Jeff Evans

In the process of developing a more efficient way to get an experimental antibody therapy across the blood-brain barrier to treat Alzheimer's disease, researchers may have raised the prospects for delivering therapeutic antibodies to the brain for other diseases.

Investigators at Genentech tested an antibody targeting beta-secretase, or beta amyloid cleavage enzyme 1 (BACE1), which creates the amyloid-beta (Abeta) peptide fragments that are believed to play a pathological role in Alzheimer's disease. They found that the anti-BACE1 antibody significantly reduced Abeta in the blood of mouse models of Alzheimer's disease and in monkeys. But brain Abeta levels were not substantially reduced.

In their experiments with anti-BACE1, Jasvinder K. Atwal, Ph.D., and colleagues found that unlike existing small-molecule inhibitors of BACE1, the antibody binds to an epitope outside of BACE1's active site and is specific only to BACE1 and not other related enzymes, such as BACE2 or cathepsin D (Sci. Transl. Med. 2011;3:84ra43).

In primary neuron cultures, anti-BACE1 significantly reduced the synthesis of Abeta peptides, whereas in mouse and monkey models of Alzheimer's disease the antibody lowered serum concentrations of Abeta by about 50%. However, concentrations of Abeta in the brains of mice declined only modestly after administration of anti-BACE1. Reductions in amyloid-beta also were observed in the cerebrospinal fluid of cynomolgus monkeys that were given anti-BACE1, serving as a proxy for brain exposure, but also were transient and lasted only 7 days. At the anti-BACE1 doses given to these animals (3 mg/kg, 30 mg/kg, and 100 mg/kg), the median inhibitory concentrations were still less than what were observed in primary neuron cultures.

To address the difficulties of anti-BACE in reaching therapeutic levels in the brain, Dr. Atwal and other researchers at Genentech, led by Y. Joy Yu, co-opted a cellular process called receptor-mediated transcytosis to cross the blood-brain barrier (BBB) and increase the concentration of an anti-BACE1 antibody in the brain (Sci. Transl. Med. 2011;3:84ra44).

This transport process normally moves macromolecules from one side of a cell to another, and is thought to assist in bringing circulating blood proteins (such as insulin and transferrin) to the brain via the capillary endothelial cells of the BBB.

In mice, Ms. Yu and her coauthors created a new antibody against BACE1 that also has low affinity for the transferrin receptor (TfR), allowing the receptor to carry it across the BBB but also dissociating the antibody readily from the receptor once it has done so. When administered to mice intravenously, this anti-TfR/BACE1 antibody was broadly distributed in the brain and reached higher, therapeutic concentrations than did anti-BACE1. At doses of 50 mg/kg, anti-TfR/BACE1 reduced Abeta peptides in the brain by 50% at 48 hours, compared with 18% for anti-BACE1.

The investigators noted that “although the anti-TfR antibody used in this study does not block binding of transferrin to TfR, the acute and chronic safety considerations of using antibodies raised against TfR to increase uptake in brain have not been explored.”

They concluded that their “findings demonstrate substantial promise for brain-penetrating bispecific therapeutic antibodies that exploit receptor-mediated transcytosis, and provide evidence that this approach may be useful in targeting a wide range of CNS diseases with antibody therapy.”

All of the investigators in both studies are employees of Genentech, which funded the research. Genentech has filed patent applications related to this work.

Adviser's Viewpoint

Second Life for Alzheimer's Drug Target?

Alzheimer's disease is the most common type of dementia found in the elderly, and its frequency and financial burden on families and societies are expected to skyrocket in the coming decades as the population age increases worldwide. Currently, there are 5.4 million Americans with Alzheimer's and 27 million worldwide. The financial impact of the disease is $160 billion, and the pharmaceutical market is estimated to be $4 billion.

The pathology features brain extracellular deposits of amyloid-beta peptides that form senile plaques and intraneuronal tangles that are made up of tau protein (Physiol. Rev. 2001;81:741-66). Both plaques and tangles are formed over several years, and only when the neuronal loss is pronounced do symptoms appear. To date, no disease-modifying treatments are approved for Alzheimer's, and new therapeutic approaches need to be explored by first using animal models of the disease.

Amyloidogenesis, the process by which amyloid-beta (Abeta) is produced, stems from the consecutive endoproteolysis of the amyloid precursor protein by beta- and gamma-secretases to generate peptides of different lengths, including Abeta40 and Abeta42, which are the main components of senile plaques (Ann. Med. 2008;40:562-83). Beta-secretase is the rate-limiting enzyme in the process. Genetic manipulations in mice have shown that the major beta-secretase in the brain, and likely in Alzheimer's, is BACE1 (Nat. Neurosci. 2001;4:231-32). Therefore, intensive effort has been invested into the development of specific BACE1 inhibitors that can cross the BBB, but none has been successful until now.

The reports by Dr. Atwal and Ms. Yu and their colleagues offer encouraging news about the development of selective anti-BACE1 antibodies and anti-TfR antibodies. These reports are encouraging because targeting gamma-secretase with inhibitors has been fraught with systemic complications, including hematologic, GI, and more recently, neoplastic. Complicating matters further for gamma-secretase inhibitors (GSIs) is the report that the GSI semagecestat was halted in phase III clinical trials (

BACE1 antibodies would be desirable because they are more specific to the Alzheimer's disease process and pathophysiology. Still, antibodies are confounded by BBB permeability issues, and so enthusiasm for the reports by Dr. Atwal and Ms. Yu will need to be tempered until we are further along in the drug development process. Enthusiasm for amyloid approaches is waning overall. However, critical consideration should be given to not only whether anti-amyloid approaches are appropriate but also the timing of administration of these approaches. Until now, all GSIs and immunotherapies have been administered to symptomatic individuals who are carrying established and heavy amyloid burdens. One has to wonder whether these agents would be more effective if administered earlier in the disease process.

MARWAN N. SABBAGH, M.D., is director of the Banner Sun Health Research Institute, Sun City, Ariz. He was an investigator in trials for semagacestat. He has received research grants from Lilly, Pfizer, Eisai, Celgene, Bristol-Myers Squibb, Bayer, Baxter, GE Healthcare, Avid, and Janssen, and is a consultant to or is on advisory boards of Takeda, Bristol-Myers Squibb, Amerisciences, Eisai, and Bayer. He has received royalties from Amerisciences.

Vitals

In the process of developing a more efficient way to get an experimental antibody therapy across the blood-brain barrier to treat Alzheimer's disease, researchers may have raised the prospects for delivering therapeutic antibodies to the brain for other diseases.

Investigators at Genentech tested an antibody targeting beta-secretase, or beta amyloid cleavage enzyme 1 (BACE1), which creates the amyloid-beta (Abeta) peptide fragments that are believed to play a pathological role in Alzheimer's disease. They found that the anti-BACE1 antibody significantly reduced Abeta in the blood of mouse models of Alzheimer's disease and in monkeys. But brain Abeta levels were not substantially reduced.

In their experiments with anti-BACE1, Jasvinder K. Atwal, Ph.D., and colleagues found that unlike existing small-molecule inhibitors of BACE1, the antibody binds to an epitope outside of BACE1's active site and is specific only to BACE1 and not other related enzymes, such as BACE2 or cathepsin D (Sci. Transl. Med. 2011;3:84ra43).

In primary neuron cultures, anti-BACE1 significantly reduced the synthesis of Abeta peptides, whereas in mouse and monkey models of Alzheimer's disease the antibody lowered serum concentrations of Abeta by about 50%. However, concentrations of Abeta in the brains of mice declined only modestly after administration of anti-BACE1. Reductions in amyloid-beta also were observed in the cerebrospinal fluid of cynomolgus monkeys that were given anti-BACE1, serving as a proxy for brain exposure, but also were transient and lasted only 7 days. At the anti-BACE1 doses given to these animals (3 mg/kg, 30 mg/kg, and 100 mg/kg), the median inhibitory concentrations were still less than what were observed in primary neuron cultures.

To address the difficulties of anti-BACE in reaching therapeutic levels in the brain, Dr. Atwal and other researchers at Genentech, led by Y. Joy Yu, co-opted a cellular process called receptor-mediated transcytosis to cross the blood-brain barrier (BBB) and increase the concentration of an anti-BACE1 antibody in the brain (Sci. Transl. Med. 2011;3:84ra44).

This transport process normally moves macromolecules from one side of a cell to another, and is thought to assist in bringing circulating blood proteins (such as insulin and transferrin) to the brain via the capillary endothelial cells of the BBB.

In mice, Ms. Yu and her coauthors created a new antibody against BACE1 that also has low affinity for the transferrin receptor (TfR), allowing the receptor to carry it across the BBB but also dissociating the antibody readily from the receptor once it has done so. When administered to mice intravenously, this anti-TfR/BACE1 antibody was broadly distributed in the brain and reached higher, therapeutic concentrations than did anti-BACE1. At doses of 50 mg/kg, anti-TfR/BACE1 reduced Abeta peptides in the brain by 50% at 48 hours, compared with 18% for anti-BACE1.

The investigators noted that “although the anti-TfR antibody used in this study does not block binding of transferrin to TfR, the acute and chronic safety considerations of using antibodies raised against TfR to increase uptake in brain have not been explored.”

They concluded that their “findings demonstrate substantial promise for brain-penetrating bispecific therapeutic antibodies that exploit receptor-mediated transcytosis, and provide evidence that this approach may be useful in targeting a wide range of CNS diseases with antibody therapy.”

All of the investigators in both studies are employees of Genentech, which funded the research. Genentech has filed patent applications related to this work.

Adviser's Viewpoint

Second Life for Alzheimer's Drug Target?

Alzheimer's disease is the most common type of dementia found in the elderly, and its frequency and financial burden on families and societies are expected to skyrocket in the coming decades as the population age increases worldwide. Currently, there are 5.4 million Americans with Alzheimer's and 27 million worldwide. The financial impact of the disease is $160 billion, and the pharmaceutical market is estimated to be $4 billion.

The pathology features brain extracellular deposits of amyloid-beta peptides that form senile plaques and intraneuronal tangles that are made up of tau protein (Physiol. Rev. 2001;81:741-66). Both plaques and tangles are formed over several years, and only when the neuronal loss is pronounced do symptoms appear. To date, no disease-modifying treatments are approved for Alzheimer's, and new therapeutic approaches need to be explored by first using animal models of the disease.

Amyloidogenesis, the process by which amyloid-beta (Abeta) is produced, stems from the consecutive endoproteolysis of the amyloid precursor protein by beta- and gamma-secretases to generate peptides of different lengths, including Abeta40 and Abeta42, which are the main components of senile plaques (Ann. Med. 2008;40:562-83). Beta-secretase is the rate-limiting enzyme in the process. Genetic manipulations in mice have shown that the major beta-secretase in the brain, and likely in Alzheimer's, is BACE1 (Nat. Neurosci. 2001;4:231-32). Therefore, intensive effort has been invested into the development of specific BACE1 inhibitors that can cross the BBB, but none has been successful until now.

The reports by Dr. Atwal and Ms. Yu and their colleagues offer encouraging news about the development of selective anti-BACE1 antibodies and anti-TfR antibodies. These reports are encouraging because targeting gamma-secretase with inhibitors has been fraught with systemic complications, including hematologic, GI, and more recently, neoplastic. Complicating matters further for gamma-secretase inhibitors (GSIs) is the report that the GSI semagecestat was halted in phase III clinical trials (

BACE1 antibodies would be desirable because they are more specific to the Alzheimer's disease process and pathophysiology. Still, antibodies are confounded by BBB permeability issues, and so enthusiasm for the reports by Dr. Atwal and Ms. Yu will need to be tempered until we are further along in the drug development process. Enthusiasm for amyloid approaches is waning overall. However, critical consideration should be given to not only whether anti-amyloid approaches are appropriate but also the timing of administration of these approaches. Until now, all GSIs and immunotherapies have been administered to symptomatic individuals who are carrying established and heavy amyloid burdens. One has to wonder whether these agents would be more effective if administered earlier in the disease process.

MARWAN N. SABBAGH, M.D., is director of the Banner Sun Health Research Institute, Sun City, Ariz. He was an investigator in trials for semagacestat. He has received research grants from Lilly, Pfizer, Eisai, Celgene, Bristol-Myers Squibb, Bayer, Baxter, GE Healthcare, Avid, and Janssen, and is a consultant to or is on advisory boards of Takeda, Bristol-Myers Squibb, Amerisciences, Eisai, and Bayer. He has received royalties from Amerisciences.

Vitals

In the process of developing a more efficient way to get an experimental antibody therapy across the blood-brain barrier to treat Alzheimer's disease, researchers may have raised the prospects for delivering therapeutic antibodies to the brain for other diseases.

Investigators at Genentech tested an antibody targeting beta-secretase, or beta amyloid cleavage enzyme 1 (BACE1), which creates the amyloid-beta (Abeta) peptide fragments that are believed to play a pathological role in Alzheimer's disease. They found that the anti-BACE1 antibody significantly reduced Abeta in the blood of mouse models of Alzheimer's disease and in monkeys. But brain Abeta levels were not substantially reduced.

In their experiments with anti-BACE1, Jasvinder K. Atwal, Ph.D., and colleagues found that unlike existing small-molecule inhibitors of BACE1, the antibody binds to an epitope outside of BACE1's active site and is specific only to BACE1 and not other related enzymes, such as BACE2 or cathepsin D (Sci. Transl. Med. 2011;3:84ra43).

In primary neuron cultures, anti-BACE1 significantly reduced the synthesis of Abeta peptides, whereas in mouse and monkey models of Alzheimer's disease the antibody lowered serum concentrations of Abeta by about 50%. However, concentrations of Abeta in the brains of mice declined only modestly after administration of anti-BACE1. Reductions in amyloid-beta also were observed in the cerebrospinal fluid of cynomolgus monkeys that were given anti-BACE1, serving as a proxy for brain exposure, but also were transient and lasted only 7 days. At the anti-BACE1 doses given to these animals (3 mg/kg, 30 mg/kg, and 100 mg/kg), the median inhibitory concentrations were still less than what were observed in primary neuron cultures.

To address the difficulties of anti-BACE in reaching therapeutic levels in the brain, Dr. Atwal and other researchers at Genentech, led by Y. Joy Yu, co-opted a cellular process called receptor-mediated transcytosis to cross the blood-brain barrier (BBB) and increase the concentration of an anti-BACE1 antibody in the brain (Sci. Transl. Med. 2011;3:84ra44).

This transport process normally moves macromolecules from one side of a cell to another, and is thought to assist in bringing circulating blood proteins (such as insulin and transferrin) to the brain via the capillary endothelial cells of the BBB.

In mice, Ms. Yu and her coauthors created a new antibody against BACE1 that also has low affinity for the transferrin receptor (TfR), allowing the receptor to carry it across the BBB but also dissociating the antibody readily from the receptor once it has done so. When administered to mice intravenously, this anti-TfR/BACE1 antibody was broadly distributed in the brain and reached higher, therapeutic concentrations than did anti-BACE1. At doses of 50 mg/kg, anti-TfR/BACE1 reduced Abeta peptides in the brain by 50% at 48 hours, compared with 18% for anti-BACE1.

The investigators noted that “although the anti-TfR antibody used in this study does not block binding of transferrin to TfR, the acute and chronic safety considerations of using antibodies raised against TfR to increase uptake in brain have not been explored.”

They concluded that their “findings demonstrate substantial promise for brain-penetrating bispecific therapeutic antibodies that exploit receptor-mediated transcytosis, and provide evidence that this approach may be useful in targeting a wide range of CNS diseases with antibody therapy.”

All of the investigators in both studies are employees of Genentech, which funded the research. Genentech has filed patent applications related to this work.

Adviser's Viewpoint

Second Life for Alzheimer's Drug Target?

Alzheimer's disease is the most common type of dementia found in the elderly, and its frequency and financial burden on families and societies are expected to skyrocket in the coming decades as the population age increases worldwide. Currently, there are 5.4 million Americans with Alzheimer's and 27 million worldwide. The financial impact of the disease is $160 billion, and the pharmaceutical market is estimated to be $4 billion.

The pathology features brain extracellular deposits of amyloid-beta peptides that form senile plaques and intraneuronal tangles that are made up of tau protein (Physiol. Rev. 2001;81:741-66). Both plaques and tangles are formed over several years, and only when the neuronal loss is pronounced do symptoms appear. To date, no disease-modifying treatments are approved for Alzheimer's, and new therapeutic approaches need to be explored by first using animal models of the disease.

Amyloidogenesis, the process by which amyloid-beta (Abeta) is produced, stems from the consecutive endoproteolysis of the amyloid precursor protein by beta- and gamma-secretases to generate peptides of different lengths, including Abeta40 and Abeta42, which are the main components of senile plaques (Ann. Med. 2008;40:562-83). Beta-secretase is the rate-limiting enzyme in the process. Genetic manipulations in mice have shown that the major beta-secretase in the brain, and likely in Alzheimer's, is BACE1 (Nat. Neurosci. 2001;4:231-32). Therefore, intensive effort has been invested into the development of specific BACE1 inhibitors that can cross the BBB, but none has been successful until now.

The reports by Dr. Atwal and Ms. Yu and their colleagues offer encouraging news about the development of selective anti-BACE1 antibodies and anti-TfR antibodies. These reports are encouraging because targeting gamma-secretase with inhibitors has been fraught with systemic complications, including hematologic, GI, and more recently, neoplastic. Complicating matters further for gamma-secretase inhibitors (GSIs) is the report that the GSI semagecestat was halted in phase III clinical trials (

BACE1 antibodies would be desirable because they are more specific to the Alzheimer's disease process and pathophysiology. Still, antibodies are confounded by BBB permeability issues, and so enthusiasm for the reports by Dr. Atwal and Ms. Yu will need to be tempered until we are further along in the drug development process. Enthusiasm for amyloid approaches is waning overall. However, critical consideration should be given to not only whether anti-amyloid approaches are appropriate but also the timing of administration of these approaches. Until now, all GSIs and immunotherapies have been administered to symptomatic individuals who are carrying established and heavy amyloid burdens. One has to wonder whether these agents would be more effective if administered earlier in the disease process.

MARWAN N. SABBAGH, M.D., is director of the Banner Sun Health Research Institute, Sun City, Ariz. He was an investigator in trials for semagacestat. He has received research grants from Lilly, Pfizer, Eisai, Celgene, Bristol-Myers Squibb, Bayer, Baxter, GE Healthcare, Avid, and Janssen, and is a consultant to or is on advisory boards of Takeda, Bristol-Myers Squibb, Amerisciences, Eisai, and Bayer. He has received royalties from Amerisciences.

Vitals

Mutations in the voltage-gated sodium channel Na_v1.7 appear to be the source of chronic pain in nearly 30% of patients with idiopathic small fiber neuropathy, according to a genetic and electrophysiological study of patients with the mutations.

Other gain-of-function mutations in the SCN9A gene that encodes Na_v1.7 have been known to cause inherited erythromelalgia and paroxysmal extreme pain disorder, but this is the first time that such mutations have been reported in patients with biopsy-proven idiopathic small fiber neuropathy (I-SFN), reported Dr. Catharina G. Faber of University Medical Centre Maastricht (Netherlands) and her colleagues (Ann. Neurol. 2011 May 20 [doi:10.1002/ana.22485]).

The researchers advised that SCN9A gene analysis might be considered for patients with small fiber neuropathy in whom other causes are excluded, particularly patients with younger ages of onset.

During 2006-2009, Dr. Faber and her coauthors assessed 248 patients who were 18 years and older with a suspected clinical diagnosis of SFN. A total of 185 patients had an underlying cause of SFN, and 19 were lost to follow-up or refused to participate. Inclusion and exclusion criteria were met by the remaining 44 patients. These patients had no identifiable underlying cause of SFN and had normal strength, tendon reflexes, vibration sense, and nerve conduction studies. They also had at least two neuropathic or autonomic symptoms.

Following skin biopsy and quantitative sensory testing (QST), 28 patients met criteria for I-SFN, which included reduced intraepidermal nerve fiber density and abnormal QST. All 28 patients were white.

Overall, 8 (29%) of the 28 patients with I-SFN had a missense mutation in the SCN9A gene. All patients were heterozygous for the mutation. No mutations were detected in SCN9A in 100 healthy control patients. Patients with SCN9A mutations were younger, albeit not significantly, than were the 20 patients without mutations (32.4 years vs. 42.7 years). No other clinical characteristics differed between the two groups.

All but two of the eight reported that their pain, which varied in intensity and quality from patient to patient, began in their distal extremities. Seven of the patients with mutations described autonomic problems.

Electrophysiological analyses of cultured dorsal root ganglion neurons that were transfected with the mutated sodium channels indicated that the mutations changed the function of the channel such that they conferred a hyperexcitable state to the neurons.

Dr. Faber and her associates wrote that the mutations in Na_v1.7 may trigger axonal degeneration because “sodium influx is known to impose an energetic load on neurons and neuronal processes, and increased activity of mutant Na_v1.7 channels would be expected to have an especially large effect on small-diameter intracutaneous axons.”

The research was supported by funds from the University Hospital Maastricht and the Rehabilitation Research Service and Medical Research Service of the U.S. Department of Veterans Affairs. The authors declared having no financial interests.

View on the News

A Little Less Idiopathic

Small fiber polyneuropathy (SFPN) is one of those common diseases that many have never heard of. Neurologists focus on diseases of myelinated axons, but most axons are unmyelinated and thinly myelinated “small fibers.” These tiny axons are invisible to light microscopy and conventional electrophysiology; thus, small fiber diseases remain largely unexplored. In addition, their cardinal symptom is chronic pain, a condition often avoided like a modern plague.

Two recent objective tests, neurodiagnostic skin biopsy and autonomic function testing, now facilitate the diagnosis of small fiber diseases (Neurology 2009;72:177-84) but do not identify their cause. Most SFPN is labeled “idiopathic,” which translates from Latin as “we are idiots” and translates for our patients as “no possibility of cure.” This study reports that a substantial minority of Dutch SFPN patients have gain-of-function mutations in a sodium channel enriched in small fibers. It will be important to replicate these findings because they come from a carefully selected subset of patients.

These findings remind us that a substantial portion of unexplained chronic pain is neurological, and that neurologists need to engage with such patients. If such mutations are common, testing may develop, along with family-planning questions. The patients will increasingly seek testing and treatment for SFPN, but few neurology groups are currently equipped to do this. Fortunately, any physician can perform skin biopsy and mail the punches to academic or commercial laboratories for analysis. Sodium channel blockers will be used more for treating SFPN and other neuropathic pain. Neurologists will need to learn to prescribe mexiletine and continuous subcutaneous lidocaine along with carbamazepine (Neurology 2004;62:218-25).

ANNE LOUISE OAKLANDER, M.D., directs Massachusetts General Hospital's neurodiagnostic skin biopsy laboratory. She investigates neurological causes of chronic pain and wrote her commentary upon request. She has no disclosures.

Mutations in the voltage-gated sodium channel Na_v1.7 appear to be the source of chronic pain in nearly 30% of patients with idiopathic small fiber neuropathy, according to a genetic and electrophysiological study of patients with the mutations.

Other gain-of-function mutations in the SCN9A gene that encodes Na_v1.7 have been known to cause inherited erythromelalgia and paroxysmal extreme pain disorder, but this is the first time that such mutations have been reported in patients with biopsy-proven idiopathic small fiber neuropathy (I-SFN), reported Dr. Catharina G. Faber of University Medical Centre Maastricht (Netherlands) and her colleagues (Ann. Neurol. 2011 May 20 [doi:10.1002/ana.22485]).

The researchers advised that SCN9A gene analysis might be considered for patients with small fiber neuropathy in whom other causes are excluded, particularly patients with younger ages of onset.

During 2006-2009, Dr. Faber and her coauthors assessed 248 patients who were 18 years and older with a suspected clinical diagnosis of SFN. A total of 185 patients had an underlying cause of SFN, and 19 were lost to follow-up or refused to participate. Inclusion and exclusion criteria were met by the remaining 44 patients. These patients had no identifiable underlying cause of SFN and had normal strength, tendon reflexes, vibration sense, and nerve conduction studies. They also had at least two neuropathic or autonomic symptoms.

Following skin biopsy and quantitative sensory testing (QST), 28 patients met criteria for I-SFN, which included reduced intraepidermal nerve fiber density and abnormal QST. All 28 patients were white.

Overall, 8 (29%) of the 28 patients with I-SFN had a missense mutation in the SCN9A gene. All patients were heterozygous for the mutation. No mutations were detected in SCN9A in 100 healthy control patients. Patients with SCN9A mutations were younger, albeit not significantly, than were the 20 patients without mutations (32.4 years vs. 42.7 years). No other clinical characteristics differed between the two groups.

All but two of the eight reported that their pain, which varied in intensity and quality from patient to patient, began in their distal extremities. Seven of the patients with mutations described autonomic problems.

Electrophysiological analyses of cultured dorsal root ganglion neurons that were transfected with the mutated sodium channels indicated that the mutations changed the function of the channel such that they conferred a hyperexcitable state to the neurons.

Dr. Faber and her associates wrote that the mutations in Na_v1.7 may trigger axonal degeneration because “sodium influx is known to impose an energetic load on neurons and neuronal processes, and increased activity of mutant Na_v1.7 channels would be expected to have an especially large effect on small-diameter intracutaneous axons.”

The research was supported by funds from the University Hospital Maastricht and the Rehabilitation Research Service and Medical Research Service of the U.S. Department of Veterans Affairs. The authors declared having no financial interests.

View on the News

A Little Less Idiopathic

Small fiber polyneuropathy (SFPN) is one of those common diseases that many have never heard of. Neurologists focus on diseases of myelinated axons, but most axons are unmyelinated and thinly myelinated “small fibers.” These tiny axons are invisible to light microscopy and conventional electrophysiology; thus, small fiber diseases remain largely unexplored. In addition, their cardinal symptom is chronic pain, a condition often avoided like a modern plague.

Two recent objective tests, neurodiagnostic skin biopsy and autonomic function testing, now facilitate the diagnosis of small fiber diseases (Neurology 2009;72:177-84) but do not identify their cause. Most SFPN is labeled “idiopathic,” which translates from Latin as “we are idiots” and translates for our patients as “no possibility of cure.” This study reports that a substantial minority of Dutch SFPN patients have gain-of-function mutations in a sodium channel enriched in small fibers. It will be important to replicate these findings because they come from a carefully selected subset of patients.

These findings remind us that a substantial portion of unexplained chronic pain is neurological, and that neurologists need to engage with such patients. If such mutations are common, testing may develop, along with family-planning questions. The patients will increasingly seek testing and treatment for SFPN, but few neurology groups are currently equipped to do this. Fortunately, any physician can perform skin biopsy and mail the punches to academic or commercial laboratories for analysis. Sodium channel blockers will be used more for treating SFPN and other neuropathic pain. Neurologists will need to learn to prescribe mexiletine and continuous subcutaneous lidocaine along with carbamazepine (Neurology 2004;62:218-25).

ANNE LOUISE OAKLANDER, M.D., directs Massachusetts General Hospital's neurodiagnostic skin biopsy laboratory. She investigates neurological causes of chronic pain and wrote her commentary upon request. She has no disclosures.

Mutations in the voltage-gated sodium channel Na_v1.7 appear to be the source of chronic pain in nearly 30% of patients with idiopathic small fiber neuropathy, according to a genetic and electrophysiological study of patients with the mutations.

Other gain-of-function mutations in the SCN9A gene that encodes Na_v1.7 have been known to cause inherited erythromelalgia and paroxysmal extreme pain disorder, but this is the first time that such mutations have been reported in patients with biopsy-proven idiopathic small fiber neuropathy (I-SFN), reported Dr. Catharina G. Faber of University Medical Centre Maastricht (Netherlands) and her colleagues (Ann. Neurol. 2011 May 20 [doi:10.1002/ana.22485]).

The researchers advised that SCN9A gene analysis might be considered for patients with small fiber neuropathy in whom other causes are excluded, particularly patients with younger ages of onset.

During 2006-2009, Dr. Faber and her coauthors assessed 248 patients who were 18 years and older with a suspected clinical diagnosis of SFN. A total of 185 patients had an underlying cause of SFN, and 19 were lost to follow-up or refused to participate. Inclusion and exclusion criteria were met by the remaining 44 patients. These patients had no identifiable underlying cause of SFN and had normal strength, tendon reflexes, vibration sense, and nerve conduction studies. They also had at least two neuropathic or autonomic symptoms.

Following skin biopsy and quantitative sensory testing (QST), 28 patients met criteria for I-SFN, which included reduced intraepidermal nerve fiber density and abnormal QST. All 28 patients were white.

Overall, 8 (29%) of the 28 patients with I-SFN had a missense mutation in the SCN9A gene. All patients were heterozygous for the mutation. No mutations were detected in SCN9A in 100 healthy control patients. Patients with SCN9A mutations were younger, albeit not significantly, than were the 20 patients without mutations (32.4 years vs. 42.7 years). No other clinical characteristics differed between the two groups.

All but two of the eight reported that their pain, which varied in intensity and quality from patient to patient, began in their distal extremities. Seven of the patients with mutations described autonomic problems.

Electrophysiological analyses of cultured dorsal root ganglion neurons that were transfected with the mutated sodium channels indicated that the mutations changed the function of the channel such that they conferred a hyperexcitable state to the neurons.

Dr. Faber and her associates wrote that the mutations in Na_v1.7 may trigger axonal degeneration because “sodium influx is known to impose an energetic load on neurons and neuronal processes, and increased activity of mutant Na_v1.7 channels would be expected to have an especially large effect on small-diameter intracutaneous axons.”

The research was supported by funds from the University Hospital Maastricht and the Rehabilitation Research Service and Medical Research Service of the U.S. Department of Veterans Affairs. The authors declared having no financial interests.

View on the News

A Little Less Idiopathic

Small fiber polyneuropathy (SFPN) is one of those common diseases that many have never heard of. Neurologists focus on diseases of myelinated axons, but most axons are unmyelinated and thinly myelinated “small fibers.” These tiny axons are invisible to light microscopy and conventional electrophysiology; thus, small fiber diseases remain largely unexplored. In addition, their cardinal symptom is chronic pain, a condition often avoided like a modern plague.

Two recent objective tests, neurodiagnostic skin biopsy and autonomic function testing, now facilitate the diagnosis of small fiber diseases (Neurology 2009;72:177-84) but do not identify their cause. Most SFPN is labeled “idiopathic,” which translates from Latin as “we are idiots” and translates for our patients as “no possibility of cure.” This study reports that a substantial minority of Dutch SFPN patients have gain-of-function mutations in a sodium channel enriched in small fibers. It will be important to replicate these findings because they come from a carefully selected subset of patients.

These findings remind us that a substantial portion of unexplained chronic pain is neurological, and that neurologists need to engage with such patients. If such mutations are common, testing may develop, along with family-planning questions. The patients will increasingly seek testing and treatment for SFPN, but few neurology groups are currently equipped to do this. Fortunately, any physician can perform skin biopsy and mail the punches to academic or commercial laboratories for analysis. Sodium channel blockers will be used more for treating SFPN and other neuropathic pain. Neurologists will need to learn to prescribe mexiletine and continuous subcutaneous lidocaine along with carbamazepine (Neurology 2004;62:218-25).

ANNE LOUISE OAKLANDER, M.D., directs Massachusetts General Hospital's neurodiagnostic skin biopsy laboratory. She investigates neurological causes of chronic pain and wrote her commentary upon request. She has no disclosures.

Children with Tourette syndrome appear to undergo changes in brain structure and function that allow them to gain control over their symptoms, according to a prospective study.

These changes, manifested by faster manual response times to tasks presenting conflicting information, lend strength to the premise that children with Tourette syndrome have a “generalized increase in cognitive control over motor activity” because of their constant need to suppress tics, wrote Stephen R. Jackson, Ph.D., of the University of Nottingham and his associates (Curr. Biol. 2011;21:580–5).

The enhanced motor control that Dr. Jackson and his colleagues observed in children with Tourette syndrome was associated with changes in brain white matter microstructure within the prefrontal cortex and greater metabolic activity in the prefrontal cortex.

The investigators conducted a manual task-switching experiment on 13 children (including two females) at an average age of 14 years who had Tourette syndrome and 13 age- and gender-matched neurologically healthy children. None of the children had attention-deficit/hyperactivity disorder or obsessive-compulsive disorder.

In “pure block” trials, the children were presented with a green arrow pointing either right or left. They had to respond as quickly as possible by pushing a corresponding right or left key. When the arrow was red, the investigators asked the participants to push the key for the opposite direction. “Mixed block” trials included those in which green or red arrows could be randomly shown. These trials were repeated during functional MRI studies measuring blood oxygen level–dependent (BOLD) activation.

Both groups had similar response times in pure block trials and similar error rates in both types of trials. But Tourette children had significantly faster response times in mixed block trials. Tourette children also had significantly faster response times in mixed block trials when the type of key press that was required differed from that of the previous trial. This reduced response time to switching manual tasks was strongly and positively associated with tic severity as measured by the motor score on the Yale Global Tics Severity Scale, such that children with better cognitive control and faster response to switching manual tasks exhibited reduced levels of tic severity.

Diffusion-weighted imaging revealed widespread differences in white matter microstructure between 14 Tourette children and 14 controls, most notably in the corpus callosum and the forceps minor, which connects the lateral and medial areas of the prefrontal cortex. This is consistent with previous studies in individuals with Tourette syndrome, according to the authors.

In the corpus callosum and forceps minor, voxel-based measurements of fractional anisotropy and mean diffusivity, which reflect myelination and axonal fiber density, were positively associated with tic severity. Dr. Jackson and his colleagues said these changes in cortical white matter volume “most likely reflect a functional adaptation to Tourette syndrome rather than a core symptom of the disorder,” which is supported by a previous study that indicated that the size of the corpus callosum is smaller in children with Tourette, is inversely associated with frontal cortex volumes and is positively associated with greater tic severity. Whether the differences in white matter between neurologically normal and Tourette children might reflect individual variation rather than a reorganization of the brain to suppress tics will require a longitudinal study, they noted.

The amount of white matter of the forceps minor predicted task response time only in the Tourette children. However, white matter in the corpus callosum was strongly associated with response time in healthy controls, but not in Tourette children. The results support the “hypothesis that for the Tourette syndrome group, the normal role performed by the corpus callosum in resolving the selection of motor outputs may be reduced in favor of an increased role for prefrontal cortex,” the investigators wrote.

Functional MRI measurement of BOLD data taken during testing with the mixed blocks task in 10 Tourette children and 15 controls showed that BOLD activation in regions of interest within the left and right hemisphere motor cortex was similar between the groups across the various types of task trials, “suggesting that motor execution was equivalent across the groups.” But in consecutive trials that involved switches of the red arrow's direction relative to consecutive trials in which the red arrow did not change direction, BOLD activation in regions of interest in the right prefrontal cortex adjacent to the forceps minor was significantly greater among Tourette children than in controls, which is consistent with evidence from monkey and human trials that suggest “the right prefrontal cortex is implicated in inhibitory processes underlying task switching.” BOLD activation also was strongly and linearly associated with increased response time in consecutive trials that involved switches of the red arrow's direction in only Tourette children, confirming that “the prefrontal cortex is significantly involved in the cognitive control of motor outputs.”

The study was funded by grants from the Tourette Syndrome Association, Tourettes Action, the U.K. Medical Research Council, the National Research Foundation of Korea, and the Korean Ministry of Education, Science and Technology. The authors did not declare any conflicts of interest.

Adviser's Viewpoint

Study Finds Altered Activity

Tourette syndrome (TS) is an age-dependent movement disorder characterized by simple and/or complex motor and vocal tics that have occurred intermittently over a 1-year period. Motor tics usually begin at 3–5 years of age followed by onset of vocal tics several years later. In the mid- to late teen years, approximately one-third of children will stop and have complete resolution of their tics, with another third experiencing significant decrease in symptoms. Although TS occurs in approximately 1%-2% of the pediatric population, it is estimated that as many as 20% of children will have a motor or vocal tic. An important feature of tic phenomenology is the ability of the individual to temporarily suppress the tic and if the effort is sustained, the affected individual may report mental fatigue or exhaustion.

Thus, tics appear to follow a neurodevelopmental sequence characterized by specific ranges of onset, peak, and resolution or amelioration. The latter has given rise to the concept that tics are a “normal” part of the developmental process. That process can be considered part of the adolescents' progressive command of motor, behavioral, and emotional experiences. Dysregulation of these complex control processes can result in the occurrence of the attentional disorders, impulsivity and hyperactivity, and the obsessive thoughts and compulsive actions that are the major comorbidities of TS.

One way to conceive of the active control processes that must take place during development is an alteration in neuronal function and perhaps anatomy, that is, neuroplasticity. As neurologists, we tend to think of neuroplasticity as the brain's response to acquired damage such as stroke or traumatic brain injury or recovery from resective surgery. However, the alteration of brain physiology and anatomy based upon activity in a pathway or network is a fundamental property that literally shapes the nervous system during development. Just as apoptosis eliminates neurons, activity in circuits increases synaptic strength and preservation of the involved neural elements.

MRI has allowed us to explore potential structural and functional alterations that accompany normal development as well as seemingly aberrant states such as TS. Several of the most interesting and reproducible findings from the recent imaging in TS literature include small caudate volumes in children and adults with TS, suggesting that this may be a trait characteristic of refractory tics; thinning of the sensorimotor cortex in children with TS; and enlargement of corpus callosum in adults, but reduction in children with TS.

Recently, the use of modern MRI technology, combined with rigorous behavioral study design and statistical analysis has provided evidence for an active process by which individuals with TS have an enhanced ability to suppress extraneous or conflicting information leading to motor task. In the experiments performed by Dr. Jackson and his colleagues, children with TS exhibited superior control over motor activity when compared with controls, suggesting that their previous cognitive “training” in tic suppression resulted in persistent functional changes. Furthermore, this group had anatomic differences in the white matter of the corpus callosum and forceps minor that correlated with tic severity. Of note, these structures are directly connected to the prefrontal cortex that provides the anatomic substrate for volitional tic suppression. Viewed from the perspective of normal development, the prefrontal cortex is known to be involved in the regulation of motor function. The authors also demonstrate that the right prefrontal cortex has a larger BOLD response during the motor task in which the TS cohort demonstrated better performance.

Taken together, the findings of Dr. Jackson and his associates suggest that the developmental processes by which children learn to control nonvolitional movements are the same that are used to compensate for the excessive motor overflow that characterizes TS. The implications for treatment of both developmental disorders and acquired injury to the nervous system may be profound if existing mechanisms that mediate normal development can be used as part of specific therapeutic regimens.

DR. BUCHHALTER is chief of pediatric neurology and director of the comprehensive pediatric epilepsy program at Phoenix Children's Hospital.

JEFFREY R. BUCHHALTER, M.D., PH.D.

Children with Tourette syndrome appear to undergo changes in brain structure and function that allow them to gain control over their symptoms, according to a prospective study.

These changes, manifested by faster manual response times to tasks presenting conflicting information, lend strength to the premise that children with Tourette syndrome have a “generalized increase in cognitive control over motor activity” because of their constant need to suppress tics, wrote Stephen R. Jackson, Ph.D., of the University of Nottingham and his associates (Curr. Biol. 2011;21:580–5).

The enhanced motor control that Dr. Jackson and his colleagues observed in children with Tourette syndrome was associated with changes in brain white matter microstructure within the prefrontal cortex and greater metabolic activity in the prefrontal cortex.

The investigators conducted a manual task-switching experiment on 13 children (including two females) at an average age of 14 years who had Tourette syndrome and 13 age- and gender-matched neurologically healthy children. None of the children had attention-deficit/hyperactivity disorder or obsessive-compulsive disorder.

In “pure block” trials, the children were presented with a green arrow pointing either right or left. They had to respond as quickly as possible by pushing a corresponding right or left key. When the arrow was red, the investigators asked the participants to push the key for the opposite direction. “Mixed block” trials included those in which green or red arrows could be randomly shown. These trials were repeated during functional MRI studies measuring blood oxygen level–dependent (BOLD) activation.

Both groups had similar response times in pure block trials and similar error rates in both types of trials. But Tourette children had significantly faster response times in mixed block trials. Tourette children also had significantly faster response times in mixed block trials when the type of key press that was required differed from that of the previous trial. This reduced response time to switching manual tasks was strongly and positively associated with tic severity as measured by the motor score on the Yale Global Tics Severity Scale, such that children with better cognitive control and faster response to switching manual tasks exhibited reduced levels of tic severity.

Diffusion-weighted imaging revealed widespread differences in white matter microstructure between 14 Tourette children and 14 controls, most notably in the corpus callosum and the forceps minor, which connects the lateral and medial areas of the prefrontal cortex. This is consistent with previous studies in individuals with Tourette syndrome, according to the authors.

In the corpus callosum and forceps minor, voxel-based measurements of fractional anisotropy and mean diffusivity, which reflect myelination and axonal fiber density, were positively associated with tic severity. Dr. Jackson and his colleagues said these changes in cortical white matter volume “most likely reflect a functional adaptation to Tourette syndrome rather than a core symptom of the disorder,” which is supported by a previous study that indicated that the size of the corpus callosum is smaller in children with Tourette, is inversely associated with frontal cortex volumes and is positively associated with greater tic severity. Whether the differences in white matter between neurologically normal and Tourette children might reflect individual variation rather than a reorganization of the brain to suppress tics will require a longitudinal study, they noted.

The amount of white matter of the forceps minor predicted task response time only in the Tourette children. However, white matter in the corpus callosum was strongly associated with response time in healthy controls, but not in Tourette children. The results support the “hypothesis that for the Tourette syndrome group, the normal role performed by the corpus callosum in resolving the selection of motor outputs may be reduced in favor of an increased role for prefrontal cortex,” the investigators wrote.

Functional MRI measurement of BOLD data taken during testing with the mixed blocks task in 10 Tourette children and 15 controls showed that BOLD activation in regions of interest within the left and right hemisphere motor cortex was similar between the groups across the various types of task trials, “suggesting that motor execution was equivalent across the groups.” But in consecutive trials that involved switches of the red arrow's direction relative to consecutive trials in which the red arrow did not change direction, BOLD activation in regions of interest in the right prefrontal cortex adjacent to the forceps minor was significantly greater among Tourette children than in controls, which is consistent with evidence from monkey and human trials that suggest “the right prefrontal cortex is implicated in inhibitory processes underlying task switching.” BOLD activation also was strongly and linearly associated with increased response time in consecutive trials that involved switches of the red arrow's direction in only Tourette children, confirming that “the prefrontal cortex is significantly involved in the cognitive control of motor outputs.”

The study was funded by grants from the Tourette Syndrome Association, Tourettes Action, the U.K. Medical Research Council, the National Research Foundation of Korea, and the Korean Ministry of Education, Science and Technology. The authors did not declare any conflicts of interest.

Adviser's Viewpoint

Study Finds Altered Activity

Tourette syndrome (TS) is an age-dependent movement disorder characterized by simple and/or complex motor and vocal tics that have occurred intermittently over a 1-year period. Motor tics usually begin at 3–5 years of age followed by onset of vocal tics several years later. In the mid- to late teen years, approximately one-third of children will stop and have complete resolution of their tics, with another third experiencing significant decrease in symptoms. Although TS occurs in approximately 1%-2% of the pediatric population, it is estimated that as many as 20% of children will have a motor or vocal tic. An important feature of tic phenomenology is the ability of the individual to temporarily suppress the tic and if the effort is sustained, the affected individual may report mental fatigue or exhaustion.

Thus, tics appear to follow a neurodevelopmental sequence characterized by specific ranges of onset, peak, and resolution or amelioration. The latter has given rise to the concept that tics are a “normal” part of the developmental process. That process can be considered part of the adolescents' progressive command of motor, behavioral, and emotional experiences. Dysregulation of these complex control processes can result in the occurrence of the attentional disorders, impulsivity and hyperactivity, and the obsessive thoughts and compulsive actions that are the major comorbidities of TS.

One way to conceive of the active control processes that must take place during development is an alteration in neuronal function and perhaps anatomy, that is, neuroplasticity. As neurologists, we tend to think of neuroplasticity as the brain's response to acquired damage such as stroke or traumatic brain injury or recovery from resective surgery. However, the alteration of brain physiology and anatomy based upon activity in a pathway or network is a fundamental property that literally shapes the nervous system during development. Just as apoptosis eliminates neurons, activity in circuits increases synaptic strength and preservation of the involved neural elements.

MRI has allowed us to explore potential structural and functional alterations that accompany normal development as well as seemingly aberrant states such as TS. Several of the most interesting and reproducible findings from the recent imaging in TS literature include small caudate volumes in children and adults with TS, suggesting that this may be a trait characteristic of refractory tics; thinning of the sensorimotor cortex in children with TS; and enlargement of corpus callosum in adults, but reduction in children with TS.

Recently, the use of modern MRI technology, combined with rigorous behavioral study design and statistical analysis has provided evidence for an active process by which individuals with TS have an enhanced ability to suppress extraneous or conflicting information leading to motor task. In the experiments performed by Dr. Jackson and his colleagues, children with TS exhibited superior control over motor activity when compared with controls, suggesting that their previous cognitive “training” in tic suppression resulted in persistent functional changes. Furthermore, this group had anatomic differences in the white matter of the corpus callosum and forceps minor that correlated with tic severity. Of note, these structures are directly connected to the prefrontal cortex that provides the anatomic substrate for volitional tic suppression. Viewed from the perspective of normal development, the prefrontal cortex is known to be involved in the regulation of motor function. The authors also demonstrate that the right prefrontal cortex has a larger BOLD response during the motor task in which the TS cohort demonstrated better performance.

Taken together, the findings of Dr. Jackson and his associates suggest that the developmental processes by which children learn to control nonvolitional movements are the same that are used to compensate for the excessive motor overflow that characterizes TS. The implications for treatment of both developmental disorders and acquired injury to the nervous system may be profound if existing mechanisms that mediate normal development can be used as part of specific therapeutic regimens.

DR. BUCHHALTER is chief of pediatric neurology and director of the comprehensive pediatric epilepsy program at Phoenix Children's Hospital.

JEFFREY R. BUCHHALTER, M.D., PH.D.

Children with Tourette syndrome appear to undergo changes in brain structure and function that allow them to gain control over their symptoms, according to a prospective study.

These changes, manifested by faster manual response times to tasks presenting conflicting information, lend strength to the premise that children with Tourette syndrome have a “generalized increase in cognitive control over motor activity” because of their constant need to suppress tics, wrote Stephen R. Jackson, Ph.D., of the University of Nottingham and his associates (Curr. Biol. 2011;21:580–5).

The enhanced motor control that Dr. Jackson and his colleagues observed in children with Tourette syndrome was associated with changes in brain white matter microstructure within the prefrontal cortex and greater metabolic activity in the prefrontal cortex.

The investigators conducted a manual task-switching experiment on 13 children (including two females) at an average age of 14 years who had Tourette syndrome and 13 age- and gender-matched neurologically healthy children. None of the children had attention-deficit/hyperactivity disorder or obsessive-compulsive disorder.

In “pure block” trials, the children were presented with a green arrow pointing either right or left. They had to respond as quickly as possible by pushing a corresponding right or left key. When the arrow was red, the investigators asked the participants to push the key for the opposite direction. “Mixed block” trials included those in which green or red arrows could be randomly shown. These trials were repeated during functional MRI studies measuring blood oxygen level–dependent (BOLD) activation.

Both groups had similar response times in pure block trials and similar error rates in both types of trials. But Tourette children had significantly faster response times in mixed block trials. Tourette children also had significantly faster response times in mixed block trials when the type of key press that was required differed from that of the previous trial. This reduced response time to switching manual tasks was strongly and positively associated with tic severity as measured by the motor score on the Yale Global Tics Severity Scale, such that children with better cognitive control and faster response to switching manual tasks exhibited reduced levels of tic severity.

Diffusion-weighted imaging revealed widespread differences in white matter microstructure between 14 Tourette children and 14 controls, most notably in the corpus callosum and the forceps minor, which connects the lateral and medial areas of the prefrontal cortex. This is consistent with previous studies in individuals with Tourette syndrome, according to the authors.

In the corpus callosum and forceps minor, voxel-based measurements of fractional anisotropy and mean diffusivity, which reflect myelination and axonal fiber density, were positively associated with tic severity. Dr. Jackson and his colleagues said these changes in cortical white matter volume “most likely reflect a functional adaptation to Tourette syndrome rather than a core symptom of the disorder,” which is supported by a previous study that indicated that the size of the corpus callosum is smaller in children with Tourette, is inversely associated with frontal cortex volumes and is positively associated with greater tic severity. Whether the differences in white matter between neurologically normal and Tourette children might reflect individual variation rather than a reorganization of the brain to suppress tics will require a longitudinal study, they noted.

The amount of white matter of the forceps minor predicted task response time only in the Tourette children. However, white matter in the corpus callosum was strongly associated with response time in healthy controls, but not in Tourette children. The results support the “hypothesis that for the Tourette syndrome group, the normal role performed by the corpus callosum in resolving the selection of motor outputs may be reduced in favor of an increased role for prefrontal cortex,” the investigators wrote.

Functional MRI measurement of BOLD data taken during testing with the mixed blocks task in 10 Tourette children and 15 controls showed that BOLD activation in regions of interest within the left and right hemisphere motor cortex was similar between the groups across the various types of task trials, “suggesting that motor execution was equivalent across the groups.” But in consecutive trials that involved switches of the red arrow's direction relative to consecutive trials in which the red arrow did not change direction, BOLD activation in regions of interest in the right prefrontal cortex adjacent to the forceps minor was significantly greater among Tourette children than in controls, which is consistent with evidence from monkey and human trials that suggest “the right prefrontal cortex is implicated in inhibitory processes underlying task switching.” BOLD activation also was strongly and linearly associated with increased response time in consecutive trials that involved switches of the red arrow's direction in only Tourette children, confirming that “the prefrontal cortex is significantly involved in the cognitive control of motor outputs.”

The study was funded by grants from the Tourette Syndrome Association, Tourettes Action, the U.K. Medical Research Council, the National Research Foundation of Korea, and the Korean Ministry of Education, Science and Technology. The authors did not declare any conflicts of interest.

Adviser's Viewpoint

Study Finds Altered Activity

Tourette syndrome (TS) is an age-dependent movement disorder characterized by simple and/or complex motor and vocal tics that have occurred intermittently over a 1-year period. Motor tics usually begin at 3–5 years of age followed by onset of vocal tics several years later. In the mid- to late teen years, approximately one-third of children will stop and have complete resolution of their tics, with another third experiencing significant decrease in symptoms. Although TS occurs in approximately 1%-2% of the pediatric population, it is estimated that as many as 20% of children will have a motor or vocal tic. An important feature of tic phenomenology is the ability of the individual to temporarily suppress the tic and if the effort is sustained, the affected individual may report mental fatigue or exhaustion.

Thus, tics appear to follow a neurodevelopmental sequence characterized by specific ranges of onset, peak, and resolution or amelioration. The latter has given rise to the concept that tics are a “normal” part of the developmental process. That process can be considered part of the adolescents' progressive command of motor, behavioral, and emotional experiences. Dysregulation of these complex control processes can result in the occurrence of the attentional disorders, impulsivity and hyperactivity, and the obsessive thoughts and compulsive actions that are the major comorbidities of TS.

One way to conceive of the active control processes that must take place during development is an alteration in neuronal function and perhaps anatomy, that is, neuroplasticity. As neurologists, we tend to think of neuroplasticity as the brain's response to acquired damage such as stroke or traumatic brain injury or recovery from resective surgery. However, the alteration of brain physiology and anatomy based upon activity in a pathway or network is a fundamental property that literally shapes the nervous system during development. Just as apoptosis eliminates neurons, activity in circuits increases synaptic strength and preservation of the involved neural elements.

MRI has allowed us to explore potential structural and functional alterations that accompany normal development as well as seemingly aberrant states such as TS. Several of the most interesting and reproducible findings from the recent imaging in TS literature include small caudate volumes in children and adults with TS, suggesting that this may be a trait characteristic of refractory tics; thinning of the sensorimotor cortex in children with TS; and enlargement of corpus callosum in adults, but reduction in children with TS.

Recently, the use of modern MRI technology, combined with rigorous behavioral study design and statistical analysis has provided evidence for an active process by which individuals with TS have an enhanced ability to suppress extraneous or conflicting information leading to motor task. In the experiments performed by Dr. Jackson and his colleagues, children with TS exhibited superior control over motor activity when compared with controls, suggesting that their previous cognitive “training” in tic suppression resulted in persistent functional changes. Furthermore, this group had anatomic differences in the white matter of the corpus callosum and forceps minor that correlated with tic severity. Of note, these structures are directly connected to the prefrontal cortex that provides the anatomic substrate for volitional tic suppression. Viewed from the perspective of normal development, the prefrontal cortex is known to be involved in the regulation of motor function. The authors also demonstrate that the right prefrontal cortex has a larger BOLD response during the motor task in which the TS cohort demonstrated better performance.

Taken together, the findings of Dr. Jackson and his associates suggest that the developmental processes by which children learn to control nonvolitional movements are the same that are used to compensate for the excessive motor overflow that characterizes TS. The implications for treatment of both developmental disorders and acquired injury to the nervous system may be profound if existing mechanisms that mediate normal development can be used as part of specific therapeutic regimens.

DR. BUCHHALTER is chief of pediatric neurology and director of the comprehensive pediatric epilepsy program at Phoenix Children's Hospital.

JEFFREY R. BUCHHALTER, M.D., PH.D.

LOS ANGELES – Efforts to develop a drug to enhance poststroke recovery yielded promising results in a recent study in mice.

Dr. Marion Buckwalter of Stanford (Calif.) University and her colleagues found that a synthetic compound that mimics the positive effects of brain-derived neurotrophic factor (BDNF) significantly improved motor function and increased neurogenesis in mice when given 3 days after a stroke.

“An ideal pro-recovery agent would be something that didn't need to be given within the first 3 or 4.5 or 6 hours but could be given days after a stroke,” Dr. Buckwalter said at the conference, sponsored by the American Heart Association.

Although little is known about how the brain recovers from stroke at cellular and molecular levels, Dr. Buckwalter said the process “might include neurogenesis, the formation of new connections between neurons, and the strengthening of existing, useful synapses.”

BDNF is critical for synaptic plasticity and learning, especially motor learning and memory. It has been shown to be involved in the enlargement of motor maps during learning, in the promotion of neurogenesis, and in axonal and dendritic sprouting.

BDNF binds to two different receptors, TrkB and p75. Activation of TrkB is neuroprotective, promotes neurogenesis and axonal and dendritic sprouting, and is essential for learning and synaptic plasticity; p75 activation is known to increase neuropathic pain.

One of Dr. Buckwalter's coauthors at Stanford, Dr. Frank M. Longo, worked around the problem of p75 activation in an earlier study by designing a compound that would activate only TrkB. Dr. Longo and his associate, Dr. Stephen M. Massa, wrote a computer program that sifted through a library of compounds that might theoretically bind and activate TrkB. They found that one of the compounds in the library, called LM22A-4, activated TrkB without activating other Trk receptors or p75.

In subsequent experiments, Dr. Buckwalter and her associates randomized mice to 10 weeks of daily intranasal administration of LM22A-4 or placebo, beginning 3 days after stroke. They found that after 3 weeks, the compound significantly improved gait accuracy and increased the speed of their use of the contralateral paw, based on ladder and catwalk testing, in comparison with saline-treated mice. These results were comparable to those obtained with sham-treated mice given saline. The rate of neurogenesis of both mature and immature neurons more than doubled in regions near the stroke in mice treated with LM22A-4, compared with saline-treated mice after stroke.

The study was funded by the National Institute for Neurological Disorders and Stroke and the Stanford Stroke Center. Dr. Buckwalter had no relevant financial disclosures. Dr. Longo is the founder of PharmatrophiX, a company focused on the development of small-molecule ligands for neurotrophin receptors.

Advisers' Viewpoint

Unique Targeted Approach

Endogenous growth factor ligands and their receptors have a lot to teach us about physiology, development, and repair mechanisms. Much research has shown that BDNF exerts effects that could be beneficial in a variety of neurologic disease categories, including degenerative, ischemic, and traumatic conditions.

BDNF itself has been an impractical and ineffective agent in the few trials that have utilized it, because of both its inability to cross the blood-brain barrier and its short half life.

The exciting study by Dr. Buckwalter and her colleagues was made possible by Dr. Stephen Massa and his associates' groundbreaking discovery of LM22A-4. They showed that TrkB activation with LM22A-4 resulted in protection against neurodegeneration in in vitro models and against traumatic brain injury in an in vivo model (J. Clin. Invest. 2010;120:1774-85).

Just as Dr. Massa and his colleagues considered what properties a BDNF-like ligand required to achieve practical utility, so too did Dr. Buckwalter and her coauthors consider what clinical parameters would be useful to show that a neurotrophic strategy could enhance clinical outcomes after stroke. The administration of LM22A-4 on day 3 following ischemic injury was one such consideration, although it is premature to extrapolate from mouse models to humans based on that.

While TrkB activation may prevent neurodegeneration and promote neurogenesis, it also appears to be oncogenic (Blood 2009;113:2028-37). Therefore, oncologists are not in search of TrkB activators but rather TrkB inhibitors (Mol. Cancer Ther. 2009;8:1818-27).

Dr. Buckwalter and her coauthors found no evidence of angiogenesis, glial scar formation, or contralateral neurogenesis, which provides some reassurance, but clearly more work is needed.

How soon we might see clinical trials is not clear. To date, there are no drugs with an indication for poststroke recovery that have been approved by the Food and Drug Administration. An agent that promotes recovery on a cellular level but also results in clinical improvement would be a milestone.

SUSANNA HORVATH, M.D., is chief of the neurology service at New York-Presbyterian/Allen Hospital, New York. She has no relevant disclosures.

RICHARD J. CASELLI, M.D., is a professor of neurology at the Mayo Clinic, Scottsdale, Ariz. He has no relevant disclosures.

LOS ANGELES – Efforts to develop a drug to enhance poststroke recovery yielded promising results in a recent study in mice.

Dr. Marion Buckwalter of Stanford (Calif.) University and her colleagues found that a synthetic compound that mimics the positive effects of brain-derived neurotrophic factor (BDNF) significantly improved motor function and increased neurogenesis in mice when given 3 days after a stroke.

“An ideal pro-recovery agent would be something that didn't need to be given within the first 3 or 4.5 or 6 hours but could be given days after a stroke,” Dr. Buckwalter said at the conference, sponsored by the American Heart Association.

Although little is known about how the brain recovers from stroke at cellular and molecular levels, Dr. Buckwalter said the process “might include neurogenesis, the formation of new connections between neurons, and the strengthening of existing, useful synapses.”

BDNF is critical for synaptic plasticity and learning, especially motor learning and memory. It has been shown to be involved in the enlargement of motor maps during learning, in the promotion of neurogenesis, and in axonal and dendritic sprouting.

BDNF binds to two different receptors, TrkB and p75. Activation of TrkB is neuroprotective, promotes neurogenesis and axonal and dendritic sprouting, and is essential for learning and synaptic plasticity; p75 activation is known to increase neuropathic pain.

One of Dr. Buckwalter's coauthors at Stanford, Dr. Frank M. Longo, worked around the problem of p75 activation in an earlier study by designing a compound that would activate only TrkB. Dr. Longo and his associate, Dr. Stephen M. Massa, wrote a computer program that sifted through a library of compounds that might theoretically bind and activate TrkB. They found that one of the compounds in the library, called LM22A-4, activated TrkB without activating other Trk receptors or p75.

In subsequent experiments, Dr. Buckwalter and her associates randomized mice to 10 weeks of daily intranasal administration of LM22A-4 or placebo, beginning 3 days after stroke. They found that after 3 weeks, the compound significantly improved gait accuracy and increased the speed of their use of the contralateral paw, based on ladder and catwalk testing, in comparison with saline-treated mice. These results were comparable to those obtained with sham-treated mice given saline. The rate of neurogenesis of both mature and immature neurons more than doubled in regions near the stroke in mice treated with LM22A-4, compared with saline-treated mice after stroke.

The study was funded by the National Institute for Neurological Disorders and Stroke and the Stanford Stroke Center. Dr. Buckwalter had no relevant financial disclosures. Dr. Longo is the founder of PharmatrophiX, a company focused on the development of small-molecule ligands for neurotrophin receptors.

Advisers' Viewpoint

Unique Targeted Approach

Endogenous growth factor ligands and their receptors have a lot to teach us about physiology, development, and repair mechanisms. Much research has shown that BDNF exerts effects that could be beneficial in a variety of neurologic disease categories, including degenerative, ischemic, and traumatic conditions.

BDNF itself has been an impractical and ineffective agent in the few trials that have utilized it, because of both its inability to cross the blood-brain barrier and its short half life.

The exciting study by Dr. Buckwalter and her colleagues was made possible by Dr. Stephen Massa and his associates' groundbreaking discovery of LM22A-4. They showed that TrkB activation with LM22A-4 resulted in protection against neurodegeneration in in vitro models and against traumatic brain injury in an in vivo model (J. Clin. Invest. 2010;120:1774-85).

Just as Dr. Massa and his colleagues considered what properties a BDNF-like ligand required to achieve practical utility, so too did Dr. Buckwalter and her coauthors consider what clinical parameters would be useful to show that a neurotrophic strategy could enhance clinical outcomes after stroke. The administration of LM22A-4 on day 3 following ischemic injury was one such consideration, although it is premature to extrapolate from mouse models to humans based on that.

While TrkB activation may prevent neurodegeneration and promote neurogenesis, it also appears to be oncogenic (Blood 2009;113:2028-37). Therefore, oncologists are not in search of TrkB activators but rather TrkB inhibitors (Mol. Cancer Ther. 2009;8:1818-27).

Dr. Buckwalter and her coauthors found no evidence of angiogenesis, glial scar formation, or contralateral neurogenesis, which provides some reassurance, but clearly more work is needed.

How soon we might see clinical trials is not clear. To date, there are no drugs with an indication for poststroke recovery that have been approved by the Food and Drug Administration. An agent that promotes recovery on a cellular level but also results in clinical improvement would be a milestone.

SUSANNA HORVATH, M.D., is chief of the neurology service at New York-Presbyterian/Allen Hospital, New York. She has no relevant disclosures.

RICHARD J. CASELLI, M.D., is a professor of neurology at the Mayo Clinic, Scottsdale, Ariz. He has no relevant disclosures.

LOS ANGELES – Efforts to develop a drug to enhance poststroke recovery yielded promising results in a recent study in mice.

Dr. Marion Buckwalter of Stanford (Calif.) University and her colleagues found that a synthetic compound that mimics the positive effects of brain-derived neurotrophic factor (BDNF) significantly improved motor function and increased neurogenesis in mice when given 3 days after a stroke.

“An ideal pro-recovery agent would be something that didn't need to be given within the first 3 or 4.5 or 6 hours but could be given days after a stroke,” Dr. Buckwalter said at the conference, sponsored by the American Heart Association.

Although little is known about how the brain recovers from stroke at cellular and molecular levels, Dr. Buckwalter said the process “might include neurogenesis, the formation of new connections between neurons, and the strengthening of existing, useful synapses.”

BDNF is critical for synaptic plasticity and learning, especially motor learning and memory. It has been shown to be involved in the enlargement of motor maps during learning, in the promotion of neurogenesis, and in axonal and dendritic sprouting.

BDNF binds to two different receptors, TrkB and p75. Activation of TrkB is neuroprotective, promotes neurogenesis and axonal and dendritic sprouting, and is essential for learning and synaptic plasticity; p75 activation is known to increase neuropathic pain.

One of Dr. Buckwalter's coauthors at Stanford, Dr. Frank M. Longo, worked around the problem of p75 activation in an earlier study by designing a compound that would activate only TrkB. Dr. Longo and his associate, Dr. Stephen M. Massa, wrote a computer program that sifted through a library of compounds that might theoretically bind and activate TrkB. They found that one of the compounds in the library, called LM22A-4, activated TrkB without activating other Trk receptors or p75.

In subsequent experiments, Dr. Buckwalter and her associates randomized mice to 10 weeks of daily intranasal administration of LM22A-4 or placebo, beginning 3 days after stroke. They found that after 3 weeks, the compound significantly improved gait accuracy and increased the speed of their use of the contralateral paw, based on ladder and catwalk testing, in comparison with saline-treated mice. These results were comparable to those obtained with sham-treated mice given saline. The rate of neurogenesis of both mature and immature neurons more than doubled in regions near the stroke in mice treated with LM22A-4, compared with saline-treated mice after stroke.

The study was funded by the National Institute for Neurological Disorders and Stroke and the Stanford Stroke Center. Dr. Buckwalter had no relevant financial disclosures. Dr. Longo is the founder of PharmatrophiX, a company focused on the development of small-molecule ligands for neurotrophin receptors.

Advisers' Viewpoint

Unique Targeted Approach

Endogenous growth factor ligands and their receptors have a lot to teach us about physiology, development, and repair mechanisms. Much research has shown that BDNF exerts effects that could be beneficial in a variety of neurologic disease categories, including degenerative, ischemic, and traumatic conditions.

BDNF itself has been an impractical and ineffective agent in the few trials that have utilized it, because of both its inability to cross the blood-brain barrier and its short half life.

The exciting study by Dr. Buckwalter and her colleagues was made possible by Dr. Stephen Massa and his associates' groundbreaking discovery of LM22A-4. They showed that TrkB activation with LM22A-4 resulted in protection against neurodegeneration in in vitro models and against traumatic brain injury in an in vivo model (J. Clin. Invest. 2010;120:1774-85).

Just as Dr. Massa and his colleagues considered what properties a BDNF-like ligand required to achieve practical utility, so too did Dr. Buckwalter and her coauthors consider what clinical parameters would be useful to show that a neurotrophic strategy could enhance clinical outcomes after stroke. The administration of LM22A-4 on day 3 following ischemic injury was one such consideration, although it is premature to extrapolate from mouse models to humans based on that.

While TrkB activation may prevent neurodegeneration and promote neurogenesis, it also appears to be oncogenic (Blood 2009;113:2028-37). Therefore, oncologists are not in search of TrkB activators but rather TrkB inhibitors (Mol. Cancer Ther. 2009;8:1818-27).

Dr. Buckwalter and her coauthors found no evidence of angiogenesis, glial scar formation, or contralateral neurogenesis, which provides some reassurance, but clearly more work is needed.

How soon we might see clinical trials is not clear. To date, there are no drugs with an indication for poststroke recovery that have been approved by the Food and Drug Administration. An agent that promotes recovery on a cellular level but also results in clinical improvement would be a milestone.

SUSANNA HORVATH, M.D., is chief of the neurology service at New York-Presbyterian/Allen Hospital, New York. She has no relevant disclosures.

RICHARD J. CASELLI, M.D., is a professor of neurology at the Mayo Clinic, Scottsdale, Ariz. He has no relevant disclosures.

Investigators for the first time have used electrode recordings of the firing patterns of small clusters of neurons to predict voluntary movement in people more than 1 second before they are even aware of their decision or urge to act.

The experiment, conducted by Dr. Itzhak Fried of the University of California, Los Angeles, and his associates, detected sets of neurons in the supplementary and presupplementary motor areas and the anterior cingulate cortex (ACC) with firing rates that would progressively increase or decrease before the participants had even reported the urge to push a button on a laptop.

The investigators then constructed algorithms that could successfully predict the impending decision to move at a rate of 70% or greater, depending on the location and size of the set of neurons chosen (Neuron 2011;69:548-62).

Dr. Fried and his colleagues recruited 12 patients with drug-refractory epilepsy who had chronic depth electrodes implanted to determine their seizure focus for possible surgical resection. While the patients sat in bed, they watched an analog clock on a laptop computer and were instructed to push a button after at least one rotation of the clock's hand whenever “they felt the urge to do so.” Each time that the individuals pushed the button, called time P, the researchers asked them to indicate where the clock handle had been when they first felt the urge to move, called time W.

The participants reported a mean W time of 193 ms prior to P, but this varied from trial to trial. In the trials, the greatest proportion of neurons that changed their activity before W was located in parts of the medial frontal lobe of the brain: the supplementary motor area (SMA), the pre-SMA, and the dorsal and rostral regions of the ACC. In some of these areas, the researchers observed rises in neuronal firing rates beginning several hundreds to several thousands of milliseconds prior to W, whereas progressive declines in firing rates were recorded in a similar time span prior to W. The number of neurons that changed their firing rate also increased as W approached.

The study data did not indicate that the subjects were cued to respond by the completion of the clock hand's first rotation. To sort out concerns related to potentially inaccurate reporting of W and the subjective nature of its determination, the investigators' manipulated the timing of W either forward or backward in time by fixed amounts or by adjusting its timing by a random amount. These analyses indicated that small temporal shifts in W on the order of 200 ms or less are still compatible with the changes in firing rates seen in recorded neurons and matched what was observed within each participant's trials.

With an algorithm that considered the responses of electrodes to be independent of each other across all participants, Dr. Fried and his associates found that they could predict W on a trial-by-trial basis across all participants. The algorithm could detect changes in the neural activity of 512 neurons in frontal lobe regions 500 ms before W in nearly 90% of the trials. The changes in activity could be detected in more than 70% of trials at 1,000 ms before W.

When the algorithm was constructed on the basis of firing patterns from 256 neurons in the SMA, it detected the neurons' change in activity at 500 ms before W in more than 80% of the trials. In comparison, the change in activity of 256 neurons in the ACC at 500 ms before W could be detected in only 70% of trials.

The research was supported by federal grants, the Klingenstein Fund, the Whitehall Foundation, and a Human Frontiers Science Programs Organization fellowship.

Adviser's Viewpoint

Minding Your Brain's Free Will

Neurologists, physiologists, and philosophers were tossed a hot potato in 1983 with Benjamin Libet, Ph.D., and his colleagues' publication of the first attempt to measure the time of the perception of intent to make a “voluntary” movement (Brain 1983;106:623-42). Called W, it happened about 250 ms prior to the movement itself. They compared this time to the onset of the Bereitschaftspotential or Readiness potential (RP), an EEG potential that had been previously described by Dr. Hans Kornhuber and Dr. Lüder Deecke (Pflugers Arch. Gesamte Physiol. Menschen Tiere 1965;284:1-17). The RP starts about a second prior to movement. This was a shock. It appeared that the brain was preparing to make a “voluntary” movement before the person was aware of it! The experiment has been repeated many times, so there is no disputing the data; the controversy is the interpretation.

In this new paper by Dr. Fried and his colleagues, they have first repeated the experiment using recording from neurons in the brain rather than the EEG. Their finding about the timing of W was similar to all the other experiments. Since the EEG comes from neuronal activity, it should not be a great surprise that they were able to find neurons that changed their activity in the second or so prior to movement. They then took the data one step further. By analyzing a small number of the neurons, they could predict with a high degree of accuracy, prior to W, when a movement would occur. Hence, it appears that the neuronal activity prior to awareness of intention is marching toward the motor command. Recently, our group, led by Ou Bai, Ph.D., has done the same thing using EEG, although not with the same high degree of accuracy (Clin. Neurophysiol. 2011;122:364-72).

So what does this mean? If people have free will in making voluntary movements, doesn't the decision have to be made before the motor command? Here, it looks like the motor command is being made before the “decision.” The situation is actually easy to resolve, but it does involve some careful thinking. The first point to settle is that the mind is generated by the brain; it is not separate from the brain. Most people agree with that, even though it is easy to fall into dualistic thinking. We are our brains; what the brain is doing, we are doing. Hence, it appears that the decision to make a movement, in this circumstance, arises unconsciously. The decision becomes conscious, or at least we have the impression it becomes conscious, just slightly before the movement. The priority is important. That we have the perception of willing before the perception that the movement occurs allows us to draw the conclusion that we are causal in the production of the movement; that is, that we freely willed the movement.

Is this compatible with the idea that we actually have free will? It depends on what that means. If we are our brains, and our brain is choosing to do this without external coercion, then the movement is free. We become aware of this, in fact, only some of the time. Much of the time, we go about our business without worrying whether our movements are freely chosen or not. But, if we think about it, we can appreciate a sense of willing, or intention, that does occur prior to the movement. In fact, the timing of when we can appreciate the upcoming movement may depend on how we interrogate our brain. Dr. Masao Matsuhashi and I showed that if you probe a person, the knowledge that the movement is coming can be earlier than if you ask after the fact when the intention occurred (Eur. J. Neurosci. 2008;28:2344).

All of this has relevance for the clinical practice of neurology. My favorite example in this regard is trying to understand why patients with psychogenic movement disorders believe their movements to be involuntary when they look so voluntary.

MARK HALLETT, M.D., is chief of the Medical Neurology Branch and chief of the Human Motor Control Section of the National Institute for Neurological Disorders and Stroke. He has no relevant disclosures.

Vitals

Investigators for the first time have used electrode recordings of the firing patterns of small clusters of neurons to predict voluntary movement in people more than 1 second before they are even aware of their decision or urge to act.

The experiment, conducted by Dr. Itzhak Fried of the University of California, Los Angeles, and his associates, detected sets of neurons in the supplementary and presupplementary motor areas and the anterior cingulate cortex (ACC) with firing rates that would progressively increase or decrease before the participants had even reported the urge to push a button on a laptop.

The investigators then constructed algorithms that could successfully predict the impending decision to move at a rate of 70% or greater, depending on the location and size of the set of neurons chosen (Neuron 2011;69:548-62).

Dr. Fried and his colleagues recruited 12 patients with drug-refractory epilepsy who had chronic depth electrodes implanted to determine their seizure focus for possible surgical resection. While the patients sat in bed, they watched an analog clock on a laptop computer and were instructed to push a button after at least one rotation of the clock's hand whenever “they felt the urge to do so.” Each time that the individuals pushed the button, called time P, the researchers asked them to indicate where the clock handle had been when they first felt the urge to move, called time W.

The participants reported a mean W time of 193 ms prior to P, but this varied from trial to trial. In the trials, the greatest proportion of neurons that changed their activity before W was located in parts of the medial frontal lobe of the brain: the supplementary motor area (SMA), the pre-SMA, and the dorsal and rostral regions of the ACC. In some of these areas, the researchers observed rises in neuronal firing rates beginning several hundreds to several thousands of milliseconds prior to W, whereas progressive declines in firing rates were recorded in a similar time span prior to W. The number of neurons that changed their firing rate also increased as W approached.

The study data did not indicate that the subjects were cued to respond by the completion of the clock hand's first rotation. To sort out concerns related to potentially inaccurate reporting of W and the subjective nature of its determination, the investigators' manipulated the timing of W either forward or backward in time by fixed amounts or by adjusting its timing by a random amount. These analyses indicated that small temporal shifts in W on the order of 200 ms or less are still compatible with the changes in firing rates seen in recorded neurons and matched what was observed within each participant's trials.

With an algorithm that considered the responses of electrodes to be independent of each other across all participants, Dr. Fried and his associates found that they could predict W on a trial-by-trial basis across all participants. The algorithm could detect changes in the neural activity of 512 neurons in frontal lobe regions 500 ms before W in nearly 90% of the trials. The changes in activity could be detected in more than 70% of trials at 1,000 ms before W.

When the algorithm was constructed on the basis of firing patterns from 256 neurons in the SMA, it detected the neurons' change in activity at 500 ms before W in more than 80% of the trials. In comparison, the change in activity of 256 neurons in the ACC at 500 ms before W could be detected in only 70% of trials.

The research was supported by federal grants, the Klingenstein Fund, the Whitehall Foundation, and a Human Frontiers Science Programs Organization fellowship.

Adviser's Viewpoint

Minding Your Brain's Free Will

Neurologists, physiologists, and philosophers were tossed a hot potato in 1983 with Benjamin Libet, Ph.D., and his colleagues' publication of the first attempt to measure the time of the perception of intent to make a “voluntary” movement (Brain 1983;106:623-42). Called W, it happened about 250 ms prior to the movement itself. They compared this time to the onset of the Bereitschaftspotential or Readiness potential (RP), an EEG potential that had been previously described by Dr. Hans Kornhuber and Dr. Lüder Deecke (Pflugers Arch. Gesamte Physiol. Menschen Tiere 1965;284:1-17). The RP starts about a second prior to movement. This was a shock. It appeared that the brain was preparing to make a “voluntary” movement before the person was aware of it! The experiment has been repeated many times, so there is no disputing the data; the controversy is the interpretation.

In this new paper by Dr. Fried and his colleagues, they have first repeated the experiment using recording from neurons in the brain rather than the EEG. Their finding about the timing of W was similar to all the other experiments. Since the EEG comes from neuronal activity, it should not be a great surprise that they were able to find neurons that changed their activity in the second or so prior to movement. They then took the data one step further. By analyzing a small number of the neurons, they could predict with a high degree of accuracy, prior to W, when a movement would occur. Hence, it appears that the neuronal activity prior to awareness of intention is marching toward the motor command. Recently, our group, led by Ou Bai, Ph.D., has done the same thing using EEG, although not with the same high degree of accuracy (Clin. Neurophysiol. 2011;122:364-72).

So what does this mean? If people have free will in making voluntary movements, doesn't the decision have to be made before the motor command? Here, it looks like the motor command is being made before the “decision.” The situation is actually easy to resolve, but it does involve some careful thinking. The first point to settle is that the mind is generated by the brain; it is not separate from the brain. Most people agree with that, even though it is easy to fall into dualistic thinking. We are our brains; what the brain is doing, we are doing. Hence, it appears that the decision to make a movement, in this circumstance, arises unconsciously. The decision becomes conscious, or at least we have the impression it becomes conscious, just slightly before the movement. The priority is important. That we have the perception of willing before the perception that the movement occurs allows us to draw the conclusion that we are causal in the production of the movement; that is, that we freely willed the movement.

Is this compatible with the idea that we actually have free will? It depends on what that means. If we are our brains, and our brain is choosing to do this without external coercion, then the movement is free. We become aware of this, in fact, only some of the time. Much of the time, we go about our business without worrying whether our movements are freely chosen or not. But, if we think about it, we can appreciate a sense of willing, or intention, that does occur prior to the movement. In fact, the timing of when we can appreciate the upcoming movement may depend on how we interrogate our brain. Dr. Masao Matsuhashi and I showed that if you probe a person, the knowledge that the movement is coming can be earlier than if you ask after the fact when the intention occurred (Eur. J. Neurosci. 2008;28:2344).

All of this has relevance for the clinical practice of neurology. My favorite example in this regard is trying to understand why patients with psychogenic movement disorders believe their movements to be involuntary when they look so voluntary.

MARK HALLETT, M.D., is chief of the Medical Neurology Branch and chief of the Human Motor Control Section of the National Institute for Neurological Disorders and Stroke. He has no relevant disclosures.

Vitals

Investigators for the first time have used electrode recordings of the firing patterns of small clusters of neurons to predict voluntary movement in people more than 1 second before they are even aware of their decision or urge to act.

The experiment, conducted by Dr. Itzhak Fried of the University of California, Los Angeles, and his associates, detected sets of neurons in the supplementary and presupplementary motor areas and the anterior cingulate cortex (ACC) with firing rates that would progressively increase or decrease before the participants had even reported the urge to push a button on a laptop.

The investigators then constructed algorithms that could successfully predict the impending decision to move at a rate of 70% or greater, depending on the location and size of the set of neurons chosen (Neuron 2011;69:548-62).

Dr. Fried and his colleagues recruited 12 patients with drug-refractory epilepsy who had chronic depth electrodes implanted to determine their seizure focus for possible surgical resection. While the patients sat in bed, they watched an analog clock on a laptop computer and were instructed to push a button after at least one rotation of the clock's hand whenever “they felt the urge to do so.” Each time that the individuals pushed the button, called time P, the researchers asked them to indicate where the clock handle had been when they first felt the urge to move, called time W.

The participants reported a mean W time of 193 ms prior to P, but this varied from trial to trial. In the trials, the greatest proportion of neurons that changed their activity before W was located in parts of the medial frontal lobe of the brain: the supplementary motor area (SMA), the pre-SMA, and the dorsal and rostral regions of the ACC. In some of these areas, the researchers observed rises in neuronal firing rates beginning several hundreds to several thousands of milliseconds prior to W, whereas progressive declines in firing rates were recorded in a similar time span prior to W. The number of neurons that changed their firing rate also increased as W approached.

The study data did not indicate that the subjects were cued to respond by the completion of the clock hand's first rotation. To sort out concerns related to potentially inaccurate reporting of W and the subjective nature of its determination, the investigators' manipulated the timing of W either forward or backward in time by fixed amounts or by adjusting its timing by a random amount. These analyses indicated that small temporal shifts in W on the order of 200 ms or less are still compatible with the changes in firing rates seen in recorded neurons and matched what was observed within each participant's trials.

With an algorithm that considered the responses of electrodes to be independent of each other across all participants, Dr. Fried and his associates found that they could predict W on a trial-by-trial basis across all participants. The algorithm could detect changes in the neural activity of 512 neurons in frontal lobe regions 500 ms before W in nearly 90% of the trials. The changes in activity could be detected in more than 70% of trials at 1,000 ms before W.

When the algorithm was constructed on the basis of firing patterns from 256 neurons in the SMA, it detected the neurons' change in activity at 500 ms before W in more than 80% of the trials. In comparison, the change in activity of 256 neurons in the ACC at 500 ms before W could be detected in only 70% of trials.

The research was supported by federal grants, the Klingenstein Fund, the Whitehall Foundation, and a Human Frontiers Science Programs Organization fellowship.

Adviser's Viewpoint

Minding Your Brain's Free Will

Neurologists, physiologists, and philosophers were tossed a hot potato in 1983 with Benjamin Libet, Ph.D., and his colleagues' publication of the first attempt to measure the time of the perception of intent to make a “voluntary” movement (Brain 1983;106:623-42). Called W, it happened about 250 ms prior to the movement itself. They compared this time to the onset of the Bereitschaftspotential or Readiness potential (RP), an EEG potential that had been previously described by Dr. Hans Kornhuber and Dr. Lüder Deecke (Pflugers Arch. Gesamte Physiol. Menschen Tiere 1965;284:1-17). The RP starts about a second prior to movement. This was a shock. It appeared that the brain was preparing to make a “voluntary” movement before the person was aware of it! The experiment has been repeated many times, so there is no disputing the data; the controversy is the interpretation.

In this new paper by Dr. Fried and his colleagues, they have first repeated the experiment using recording from neurons in the brain rather than the EEG. Their finding about the timing of W was similar to all the other experiments. Since the EEG comes from neuronal activity, it should not be a great surprise that they were able to find neurons that changed their activity in the second or so prior to movement. They then took the data one step further. By analyzing a small number of the neurons, they could predict with a high degree of accuracy, prior to W, when a movement would occur. Hence, it appears that the neuronal activity prior to awareness of intention is marching toward the motor command. Recently, our group, led by Ou Bai, Ph.D., has done the same thing using EEG, although not with the same high degree of accuracy (Clin. Neurophysiol. 2011;122:364-72).

So what does this mean? If people have free will in making voluntary movements, doesn't the decision have to be made before the motor command? Here, it looks like the motor command is being made before the “decision.” The situation is actually easy to resolve, but it does involve some careful thinking. The first point to settle is that the mind is generated by the brain; it is not separate from the brain. Most people agree with that, even though it is easy to fall into dualistic thinking. We are our brains; what the brain is doing, we are doing. Hence, it appears that the decision to make a movement, in this circumstance, arises unconsciously. The decision becomes conscious, or at least we have the impression it becomes conscious, just slightly before the movement. The priority is important. That we have the perception of willing before the perception that the movement occurs allows us to draw the conclusion that we are causal in the production of the movement; that is, that we freely willed the movement.

Is this compatible with the idea that we actually have free will? It depends on what that means. If we are our brains, and our brain is choosing to do this without external coercion, then the movement is free. We become aware of this, in fact, only some of the time. Much of the time, we go about our business without worrying whether our movements are freely chosen or not. But, if we think about it, we can appreciate a sense of willing, or intention, that does occur prior to the movement. In fact, the timing of when we can appreciate the upcoming movement may depend on how we interrogate our brain. Dr. Masao Matsuhashi and I showed that if you probe a person, the knowledge that the movement is coming can be earlier than if you ask after the fact when the intention occurred (Eur. J. Neurosci. 2008;28:2344).

All of this has relevance for the clinical practice of neurology. My favorite example in this regard is trying to understand why patients with psychogenic movement disorders believe their movements to be involuntary when they look so voluntary.

MARK HALLETT, M.D., is chief of the Medical Neurology Branch and chief of the Human Motor Control Section of the National Institute for Neurological Disorders and Stroke. He has no relevant disclosures.

Vitals

Primary and secondary prevention measures for children at risk for idiopathic arterial ischemic stroke need to target disease mechanisms unique to nonatherosclerotic arteriopathies, according to pediatric stroke researchers.

Risk factors, signs, and symptoms differ for arterial ischemic stroke (AIS) in adults and children. Early recognition of factors unique to at-risk children can prompt the initiation of prophylactic treatment with antiplatelet drugs, anti-inflammatory drugs, and anticoagulants when thrombosis and inflammation play important roles in the pathogenesis, Dr. Pinki Munot of Great Ormond Street Hospital for Children NHS Trust, London, and coauthors wrote in a review (Lancet Neurol. 2011;10:264-74).

Many of these arteriopathies appear to be caused by single-gene mutations that affect various parts of an artery’s structure at different points in its development, homeostasis, or response to environmental stress, offering a range of different targets for research.

To detect the underlying genetic disorder, Dr. Munot and colleagues advised asking about clinical history of stroke, migraine, porencephaly, learning difficulties, and static motor disorders, and to look for disease in vascular beds outside the brain. They recommended pursuing genetic investigations only in patients with cerebrovascular and noncerebrovascular features that are suggestive of a genetic cause.

Dr. Munot and colleagues described how single-gene mutations contribute to known phenotypes described in various pediatric cerebral arteriopathies (not including inherited metabolic disorders).

Abnormalities in Vascular Development

The deletion of a region of chromosome 7 that contains the gene for elastin (ELN) causes Williams-Beuren syndrome. Arteriopathy in most cases of the syndrome (70%) results in supravalvular aortic stenosis but can involve other vascular beds, and causes an overgrowth of smooth-muscle cells. Occlusive disease most often results from the overgrowth of smooth-muscle cells caused by the lack of elastin; aneurysmal disease has not been reported.

ACTA2, the gene for a member of the highly-conserved actin proteins, actin alpha 2, codes for a main contractile protein in vascular smooth-muscle cells. Mutations affecting it result in dysfunctional smooth-muscle cell contraction and the proliferation of smooth-muscle cells that occlude smaller arteries but appear to make larger arteries vulnerable to aneurysmal disease. A diverse number of vascular beds can be involved, which is most noticeable in the fact that all mutation carriers have livedo reticularis.

Abnormal Vascular Homeostasis and Remodeling

The Notch signaling pathway is essential in determining the differentiation of smooth-muscle cells and their response to vascular injury. Mutations in NOTCH3 and JAG1 genes affect this pathway.

NOTCH3 mutations lead to arterial wall thickening and stenosis in mostly small vessels in the condition called CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). Most reports of cerebral infarction have been reported in adults but might be underrecognized in childhood.

The jagged-1 surface protein encoded by JAG1 is mutated in nearly 90% of individuals with Alagille syndrome. Individuals with this syndrome appear to harbor abnormally thin-walled vessels with myointimal hyperplasia of the vascular wall. Occlusive and aneurysmal arterial disease observed in the syndrome are associated with ischemic and hemorrhagic strokes.

Dysregulation of transforming growth factor beta (TGF-beta) signaling caused by mutations in the gene coding for HtrA serine peptidase-1, HTRA1, is known to result in the condition called CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy). The disease causes a dysfunction in vascular homeostasis, resulting in diseased cerebral small arteries, which usually arises in adulthood. They show arteriosclerosis with intimal thickening and dense collagen fibers, loss of vascular smooth-muscle cells, and hyaline degeneration in arterial media. Other features of CARASIL such as alopecia can begin in adolescence. Mutations in genes for TGF-beta receptors, TGFBR1 and TGFBR2, cause Loeys-Dietz syndrome, which is characterized by arterial tortuosity and large-vessel, noncerebrovascular aneurysmal disease. In arterial tortuosity syndrome, the loss of function of a facilitative glucose transporter encoded by SLC2A10 (or GLUT10) leads to defective collagen, elastin, or both, and activates TGF-beta as a secondary response to a defective extracellular matrix.

Abnormal vascular homeostasis in pseudoxanthoma elasticum, caused by a mutated ABCC6 gene, leads to a calcification of elastic fibers and might be seen with cutaneous signs in childhood, although it is most often diagnosed in teenagers and individuals in their 20s when AIS and peripheral vascular disease become prominent.

Persons with mutations in the pericentrin gene PCNT that cause the autosomal recessive disorder microcephalic osteodysplastic primordial dwarfism type II (MOPD II) have an emergent and progressive cerebrovascular disease in childhood such as moyamoya syndrome and, less often, aneurysmal disease that support a role of the centrosomal protein pericentrin in vascular homeostasis. The mutations also cause vascular disease in many areas outside of the cerebral circulation in individuals with MOPD II, which is characterized by microcephaly, pre- and postnatal growth failure, skeletal dysplasia, and dysmorphism.

The rare, nonatheromatous arteriopathy called moyamoya usually causes bilateral occlusive disease of the terminal internal carotid arteries and is considered one of the most severe childhood cerebral arteriopathies. The overproliferation of smooth-muscle cells in the syndrome, with colocalization of inflammatory cells such as macrophages and T cells, is "probably genetically mediated," according to Dr. Munot and associates. But genotype-phenotype correlations have been difficult because of varying degrees of precision used to describe moyamoya in the literature. Most cases of idiopathic disease or secondary syndrome appear to be sporadic, based on a familial rate of 10%-15% of cases in Japan and in about 6% of cases in the United States.

"Identification of single-gene disorders associated with moyamoya might lead to a better understanding of childhood cerebral arteriopathy," Dr. Munot and colleagues wrote, because the disorder "often represents one aspect of a more diffuse arteriopathy."

Abnormal Response to Injury

Stroke phenotypes in some single-gene disorders have been associated with physical trauma to the head or neck, abnormal inflammatory response, or oxidative injury.

A wide range of phenotypes has been associated with mutations in the gene that encodes the alpha-1 chain of type IV collagen, COL4A1. It reduces the stability of vascular basement membranes and can lead to idiopathic small-vessel disease in children, including occlusive and aneurysmal cerebral arteriopathies associated with ischemic and hemorrhagic stroke phenotypes. Cerebral hemorrhage in individuals with COL4A1 mutations might be associated with trauma, based on a study that identified trauma to the head or neck in the preceding 2 weeks as a risk factor in previously healthy children.

A mutated form of SAMHD1 is one of five genes that have been associated with the encephalopathic syndrome called Aicardi-Goutières. Children with this mutation had cerebral arteriopathy with either occlusive or aneurysmal features, peripheral vascular disease, which shows that "as with ACTA2-related disease, the skin can indicate the presence of cerebrovascular disease." Some patients with SAMHD1 mutations have had evidence of arterial inflammation or systemic inflammatory disease.

Excessive smooth-muscle cell proliferation and vascular occlusion occur in individuals with neurofibromatosis type 1 (NF1), which is caused by mutations in the NF1 tumor-suppressor gene. NF1 normally inhibits activity of the Ras signaling pathway, but its disinhibition results in intimal proliferation, smooth-muscle nodules, and fibrosis of the vascular media and adventitia. About 6% of children with NF1 have diffuse cerebral arteriopathy with features of occlusive and aneurysmal disease. Evidence suggests that chronic inflammation is an important factor in NF1 arteriopathy, but the trigger for this unclear, Dr. Munot and coauthors wrote.

Mutations in ATP7A, which occur in X-linked recessive Menkes disease (also known as kinky-hair syndrome), affect copper transport. These individuals have "sparse and friable hair" and present with varying phenotypes and degrees of severity. The disorder mainly causes connective-tissue abnormalities but can cause a progressive neurodegenerative disorder that results in death in infancy. Ischemic and hemorrhagic stroke, structural abnormalities in cerebral arteries, oxidative injury, and energy failure have been reported with the vascular phenotype.

Accumulation of Abnormal Metabolites

The X-linked lysosomal storage disorder called Fabry’s disease is caused by a deficiency of alpha-galactosidase that arises from mutations in the GLA gene that encodes the enzyme. The metabolite globotriaosylceramide builds up in vascular endothelium, causing injury and progressive arteriopathy in large and small vessels. About 40% of hemizygous men develop stroke with vessel ectasia.

The autosomal recessive disorder homocystinuria leads to a deficiency in cystathione-beta synthase and an increased risk of stroke and abnormal blood clots. These effects of hyperhomocysteinemia are suspected to occur through a dysfunction of the vascular endothelium and procoagulation effects.

The authors had no financial conflicts to report.

Primary and secondary prevention measures for children at risk for idiopathic arterial ischemic stroke need to target disease mechanisms unique to nonatherosclerotic arteriopathies, according to pediatric stroke researchers.

Risk factors, signs, and symptoms differ for arterial ischemic stroke (AIS) in adults and children. Early recognition of factors unique to at-risk children can prompt the initiation of prophylactic treatment with antiplatelet drugs, anti-inflammatory drugs, and anticoagulants when thrombosis and inflammation play important roles in the pathogenesis, Dr. Pinki Munot of Great Ormond Street Hospital for Children NHS Trust, London, and coauthors wrote in a review (Lancet Neurol. 2011;10:264-74).

Many of these arteriopathies appear to be caused by single-gene mutations that affect various parts of an artery’s structure at different points in its development, homeostasis, or response to environmental stress, offering a range of different targets for research.

To detect the underlying genetic disorder, Dr. Munot and colleagues advised asking about clinical history of stroke, migraine, porencephaly, learning difficulties, and static motor disorders, and to look for disease in vascular beds outside the brain. They recommended pursuing genetic investigations only in patients with cerebrovascular and noncerebrovascular features that are suggestive of a genetic cause.

Dr. Munot and colleagues described how single-gene mutations contribute to known phenotypes described in various pediatric cerebral arteriopathies (not including inherited metabolic disorders).

Abnormalities in Vascular Development

The deletion of a region of chromosome 7 that contains the gene for elastin (ELN) causes Williams-Beuren syndrome. Arteriopathy in most cases of the syndrome (70%) results in supravalvular aortic stenosis but can involve other vascular beds, and causes an overgrowth of smooth-muscle cells. Occlusive disease most often results from the overgrowth of smooth-muscle cells caused by the lack of elastin; aneurysmal disease has not been reported.

ACTA2, the gene for a member of the highly-conserved actin proteins, actin alpha 2, codes for a main contractile protein in vascular smooth-muscle cells. Mutations affecting it result in dysfunctional smooth-muscle cell contraction and the proliferation of smooth-muscle cells that occlude smaller arteries but appear to make larger arteries vulnerable to aneurysmal disease. A diverse number of vascular beds can be involved, which is most noticeable in the fact that all mutation carriers have livedo reticularis.

Abnormal Vascular Homeostasis and Remodeling

The Notch signaling pathway is essential in determining the differentiation of smooth-muscle cells and their response to vascular injury. Mutations in NOTCH3 and JAG1 genes affect this pathway.

NOTCH3 mutations lead to arterial wall thickening and stenosis in mostly small vessels in the condition called CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). Most reports of cerebral infarction have been reported in adults but might be underrecognized in childhood.

The jagged-1 surface protein encoded by JAG1 is mutated in nearly 90% of individuals with Alagille syndrome. Individuals with this syndrome appear to harbor abnormally thin-walled vessels with myointimal hyperplasia of the vascular wall. Occlusive and aneurysmal arterial disease observed in the syndrome are associated with ischemic and hemorrhagic strokes.

Dysregulation of transforming growth factor beta (TGF-beta) signaling caused by mutations in the gene coding for HtrA serine peptidase-1, HTRA1, is known to result in the condition called CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy). The disease causes a dysfunction in vascular homeostasis, resulting in diseased cerebral small arteries, which usually arises in adulthood. They show arteriosclerosis with intimal thickening and dense collagen fibers, loss of vascular smooth-muscle cells, and hyaline degeneration in arterial media. Other features of CARASIL such as alopecia can begin in adolescence. Mutations in genes for TGF-beta receptors, TGFBR1 and TGFBR2, cause Loeys-Dietz syndrome, which is characterized by arterial tortuosity and large-vessel, noncerebrovascular aneurysmal disease. In arterial tortuosity syndrome, the loss of function of a facilitative glucose transporter encoded by SLC2A10 (or GLUT10) leads to defective collagen, elastin, or both, and activates TGF-beta as a secondary response to a defective extracellular matrix.

Abnormal vascular homeostasis in pseudoxanthoma elasticum, caused by a mutated ABCC6 gene, leads to a calcification of elastic fibers and might be seen with cutaneous signs in childhood, although it is most often diagnosed in teenagers and individuals in their 20s when AIS and peripheral vascular disease become prominent.

Persons with mutations in the pericentrin gene PCNT that cause the autosomal recessive disorder microcephalic osteodysplastic primordial dwarfism type II (MOPD II) have an emergent and progressive cerebrovascular disease in childhood such as moyamoya syndrome and, less often, aneurysmal disease that support a role of the centrosomal protein pericentrin in vascular homeostasis. The mutations also cause vascular disease in many areas outside of the cerebral circulation in individuals with MOPD II, which is characterized by microcephaly, pre- and postnatal growth failure, skeletal dysplasia, and dysmorphism.

The rare, nonatheromatous arteriopathy called moyamoya usually causes bilateral occlusive disease of the terminal internal carotid arteries and is considered one of the most severe childhood cerebral arteriopathies. The overproliferation of smooth-muscle cells in the syndrome, with colocalization of inflammatory cells such as macrophages and T cells, is "probably genetically mediated," according to Dr. Munot and associates. But genotype-phenotype correlations have been difficult because of varying degrees of precision used to describe moyamoya in the literature. Most cases of idiopathic disease or secondary syndrome appear to be sporadic, based on a familial rate of 10%-15% of cases in Japan and in about 6% of cases in the United States.

"Identification of single-gene disorders associated with moyamoya might lead to a better understanding of childhood cerebral arteriopathy," Dr. Munot and colleagues wrote, because the disorder "often represents one aspect of a more diffuse arteriopathy."

Abnormal Response to Injury

Stroke phenotypes in some single-gene disorders have been associated with physical trauma to the head or neck, abnormal inflammatory response, or oxidative injury.

A wide range of phenotypes has been associated with mutations in the gene that encodes the alpha-1 chain of type IV collagen, COL4A1. It reduces the stability of vascular basement membranes and can lead to idiopathic small-vessel disease in children, including occlusive and aneurysmal cerebral arteriopathies associated with ischemic and hemorrhagic stroke phenotypes. Cerebral hemorrhage in individuals with COL4A1 mutations might be associated with trauma, based on a study that identified trauma to the head or neck in the preceding 2 weeks as a risk factor in previously healthy children.

A mutated form of SAMHD1 is one of five genes that have been associated with the encephalopathic syndrome called Aicardi-Goutières. Children with this mutation had cerebral arteriopathy with either occlusive or aneurysmal features, peripheral vascular disease, which shows that "as with ACTA2-related disease, the skin can indicate the presence of cerebrovascular disease." Some patients with SAMHD1 mutations have had evidence of arterial inflammation or systemic inflammatory disease.

Excessive smooth-muscle cell proliferation and vascular occlusion occur in individuals with neurofibromatosis type 1 (NF1), which is caused by mutations in the NF1 tumor-suppressor gene. NF1 normally inhibits activity of the Ras signaling pathway, but its disinhibition results in intimal proliferation, smooth-muscle nodules, and fibrosis of the vascular media and adventitia. About 6% of children with NF1 have diffuse cerebral arteriopathy with features of occlusive and aneurysmal disease. Evidence suggests that chronic inflammation is an important factor in NF1 arteriopathy, but the trigger for this unclear, Dr. Munot and coauthors wrote.

Mutations in ATP7A, which occur in X-linked recessive Menkes disease (also known as kinky-hair syndrome), affect copper transport. These individuals have "sparse and friable hair" and present with varying phenotypes and degrees of severity. The disorder mainly causes connective-tissue abnormalities but can cause a progressive neurodegenerative disorder that results in death in infancy. Ischemic and hemorrhagic stroke, structural abnormalities in cerebral arteries, oxidative injury, and energy failure have been reported with the vascular phenotype.

Accumulation of Abnormal Metabolites

The X-linked lysosomal storage disorder called Fabry’s disease is caused by a deficiency of alpha-galactosidase that arises from mutations in the GLA gene that encodes the enzyme. The metabolite globotriaosylceramide builds up in vascular endothelium, causing injury and progressive arteriopathy in large and small vessels. About 40% of hemizygous men develop stroke with vessel ectasia.

The autosomal recessive disorder homocystinuria leads to a deficiency in cystathione-beta synthase and an increased risk of stroke and abnormal blood clots. These effects of hyperhomocysteinemia are suspected to occur through a dysfunction of the vascular endothelium and procoagulation effects.

The authors had no financial conflicts to report.

Primary and secondary prevention measures for children at risk for idiopathic arterial ischemic stroke need to target disease mechanisms unique to nonatherosclerotic arteriopathies, according to pediatric stroke researchers.

Risk factors, signs, and symptoms differ for arterial ischemic stroke (AIS) in adults and children. Early recognition of factors unique to at-risk children can prompt the initiation of prophylactic treatment with antiplatelet drugs, anti-inflammatory drugs, and anticoagulants when thrombosis and inflammation play important roles in the pathogenesis, Dr. Pinki Munot of Great Ormond Street Hospital for Children NHS Trust, London, and coauthors wrote in a review (Lancet Neurol. 2011;10:264-74).

Many of these arteriopathies appear to be caused by single-gene mutations that affect various parts of an artery’s structure at different points in its development, homeostasis, or response to environmental stress, offering a range of different targets for research.

To detect the underlying genetic disorder, Dr. Munot and colleagues advised asking about clinical history of stroke, migraine, porencephaly, learning difficulties, and static motor disorders, and to look for disease in vascular beds outside the brain. They recommended pursuing genetic investigations only in patients with cerebrovascular and noncerebrovascular features that are suggestive of a genetic cause.

Dr. Munot and colleagues described how single-gene mutations contribute to known phenotypes described in various pediatric cerebral arteriopathies (not including inherited metabolic disorders).

Abnormalities in Vascular Development

The deletion of a region of chromosome 7 that contains the gene for elastin (ELN) causes Williams-Beuren syndrome. Arteriopathy in most cases of the syndrome (70%) results in supravalvular aortic stenosis but can involve other vascular beds, and causes an overgrowth of smooth-muscle cells. Occlusive disease most often results from the overgrowth of smooth-muscle cells caused by the lack of elastin; aneurysmal disease has not been reported.

ACTA2, the gene for a member of the highly-conserved actin proteins, actin alpha 2, codes for a main contractile protein in vascular smooth-muscle cells. Mutations affecting it result in dysfunctional smooth-muscle cell contraction and the proliferation of smooth-muscle cells that occlude smaller arteries but appear to make larger arteries vulnerable to aneurysmal disease. A diverse number of vascular beds can be involved, which is most noticeable in the fact that all mutation carriers have livedo reticularis.

Abnormal Vascular Homeostasis and Remodeling

The Notch signaling pathway is essential in determining the differentiation of smooth-muscle cells and their response to vascular injury. Mutations in NOTCH3 and JAG1 genes affect this pathway.

NOTCH3 mutations lead to arterial wall thickening and stenosis in mostly small vessels in the condition called CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). Most reports of cerebral infarction have been reported in adults but might be underrecognized in childhood.

The jagged-1 surface protein encoded by JAG1 is mutated in nearly 90% of individuals with Alagille syndrome. Individuals with this syndrome appear to harbor abnormally thin-walled vessels with myointimal hyperplasia of the vascular wall. Occlusive and aneurysmal arterial disease observed in the syndrome are associated with ischemic and hemorrhagic strokes.

Dysregulation of transforming growth factor beta (TGF-beta) signaling caused by mutations in the gene coding for HtrA serine peptidase-1, HTRA1, is known to result in the condition called CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy). The disease causes a dysfunction in vascular homeostasis, resulting in diseased cerebral small arteries, which usually arises in adulthood. They show arteriosclerosis with intimal thickening and dense collagen fibers, loss of vascular smooth-muscle cells, and hyaline degeneration in arterial media. Other features of CARASIL such as alopecia can begin in adolescence. Mutations in genes for TGF-beta receptors, TGFBR1 and TGFBR2, cause Loeys-Dietz syndrome, which is characterized by arterial tortuosity and large-vessel, noncerebrovascular aneurysmal disease. In arterial tortuosity syndrome, the loss of function of a facilitative glucose transporter encoded by SLC2A10 (or GLUT10) leads to defective collagen, elastin, or both, and activates TGF-beta as a secondary response to a defective extracellular matrix.

Abnormal vascular homeostasis in pseudoxanthoma elasticum, caused by a mutated ABCC6 gene, leads to a calcification of elastic fibers and might be seen with cutaneous signs in childhood, although it is most often diagnosed in teenagers and individuals in their 20s when AIS and peripheral vascular disease become prominent.

Persons with mutations in the pericentrin gene PCNT that cause the autosomal recessive disorder microcephalic osteodysplastic primordial dwarfism type II (MOPD II) have an emergent and progressive cerebrovascular disease in childhood such as moyamoya syndrome and, less often, aneurysmal disease that support a role of the centrosomal protein pericentrin in vascular homeostasis. The mutations also cause vascular disease in many areas outside of the cerebral circulation in individuals with MOPD II, which is characterized by microcephaly, pre- and postnatal growth failure, skeletal dysplasia, and dysmorphism.

The rare, nonatheromatous arteriopathy called moyamoya usually causes bilateral occlusive disease of the terminal internal carotid arteries and is considered one of the most severe childhood cerebral arteriopathies. The overproliferation of smooth-muscle cells in the syndrome, with colocalization of inflammatory cells such as macrophages and T cells, is "probably genetically mediated," according to Dr. Munot and associates. But genotype-phenotype correlations have been difficult because of varying degrees of precision used to describe moyamoya in the literature. Most cases of idiopathic disease or secondary syndrome appear to be sporadic, based on a familial rate of 10%-15% of cases in Japan and in about 6% of cases in the United States.

"Identification of single-gene disorders associated with moyamoya might lead to a better understanding of childhood cerebral arteriopathy," Dr. Munot and colleagues wrote, because the disorder "often represents one aspect of a more diffuse arteriopathy."

Abnormal Response to Injury

Stroke phenotypes in some single-gene disorders have been associated with physical trauma to the head or neck, abnormal inflammatory response, or oxidative injury.

A wide range of phenotypes has been associated with mutations in the gene that encodes the alpha-1 chain of type IV collagen, COL4A1. It reduces the stability of vascular basement membranes and can lead to idiopathic small-vessel disease in children, including occlusive and aneurysmal cerebral arteriopathies associated with ischemic and hemorrhagic stroke phenotypes. Cerebral hemorrhage in individuals with COL4A1 mutations might be associated with trauma, based on a study that identified trauma to the head or neck in the preceding 2 weeks as a risk factor in previously healthy children.

A mutated form of SAMHD1 is one of five genes that have been associated with the encephalopathic syndrome called Aicardi-Goutières. Children with this mutation had cerebral arteriopathy with either occlusive or aneurysmal features, peripheral vascular disease, which shows that "as with ACTA2-related disease, the skin can indicate the presence of cerebrovascular disease." Some patients with SAMHD1 mutations have had evidence of arterial inflammation or systemic inflammatory disease.

Excessive smooth-muscle cell proliferation and vascular occlusion occur in individuals with neurofibromatosis type 1 (NF1), which is caused by mutations in the NF1 tumor-suppressor gene. NF1 normally inhibits activity of the Ras signaling pathway, but its disinhibition results in intimal proliferation, smooth-muscle nodules, and fibrosis of the vascular media and adventitia. About 6% of children with NF1 have diffuse cerebral arteriopathy with features of occlusive and aneurysmal disease. Evidence suggests that chronic inflammation is an important factor in NF1 arteriopathy, but the trigger for this unclear, Dr. Munot and coauthors wrote.

Mutations in ATP7A, which occur in X-linked recessive Menkes disease (also known as kinky-hair syndrome), affect copper transport. These individuals have "sparse and friable hair" and present with varying phenotypes and degrees of severity. The disorder mainly causes connective-tissue abnormalities but can cause a progressive neurodegenerative disorder that results in death in infancy. Ischemic and hemorrhagic stroke, structural abnormalities in cerebral arteries, oxidative injury, and energy failure have been reported with the vascular phenotype.

Accumulation of Abnormal Metabolites

The X-linked lysosomal storage disorder called Fabry’s disease is caused by a deficiency of alpha-galactosidase that arises from mutations in the GLA gene that encodes the enzyme. The metabolite globotriaosylceramide builds up in vascular endothelium, causing injury and progressive arteriopathy in large and small vessels. About 40% of hemizygous men develop stroke with vessel ectasia.

The autosomal recessive disorder homocystinuria leads to a deficiency in cystathione-beta synthase and an increased risk of stroke and abnormal blood clots. These effects of hyperhomocysteinemia are suspected to occur through a dysfunction of the vascular endothelium and procoagulation effects.

The authors had no financial conflicts to report.

Primary and secondary prevention measures for children at risk for idiopathic arterial ischemic stroke need to target disease mechanisms unique to nonatherosclerotic arteriopathies, according to pediatric stroke researchers.

Risk factors, signs, and symptoms differ for arterial ischemic stroke (AIS) in adults and children. Early recognition of factors unique to at-risk children can prompt the initiation of prophylactic treatment with antiplatelet drugs, anti-inflammatory drugs, and anticoagulants when thrombosis and inflammation play important roles in the pathogenesis, Dr. Pinki Munot of Great Ormond Street Hospital for Children NHS Trust, London, and coauthors wrote in a review (Lancet Neurol. 2011;10:264-74).

Many of these arteriopathies appear to be caused by single-gene mutations that affect various parts of an artery’s structure at different points in its development, homeostasis, or response to environmental stress, offering a range of different targets for research.

To detect the underlying genetic disorder, Dr. Munot and colleagues advised asking about clinical history of stroke, migraine, porencephaly, learning difficulties, and static motor disorders, and to look for disease in vascular beds outside the brain. They recommended pursuing genetic investigations only in patients with cerebrovascular and noncerebrovascular features that are suggestive of a genetic cause.

Dr. Munot and colleagues described how single-gene mutations contribute to known phenotypes described in various pediatric cerebral arteriopathies (not including inherited metabolic disorders).

Abnormalities in Vascular Development

The deletion of a region of chromosome 7 that contains the gene for elastin (ELN) causes Williams-Beuren syndrome. Arteriopathy in most cases of the syndrome (70%) results in supravalvular aortic stenosis but can involve other vascular beds, and causes an overgrowth of smooth-muscle cells. Occlusive disease most often results from the overgrowth of smooth-muscle cells caused by the lack of elastin; aneurysmal disease has not been reported.

ACTA2, the gene for a member of the highly-conserved actin proteins, actin alpha 2, codes for a main contractile protein in vascular smooth-muscle cells. Mutations affecting it result in dysfunctional smooth-muscle cell contraction and the proliferation of smooth-muscle cells that occlude smaller arteries but appear to make larger arteries vulnerable to aneurysmal disease. A diverse number of vascular beds can be involved, which is most noticeable in the fact that all mutation carriers have livedo reticularis.

Abnormal Vascular Homeostasis and Remodeling

The Notch signaling pathway is essential in determining the differentiation of smooth-muscle cells and their response to vascular injury. Mutations in NOTCH3 and JAG1 genes affect this pathway.

NOTCH3 mutations lead to arterial wall thickening and stenosis in mostly small vessels in the condition called CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). Most reports of cerebral infarction have been reported in adults but might be underrecognized in childhood.

The jagged-1 surface protein encoded by JAG1 is mutated in nearly 90% of individuals with Alagille syndrome. Individuals with this syndrome appear to harbor abnormally thin-walled vessels with myointimal hyperplasia of the vascular wall. Occlusive and aneurysmal arterial disease observed in the syndrome are associated with ischemic and hemorrhagic strokes.

Dysregulation of transforming growth factor beta (TGF-beta) signaling caused by mutations in the gene coding for HtrA serine peptidase-1, HTRA1, is known to result in the condition called CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy). The disease causes a dysfunction in vascular homeostasis, resulting in diseased cerebral small arteries, which usually arises in adulthood. They show arteriosclerosis with intimal thickening and dense collagen fibers, loss of vascular smooth-muscle cells, and hyaline degeneration in arterial media. Other features of CARASIL such as alopecia can begin in adolescence. Mutations in genes for TGF-beta receptors, TGFBR1 and TGFBR2, cause Loeys-Dietz syndrome, which is characterized by arterial tortuosity and large-vessel, noncerebrovascular aneurysmal disease. In arterial tortuosity syndrome, the loss of function of a facilitative glucose transporter encoded by SLC2A10 (or GLUT10) leads to defective collagen, elastin, or both, and activates TGF-beta as a secondary response to a defective extracellular matrix.

Abnormal vascular homeostasis in pseudoxanthoma elasticum, caused by a mutated ABCC6 gene, leads to a calcification of elastic fibers and might be seen with cutaneous signs in childhood, although it is most often diagnosed in teenagers and individuals in their 20s when AIS and peripheral vascular disease become prominent.

Persons with mutations in the pericentrin gene PCNT that cause the autosomal recessive disorder microcephalic osteodysplastic primordial dwarfism type II (MOPD II) have an emergent and progressive cerebrovascular disease in childhood such as moyamoya syndrome and, less often, aneurysmal disease that support a role of the centrosomal protein pericentrin in vascular homeostasis. The mutations also cause vascular disease in many areas outside of the cerebral circulation in individuals with MOPD II, which is characterized by microcephaly, pre- and postnatal growth failure, skeletal dysplasia, and dysmorphism.

The rare, nonatheromatous arteriopathy called moyamoya usually causes bilateral occlusive disease of the terminal internal carotid arteries and is considered one of the most severe childhood cerebral arteriopathies. The overproliferation of smooth-muscle cells in the syndrome, with colocalization of inflammatory cells such as macrophages and T cells, is "probably genetically mediated," according to Dr. Munot and associates. But genotype-phenotype correlations have been difficult because of varying degrees of precision used to describe moyamoya in the literature. Most cases of idiopathic disease or secondary syndrome appear to be sporadic, based on a familial rate of 10%-15% of cases in Japan and in about 6% of cases in the United States.

"Identification of single-gene disorders associated with moyamoya might lead to a better understanding of childhood cerebral arteriopathy," Dr. Munot and colleagues wrote, because the disorder "often represents one aspect of a more diffuse arteriopathy."

Abnormal Response to Injury

Stroke phenotypes in some single-gene disorders have been associated with physical trauma to the head or neck, abnormal inflammatory response, or oxidative injury.

A wide range of phenotypes has been associated with mutations in the gene that encodes the alpha-1 chain of type IV collagen, COL4A1. It reduces the stability of vascular basement membranes and can lead to idiopathic small-vessel disease in children, including occlusive and aneurysmal cerebral arteriopathies associated with ischemic and hemorrhagic stroke phenotypes. Cerebral hemorrhage in individuals with COL4A1 mutations might be associated with trauma, based on a study that identified trauma to the head or neck in the preceding 2 weeks as a risk factor in previously healthy children.

A mutated form of SAMHD1 is one of five genes that have been associated with the encephalopathic syndrome called Aicardi-Goutières. Children with this mutation had cerebral arteriopathy with either occlusive or aneurysmal features, peripheral vascular disease, which shows that "as with ACTA2-related disease, the skin can indicate the presence of cerebrovascular disease." Some patients with SAMHD1 mutations have had evidence of arterial inflammation or systemic inflammatory disease.

Excessive smooth-muscle cell proliferation and vascular occlusion occur in individuals with neurofibromatosis type 1 (NF1), which is caused by mutations in the NF1 tumor-suppressor gene. NF1 normally inhibits activity of the Ras signaling pathway, but its disinhibition results in intimal proliferation, smooth-muscle nodules, and fibrosis of the vascular media and adventitia. About 6% of children with NF1 have diffuse cerebral arteriopathy with features of occlusive and aneurysmal disease. Evidence suggests that chronic inflammation is an important factor in NF1 arteriopathy, but the trigger for this unclear, Dr. Munot and coauthors wrote.

Mutations in ATP7A, which occur in X-linked recessive Menkes disease (also known as kinky-hair syndrome), affect copper transport. These individuals have "sparse and friable hair" and present with varying phenotypes and degrees of severity. The disorder mainly causes connective-tissue abnormalities but can cause a progressive neurodegenerative disorder that results in death in infancy. Ischemic and hemorrhagic stroke, structural abnormalities in cerebral arteries, oxidative injury, and energy failure have been reported with the vascular phenotype.

Accumulation of Abnormal Metabolites

The X-linked lysosomal storage disorder called Fabry’s disease is caused by a deficiency of alpha-galactosidase that arises from mutations in the GLA gene that encodes the enzyme. The metabolite globotriaosylceramide builds up in vascular endothelium, causing injury and progressive arteriopathy in large and small vessels. About 40% of hemizygous men develop stroke with vessel ectasia.

The autosomal recessive disorder homocystinuria leads to a deficiency in cystathione-beta synthase and an increased risk of stroke and abnormal blood clots. These effects of hyperhomocysteinemia are suspected to occur through a dysfunction of the vascular endothelium and procoagulation effects.

The authors had no financial conflicts to report.

Primary and secondary prevention measures for children at risk for idiopathic arterial ischemic stroke need to target disease mechanisms unique to nonatherosclerotic arteriopathies, according to pediatric stroke researchers.

Risk factors, signs, and symptoms differ for arterial ischemic stroke (AIS) in adults and children. Early recognition of factors unique to at-risk children can prompt the initiation of prophylactic treatment with antiplatelet drugs, anti-inflammatory drugs, and anticoagulants when thrombosis and inflammation play important roles in the pathogenesis, Dr. Pinki Munot of Great Ormond Street Hospital for Children NHS Trust, London, and coauthors wrote in a review (Lancet Neurol. 2011;10:264-74).

Many of these arteriopathies appear to be caused by single-gene mutations that affect various parts of an artery’s structure at different points in its development, homeostasis, or response to environmental stress, offering a range of different targets for research.

To detect the underlying genetic disorder, Dr. Munot and colleagues advised asking about clinical history of stroke, migraine, porencephaly, learning difficulties, and static motor disorders, and to look for disease in vascular beds outside the brain. They recommended pursuing genetic investigations only in patients with cerebrovascular and noncerebrovascular features that are suggestive of a genetic cause.

Dr. Munot and colleagues described how single-gene mutations contribute to known phenotypes described in various pediatric cerebral arteriopathies (not including inherited metabolic disorders).

Abnormalities in Vascular Development

The deletion of a region of chromosome 7 that contains the gene for elastin (ELN) causes Williams-Beuren syndrome. Arteriopathy in most cases of the syndrome (70%) results in supravalvular aortic stenosis but can involve other vascular beds, and causes an overgrowth of smooth-muscle cells. Occlusive disease most often results from the overgrowth of smooth-muscle cells caused by the lack of elastin; aneurysmal disease has not been reported.

ACTA2, the gene for a member of the highly-conserved actin proteins, actin alpha 2, codes for a main contractile protein in vascular smooth-muscle cells. Mutations affecting it result in dysfunctional smooth-muscle cell contraction and the proliferation of smooth-muscle cells that occlude smaller arteries but appear to make larger arteries vulnerable to aneurysmal disease. A diverse number of vascular beds can be involved, which is most noticeable in the fact that all mutation carriers have livedo reticularis.

Abnormal Vascular Homeostasis and Remodeling

The Notch signaling pathway is essential in determining the differentiation of smooth-muscle cells and their response to vascular injury. Mutations in NOTCH3 and JAG1 genes affect this pathway.

NOTCH3 mutations lead to arterial wall thickening and stenosis in mostly small vessels in the condition called CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). Most reports of cerebral infarction have been reported in adults but might be underrecognized in childhood.

The jagged-1 surface protein encoded by JAG1 is mutated in nearly 90% of individuals with Alagille syndrome. Individuals with this syndrome appear to harbor abnormally thin-walled vessels with myointimal hyperplasia of the vascular wall. Occlusive and aneurysmal arterial disease observed in the syndrome are associated with ischemic and hemorrhagic strokes.

Dysregulation of transforming growth factor beta (TGF-beta) signaling caused by mutations in the gene coding for HtrA serine peptidase-1, HTRA1, is known to result in the condition called CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy). The disease causes a dysfunction in vascular homeostasis, resulting in diseased cerebral small arteries, which usually arises in adulthood. They show arteriosclerosis with intimal thickening and dense collagen fibers, loss of vascular smooth-muscle cells, and hyaline degeneration in arterial media. Other features of CARASIL such as alopecia can begin in adolescence. Mutations in genes for TGF-beta receptors, TGFBR1 and TGFBR2, cause Loeys-Dietz syndrome, which is characterized by arterial tortuosity and large-vessel, noncerebrovascular aneurysmal disease. In arterial tortuosity syndrome, the loss of function of a facilitative glucose transporter encoded by SLC2A10 (or GLUT10) leads to defective collagen, elastin, or both, and activates TGF-beta as a secondary response to a defective extracellular matrix.

Abnormal vascular homeostasis in pseudoxanthoma elasticum, caused by a mutated ABCC6 gene, leads to a calcification of elastic fibers and might be seen with cutaneous signs in childhood, although it is most often diagnosed in teenagers and individuals in their 20s when AIS and peripheral vascular disease become prominent.

Persons with mutations in the pericentrin gene PCNT that cause the autosomal recessive disorder microcephalic osteodysplastic primordial dwarfism type II (MOPD II) have an emergent and progressive cerebrovascular disease in childhood such as moyamoya syndrome and, less often, aneurysmal disease that support a role of the centrosomal protein pericentrin in vascular homeostasis. The mutations also cause vascular disease in many areas outside of the cerebral circulation in individuals with MOPD II, which is characterized by microcephaly, pre- and postnatal growth failure, skeletal dysplasia, and dysmorphism.

The rare, nonatheromatous arteriopathy called moyamoya usually causes bilateral occlusive disease of the terminal internal carotid arteries and is considered one of the most severe childhood cerebral arteriopathies. The overproliferation of smooth-muscle cells in the syndrome, with colocalization of inflammatory cells such as macrophages and T cells, is "probably genetically mediated," according to Dr. Munot and associates. But genotype-phenotype correlations have been difficult because of varying degrees of precision used to describe moyamoya in the literature. Most cases of idiopathic disease or secondary syndrome appear to be sporadic, based on a familial rate of 10%-15% of cases in Japan and in about 6% of cases in the United States.

"Identification of single-gene disorders associated with moyamoya might lead to a better understanding of childhood cerebral arteriopathy," Dr. Munot and colleagues wrote, because the disorder "often represents one aspect of a more diffuse arteriopathy."

Abnormal Response to Injury

Stroke phenotypes in some single-gene disorders have been associated with physical trauma to the head or neck, abnormal inflammatory response, or oxidative injury.

A wide range of phenotypes has been associated with mutations in the gene that encodes the alpha-1 chain of type IV collagen, COL4A1. It reduces the stability of vascular basement membranes and can lead to idiopathic small-vessel disease in children, including occlusive and aneurysmal cerebral arteriopathies associated with ischemic and hemorrhagic stroke phenotypes. Cerebral hemorrhage in individuals with COL4A1 mutations might be associated with trauma, based on a study that identified trauma to the head or neck in the preceding 2 weeks as a risk factor in previously healthy children.

A mutated form of SAMHD1 is one of five genes that have been associated with the encephalopathic syndrome called Aicardi-Goutières. Children with this mutation had cerebral arteriopathy with either occlusive or aneurysmal features, peripheral vascular disease, which shows that "as with ACTA2-related disease, the skin can indicate the presence of cerebrovascular disease." Some patients with SAMHD1 mutations have had evidence of arterial inflammation or systemic inflammatory disease.

Excessive smooth-muscle cell proliferation and vascular occlusion occur in individuals with neurofibromatosis type 1 (NF1), which is caused by mutations in the NF1 tumor-suppressor gene. NF1 normally inhibits activity of the Ras signaling pathway, but its disinhibition results in intimal proliferation, smooth-muscle nodules, and fibrosis of the vascular media and adventitia. About 6% of children with NF1 have diffuse cerebral arteriopathy with features of occlusive and aneurysmal disease. Evidence suggests that chronic inflammation is an important factor in NF1 arteriopathy, but the trigger for this unclear, Dr. Munot and coauthors wrote.

Mutations in ATP7A, which occur in X-linked recessive Menkes disease (also known as kinky-hair syndrome), affect copper transport. These individuals have "sparse and friable hair" and present with varying phenotypes and degrees of severity. The disorder mainly causes connective-tissue abnormalities but can cause a progressive neurodegenerative disorder that results in death in infancy. Ischemic and hemorrhagic stroke, structural abnormalities in cerebral arteries, oxidative injury, and energy failure have been reported with the vascular phenotype.

Accumulation of Abnormal Metabolites

The X-linked lysosomal storage disorder called Fabry’s disease is caused by a deficiency of alpha-galactosidase that arises from mutations in the GLA gene that encodes the enzyme. The metabolite globotriaosylceramide builds up in vascular endothelium, causing injury and progressive arteriopathy in large and small vessels. About 40% of hemizygous men develop stroke with vessel ectasia.

The autosomal recessive disorder homocystinuria leads to a deficiency in cystathione-beta synthase and an increased risk of stroke and abnormal blood clots. These effects of hyperhomocysteinemia are suspected to occur through a dysfunction of the vascular endothelium and procoagulation effects.

The authors had no financial conflicts to report.

Primary and secondary prevention measures for children at risk for idiopathic arterial ischemic stroke need to target disease mechanisms unique to nonatherosclerotic arteriopathies, according to pediatric stroke researchers.

Risk factors, signs, and symptoms differ for arterial ischemic stroke (AIS) in adults and children. Early recognition of factors unique to at-risk children can prompt the initiation of prophylactic treatment with antiplatelet drugs, anti-inflammatory drugs, and anticoagulants when thrombosis and inflammation play important roles in the pathogenesis, Dr. Pinki Munot of Great Ormond Street Hospital for Children NHS Trust, London, and coauthors wrote in a review (Lancet Neurol. 2011;10:264-74).

Many of these arteriopathies appear to be caused by single-gene mutations that affect various parts of an artery’s structure at different points in its development, homeostasis, or response to environmental stress, offering a range of different targets for research.

To detect the underlying genetic disorder, Dr. Munot and colleagues advised asking about clinical history of stroke, migraine, porencephaly, learning difficulties, and static motor disorders, and to look for disease in vascular beds outside the brain. They recommended pursuing genetic investigations only in patients with cerebrovascular and noncerebrovascular features that are suggestive of a genetic cause.

Dr. Munot and colleagues described how single-gene mutations contribute to known phenotypes described in various pediatric cerebral arteriopathies (not including inherited metabolic disorders).

Abnormalities in Vascular Development

The deletion of a region of chromosome 7 that contains the gene for elastin (ELN) causes Williams-Beuren syndrome. Arteriopathy in most cases of the syndrome (70%) results in supravalvular aortic stenosis but can involve other vascular beds, and causes an overgrowth of smooth-muscle cells. Occlusive disease most often results from the overgrowth of smooth-muscle cells caused by the lack of elastin; aneurysmal disease has not been reported.

ACTA2, the gene for a member of the highly-conserved actin proteins, actin alpha 2, codes for a main contractile protein in vascular smooth-muscle cells. Mutations affecting it result in dysfunctional smooth-muscle cell contraction and the proliferation of smooth-muscle cells that occlude smaller arteries but appear to make larger arteries vulnerable to aneurysmal disease. A diverse number of vascular beds can be involved, which is most noticeable in the fact that all mutation carriers have livedo reticularis.

Abnormal Vascular Homeostasis and Remodeling

The Notch signaling pathway is essential in determining the differentiation of smooth-muscle cells and their response to vascular injury. Mutations in NOTCH3 and JAG1 genes affect this pathway.

NOTCH3 mutations lead to arterial wall thickening and stenosis in mostly small vessels in the condition called CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). Most reports of cerebral infarction have been reported in adults but might be underrecognized in childhood.

The jagged-1 surface protein encoded by JAG1 is mutated in nearly 90% of individuals with Alagille syndrome. Individuals with this syndrome appear to harbor abnormally thin-walled vessels with myointimal hyperplasia of the vascular wall. Occlusive and aneurysmal arterial disease observed in the syndrome are associated with ischemic and hemorrhagic strokes.

Dysregulation of transforming growth factor beta (TGF-beta) signaling caused by mutations in the gene coding for HtrA serine peptidase-1, HTRA1, is known to result in the condition called CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy). The disease causes a dysfunction in vascular homeostasis, resulting in diseased cerebral small arteries, which usually arises in adulthood. They show arteriosclerosis with intimal thickening and dense collagen fibers, loss of vascular smooth-muscle cells, and hyaline degeneration in arterial media. Other features of CARASIL such as alopecia can begin in adolescence. Mutations in genes for TGF-beta receptors, TGFBR1 and TGFBR2, cause Loeys-Dietz syndrome, which is characterized by arterial tortuosity and large-vessel, noncerebrovascular aneurysmal disease. In arterial tortuosity syndrome, the loss of function of a facilitative glucose transporter encoded by SLC2A10 (or GLUT10) leads to defective collagen, elastin, or both, and activates TGF-beta as a secondary response to a defective extracellular matrix.

Abnormal vascular homeostasis in pseudoxanthoma elasticum, caused by a mutated ABCC6 gene, leads to a calcification of elastic fibers and might be seen with cutaneous signs in childhood, although it is most often diagnosed in teenagers and individuals in their 20s when AIS and peripheral vascular disease become prominent.

Persons with mutations in the pericentrin gene PCNT that cause the autosomal recessive disorder microcephalic osteodysplastic primordial dwarfism type II (MOPD II) have an emergent and progressive cerebrovascular disease in childhood such as moyamoya syndrome and, less often, aneurysmal disease that support a role of the centrosomal protein pericentrin in vascular homeostasis. The mutations also cause vascular disease in many areas outside of the cerebral circulation in individuals with MOPD II, which is characterized by microcephaly, pre- and postnatal growth failure, skeletal dysplasia, and dysmorphism.

The rare, nonatheromatous arteriopathy called moyamoya usually causes bilateral occlusive disease of the terminal internal carotid arteries and is considered one of the most severe childhood cerebral arteriopathies. The overproliferation of smooth-muscle cells in the syndrome, with colocalization of inflammatory cells such as macrophages and T cells, is "probably genetically mediated," according to Dr. Munot and associates. But genotype-phenotype correlations have been difficult because of varying degrees of precision used to describe moyamoya in the literature. Most cases of idiopathic disease or secondary syndrome appear to be sporadic, based on a familial rate of 10%-15% of cases in Japan and in about 6% of cases in the United States.

"Identification of single-gene disorders associated with moyamoya might lead to a better understanding of childhood cerebral arteriopathy," Dr. Munot and colleagues wrote, because the disorder "often represents one aspect of a more diffuse arteriopathy."

Abnormal Response to Injury

Stroke phenotypes in some single-gene disorders have been associated with physical trauma to the head or neck, abnormal inflammatory response, or oxidative injury.

A wide range of phenotypes has been associated with mutations in the gene that encodes the alpha-1 chain of type IV collagen, COL4A1. It reduces the stability of vascular basement membranes and can lead to idiopathic small-vessel disease in children, including occlusive and aneurysmal cerebral arteriopathies associated with ischemic and hemorrhagic stroke phenotypes. Cerebral hemorrhage in individuals with COL4A1 mutations might be associated with trauma, based on a study that identified trauma to the head or neck in the preceding 2 weeks as a risk factor in previously healthy children.

A mutated form of SAMHD1 is one of five genes that have been associated with the encephalopathic syndrome called Aicardi-Goutières. Children with this mutation had cerebral arteriopathy with either occlusive or aneurysmal features, peripheral vascular disease, which shows that "as with ACTA2-related disease, the skin can indicate the presence of cerebrovascular disease." Some patients with SAMHD1 mutations have had evidence of arterial inflammation or systemic inflammatory disease.

Excessive smooth-muscle cell proliferation and vascular occlusion occur in individuals with neurofibromatosis type 1 (NF1), which is caused by mutations in the NF1 tumor-suppressor gene. NF1 normally inhibits activity of the Ras signaling pathway, but its disinhibition results in intimal proliferation, smooth-muscle nodules, and fibrosis of the vascular media and adventitia. About 6% of children with NF1 have diffuse cerebral arteriopathy with features of occlusive and aneurysmal disease. Evidence suggests that chronic inflammation is an important factor in NF1 arteriopathy, but the trigger for this unclear, Dr. Munot and coauthors wrote.

Mutations in ATP7A, which occur in X-linked recessive Menkes disease (also known as kinky-hair syndrome), affect copper transport. These individuals have "sparse and friable hair" and present with varying phenotypes and degrees of severity. The disorder mainly causes connective-tissue abnormalities but can cause a progressive neurodegenerative disorder that results in death in infancy. Ischemic and hemorrhagic stroke, structural abnormalities in cerebral arteries, oxidative injury, and energy failure have been reported with the vascular phenotype.

Accumulation of Abnormal Metabolites

The X-linked lysosomal storage disorder called Fabry’s disease is caused by a deficiency of alpha-galactosidase that arises from mutations in the GLA gene that encodes the enzyme. The metabolite globotriaosylceramide builds up in vascular endothelium, causing injury and progressive arteriopathy in large and small vessels. About 40% of hemizygous men develop stroke with vessel ectasia.

The autosomal recessive disorder homocystinuria leads to a deficiency in cystathione-beta synthase and an increased risk of stroke and abnormal blood clots. These effects of hyperhomocysteinemia are suspected to occur through a dysfunction of the vascular endothelium and procoagulation effects.

The authors had no financial conflicts to report.

Primary and secondary prevention measures for children at risk for idiopathic arterial ischemic stroke need to target disease mechanisms unique to nonatherosclerotic arteriopathies, according to pediatric stroke researchers.

Risk factors, signs, and symptoms differ for arterial ischemic stroke (AIS) in adults and children. Early recognition of factors unique to at-risk children can prompt the initiation of prophylactic treatment with antiplatelet drugs, anti-inflammatory drugs, and anticoagulants when thrombosis and inflammation play important roles in the pathogenesis, Dr. Pinki Munot of Great Ormond Street Hospital for Children NHS Trust, London, and coauthors wrote in a review (Lancet Neurol. 2011;10:264-74).

Many of these arteriopathies appear to be caused by single-gene mutations that affect various parts of an artery’s structure at different points in its development, homeostasis, or response to environmental stress, offering a range of different targets for research.

To detect the underlying genetic disorder, Dr. Munot and colleagues advised asking about clinical history of stroke, migraine, porencephaly, learning difficulties, and static motor disorders, and to look for disease in vascular beds outside the brain. They recommended pursuing genetic investigations only in patients with cerebrovascular and noncerebrovascular features that are suggestive of a genetic cause.

Dr. Munot and colleagues described how single-gene mutations contribute to known phenotypes described in various pediatric cerebral arteriopathies (not including inherited metabolic disorders).

Abnormalities in Vascular Development

The deletion of a region of chromosome 7 that contains the gene for elastin (ELN) causes Williams-Beuren syndrome. Arteriopathy in most cases of the syndrome (70%) results in supravalvular aortic stenosis but can involve other vascular beds, and causes an overgrowth of smooth-muscle cells. Occlusive disease most often results from the overgrowth of smooth-muscle cells caused by the lack of elastin; aneurysmal disease has not been reported.

ACTA2, the gene for a member of the highly-conserved actin proteins, actin alpha 2, codes for a main contractile protein in vascular smooth-muscle cells. Mutations affecting it result in dysfunctional smooth-muscle cell contraction and the proliferation of smooth-muscle cells that occlude smaller arteries but appear to make larger arteries vulnerable to aneurysmal disease. A diverse number of vascular beds can be involved, which is most noticeable in the fact that all mutation carriers have livedo reticularis.

Abnormal Vascular Homeostasis and Remodeling

The Notch signaling pathway is essential in determining the differentiation of smooth-muscle cells and their response to vascular injury. Mutations in NOTCH3 and JAG1 genes affect this pathway.

NOTCH3 mutations lead to arterial wall thickening and stenosis in mostly small vessels in the condition called CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). Most reports of cerebral infarction have been reported in adults but might be underrecognized in childhood.

The jagged-1 surface protein encoded by JAG1 is mutated in nearly 90% of individuals with Alagille syndrome. Individuals with this syndrome appear to harbor abnormally thin-walled vessels with myointimal hyperplasia of the vascular wall. Occlusive and aneurysmal arterial disease observed in the syndrome are associated with ischemic and hemorrhagic strokes.

Dysregulation of transforming growth factor beta (TGF-beta) signaling caused by mutations in the gene coding for HtrA serine peptidase-1, HTRA1, is known to result in the condition called CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy). The disease causes a dysfunction in vascular homeostasis, resulting in diseased cerebral small arteries, which usually arises in adulthood. They show arteriosclerosis with intimal thickening and dense collagen fibers, loss of vascular smooth-muscle cells, and hyaline degeneration in arterial media. Other features of CARASIL such as alopecia can begin in adolescence. Mutations in genes for TGF-beta receptors, TGFBR1 and TGFBR2, cause Loeys-Dietz syndrome, which is characterized by arterial tortuosity and large-vessel, noncerebrovascular aneurysmal disease. In arterial tortuosity syndrome, the loss of function of a facilitative glucose transporter encoded by SLC2A10 (or GLUT10) leads to defective collagen, elastin, or both, and activates TGF-beta as a secondary response to a defective extracellular matrix.

Abnormal vascular homeostasis in pseudoxanthoma elasticum, caused by a mutated ABCC6 gene, leads to a calcification of elastic fibers and might be seen with cutaneous signs in childhood, although it is most often diagnosed in teenagers and individuals in their 20s when AIS and peripheral vascular disease become prominent.

Persons with mutations in the pericentrin gene PCNT that cause the autosomal recessive disorder microcephalic osteodysplastic primordial dwarfism type II (MOPD II) have an emergent and progressive cerebrovascular disease in childhood such as moyamoya syndrome and, less often, aneurysmal disease that support a role of the centrosomal protein pericentrin in vascular homeostasis. The mutations also cause vascular disease in many areas outside of the cerebral circulation in individuals with MOPD II, which is characterized by microcephaly, pre- and postnatal growth failure, skeletal dysplasia, and dysmorphism.

The rare, nonatheromatous arteriopathy called moyamoya usually causes bilateral occlusive disease of the terminal internal carotid arteries and is considered one of the most severe childhood cerebral arteriopathies. The overproliferation of smooth-muscle cells in the syndrome, with colocalization of inflammatory cells such as macrophages and T cells, is "probably genetically mediated," according to Dr. Munot and associates. But genotype-phenotype correlations have been difficult because of varying degrees of precision used to describe moyamoya in the literature. Most cases of idiopathic disease or secondary syndrome appear to be sporadic, based on a familial rate of 10%-15% of cases in Japan and in about 6% of cases in the United States.

"Identification of single-gene disorders associated with moyamoya might lead to a better understanding of childhood cerebral arteriopathy," Dr. Munot and colleagues wrote, because the disorder "often represents one aspect of a more diffuse arteriopathy."

Abnormal Response to Injury

Stroke phenotypes in some single-gene disorders have been associated with physical trauma to the head or neck, abnormal inflammatory response, or oxidative injury.

A wide range of phenotypes has been associated with mutations in the gene that encodes the alpha-1 chain of type IV collagen, COL4A1. It reduces the stability of vascular basement membranes and can lead to idiopathic small-vessel disease in children, including occlusive and aneurysmal cerebral arteriopathies associated with ischemic and hemorrhagic stroke phenotypes. Cerebral hemorrhage in individuals with COL4A1 mutations might be associated with trauma, based on a study that identified trauma to the head or neck in the preceding 2 weeks as a risk factor in previously healthy children.

A mutated form of SAMHD1 is one of five genes that have been associated with the encephalopathic syndrome called Aicardi-Goutières. Children with this mutation had cerebral arteriopathy with either occlusive or aneurysmal features, peripheral vascular disease, which shows that "as with ACTA2-related disease, the skin can indicate the presence of cerebrovascular disease." Some patients with SAMHD1 mutations have had evidence of arterial inflammation or systemic inflammatory disease.

Excessive smooth-muscle cell proliferation and vascular occlusion occur in individuals with neurofibromatosis type 1 (NF1), which is caused by mutations in the NF1 tumor-suppressor gene. NF1 normally inhibits activity of the Ras signaling pathway, but its disinhibition results in intimal proliferation, smooth-muscle nodules, and fibrosis of the vascular media and adventitia. About 6% of children with NF1 have diffuse cerebral arteriopathy with features of occlusive and aneurysmal disease. Evidence suggests that chronic inflammation is an important factor in NF1 arteriopathy, but the trigger for this unclear, Dr. Munot and coauthors wrote.

Mutations in ATP7A, which occur in X-linked recessive Menkes disease (also known as kinky-hair syndrome), affect copper transport. These individuals have "sparse and friable hair" and present with varying phenotypes and degrees of severity. The disorder mainly causes connective-tissue abnormalities but can cause a progressive neurodegenerative disorder that results in death in infancy. Ischemic and hemorrhagic stroke, structural abnormalities in cerebral arteries, oxidative injury, and energy failure have been reported with the vascular phenotype.

Accumulation of Abnormal Metabolites

The X-linked lysosomal storage disorder called Fabry’s disease is caused by a deficiency of alpha-galactosidase that arises from mutations in the GLA gene that encodes the enzyme. The metabolite globotriaosylceramide builds up in vascular endothelium, causing injury and progressive arteriopathy in large and small vessels. About 40% of hemizygous men develop stroke with vessel ectasia.

The autosomal recessive disorder homocystinuria leads to a deficiency in cystathione-beta synthase and an increased risk of stroke and abnormal blood clots. These effects of hyperhomocysteinemia are suspected to occur through a dysfunction of the vascular endothelium and procoagulation effects.

The authors had no financial conflicts to report.

Primary and secondary prevention measures for children at risk for idiopathic arterial ischemic stroke need to target disease mechanisms unique to nonatherosclerotic arteriopathies, according to pediatric stroke researchers.

Risk factors, signs, and symptoms differ for arterial ischemic stroke (AIS) in adults and children. Early recognition of factors unique to at-risk children can prompt the initiation of prophylactic treatment with antiplatelet drugs, anti-inflammatory drugs, and anticoagulants when thrombosis and inflammation play important roles in the pathogenesis, Dr. Pinki Munot of Great Ormond Street Hospital for Children NHS Trust, London, and coauthors wrote in a review (Lancet Neurol. 2011;10:264-74).

Many of these arteriopathies appear to be caused by single-gene mutations that affect various parts of an artery’s structure at different points in its development, homeostasis, or response to environmental stress, offering a range of different targets for research.

To detect the underlying genetic disorder, Dr. Munot and colleagues advised asking about clinical history of stroke, migraine, porencephaly, learning difficulties, and static motor disorders, and to look for disease in vascular beds outside the brain. They recommended pursuing genetic investigations only in patients with cerebrovascular and noncerebrovascular features that are suggestive of a genetic cause.

Dr. Munot and colleagues described how single-gene mutations contribute to known phenotypes described in various pediatric cerebral arteriopathies (not including inherited metabolic disorders).

Abnormalities in Vascular Development

The deletion of a region of chromosome 7 that contains the gene for elastin (ELN) causes Williams-Beuren syndrome. Arteriopathy in most cases of the syndrome (70%) results in supravalvular aortic stenosis but can involve other vascular beds, and causes an overgrowth of smooth-muscle cells. Occlusive disease most often results from the overgrowth of smooth-muscle cells caused by the lack of elastin; aneurysmal disease has not been reported.

ACTA2, the gene for a member of the highly-conserved actin proteins, actin alpha 2, codes for a main contractile protein in vascular smooth-muscle cells. Mutations affecting it result in dysfunctional smooth-muscle cell contraction and the proliferation of smooth-muscle cells that occlude smaller arteries but appear to make larger arteries vulnerable to aneurysmal disease. A diverse number of vascular beds can be involved, which is most noticeable in the fact that all mutation carriers have livedo reticularis.

Abnormal Vascular Homeostasis and Remodeling

The Notch signaling pathway is essential in determining the differentiation of smooth-muscle cells and their response to vascular injury. Mutations in NOTCH3 and JAG1 genes affect this pathway.

NOTCH3 mutations lead to arterial wall thickening and stenosis in mostly small vessels in the condition called CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). Most reports of cerebral infarction have been reported in adults but might be underrecognized in childhood.

The jagged-1 surface protein encoded by JAG1 is mutated in nearly 90% of individuals with Alagille syndrome. Individuals with this syndrome appear to harbor abnormally thin-walled vessels with myointimal hyperplasia of the vascular wall. Occlusive and aneurysmal arterial disease observed in the syndrome are associated with ischemic and hemorrhagic strokes.

Dysregulation of transforming growth factor beta (TGF-beta) signaling caused by mutations in the gene coding for HtrA serine peptidase-1, HTRA1, is known to result in the condition called CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy). The disease causes a dysfunction in vascular homeostasis, resulting in diseased cerebral small arteries, which usually arises in adulthood. They show arteriosclerosis with intimal thickening and dense collagen fibers, loss of vascular smooth-muscle cells, and hyaline degeneration in arterial media. Other features of CARASIL such as alopecia can begin in adolescence. Mutations in genes for TGF-beta receptors, TGFBR1 and TGFBR2, cause Loeys-Dietz syndrome, which is characterized by arterial tortuosity and large-vessel, noncerebrovascular aneurysmal disease. In arterial tortuosity syndrome, the loss of function of a facilitative glucose transporter encoded by SLC2A10 (or GLUT10) leads to defective collagen, elastin, or both, and activates TGF-beta as a secondary response to a defective extracellular matrix.

Abnormal vascular homeostasis in pseudoxanthoma elasticum, caused by a mutated ABCC6 gene, leads to a calcification of elastic fibers and might be seen with cutaneous signs in childhood, although it is most often diagnosed in teenagers and individuals in their 20s when AIS and peripheral vascular disease become prominent.

Persons with mutations in the pericentrin gene PCNT that cause the autosomal recessive disorder microcephalic osteodysplastic primordial dwarfism type II (MOPD II) have an emergent and progressive cerebrovascular disease in childhood such as moyamoya syndrome and, less often, aneurysmal disease that support a role of the centrosomal protein pericentrin in vascular homeostasis. The mutations also cause vascular disease in many areas outside of the cerebral circulation in individuals with MOPD II, which is characterized by microcephaly, pre- and postnatal growth failure, skeletal dysplasia, and dysmorphism.

The rare, nonatheromatous arteriopathy called moyamoya usually causes bilateral occlusive disease of the terminal internal carotid arteries and is considered one of the most severe childhood cerebral arteriopathies. The overproliferation of smooth-muscle cells in the syndrome, with colocalization of inflammatory cells such as macrophages and T cells, is "probably genetically mediated," according to Dr. Munot and associates. But genotype-phenotype correlations have been difficult because of varying degrees of precision used to describe moyamoya in the literature. Most cases of idiopathic disease or secondary syndrome appear to be sporadic, based on a familial rate of 10%-15% of cases in Japan and in about 6% of cases in the United States.

"Identification of single-gene disorders associated with moyamoya might lead to a better understanding of childhood cerebral arteriopathy," Dr. Munot and colleagues wrote, because the disorder "often represents one aspect of a more diffuse arteriopathy."

Abnormal Response to Injury

Stroke phenotypes in some single-gene disorders have been associated with physical trauma to the head or neck, abnormal inflammatory response, or oxidative injury.

A wide range of phenotypes has been associated with mutations in the gene that encodes the alpha-1 chain of type IV collagen, COL4A1. It reduces the stability of vascular basement membranes and can lead to idiopathic small-vessel disease in children, including occlusive and aneurysmal cerebral arteriopathies associated with ischemic and hemorrhagic stroke phenotypes. Cerebral hemorrhage in individuals with COL4A1 mutations might be associated with trauma, based on a study that identified trauma to the head or neck in the preceding 2 weeks as a risk factor in previously healthy children.

A mutated form of SAMHD1 is one of five genes that have been associated with the encephalopathic syndrome called Aicardi-Goutières. Children with this mutation had cerebral arteriopathy with either occlusive or aneurysmal features, peripheral vascular disease, which shows that "as with ACTA2-related disease, the skin can indicate the presence of cerebrovascular disease." Some patients with SAMHD1 mutations have had evidence of arterial inflammation or systemic inflammatory disease.

Excessive smooth-muscle cell proliferation and vascular occlusion occur in individuals with neurofibromatosis type 1 (NF1), which is caused by mutations in the NF1 tumor-suppressor gene. NF1 normally inhibits activity of the Ras signaling pathway, but its disinhibition results in intimal proliferation, smooth-muscle nodules, and fibrosis of the vascular media and adventitia. About 6% of children with NF1 have diffuse cerebral arteriopathy with features of occlusive and aneurysmal disease. Evidence suggests that chronic inflammation is an important factor in NF1 arteriopathy, but the trigger for this unclear, Dr. Munot and coauthors wrote.

Mutations in ATP7A, which occur in X-linked recessive Menkes disease (also known as kinky-hair syndrome), affect copper transport. These individuals have "sparse and friable hair" and present with varying phenotypes and degrees of severity. The disorder mainly causes connective-tissue abnormalities but can cause a progressive neurodegenerative disorder that results in death in infancy. Ischemic and hemorrhagic stroke, structural abnormalities in cerebral arteries, oxidative injury, and energy failure have been reported with the vascular phenotype.

Accumulation of Abnormal Metabolites

The X-linked lysosomal storage disorder called Fabry’s disease is caused by a deficiency of alpha-galactosidase that arises from mutations in the GLA gene that encodes the enzyme. The metabolite globotriaosylceramide builds up in vascular endothelium, causing injury and progressive arteriopathy in large and small vessels. About 40% of hemizygous men develop stroke with vessel ectasia.

The autosomal recessive disorder homocystinuria leads to a deficiency in cystathione-beta synthase and an increased risk of stroke and abnormal blood clots. These effects of hyperhomocysteinemia are suspected to occur through a dysfunction of the vascular endothelium and procoagulation effects.

The authors had no financial conflicts to report.

Primary and secondary prevention measures for children at risk for idiopathic arterial ischemic stroke need to target disease mechanisms unique to nonatherosclerotic arteriopathies, according to pediatric stroke researchers.

Risk factors, signs, and symptoms differ for arterial ischemic stroke (AIS) in adults and children. Early recognition of factors unique to at-risk children can prompt the initiation of prophylactic treatment with antiplatelet drugs, anti-inflammatory drugs, and anticoagulants when thrombosis and inflammation play important roles in the pathogenesis, Dr. Pinki Munot of Great Ormond Street Hospital for Children NHS Trust, London, and coauthors wrote in a review (Lancet Neurol. 2011;10:264-74).

Many of these arteriopathies appear to be caused by single-gene mutations that affect various parts of an artery’s structure at different points in its development, homeostasis, or response to environmental stress, offering a range of different targets for research.

To detect the underlying genetic disorder, Dr. Munot and colleagues advised asking about clinical history of stroke, migraine, porencephaly, learning difficulties, and static motor disorders, and to look for disease in vascular beds outside the brain. They recommended pursuing genetic investigations only in patients with cerebrovascular and noncerebrovascular features that are suggestive of a genetic cause.

Dr. Munot and colleagues described how single-gene mutations contribute to known phenotypes described in various pediatric cerebral arteriopathies (not including inherited metabolic disorders).

Abnormalities in Vascular Development

The deletion of a region of chromosome 7 that contains the gene for elastin (ELN) causes Williams-Beuren syndrome. Arteriopathy in most cases of the syndrome (70%) results in supravalvular aortic stenosis but can involve other vascular beds, and causes an overgrowth of smooth-muscle cells. Occlusive disease most often results from the overgrowth of smooth-muscle cells caused by the lack of elastin; aneurysmal disease has not been reported.

ACTA2, the gene for a member of the highly-conserved actin proteins, actin alpha 2, codes for a main contractile protein in vascular smooth-muscle cells. Mutations affecting it result in dysfunctional smooth-muscle cell contraction and the proliferation of smooth-muscle cells that occlude smaller arteries but appear to make larger arteries vulnerable to aneurysmal disease. A diverse number of vascular beds can be involved, which is most noticeable in the fact that all mutation carriers have livedo reticularis.

Abnormal Vascular Homeostasis and Remodeling

The Notch signaling pathway is essential in determining the differentiation of smooth-muscle cells and their response to vascular injury. Mutations in NOTCH3 and JAG1 genes affect this pathway.

NOTCH3 mutations lead to arterial wall thickening and stenosis in mostly small vessels in the condition called CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). Most reports of cerebral infarction have been reported in adults but might be underrecognized in childhood.

The jagged-1 surface protein encoded by JAG1 is mutated in nearly 90% of individuals with Alagille syndrome. Individuals with this syndrome appear to harbor abnormally thin-walled vessels with myointimal hyperplasia of the vascular wall. Occlusive and aneurysmal arterial disease observed in the syndrome are associated with ischemic and hemorrhagic strokes.

Dysregulation of transforming growth factor beta (TGF-beta) signaling caused by mutations in the gene coding for HtrA serine peptidase-1, HTRA1, is known to result in the condition called CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy). The disease causes a dysfunction in vascular homeostasis, resulting in diseased cerebral small arteries, which usually arises in adulthood. They show arteriosclerosis with intimal thickening and dense collagen fibers, loss of vascular smooth-muscle cells, and hyaline degeneration in arterial media. Other features of CARASIL such as alopecia can begin in adolescence. Mutations in genes for TGF-beta receptors, TGFBR1 and TGFBR2, cause Loeys-Dietz syndrome, which is characterized by arterial tortuosity and large-vessel, noncerebrovascular aneurysmal disease. In arterial tortuosity syndrome, the loss of function of a facilitative glucose transporter encoded by SLC2A10 (or GLUT10) leads to defective collagen, elastin, or both, and activates TGF-beta as a secondary response to a defective extracellular matrix.

Abnormal vascular homeostasis in pseudoxanthoma elasticum, caused by a mutated ABCC6 gene, leads to a calcification of elastic fibers and might be seen with cutaneous signs in childhood, although it is most often diagnosed in teenagers and individuals in their 20s when AIS and peripheral vascular disease become prominent.

Persons with mutations in the pericentrin gene PCNT that cause the autosomal recessive disorder microcephalic osteodysplastic primordial dwarfism type II (MOPD II) have an emergent and progressive cerebrovascular disease in childhood such as moyamoya syndrome and, less often, aneurysmal disease that support a role of the centrosomal protein pericentrin in vascular homeostasis. The mutations also cause vascular disease in many areas outside of the cerebral circulation in individuals with MOPD II, which is characterized by microcephaly, pre- and postnatal growth failure, skeletal dysplasia, and dysmorphism.

The rare, nonatheromatous arteriopathy called moyamoya usually causes bilateral occlusive disease of the terminal internal carotid arteries and is considered one of the most severe childhood cerebral arteriopathies. The overproliferation of smooth-muscle cells in the syndrome, with colocalization of inflammatory cells such as macrophages and T cells, is "probably genetically mediated," according to Dr. Munot and associates. But genotype-phenotype correlations have been difficult because of varying degrees of precision used to describe moyamoya in the literature. Most cases of idiopathic disease or secondary syndrome appear to be sporadic, based on a familial rate of 10%-15% of cases in Japan and in about 6% of cases in the United States.

"Identification of single-gene disorders associated with moyamoya might lead to a better understanding of childhood cerebral arteriopathy," Dr. Munot and colleagues wrote, because the disorder "often represents one aspect of a more diffuse arteriopathy."

Abnormal Response to Injury

Stroke phenotypes in some single-gene disorders have been associated with physical trauma to the head or neck, abnormal inflammatory response, or oxidative injury.

A wide range of phenotypes has been associated with mutations in the gene that encodes the alpha-1 chain of type IV collagen, COL4A1. It reduces the stability of vascular basement membranes and can lead to idiopathic small-vessel disease in children, including occlusive and aneurysmal cerebral arteriopathies associated with ischemic and hemorrhagic stroke phenotypes. Cerebral hemorrhage in individuals with COL4A1 mutations might be associated with trauma, based on a study that identified trauma to the head or neck in the preceding 2 weeks as a risk factor in previously healthy children.

A mutated form of SAMHD1 is one of five genes that have been associated with the encephalopathic syndrome called Aicardi-Goutières. Children with this mutation had cerebral arteriopathy with either occlusive or aneurysmal features, peripheral vascular disease, which shows that "as with ACTA2-related disease, the skin can indicate the presence of cerebrovascular disease." Some patients with SAMHD1 mutations have had evidence of arterial inflammation or systemic inflammatory disease.

Excessive smooth-muscle cell proliferation and vascular occlusion occur in individuals with neurofibromatosis type 1 (NF1), which is caused by mutations in the NF1 tumor-suppressor gene. NF1 normally inhibits activity of the Ras signaling pathway, but its disinhibition results in intimal proliferation, smooth-muscle nodules, and fibrosis of the vascular media and adventitia. About 6% of children with NF1 have diffuse cerebral arteriopathy with features of occlusive and aneurysmal disease. Evidence suggests that chronic inflammation is an important factor in NF1 arteriopathy, but the trigger for this unclear, Dr. Munot and coauthors wrote.

Mutations in ATP7A, which occur in X-linked recessive Menkes disease (also known as kinky-hair syndrome), affect copper transport. These individuals have "sparse and friable hair" and present with varying phenotypes and degrees of severity. The disorder mainly causes connective-tissue abnormalities but can cause a progressive neurodegenerative disorder that results in death in infancy. Ischemic and hemorrhagic stroke, structural abnormalities in cerebral arteries, oxidative injury, and energy failure have been reported with the vascular phenotype.

Accumulation of Abnormal Metabolites

The X-linked lysosomal storage disorder called Fabry’s disease is caused by a deficiency of alpha-galactosidase that arises from mutations in the GLA gene that encodes the enzyme. The metabolite globotriaosylceramide builds up in vascular endothelium, causing injury and progressive arteriopathy in large and small vessels. About 40% of hemizygous men develop stroke with vessel ectasia.

The autosomal recessive disorder homocystinuria leads to a deficiency in cystathione-beta synthase and an increased risk of stroke and abnormal blood clots. These effects of hyperhomocysteinemia are suspected to occur through a dysfunction of the vascular endothelium and procoagulation effects.

The authors had no financial conflicts to report.

Investigators for the first time have used electrode recordings of the firing patterns of small clusters of neurons to predict voluntary movement in people more than 1 second before they are even aware of their decision or urge to act.

The experiment, conducted by Dr. Itzhak Fried of the University of California, Los Angeles, and his associates, and published in Neuron, detected sets of neurons in the supplementary and presupplementary motor areas and the anterior cingulate cortex with firing rates that would progressively increase or decrease before the participants had even reported the urge to push a button on a laptop. The investigators then constructed algorithms that could successfully predict the impending decision to move at a rate of 70% or greater, depending on the location and size of the set of neurons chosen (Neuron 2011;69:548-62).

Dr. Fried and his colleagues recruited a group of 12 patients with drug-refractory epilepsy who had chronic depth electrodes implanted to determine their seizure focus for possible surgical resection. While the patients sat in bed, they watched an analog clock on a laptop computer and were instructed to push a button after at least one rotation of the clock’s hand whenever "they felt the urge to do so." Each time that the individuals pushed the button, called time P, the investigators asked them to indicate where the clock handle had been when they first felt the urge to move, called time W.

The participants reported a mean W time of 193 ms prior to P, but this varied from trial to trial. In the trials, the greatest proportion of neurons that changed their activity before W was located in parts of the medial frontal lobe of the brain: the supplementary motor area (SMA), the pre-SMA, and the dorsal and rostral regions of the anterior cingulate cortex (ACC). In some of these areas, the researchers observed rises in neuronal firing rates beginning several hundreds to several thousands of milliseconds prior to W, whereas progressive declines in firing rates were recorded in a similar time span prior to W. The number of neurons that changed their firing rate also increased as W approached.

The data gathered by the investigators did not indicate that the subjects were cued to respond by the completion of the clock hand’s first rotation. To sort out concerns related to potentially inaccurate reporting of W and the subjective nature of its determination, the investigators’ manipulated the timing of W either forward or backward in time by fixed amounts or by adjusting its timing by a random amount. These analyses indicated that small temporal shifts in W on the order of 200 ms or less are still compatible with the changes in firing rates seen in recorded neurons and matched what was observed within each participant’s individual trials.

With an algorithm that considered the responses of electrodes to be independent of each other across all participants, Dr. Fried and his associates found that they could predict W on a trial-by-trial basis across all participants. The algorithm could detect changes in the neural activity of 512 neurons in frontal lobe regions 500 ms before W in nearly 90% of the trials. The changes in activity could be detected in more than 70% of trials at 1,000 ms before W.

When the algorithm was constructed on the basis of firing patterns from 256 neurons in the SMA, it could detect the neurons’ change in activity at 500 ms before W in greater than 80% of the trials. In comparison, the change in activity of 256 neurons in the ACC at 500 ms before W could be detected in only 70% of trials.

The algorithm also was able to predict the time of W to within several hundred milliseconds of the actual W reported by the participants.

"This neuronal process suggests a mechanism whereby the feeling of will arises once integration of firing of recruited medial frontal neurons crosses a threshold," the investigators concluded.

The research was supported by grants from three different institutes of the National Institutes of Health, the National Science Foundation, the Klingenstein Fund, the Whitehall Foundation, and a Human Frontiers Science Programs Organization fellowship. No disclosure information was provided by the journal.

Investigators for the first time have used electrode recordings of the firing patterns of small clusters of neurons to predict voluntary movement in people more than 1 second before they are even aware of their decision or urge to act.

The experiment, conducted by Dr. Itzhak Fried of the University of California, Los Angeles, and his associates, and published in Neuron, detected sets of neurons in the supplementary and presupplementary motor areas and the anterior cingulate cortex with firing rates that would progressively increase or decrease before the participants had even reported the urge to push a button on a laptop. The investigators then constructed algorithms that could successfully predict the impending decision to move at a rate of 70% or greater, depending on the location and size of the set of neurons chosen (Neuron 2011;69:548-62).

Dr. Fried and his colleagues recruited a group of 12 patients with drug-refractory epilepsy who had chronic depth electrodes implanted to determine their seizure focus for possible surgical resection. While the patients sat in bed, they watched an analog clock on a laptop computer and were instructed to push a button after at least one rotation of the clock’s hand whenever "they felt the urge to do so." Each time that the individuals pushed the button, called time P, the investigators asked them to indicate where the clock handle had been when they first felt the urge to move, called time W.

The participants reported a mean W time of 193 ms prior to P, but this varied from trial to trial. In the trials, the greatest proportion of neurons that changed their activity before W was located in parts of the medial frontal lobe of the brain: the supplementary motor area (SMA), the pre-SMA, and the dorsal and rostral regions of the anterior cingulate cortex (ACC). In some of these areas, the researchers observed rises in neuronal firing rates beginning several hundreds to several thousands of milliseconds prior to W, whereas progressive declines in firing rates were recorded in a similar time span prior to W. The number of neurons that changed their firing rate also increased as W approached.

The data gathered by the investigators did not indicate that the subjects were cued to respond by the completion of the clock hand’s first rotation. To sort out concerns related to potentially inaccurate reporting of W and the subjective nature of its determination, the investigators’ manipulated the timing of W either forward or backward in time by fixed amounts or by adjusting its timing by a random amount. These analyses indicated that small temporal shifts in W on the order of 200 ms or less are still compatible with the changes in firing rates seen in recorded neurons and matched what was observed within each participant’s individual trials.

With an algorithm that considered the responses of electrodes to be independent of each other across all participants, Dr. Fried and his associates found that they could predict W on a trial-by-trial basis across all participants. The algorithm could detect changes in the neural activity of 512 neurons in frontal lobe regions 500 ms before W in nearly 90% of the trials. The changes in activity could be detected in more than 70% of trials at 1,000 ms before W.

When the algorithm was constructed on the basis of firing patterns from 256 neurons in the SMA, it could detect the neurons’ change in activity at 500 ms before W in greater than 80% of the trials. In comparison, the change in activity of 256 neurons in the ACC at 500 ms before W could be detected in only 70% of trials.

The algorithm also was able to predict the time of W to within several hundred milliseconds of the actual W reported by the participants.

"This neuronal process suggests a mechanism whereby the feeling of will arises once integration of firing of recruited medial frontal neurons crosses a threshold," the investigators concluded.

The research was supported by grants from three different institutes of the National Institutes of Health, the National Science Foundation, the Klingenstein Fund, the Whitehall Foundation, and a Human Frontiers Science Programs Organization fellowship. No disclosure information was provided by the journal.

Investigators for the first time have used electrode recordings of the firing patterns of small clusters of neurons to predict voluntary movement in people more than 1 second before they are even aware of their decision or urge to act.

The experiment, conducted by Dr. Itzhak Fried of the University of California, Los Angeles, and his associates, and published in Neuron, detected sets of neurons in the supplementary and presupplementary motor areas and the anterior cingulate cortex with firing rates that would progressively increase or decrease before the participants had even reported the urge to push a button on a laptop. The investigators then constructed algorithms that could successfully predict the impending decision to move at a rate of 70% or greater, depending on the location and size of the set of neurons chosen (Neuron 2011;69:548-62).

Dr. Fried and his colleagues recruited a group of 12 patients with drug-refractory epilepsy who had chronic depth electrodes implanted to determine their seizure focus for possible surgical resection. While the patients sat in bed, they watched an analog clock on a laptop computer and were instructed to push a button after at least one rotation of the clock’s hand whenever "they felt the urge to do so." Each time that the individuals pushed the button, called time P, the investigators asked them to indicate where the clock handle had been when they first felt the urge to move, called time W.

The participants reported a mean W time of 193 ms prior to P, but this varied from trial to trial. In the trials, the greatest proportion of neurons that changed their activity before W was located in parts of the medial frontal lobe of the brain: the supplementary motor area (SMA), the pre-SMA, and the dorsal and rostral regions of the anterior cingulate cortex (ACC). In some of these areas, the researchers observed rises in neuronal firing rates beginning several hundreds to several thousands of milliseconds prior to W, whereas progressive declines in firing rates were recorded in a similar time span prior to W. The number of neurons that changed their firing rate also increased as W approached.

The data gathered by the investigators did not indicate that the subjects were cued to respond by the completion of the clock hand’s first rotation. To sort out concerns related to potentially inaccurate reporting of W and the subjective nature of its determination, the investigators’ manipulated the timing of W either forward or backward in time by fixed amounts or by adjusting its timing by a random amount. These analyses indicated that small temporal shifts in W on the order of 200 ms or less are still compatible with the changes in firing rates seen in recorded neurons and matched what was observed within each participant’s individual trials.

With an algorithm that considered the responses of electrodes to be independent of each other across all participants, Dr. Fried and his associates found that they could predict W on a trial-by-trial basis across all participants. The algorithm could detect changes in the neural activity of 512 neurons in frontal lobe regions 500 ms before W in nearly 90% of the trials. The changes in activity could be detected in more than 70% of trials at 1,000 ms before W.

When the algorithm was constructed on the basis of firing patterns from 256 neurons in the SMA, it could detect the neurons’ change in activity at 500 ms before W in greater than 80% of the trials. In comparison, the change in activity of 256 neurons in the ACC at 500 ms before W could be detected in only 70% of trials.

The algorithm also was able to predict the time of W to within several hundred milliseconds of the actual W reported by the participants.

"This neuronal process suggests a mechanism whereby the feeling of will arises once integration of firing of recruited medial frontal neurons crosses a threshold," the investigators concluded.

The research was supported by grants from three different institutes of the National Institutes of Health, the National Science Foundation, the Klingenstein Fund, the Whitehall Foundation, and a Human Frontiers Science Programs Organization fellowship. No disclosure information was provided by the journal.

Investigators for the first time have used electrode recordings of the firing patterns of small clusters of neurons to predict voluntary movement in people more than 1 second before they are even aware of their decision or urge to act.

The experiment, conducted by Dr. Itzhak Fried of the University of California, Los Angeles, and his associates, and published in Neuron, detected sets of neurons in the supplementary and presupplementary motor areas and the anterior cingulate cortex with firing rates that would progressively increase or decrease before the participants had even reported the urge to push a button on a laptop. The investigators then constructed algorithms that could successfully predict the impending decision to move at a rate of 70% or greater, depending on the location and size of the set of neurons chosen (Neuron 2011;69:548-62).

Dr. Fried and his colleagues recruited a group of 12 patients with drug-refractory epilepsy who had chronic depth electrodes implanted to determine their seizure focus for possible surgical resection. While the patients sat in bed, they watched an analog clock on a laptop computer and were instructed to push a button after at least one rotation of the clock’s hand whenever "they felt the urge to do so." Each time that the individuals pushed the button, called time P, the investigators asked them to indicate where the clock handle had been when they first felt the urge to move, called time W.

The participants reported a mean W time of 193 ms prior to P, but this varied from trial to trial. In the trials, the greatest proportion of neurons that changed their activity before W was located in parts of the medial frontal lobe of the brain: the supplementary motor area (SMA), the pre-SMA, and the dorsal and rostral regions of the anterior cingulate cortex (ACC). In some of these areas, the researchers observed rises in neuronal firing rates beginning several hundreds to several thousands of milliseconds prior to W, whereas progressive declines in firing rates were recorded in a similar time span prior to W. The number of neurons that changed their firing rate also increased as W approached.

The data gathered by the investigators did not indicate that the subjects were cued to respond by the completion of the clock hand’s first rotation. To sort out concerns related to potentially inaccurate reporting of W and the subjective nature of its determination, the investigators’ manipulated the timing of W either forward or backward in time by fixed amounts or by adjusting its timing by a random amount. These analyses indicated that small temporal shifts in W on the order of 200 ms or less are still compatible with the changes in firing rates seen in recorded neurons and matched what was observed within each participant’s individual trials.

With an algorithm that considered the responses of electrodes to be independent of each other across all participants, Dr. Fried and his associates found that they could predict W on a trial-by-trial basis across all participants. The algorithm could detect changes in the neural activity of 512 neurons in frontal lobe regions 500 ms before W in nearly 90% of the trials. The changes in activity could be detected in more than 70% of trials at 1,000 ms before W.

When the algorithm was constructed on the basis of firing patterns from 256 neurons in the SMA, it could detect the neurons’ change in activity at 500 ms before W in greater than 80% of the trials. In comparison, the change in activity of 256 neurons in the ACC at 500 ms before W could be detected in only 70% of trials.

The algorithm also was able to predict the time of W to within several hundred milliseconds of the actual W reported by the participants.

"This neuronal process suggests a mechanism whereby the feeling of will arises once integration of firing of recruited medial frontal neurons crosses a threshold," the investigators concluded.

The research was supported by grants from three different institutes of the National Institutes of Health, the National Science Foundation, the Klingenstein Fund, the Whitehall Foundation, and a Human Frontiers Science Programs Organization fellowship. No disclosure information was provided by the journal.

Investigators for the first time have used electrode recordings of the firing patterns of small clusters of neurons to predict voluntary movement in people more than 1 second before they are even aware of their decision or urge to act.

The experiment, conducted by Dr. Itzhak Fried of the University of California, Los Angeles, and his associates, and published in Neuron, detected sets of neurons in the supplementary and presupplementary motor areas and the anterior cingulate cortex with firing rates that would progressively increase or decrease before the participants had even reported the urge to push a button on a laptop. The investigators then constructed algorithms that could successfully predict the impending decision to move at a rate of 70% or greater, depending on the location and size of the set of neurons chosen (Neuron 2011;69:548-62).

Dr. Fried and his colleagues recruited a group of 12 patients with drug-refractory epilepsy who had chronic depth electrodes implanted to determine their seizure focus for possible surgical resection. While the patients sat in bed, they watched an analog clock on a laptop computer and were instructed to push a button after at least one rotation of the clock’s hand whenever "they felt the urge to do so." Each time that the individuals pushed the button, called time P, the investigators asked them to indicate where the clock handle had been when they first felt the urge to move, called time W.

The participants reported a mean W time of 193 ms prior to P, but this varied from trial to trial. In the trials, the greatest proportion of neurons that changed their activity before W was located in parts of the medial frontal lobe of the brain: the supplementary motor area (SMA), the pre-SMA, and the dorsal and rostral regions of the anterior cingulate cortex (ACC). In some of these areas, the researchers observed rises in neuronal firing rates beginning several hundreds to several thousands of milliseconds prior to W, whereas progressive declines in firing rates were recorded in a similar time span prior to W. The number of neurons that changed their firing rate also increased as W approached.

The data gathered by the investigators did not indicate that the subjects were cued to respond by the completion of the clock hand’s first rotation. To sort out concerns related to potentially inaccurate reporting of W and the subjective nature of its determination, the investigators’ manipulated the timing of W either forward or backward in time by fixed amounts or by adjusting its timing by a random amount. These analyses indicated that small temporal shifts in W on the order of 200 ms or less are still compatible with the changes in firing rates seen in recorded neurons and matched what was observed within each participant’s individual trials.

With an algorithm that considered the responses of electrodes to be independent of each other across all participants, Dr. Fried and his associates found that they could predict W on a trial-by-trial basis across all participants. The algorithm could detect changes in the neural activity of 512 neurons in frontal lobe regions 500 ms before W in nearly 90% of the trials. The changes in activity could be detected in more than 70% of trials at 1,000 ms before W.

When the algorithm was constructed on the basis of firing patterns from 256 neurons in the SMA, it could detect the neurons’ change in activity at 500 ms before W in greater than 80% of the trials. In comparison, the change in activity of 256 neurons in the ACC at 500 ms before W could be detected in only 70% of trials.

The algorithm also was able to predict the time of W to within several hundred milliseconds of the actual W reported by the participants.

"This neuronal process suggests a mechanism whereby the feeling of will arises once integration of firing of recruited medial frontal neurons crosses a threshold," the investigators concluded.

The research was supported by grants from three different institutes of the National Institutes of Health, the National Science Foundation, the Klingenstein Fund, the Whitehall Foundation, and a Human Frontiers Science Programs Organization fellowship. No disclosure information was provided by the journal.

Investigators for the first time have used electrode recordings of the firing patterns of small clusters of neurons to predict voluntary movement in people more than 1 second before they are even aware of their decision or urge to act.

The experiment, conducted by Dr. Itzhak Fried of the University of California, Los Angeles, and his associates, and published in Neuron, detected sets of neurons in the supplementary and presupplementary motor areas and the anterior cingulate cortex with firing rates that would progressively increase or decrease before the participants had even reported the urge to push a button on a laptop. The investigators then constructed algorithms that could successfully predict the impending decision to move at a rate of 70% or greater, depending on the location and size of the set of neurons chosen (Neuron 2011;69:548-62).

Dr. Fried and his colleagues recruited a group of 12 patients with drug-refractory epilepsy who had chronic depth electrodes implanted to determine their seizure focus for possible surgical resection. While the patients sat in bed, they watched an analog clock on a laptop computer and were instructed to push a button after at least one rotation of the clock’s hand whenever "they felt the urge to do so." Each time that the individuals pushed the button, called time P, the investigators asked them to indicate where the clock handle had been when they first felt the urge to move, called time W.

The participants reported a mean W time of 193 ms prior to P, but this varied from trial to trial. In the trials, the greatest proportion of neurons that changed their activity before W was located in parts of the medial frontal lobe of the brain: the supplementary motor area (SMA), the pre-SMA, and the dorsal and rostral regions of the anterior cingulate cortex (ACC). In some of these areas, the researchers observed rises in neuronal firing rates beginning several hundreds to several thousands of milliseconds prior to W, whereas progressive declines in firing rates were recorded in a similar time span prior to W. The number of neurons that changed their firing rate also increased as W approached.

The data gathered by the investigators did not indicate that the subjects were cued to respond by the completion of the clock hand’s first rotation. To sort out concerns related to potentially inaccurate reporting of W and the subjective nature of its determination, the investigators’ manipulated the timing of W either forward or backward in time by fixed amounts or by adjusting its timing by a random amount. These analyses indicated that small temporal shifts in W on the order of 200 ms or less are still compatible with the changes in firing rates seen in recorded neurons and matched what was observed within each participant’s individual trials.

With an algorithm that considered the responses of electrodes to be independent of each other across all participants, Dr. Fried and his associates found that they could predict W on a trial-by-trial basis across all participants. The algorithm could detect changes in the neural activity of 512 neurons in frontal lobe regions 500 ms before W in nearly 90% of the trials. The changes in activity could be detected in more than 70% of trials at 1,000 ms before W.

When the algorithm was constructed on the basis of firing patterns from 256 neurons in the SMA, it could detect the neurons’ change in activity at 500 ms before W in greater than 80% of the trials. In comparison, the change in activity of 256 neurons in the ACC at 500 ms before W could be detected in only 70% of trials.

The algorithm also was able to predict the time of W to within several hundred milliseconds of the actual W reported by the participants.

"This neuronal process suggests a mechanism whereby the feeling of will arises once integration of firing of recruited medial frontal neurons crosses a threshold," the investigators concluded.

The research was supported by grants from three different institutes of the National Institutes of Health, the National Science Foundation, the Klingenstein Fund, the Whitehall Foundation, and a Human Frontiers Science Programs Organization fellowship. No disclosure information was provided by the journal.