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Biomedical subjects

Hal Blumenfeld

Publications and source records attributed to Hal Blumenfeld.

At least 19 recordsLinked to original sources
PubMed2005

Lamotrigine suppresses neurophysiological responses to somatosensory stimulation in the rodent.

Neurotransmitter release and voltage-gated ion channel activity in excitatory neurons are critical for understanding and interpreting neuroimaging signals. Couplings between changes in neural activity and energetic/vascular responses are assumed for interpretation of neuroimaging signals. To investigate involvement of neural events to neuroenergetic/neurovascular responses, we conducted multi-modal magnetic resonance imaging (MRI) measurements (at 7.0 T) and electrophysiological recordings (with high impedance microelectrodes) for local field potential (LFP) and spiking frequency (nu) in alpha-chloralose-anesthetized rats. The rats underwent forepaw stimulation before and after treatment of lamotrigine, a neuronal voltage-gated ion channel blocker and glutamate release inhibitor. Multi-modal MRI measurements of cerebral blood flow (CBF) and blood oxygenation level-dependent (BOLD) signal were combined to estimate changes in cerebral metabolic rate of oxygen consumption (CMRo2). Lamotrigine did not appreciably affect values of nu, CBF, and CMRo2 in the resting state. After lamotrigine treatment, evoked changes in LFP and nu were attenuated, which were consistent with commensurate declines in deltaCBF and deltaCMRo2. While number of evoked BOLD-activated voxels was considerably reduced with lamotrigine, intensities of voxels in middle cortical layers were affected to a lesser degree by lamotrigine. The results suggest that lamotrigine suppresses evoked neurophysiological (i.e., neural/energetic/vascular) responses, both in terms of volume of tissue activated and degree of activation in the foci. Since lamotrigine affects evoked responses but not the basal signals, it can be suggested that glutamate release and activity of voltage-gated ion channels are essential for initiating evoked energetic/vascular responses, and thereby important for interpretation of incremental changes in neuroimaging signal.

Algorithms↗
PubMed2005

Consciousness and epilepsy: why are patients with absence seizures absent?

Epileptic seizures cause dynamic, reversible changes in brain function and are often associated with loss of consciousness. Of all seizure types, absence seizures lead to the most selective deficits in consciousness, with relatively little motor or other manifestations. Impaired consciousness in absence seizures is not monolithic, but varies in severity between patients and even between episodes in the same patient. In addition, some aspects of consciousness may be more severely involved than other aspects. The mechanisms for this variability are not known. Here we review the literature on human absence seizures and discuss a hypothesis for why effects on consciousness may be variable. Based on behavioral studies, electrophysiology, and recent neuroimaging and molecular investigations, we propose absence seizures impair focal, not generalized brain functions. Impaired consciousness in absence seizures may be caused by focal disruption of information processing in specific corticothalamic networks, while other networks are spared. Deficits in selective and varying cognitive functions may lead to impairment in different aspects of consciousness. Further investigations of the relationship between behavior and altered network function in absence seizures may improve our understanding of both normal and impaired consciousness.

Behavior↗
PubMed2005

Cellular and network mechanisms of spike-wave seizures.

Spike-wave seizures are often considered a relatively "pure" form of epilepsy, with a uniform defect present in all patients and involvement of the whole brain homogeneously. Here, we present evidence against these common misconceptions. Rather than a uniform disorder, spike-wave rhythms arise from the normal inherent network properties of brain excitatory and inhibitory circuits, where they can be provoked by many different insults in several different brain networks. Here we discuss several different cellular and molecular mechanisms that may contribute to the generation of spike-wave seizures, particularly in idiopathic generalized epilepsy. In addition, we discuss growing evidence that electrical, neuroimaging, and molecular changes in spike-wave seizures do not involve the entire brain homogeneously. Rather, spike-wave discharges occur selectively in some thalamocortical networks, while sparing others. It is hoped that improved understanding of the heterogeneous defects and selective brain regions involved will ultimately lead to more effective treatments for spike-wave seizures.

Action Potentials↗
PubMed2005

Localizing value of ictal-interictal SPECT analyzed by SPM (ISAS).

PURPOSE: The goal of neuroimaging in epilepsy is to localize the region of seizure onset. Single-photon emission computed tomography with tracer injection during seizures (ictal SPECT) is a promising tool for localizing seizures. However, much uncertainty exists about how to interpret late injections, or injections done after seizure end (postictal SPECT). A widely available and objective method is needed to interpret ambiguous ictal and postictal scans, with changes in multiple brain regions. METHODS: Ictal or postictal SPECT scans were performed by using [99mTc]-labeled hexamethyl-propylene-amine-oxime (HMPAO), and images were analyzed by comparison with interictal scans for each patient. Forty-seven cases of localized epilepsy were studied. We used methods that can be implemented anywhere, based on freely downloadable software and normal SPECT databases (http://spect.yale.edu). Statistical parametric mapping (SPM) was used to localize a single region of seizure onset based on ictal (or postictal) versus interictal difference images for each patient. We refer to this method as ictal-interictal SPECT analyzed by SPM (ISAS). RESULTS: With this approach, ictal SPECT identified a single unambiguous region of seizure onset in 71% of mesial temporal and 83% of neocortical epilepsy cases, even with late injections, and the localization was correct in all (100%) cases. Postictal SPECT, conversely, with injections performed soon after seizures, was very poor at localizing a single region based on either perfusion increases or decreases, often because changes were similar in multiple brain regions. However, measuring which hemisphere overall had more decreased perfusion with postictal SPECT, lateralized seizure onset to the correct side in approximately 80% of cases. CONCLUSIONS: ISAS provides a validated and readily available method for epilepsy SPECT analysis and interpretation. The results also emphasize the need to obtain SPECT injections during seizures to achieve unambiguous localization.

Adolescent↗
PubMed2004

Positive and negative network correlations in temporal lobe epilepsy.

Temporal lobe seizures are accompanied by complex behavioral phenomena including loss of consciousness, dystonic movements and neuroendocrine changes. These phenomena may arise from extended neural networks beyond the temporal lobe. To investigate this, we imaged cerebral blood flow (CBF) changes during human temporal lobe seizures with single photon emission computed tomography (SPECT) while performing continuous video/EEG monitoring. We found that temporal lobe seizures associated with loss of consciousness produced CBF increases in the temporal lobe, followed by increases in bilateral midline subcortical structures. These changes were accompanied by marked bilateral CBF decreases in the frontal and parietal association cortex. In contrast, temporal lobe seizures in which consciousness was spared were not accompanied by these widespread CBF changes. The CBF decreases in frontal and parietal association cortex were strongly correlated with increases in midline structures such as the mediodorsal thalamus. These results suggest that impaired consciousness in temporal lobe seizures may result from focal abnormal activity in temporal and subcortical networks linked to widespread impaired function of the association cortex.

Adolescent↗
PubMed2004

Dysregulation of sodium channel expression in cortical neurons in a rodent model of absence epilepsy.

Due to the involvement of cortical neurons in spike-wave discharge (SWD) initiation, and the contribution of voltage-gated sodium channels (VGSCs) to neuronal firing, we examined alterations in the expression of VGSC mRNA and protein in cortical neurons in the WAG/Rij absence epileptic rat. WAG/Rij rats were compared to age-matched Wistar control rats at 2, 4, and 6 months. Continuous EEG data was recorded, and percent time in SWD was determined. Tissue from different cortical locations from WAG/Rij and Wistar rats was analyzed for VGSC mRNA (by quantitative PCR) and protein (by immunocytochemistry). SWDs increased with age in WAG/Rij rats. mRNA levels for sodium channels Nav1.1 and Nav1.6, but not Nav1.2, were found to be up-regulated selectively within the facial somatosensory cortex (at AP +0.0, ML +6.0 mm). Protein levels for Nav1.1 and Nav1.6 were up-regulated in layer II-IV cortical neurons in this region of cortex. No significant changes were seen in adjacent regions or other brain areas, including the pre-frontal and occipital cortex. In the WAG/Rij model of absence epilepsy, we identified a specific region of cortex, in layer II-IV neurons on the lateral convexity of the cortex in the facial somatosensory area, where mRNA and protein expression of sodium channel genes Nav1.1 and Nav1.6 are up-regulated. This region of cortex approximately matches the electrophysiologically determined region of seizure onset. Changes in the expression of Nav1.1 and Nav1.6 parallel age-dependent increases in seizure frequency and duration.

Action Potentials↗
PubMed2004

Focal network involvement in generalized seizures: new insights from electroconvulsive therapy.

Generalized seizures are commonly thought to involve the entire brain homogeneously. However, recent evidence suggests that selective cortical-subcortical networks may be crucial for the initiation, propagation, and behavioral manifestations of generalized seizures, while other brain regions are relatively spared. Here we review previous studies, and describe a new human model system for the investigation of generalized seizures: single-photon emission computed tomography, ictal-interictal difference imaging of generalized tonic-clonic seizures induced by electroconvulsive therapy (ECT). Bitemporal ECT activates focal bilateral frontotemporal and parietal association cortex, sparing other regions; bifrontal ECT activates mainly prefrontal cortex; while in right unilateral ECT the left frontotemporal region is relatively spared. Associated midline subcortical networks are also involved. Focal verbal memory deficits parallel the focal regions involved in these neuroimaging studies. Further studies of this kind may elucidate specific networks in generalized tonic-clonic seizures, providing targets for new therapeutic interventions in epilepsy.

Brain Mapping↗
PubMed2004

Dynamic fMRI and EEG recordings during spike-wave seizures and generalized tonic-clonic seizures in WAG/Rij rats.

Generalized epileptic seizures produce widespread physiological changes in the brain. Recent studies suggest that "generalized" seizures may not involve the whole brain homogeneously. For example, electrophysiological recordings in WAG/Rij rats, an established model of human absence seizures, have shown that spike-and-wave discharges are most intense in the perioral somatosensory cortex and thalamus, but spare the occipital cortex. Is this heterogeneous increased neuronal activity matched by changes in local cerebral blood flow sufficient to meet or exceed cerebral oxygen consumption? To investigate this, we performed blood oxygen level-dependent functional magnetic resonance imaging (fMRI) measurements at 7T with simultaneous electroencephalogram recordings. During spontaneous spike-wave seizures in WAG/Rij rats under fentanylhaloperidol anesthesia, we found increased fMRI signals in focal regions including the perioral somatosensory cortex, known to be intensely involved during seizures, whereas the occipital cortex was spared. For comparison, we also studied bicuculline-induced generalized tonic-clonic seizures under the same conditions, and found fMRI increases to be larger and more widespread than during spike-and-wave seizures. These findings suggest that even in regions with intense neuronal activity during epileptic seizures, oxygen delivery exceeds metabolic needs, enabling fMRI to be used for investigation of dynamic cortical and subcortical network involvement in this disorder.

Animals↗
PubMed2004

Relative changes in cerebral blood flow and neuronal activity in local microdomains during generalized seizures.

There is broad agreement that generalized tonic-clonic seizures (GTCS) and normal somatosensory stimulation are associated with increases in regional CBF. However, the data regarding CBF changes during absence seizures are controversial. Electrophysiologic studies in WAG/Rij rats, an established animal model of absence seizures, have shown spike-wave discharges (SWD) that are largest in the perioral somatosensory cortex while sparing the visual cortex. Recent functional magnetic resonance imaging (fMRI) studies in the same model have also shown localized increases in fMRI signals in the perioral somatosensory cortex during SWD. Because fMRI signals are only indirectly related to neuronal activity, the authors directly measured CBF and neuronal activity from specific microdomains of the WAG/Rij cortex using a specially designed probe combining laser-Doppler flowmetry and extra-cellular microelectrode recordings under fentanyl/haloperidol anesthesia. Using this approach, parallel increases in neuronal activity and CBF were observed during SWD in the whisker somatosensory (barrel) cortex, whereas the visual cortex showed no significant changes. For comparison, these measurements were repeated during somatosensory (whisker) stimulation, and bicuculline-induced GTCS in the same animals. Interestingly, whisker stimulation increased neuronal activity and CBF in the barrel cortex more than during SWD. During GTCS, much larger increases that included both the somatosensory and visual cortex were observed. Thus, SWD in this model produce parallel localized increases in neuronal activity and CBF with similar distribution to somatosensory stimulation, whereas GTCS produce larger and more widespread changes. The normal response to somatosensory stimulation appears to be poised between two abnormal responses produced by two physiologically different types of seizures.

Animals↗
PubMed2003

Targeted prefrontal cortical activation with bifrontal ECT.

The anatomical brain regions involved in the therapeutic and adverse actions of electroconvulsive therapy (ECT) are unknown. Previous studies suggest that bifrontal vs. bitemporal ECT differ in therapeutic efficacy and cognitive side effects. We therefore performed cerebral blood flow (CBF) imaging during bitemporal vs. bifrontal ECT-induced seizures to identify regions crucial for the differences between these treatments. Patients with major depression, undergoing bitemporal or bifrontal ECT, were studied. Ictal-interictal SPECT images were analyzed with statistical parametric mapping for bitemporal (n=11 image pairs in 8 patients) and bifrontal (n=4 image pairs in 2 patients) ECT-induced seizures to identify regions of ictal CBF changes. Bifrontal ECT was found to cause increases in CBF in prefrontal and anterior cingulate regions. Bitemporal ECT, however, caused CBF increases in the lateral frontal cortex and in the anterior temporal lobes. In bifrontal ECT, a greater increase in prefrontal activation, while sparing the temporal lobes, may result in a better therapeutic response and fewer adverse effects on memory than bitemporal ECT.

Cerebrovascular Circulation↗
PubMed2003

Selective frontal, parietal, and temporal networks in generalized seizures.

Are "generalized" seizures truly generalized? Generalized tonic-clonic seizures are classified as either secondarily generalized with local onset or primarily generalized, without known focal onset. In both types of generalized seizures widespread regions of the nervous system engage in abnormally synchronous and high-frequency neuronal firing. However, emerging evidence suggests that all neurons are not homogeneously involved; specific nodes within the network may be crucial for the propagation and behavioral manifestations of generalized tonic-clonic seizures. Study of human tonic-clonic seizures has been limited by problems with patient movement and variable seizure types. To circumvent these problems, we imaged generalized tonic-clonic seizures during electroconvulsive therapy, in which seizure type and timing are well controlled. (99m)Tc-hexamethylpropylene amine oxime injections during seizures provide a "snapshot" of cerebral blood flow that can be imaged by single photon emission computed tomography (SPECT) after seizure termination. Here we show that focal regions of frontal and parietal association cortex show the greatest relative signal increases. Involvement of the higher-order association cortex may explain the profound impairment of consciousness seen in generalized seizures. In addition, focal involvement of the dominant temporal lobe was associated with impaired retrograde verbal memory. Similar focal increases were also seen in imaging of spontaneous secondarily generalized tonic-clonic seizures. Relative sparing of many brain regions during both spontaneous and induced seizures suggests that specific networks may be more important than others in so-called generalized seizures.

Adult↗
PubMed2003

Levetiracetam efficacy in refractory partial-onset seizures, especially after failed epilepsy surgery.

PURPOSE: We conducted a retrospective study to evaluate the efficacy of levetiracetam as adjunctive therapy in patients with localization-related epilepsy, and specifically in the subset of patients for whom epilepsy surgery failed. METHODS: Eighty-two patients with uncontrolled partial-onset seizures treated with levetiracetam were identified; epilepsy surgery had failed for 21 (25.6%; group I), and 61 (74.4%) had no prior surgery (group II). Group I and group II patients were comparable in age (mean, 40.7 vs. 41.5 years) and age at seizure onset (mean, 14.4 vs. 18.2 years). Patients who had >/=50% reduction in seizure frequency were considered responders; the remaining patients were considered nonresponders. RESULTS: In patients (group I) for whom surgery had failed, responder rate was 76.1% (16 of 21), including 10 (47.6%) patients who became seizure free. In nonsurgical patients (group II), responder rate was 34.3% (21 of 61), including nine (14.7%) patients who became seizure free. In group I, 11 (91.6%) of 12 temporal resection patients were responders, of whom eight were seizure free; of the remaining nine operated (extratemporal) patients, five (55.5%) were responders, and two were seizure free. In three responders, all in group I, a severe, delayed psychotic syndrome developed 4 to 9 months after levetiracetam introduction, leading to its discontinuation. CONCLUSIONS: These findings suggest that adjunctive levetiracetam therapy should be considered early after failed epilepsy surgery, especially after temporal resection, and may have implications for its use before surgical intervention. Patients should be under close psychiatric observation in this clinical setting.

Adolescent↗
PubMed2003

From molecules to networks: cortical/subcortical interactions in the pathophysiology of idiopathic generalized epilepsy.

Generalized epilepsy involves abnormally synchronized activity in large-scale neuronal networks. Burst firing of action potentials is a potent mechanism for increasing neural synchrony and is thought to enhance cortical and thalamic rhythmic network activity. Absence seizures, a form of generalized epilepsy, occur in children as brief 5- to 10-s periods of behavioral arrest associated with massive 3- to 4-Hz spike-wave discharges in cortical and thalamic networks. Prior research has shown that enhanced burst firing may be crucial for the transition from normal to epileptic activity. Can enhanced burst firing in one region of the nervous system, such as the cortex, transform the entire thalamocortical network from normal activity to spike-and-wave seizures? Enhanced burst firing in corticothalamic neurons may increase gamma-aminobutyric acid-B (GABAB) receptor activation in the thalamus, leading to the slower, more synchronous oscillations seen in spike-and-wave seizures. Does "generalized" spike-wave activity homogeneously involve the entire brain, or are there crucial nodes that are more important than others for the generation and behavioral manifestations of generalized seizures? Animal and human data suggest that so-called generalized seizures involve selective thalamocortical networks while sparing others. A greater understanding of these molecular and network mechanisms will ultimately lead to improved targeted therapies for generalized epilepsy.

Animals↗
PubMed2003

Why do seizures cause loss of consciousness?

Model systems are needed for the scientific investigation of consciousness. A good model system should include variable states of consciousness, allowing the relationship between brain activity and consciousness to be investigated. Examples include sleep, anesthesia, focal brain lesions, development, evolution, and epilepsy. One advantage of epilepsy is that changes are dynamic and rapidly reversible. The authors review previous investigations of impaired consciousness in epilepsy and describe new findings that may shed light on both normal and abnormal mechanisms of consciousness. Abnormal increased activity in fronto-parietal association cortex and related subcortical structures is associated with loss of consciousness in generalized seizures. Abnormal decreased activity in these same networks may cause loss of consciousness in complex partial seizures. Thus, abnormally increased or decreased activity in the same networks can cause loss of consciousness. Information flow during normal conscious processing may require a dynamic balance between these two extremes of excitation and inhibition.

Animals↗
PubMed2002

Cerebral energetics and spiking frequency: the neurophysiological basis of fMRI.

Functional MRI (fMRI) is widely assumed to measure neuronal activity, but no satisfactory mechanism for this linkage has been identified. Here we derived the changes in the energetic component from the blood oxygenation level-dependent (BOLD) fMRI signal and related it to changes in the neuronal spiking frequency in the activated voxels. Extracellular recordings were used to measure changes in cerebral spiking frequency (Deltanu/nu) of a neuronal ensemble during forepaw stimulation in the alpha-chloralose anesthetized rat. Under the same conditions localized changes in brain energy metabolism (DeltaCMR(O2)/CMR(O2)) were obtained from BOLD fMRI data in conjunction with measured changes in cerebral blood flow (DeltaCBF/CBF), cerebral blood volume (DeltaCBV/CBV), and transverse relaxation rates of tissue water (T(2)(*) and T(2)) by MRI methods at 7T. On stimulation from two different depths of anesthesia DeltaCMR(O2)/CMR(O2) approximately Deltanu/nu. Previous (13)C magnetic resonance spectroscopy studies, under similar conditions, had shown that DeltaCMR(O2)/CMR(O2) was proportional to changes in glutamatergic neurotransmitter flux (DeltaV(cyc)/V(cyc)). These combined results show that DeltaCMR(O2)/CMR(O2) approximately DeltaV(cyc)/V(cyc) approximately Deltanu/nu, thereby relating the energetic basis of brain activity to neuronal spiking frequency and neurotransmitter flux. Because DeltaCMR(O2)/CMR(O2) had the same high spatial and temporal resolutions of the fMRI signal, these results show how BOLD imaging, when converted to DeltaCMR(O2)/CMR(O2), responds to localized changes in neuronal spike frequency.

Animals↗
PubMed2002

The role of subcortical structures in human epilepsy.

Like normal cerebral function, epileptic seizures involve widespread network interactions between cortical and subcortical structures. Although the cortex is often emphasized as the site of seizure origin, accumulating evidence points to a crucial role for subcortical structures in behavioral manifestations, propagation, and, in some cases, initiation of epileptic seizures. Extensive previous studies have shown the importance of subcortical structures in animal seizure models, but corresponding human studies have been relatively few. We review the existing evidence supporting the importance of the thalamus, basal ganglia, hypothalamus, cerebellum, and brain stem in human epilepsy. We also propose a "network inhibition hypothesis" through which focal cortical seizures disrupt function in subcortical structures (such as the medial diencephalon and pontomesencephalic reticular formation), leading secondarily to widespread inhibition of nonseizing cortical regions, which may in turn be responsible for behavioral manifestations such as loss of consciousness during complex partial seizures.

Journal Article↗
PubMed2002

Comparison of statistical parametric mapping and SPECT difference imaging in patients with temporal lobe epilepsy.

PURPOSE: Statistical parametric mapping (SPM) is an image-analysis tool that assesses the statistical significance of cerebral blood flow (CBF) changes on a voxel-by-voxel basis, thereby removing the subjectivity inherent in conventional region-of-interest (ROI) analysis. Our platform of single-photon emission computed tomography (SPECT) ictal-interictal difference imaging in clinical epilepsy has been validated for localizing seizure onset. We extend the tools of SPM by further applying statistical measures for the significance of perfusion changes in individual patients to localize epileptogenic foci in patients with defined temporal lobe epilepsy by using paired scans in this preliminary study. METHODS: Twelve patients with pairs of periictal and interictal SPECT scans were analyzed in this comparison study between SPECT difference imaging and SPM difference analysis by using a reference database of paired normal healthy images. These 12 patients possessed seizure foci localized to the mesial temporal lobe as confirmed by surgical outcome and by hippocampal sclerosis on pathology. SPM was used to identify clusters of increased or decreased CBF in each patient in contrast to our control group. RESULTS: The regions having the most significant increased or decreased CBF by SPM analysis were in agreement with regions identified by conventional difference imaging and visual analysis by viewers blinded to the results of the SPM analysis. Differentiated further by time of radiopharmaceutical injection, six of seven patients injected within 100 s of seizure onset displayed hyperperfusion changes localized to the corresponding epileptogenic temporal lobe by both techniques. Among patients receiving injections after 100 s, both techniques showed primarily regions of hypoperfusion, which again were similar between these two methods. CONCLUSIONS: The results provide strong evidence supporting SPM difference analysis in assessing regions of significant CBF change from baseline in concordance with our current clinically used technique of SPECT ictal--interictal difference imaging in epilepsy patients. Difference analysis using SPM could serve as a useful diagnostic tool in the evaluation of seizure focus in temporal lobe epilepsy.

Adolescent↗