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Doubts about functional MRI resolved
Newsdesk
New hope for cerebral malaria treatment? Inhibiting the upregulation of adhesion molecules on the surface of endothelial cells with a new compound might be a way to treat cerebral malaria, scientists report (PLoS Med 2005; 2: e245). Cerebral malaria, which is particularly common in children, is a lifethreatening disease caused by Plasmodium falciparum in which brain capillaries and venules become clogged by parasitised blood cells sticking to the
Suprotik Basu/World Bank
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
Cerebral malaria mostly affects children
vessel endothelium. Serum concentrations of tumour necrosis factor (TNF) and lymphotoxin-, two related cytokines that upregulate the production of adhesion molecules in endothelial cells, are high in patients with cerebral malaria. “We wondered whether inhibiting the production of TNF might reduce the production of these adhesion molecules and therefore the sticking of parasitised blood cells to the endothelium—this might help prevent or treat cerebral malaria”, explains study leader Georges Grau (Université de la Méditerranée, Marseilles, France). Although protein-based TNF inhibitors are commercially available, the team studied a newly designed inhibitor: LMP-420. “Unlike the protein-based inhibitors, this small molecule has a much better chance of crossing the blood–brain barrier and getting to the cells where it is needed”, explains Grau. When the team exposed human brain endothelial cultures to TNF they observed upregulation of adhesion molecules VCAM-1 and ICAM-1. However, when they added LMP-420,
either before or at the same time as exposure, upregulation stopped. Blood cells that were parasitised with different P falciparum strains did not adhere to the endothelial cells. In addition, the treated endothelial cells no longer released microparticles—a hallmark of cerebral malaria. A similar, though less intense, inhibition of the effects of lymphotoxin- was also observed. “We need to remember these are still in vitro results”, cautions Grau. “Also, we applied the drug at what would be an extremely early stage of the disease: people who have already developed cerebral malaria might have too much damage for the drug to help. However, this line of research certainly looks promising.” “A logistic advantage offered by this molecule is its heat stability; it would not require such strict refrigeration conditions, making it much easier to transport”, remarks Sabino Puente (Hospital Carlos III, Madrid, Spain). “But the next step is to see if it can do the same in an animal model.”
Adrian Burton
Doubts about functional MRI resolved Use of functional MRI (fMRI) has revolutionised our understanding of the human brain, but uncertainty remains about whether the fMRI signal does in fact reflect underlying neuronal activity. In a new study, Rafael Malach (Weizmann Institute of Science, Rehovot, Israel) and colleagues take a major step towards resolving these doubts. In 2004, Malach and co-workers showed that different individuals who watch the same movie have very similar patterns of brain activity (Science 2004; 303: 1634–40). “This intersubject ‘synchronisation’ allows us to compare the signals measured with fMRI to the electrical activity 600
patterns of single neurons in the human brain”, explains Malach. In the present study, researchers recorded the spiking activity of 53 single neurons in the auditory cortex of two patients with epilepsy, in whom electrodes had been implanted for potential surgical treatment, while they watched a short clip from a popular movie. They then compared the average firing rate of the neurons to the fMRI signal recorded from 11 healthy individuals who were scanned while watching the same movie clip (Science 2005; 309: 951–54). The average neuronal firing rate measured in the patients showed a very high correlation with the fMRI
signal obtained from the auditory cortex of the healthy volunteers. The linear correlation between the measured fMRI signal and the neuronally derived signal from the patients was highly significant (r=0·75, p<10–47). “We already know that fMRI signals reflect changes in local blood oxygenation, but it is important to understand how these changes measured at a large spatial scale reflect activity in single neurons at a fine spatial scale”, comments Geraint Rees (Institute of Neurology, London, UK). “This study shows that in humans, fMRI and single neuron signals can be closely linked.” http://neurology.thelancet.com Vol 4 October 2005
Newsdesk
The work builds on previous studies in animals, which found a direct relation between neuronal activity and the fMRI signal in anaesthetised monkeys. But, says Malach, the anaesthetised monkey scenario is very different to studies in conscious human beings. “For example, aesthetic effects, species differences, and use of repetitive stimulation may all have a critical role in the results.”
“Although our results are confined to human auditory cortex, they are critical in showing that at least under natural stimulus conditions, we can safely interpret the fMRI signals as faithfully reflecting the underlying neuronal firing in the conscious human brain”, says Malach. “Furthermore, these results now open the way to bridging the gap between single unit recordings and fMRI in other cortical areas.”
The results have important clinical implications, since they show that fMRI scans can provide an accurate measure of neuronal activity in the conscious human brain, he adds. Thus interpretation of such patterns —both in normal and abnormal brains—can now be made with greater confidence as to their neuronal origin.
Helen Frankish
A new study suggests that astrocytic glutamate might have a key function in the pathogenesis of epilepsy. “Our study suggests that, in addition to well-established neurogenic mechanisms, pathologic activation of astrocytes may play a causal role in the genesis of epilepsy”, Guo-Feng Tian (University of Rochester Medical Center, Rochester, NY, USA) told The Lancet Neurology. During epileptic seizures the normal pattern of neuronal activity is disturbed by intensive bursts of activity that are in part initiated by paroxysmal depolarisation shifts (PDS) —abnormal prolonged neuronal depolarisations that drive intensive electrical firing. Until recently glutamate release from neurons was thought to trigger PDS but now researchers report that PDS can be activated by glutamate release from extrasynaptic sources or by photolysis of caged Ca2+ in astrocytes. In their study, Tian and colleagues (Nature Med 2005; published online August 14, DOI:10.1038/nm1277) triggered PDS in brain slices by use of 4-aminopyridine even in the presence of the neurotoxin, tetrodotoxin (TTX), which eliminates neuronal firing. Further experiments showed that glutamate was released from action potential-independent sources. The researchers also simulated epilepticlike seizures with other seizureinducing convulsant agents, including http://neurology.thelancet.com Vol 4 October 2005
bicuclline and penicillin, or by removing, extracellular Mg2+ or Ca2+. The researchers found that glutamate released from astrocytes could trigger local PDS in all experimental seizures. “A unifying feature of seizure activity was its consistent association with antecedent astrocytic Ca2+ signalling. Oscillatory, TTX-insensitive increases in astrocytic Ca2+ preceded or occurred concomitantly with PDS, and targeted astrocytes by photolysis of caged Ca2+ evoked PDS”, says Tian. Furthermore, several antiepileptic agents, including valproate, gabapentin, and pheytoin, potently reduced astrocytic Ca2+ signalling detected by two-photon imaging in live animals.” “This paper represents an extraordinary amount of work that clearly supports the authors’ central conclusion that PDS in experimental models of seizure-like activity is not due to neuronal-activity-relatedglutamate release but to glutamate released from astrocytes, and that such glutamate is dependent on an increase in astrocytic Ca2+ signalling”, comments Nihal De Lanerolle (Yale School of Medicine, New Haven, CT, USA). Current antiepileptic drugs work by inhibiting or slowing down neuronal firing to prevent seizures from occurring, and because they target fundamental brain excitability
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
Astrocytes could have a key function in epilepsy
mechanisms they can have unpleasant side-effects. Tian and colleagues hope that this study will help develop new treatments that will be more specific. “The new work of Tian and colleagues suggests that it may be possible to develop antiepileptic drugs, which protect against seizures by specifically affecting astrocytic signalling”, comments Michael Rogawski (National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA). “Such drugs might be able to protect against seizures with reduced side-effects compared with drugs that target neurons (or neurons and glia).”
Nayanah Siva 601
Nancy Kedersha/Science Photo Library
Astrocytes have a key role in epilepsy
New hope for cerebral malaria treatment? Inhibiting the upregulation of adhesion molecules on the surface of endothelial cells with a new compound might be a way to treat cerebral malaria, scientists report (PLoS Med 2005; 2: e245). Cerebral malaria, which is particularly common in children, is a lifethreatening disease caused by Plasmodium falciparum in which brain capillaries and venules become clogged by parasitised blood cells sticking to the
Suprotik Basu/World Bank
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
Cerebral malaria mostly affects children
vessel endothelium. Serum concentrations of tumour necrosis factor (TNF) and lymphotoxin-, two related cytokines that upregulate the production of adhesion molecules in endothelial cells, are high in patients with cerebral malaria. “We wondered whether inhibiting the production of TNF might reduce the production of these adhesion molecules and therefore the sticking of parasitised blood cells to the endothelium—this might help prevent or treat cerebral malaria”, explains study leader Georges Grau (Université de la Méditerranée, Marseilles, France). Although protein-based TNF inhibitors are commercially available, the team studied a newly designed inhibitor: LMP-420. “Unlike the protein-based inhibitors, this small molecule has a much better chance of crossing the blood–brain barrier and getting to the cells where it is needed”, explains Grau. When the team exposed human brain endothelial cultures to TNF they observed upregulation of adhesion molecules VCAM-1 and ICAM-1. However, when they added LMP-420,
either before or at the same time as exposure, upregulation stopped. Blood cells that were parasitised with different P falciparum strains did not adhere to the endothelial cells. In addition, the treated endothelial cells no longer released microparticles—a hallmark of cerebral malaria. A similar, though less intense, inhibition of the effects of lymphotoxin- was also observed. “We need to remember these are still in vitro results”, cautions Grau. “Also, we applied the drug at what would be an extremely early stage of the disease: people who have already developed cerebral malaria might have too much damage for the drug to help. However, this line of research certainly looks promising.” “A logistic advantage offered by this molecule is its heat stability; it would not require such strict refrigeration conditions, making it much easier to transport”, remarks Sabino Puente (Hospital Carlos III, Madrid, Spain). “But the next step is to see if it can do the same in an animal model.”
Adrian Burton
Doubts about functional MRI resolved Use of functional MRI (fMRI) has revolutionised our understanding of the human brain, but uncertainty remains about whether the fMRI signal does in fact reflect underlying neuronal activity. In a new study, Rafael Malach (Weizmann Institute of Science, Rehovot, Israel) and colleagues take a major step towards resolving these doubts. In 2004, Malach and co-workers showed that different individuals who watch the same movie have very similar patterns of brain activity (Science 2004; 303: 1634–40). “This intersubject ‘synchronisation’ allows us to compare the signals measured with fMRI to the electrical activity 600
patterns of single neurons in the human brain”, explains Malach. In the present study, researchers recorded the spiking activity of 53 single neurons in the auditory cortex of two patients with epilepsy, in whom electrodes had been implanted for potential surgical treatment, while they watched a short clip from a popular movie. They then compared the average firing rate of the neurons to the fMRI signal recorded from 11 healthy individuals who were scanned while watching the same movie clip (Science 2005; 309: 951–54). The average neuronal firing rate measured in the patients showed a very high correlation with the fMRI
signal obtained from the auditory cortex of the healthy volunteers. The linear correlation between the measured fMRI signal and the neuronally derived signal from the patients was highly significant (r=0·75, p<10–47). “We already know that fMRI signals reflect changes in local blood oxygenation, but it is important to understand how these changes measured at a large spatial scale reflect activity in single neurons at a fine spatial scale”, comments Geraint Rees (Institute of Neurology, London, UK). “This study shows that in humans, fMRI and single neuron signals can be closely linked.” http://neurology.thelancet.com Vol 4 October 2005
Newsdesk
The work builds on previous studies in animals, which found a direct relation between neuronal activity and the fMRI signal in anaesthetised monkeys. But, says Malach, the anaesthetised monkey scenario is very different to studies in conscious human beings. “For example, aesthetic effects, species differences, and use of repetitive stimulation may all have a critical role in the results.”
“Although our results are confined to human auditory cortex, they are critical in showing that at least under natural stimulus conditions, we can safely interpret the fMRI signals as faithfully reflecting the underlying neuronal firing in the conscious human brain”, says Malach. “Furthermore, these results now open the way to bridging the gap between single unit recordings and fMRI in other cortical areas.”
The results have important clinical implications, since they show that fMRI scans can provide an accurate measure of neuronal activity in the conscious human brain, he adds. Thus interpretation of such patterns —both in normal and abnormal brains—can now be made with greater confidence as to their neuronal origin.
Helen Frankish
A new study suggests that astrocytic glutamate might have a key function in the pathogenesis of epilepsy. “Our study suggests that, in addition to well-established neurogenic mechanisms, pathologic activation of astrocytes may play a causal role in the genesis of epilepsy”, Guo-Feng Tian (University of Rochester Medical Center, Rochester, NY, USA) told The Lancet Neurology. During epileptic seizures the normal pattern of neuronal activity is disturbed by intensive bursts of activity that are in part initiated by paroxysmal depolarisation shifts (PDS) —abnormal prolonged neuronal depolarisations that drive intensive electrical firing. Until recently glutamate release from neurons was thought to trigger PDS but now researchers report that PDS can be activated by glutamate release from extrasynaptic sources or by photolysis of caged Ca2+ in astrocytes. In their study, Tian and colleagues (Nature Med 2005; published online August 14, DOI:10.1038/nm1277) triggered PDS in brain slices by use of 4-aminopyridine even in the presence of the neurotoxin, tetrodotoxin (TTX), which eliminates neuronal firing. Further experiments showed that glutamate was released from action potential-independent sources. The researchers also simulated epilepticlike seizures with other seizureinducing convulsant agents, including http://neurology.thelancet.com Vol 4 October 2005
bicuclline and penicillin, or by removing, extracellular Mg2+ or Ca2+. The researchers found that glutamate released from astrocytes could trigger local PDS in all experimental seizures. “A unifying feature of seizure activity was its consistent association with antecedent astrocytic Ca2+ signalling. Oscillatory, TTX-insensitive increases in astrocytic Ca2+ preceded or occurred concomitantly with PDS, and targeted astrocytes by photolysis of caged Ca2+ evoked PDS”, says Tian. Furthermore, several antiepileptic agents, including valproate, gabapentin, and pheytoin, potently reduced astrocytic Ca2+ signalling detected by two-photon imaging in live animals.” “This paper represents an extraordinary amount of work that clearly supports the authors’ central conclusion that PDS in experimental models of seizure-like activity is not due to neuronal-activity-relatedglutamate release but to glutamate released from astrocytes, and that such glutamate is dependent on an increase in astrocytic Ca2+ signalling”, comments Nihal De Lanerolle (Yale School of Medicine, New Haven, CT, USA). Current antiepileptic drugs work by inhibiting or slowing down neuronal firing to prevent seizures from occurring, and because they target fundamental brain excitability
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
Astrocytes could have a key function in epilepsy
mechanisms they can have unpleasant side-effects. Tian and colleagues hope that this study will help develop new treatments that will be more specific. “The new work of Tian and colleagues suggests that it may be possible to develop antiepileptic drugs, which protect against seizures by specifically affecting astrocytic signalling”, comments Michael Rogawski (National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA). “Such drugs might be able to protect against seizures with reduced side-effects compared with drugs that target neurons (or neurons and glia).”
Nayanah Siva 601
Nancy Kedersha/Science Photo Library
Astrocytes have a key role in epilepsy