Edmund S. Higgins, MD

Advances in neuroimaging, cell biology, and post mortem analysis are starting to explain what happens in the brain of a person who develops schizophrenia. Schizophrenia appears to be a developmental disorder of disrupted neural connection within and between regions of the brain. These disruptions seem to result from genetic predispositions interacting with negative environmental events.

A matter of gray and white

Individuals with schizophrenia have deficits in gray matter and white matter, as illustrated by studies linking auditory hallucinations with brain regions associated with normal hearing (Box).

Gray matter. Magnetic resonance imaging (MRI) indicates that gray matter volume peaks in early adolescence and declines with age. The normal adolescent brain shrinks as inefficient neural connections are pruned away, a process that refines and matures gray matter. In individuals with schizophrenia, this reduction is more aggressive—perhaps because of excessive pruning—and occurs in the time frame when schizophrenia symptoms typically emerge.

Rapoport et al¹ documented this process through sequential MRI scans in children with early-onset schizophrenia (mean age 14.5). Compared with age-matched healthy controls, youths with schizophrenia show greater and more rapid gray matter loss during late adolescence (Figure 1).²

Increased density. Reduced neuronal branching and spine formation also likely causes subtle reductions in gray matter volume (Figure 2). The resulting lack of dendritic connectivity may produce cognitive impairments and negative symptoms seen in schizophrenia.

Postmortem studies of gray matter cells show increased neuron density in patients with schizophrenia when compared with controls.³ Patients with schizophrenia have the same number of neurons as controls, but the neurons are more tightly packed because of reduced cell size, branching, and synapse formation.⁴

Research over the past decade has revealed schizophrenia to be a neurodegenerative disorder characterized by substantial brain tissue loss during first and subsequent psychotic episodes.⁵ Neuroimaging studies show that clinical and functional deterioration accompanies progressive loss of cortical gray matter volume and enlargement of cerebral ventricles. Thus, preventing relapses has come to be regarded as critical to long-term schizophrenia management.

Box

Do auditory hallucinations follow sound pathways in the brain?

Auditory hallucinations appear to emanate from the temporal lobe, the same brain region that processes external sound. Thus, it may be that patients experiencing hallucinations are misidentifying inner speech as coming from an outside source.

Using functional MRI to differentiate brain activity signals associated with hallucinating and nonhallucinating states, Dierks et al²¹ documented increased activity in auditory cortical gray matter during hallucinations in schizophrenia patients.

Auditory signals make synaptic connections in the thalamus (left) before reaching the auditory cortex. White matter fiber tracts called the arcuate fasciculus (right) connect the auditory cortex in the temporal lobe with Broca’s area in the frontal cortex.

Source: Adapted from reference 2

Using MR diffusion tensor imaging, Hubl et al²² identified white matter changes in the arcuate fasciculus of schizophrenia patients prone to hallucinations, compared with healthy controls and patients who had schizophrenia but not hallucinations.

These findings support the understanding that auditory hallucinations originate from altered connectivity of the same regions that process normal hearing and speech. The schizophrenia patient may perceive external voices from aberrant internal signals.

Figure 1 Rates of gray matter volume loss during adolescence

Youths with early-onset schizophrenia show greater gray matter volume loss during adolescence, compared with normal controls.

Source: Adapted from reference 2

Figure 2 Structural differences between neurons
in patients with schizophrenia and controls

Schizophrenic neurons show reduced soma size, spine formation, and dendritic branching

Source: Adapted from reference 2White matter. Recent research suggests that white matter deficits also may be involved in schizophrenia’s pathophysiology. Studies using diffusion tensor imaging (DTI)—which measures the sum of vectors of water diffusion along axons—have documented white matter impairments in patients with schizophrenia.⁶

White matter tracks—myelinated axons that transport electrical signals among neurons—connect regions within the cortex and between the cortex and deeper brain structures. Disruption of white matter tracks may degrade signals and confuse neuronal communication.

Myelination. Genetic studies in patients with schizophrenia also have suggested that decreased neuron myelination may play a role in white matter deficits. Hakak et al⁸ examined more than 6,000 genes using microarray analysis and found only 17 genes were significantly down-regulated in patients with schizophrenia. Of those 17 genes, 6 were related to myelin and 11 showed no pattern.

Oligodendrocytes are glial cells that insulate axons with myelin and allow faster transmission of electrical impulses in the brain. In a postmortem study, Hof et al⁷ found 7 patients schizophrenia had 28% fewer oligodendrocytes per section of the superior frontal gyrus and 27% less white matter compared with 7 age-matched controls (Figure 3).

Figure 3 Reduced neuron myelination possible in schizophrenia

In a postmortem analysis, stained white matter sections taken from schizophrenia patients had fewer oligodendrocytes, cells that insulate axons with myelin and facilitate electrical transmission.

Source: Adapted from reference 2

Genes and the environment

Schizophrenia’s heritability is among the most repeated research findings in psychiatry.⁹ Other mechanisms besides genetics must be involved, however, as studies consistently show that monozygotic twins have a concordance rate of approximately 50% for the development of schizophrenia.

Environmental factors. Adverse environmental events may act in conjuction with genetic predisposition to trigger schizophrenia development. Ischemia or an impoverished diet, for example, have the potential to change DNA methylation.

Environmental factors associated with increased risk for schizophrenia include:

• maternal starvation during pregnancy¹⁰
• prenatal exposure to influenza¹¹
• obstetrical complications with hypoxia¹²
• being born and raised in an urban environment¹³
• using marijuana during adolescence.¹⁴

Gene expression. Important genes may be silenced in individuals with increased DNA methylation and a susceptible genetic profile. Alterations in gene expression are the fundamental mechanism of behavioral change. Research shows that environmental events can alter gene expression without changing the genetic code, such as by adding methyl groups to DNA.^15,16 The silencing of important developmental genes in this way can have devastating effects on development.

One explanation for the development of schizophrenia is that environmental events in susceptible individuals silence the production of proteins essential for maintaining neuronal connections through methylation of DNA. Postmortem analysis of brains of patients with schizophrenia show reduced mRNA of reelin,¹⁷ a protein produced in gamma-aminobutyric acid neurons involved in neuronal migration, axon branching, and synapse formation during brain development. Lowered production of proteins such as reelin may reduce connections between neurons and cause schizophrenia symptoms. Two research groups also have reported increased methylation of reelin DNA in postmortem studies of the brains of patients with schizophrenia.^18,19 Increased methylation of DNA would silence production of this important protein.

Preventing neural disconnects? If schizophrenia is a developmental disorder resulting from failures in brain connectivity, then the ultimate treatment may be prevention. Recent research suggests that intervening with second-generation antipsychotics during the prodromal stage can prevent or delay the emergence of the disorder.²⁰ Further research is needed to establish whether early intervention can prevent schizophrenia’s neuronal disruption.

Advances in neuroimaging, cell biology, and post mortem analysis are starting to explain what happens in the brain of a person who develops schizophrenia. Schizophrenia appears to be a developmental disorder of disrupted neural connection within and between regions of the brain. These disruptions seem to result from genetic predispositions interacting with negative environmental events.

A matter of gray and white

Individuals with schizophrenia have deficits in gray matter and white matter, as illustrated by studies linking auditory hallucinations with brain regions associated with normal hearing (Box).

Gray matter. Magnetic resonance imaging (MRI) indicates that gray matter volume peaks in early adolescence and declines with age. The normal adolescent brain shrinks as inefficient neural connections are pruned away, a process that refines and matures gray matter. In individuals with schizophrenia, this reduction is more aggressive—perhaps because of excessive pruning—and occurs in the time frame when schizophrenia symptoms typically emerge.

Rapoport et al¹ documented this process through sequential MRI scans in children with early-onset schizophrenia (mean age 14.5). Compared with age-matched healthy controls, youths with schizophrenia show greater and more rapid gray matter loss during late adolescence (Figure 1).²

Increased density. Reduced neuronal branching and spine formation also likely causes subtle reductions in gray matter volume (Figure 2). The resulting lack of dendritic connectivity may produce cognitive impairments and negative symptoms seen in schizophrenia.

Postmortem studies of gray matter cells show increased neuron density in patients with schizophrenia when compared with controls.³ Patients with schizophrenia have the same number of neurons as controls, but the neurons are more tightly packed because of reduced cell size, branching, and synapse formation.⁴

Research over the past decade has revealed schizophrenia to be a neurodegenerative disorder characterized by substantial brain tissue loss during first and subsequent psychotic episodes.⁵ Neuroimaging studies show that clinical and functional deterioration accompanies progressive loss of cortical gray matter volume and enlargement of cerebral ventricles. Thus, preventing relapses has come to be regarded as critical to long-term schizophrenia management.

Box

Do auditory hallucinations follow sound pathways in the brain?

Auditory hallucinations appear to emanate from the temporal lobe, the same brain region that processes external sound. Thus, it may be that patients experiencing hallucinations are misidentifying inner speech as coming from an outside source.

Using functional MRI to differentiate brain activity signals associated with hallucinating and nonhallucinating states, Dierks et al²¹ documented increased activity in auditory cortical gray matter during hallucinations in schizophrenia patients.

Auditory signals make synaptic connections in the thalamus (left) before reaching the auditory cortex. White matter fiber tracts called the arcuate fasciculus (right) connect the auditory cortex in the temporal lobe with Broca’s area in the frontal cortex.

Source: Adapted from reference 2

Using MR diffusion tensor imaging, Hubl et al²² identified white matter changes in the arcuate fasciculus of schizophrenia patients prone to hallucinations, compared with healthy controls and patients who had schizophrenia but not hallucinations.

These findings support the understanding that auditory hallucinations originate from altered connectivity of the same regions that process normal hearing and speech. The schizophrenia patient may perceive external voices from aberrant internal signals.

Figure 1 Rates of gray matter volume loss during adolescence

Youths with early-onset schizophrenia show greater gray matter volume loss during adolescence, compared with normal controls.

Source: Adapted from reference 2

Figure 2 Structural differences between neurons
in patients with schizophrenia and controls

Schizophrenic neurons show reduced soma size, spine formation, and dendritic branching

Source: Adapted from reference 2White matter. Recent research suggests that white matter deficits also may be involved in schizophrenia’s pathophysiology. Studies using diffusion tensor imaging (DTI)—which measures the sum of vectors of water diffusion along axons—have documented white matter impairments in patients with schizophrenia.⁶

White matter tracks—myelinated axons that transport electrical signals among neurons—connect regions within the cortex and between the cortex and deeper brain structures. Disruption of white matter tracks may degrade signals and confuse neuronal communication.

Myelination. Genetic studies in patients with schizophrenia also have suggested that decreased neuron myelination may play a role in white matter deficits. Hakak et al⁸ examined more than 6,000 genes using microarray analysis and found only 17 genes were significantly down-regulated in patients with schizophrenia. Of those 17 genes, 6 were related to myelin and 11 showed no pattern.

Oligodendrocytes are glial cells that insulate axons with myelin and allow faster transmission of electrical impulses in the brain. In a postmortem study, Hof et al⁷ found 7 patients schizophrenia had 28% fewer oligodendrocytes per section of the superior frontal gyrus and 27% less white matter compared with 7 age-matched controls (Figure 3).

Figure 3 Reduced neuron myelination possible in schizophrenia

In a postmortem analysis, stained white matter sections taken from schizophrenia patients had fewer oligodendrocytes, cells that insulate axons with myelin and facilitate electrical transmission.

Source: Adapted from reference 2

Genes and the environment

Schizophrenia’s heritability is among the most repeated research findings in psychiatry.⁹ Other mechanisms besides genetics must be involved, however, as studies consistently show that monozygotic twins have a concordance rate of approximately 50% for the development of schizophrenia.

Environmental factors. Adverse environmental events may act in conjuction with genetic predisposition to trigger schizophrenia development. Ischemia or an impoverished diet, for example, have the potential to change DNA methylation.

Environmental factors associated with increased risk for schizophrenia include:

• maternal starvation during pregnancy¹⁰
• prenatal exposure to influenza¹¹
• obstetrical complications with hypoxia¹²
• being born and raised in an urban environment¹³
• using marijuana during adolescence.¹⁴

Gene expression. Important genes may be silenced in individuals with increased DNA methylation and a susceptible genetic profile. Alterations in gene expression are the fundamental mechanism of behavioral change. Research shows that environmental events can alter gene expression without changing the genetic code, such as by adding methyl groups to DNA.^15,16 The silencing of important developmental genes in this way can have devastating effects on development.

One explanation for the development of schizophrenia is that environmental events in susceptible individuals silence the production of proteins essential for maintaining neuronal connections through methylation of DNA. Postmortem analysis of brains of patients with schizophrenia show reduced mRNA of reelin,¹⁷ a protein produced in gamma-aminobutyric acid neurons involved in neuronal migration, axon branching, and synapse formation during brain development. Lowered production of proteins such as reelin may reduce connections between neurons and cause schizophrenia symptoms. Two research groups also have reported increased methylation of reelin DNA in postmortem studies of the brains of patients with schizophrenia.^18,19 Increased methylation of DNA would silence production of this important protein.

Preventing neural disconnects? If schizophrenia is a developmental disorder resulting from failures in brain connectivity, then the ultimate treatment may be prevention. Recent research suggests that intervening with second-generation antipsychotics during the prodromal stage can prevent or delay the emergence of the disorder.²⁰ Further research is needed to establish whether early intervention can prevent schizophrenia’s neuronal disruption.

Advances in neuroimaging, cell biology, and post mortem analysis are starting to explain what happens in the brain of a person who develops schizophrenia. Schizophrenia appears to be a developmental disorder of disrupted neural connection within and between regions of the brain. These disruptions seem to result from genetic predispositions interacting with negative environmental events.

A matter of gray and white

Individuals with schizophrenia have deficits in gray matter and white matter, as illustrated by studies linking auditory hallucinations with brain regions associated with normal hearing (Box).

Gray matter. Magnetic resonance imaging (MRI) indicates that gray matter volume peaks in early adolescence and declines with age. The normal adolescent brain shrinks as inefficient neural connections are pruned away, a process that refines and matures gray matter. In individuals with schizophrenia, this reduction is more aggressive—perhaps because of excessive pruning—and occurs in the time frame when schizophrenia symptoms typically emerge.

Rapoport et al¹ documented this process through sequential MRI scans in children with early-onset schizophrenia (mean age 14.5). Compared with age-matched healthy controls, youths with schizophrenia show greater and more rapid gray matter loss during late adolescence (Figure 1).²

Increased density. Reduced neuronal branching and spine formation also likely causes subtle reductions in gray matter volume (Figure 2). The resulting lack of dendritic connectivity may produce cognitive impairments and negative symptoms seen in schizophrenia.

Postmortem studies of gray matter cells show increased neuron density in patients with schizophrenia when compared with controls.³ Patients with schizophrenia have the same number of neurons as controls, but the neurons are more tightly packed because of reduced cell size, branching, and synapse formation.⁴

Research over the past decade has revealed schizophrenia to be a neurodegenerative disorder characterized by substantial brain tissue loss during first and subsequent psychotic episodes.⁵ Neuroimaging studies show that clinical and functional deterioration accompanies progressive loss of cortical gray matter volume and enlargement of cerebral ventricles. Thus, preventing relapses has come to be regarded as critical to long-term schizophrenia management.

Box

Do auditory hallucinations follow sound pathways in the brain?

Auditory hallucinations appear to emanate from the temporal lobe, the same brain region that processes external sound. Thus, it may be that patients experiencing hallucinations are misidentifying inner speech as coming from an outside source.

Using functional MRI to differentiate brain activity signals associated with hallucinating and nonhallucinating states, Dierks et al²¹ documented increased activity in auditory cortical gray matter during hallucinations in schizophrenia patients.

Auditory signals make synaptic connections in the thalamus (left) before reaching the auditory cortex. White matter fiber tracts called the arcuate fasciculus (right) connect the auditory cortex in the temporal lobe with Broca’s area in the frontal cortex.

Source: Adapted from reference 2

Using MR diffusion tensor imaging, Hubl et al²² identified white matter changes in the arcuate fasciculus of schizophrenia patients prone to hallucinations, compared with healthy controls and patients who had schizophrenia but not hallucinations.

These findings support the understanding that auditory hallucinations originate from altered connectivity of the same regions that process normal hearing and speech. The schizophrenia patient may perceive external voices from aberrant internal signals.

Figure 1 Rates of gray matter volume loss during adolescence

Youths with early-onset schizophrenia show greater gray matter volume loss during adolescence, compared with normal controls.

Source: Adapted from reference 2

Figure 2 Structural differences between neurons
in patients with schizophrenia and controls

Schizophrenic neurons show reduced soma size, spine formation, and dendritic branching

Source: Adapted from reference 2White matter. Recent research suggests that white matter deficits also may be involved in schizophrenia’s pathophysiology. Studies using diffusion tensor imaging (DTI)—which measures the sum of vectors of water diffusion along axons—have documented white matter impairments in patients with schizophrenia.⁶

White matter tracks—myelinated axons that transport electrical signals among neurons—connect regions within the cortex and between the cortex and deeper brain structures. Disruption of white matter tracks may degrade signals and confuse neuronal communication.

Myelination. Genetic studies in patients with schizophrenia also have suggested that decreased neuron myelination may play a role in white matter deficits. Hakak et al⁸ examined more than 6,000 genes using microarray analysis and found only 17 genes were significantly down-regulated in patients with schizophrenia. Of those 17 genes, 6 were related to myelin and 11 showed no pattern.

Oligodendrocytes are glial cells that insulate axons with myelin and allow faster transmission of electrical impulses in the brain. In a postmortem study, Hof et al⁷ found 7 patients schizophrenia had 28% fewer oligodendrocytes per section of the superior frontal gyrus and 27% less white matter compared with 7 age-matched controls (Figure 3).

Figure 3 Reduced neuron myelination possible in schizophrenia

In a postmortem analysis, stained white matter sections taken from schizophrenia patients had fewer oligodendrocytes, cells that insulate axons with myelin and facilitate electrical transmission.

Source: Adapted from reference 2

Genes and the environment

Schizophrenia’s heritability is among the most repeated research findings in psychiatry.⁹ Other mechanisms besides genetics must be involved, however, as studies consistently show that monozygotic twins have a concordance rate of approximately 50% for the development of schizophrenia.

Environmental factors. Adverse environmental events may act in conjuction with genetic predisposition to trigger schizophrenia development. Ischemia or an impoverished diet, for example, have the potential to change DNA methylation.

Environmental factors associated with increased risk for schizophrenia include:

• maternal starvation during pregnancy¹⁰
• prenatal exposure to influenza¹¹
• obstetrical complications with hypoxia¹²
• being born and raised in an urban environment¹³
• using marijuana during adolescence.¹⁴

Gene expression. Important genes may be silenced in individuals with increased DNA methylation and a susceptible genetic profile. Alterations in gene expression are the fundamental mechanism of behavioral change. Research shows that environmental events can alter gene expression without changing the genetic code, such as by adding methyl groups to DNA.^15,16 The silencing of important developmental genes in this way can have devastating effects on development.

One explanation for the development of schizophrenia is that environmental events in susceptible individuals silence the production of proteins essential for maintaining neuronal connections through methylation of DNA. Postmortem analysis of brains of patients with schizophrenia show reduced mRNA of reelin,¹⁷ a protein produced in gamma-aminobutyric acid neurons involved in neuronal migration, axon branching, and synapse formation during brain development. Lowered production of proteins such as reelin may reduce connections between neurons and cause schizophrenia symptoms. Two research groups also have reported increased methylation of reelin DNA in postmortem studies of the brains of patients with schizophrenia.^18,19 Increased methylation of DNA would silence production of this important protein.

Preventing neural disconnects? If schizophrenia is a developmental disorder resulting from failures in brain connectivity, then the ultimate treatment may be prevention. Recent research suggests that intervening with second-generation antipsychotics during the prodromal stage can prevent or delay the emergence of the disorder.²⁰ Further research is needed to establish whether early intervention can prevent schizophrenia’s neuronal disruption.

Fighting cravings’ intense desire and obsessive thinking may be an addict’s most formidable challenge.¹ Patients in recovery—desperate to stop abusing the substance—cannot control themselves after the craving is triggered. Remarkably, even after years of abstinence, cues reminding the addict of the substance—smells, sounds, or familiar surroundings—can ignite cravings and lead to relapse.

Dopamine and dope

A recent imaging study suggests that dopamine may be the culprit behind cravings. Research with cocaine and rodents suggests that dopamine released in the dorsal striatum is associated with drug-seeking behavior. Measuring craving in a rodent is impossible, but a recent imaging study examined how drug cues affect the brains of drug-addicted humans (Figure 1).²

Figure 1 Dopamine increase is associated with drug craving

Changes in craving, as measured by Cocaine Craving Questionnaire scores, correlated with increased dopamine concentration in the putamen and caudate.

Source: Reference 2Volkow et al² injected 18 cocaine-addicted patients with a dopamine D₂ ligand that competes with endogenous dopamine and can be seen on positron emission tomography (PET). PET scans were then taken while each patient viewed a video of nature scenery (control) and then while watching scenes of drug preparation and simulated crack cocaine smoking.

When the control scan was subtracted from the cocaine-cued scan, the dorsal striatum—activated by the cocaine preparation cues—stood out (Figure 2), suggesting the neurobiological mechanisms responsible for craving.

The dorsal striatum is thought to be involved with selecting and initiating actions. In this study, the cocaine video caused a release of dopamine into the dorsal striatum and a desire for the drug. In an earlier study, hungry subjects who were shown food cues also showed increased dopamine activity in the dorsal striatum in association with a desire for food.³

Figure 2 Dopamine release in the dorsal striatum is linked with craving

When cocaine-addicted patients watched a video depicting drug preparation and simulated crack cocaine smoking, PET scans of their brains showed dopamine release in the dorsal striatum.

Source: Reference 2Taken together, these studies suggest that dopamine in the dorsal striatum mediates craving for a desired object. The primary source of this neurotransmitter in the dorsal striatum is dopamine cells in the substantia nigra. The visual stimulus must activate these neurons in the substantia nigra to induce craving.

Caving into cravings

Desire precedes action and motivates behavior necessary for survival. Cocaine addiction apparently usurps the neurobiological mechanisms that motivate individuals to seek sustenance.

Developing an effective treatment for cocaine craving is a high priority at the National Institute on Drug Abuse.⁴ Medications including modafinil, propranolol, and disulfiram have been found effective for cocaine addiction in randomized, controlled trials, although none are FDA-approved for this use.⁴

One could speculate that antipsychotics—which are potent dopamine receptor blockers—might calm the cravings associated with cocaine addiction. Unfortunately, it is not that simple. Older antipsychotics might increase substance use in patients with schizophrenia and substance abuse.⁵ However, compelling evidence suggests that clozapine can reduce drug and alcohol use in dually diagnosed patients with schizophrenia.⁶ This provides some hope that the newer antipsychotic medications could provide a broad spectrum of pharmacologic activity that has the capacity to cool off cravings that stimulate drug-seeking behavior.

Drug brand names

• Clozapine • Clozaril
• Disulfiram • Antabuse
• Modafinil • Provigil
• Propranolol • Inderal

Fighting cravings’ intense desire and obsessive thinking may be an addict’s most formidable challenge.¹ Patients in recovery—desperate to stop abusing the substance—cannot control themselves after the craving is triggered. Remarkably, even after years of abstinence, cues reminding the addict of the substance—smells, sounds, or familiar surroundings—can ignite cravings and lead to relapse.

Dopamine and dope

A recent imaging study suggests that dopamine may be the culprit behind cravings. Research with cocaine and rodents suggests that dopamine released in the dorsal striatum is associated with drug-seeking behavior. Measuring craving in a rodent is impossible, but a recent imaging study examined how drug cues affect the brains of drug-addicted humans (Figure 1).²

Figure 1 Dopamine increase is associated with drug craving

Changes in craving, as measured by Cocaine Craving Questionnaire scores, correlated with increased dopamine concentration in the putamen and caudate.

Source: Reference 2Volkow et al² injected 18 cocaine-addicted patients with a dopamine D₂ ligand that competes with endogenous dopamine and can be seen on positron emission tomography (PET). PET scans were then taken while each patient viewed a video of nature scenery (control) and then while watching scenes of drug preparation and simulated crack cocaine smoking.

When the control scan was subtracted from the cocaine-cued scan, the dorsal striatum—activated by the cocaine preparation cues—stood out (Figure 2), suggesting the neurobiological mechanisms responsible for craving.

The dorsal striatum is thought to be involved with selecting and initiating actions. In this study, the cocaine video caused a release of dopamine into the dorsal striatum and a desire for the drug. In an earlier study, hungry subjects who were shown food cues also showed increased dopamine activity in the dorsal striatum in association with a desire for food.³

Figure 2 Dopamine release in the dorsal striatum is linked with craving

When cocaine-addicted patients watched a video depicting drug preparation and simulated crack cocaine smoking, PET scans of their brains showed dopamine release in the dorsal striatum.

Source: Reference 2Taken together, these studies suggest that dopamine in the dorsal striatum mediates craving for a desired object. The primary source of this neurotransmitter in the dorsal striatum is dopamine cells in the substantia nigra. The visual stimulus must activate these neurons in the substantia nigra to induce craving.

Caving into cravings

Desire precedes action and motivates behavior necessary for survival. Cocaine addiction apparently usurps the neurobiological mechanisms that motivate individuals to seek sustenance.

Developing an effective treatment for cocaine craving is a high priority at the National Institute on Drug Abuse.⁴ Medications including modafinil, propranolol, and disulfiram have been found effective for cocaine addiction in randomized, controlled trials, although none are FDA-approved for this use.⁴

One could speculate that antipsychotics—which are potent dopamine receptor blockers—might calm the cravings associated with cocaine addiction. Unfortunately, it is not that simple. Older antipsychotics might increase substance use in patients with schizophrenia and substance abuse.⁵ However, compelling evidence suggests that clozapine can reduce drug and alcohol use in dually diagnosed patients with schizophrenia.⁶ This provides some hope that the newer antipsychotic medications could provide a broad spectrum of pharmacologic activity that has the capacity to cool off cravings that stimulate drug-seeking behavior.

Drug brand names

• Clozapine • Clozaril
• Disulfiram • Antabuse
• Modafinil • Provigil
• Propranolol • Inderal

Fighting cravings’ intense desire and obsessive thinking may be an addict’s most formidable challenge.¹ Patients in recovery—desperate to stop abusing the substance—cannot control themselves after the craving is triggered. Remarkably, even after years of abstinence, cues reminding the addict of the substance—smells, sounds, or familiar surroundings—can ignite cravings and lead to relapse.

Dopamine and dope

A recent imaging study suggests that dopamine may be the culprit behind cravings. Research with cocaine and rodents suggests that dopamine released in the dorsal striatum is associated with drug-seeking behavior. Measuring craving in a rodent is impossible, but a recent imaging study examined how drug cues affect the brains of drug-addicted humans (Figure 1).²

Figure 1 Dopamine increase is associated with drug craving

Changes in craving, as measured by Cocaine Craving Questionnaire scores, correlated with increased dopamine concentration in the putamen and caudate.

Source: Reference 2Volkow et al² injected 18 cocaine-addicted patients with a dopamine D₂ ligand that competes with endogenous dopamine and can be seen on positron emission tomography (PET). PET scans were then taken while each patient viewed a video of nature scenery (control) and then while watching scenes of drug preparation and simulated crack cocaine smoking.

When the control scan was subtracted from the cocaine-cued scan, the dorsal striatum—activated by the cocaine preparation cues—stood out (Figure 2), suggesting the neurobiological mechanisms responsible for craving.

The dorsal striatum is thought to be involved with selecting and initiating actions. In this study, the cocaine video caused a release of dopamine into the dorsal striatum and a desire for the drug. In an earlier study, hungry subjects who were shown food cues also showed increased dopamine activity in the dorsal striatum in association with a desire for food.³

Figure 2 Dopamine release in the dorsal striatum is linked with craving

When cocaine-addicted patients watched a video depicting drug preparation and simulated crack cocaine smoking, PET scans of their brains showed dopamine release in the dorsal striatum.

Source: Reference 2Taken together, these studies suggest that dopamine in the dorsal striatum mediates craving for a desired object. The primary source of this neurotransmitter in the dorsal striatum is dopamine cells in the substantia nigra. The visual stimulus must activate these neurons in the substantia nigra to induce craving.

Caving into cravings

Desire precedes action and motivates behavior necessary for survival. Cocaine addiction apparently usurps the neurobiological mechanisms that motivate individuals to seek sustenance.

Developing an effective treatment for cocaine craving is a high priority at the National Institute on Drug Abuse.⁴ Medications including modafinil, propranolol, and disulfiram have been found effective for cocaine addiction in randomized, controlled trials, although none are FDA-approved for this use.⁴

One could speculate that antipsychotics—which are potent dopamine receptor blockers—might calm the cravings associated with cocaine addiction. Unfortunately, it is not that simple. Older antipsychotics might increase substance use in patients with schizophrenia and substance abuse.⁵ However, compelling evidence suggests that clozapine can reduce drug and alcohol use in dually diagnosed patients with schizophrenia.⁶ This provides some hope that the newer antipsychotic medications could provide a broad spectrum of pharmacologic activity that has the capacity to cool off cravings that stimulate drug-seeking behavior.

Drug brand names

• Clozapine • Clozaril
• Disulfiram • Antabuse
• Modafinil • Provigil
• Propranolol • Inderal

The serendipitous discovery of medications that can improve mood transformed depression treatment more than 50 years ago.¹ Most antidepressants produced since then could be called “me-too” medications because they all work by affecting the release of monoamines—serotonin, norepinephrine, and dopamine—which, in turn, modulate the activity of neurons that release glutamate.

Weeks may pass before antidepressants’ effect on monoamine-releasing neurons produces a therapeutic benefit, however, leaving many patients impaired or even suicidal. This delayed onset of action might be explained by antidepressants’ indirect blockade of glutamate. The route to more rapid results, therefore, might be to cut out the monoamine middlemen.

Glutamate clues

Glutamate, instead of monoamines, might offer a more direct means to affect mood and could be a new target for antidepressant treatment:²

• Positron-emission tomography of neuron function in depressed patients shows abnormal activity in neurons that release glutamate—so-called glutamate neurons.
• Approximately 60 % of neurons are glutamate neurons, the largest network of neurons in the brain.
• Increased glutamate activity is seen in depressed patients.
• Animal studies have shown that blocking the N-methyl-D-aspartate (NMDA) receptor—1 of 3 types of glutamate receptors—decreases depressive behavior.
• Chronic administration of antidepressant medication reduces the expression of NMDA receptors.

Rapid glutamate blockade

Prompted by evidence that glutamate may be involved in mood disorders, researchers at the National Institute of Mental Health designed a study to determine if blocking the NMDA receptor can produce a rapid antidepressant effect.³ They chose the agent ketamine for this study because of its potent affinity for the NMDA receptor.

Ketamine was developed in the 1960s as a general anaesthetic, and its use in the United States is limited almost exclusively to veterinary medicine. The drug’s propensity to induce perceptual disturbances limits its clinical use but enhances its illicit use.

Eighteen patients with treatment-resistant depression were enrolled in a randomized, placebo-controlled, double-blind, crossover study. After 2 weeks without medication, they received a single infusion of IV ketamine or placebo. One week later they received the alternate intervention. Changes in Hamilton Rating Scale for Depression scores were assessed after each infusion.

Figure Decrease in depressive symptoms with IV ketamine

* = P <0.05

Patients who received ketamine (blue) showed a marked reduction of depressive symptoms within 2 hours compared with those who received placebo (red).

Source: Reference 3Patients receiving ketamine showed a robust and sustained reduction in depressive symptoms compared with placebo within 110 minutes (Figure). “To our knowledge,” the authors wrote, “there has never been a report of any other drug or somatic treatment—such as sleep deprivation, thyrotropin-releasing hormone, antidepressant, dexamethasone, or electroconvulsive therapy—that results in such a dramatic rapid and prolonged response with a single administration.”

Seventy-one percent of patients responded to IV ketamine within 24 hours, which is comparable to reported response rates after 8 weeks with oral antidepressants such as bupropion (62%), selective serotonin reuptake inhibitors (63%), and venlafaxine (65%).^4,5

Caution and caveats

Despite these “dramatic” results, we must be cautious about extrapolating too much from this small study. Glutamate blockers such as ketamine can have serious adverse effects—including psychosis—and patients may not tolerate long-term interventions. Likewise, oral administration of memantine—another NMDA blocker—in a double-blind study did not effectively treat depression.⁶ Finally, subjects in the ketamine trial had chronic, treatment-resistant depression, and the results might not apply to other forms of depression.

The results suggest the possibility of a new option for depression treatment, however. Specifically, this option could expedite response and “jump-start” treatment through a novel mechanism so that persons with depression can get back on their feet more rapidly.

Drug brand names

• Bupropion • Wellbutrin
• Ketamine • Ketalar
• Memantine • Namenda
• Venlafaxine • Effexor

The serendipitous discovery of medications that can improve mood transformed depression treatment more than 50 years ago.¹ Most antidepressants produced since then could be called “me-too” medications because they all work by affecting the release of monoamines—serotonin, norepinephrine, and dopamine—which, in turn, modulate the activity of neurons that release glutamate.

Weeks may pass before antidepressants’ effect on monoamine-releasing neurons produces a therapeutic benefit, however, leaving many patients impaired or even suicidal. This delayed onset of action might be explained by antidepressants’ indirect blockade of glutamate. The route to more rapid results, therefore, might be to cut out the monoamine middlemen.

Glutamate clues

Glutamate, instead of monoamines, might offer a more direct means to affect mood and could be a new target for antidepressant treatment:²

• Positron-emission tomography of neuron function in depressed patients shows abnormal activity in neurons that release glutamate—so-called glutamate neurons.
• Approximately 60 % of neurons are glutamate neurons, the largest network of neurons in the brain.
• Increased glutamate activity is seen in depressed patients.
• Animal studies have shown that blocking the N-methyl-D-aspartate (NMDA) receptor—1 of 3 types of glutamate receptors—decreases depressive behavior.
• Chronic administration of antidepressant medication reduces the expression of NMDA receptors.

Rapid glutamate blockade

Prompted by evidence that glutamate may be involved in mood disorders, researchers at the National Institute of Mental Health designed a study to determine if blocking the NMDA receptor can produce a rapid antidepressant effect.³ They chose the agent ketamine for this study because of its potent affinity for the NMDA receptor.

Ketamine was developed in the 1960s as a general anaesthetic, and its use in the United States is limited almost exclusively to veterinary medicine. The drug’s propensity to induce perceptual disturbances limits its clinical use but enhances its illicit use.

Eighteen patients with treatment-resistant depression were enrolled in a randomized, placebo-controlled, double-blind, crossover study. After 2 weeks without medication, they received a single infusion of IV ketamine or placebo. One week later they received the alternate intervention. Changes in Hamilton Rating Scale for Depression scores were assessed after each infusion.

Figure Decrease in depressive symptoms with IV ketamine

* = P <0.05

Patients who received ketamine (blue) showed a marked reduction of depressive symptoms within 2 hours compared with those who received placebo (red).

Source: Reference 3Patients receiving ketamine showed a robust and sustained reduction in depressive symptoms compared with placebo within 110 minutes (Figure). “To our knowledge,” the authors wrote, “there has never been a report of any other drug or somatic treatment—such as sleep deprivation, thyrotropin-releasing hormone, antidepressant, dexamethasone, or electroconvulsive therapy—that results in such a dramatic rapid and prolonged response with a single administration.”

Seventy-one percent of patients responded to IV ketamine within 24 hours, which is comparable to reported response rates after 8 weeks with oral antidepressants such as bupropion (62%), selective serotonin reuptake inhibitors (63%), and venlafaxine (65%).^4,5

Caution and caveats

Despite these “dramatic” results, we must be cautious about extrapolating too much from this small study. Glutamate blockers such as ketamine can have serious adverse effects—including psychosis—and patients may not tolerate long-term interventions. Likewise, oral administration of memantine—another NMDA blocker—in a double-blind study did not effectively treat depression.⁶ Finally, subjects in the ketamine trial had chronic, treatment-resistant depression, and the results might not apply to other forms of depression.

The results suggest the possibility of a new option for depression treatment, however. Specifically, this option could expedite response and “jump-start” treatment through a novel mechanism so that persons with depression can get back on their feet more rapidly.

Drug brand names

• Bupropion • Wellbutrin
• Ketamine • Ketalar
• Memantine • Namenda
• Venlafaxine • Effexor

The serendipitous discovery of medications that can improve mood transformed depression treatment more than 50 years ago.¹ Most antidepressants produced since then could be called “me-too” medications because they all work by affecting the release of monoamines—serotonin, norepinephrine, and dopamine—which, in turn, modulate the activity of neurons that release glutamate.

Weeks may pass before antidepressants’ effect on monoamine-releasing neurons produces a therapeutic benefit, however, leaving many patients impaired or even suicidal. This delayed onset of action might be explained by antidepressants’ indirect blockade of glutamate. The route to more rapid results, therefore, might be to cut out the monoamine middlemen.

Glutamate clues

Glutamate, instead of monoamines, might offer a more direct means to affect mood and could be a new target for antidepressant treatment:²

• Positron-emission tomography of neuron function in depressed patients shows abnormal activity in neurons that release glutamate—so-called glutamate neurons.
• Approximately 60 % of neurons are glutamate neurons, the largest network of neurons in the brain.
• Increased glutamate activity is seen in depressed patients.
• Animal studies have shown that blocking the N-methyl-D-aspartate (NMDA) receptor—1 of 3 types of glutamate receptors—decreases depressive behavior.
• Chronic administration of antidepressant medication reduces the expression of NMDA receptors.

Rapid glutamate blockade

Prompted by evidence that glutamate may be involved in mood disorders, researchers at the National Institute of Mental Health designed a study to determine if blocking the NMDA receptor can produce a rapid antidepressant effect.³ They chose the agent ketamine for this study because of its potent affinity for the NMDA receptor.

Ketamine was developed in the 1960s as a general anaesthetic, and its use in the United States is limited almost exclusively to veterinary medicine. The drug’s propensity to induce perceptual disturbances limits its clinical use but enhances its illicit use.

Eighteen patients with treatment-resistant depression were enrolled in a randomized, placebo-controlled, double-blind, crossover study. After 2 weeks without medication, they received a single infusion of IV ketamine or placebo. One week later they received the alternate intervention. Changes in Hamilton Rating Scale for Depression scores were assessed after each infusion.

Figure Decrease in depressive symptoms with IV ketamine

* = P <0.05

Patients who received ketamine (blue) showed a marked reduction of depressive symptoms within 2 hours compared with those who received placebo (red).

Source: Reference 3Patients receiving ketamine showed a robust and sustained reduction in depressive symptoms compared with placebo within 110 minutes (Figure). “To our knowledge,” the authors wrote, “there has never been a report of any other drug or somatic treatment—such as sleep deprivation, thyrotropin-releasing hormone, antidepressant, dexamethasone, or electroconvulsive therapy—that results in such a dramatic rapid and prolonged response with a single administration.”

Seventy-one percent of patients responded to IV ketamine within 24 hours, which is comparable to reported response rates after 8 weeks with oral antidepressants such as bupropion (62%), selective serotonin reuptake inhibitors (63%), and venlafaxine (65%).^4,5

Caution and caveats

Despite these “dramatic” results, we must be cautious about extrapolating too much from this small study. Glutamate blockers such as ketamine can have serious adverse effects—including psychosis—and patients may not tolerate long-term interventions. Likewise, oral administration of memantine—another NMDA blocker—in a double-blind study did not effectively treat depression.⁶ Finally, subjects in the ketamine trial had chronic, treatment-resistant depression, and the results might not apply to other forms of depression.

The results suggest the possibility of a new option for depression treatment, however. Specifically, this option could expedite response and “jump-start” treatment through a novel mechanism so that persons with depression can get back on their feet more rapidly.

Drug brand names

• Bupropion • Wellbutrin
• Ketamine • Ketalar
• Memantine • Namenda
• Venlafaxine • Effexor

Research over the past decade suggests that the brain, like muscles, might get stronger after a good workout. Some evidence suggests that patients with attention-deficit/hyperactivity disorder (ADHD) can improve focus and concentration with mental exercises.

Research has unveiled the brain’s remarkable capacity for structural change as the result of experience. Repeating a specific brain function enhances neural mechanisms by increasing synapse formation or generating new neurons.¹ Increased use of neurons likely activates growth factor proteins that stimulate neural growth.

Healing the brain by exercising an impaired region is of great interest to physicians. For example, a group at Yale University showed that children with dyslexia who receive proper reading instruction read more fluently and show increased activity in the left hemisphere regions that decode words.² Other research has shown that constraint-induced movement therapy—when a stroke patient is forced to use his or her impaired arm or leg by restraining the good one—can “reawaken” parts of the brain damaged by a stroke.³ Researchers also are studying whether intellectual exercises such as reading or learning new skills can forestall Alzheimer’s disease.

Neurofeedback basics

Can the brain’s malleability help children with ADHD? Imaging studies show that children with ADHD have structural and functional deficits in the prefrontal cortex, the area associated with attention. Stimulant medications prescribed for ADHD compensate for this defect by increasing dopaminergic neuron activity in the prefrontal cortex.

Neurofeedback—also called EEG biofeedback—also could alleviate ADHD symptoms. For 30 years, neurofeedback has been studied as an ADHD treatment with promising results.⁵ Improvement in attention, concentration, and working memory has been reported in up to 75% of cases in the literature, although randomized controlled trials have not been conducted.

Neurofeedback teaches an individual to regulate the electrical activity of his or her brain with mental exercises.⁴ EEG frequencies generally can be divided into four basic rhythms:

• beta rhythm is alert and focused
• alpha is relaxed
• theta is between awake and asleep
• delta is deep sleep (Figure 1).

The patient aims to spend more time in the alert beta rhythm and less time in the slower, more relaxed rhythms by thinking thoughts that generate the appropriate rhythm. More time spent in beta rhythm means better attention and concentration. A computer monitoring EEG frequencies helps the patient learn to regulate his or her brain rhythms.

Figure 1 EEG frequencies characterizing 4 basic brain rhythms

Adhd help

A University of Montreal research group recently completed an open, randomized, neurofeedback trial of 20 children ages 8 to 12 with ADHD who do not take psychostimulants or other medications for ADHD.⁶ Fifteen received neurofeedback therapy consisting of 40 one-hour sessions over 15 weeks. Five children who did not receive treatment served as the control group. All subjects took several neuropsychological tests measuring attention and hyperactivity before and after the study (Figure 2a). On average the neurofeedback group scored significantly higher on all measures of attention without side effects compared with the control group.

A comparison of functional brain imaging scans taken before and after the study showed increased anterior cingulate gyrus activity in the frontal cortex in the neurofeedback group but not the controls (Figure 2b). Subjects took the Counting Stroop Test—a mental exercise that involves the anterior cingulate gyrus—while in the scanner. The imaging studies were averaged within the groups, and the before and after scans were subtracted from each other. The increased activity translates into improved attention and concentration and decreased impulsivity, allowing children to perform better in school, get into less trouble, and have better relationships with parents.

Although we need more studies, this research suggests that neurofeedback might be a treatment option for patients with ADHD who cannot tolerate or do not wish to take medications.

Figure 2 Neurofeedback training: Improvement in neuropsychological and imaging studies

A. Neuropsychological testing

Figure 2 Neurofeedback training: Improvement in neuropsychological and imaging studies

B. Imaging study

Research over the past decade suggests that the brain, like muscles, might get stronger after a good workout. Some evidence suggests that patients with attention-deficit/hyperactivity disorder (ADHD) can improve focus and concentration with mental exercises.

Research has unveiled the brain’s remarkable capacity for structural change as the result of experience. Repeating a specific brain function enhances neural mechanisms by increasing synapse formation or generating new neurons.¹ Increased use of neurons likely activates growth factor proteins that stimulate neural growth.

Healing the brain by exercising an impaired region is of great interest to physicians. For example, a group at Yale University showed that children with dyslexia who receive proper reading instruction read more fluently and show increased activity in the left hemisphere regions that decode words.² Other research has shown that constraint-induced movement therapy—when a stroke patient is forced to use his or her impaired arm or leg by restraining the good one—can “reawaken” parts of the brain damaged by a stroke.³ Researchers also are studying whether intellectual exercises such as reading or learning new skills can forestall Alzheimer’s disease.

Neurofeedback basics

Can the brain’s malleability help children with ADHD? Imaging studies show that children with ADHD have structural and functional deficits in the prefrontal cortex, the area associated with attention. Stimulant medications prescribed for ADHD compensate for this defect by increasing dopaminergic neuron activity in the prefrontal cortex.

Neurofeedback—also called EEG biofeedback—also could alleviate ADHD symptoms. For 30 years, neurofeedback has been studied as an ADHD treatment with promising results.⁵ Improvement in attention, concentration, and working memory has been reported in up to 75% of cases in the literature, although randomized controlled trials have not been conducted.

Neurofeedback teaches an individual to regulate the electrical activity of his or her brain with mental exercises.⁴ EEG frequencies generally can be divided into four basic rhythms:

• beta rhythm is alert and focused
• alpha is relaxed
• theta is between awake and asleep
• delta is deep sleep (Figure 1).

The patient aims to spend more time in the alert beta rhythm and less time in the slower, more relaxed rhythms by thinking thoughts that generate the appropriate rhythm. More time spent in beta rhythm means better attention and concentration. A computer monitoring EEG frequencies helps the patient learn to regulate his or her brain rhythms.

Figure 1 EEG frequencies characterizing 4 basic brain rhythms

Adhd help

A University of Montreal research group recently completed an open, randomized, neurofeedback trial of 20 children ages 8 to 12 with ADHD who do not take psychostimulants or other medications for ADHD.⁶ Fifteen received neurofeedback therapy consisting of 40 one-hour sessions over 15 weeks. Five children who did not receive treatment served as the control group. All subjects took several neuropsychological tests measuring attention and hyperactivity before and after the study (Figure 2a). On average the neurofeedback group scored significantly higher on all measures of attention without side effects compared with the control group.

A comparison of functional brain imaging scans taken before and after the study showed increased anterior cingulate gyrus activity in the frontal cortex in the neurofeedback group but not the controls (Figure 2b). Subjects took the Counting Stroop Test—a mental exercise that involves the anterior cingulate gyrus—while in the scanner. The imaging studies were averaged within the groups, and the before and after scans were subtracted from each other. The increased activity translates into improved attention and concentration and decreased impulsivity, allowing children to perform better in school, get into less trouble, and have better relationships with parents.

Although we need more studies, this research suggests that neurofeedback might be a treatment option for patients with ADHD who cannot tolerate or do not wish to take medications.

Figure 2 Neurofeedback training: Improvement in neuropsychological and imaging studies

A. Neuropsychological testing

Figure 2 Neurofeedback training: Improvement in neuropsychological and imaging studies

B. Imaging study

Research over the past decade suggests that the brain, like muscles, might get stronger after a good workout. Some evidence suggests that patients with attention-deficit/hyperactivity disorder (ADHD) can improve focus and concentration with mental exercises.

Research has unveiled the brain’s remarkable capacity for structural change as the result of experience. Repeating a specific brain function enhances neural mechanisms by increasing synapse formation or generating new neurons.¹ Increased use of neurons likely activates growth factor proteins that stimulate neural growth.

Healing the brain by exercising an impaired region is of great interest to physicians. For example, a group at Yale University showed that children with dyslexia who receive proper reading instruction read more fluently and show increased activity in the left hemisphere regions that decode words.² Other research has shown that constraint-induced movement therapy—when a stroke patient is forced to use his or her impaired arm or leg by restraining the good one—can “reawaken” parts of the brain damaged by a stroke.³ Researchers also are studying whether intellectual exercises such as reading or learning new skills can forestall Alzheimer’s disease.

Neurofeedback basics

Can the brain’s malleability help children with ADHD? Imaging studies show that children with ADHD have structural and functional deficits in the prefrontal cortex, the area associated with attention. Stimulant medications prescribed for ADHD compensate for this defect by increasing dopaminergic neuron activity in the prefrontal cortex.

Neurofeedback—also called EEG biofeedback—also could alleviate ADHD symptoms. For 30 years, neurofeedback has been studied as an ADHD treatment with promising results.⁵ Improvement in attention, concentration, and working memory has been reported in up to 75% of cases in the literature, although randomized controlled trials have not been conducted.

Neurofeedback teaches an individual to regulate the electrical activity of his or her brain with mental exercises.⁴ EEG frequencies generally can be divided into four basic rhythms:

• beta rhythm is alert and focused
• alpha is relaxed
• theta is between awake and asleep
• delta is deep sleep (Figure 1).

The patient aims to spend more time in the alert beta rhythm and less time in the slower, more relaxed rhythms by thinking thoughts that generate the appropriate rhythm. More time spent in beta rhythm means better attention and concentration. A computer monitoring EEG frequencies helps the patient learn to regulate his or her brain rhythms.

Figure 1 EEG frequencies characterizing 4 basic brain rhythms

Adhd help

A University of Montreal research group recently completed an open, randomized, neurofeedback trial of 20 children ages 8 to 12 with ADHD who do not take psychostimulants or other medications for ADHD.⁶ Fifteen received neurofeedback therapy consisting of 40 one-hour sessions over 15 weeks. Five children who did not receive treatment served as the control group. All subjects took several neuropsychological tests measuring attention and hyperactivity before and after the study (Figure 2a). On average the neurofeedback group scored significantly higher on all measures of attention without side effects compared with the control group.

A comparison of functional brain imaging scans taken before and after the study showed increased anterior cingulate gyrus activity in the frontal cortex in the neurofeedback group but not the controls (Figure 2b). Subjects took the Counting Stroop Test—a mental exercise that involves the anterior cingulate gyrus—while in the scanner. The imaging studies were averaged within the groups, and the before and after scans were subtracted from each other. The increased activity translates into improved attention and concentration and decreased impulsivity, allowing children to perform better in school, get into less trouble, and have better relationships with parents.

Although we need more studies, this research suggests that neurofeedback might be a treatment option for patients with ADHD who cannot tolerate or do not wish to take medications.

Figure 2 Neurofeedback training: Improvement in neuropsychological and imaging studies

A. Neuropsychological testing

Figure 2 Neurofeedback training: Improvement in neuropsychological and imaging studies

B. Imaging study

What’s a woman to do when sexual encounters become difficult or less satisfying?

• Vascularly directed sexual dysfunction treatments for men are not the answer; phosphodiesterase inhibitors such as sildenafil did no better than placebo among 800 women with various sexual problems.¹
• The testosterone patch increases sexual interest for some women but failed to win FDA approval because of long-term safety concerns.

Even more frustrating, libido loss is a common side effect with some widely prescribed psychotropics—such as selective serotonin reuptake inhibitors. But an agent shown to boost libido in female rats may give women with sexual dysfunction a pharmaceutical option.

From sunscreen to aphrodisiac

Approximately 10 years ago, University of Arizona researchers studied a melanocortin-stimulating hormone analogue while trying to develop a product to allow light-skinned persons to tan without ultraviolet ray exposure. The product indeed darkened skin, but it also triggered spontaneous erections in all 3 men in the pilot study.² A modified version of the erection-inducing peptide—now called bremelanotide—is being tested in phase 3 clinical trials as a prospective erectile dysfunction treatment.³

Unlike its predecessors, bremelanotide works directly on neural pathways that control sexual function, rather than on the vascular system. But its highest-interest feature may be its effect on female sexual desire—at least in rats.

Behavioral neurologist James Pfaus, PhD, identified behaviors female rats use to arouse males—what might be called the rodent equivalent of flirtation. These behaviors include solicitations (meeting head to head with males, then abruptly fleeing), pacing, hops, and darts.

His group then tested the effect of various doses of subcutaneous bremelanotide on 40 ovariectomized female rats primed with estradiol and progesterone.⁴ Researchers paired each female with a male for 30 minutes and recorded their behaviors. Compared with females who received placebo or low-dose bremelanotide, high-dose bremelanotide females performed significantly more “flirtatious” behaviors (Figure). The researchers attributed this difference to increased sexual desire.

The drug’s mechanism of action remains in question, but it appears to act centrally. Injecting it directly into female rats’ ventricles produced similar behaviors when they were paired with receptive males. Also, markers of neuronal activity have been found in the anterior aspect of the hypothalamus and nucleus accumbens—areas associated with sexual activity and pleasure.

FigureBremelanotide increases sexually solicitous behaviors in female rats

Source: Reference 4. Reprinted with permission. Copyright 2004, National Academy of Sciences, USA.

Pilot study in women

A randomized, double-blind, placebo-controlled, crossover trial suggests that bremelanotide as a nasal spray might increase desire in women with female sexual dysfunction (FSD).⁵ When 18 perimenopausal women with FSD were given bremelanotide or placebo, the bremelanotide group reported greater sexual desire and genital arousal while watching a sexually explicit video.

Specifically, this pilot study—part of the drug’s phase 2 trials in women—found that:

• 72% of women who took bremelanotide reported feelings of genital arousal, compared with 39% in the placebo group
• 67% of treated women experienced sexual desire versus 22% of controls.

Is fsd a pathology?

Some clinicians worry that FSD is a “disease” made up by pharmaceutical industry marketers. They argue that hypoactive sexual desire is not a disorder but an adaptive response to physical changes or relationship difficulties.⁶

On the other hand, a national survey of 1,749 women and 1,410 men ages 18 to 59 found sexual difficulties to be more prevalent in women than in men:⁷

• 43% of women reported sexual dysfunction, compared with 31% of men.
• 26% of women reported inability to achieve orgasm compared with 8% of men.

An effective and safe medication targeted at improving women’s sexual desire might help some patients, such as peri- or postmenopausal women, in otherwise healthy relationships.

What’s a woman to do when sexual encounters become difficult or less satisfying?

• Vascularly directed sexual dysfunction treatments for men are not the answer; phosphodiesterase inhibitors such as sildenafil did no better than placebo among 800 women with various sexual problems.¹
• The testosterone patch increases sexual interest for some women but failed to win FDA approval because of long-term safety concerns.

Even more frustrating, libido loss is a common side effect with some widely prescribed psychotropics—such as selective serotonin reuptake inhibitors. But an agent shown to boost libido in female rats may give women with sexual dysfunction a pharmaceutical option.

From sunscreen to aphrodisiac

Approximately 10 years ago, University of Arizona researchers studied a melanocortin-stimulating hormone analogue while trying to develop a product to allow light-skinned persons to tan without ultraviolet ray exposure. The product indeed darkened skin, but it also triggered spontaneous erections in all 3 men in the pilot study.² A modified version of the erection-inducing peptide—now called bremelanotide—is being tested in phase 3 clinical trials as a prospective erectile dysfunction treatment.³

Unlike its predecessors, bremelanotide works directly on neural pathways that control sexual function, rather than on the vascular system. But its highest-interest feature may be its effect on female sexual desire—at least in rats.

Behavioral neurologist James Pfaus, PhD, identified behaviors female rats use to arouse males—what might be called the rodent equivalent of flirtation. These behaviors include solicitations (meeting head to head with males, then abruptly fleeing), pacing, hops, and darts.

His group then tested the effect of various doses of subcutaneous bremelanotide on 40 ovariectomized female rats primed with estradiol and progesterone.⁴ Researchers paired each female with a male for 30 minutes and recorded their behaviors. Compared with females who received placebo or low-dose bremelanotide, high-dose bremelanotide females performed significantly more “flirtatious” behaviors (Figure). The researchers attributed this difference to increased sexual desire.

The drug’s mechanism of action remains in question, but it appears to act centrally. Injecting it directly into female rats’ ventricles produced similar behaviors when they were paired with receptive males. Also, markers of neuronal activity have been found in the anterior aspect of the hypothalamus and nucleus accumbens—areas associated with sexual activity and pleasure.

FigureBremelanotide increases sexually solicitous behaviors in female rats

Source: Reference 4. Reprinted with permission. Copyright 2004, National Academy of Sciences, USA.

Pilot study in women

A randomized, double-blind, placebo-controlled, crossover trial suggests that bremelanotide as a nasal spray might increase desire in women with female sexual dysfunction (FSD).⁵ When 18 perimenopausal women with FSD were given bremelanotide or placebo, the bremelanotide group reported greater sexual desire and genital arousal while watching a sexually explicit video.

Specifically, this pilot study—part of the drug’s phase 2 trials in women—found that:

• 72% of women who took bremelanotide reported feelings of genital arousal, compared with 39% in the placebo group
• 67% of treated women experienced sexual desire versus 22% of controls.

Is fsd a pathology?

Some clinicians worry that FSD is a “disease” made up by pharmaceutical industry marketers. They argue that hypoactive sexual desire is not a disorder but an adaptive response to physical changes or relationship difficulties.⁶

On the other hand, a national survey of 1,749 women and 1,410 men ages 18 to 59 found sexual difficulties to be more prevalent in women than in men:⁷

• 43% of women reported sexual dysfunction, compared with 31% of men.
• 26% of women reported inability to achieve orgasm compared with 8% of men.

An effective and safe medication targeted at improving women’s sexual desire might help some patients, such as peri- or postmenopausal women, in otherwise healthy relationships.

What’s a woman to do when sexual encounters become difficult or less satisfying?

• Vascularly directed sexual dysfunction treatments for men are not the answer; phosphodiesterase inhibitors such as sildenafil did no better than placebo among 800 women with various sexual problems.¹
• The testosterone patch increases sexual interest for some women but failed to win FDA approval because of long-term safety concerns.

Even more frustrating, libido loss is a common side effect with some widely prescribed psychotropics—such as selective serotonin reuptake inhibitors. But an agent shown to boost libido in female rats may give women with sexual dysfunction a pharmaceutical option.

From sunscreen to aphrodisiac

Approximately 10 years ago, University of Arizona researchers studied a melanocortin-stimulating hormone analogue while trying to develop a product to allow light-skinned persons to tan without ultraviolet ray exposure. The product indeed darkened skin, but it also triggered spontaneous erections in all 3 men in the pilot study.² A modified version of the erection-inducing peptide—now called bremelanotide—is being tested in phase 3 clinical trials as a prospective erectile dysfunction treatment.³

Unlike its predecessors, bremelanotide works directly on neural pathways that control sexual function, rather than on the vascular system. But its highest-interest feature may be its effect on female sexual desire—at least in rats.

Behavioral neurologist James Pfaus, PhD, identified behaviors female rats use to arouse males—what might be called the rodent equivalent of flirtation. These behaviors include solicitations (meeting head to head with males, then abruptly fleeing), pacing, hops, and darts.

His group then tested the effect of various doses of subcutaneous bremelanotide on 40 ovariectomized female rats primed with estradiol and progesterone.⁴ Researchers paired each female with a male for 30 minutes and recorded their behaviors. Compared with females who received placebo or low-dose bremelanotide, high-dose bremelanotide females performed significantly more “flirtatious” behaviors (Figure). The researchers attributed this difference to increased sexual desire.

The drug’s mechanism of action remains in question, but it appears to act centrally. Injecting it directly into female rats’ ventricles produced similar behaviors when they were paired with receptive males. Also, markers of neuronal activity have been found in the anterior aspect of the hypothalamus and nucleus accumbens—areas associated with sexual activity and pleasure.

FigureBremelanotide increases sexually solicitous behaviors in female rats

Source: Reference 4. Reprinted with permission. Copyright 2004, National Academy of Sciences, USA.

Pilot study in women

A randomized, double-blind, placebo-controlled, crossover trial suggests that bremelanotide as a nasal spray might increase desire in women with female sexual dysfunction (FSD).⁵ When 18 perimenopausal women with FSD were given bremelanotide or placebo, the bremelanotide group reported greater sexual desire and genital arousal while watching a sexually explicit video.

Specifically, this pilot study—part of the drug’s phase 2 trials in women—found that:

• 72% of women who took bremelanotide reported feelings of genital arousal, compared with 39% in the placebo group
• 67% of treated women experienced sexual desire versus 22% of controls.

Is fsd a pathology?

Some clinicians worry that FSD is a “disease” made up by pharmaceutical industry marketers. They argue that hypoactive sexual desire is not a disorder but an adaptive response to physical changes or relationship difficulties.⁶

On the other hand, a national survey of 1,749 women and 1,410 men ages 18 to 59 found sexual difficulties to be more prevalent in women than in men:⁷

• 43% of women reported sexual dysfunction, compared with 31% of men.
• 26% of women reported inability to achieve orgasm compared with 8% of men.

An effective and safe medication targeted at improving women’s sexual desire might help some patients, such as peri- or postmenopausal women, in otherwise healthy relationships.

Chronic pain—particularly lower back pain—is frustrating to both patient and clinician. Because most cases lack an obvious physical explanation, the doctor may wonder if the patient is faking or exaggerating—that the pain is “in the patient’s head.” Studies suggest this cerebral component may exist—but not in ways you might expect.

How the brain processes pain

According to traditional belief, the brain passively receives noxious signals from injured tissue (nociceptive) or damaged nerve (neuropathic). Extensive—some would say excessive—tests are often conducted in search of a bone or muscle injury that might explain the pain.

Functional imaging studies across 15 years have shown activity in various brain regions when subjects feel pain. In addition to the somatosensory cortex, pain also activates brain areas involved with mood, attention, and anxiety. More important, the brain does not passively receive signals from the periphery but can inhibit ascending signals with endogenous opioids, such as endorphins and enkephalins.

Apkarian et al^{Posttraumatic stress disorder: Nature and nurture?, May 2004.)}

Drugs. Medications and other substances taken to alleviate pain might also reduce gray matter. Excessive alcohol and opioid use have long-term adverse effects on the CNS.³ Is treatment or self-medication mildly toxic to the brain?

Overuse atrophy. Apkarian et al¹ propose that cortical loss may be secondary to overuse. They suggest that persistent pain perception— and the resultant negative affect and stress—causes an excitotoxic and inflammatory state that wears out portions of the brain circuitry. If this is true, then chronic pain itself causes cerebral atrophy.

Whatever the explanation, this study indicates that chronic lower back pain pathology extends beyond the lower back.

Related resources

• Deyo RA, Weinstein JN. Low back pain. N Engl J Med 2001;344:363-70.
• International Association for the Study of Pain. www.iasp-pain.org.

Chronic pain—particularly lower back pain—is frustrating to both patient and clinician. Because most cases lack an obvious physical explanation, the doctor may wonder if the patient is faking or exaggerating—that the pain is “in the patient’s head.” Studies suggest this cerebral component may exist—but not in ways you might expect.

How the brain processes pain

According to traditional belief, the brain passively receives noxious signals from injured tissue (nociceptive) or damaged nerve (neuropathic). Extensive—some would say excessive—tests are often conducted in search of a bone or muscle injury that might explain the pain.

Functional imaging studies across 15 years have shown activity in various brain regions when subjects feel pain. In addition to the somatosensory cortex, pain also activates brain areas involved with mood, attention, and anxiety. More important, the brain does not passively receive signals from the periphery but can inhibit ascending signals with endogenous opioids, such as endorphins and enkephalins.

Apkarian et al^{Posttraumatic stress disorder: Nature and nurture?, May 2004.)}

Drugs. Medications and other substances taken to alleviate pain might also reduce gray matter. Excessive alcohol and opioid use have long-term adverse effects on the CNS.³ Is treatment or self-medication mildly toxic to the brain?

Overuse atrophy. Apkarian et al¹ propose that cortical loss may be secondary to overuse. They suggest that persistent pain perception— and the resultant negative affect and stress—causes an excitotoxic and inflammatory state that wears out portions of the brain circuitry. If this is true, then chronic pain itself causes cerebral atrophy.

Whatever the explanation, this study indicates that chronic lower back pain pathology extends beyond the lower back.

Related resources

• Deyo RA, Weinstein JN. Low back pain. N Engl J Med 2001;344:363-70.
• International Association for the Study of Pain. www.iasp-pain.org.

Chronic pain—particularly lower back pain—is frustrating to both patient and clinician. Because most cases lack an obvious physical explanation, the doctor may wonder if the patient is faking or exaggerating—that the pain is “in the patient’s head.” Studies suggest this cerebral component may exist—but not in ways you might expect.

How the brain processes pain

According to traditional belief, the brain passively receives noxious signals from injured tissue (nociceptive) or damaged nerve (neuropathic). Extensive—some would say excessive—tests are often conducted in search of a bone or muscle injury that might explain the pain.

Functional imaging studies across 15 years have shown activity in various brain regions when subjects feel pain. In addition to the somatosensory cortex, pain also activates brain areas involved with mood, attention, and anxiety. More important, the brain does not passively receive signals from the periphery but can inhibit ascending signals with endogenous opioids, such as endorphins and enkephalins.

Apkarian et al^{Posttraumatic stress disorder: Nature and nurture?, May 2004.)}

Drugs. Medications and other substances taken to alleviate pain might also reduce gray matter. Excessive alcohol and opioid use have long-term adverse effects on the CNS.³ Is treatment or self-medication mildly toxic to the brain?

Overuse atrophy. Apkarian et al¹ propose that cortical loss may be secondary to overuse. They suggest that persistent pain perception— and the resultant negative affect and stress—causes an excitotoxic and inflammatory state that wears out portions of the brain circuitry. If this is true, then chronic pain itself causes cerebral atrophy.

Whatever the explanation, this study indicates that chronic lower back pain pathology extends beyond the lower back.

Related resources

• Deyo RA, Weinstein JN. Low back pain. N Engl J Med 2001;344:363-70.
• International Association for the Study of Pain. www.iasp-pain.org.

Why do some people stay married for decades while others jump from one relationship to the next? If humans are like rodents, recent research suggests that neuropeptides may help forge the ties that bind.

FOLLOWING VOLE BEHAVIOR

The vole, which inhabits many grasslands in the United States, is a rodent resembling a mouse but related to the lemming. Males in some vole species (such as meadow voles) show no partner preference whereas males in other species prefer one partner, share the same nest with her, and help care for their offspring.¹

The neuropeptides oxytocin and arginine vasopressin are mediators of pair bonding. The brain of a prairie vole—a species in which males tend to bond with female partners—has more vasopressin receptors than that of the solitary meadow vole (Figure 1).

Figure 1 More vasopressin in bonding voles

Ventral forebrain autoradiograms show greater vasopressin (VP) expression in prairie voles (top) than meadow voles.

Reprinted with permission. © 2004, Nature Publishing Group.Lim et al, however, found that meadow voles were more likely to bond with a single female after the males’ vasopressin receptors were increased.² The researchers isolated and replicated the gene sequence responsible for the vasopressin receptor in the prairie vole. Then, using a viral vector, they injected the gene into the ventral pallidum of 11 male meadow voles. Eleven other voles received placebo.

Two weeks later, each sexually naïve male vole was housed for 24 hours with a sexually receptive female vole. Then, each male was placed for 3 hours in a three-chamber apparatus with the partner female in one chamber and a novel female in another. The time spent huddling with each female was recorded.

Across 3 hours, the placebo group voles spent 10 to 15 minutes with either female—normal behavior for this species. By contrast, the voles that received the vasopressin receptors spent approximately 40 minutes with their partners but only about 5 minutes with the novel voles, thus showing more affiliative behavior and a clear preference for their mates (Figure 2). The findings suggest that the researchers may have produced a profound change in social behavior by altering one gene.

IMPLICATIONS FOR HUMANS

How this research relates to humans is unknown, as there is no sound evidence of a link between vole and human pair bonding. Likewise, the influence of the higher cortical areas in orchestrating human behaviors cannot be underestimated.

Neuroimaging, however, has shown that brain regions rich with oxytocin and vasopressin receptors are activated while a person views pictures of loved ones.³ Additionally, mens’ vasopressin levels have been shown to increase when they are sexually aroused.⁴ Whether these findings one day lead to a medicine that promotes monogamous behavior in men remains to be seen.⁵

Figure 2 Male meadow voles’ interactions with females after vasopressin or placebo treatment

Source: Adapted from reference 2

Why do some people stay married for decades while others jump from one relationship to the next? If humans are like rodents, recent research suggests that neuropeptides may help forge the ties that bind.

FOLLOWING VOLE BEHAVIOR

The vole, which inhabits many grasslands in the United States, is a rodent resembling a mouse but related to the lemming. Males in some vole species (such as meadow voles) show no partner preference whereas males in other species prefer one partner, share the same nest with her, and help care for their offspring.¹

The neuropeptides oxytocin and arginine vasopressin are mediators of pair bonding. The brain of a prairie vole—a species in which males tend to bond with female partners—has more vasopressin receptors than that of the solitary meadow vole (Figure 1).

Figure 1 More vasopressin in bonding voles

Ventral forebrain autoradiograms show greater vasopressin (VP) expression in prairie voles (top) than meadow voles.

Reprinted with permission. © 2004, Nature Publishing Group.Lim et al, however, found that meadow voles were more likely to bond with a single female after the males’ vasopressin receptors were increased.² The researchers isolated and replicated the gene sequence responsible for the vasopressin receptor in the prairie vole. Then, using a viral vector, they injected the gene into the ventral pallidum of 11 male meadow voles. Eleven other voles received placebo.

Two weeks later, each sexually naïve male vole was housed for 24 hours with a sexually receptive female vole. Then, each male was placed for 3 hours in a three-chamber apparatus with the partner female in one chamber and a novel female in another. The time spent huddling with each female was recorded.

Across 3 hours, the placebo group voles spent 10 to 15 minutes with either female—normal behavior for this species. By contrast, the voles that received the vasopressin receptors spent approximately 40 minutes with their partners but only about 5 minutes with the novel voles, thus showing more affiliative behavior and a clear preference for their mates (Figure 2). The findings suggest that the researchers may have produced a profound change in social behavior by altering one gene.

IMPLICATIONS FOR HUMANS

How this research relates to humans is unknown, as there is no sound evidence of a link between vole and human pair bonding. Likewise, the influence of the higher cortical areas in orchestrating human behaviors cannot be underestimated.

Neuroimaging, however, has shown that brain regions rich with oxytocin and vasopressin receptors are activated while a person views pictures of loved ones.³ Additionally, mens’ vasopressin levels have been shown to increase when they are sexually aroused.⁴ Whether these findings one day lead to a medicine that promotes monogamous behavior in men remains to be seen.⁵

Figure 2 Male meadow voles’ interactions with females after vasopressin or placebo treatment

Source: Adapted from reference 2

Why do some people stay married for decades while others jump from one relationship to the next? If humans are like rodents, recent research suggests that neuropeptides may help forge the ties that bind.

FOLLOWING VOLE BEHAVIOR

The vole, which inhabits many grasslands in the United States, is a rodent resembling a mouse but related to the lemming. Males in some vole species (such as meadow voles) show no partner preference whereas males in other species prefer one partner, share the same nest with her, and help care for their offspring.¹

The neuropeptides oxytocin and arginine vasopressin are mediators of pair bonding. The brain of a prairie vole—a species in which males tend to bond with female partners—has more vasopressin receptors than that of the solitary meadow vole (Figure 1).

Figure 1 More vasopressin in bonding voles

Ventral forebrain autoradiograms show greater vasopressin (VP) expression in prairie voles (top) than meadow voles.

Reprinted with permission. © 2004, Nature Publishing Group.Lim et al, however, found that meadow voles were more likely to bond with a single female after the males’ vasopressin receptors were increased.² The researchers isolated and replicated the gene sequence responsible for the vasopressin receptor in the prairie vole. Then, using a viral vector, they injected the gene into the ventral pallidum of 11 male meadow voles. Eleven other voles received placebo.

Two weeks later, each sexually naïve male vole was housed for 24 hours with a sexually receptive female vole. Then, each male was placed for 3 hours in a three-chamber apparatus with the partner female in one chamber and a novel female in another. The time spent huddling with each female was recorded.

Across 3 hours, the placebo group voles spent 10 to 15 minutes with either female—normal behavior for this species. By contrast, the voles that received the vasopressin receptors spent approximately 40 minutes with their partners but only about 5 minutes with the novel voles, thus showing more affiliative behavior and a clear preference for their mates (Figure 2). The findings suggest that the researchers may have produced a profound change in social behavior by altering one gene.

IMPLICATIONS FOR HUMANS

How this research relates to humans is unknown, as there is no sound evidence of a link between vole and human pair bonding. Likewise, the influence of the higher cortical areas in orchestrating human behaviors cannot be underestimated.

Neuroimaging, however, has shown that brain regions rich with oxytocin and vasopressin receptors are activated while a person views pictures of loved ones.³ Additionally, mens’ vasopressin levels have been shown to increase when they are sexually aroused.⁴ Whether these findings one day lead to a medicine that promotes monogamous behavior in men remains to be seen.⁵

Figure 2 Male meadow voles’ interactions with females after vasopressin or placebo treatment

Source: Adapted from reference 2