. Notably, heart rate variability is reduced with increased age.¹⁸ By measuring heart rate variability, Taggart et al showed that autonomic balance was improved in patients under induced stress when they were in a hypnotic state.¹⁹ Although no attempts were made to determine heart rate variability in our patient set, other studies have demonstrated an increase in heart rate variability during hypnosis. The results of our study suggest that clinical hypnosis using a personalized Ericksonian approach may have a beneficial effect on the incidence of PAF.

CONCLUSIONS

Clinical hypnosis appears to lower the incidence of PAF in patients undergoing CABG as well as to yield favorable trends toward reduced ICU and postoperative hospital stays, reduced hospital charges, and reduced use of narcotics. Although our study had a small sample size and lacked randomization, its positive results and the absence of side effects suggest that prospective randomized trials should be conducted to further delineate the role of hypnosis in the prevention of PAF. A better understanding of AF, and of the autonomic nervous system’s role in triggering and maintaining PAF, will allow more appropriate treatment of this condition.

Postoperative atrial fibrillation (PAF) is the most common complication of coronary artery bypass graft surgery (CABG), affecting approximately 20% to 40% of patients undergoing this procedure.¹ Occurrence of PAF has been associated with prolonged hospital and intensive care unit (ICU) stays, a decline in neurocognitive ability, an increased risk of stroke and transient ischemic attacks, increased surgical mortality, and increased resource utilization and cost.²

The role of the autonomic nervous system in atrial fibrillation (AF) has been studied extensively, but the impact of the autonomic nervous system on PAF has received little attention. Research on the mechanisms of AF has shown imbalance in the autonomic nervous system when measured using heart rate variability. These studies have demonstrated an increase in sympathetic activity approximately 20 minutes prior to the onset of AF, with a shift to parasympathetic activity directly prior to onset. A correlation between mental stress and changes in the autonomic nervous system, as assessed by heart rate variability, has also been shown.^3–7

Pharmacologic interventions, including beta-blockers and amiodarone, have been proposed as preventive measures for PAF, but the incidence of PAF remains high.¹ Beta-blockade may not be tolerated by patients postoperatively, and there is no consensus on dosing parameters. A meta-analysis on the use of amiodarone in the prevention of PAF was inconclusive,⁸ and the optimal dosing regimen and incidence of adverse events with amiodarone have not been determined.

There are a small number of studies linking clinical hypnosis to changes in the autonomic nervous system.⁹ Clinical hypnosis also has been associated with reductions in anxiety and depression before and after surgical procedures.^10,11 If PAF is a result of transient autonomic dysfunction, then interventions that alter autonomic tone should influence the incidence and duration of PAF. We report here a retrospective analysis of the impact of clinical hypnosis on the occurrence of PAF in patients undergoing CABG.

METHODOLOGY

Fifty consecutive patients undergoing first-time CABG between October 2004 and May 2005 received preoperative hypnoidal explanation of the surgical procedure as part of their preparation for surgery. A group of 50 case-matched patients who had undergone CABG at the same center between October 2003 and May 2004 were chosen as historical controls.

The treatment group (hypnosis group) and the control group were case-matched for presence of diabetes mellitus, use of beta-adrenergic blocking agents, and use of antiarrhythmic medications. The groups were also matched for various predictors of postoperative PAF, such as age, gender, and coronary artery disease. The patients were all treated by the same surgeon (R.N.), with no significant alterations to surgical or pharmacologic protocols.

The surgeon used indirect Ericksonian techniques during the preoperative explanation of the surgery. Milton Erickson, one of the most prominent hypnotherapists in recent times, used an indirect approach to weave suggestions into the dialogue rather than giving direct commands. This approach encourages active participation and gives the patient a sense of greater control in the hospital environment. The surgeon also instructed patients in self-hypnosis using respiration and imagery.

RESULTS

Table 2 presents outcomes in the two study groups. Patients who were treated with clinical hypnosis were less likely to experience PAF: the percentage of patients with one or more episodes of PAF was 6.0% in the treat­ment group versus 24.0% in the control group (P = .003). Likewise, the percentage of patients who were discharged on amiodarone was 14.0% in the treatment group versus 28.0% in the control group (P = .03).

Clinical characteristics were tabulated and compared between the subjects who experienced new-onset PAF and those who did not experience PAF to determine whether there was a covariate responsible for the results observed. With the exception of age, the difference in clinical characteristics between these groups of patients was not statistically significant (using P > .10 as the threshold for significance) (Table 3).

Adverse effects of PAF are well established

The onset of PAF following CABG is a common complication that has been linked to increases in morbidity and mortality, length of stay in the ICU and hospital, and total hospital charges. Villareal et al found that the odds ratio for early mortality (within 30 days) for patients who experienced PAF after CABG was 1.4 (95% confidence interval, 1.12 to 1.68; P = .002).¹² In addition, patients with PAF had significantly higher rates of postoperative infections, renal failure, shock, failure of multiple organ systems, and cardiac arrest compared with those who did not have PAF.¹² A literature analysis by Maisel et al found that PAF increases the likelihood that cardiac surgery patients will need to return to the operating room, be readmitted to the ICU, and require prolonged ventilation or reintubation.¹³ Nickerson et al showed that PAF following cardiac surgery corresponded with an increase in length of stay in both the ICU and hospital.¹⁴

Our study showed statistically significant increases in postoperative hospital charges, postoperative hospital stay, and ICU stay among patients who experi­enced PAF following CABG. These findings are consistent with the current literature. In a study of 720 subjects undergoing CABG, Hravnak et al reported a 1.4-day increase in length of hospital stay and a 0.3­day increase in length of ICU stay among patients who had PAF compared with those who did not.¹⁵ A significant increase in postoperative hospital charges was also observed.¹⁵ Similarly, in a multicenter study of 2,417 patients undergoing isolated CABG procedures, Mathew et al observed increases in ICU stay and hospital stay among those patients who experienced PAF.² These findings indicate that the onset of PAF after CABG is a serious complication and that further study is warranted.

Hypnosis to prevent PAF: Suggestive evidence and mechanisms

Clinical hypnosis has been shown to reduce stress and anxiety in surgical patients and can be highly individualized to address the patient’s needs during the stress­ful preoperative period. Saadat et al found that hypnosis administered directly before ambulatory surgery using Ericksonian techniques reduced patients’ levels of anxiety by 56% from baseline.¹¹ In a South African study specifically in men undergoing CABG, de Klerk et al found that preoperative hypnotherapy led to reductions in both anxiety and depression at discharge that were maintained through 6-week follow-up.¹⁰

These findings, taken together with research linking clinical hypnosis to changes in the autonomic nervous system⁹ and the belief that PAF may result from transient autonomic dysfunction, suggest that hypnosis may reduce the incidence of PAF.

In a study of R-R interval dynamics prior to PAF in patients who had undergone CABG, Hogue et al showed that patients who experienced PAF had higher heart rates directly before PAF onset.¹⁶ Higher heart rates are associated with increased activity of the sympathetic nervous system and/or decreased activity of the parasympathetic nervous system. This finding supports our hypothesis of a relationship between PAF following CABG and excessive adrenergic activation. Chen et al have noted that catecholamine-mediated AF usually occurs in the presence of heart disease and that these types of attacks often happen during the day­time in association with physical or emotional stress.⁴

Bettoni and Zimmermann found that the onset of AF is preceded by a primary increase in adrenergic drive, which changes to increased vagal activity immediately before the occurrence.³ Tomita et al reported that sympathetic tone increases immediately before an occurrence of daytime AF.⁷ These results were supported by Lombardi et al, who detected signs of predominant sympathetic modulation and reduced vagal modulation of sinus node in AF episodes that started during the daytime.⁶ These episodes were characterized by atrial ectopic beats prior to onset.⁶

Modulations in baroreceptor reflex activity may provide further evidence of the importance of the sympathetic/parasympathetic balance in the initiation of AF. Suboptimal functioning of the baroreceptor reflex has been associated with arrhythmias and adverse cardiac events in patients and animal models. Loss of the protective effects of vagal activation has been postulated to increase vulnerability to sympathetically driven ischemia and malignant arrhythmias.¹⁷

Multiple studies have shown that the only conclusive predictor of PAF is age. Notably, heart rate variability is reduced with increased age.¹⁸ By measuring heart rate variability, Taggart et al showed that autonomic balance was improved in patients under induced stress when they were in a hypnotic state.¹⁹ Although no attempts were made to determine heart rate variability in our patient set, other studies have demonstrated an increase in heart rate variability during hypnosis. The results of our study suggest that clinical hypnosis using a personalized Ericksonian approach may have a beneficial effect on the incidence of PAF.

CONCLUSIONS

Clinical hypnosis appears to lower the incidence of PAF in patients undergoing CABG as well as to yield favorable trends toward reduced ICU and postoperative hospital stays, reduced hospital charges, and reduced use of narcotics. Although our study had a small sample size and lacked randomization, its positive results and the absence of side effects suggest that prospective randomized trials should be conducted to further delineate the role of hypnosis in the prevention of PAF. A better understanding of AF, and of the autonomic nervous system’s role in triggering and maintaining PAF, will allow more appropriate treatment of this condition.

Minor depressive disorder (mDD) is not an official DSM-IV diagnosis but is used for research purposes; it is similar to MDD in duration but requires that only two to four symptoms be present.

EPIDEMIOLOGY OF DEPRESSION

Depression is a widespread and often chronic condition. Lifetime prevalence estimates for MDD are approximately 15% to 20%;^2,3 1-year prevalence estimates are 5% to 10%;^2,4 and point prevalence estimates range from 4% to 7%.^3,5 Moreover, MDD is characterized by high rates of relapse: 22% to 50% of patients suffer recurrent episodes within 6 months after recovery.⁶

Women are twice as likely as men to be diagnosed with MDD, with lifetime prevalence rates of 10% to 25% in women versus 5% to 12% in men.¹

Although rates of depression do not appear to increase with age, MDD often goes undertreated in older adults³ and in cardiac patients.⁷

DIAGNOSING AND ASSESSING DEPRESSION

The gold standard for diagnosing MDD is a clinical interview. Commonly used instruments include the Diagnostic Interview Schedule⁸ and the Composite International Diagnostic Interview.⁹ The Structured Clinical Interview for DSM-IV Axis I Disorders¹⁰ and the Schedule for Affective Disorders and Schizophrenia¹¹ are frequently used semistructured interviews.

The most common clinical instruments for assessing the severity of depressive symptoms are the Hamilton Rating Scale for Depression (HAM-D),¹² which is a clinician-rated scale, and various psychometric questionnaires, including the Beck Depression Inventory (BDI)^13,14 and the Center for Epidemiological Studies Depression Scale (CES-D).¹⁵

THE DEPRESSION–HEART DISEASE LINK

Depression as a primary risk factor

Reprinted from Rozanski A, et al. The epidemiology, pathophysiology, and management of psychosocial risk factors in cardiac practice: the emerging field of behavioral cardiology. J Am Coll Cardiol 2005; 45:637–651, © 2005, with permission from the ACC.

Depression as a secondary risk factor

Depression is an even stronger risk factor for cardiac events in patients with established CHD. Point estimates range from 14% to as high as 47%, with higher rates in patients with unstable angina and in patients awaiting coronary artery bypass graft (CABG) surgery; an additional 20% of patients exhibit elevated depressive symptoms or minor depression (mDD).^19–25

Prospective studies have shown that depression increases the risk for death or nonfatal cardiac events approximately 2.5-fold in patients with CHD. For instance, Frasure-Smith et al followed 896 patients with a recent acute MI and found that the presence of depressive symptoms as indicated by an elevated BDI score was a significant predictor of cardiac mortality after controlling for multivariate predictors of mortality (odds ratio [OR] = 3.29 for women and 3.05 for men).²⁶

Two recent meta-analyses confirmed the association between depression and adverse clinical outcomes in patients with CHD.^27,28 For example, van Melle et al reported that post-MI depression was associated with a 2- to 2.5-fold increase in the risk of adverse health outcomes.²⁸ In this analysis, depression’s effect on cardiac mortality and all-cause mortality was especially pronounced in older studies (before 1992) (OR = 3.2) compared with more recent studies (after 1992) (OR = 2.01).²⁸

Duke University researchers have conducted several prospective studies in various cardiac populations.^29–31 Barefoot et al assessed 1,250 patients with documented CHD using the Zung Self-Rating Depression Scale at the time of diagnostic coronary angiography and followed them for up to 19.4 years.²⁹ Results showed that patients with moderate to severe depression were at 69% greater risk for cardiac death and 78% greater risk for all-cause death than were their nondepressed counterparts.

Reprinted from The Lancet (Blumenthal JA, et al. Depression as a risk factor for mortality after coronary artery bypass surgery. Lancet 2003; 362:604–609.), copyright 2003, with permission from Elsevier.

We also recently reported results from a prospective study that followed 204 patients with heart failure over a median interval of 3 years.³¹ Clinically significant symptoms of depression (BDI score ≥ 10) were associated with a hazard ratio of 1.56 (95% CI, 1.07 to 2.29) for the combined end point of death or cardiovascular hospitalization. These observations included adjustment for plasma NT-proBNP level, ejection fraction, and other established risk factors, suggesting that heightened risk of adverse clinical outcomes associated with depressive symptoms is not simply a reflection of the severity of heart failure.

In summary, a number of observational studies have demonstrated that depression is associated with increased risk of morbidity and mortality both in healthy populations and in a variety of populations with established cardiac disease.

BIOBEHAVIORAL MECHANISMS LINKING DEPRESSION AND CHD

A number of biobehavioral mechanisms have been hypothesized to underlie the relationship between depression and CHD. Most evidence is derived from cross-sectional studies and suggests that depression is associated with traditional risk factors for CHD, such as hypertension, diabetes, and insulin resistance,^32,33 as well as changes in platelet reactivity,³⁴ dysregulation of the autonomic nervous system³⁵ and hypothalamic-pituitary-adrenal axis,³⁶ and alterations in the immune response/inflammation.³⁷ Depression is also associated with behavioral factors that are in turn associated with CHD risk, such as reduced treatment adherence,³⁸ smoking,³⁹ and physical inactivity.⁴⁰

Successful treatments for depression in patients with CHD may have the potential to improve not only quality of life but also cardiovascular and physical health. Several treatments for depression exist for use in the general population, such as antidepressant medication or psychotherapy.⁴¹ However, only three studies have tested the efficacy of these treatments in patients with CHD: SADHART, ENRICHD, and CREATE.^42–44

SADHART (Sertraline Antidepressant Heart Attack Randomized Trial) was a safety and efficacy evaluation of antidepressant medication in patients with MDD and a recent MI or unstable angina.⁴² It showed only modest differences in reductions in depressive symptoms between sertraline recipients and placebo recipients, and it lacked statistical power to examine the impact of treatment on hard clinical end points.

ENRICHD (Enhancing Recovery in Coronary Heart Disease Patients) assessed the effect of psychosocial treatment on survival among more than than 2,400 post-MI patients.⁴³ Although this trial found that cognitive behavior therapy resulted in significant, albeit small, improvements in depressive symptoms compared with usual care, it failed to demonstrate that treating depression and low social support was associated with increased survival.

CREATE (Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy), a recent placebo-controlled trial, assessed the value of antidepressant medication and clinical management in patients with CHD.⁴⁴ The study’s 284 patients, all of whom had CHD as well as MDD and a HAM-D score of 20 or greater, underwent two separate randomizations: (1) to 12 weeks of interpersonal therapy plus clinical management or 12 weeks of clinical management alone, and (2) to 12 weeks of citalopram therapy or matching placebo. There was no difference between interpersonal therapy and clinical management alone; however, citalopram was superior to placebo in reducing HAM-D scores and demonstrated better remission rates (35.9% with citalopram vs 22.5% with placebo). The same therapists who provided interpersonal therapy also performed the clinical management, so it could be argued that this was why additional interpersonal therapist time did not result in greater reductions in depressive symptoms than did clinical management alone. Furthermore, this study did not examine the effects of depression therapy on clinical outcomes.

EXERCISE AS A TREATMENT FOR DEPRESSION

There is growing evidence that exercise may be an effective treatment for depression.⁴⁵ Most of the existing studies of exercise for depression have focused on aerobic exercise.

In the relatively large SMILE study (Standard Medical Intervention and Long-term Exercise),⁴⁶ conducted at Duke University, 156 adult noncardiac patients with MDD were randomized to 4 months of treatment with supervised aerobic exercise, antidepressant medication (sertraline), or a combination of exercise and medication. Although antidepressant medication was associated with faster reductions in depression in the first 4 weeks of treatment among mildly depressed patients, exercise was as effective as antidepressant medication in treating depression by the end of the 16-week intervention for all participants.

Reprinted, with permission, from Babyak MA, et al. Exercise treatment for major depression: maintenance of therapeutic benefit at 10 months. Psychosom Med 2000; 62:633–638.

Exercise generally is considered safe for most patients with stable CHD.⁴⁸ Some studies of exercise treatments for patients with CHD have tracked depressive symptoms and thus have provided insight into the potential efficacy of exercise as a treatment for depression in this population. Although most of these studies have reported significant improvements in depression after completion of an exercise program, many have had important methodologic limitations, including absence of a control group. In one of the few controlled studies in this area, Stern et al⁴⁹ randomized 106 men who had a recent acute MI and elevated depression, anxiety, or low fitness to 12 weeks of exercise training, group therapy, or usual care (control). At 1-year follow-up, subjects in both the exercise and counseling groups showed improvements in depression relative to controls.

EFFECT OF EXERCISE ON CARDIOVASCULAR RISK FACTORS AND OUTCOMES

Exercise is a particularly promising intervention for depression in patients with CHD because it has well-documented cardiovascular benefits. In addition to the well-established role of exercise interventions in primary prevention, such interventions have been shown to improve outcomes for patients with CHD.⁵⁰

Jolliffe et al conducted a meta-analysis comparing exercise-only interventions, comprehensive rehabilitation (including educational and behavioral components such as dietary changes and stress reduction in addition to exercise), and usual care.⁵¹ Exercise-only interventions were associated with reductions in both all-cause and cardiac mortality relative to usual care. Comprehensive rehabilitation, on the other hand, was not associated with statistically significant reductions in all-cause mortality relative to usual care, but it was associated with a decreased risk for cardiac mortality, to a slightly lesser extent than exercise-only interventions.

Reprinted, with permission, from Blumenthal JA, et al. Exercise, depression, and mortality after myocardial infarction in the ENRICHD trial. Med Sci Sports Exerc 2004; 36:746–755.

The evidence that exercise affects depression, CHD risk factors, and CHD outcomes suggests that exercise is a particularly promising intervention for depression in this population.

UPBEAT trial promises further insight

A new Duke University study known as UPBEAT (Understanding Prognostic Benefits of Exercise and Antidepressant Treatment) is randomizing 200 patients with elevated depressive symptoms to exercise, antidepressant therapy (sertraline), or placebo for 4 months.⁵³ A variety of “biomarkers” of risk are being assessed, including measures of heart rate variability, vascular function, inflammation, and platelet aggregation. Results of this 5-year trial should be available by 2011.

Although depression has emerged as an important risk factor for CHD, there is no consensus on the optimal way to treat depression in patients with CHD. Interventions that are guided by an understanding of the mechanisms linking depression to CHD may prove to be most effective in improving both depression and physical health outcomes.

Exercise targets many of the mechanisms by which depression may be associated with increased risk, including autonomic nervous system activity, hypothalamic-pituitary-adrenal axis function, platelet activation, vascular function, and inflammation. Moreover, a growing body of evidence suggests that exercise is an effective treatment for depression that may be comparable in effect to antidepressant medication, at least in select subgroups (eg, patients who are receptive to exercise as a treatment for depression). The value of exercise training—not only for improving quality of life, but also for improving “biomarkers” of risk and other relevant health outcomes—is the focus of our current research efforts.

Minor depressive disorder (mDD) is not an official DSM-IV diagnosis but is used for research purposes; it is similar to MDD in duration but requires that only two to four symptoms be present.

EPIDEMIOLOGY OF DEPRESSION

Depression is a widespread and often chronic condition. Lifetime prevalence estimates for MDD are approximately 15% to 20%;^2,3 1-year prevalence estimates are 5% to 10%;^2,4 and point prevalence estimates range from 4% to 7%.^3,5 Moreover, MDD is characterized by high rates of relapse: 22% to 50% of patients suffer recurrent episodes within 6 months after recovery.⁶

Women are twice as likely as men to be diagnosed with MDD, with lifetime prevalence rates of 10% to 25% in women versus 5% to 12% in men.¹

Although rates of depression do not appear to increase with age, MDD often goes undertreated in older adults³ and in cardiac patients.⁷

DIAGNOSING AND ASSESSING DEPRESSION

The gold standard for diagnosing MDD is a clinical interview. Commonly used instruments include the Diagnostic Interview Schedule⁸ and the Composite International Diagnostic Interview.⁹ The Structured Clinical Interview for DSM-IV Axis I Disorders¹⁰ and the Schedule for Affective Disorders and Schizophrenia¹¹ are frequently used semistructured interviews.

The most common clinical instruments for assessing the severity of depressive symptoms are the Hamilton Rating Scale for Depression (HAM-D),¹² which is a clinician-rated scale, and various psychometric questionnaires, including the Beck Depression Inventory (BDI)^13,14 and the Center for Epidemiological Studies Depression Scale (CES-D).¹⁵

THE DEPRESSION–HEART DISEASE LINK

Depression as a primary risk factor

Reprinted from Rozanski A, et al. The epidemiology, pathophysiology, and management of psychosocial risk factors in cardiac practice: the emerging field of behavioral cardiology. J Am Coll Cardiol 2005; 45:637–651, © 2005, with permission from the ACC.

Depression as a secondary risk factor

Depression is an even stronger risk factor for cardiac events in patients with established CHD. Point estimates range from 14% to as high as 47%, with higher rates in patients with unstable angina and in patients awaiting coronary artery bypass graft (CABG) surgery; an additional 20% of patients exhibit elevated depressive symptoms or minor depression (mDD).^19–25

Prospective studies have shown that depression increases the risk for death or nonfatal cardiac events approximately 2.5-fold in patients with CHD. For instance, Frasure-Smith et al followed 896 patients with a recent acute MI and found that the presence of depressive symptoms as indicated by an elevated BDI score was a significant predictor of cardiac mortality after controlling for multivariate predictors of mortality (odds ratio [OR] = 3.29 for women and 3.05 for men).²⁶

Two recent meta-analyses confirmed the association between depression and adverse clinical outcomes in patients with CHD.^27,28 For example, van Melle et al reported that post-MI depression was associated with a 2- to 2.5-fold increase in the risk of adverse health outcomes.²⁸ In this analysis, depression’s effect on cardiac mortality and all-cause mortality was especially pronounced in older studies (before 1992) (OR = 3.2) compared with more recent studies (after 1992) (OR = 2.01).²⁸

Duke University researchers have conducted several prospective studies in various cardiac populations.^29–31 Barefoot et al assessed 1,250 patients with documented CHD using the Zung Self-Rating Depression Scale at the time of diagnostic coronary angiography and followed them for up to 19.4 years.²⁹ Results showed that patients with moderate to severe depression were at 69% greater risk for cardiac death and 78% greater risk for all-cause death than were their nondepressed counterparts.

Reprinted from The Lancet (Blumenthal JA, et al. Depression as a risk factor for mortality after coronary artery bypass surgery. Lancet 2003; 362:604–609.), copyright 2003, with permission from Elsevier.

We also recently reported results from a prospective study that followed 204 patients with heart failure over a median interval of 3 years.³¹ Clinically significant symptoms of depression (BDI score ≥ 10) were associated with a hazard ratio of 1.56 (95% CI, 1.07 to 2.29) for the combined end point of death or cardiovascular hospitalization. These observations included adjustment for plasma NT-proBNP level, ejection fraction, and other established risk factors, suggesting that heightened risk of adverse clinical outcomes associated with depressive symptoms is not simply a reflection of the severity of heart failure.

In summary, a number of observational studies have demonstrated that depression is associated with increased risk of morbidity and mortality both in healthy populations and in a variety of populations with established cardiac disease.

BIOBEHAVIORAL MECHANISMS LINKING DEPRESSION AND CHD

A number of biobehavioral mechanisms have been hypothesized to underlie the relationship between depression and CHD. Most evidence is derived from cross-sectional studies and suggests that depression is associated with traditional risk factors for CHD, such as hypertension, diabetes, and insulin resistance,^32,33 as well as changes in platelet reactivity,³⁴ dysregulation of the autonomic nervous system³⁵ and hypothalamic-pituitary-adrenal axis,³⁶ and alterations in the immune response/inflammation.³⁷ Depression is also associated with behavioral factors that are in turn associated with CHD risk, such as reduced treatment adherence,³⁸ smoking,³⁹ and physical inactivity.⁴⁰

Successful treatments for depression in patients with CHD may have the potential to improve not only quality of life but also cardiovascular and physical health. Several treatments for depression exist for use in the general population, such as antidepressant medication or psychotherapy.⁴¹ However, only three studies have tested the efficacy of these treatments in patients with CHD: SADHART, ENRICHD, and CREATE.^42–44

SADHART (Sertraline Antidepressant Heart Attack Randomized Trial) was a safety and efficacy evaluation of antidepressant medication in patients with MDD and a recent MI or unstable angina.⁴² It showed only modest differences in reductions in depressive symptoms between sertraline recipients and placebo recipients, and it lacked statistical power to examine the impact of treatment on hard clinical end points.

ENRICHD (Enhancing Recovery in Coronary Heart Disease Patients) assessed the effect of psychosocial treatment on survival among more than than 2,400 post-MI patients.⁴³ Although this trial found that cognitive behavior therapy resulted in significant, albeit small, improvements in depressive symptoms compared with usual care, it failed to demonstrate that treating depression and low social support was associated with increased survival.

CREATE (Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy), a recent placebo-controlled trial, assessed the value of antidepressant medication and clinical management in patients with CHD.⁴⁴ The study’s 284 patients, all of whom had CHD as well as MDD and a HAM-D score of 20 or greater, underwent two separate randomizations: (1) to 12 weeks of interpersonal therapy plus clinical management or 12 weeks of clinical management alone, and (2) to 12 weeks of citalopram therapy or matching placebo. There was no difference between interpersonal therapy and clinical management alone; however, citalopram was superior to placebo in reducing HAM-D scores and demonstrated better remission rates (35.9% with citalopram vs 22.5% with placebo). The same therapists who provided interpersonal therapy also performed the clinical management, so it could be argued that this was why additional interpersonal therapist time did not result in greater reductions in depressive symptoms than did clinical management alone. Furthermore, this study did not examine the effects of depression therapy on clinical outcomes.

EXERCISE AS A TREATMENT FOR DEPRESSION

There is growing evidence that exercise may be an effective treatment for depression.⁴⁵ Most of the existing studies of exercise for depression have focused on aerobic exercise.

In the relatively large SMILE study (Standard Medical Intervention and Long-term Exercise),⁴⁶ conducted at Duke University, 156 adult noncardiac patients with MDD were randomized to 4 months of treatment with supervised aerobic exercise, antidepressant medication (sertraline), or a combination of exercise and medication. Although antidepressant medication was associated with faster reductions in depression in the first 4 weeks of treatment among mildly depressed patients, exercise was as effective as antidepressant medication in treating depression by the end of the 16-week intervention for all participants.

Reprinted, with permission, from Babyak MA, et al. Exercise treatment for major depression: maintenance of therapeutic benefit at 10 months. Psychosom Med 2000; 62:633–638.

Exercise generally is considered safe for most patients with stable CHD.⁴⁸ Some studies of exercise treatments for patients with CHD have tracked depressive symptoms and thus have provided insight into the potential efficacy of exercise as a treatment for depression in this population. Although most of these studies have reported significant improvements in depression after completion of an exercise program, many have had important methodologic limitations, including absence of a control group. In one of the few controlled studies in this area, Stern et al⁴⁹ randomized 106 men who had a recent acute MI and elevated depression, anxiety, or low fitness to 12 weeks of exercise training, group therapy, or usual care (control). At 1-year follow-up, subjects in both the exercise and counseling groups showed improvements in depression relative to controls.

EFFECT OF EXERCISE ON CARDIOVASCULAR RISK FACTORS AND OUTCOMES

Exercise is a particularly promising intervention for depression in patients with CHD because it has well-documented cardiovascular benefits. In addition to the well-established role of exercise interventions in primary prevention, such interventions have been shown to improve outcomes for patients with CHD.⁵⁰

Jolliffe et al conducted a meta-analysis comparing exercise-only interventions, comprehensive rehabilitation (including educational and behavioral components such as dietary changes and stress reduction in addition to exercise), and usual care.⁵¹ Exercise-only interventions were associated with reductions in both all-cause and cardiac mortality relative to usual care. Comprehensive rehabilitation, on the other hand, was not associated with statistically significant reductions in all-cause mortality relative to usual care, but it was associated with a decreased risk for cardiac mortality, to a slightly lesser extent than exercise-only interventions.

Reprinted, with permission, from Blumenthal JA, et al. Exercise, depression, and mortality after myocardial infarction in the ENRICHD trial. Med Sci Sports Exerc 2004; 36:746–755.

The evidence that exercise affects depression, CHD risk factors, and CHD outcomes suggests that exercise is a particularly promising intervention for depression in this population.

UPBEAT trial promises further insight

A new Duke University study known as UPBEAT (Understanding Prognostic Benefits of Exercise and Antidepressant Treatment) is randomizing 200 patients with elevated depressive symptoms to exercise, antidepressant therapy (sertraline), or placebo for 4 months.⁵³ A variety of “biomarkers” of risk are being assessed, including measures of heart rate variability, vascular function, inflammation, and platelet aggregation. Results of this 5-year trial should be available by 2011.

Although depression has emerged as an important risk factor for CHD, there is no consensus on the optimal way to treat depression in patients with CHD. Interventions that are guided by an understanding of the mechanisms linking depression to CHD may prove to be most effective in improving both depression and physical health outcomes.

Exercise targets many of the mechanisms by which depression may be associated with increased risk, including autonomic nervous system activity, hypothalamic-pituitary-adrenal axis function, platelet activation, vascular function, and inflammation. Moreover, a growing body of evidence suggests that exercise is an effective treatment for depression that may be comparable in effect to antidepressant medication, at least in select subgroups (eg, patients who are receptive to exercise as a treatment for depression). The value of exercise training—not only for improving quality of life, but also for improving “biomarkers” of risk and other relevant health outcomes—is the focus of our current research efforts.

Minor depressive disorder (mDD) is not an official DSM-IV diagnosis but is used for research purposes; it is similar to MDD in duration but requires that only two to four symptoms be present.

EPIDEMIOLOGY OF DEPRESSION

Depression is a widespread and often chronic condition. Lifetime prevalence estimates for MDD are approximately 15% to 20%;^2,3 1-year prevalence estimates are 5% to 10%;^2,4 and point prevalence estimates range from 4% to 7%.^3,5 Moreover, MDD is characterized by high rates of relapse: 22% to 50% of patients suffer recurrent episodes within 6 months after recovery.⁶

Women are twice as likely as men to be diagnosed with MDD, with lifetime prevalence rates of 10% to 25% in women versus 5% to 12% in men.¹

Although rates of depression do not appear to increase with age, MDD often goes undertreated in older adults³ and in cardiac patients.⁷

DIAGNOSING AND ASSESSING DEPRESSION

The gold standard for diagnosing MDD is a clinical interview. Commonly used instruments include the Diagnostic Interview Schedule⁸ and the Composite International Diagnostic Interview.⁹ The Structured Clinical Interview for DSM-IV Axis I Disorders¹⁰ and the Schedule for Affective Disorders and Schizophrenia¹¹ are frequently used semistructured interviews.

The most common clinical instruments for assessing the severity of depressive symptoms are the Hamilton Rating Scale for Depression (HAM-D),¹² which is a clinician-rated scale, and various psychometric questionnaires, including the Beck Depression Inventory (BDI)^13,14 and the Center for Epidemiological Studies Depression Scale (CES-D).¹⁵

THE DEPRESSION–HEART DISEASE LINK

Depression as a primary risk factor

Reprinted from Rozanski A, et al. The epidemiology, pathophysiology, and management of psychosocial risk factors in cardiac practice: the emerging field of behavioral cardiology. J Am Coll Cardiol 2005; 45:637–651, © 2005, with permission from the ACC.

Depression as a secondary risk factor

Depression is an even stronger risk factor for cardiac events in patients with established CHD. Point estimates range from 14% to as high as 47%, with higher rates in patients with unstable angina and in patients awaiting coronary artery bypass graft (CABG) surgery; an additional 20% of patients exhibit elevated depressive symptoms or minor depression (mDD).^19–25

Prospective studies have shown that depression increases the risk for death or nonfatal cardiac events approximately 2.5-fold in patients with CHD. For instance, Frasure-Smith et al followed 896 patients with a recent acute MI and found that the presence of depressive symptoms as indicated by an elevated BDI score was a significant predictor of cardiac mortality after controlling for multivariate predictors of mortality (odds ratio [OR] = 3.29 for women and 3.05 for men).²⁶

Two recent meta-analyses confirmed the association between depression and adverse clinical outcomes in patients with CHD.^27,28 For example, van Melle et al reported that post-MI depression was associated with a 2- to 2.5-fold increase in the risk of adverse health outcomes.²⁸ In this analysis, depression’s effect on cardiac mortality and all-cause mortality was especially pronounced in older studies (before 1992) (OR = 3.2) compared with more recent studies (after 1992) (OR = 2.01).²⁸

Duke University researchers have conducted several prospective studies in various cardiac populations.^29–31 Barefoot et al assessed 1,250 patients with documented CHD using the Zung Self-Rating Depression Scale at the time of diagnostic coronary angiography and followed them for up to 19.4 years.²⁹ Results showed that patients with moderate to severe depression were at 69% greater risk for cardiac death and 78% greater risk for all-cause death than were their nondepressed counterparts.

Reprinted from The Lancet (Blumenthal JA, et al. Depression as a risk factor for mortality after coronary artery bypass surgery. Lancet 2003; 362:604–609.), copyright 2003, with permission from Elsevier.

We also recently reported results from a prospective study that followed 204 patients with heart failure over a median interval of 3 years.³¹ Clinically significant symptoms of depression (BDI score ≥ 10) were associated with a hazard ratio of 1.56 (95% CI, 1.07 to 2.29) for the combined end point of death or cardiovascular hospitalization. These observations included adjustment for plasma NT-proBNP level, ejection fraction, and other established risk factors, suggesting that heightened risk of adverse clinical outcomes associated with depressive symptoms is not simply a reflection of the severity of heart failure.

In summary, a number of observational studies have demonstrated that depression is associated with increased risk of morbidity and mortality both in healthy populations and in a variety of populations with established cardiac disease.

BIOBEHAVIORAL MECHANISMS LINKING DEPRESSION AND CHD

A number of biobehavioral mechanisms have been hypothesized to underlie the relationship between depression and CHD. Most evidence is derived from cross-sectional studies and suggests that depression is associated with traditional risk factors for CHD, such as hypertension, diabetes, and insulin resistance,^32,33 as well as changes in platelet reactivity,³⁴ dysregulation of the autonomic nervous system³⁵ and hypothalamic-pituitary-adrenal axis,³⁶ and alterations in the immune response/inflammation.³⁷ Depression is also associated with behavioral factors that are in turn associated with CHD risk, such as reduced treatment adherence,³⁸ smoking,³⁹ and physical inactivity.⁴⁰

Successful treatments for depression in patients with CHD may have the potential to improve not only quality of life but also cardiovascular and physical health. Several treatments for depression exist for use in the general population, such as antidepressant medication or psychotherapy.⁴¹ However, only three studies have tested the efficacy of these treatments in patients with CHD: SADHART, ENRICHD, and CREATE.^42–44

SADHART (Sertraline Antidepressant Heart Attack Randomized Trial) was a safety and efficacy evaluation of antidepressant medication in patients with MDD and a recent MI or unstable angina.⁴² It showed only modest differences in reductions in depressive symptoms between sertraline recipients and placebo recipients, and it lacked statistical power to examine the impact of treatment on hard clinical end points.

ENRICHD (Enhancing Recovery in Coronary Heart Disease Patients) assessed the effect of psychosocial treatment on survival among more than than 2,400 post-MI patients.⁴³ Although this trial found that cognitive behavior therapy resulted in significant, albeit small, improvements in depressive symptoms compared with usual care, it failed to demonstrate that treating depression and low social support was associated with increased survival.

CREATE (Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy), a recent placebo-controlled trial, assessed the value of antidepressant medication and clinical management in patients with CHD.⁴⁴ The study’s 284 patients, all of whom had CHD as well as MDD and a HAM-D score of 20 or greater, underwent two separate randomizations: (1) to 12 weeks of interpersonal therapy plus clinical management or 12 weeks of clinical management alone, and (2) to 12 weeks of citalopram therapy or matching placebo. There was no difference between interpersonal therapy and clinical management alone; however, citalopram was superior to placebo in reducing HAM-D scores and demonstrated better remission rates (35.9% with citalopram vs 22.5% with placebo). The same therapists who provided interpersonal therapy also performed the clinical management, so it could be argued that this was why additional interpersonal therapist time did not result in greater reductions in depressive symptoms than did clinical management alone. Furthermore, this study did not examine the effects of depression therapy on clinical outcomes.

EXERCISE AS A TREATMENT FOR DEPRESSION

There is growing evidence that exercise may be an effective treatment for depression.⁴⁵ Most of the existing studies of exercise for depression have focused on aerobic exercise.

In the relatively large SMILE study (Standard Medical Intervention and Long-term Exercise),⁴⁶ conducted at Duke University, 156 adult noncardiac patients with MDD were randomized to 4 months of treatment with supervised aerobic exercise, antidepressant medication (sertraline), or a combination of exercise and medication. Although antidepressant medication was associated with faster reductions in depression in the first 4 weeks of treatment among mildly depressed patients, exercise was as effective as antidepressant medication in treating depression by the end of the 16-week intervention for all participants.

Reprinted, with permission, from Babyak MA, et al. Exercise treatment for major depression: maintenance of therapeutic benefit at 10 months. Psychosom Med 2000; 62:633–638.

Exercise generally is considered safe for most patients with stable CHD.⁴⁸ Some studies of exercise treatments for patients with CHD have tracked depressive symptoms and thus have provided insight into the potential efficacy of exercise as a treatment for depression in this population. Although most of these studies have reported significant improvements in depression after completion of an exercise program, many have had important methodologic limitations, including absence of a control group. In one of the few controlled studies in this area, Stern et al⁴⁹ randomized 106 men who had a recent acute MI and elevated depression, anxiety, or low fitness to 12 weeks of exercise training, group therapy, or usual care (control). At 1-year follow-up, subjects in both the exercise and counseling groups showed improvements in depression relative to controls.

EFFECT OF EXERCISE ON CARDIOVASCULAR RISK FACTORS AND OUTCOMES

Exercise is a particularly promising intervention for depression in patients with CHD because it has well-documented cardiovascular benefits. In addition to the well-established role of exercise interventions in primary prevention, such interventions have been shown to improve outcomes for patients with CHD.⁵⁰

Jolliffe et al conducted a meta-analysis comparing exercise-only interventions, comprehensive rehabilitation (including educational and behavioral components such as dietary changes and stress reduction in addition to exercise), and usual care.⁵¹ Exercise-only interventions were associated with reductions in both all-cause and cardiac mortality relative to usual care. Comprehensive rehabilitation, on the other hand, was not associated with statistically significant reductions in all-cause mortality relative to usual care, but it was associated with a decreased risk for cardiac mortality, to a slightly lesser extent than exercise-only interventions.

Reprinted, with permission, from Blumenthal JA, et al. Exercise, depression, and mortality after myocardial infarction in the ENRICHD trial. Med Sci Sports Exerc 2004; 36:746–755.

The evidence that exercise affects depression, CHD risk factors, and CHD outcomes suggests that exercise is a particularly promising intervention for depression in this population.

UPBEAT trial promises further insight

A new Duke University study known as UPBEAT (Understanding Prognostic Benefits of Exercise and Antidepressant Treatment) is randomizing 200 patients with elevated depressive symptoms to exercise, antidepressant therapy (sertraline), or placebo for 4 months.⁵³ A variety of “biomarkers” of risk are being assessed, including measures of heart rate variability, vascular function, inflammation, and platelet aggregation. Results of this 5-year trial should be available by 2011.

Although depression has emerged as an important risk factor for CHD, there is no consensus on the optimal way to treat depression in patients with CHD. Interventions that are guided by an understanding of the mechanisms linking depression to CHD may prove to be most effective in improving both depression and physical health outcomes.

Exercise targets many of the mechanisms by which depression may be associated with increased risk, including autonomic nervous system activity, hypothalamic-pituitary-adrenal axis function, platelet activation, vascular function, and inflammation. Moreover, a growing body of evidence suggests that exercise is an effective treatment for depression that may be comparable in effect to antidepressant medication, at least in select subgroups (eg, patients who are receptive to exercise as a treatment for depression). The value of exercise training—not only for improving quality of life, but also for improving “biomarkers” of risk and other relevant health outcomes—is the focus of our current research efforts.

The Lewy body is the pathologic hallmark of both Parkinson disease and dementia with Lewy bodies. Lewy bodies are seen microscopically as neuronal inclusions containing alpha-synuclein and associated proteins. In contrast, glial inclusions involving alpha-synuclein are seen in multiple system atrophy. Because Lewy bodies are observed in autonomic regulatory regions of the brain, they are of interest in the study of the autonomic dysfunction that figures prominently in several parkinsonian syndromes. Cardiovascular autonomic dysfunction in parkinsonian syndromes includes orthostatic hypotension, postprandial hypotension, and supine hypertension.

This article will describe the major clinical and pathologic features of movement disorders with Lewy body pathology, the likelihood of autonomic dysregulation in these disorders, and issues involved in the treatment of autonomic dysfunction in patients with these movement disorders.

OVERVIEW OF PARKINSONIAN SYNDROMES

Tauopathies versus synucleinopathies

Pathologically, parkinsonian syndromes can be divided into two groups: the tauopathies and the synucleinopathies.

The tauopathies, so named because of the presence of hyperphosphylated tau protein, include progressive supranuclear palsy and corticobasal ganglionic degeneration as well as a number of other neurodegenerative conditions (ie, Pick disease, FTDP-17, primary progressive aphasia, argyrophilic grain disease) that do not cause parkinsonian features.

Synucleinopathies, the focus of this article, are disorders in which the protein alpha-synuclein accumulates in the cytoplasm. They include idiopathic Parkinson disease, multiple system atrophy, dementia with Lewy bodies, and pure autonomic failure. In multiple system atrophy, deposits of alpha-synuclein are prominent in glial cytoplasmic inclusions. In both Parkinson disease and dementia with Lewy bodies, alpha-synuclein is present in Lewy bodies. Although primary autonomic failure is not a movement disorder, its pathology is similar to that of the other synucleinopathies, with alpha-synuclein accumulation in both the central and peripheral nervous systems, as well as the presence of Lewy bodies.

IDIOPATHIC PARKINSON DISEASE

Autonomic dysfunction usually occurs late in idiopathic Parkinson disease, and its severity is less than that observed with other parkinsonian syndromes. However, the lifetime risk of significant autonomic dysfunction in patients with Parkinson disease is approximately 1 in 3.¹ Almost 60% of patients with idiopathic Parkinson disease meet the criterion for a diagnosis of orthostatic hypotension—ie, a fall in systolic blood pressure of at least 20 mm Hg—and orthostatic hypotension is symptomatic in about 20% of patients.¹

MULTIPLE SYSTEM ATROPHY

The nomenclature of multiple system atrophy has been evolving slowly. In 1900, Dejerine and Thomas described olivopontocerebellar atrophy, a progressive cerebellar degeneration with parkinsonism. In 1960, Shy and Drager described the Shy Drager syndrome, which has prominent autonomic features common to Parkinson disease, such as orthostatic hypotension, urinary and fecal incontinence, loss of sweating, iris atrophy, external ocular palsies, rigidity, tremor, loss of associated movement, and impotence.²

Also in 1960, Van der Eecken described striatonigral degeneration, an akinetic, rigid, parkinsonian syndrome that did not respond well to medications and was associated with autonomic dysfunction.³

In 1969, Graham and Oppenheimer realized an overlap to these syndromes and coined the term multiple system atrophy. They used it to refer to a gradually progressive idiopathic neurodegenerative process of adult onset characterized by varying proportions of cerebellar dysfunction, autonomic failure, and parkinsonism, and which is poorly responsive to levodopa therapy.⁴

Newer terminology is more specific for the predominant symptoms in the syndrome. A predominance of parkinsonism with this syndrome is referred to as “parkinsonian type of multiple system atrophy” (MSA-P), whereas a predominance of cerebellar signs is termed “multiple system atrophy with cerebellar-predominant symptoms” (MSA-C). The parkinsonian type is about four times as common as the cerebellar type.⁵ Autonomic dysfunction is common to both types, and its severity varies.

Parkinsonism is the most common symptom in multiple system atrophy, followed by autonomic failure and cerebellar signs. Approximately one fourth of patients with multiple system atrophy have all three categories of symptoms. Pyramidal signs are present in approximately 60% of patients, and help distinguish this syndrome primarily from idiopathic Parkinson disease.⁶

Diagnostic criteria

Autonomic dysfunction in the form of orthostatic hypotension and/or urinary incontinence is a key diagnostic criterion for multiple system atrophy.

Parkinsonism. Parkinsonian features of the syndrome are bradykinesia, rigidity, postural instability, and tremor.

Cerebellar dysfunction. Features of cerebellar dysfunction include gait ataxia, ataxic dysarthria, limb ataxia, and sustained gaze-evoked nystagmus.

Corticospinal tract dysfunction (extensor plantar response with hyperreflexia) also helps establish the diagnosis because this feature separates multiple system atrophy from idiopathic Parkinson disease as well as some of the other parkinsonian syndromes.

Diagnostic categories

The above diagnostic criteria can be combined to make a diagnosis of possible, probable, or definite multiple system atrophy.

Possible. For a diagnosis of possible multiple system atrophy, one of the above diagnostic criteria must be present along with two features from separate domains. If the case meets the criteria for parkinsonism (bradykinesia plus at least one of the other aforementioned features of parkinsonism), a poor levodopa response qualifies as a feature.

Probable. A diagnosis of probable multiple system atrophy must meet the criterion for autonomic dysfunction plus either the criterion for parkinsonism (with poor levodopa response) or the criterion for cerebellar dysfunction.

Definite. Definite multiple system atrophy requires pathological confirmation.

Extrapyramidal features in multiple system atrophy

In addition to prominent autonomic and/or cerebellar dysfunction, differences in extrapyramidal features help distinguish multiple system atrophy from idiopathic Parkinson disease. Tremor is less common in multiple system atrophy than in idiopathic Parkinson disease, and the akinetic/rigid symptoms tend to be symmetric in multiple system atrophy, rather than asymmetric as in Parkinson disease. Postural instability occurs early in multiple system atrophy but does not occur until late in idiopathic Parkinson disease. Moreover, multiple system atrophy responds poorly to levodopa and is characterized by more rapid disease progression. The presence of early autonomic and cerebellar symptoms is diagnostic for multiple system atrophy.

Pathology

The pathologic hallmark of multiple system atrophy is alpha-synuclein deposits in the glial or glial cytoplasmic inclusions (Papp-Lantos inclusions), which are diffuse through the central nervous system but are present particularly in the brainstem and spinal cord.

Dementia with Lewy bodies is also known as diffuse Lewy body disease, senile dementia of the Lewy body type, Lewy body variant of Alzheimer disease, and Parkinson disease with dementia.

Dementia with Lewy bodies is descriptive for the entire series of these diseases. Pathologically, it is identical to Parkinson disease with dementia, with the only difference being an objective criterion based on the duration of dementia. Dementia less than 1 year after onset of parkinsonism is considered dementia with Lewy bodies, whereas dementia more than 1 year after the onset of parkinsonism is considered Parkinson disease with dementia. Whether these are separate disorders or two ends of a spectrum of disease is unclear.

Clinical criteria

Central feature: progressive cognitive decline. Dementia with Lewy bodies is characterized by prominent progressive cognitive decline that is uncharacteristic of Parkinson disease. In particular, patients with dementia with Lewy bodies have fluctuating cognition, pronounced variations in attention, and early hallucinations when either off medications or on low doses of dopamimetic medications.

Pattern of dementia is more subcortical than cortical. The cognitive changes are different from those present in Alzheimer disease. In contrast to patients with Alzheimer disease, those with dementia with Lewy bodies have more subcortical than cortical dementia, resulting in executive dysfunction and inattention, whereas patients with Alzheimer disease have dysfunction of naming and memory.⁸

Pathology: diffuse distribution of Lewy bodies. As in Parkinson disease, the pathology is characterized by the appearance of Lewy bodies (positive stain for alpha-synuclein), but their distribution is more diffuse than in Parkinson disease and includes the brainstem, subcortical nuclei, limbic cortex, and neocortex, which may lead to hallucinations in affected patients.

Autonomic features are also diffuse. Autonomic features are also more common in dementia with Lewy bodies than in idiopathic Parkinson disease, which may relate to the different distribution of pathology in these diseases. Significant autonomic failure is present in 62% of patients with dementia with Lewy bodies,⁹ and the autonomic failure is believed to result from dysfunction of peripheral postganglionic neurons in addition to numerous cortical and brainstem Lewy bodies. Patients with dementia with Lewy bodies also have significant deposits in intermediolateral columns of the spinal cord and autonomic ganglia and sympathetic neurons.

PURE AUTONOMIC FAILURE

The pathology of pure autonomic failure is similar to that of dementia with Lewy bodies and idiopathic Parkinson disease. In contrast to these disorders, however, pure autonomic failure is characterized by a less significant presence of Lewy bodies in the cortex and brainstem, although the pathology in the spinal cord and peripheral nervous system is quite prominent.

Pure autonomic failure is a sporadic disease with onset after age 60 years. It is characterized by slowly progressive isolated impairment of the autonomic nervous system, which manifests particularly as orthostatic hypotension and also as significant bladder and sexual dysfunction. The condition is ultimately disabling as a result of the orthostatic hypotension.

CARDIOVASCULAR AUTONOMIC DYSFUNCTION

Orthostatic hypotension is the most limiting of the cardiovascular autonomic dysfunctions in the neurodegenerative disorders discussed here. Postprandial hypotension is also prevalent in these disorders, as is supine hypertension, which makes successful treatment of cardiovascular autonomic dysfunction difficult.

Orthostatic hypotension is defined as a decrease in systolic blood pressure of at least 20 mm Hg, or a decrease in diastolic blood pressure of at least 10 mm Hg, upon tilting or standing.

In contrast, in normal subjects the initial response upon standing is a pooling of 500 to 1,000 mL of blood and a reduction in venous return and cardiac output. A resultant decrease in blood pressure would occur if not for the baroreceptor reflex, which increases sympathetic tone and decreases vagal parasympathetic tone. Vasopressin is then released from the posterior pituitary, which increases peripheral vascular resistance, venous return, and cardiac output. As a result, the normal response to standing is a modest decrease in systolic blood pressure—ie, by 5 to 10 mm Hg— and an increase in diastolic blood pressure by a simi­lar amount, as well as a compensatory increase in pulse rate of 10 to 25 beats per minute.

Approaches to therapy for orthostatic hypotension

Nonpharmacologic approaches to orthostatic hypotension include raising the head of the patient’s bed by 30 degrees, use of compression stockings, and liberalizing the use of fluids and salt.

Often, however, patients require pharmacologic therapy. Fluorohydrocortisone and midodrine are the primary drugs used for this purpose, but pyrodostigmine also has shown some efficacy in doses of 60 mg or greater in small clinical trials. Less-effective options include nonsteroidal anti-inflammatory drugs, vasopressin analogs, erythropoietin, and caffeine.

Management of postprandial hypotension

Reducing meal size while increasing the frequency of meals and adding caffeine are dietary approaches to treat postprandial hypotension. Somatostatin analogs may be helpful, although data to support their use for this indication are limited.

Treatment of supine hypertension is more difficult

The management of supine hypertension is difficult in patients with neurodegenerative disorders. Supine hypertension is defined as a blood pressure greater than 140/90 mm Hg, but the threshold for concern is uncertain. Most patients with neurodegenerative disorders are plagued more by hypotension than by hypertension, but the hypertension can be deleterious to their health, particularly when they are being treated for their hypotension during the day. Some clinicians choose to treat the hypertension if it is significant in the evening. Most important is to remove the midodrine at night and minimize the use of fluorohydrocortisone. Other options are nitrate derivatives, hydralazine, and calcium channel blockers. The proposed benefits of minoxidil and clonidine are controversial.

Autonomic complications of dopaminergic therapy

Complicating the management of autonomic dysfunction in patients with parkinsonian features is that drug therapies for Parkinson disease exacerbate orthostatic hypotension to varying degrees. Selegiline, amantadine, and dopamine agonists exacerbate orthostasis to a greater degree than levodopa does. Therefore, we are apt to start treatment with levodopa as patients develop more features of autonomic dysfunction, as well as in patients with advanced Parkinson disease or in patients who are older than 70 years of age.

Multiple system atrophy may respond only to high doses of levodopa (> 1 g), and when autonomic symptoms are prominent, patients with multiple system atrophy may not tolerate dopaminergic therapy at all. In patients with dementia with Lewy bodies, the use of dopaminergic therapies is limited not so much by autonomic dysfunction but because of hallucinations and cognitive decline.

SUMMARY

Central autonomic dysfunction predominates in patients with multiple system atrophy. Peripheral autonomic dysfunction predominates in the other parkinsonian disorders with Lewy body pathology, and this includes idiopathic Parkinson disease, dementia with Lewy bodies, and the related disorder, pure autonomic failure, in which there are no parkinsonian features.

The Lewy body is the pathologic hallmark of both Parkinson disease and dementia with Lewy bodies. Lewy bodies are seen microscopically as neuronal inclusions containing alpha-synuclein and associated proteins. In contrast, glial inclusions involving alpha-synuclein are seen in multiple system atrophy. Because Lewy bodies are observed in autonomic regulatory regions of the brain, they are of interest in the study of the autonomic dysfunction that figures prominently in several parkinsonian syndromes. Cardiovascular autonomic dysfunction in parkinsonian syndromes includes orthostatic hypotension, postprandial hypotension, and supine hypertension.

This article will describe the major clinical and pathologic features of movement disorders with Lewy body pathology, the likelihood of autonomic dysregulation in these disorders, and issues involved in the treatment of autonomic dysfunction in patients with these movement disorders.

OVERVIEW OF PARKINSONIAN SYNDROMES

Tauopathies versus synucleinopathies

Pathologically, parkinsonian syndromes can be divided into two groups: the tauopathies and the synucleinopathies.

The tauopathies, so named because of the presence of hyperphosphylated tau protein, include progressive supranuclear palsy and corticobasal ganglionic degeneration as well as a number of other neurodegenerative conditions (ie, Pick disease, FTDP-17, primary progressive aphasia, argyrophilic grain disease) that do not cause parkinsonian features.

Synucleinopathies, the focus of this article, are disorders in which the protein alpha-synuclein accumulates in the cytoplasm. They include idiopathic Parkinson disease, multiple system atrophy, dementia with Lewy bodies, and pure autonomic failure. In multiple system atrophy, deposits of alpha-synuclein are prominent in glial cytoplasmic inclusions. In both Parkinson disease and dementia with Lewy bodies, alpha-synuclein is present in Lewy bodies. Although primary autonomic failure is not a movement disorder, its pathology is similar to that of the other synucleinopathies, with alpha-synuclein accumulation in both the central and peripheral nervous systems, as well as the presence of Lewy bodies.

IDIOPATHIC PARKINSON DISEASE

Autonomic dysfunction usually occurs late in idiopathic Parkinson disease, and its severity is less than that observed with other parkinsonian syndromes. However, the lifetime risk of significant autonomic dysfunction in patients with Parkinson disease is approximately 1 in 3.¹ Almost 60% of patients with idiopathic Parkinson disease meet the criterion for a diagnosis of orthostatic hypotension—ie, a fall in systolic blood pressure of at least 20 mm Hg—and orthostatic hypotension is symptomatic in about 20% of patients.¹

MULTIPLE SYSTEM ATROPHY

The nomenclature of multiple system atrophy has been evolving slowly. In 1900, Dejerine and Thomas described olivopontocerebellar atrophy, a progressive cerebellar degeneration with parkinsonism. In 1960, Shy and Drager described the Shy Drager syndrome, which has prominent autonomic features common to Parkinson disease, such as orthostatic hypotension, urinary and fecal incontinence, loss of sweating, iris atrophy, external ocular palsies, rigidity, tremor, loss of associated movement, and impotence.²

Also in 1960, Van der Eecken described striatonigral degeneration, an akinetic, rigid, parkinsonian syndrome that did not respond well to medications and was associated with autonomic dysfunction.³

In 1969, Graham and Oppenheimer realized an overlap to these syndromes and coined the term multiple system atrophy. They used it to refer to a gradually progressive idiopathic neurodegenerative process of adult onset characterized by varying proportions of cerebellar dysfunction, autonomic failure, and parkinsonism, and which is poorly responsive to levodopa therapy.⁴

Newer terminology is more specific for the predominant symptoms in the syndrome. A predominance of parkinsonism with this syndrome is referred to as “parkinsonian type of multiple system atrophy” (MSA-P), whereas a predominance of cerebellar signs is termed “multiple system atrophy with cerebellar-predominant symptoms” (MSA-C). The parkinsonian type is about four times as common as the cerebellar type.⁵ Autonomic dysfunction is common to both types, and its severity varies.

Parkinsonism is the most common symptom in multiple system atrophy, followed by autonomic failure and cerebellar signs. Approximately one fourth of patients with multiple system atrophy have all three categories of symptoms. Pyramidal signs are present in approximately 60% of patients, and help distinguish this syndrome primarily from idiopathic Parkinson disease.⁶

Diagnostic criteria

Autonomic dysfunction in the form of orthostatic hypotension and/or urinary incontinence is a key diagnostic criterion for multiple system atrophy.

Parkinsonism. Parkinsonian features of the syndrome are bradykinesia, rigidity, postural instability, and tremor.

Cerebellar dysfunction. Features of cerebellar dysfunction include gait ataxia, ataxic dysarthria, limb ataxia, and sustained gaze-evoked nystagmus.

Corticospinal tract dysfunction (extensor plantar response with hyperreflexia) also helps establish the diagnosis because this feature separates multiple system atrophy from idiopathic Parkinson disease as well as some of the other parkinsonian syndromes.

Diagnostic categories

The above diagnostic criteria can be combined to make a diagnosis of possible, probable, or definite multiple system atrophy.

Possible. For a diagnosis of possible multiple system atrophy, one of the above diagnostic criteria must be present along with two features from separate domains. If the case meets the criteria for parkinsonism (bradykinesia plus at least one of the other aforementioned features of parkinsonism), a poor levodopa response qualifies as a feature.

Probable. A diagnosis of probable multiple system atrophy must meet the criterion for autonomic dysfunction plus either the criterion for parkinsonism (with poor levodopa response) or the criterion for cerebellar dysfunction.

Definite. Definite multiple system atrophy requires pathological confirmation.

Extrapyramidal features in multiple system atrophy

In addition to prominent autonomic and/or cerebellar dysfunction, differences in extrapyramidal features help distinguish multiple system atrophy from idiopathic Parkinson disease. Tremor is less common in multiple system atrophy than in idiopathic Parkinson disease, and the akinetic/rigid symptoms tend to be symmetric in multiple system atrophy, rather than asymmetric as in Parkinson disease. Postural instability occurs early in multiple system atrophy but does not occur until late in idiopathic Parkinson disease. Moreover, multiple system atrophy responds poorly to levodopa and is characterized by more rapid disease progression. The presence of early autonomic and cerebellar symptoms is diagnostic for multiple system atrophy.

Pathology

The pathologic hallmark of multiple system atrophy is alpha-synuclein deposits in the glial or glial cytoplasmic inclusions (Papp-Lantos inclusions), which are diffuse through the central nervous system but are present particularly in the brainstem and spinal cord.

Dementia with Lewy bodies is also known as diffuse Lewy body disease, senile dementia of the Lewy body type, Lewy body variant of Alzheimer disease, and Parkinson disease with dementia.

Dementia with Lewy bodies is descriptive for the entire series of these diseases. Pathologically, it is identical to Parkinson disease with dementia, with the only difference being an objective criterion based on the duration of dementia. Dementia less than 1 year after onset of parkinsonism is considered dementia with Lewy bodies, whereas dementia more than 1 year after the onset of parkinsonism is considered Parkinson disease with dementia. Whether these are separate disorders or two ends of a spectrum of disease is unclear.

Clinical criteria

Central feature: progressive cognitive decline. Dementia with Lewy bodies is characterized by prominent progressive cognitive decline that is uncharacteristic of Parkinson disease. In particular, patients with dementia with Lewy bodies have fluctuating cognition, pronounced variations in attention, and early hallucinations when either off medications or on low doses of dopamimetic medications.

Pattern of dementia is more subcortical than cortical. The cognitive changes are different from those present in Alzheimer disease. In contrast to patients with Alzheimer disease, those with dementia with Lewy bodies have more subcortical than cortical dementia, resulting in executive dysfunction and inattention, whereas patients with Alzheimer disease have dysfunction of naming and memory.⁸

Pathology: diffuse distribution of Lewy bodies. As in Parkinson disease, the pathology is characterized by the appearance of Lewy bodies (positive stain for alpha-synuclein), but their distribution is more diffuse than in Parkinson disease and includes the brainstem, subcortical nuclei, limbic cortex, and neocortex, which may lead to hallucinations in affected patients.

Autonomic features are also diffuse. Autonomic features are also more common in dementia with Lewy bodies than in idiopathic Parkinson disease, which may relate to the different distribution of pathology in these diseases. Significant autonomic failure is present in 62% of patients with dementia with Lewy bodies,⁹ and the autonomic failure is believed to result from dysfunction of peripheral postganglionic neurons in addition to numerous cortical and brainstem Lewy bodies. Patients with dementia with Lewy bodies also have significant deposits in intermediolateral columns of the spinal cord and autonomic ganglia and sympathetic neurons.

PURE AUTONOMIC FAILURE

The pathology of pure autonomic failure is similar to that of dementia with Lewy bodies and idiopathic Parkinson disease. In contrast to these disorders, however, pure autonomic failure is characterized by a less significant presence of Lewy bodies in the cortex and brainstem, although the pathology in the spinal cord and peripheral nervous system is quite prominent.

Pure autonomic failure is a sporadic disease with onset after age 60 years. It is characterized by slowly progressive isolated impairment of the autonomic nervous system, which manifests particularly as orthostatic hypotension and also as significant bladder and sexual dysfunction. The condition is ultimately disabling as a result of the orthostatic hypotension.

CARDIOVASCULAR AUTONOMIC DYSFUNCTION

Orthostatic hypotension is the most limiting of the cardiovascular autonomic dysfunctions in the neurodegenerative disorders discussed here. Postprandial hypotension is also prevalent in these disorders, as is supine hypertension, which makes successful treatment of cardiovascular autonomic dysfunction difficult.

Orthostatic hypotension is defined as a decrease in systolic blood pressure of at least 20 mm Hg, or a decrease in diastolic blood pressure of at least 10 mm Hg, upon tilting or standing.

In contrast, in normal subjects the initial response upon standing is a pooling of 500 to 1,000 mL of blood and a reduction in venous return and cardiac output. A resultant decrease in blood pressure would occur if not for the baroreceptor reflex, which increases sympathetic tone and decreases vagal parasympathetic tone. Vasopressin is then released from the posterior pituitary, which increases peripheral vascular resistance, venous return, and cardiac output. As a result, the normal response to standing is a modest decrease in systolic blood pressure—ie, by 5 to 10 mm Hg— and an increase in diastolic blood pressure by a simi­lar amount, as well as a compensatory increase in pulse rate of 10 to 25 beats per minute.

Approaches to therapy for orthostatic hypotension

Nonpharmacologic approaches to orthostatic hypotension include raising the head of the patient’s bed by 30 degrees, use of compression stockings, and liberalizing the use of fluids and salt.

Often, however, patients require pharmacologic therapy. Fluorohydrocortisone and midodrine are the primary drugs used for this purpose, but pyrodostigmine also has shown some efficacy in doses of 60 mg or greater in small clinical trials. Less-effective options include nonsteroidal anti-inflammatory drugs, vasopressin analogs, erythropoietin, and caffeine.

Management of postprandial hypotension

Reducing meal size while increasing the frequency of meals and adding caffeine are dietary approaches to treat postprandial hypotension. Somatostatin analogs may be helpful, although data to support their use for this indication are limited.

Treatment of supine hypertension is more difficult

The management of supine hypertension is difficult in patients with neurodegenerative disorders. Supine hypertension is defined as a blood pressure greater than 140/90 mm Hg, but the threshold for concern is uncertain. Most patients with neurodegenerative disorders are plagued more by hypotension than by hypertension, but the hypertension can be deleterious to their health, particularly when they are being treated for their hypotension during the day. Some clinicians choose to treat the hypertension if it is significant in the evening. Most important is to remove the midodrine at night and minimize the use of fluorohydrocortisone. Other options are nitrate derivatives, hydralazine, and calcium channel blockers. The proposed benefits of minoxidil and clonidine are controversial.

Autonomic complications of dopaminergic therapy

Complicating the management of autonomic dysfunction in patients with parkinsonian features is that drug therapies for Parkinson disease exacerbate orthostatic hypotension to varying degrees. Selegiline, amantadine, and dopamine agonists exacerbate orthostasis to a greater degree than levodopa does. Therefore, we are apt to start treatment with levodopa as patients develop more features of autonomic dysfunction, as well as in patients with advanced Parkinson disease or in patients who are older than 70 years of age.

Multiple system atrophy may respond only to high doses of levodopa (> 1 g), and when autonomic symptoms are prominent, patients with multiple system atrophy may not tolerate dopaminergic therapy at all. In patients with dementia with Lewy bodies, the use of dopaminergic therapies is limited not so much by autonomic dysfunction but because of hallucinations and cognitive decline.

SUMMARY

Central autonomic dysfunction predominates in patients with multiple system atrophy. Peripheral autonomic dysfunction predominates in the other parkinsonian disorders with Lewy body pathology, and this includes idiopathic Parkinson disease, dementia with Lewy bodies, and the related disorder, pure autonomic failure, in which there are no parkinsonian features.

The Lewy body is the pathologic hallmark of both Parkinson disease and dementia with Lewy bodies. Lewy bodies are seen microscopically as neuronal inclusions containing alpha-synuclein and associated proteins. In contrast, glial inclusions involving alpha-synuclein are seen in multiple system atrophy. Because Lewy bodies are observed in autonomic regulatory regions of the brain, they are of interest in the study of the autonomic dysfunction that figures prominently in several parkinsonian syndromes. Cardiovascular autonomic dysfunction in parkinsonian syndromes includes orthostatic hypotension, postprandial hypotension, and supine hypertension.

This article will describe the major clinical and pathologic features of movement disorders with Lewy body pathology, the likelihood of autonomic dysregulation in these disorders, and issues involved in the treatment of autonomic dysfunction in patients with these movement disorders.

OVERVIEW OF PARKINSONIAN SYNDROMES

Tauopathies versus synucleinopathies

Pathologically, parkinsonian syndromes can be divided into two groups: the tauopathies and the synucleinopathies.

The tauopathies, so named because of the presence of hyperphosphylated tau protein, include progressive supranuclear palsy and corticobasal ganglionic degeneration as well as a number of other neurodegenerative conditions (ie, Pick disease, FTDP-17, primary progressive aphasia, argyrophilic grain disease) that do not cause parkinsonian features.

Synucleinopathies, the focus of this article, are disorders in which the protein alpha-synuclein accumulates in the cytoplasm. They include idiopathic Parkinson disease, multiple system atrophy, dementia with Lewy bodies, and pure autonomic failure. In multiple system atrophy, deposits of alpha-synuclein are prominent in glial cytoplasmic inclusions. In both Parkinson disease and dementia with Lewy bodies, alpha-synuclein is present in Lewy bodies. Although primary autonomic failure is not a movement disorder, its pathology is similar to that of the other synucleinopathies, with alpha-synuclein accumulation in both the central and peripheral nervous systems, as well as the presence of Lewy bodies.

IDIOPATHIC PARKINSON DISEASE

Autonomic dysfunction usually occurs late in idiopathic Parkinson disease, and its severity is less than that observed with other parkinsonian syndromes. However, the lifetime risk of significant autonomic dysfunction in patients with Parkinson disease is approximately 1 in 3.¹ Almost 60% of patients with idiopathic Parkinson disease meet the criterion for a diagnosis of orthostatic hypotension—ie, a fall in systolic blood pressure of at least 20 mm Hg—and orthostatic hypotension is symptomatic in about 20% of patients.¹

MULTIPLE SYSTEM ATROPHY

The nomenclature of multiple system atrophy has been evolving slowly. In 1900, Dejerine and Thomas described olivopontocerebellar atrophy, a progressive cerebellar degeneration with parkinsonism. In 1960, Shy and Drager described the Shy Drager syndrome, which has prominent autonomic features common to Parkinson disease, such as orthostatic hypotension, urinary and fecal incontinence, loss of sweating, iris atrophy, external ocular palsies, rigidity, tremor, loss of associated movement, and impotence.²

Also in 1960, Van der Eecken described striatonigral degeneration, an akinetic, rigid, parkinsonian syndrome that did not respond well to medications and was associated with autonomic dysfunction.³

In 1969, Graham and Oppenheimer realized an overlap to these syndromes and coined the term multiple system atrophy. They used it to refer to a gradually progressive idiopathic neurodegenerative process of adult onset characterized by varying proportions of cerebellar dysfunction, autonomic failure, and parkinsonism, and which is poorly responsive to levodopa therapy.⁴

Newer terminology is more specific for the predominant symptoms in the syndrome. A predominance of parkinsonism with this syndrome is referred to as “parkinsonian type of multiple system atrophy” (MSA-P), whereas a predominance of cerebellar signs is termed “multiple system atrophy with cerebellar-predominant symptoms” (MSA-C). The parkinsonian type is about four times as common as the cerebellar type.⁵ Autonomic dysfunction is common to both types, and its severity varies.

Parkinsonism is the most common symptom in multiple system atrophy, followed by autonomic failure and cerebellar signs. Approximately one fourth of patients with multiple system atrophy have all three categories of symptoms. Pyramidal signs are present in approximately 60% of patients, and help distinguish this syndrome primarily from idiopathic Parkinson disease.⁶

Diagnostic criteria

Autonomic dysfunction in the form of orthostatic hypotension and/or urinary incontinence is a key diagnostic criterion for multiple system atrophy.

Parkinsonism. Parkinsonian features of the syndrome are bradykinesia, rigidity, postural instability, and tremor.

Cerebellar dysfunction. Features of cerebellar dysfunction include gait ataxia, ataxic dysarthria, limb ataxia, and sustained gaze-evoked nystagmus.

Corticospinal tract dysfunction (extensor plantar response with hyperreflexia) also helps establish the diagnosis because this feature separates multiple system atrophy from idiopathic Parkinson disease as well as some of the other parkinsonian syndromes.

Diagnostic categories

The above diagnostic criteria can be combined to make a diagnosis of possible, probable, or definite multiple system atrophy.

Possible. For a diagnosis of possible multiple system atrophy, one of the above diagnostic criteria must be present along with two features from separate domains. If the case meets the criteria for parkinsonism (bradykinesia plus at least one of the other aforementioned features of parkinsonism), a poor levodopa response qualifies as a feature.

Probable. A diagnosis of probable multiple system atrophy must meet the criterion for autonomic dysfunction plus either the criterion for parkinsonism (with poor levodopa response) or the criterion for cerebellar dysfunction.

Definite. Definite multiple system atrophy requires pathological confirmation.

Extrapyramidal features in multiple system atrophy

In addition to prominent autonomic and/or cerebellar dysfunction, differences in extrapyramidal features help distinguish multiple system atrophy from idiopathic Parkinson disease. Tremor is less common in multiple system atrophy than in idiopathic Parkinson disease, and the akinetic/rigid symptoms tend to be symmetric in multiple system atrophy, rather than asymmetric as in Parkinson disease. Postural instability occurs early in multiple system atrophy but does not occur until late in idiopathic Parkinson disease. Moreover, multiple system atrophy responds poorly to levodopa and is characterized by more rapid disease progression. The presence of early autonomic and cerebellar symptoms is diagnostic for multiple system atrophy.

Pathology

The pathologic hallmark of multiple system atrophy is alpha-synuclein deposits in the glial or glial cytoplasmic inclusions (Papp-Lantos inclusions), which are diffuse through the central nervous system but are present particularly in the brainstem and spinal cord.

Dementia with Lewy bodies is also known as diffuse Lewy body disease, senile dementia of the Lewy body type, Lewy body variant of Alzheimer disease, and Parkinson disease with dementia.

Dementia with Lewy bodies is descriptive for the entire series of these diseases. Pathologically, it is identical to Parkinson disease with dementia, with the only difference being an objective criterion based on the duration of dementia. Dementia less than 1 year after onset of parkinsonism is considered dementia with Lewy bodies, whereas dementia more than 1 year after the onset of parkinsonism is considered Parkinson disease with dementia. Whether these are separate disorders or two ends of a spectrum of disease is unclear.

Clinical criteria

Central feature: progressive cognitive decline. Dementia with Lewy bodies is characterized by prominent progressive cognitive decline that is uncharacteristic of Parkinson disease. In particular, patients with dementia with Lewy bodies have fluctuating cognition, pronounced variations in attention, and early hallucinations when either off medications or on low doses of dopamimetic medications.

Pattern of dementia is more subcortical than cortical. The cognitive changes are different from those present in Alzheimer disease. In contrast to patients with Alzheimer disease, those with dementia with Lewy bodies have more subcortical than cortical dementia, resulting in executive dysfunction and inattention, whereas patients with Alzheimer disease have dysfunction of naming and memory.⁸

Pathology: diffuse distribution of Lewy bodies. As in Parkinson disease, the pathology is characterized by the appearance of Lewy bodies (positive stain for alpha-synuclein), but their distribution is more diffuse than in Parkinson disease and includes the brainstem, subcortical nuclei, limbic cortex, and neocortex, which may lead to hallucinations in affected patients.

Autonomic features are also diffuse. Autonomic features are also more common in dementia with Lewy bodies than in idiopathic Parkinson disease, which may relate to the different distribution of pathology in these diseases. Significant autonomic failure is present in 62% of patients with dementia with Lewy bodies,⁹ and the autonomic failure is believed to result from dysfunction of peripheral postganglionic neurons in addition to numerous cortical and brainstem Lewy bodies. Patients with dementia with Lewy bodies also have significant deposits in intermediolateral columns of the spinal cord and autonomic ganglia and sympathetic neurons.

PURE AUTONOMIC FAILURE

The pathology of pure autonomic failure is similar to that of dementia with Lewy bodies and idiopathic Parkinson disease. In contrast to these disorders, however, pure autonomic failure is characterized by a less significant presence of Lewy bodies in the cortex and brainstem, although the pathology in the spinal cord and peripheral nervous system is quite prominent.

Pure autonomic failure is a sporadic disease with onset after age 60 years. It is characterized by slowly progressive isolated impairment of the autonomic nervous system, which manifests particularly as orthostatic hypotension and also as significant bladder and sexual dysfunction. The condition is ultimately disabling as a result of the orthostatic hypotension.

CARDIOVASCULAR AUTONOMIC DYSFUNCTION

Orthostatic hypotension is the most limiting of the cardiovascular autonomic dysfunctions in the neurodegenerative disorders discussed here. Postprandial hypotension is also prevalent in these disorders, as is supine hypertension, which makes successful treatment of cardiovascular autonomic dysfunction difficult.

Orthostatic hypotension is defined as a decrease in systolic blood pressure of at least 20 mm Hg, or a decrease in diastolic blood pressure of at least 10 mm Hg, upon tilting or standing.

In contrast, in normal subjects the initial response upon standing is a pooling of 500 to 1,000 mL of blood and a reduction in venous return and cardiac output. A resultant decrease in blood pressure would occur if not for the baroreceptor reflex, which increases sympathetic tone and decreases vagal parasympathetic tone. Vasopressin is then released from the posterior pituitary, which increases peripheral vascular resistance, venous return, and cardiac output. As a result, the normal response to standing is a modest decrease in systolic blood pressure—ie, by 5 to 10 mm Hg— and an increase in diastolic blood pressure by a simi­lar amount, as well as a compensatory increase in pulse rate of 10 to 25 beats per minute.

Approaches to therapy for orthostatic hypotension

Nonpharmacologic approaches to orthostatic hypotension include raising the head of the patient’s bed by 30 degrees, use of compression stockings, and liberalizing the use of fluids and salt.

Often, however, patients require pharmacologic therapy. Fluorohydrocortisone and midodrine are the primary drugs used for this purpose, but pyrodostigmine also has shown some efficacy in doses of 60 mg or greater in small clinical trials. Less-effective options include nonsteroidal anti-inflammatory drugs, vasopressin analogs, erythropoietin, and caffeine.

Management of postprandial hypotension

Reducing meal size while increasing the frequency of meals and adding caffeine are dietary approaches to treat postprandial hypotension. Somatostatin analogs may be helpful, although data to support their use for this indication are limited.

Treatment of supine hypertension is more difficult

The management of supine hypertension is difficult in patients with neurodegenerative disorders. Supine hypertension is defined as a blood pressure greater than 140/90 mm Hg, but the threshold for concern is uncertain. Most patients with neurodegenerative disorders are plagued more by hypotension than by hypertension, but the hypertension can be deleterious to their health, particularly when they are being treated for their hypotension during the day. Some clinicians choose to treat the hypertension if it is significant in the evening. Most important is to remove the midodrine at night and minimize the use of fluorohydrocortisone. Other options are nitrate derivatives, hydralazine, and calcium channel blockers. The proposed benefits of minoxidil and clonidine are controversial.

Autonomic complications of dopaminergic therapy

Complicating the management of autonomic dysfunction in patients with parkinsonian features is that drug therapies for Parkinson disease exacerbate orthostatic hypotension to varying degrees. Selegiline, amantadine, and dopamine agonists exacerbate orthostasis to a greater degree than levodopa does. Therefore, we are apt to start treatment with levodopa as patients develop more features of autonomic dysfunction, as well as in patients with advanced Parkinson disease or in patients who are older than 70 years of age.

Multiple system atrophy may respond only to high doses of levodopa (> 1 g), and when autonomic symptoms are prominent, patients with multiple system atrophy may not tolerate dopaminergic therapy at all. In patients with dementia with Lewy bodies, the use of dopaminergic therapies is limited not so much by autonomic dysfunction but because of hallucinations and cognitive decline.

SUMMARY

Central autonomic dysfunction predominates in patients with multiple system atrophy. Peripheral autonomic dysfunction predominates in the other parkinsonian disorders with Lewy body pathology, and this includes idiopathic Parkinson disease, dementia with Lewy bodies, and the related disorder, pure autonomic failure, in which there are no parkinsonian features.

Whether deep brain stimulation can dramatically help patients with Parkinson’s disease (PD) and other movement disorders is no longer questioned. Rather, how it works is not well understood: how do patients with seemingly diverse conditions show improvement with the same intervention?

Patients with advanced PD often freeze when trying to walk and have tremor, rigidity, bradykinesia, and gait and balance problems. With deep brain stimulation, a patient typically experiences a marked improvement in these motor symptoms.

Similarly, patients with hypokinetic disorders such as generalized dystonia who have extensive involuntary movements involving multiple body parts may experience a significant reduction in these movements and regain function during deep brain stimulation. In my experience, it is not unusual for patients who were not ambulatory as a result of their dystonic movements to regain function to the point where they can walk unassisted and, in some cases, participate in physical activities such as racquetball or jogging on a treadmill. One of my patients with generalized dystonia could walk no farther than several meters before deep brain stimulation but afterward was able to run on a treadmill. This patient did not gain this type of function immediately after stimulation, but after sustained efforts at programming his stimulation device over the course of 1 year he was able to travel to Europe, hike in the mountains, and jog on a treadmill.

In addition to treating movement disorders, deep brain stimulation is being used experimentally to treat patients with behavioral disorders such as depression and obsessive-compulsive disorder that are refractive to standard therapy. Broadening our understanding of the mechanisms responsible for success with deep brain stimulation is important since it may help to improve current applications and develop new ones. This article discusses our research in deep brain stimulation using microelectrode recording of structures within the basal ganglia–thalamocortical circuit in the MPTP monkey model of PD.

INSIGHTS INTO MECHANISMS OF STIMULATION PROMISE TECHNOLOGICAL REFINEMENTS

One rationale for attempting to better understand how deep brain stimulation works is that such knowledge may enable us to improve the technology to better apply the technique.

Electrode design is one important area of potential improvement. Diseases that may one day be treated with deep brain stimulation will likely require electrodes of different shapes than those used currently, to accommodate other targets in the brain. At present, a single lead shape is used to stimulate the subthalamic nucleus (STN) and the globus pallidus internus (GPi) for treating PD. Possible future targets include the globus pallidus externus (GPe), various subnuclei of the thalamus, portions of the striatum, and other subcortical and cortical structures that have different geometric configurations and physiologic characteristics. Since these structures and regions of the brain differ from one another in size and shape, it is highly likely that new electrode designs will be needed to take advantage of this geometric and physiologic variability. Future electrodes may vary in size and shape from those used currently, incorporate three-dimensional designs, and require a current source that allows the pattern of stimulation to be varied based on the physiologic changes that characterize each neurologic disorder.

Directionality may be another important feature of electrode design. With presently used electrodes, electric current spreads in all directions. To spread the current or increase the volume of tissue affected by stimulation, one must increase the voltage being passed through the lead. This results in a larger region of tissue being affected by stimulation, but the current density varies based on distance from the stimulation site, with neural tissue close to the site being affected differently from tissue that is farther away. Moreover, the current cannot be directed or aimed in one direction or the other. A split-band design could spread current in opposing directions, and a three-dimensional directional design involving several contacts could affect a volume of tissue more homogeneously. 

PROGRESS IN DEFINING PD PATHOPHYSIOLOGY

As with any disease, defining the problem and understanding the underlying pathophysiology are essential first steps to finding an effective treatment for PD. In the 1930s and 1940s, numerous attempts were made to treat PD with surgical therapies. Surgical targets were chosen throughout the length of the neuraxis, including the cortex, the internal capsule, the basal ganglia, the thalamus, the cerebral peduncle, and the spinal cord itself. The underlying pathophysiology was not well understood, however, so the rationale for surgery was weak at best. For example, lesioning the cortex improved parkinsonian tremor, but it also caused paralysis and was associated with considerable morbidity. 

Evidence of a common circuit

Reprinted, with permission, from Wichmann T, et al. Basal ganglia: anatomy and physiology. In: Factor SA, Weiner WJ, eds. Parkinson’s Disease: Diagnosis and Clinical Management, 2nd ed. New York, NY: Demos; 2008:255.

In PD, degeneration of dopamine-producing neurons in the substantia nigra pars compacta reduces dopamine levels in the striatum. In MPTP monkey models of PD there is also a loss of dopamine-producing cells in the substantia nigra pars compacta. These animals develop the cardinal motor symptoms of PD and are considered a good model of the human disorder. By recording from the basal ganglia–thalamocortical circuit in this model, we and others have observed excessive activity in the STN and GPi.^1–4 In addition, cells in these regions in the monkey model were more likely to discharge in bursts compared with cells from healthy monkeys, and they showed a higher degree of synchronized oscillatory activity among neighboring neurons.^5,6

Ultimate goal: The ability to individualize therapy

Understanding how such changes relate to parkinsonian symptoms will enable us to develop stimulation strategies that are focused on ameliorating the particular physiologic changes in PD. Since PD can lead to distinctly different clinical pictures, it would be ideal to be able to individualize therapy based on the particular motor symptoms each patient experiences. This may require stimulation strategies that affect either a particular region of the targeted structure or a particular physiologic change that occurs in the disease state.

A good model for PD was lacking prior to the 1980s. As a result, there was little understanding of the pathophysiologic basis for this disorder. A breakthrough in the mid-1980s revolutionized research in this field. A group of young people developed parkinsonian symptoms, and it was discovered that they had all used recreational “designer drugs” containing an impurity: the neurotoxin 1-methyl-4-phenyl-1,2,3,6­tetrahydropyridine (MPTP). Now given to primates to simulate PD, MPTP causes all of the classic symptoms of PD except tremor (this may vary from species to species), including freezing, slowness, stiffness, and gait and balance problems. Like humans with PD, primates with MPTP-induced PD even develop dyskinesia after prolonged treatment with levodopa.

Experimentation with MPTP monkeys in the late 1980s led to the “rate hypothesis,” which basically states that when dopamine production is reduced from the substantia nigra compacta (as in PD), changes in striatal activity lead to suppression of GPe activity and a reduction in inhibitory output from the GPe to the STN. This decrease in inhibitory output allows the STN to be overactive, which, in conjunction with a reduction of direct striatal inhibition of the GPi, causes excessive GPi activity and a suppression of thalamic activity to the cortex (Figure 1).

When recording electrodes were placed in these structures in the monkey brain, rate changes were reported to occur in each of these structures in the parkinsonian state.^1–4,7 Action potentials recorded from the GPi in MPTP-treated monkeys occurred at a much faster rate than those in healthy monkeys.

Pallidotomy revisited: Dramatic symptom improvement is possible

On the basis of the above and other studies in the MPTP monkey model of PD, investigators in the 1990s reasoned that reduced dopamine in PD led to excessive activity in portions of this circuit. While I would like to say that this led to the rationale for lesioning the STN and GPi for the treatment of PD, this approach had already been taken in the early 1930s and 1940s and continued into the 1960s; it was largely stopped with the introduction of levodopa and was restarted again after the realization that chronic levodopa therapy was associated with a variety of side effects, including the development of excessive involuntary movement and motor fluctuations.

Pallidotomy (lesioning of the pallidum), although tried as a treatment for PD in the 1930s and 1940s, had been abandoned as a result of its inconsistent benefit and lack of effect on parkinsonian tremor. It underwent a resurgence in the 1990s through the work of a group in New York⁸ that revived Lars Leksell’s pallidotomy approach of the 1960s⁹ at a time when basic science studies provided the rationale for surgical therapy to create lesions in the GPi. These basic science studies also provided critical new information about the optimal site for lesioning, which led to improved and more consistent outcomes.^10–13 In the early years, lesions were created in the anterior (nonmotor) portion of the pallidum but led to inconsistent results. In the 1990s, with a better understanding of the portion of the pallidum involved in motor control, destroying brain tissue by creating a lesion in the posterolateral “motor” region of the pallidum resulted in such dramatic improvement in motor signs that waiting lists of up to 4 years were common for patients who wanted the procedure.

Although unilateral pallidotomy led to marked improvement in motor symptoms on the contralateral side, attempts at bilateral lesions to improve both sides of the body, as well as axial symptoms, were associated with marked hypophonia and, in some reports, cognitive decline. This led physicians and scientists to search for a procedure that could be performed bilaterally without the high incidence of side effects associated with lesioning procedures—and thus to the birth of deep brain stimulation.

Deep brain stimulation as lesion simulation

During the early experience with pallidotomy, the area to be lesioned would first be stimulated with the lesioning probe to observe its effects and thereby determine the precise area in which to create a lesion. At the time, no mechanism existed to leave the stimulator in place rather than create a lesion. But after the development of implantable stimulation devices, chronic stimulation could be delivered bilaterally to the pallidum and STN, resulting in a markedly improved treatment. Since side effects associated with stimulation are reversible, the ability to perform such procedures on both sides of the brain and to adjust stimulation parameters in order to optimize benefits while minimizing side effects made deep brain stimulation the procedure of choice for patients with advanced PD and led to its exploration for treatment of other neurologic disorders.