Multiple roles of midline dorsal thalamic nuclei in induction and spread of limbic seizures

PURPOSE: Studies have suggested that the medial dorsal nucleus of the thalamus plays a role in the behavioral expression of limbic seizures, but it is unclear whether this region is a key component for the primary seizure circuitry or a path for seizure spread from one region to another. This study was undertaken to determine the potential role of this region in limbic seizure activity. METHODS: Adult male rats received kindling stimulation either under urethane anesthesia or while awake. Glutamate or its agonists or the GABA antagonist bicuculline or agonist muscimol were infused into the medial dorsal nucleus. In another series, kindling acquisition was compared among three thalamic sites as well as with the amygdala and hippocampus RESULTS: Drugs that enhanced excitatory drive or blocked GABA resulted in significant prolongation of electrographic seizure activity compared to saline infused controls. Enhanced GABA activity resulted in a significant reduction of seizure duration. Infusion of the compounds lateral to the medial dorsal nucleus did not affect seizure duration. In the kindling studies the medial dorsal region is the only thalamic nucleus from which hippocampal seizures can be induced, but with an elevated afterdischarge threshold compared to the two limbic sites. However, the seizures generalized more rapidly from the medial dorsal region. CONCLUSIONS: This study demonstrates that the medial dorsal nucleus and other dorsal midline nuclei have a significant role in the primary seizure circuits of limbic seizures as well as in spread of seizure activity to other regions.     

Different patterns of neuronal activation and neurodegeneration in the thalamus and cortex of epilepsy‐resistant Proechimys rats versus Wistar rats after pilocarpine‐induced protracted seizures

Purpose: To analyze cellular mechanisms of limbic‐seizure suppression, the response to pilocarpine‐induced seizures was investigated in cortex and thalamus, comparing epilepsy‐resistant rats Proechimys guyannensis with Wistar rats. Methods: Fos immunoreactivity revealing neuronal activation, and degenerating neurons labeled by Fluoro‐Jade B (FJB) histochemistry were analyzed on the first day after onset of seizures lasting 3 h. Subpopulations of γ‐aminobutyric acid (GABA)ergic cells were characterized with double Fos‐parvalbumin immunohistochemistry. Results: In both cortex and thalamus, degenerating neurons were much fewer in Proechimys than Wistar rats. Fos persisted at high levels at 24 h only in the Proechimys thalamus and cortex, especially in layer VI where corticothalamic neurons reside. In the parietal cortex, about 50% of parvalbumin‐containing interneurons at 8 h, and 10–20% at 24 h, were Fos‐positive in Wistar rats, but in Proechimys, Fos was expressed in almost all parvalbumin‐containing interneurons at 8 h and dropped at 24 h. Fos positivity in cingulate cortex interneurons was similar in both species. In the Wistar rat thalamus, Fos was induced in medial and midline nuclei up to 8 h, when <30% of reticular nucleus cells were Fos‐positive, and then decreased, with no relationship with cell loss, evaluated in Nissl‐stained sections. In Proechimys, almost all reticular nucleus neurons were Fos‐positive at 24 h. Discussion: At variance with laboratory rats, pilocarpine‐induced protracted seizures elicit in Proechimys limited neuronal death, and marked and long‐lasting Fos induction in excitatory and inhibitory cortical and thalamic cell subsets. The findings implicate intrathalamic and intracortical regulation, and circuits linking thalamus and cortex in limbic seizure suppression leading to epilepsy resistance.     

Increased GABAergic inhibition in the midline thalamus affects signaling and seizure spread in the hippocampus-prefrontal cortex pathway

Purpose: The midline thalamus is an important component of the circuitry in limbic seizures, but it is unclear how synaptic modulation of the thalamus affects that circuitry. In this study, we wished to understand how synaptic modulation of the thalamus can affect interregional signaling and seizure spread in the limbic network. Methods: We examined the effect of γ‐aminobutyric acid (GABA) modulation of the mediodorsal (MD) region of the thalamus on responses in the prefrontal cortex (PFC) by stimulation of the subiculum (SB). Muscimol, a GABA_A agonist, was injected into the MD, and the effect on local responses to subiculum stimulation was examined. Evoked potentials were induced in the MD and the PFC by low‐frequency stimulation of the SB, and seizures were generated in the subiculum by repeated 20‐Hz stimulations. The effect of muscimol in the MD on the evoked potentials and seizures was measured. Key Findings: Thalamic responses to stimulation of the subiculum were reduced in the presence of muscimol. Reduction of the amplitudes of evoked potentials in the MD resulted in an attenuation of the late, thalamic components of the responses in the PFC, as well as of seizure durations. Significance: Activation of GABA_A receptors in the midline thalamus not only causes changes within the thalamus, but it has broader effects on the limbic network. This work provides further evidence that synaptic modulation within the midline thalamus alters system excitability more broadly and reduces seizure activity.     

Subcortical structures and pathways involved in convulsive seizure generation.

Convulsive seizures in animal models usually involve one or more of the following components: (1) limbic motor seizures, (2) explosive running-bouncing clonic seizures, and (3) tonic extensor seizures. Each of these components depends on specific and experimentally separable anatomic substrates. Limbic motor seizures depend on forebrain structures for their initiation and propagation, with the prepiriform, piriform, and entorhinal cortices playing a prominent role in conjunction with hippocampus, amygdala, substantia innominata, and mediodorsal thalamus. In contrast, seizures involving running-bouncing clonus or tonic extension depend on neural substrates in the brainstem and do not appear to require the integrity of the forebrain for their development or expression. The inferior colliculus is a region from which running-bouncing seizures can be elicited by chemical or electrical stimulation. Tonic extensor seizures depend on the integrity of the nucleus reticularis pontis oralis, but a specific locus responsible for triggering these seizures has yet to be identified. Under conditions of chronic or repeated seizure activity over prolonged time periods, seizures evoked from the hindbrain can recruit forebrain circuits; conversely, repeated stimulation of forebrain limbic circuits (e.g., kindling) can modify susceptibility to brainstem convulsions. These long-term alterations may result from changes in the activity of seizure "gating" pathways, which are circuits that influence seizure susceptibility by modulating the threshold for the initiation and/or propagation of the seizures. In general, these pathways are not part of any core seizure propagation pathway per se. In many cases, the gating substrates are relatively nonselective as to the type of seizure they can influence. In this category, the substantia nigra and its related circuits within the basal ganglia serve a prominent role. In addition, ascending noradrenergic projections have been implicated in the regulation of seizure threshold. Other gating mechanisms involve thalamic circuitry and pathways originating in cerebellum.     

Role of the nonspecific thalamus in amygdaloid kindling

The effects of lesions of the inferior thalamic peduncle, rostral thalamic nuclei, dorsomedial nucleus, and ventroanterior nucleus on the developing and established kindled amygdaloid convulsion were examined. Lesions of these regions made before kindling produced a slight but nonsignificant facilitation in the rate of primary-site seizure development. However, lesions of these same regions made after primary-site kindling resulted in a transient but significant disruption in subsequent seizures. These data suggest that the nonspecific thalamic projection system does not critically participate in amygdaloid kindling. Furthermore, because previous studies established a major role for the nonspecific thalamus in partial epilepsy of neocortical origin, we suggest that the mechanisms that underlie seizures of neocortical origin may differ from those of limbic origin.     

Glucose and [11C]flumazenil positron emission tomography abnormalities of thalamic nuclei in temporal lobe epilepsy

OBJECTIVES: To analyze interictal patterns of thalamic nuclei glucose metabolism and benzodiazepine receptor binding in patients with medically intractable temporal lobe epilepsy (TLE) using high-resolution 2-deoxy-2-[18F]fluoro-D-glucose (FDG) and [11C]flumazenil (FMZ) PET. BACKGROUND: Structural and glucose metabolic abnormalities of the thalamus are considered important in the pathophysiology of TLE. The differential involvement of various thalamic nuclei in humans is not known. METHODS: Twelve patients with TLE underwent volumetric MRI, FDG and FMZ PET, and prolonged video-EEG monitoring. Normalized values and asymmetries of glucose metabolism and FMZ binding were obtained in three thalamic regions (dorsomedial nucleus [DMN], pulvinar, and lateral thalamus [LAT]) defined on MRI and copied to coregistered, partial-volume-corrected FDG and FMZ PET images. Hippocampal and amygdaloid FMZ binding asymmetries and thalamic volumes also were measured. RESULTS: The DMN showed significantly lower glucose metabolism and FMZ binding on the side of the epileptic focus. The LAT showed bilateral hypermetabolism and increased FMZ binding. There was a significant correlation between the FMZ binding asymmetries of the DMN and amygdala. The PET abnormalities were associated with a significant volume loss of the thalamus ipsilateral to the seizure focus. CONCLUSIONS: Decreased [11C]flumazenil (FMZ) binding and glucose metabolism of the dorsomedial nucleus (DMN) are common and have strong lateralization value for the seizure focus in human temporal lobe epilepsy. Decreased benzodiazepine receptor binding can be due to neuronal loss, as suggested by volume loss, but also may indicate impaired gamma-aminobutyric acid (GABA)ergic transmission in the DMN, which has strong reciprocal connections with other parts of the limbic system. Increased glucose metabolism and FMZ binding in the lateral thalamus could represent an upregulation of GABA-mediated inhibitory circuits.     

Altered pharmacology and GABA-A receptor subunit expression in dorsal midline thalamic neurons in limbic epilepsy

The mediodorsal (MD) and paraventricular (PV) thalamic nuclei play a significant role in limbic epilepsy, and previous reports have shown changes in GABA-A receptor (GABAAR) mediated synaptic function. In this study, we examined changes in the pharmacology of GABAergic drugs and the expression of the GABAAR subunits in the MD and PV neurons in epilepsy. We observed nucleus specific changes in the sensitivity of sIPSCs to zolpidem and phenobarbital in MD and PV neurons from epileptic animals. In contrast, the magnitude of change in electrically evoked response (eIPSC) to zolpidem and phenobarbital were uniformly diminished in both MD and PV neurons in epilepsy. Immunohistochemical studies revealed that in epilepsy, there was a reduction in GAD65 expression and NeuN positive neurons in the MD neurons. Also, there was a decrease in immunoreactivity of the alpha1 and beta2/3 subunit of GABAARs, but not the gamma2 of the GABAAR in both MD and PV in epilepsy. These findings demonstrate significant alterations in the pharmacology of GABA and GABAARs in a key region for seizure generation, which may have implications for the physiology and pharmacology of limbic epilepsy.     

The Pathological Substrate of Limbic Epilepsy: Neuronal Loss in the Medial Dorsal Thalamic Nucleus as the Consistent Change

Summary: Purpose : The focus of research in limbic epilepsy has been the hippocampus because of its well-known pathology of hippocampal atrophy and sclerosis as well as the strong propensity for this structure to seize under a variety of circumstances. There is ample evidence, however, for pathological alterations in other regions of the limbic system in limbic/mesial temporal lobe epilepsy, including the amygdala, the entorhinal cortex, and, in some cases, the thalamus. In this preliminary evaluation of the pathological substrate for limbic epilepsy, we wished to determine if there was consistent anatomic change at extrahippocampal sites.
Methods : We compared paraffin sections of brains from rats with chronic spontaneous limbic epilepsy and age-matched controls to determine the consistency of the pathology at five sites: the hippocampus, amygdala, entorhinal cortex, piriform cortex, and medial dorsal thalamus.
Results : In a qualitative evaluation of these sections taken from standardized positions, we found that the medial dorsal thalamic nucleus in the epileptic animals was the site that was consistently involved with neuronal loss. With all other sites, at least several animals had qualitatively normal tissue.
Conclusions : This finding suggests that neuronal loss in the medial dorsal thalamus may be the consistent pathology in limbic epilepsy, at least in an animal model of the disorder. The presence of a structurally abnormal subcortical region with broad connections to the limbic sites involved with chronic epilepsy may have implications for our understanding of the pathophysiology of this disorder.     

Identification of a Median Thalamic System Regulating Seizures and Arousal

This study better defines the way in which the thalamus controls expression of experimental generalized seizures. The effects of small intrathalamic injections of the direct GABA agonist muscimol on the thresholds of pentylenetetrazol (PTZ)-induced seizures and on spontaneous behavior were determined in the rat and compared with the effects of injections of gamma-vinyl-GABA (GVG), an irreversible inhibitor of GABA transaminase. Muscimol injections produced neuronal inhibition in a relatively small area of thalamus, whereas GVG injections produced inhibition in a much larger area. Muscimol injections in the midline thalamus in the vicinity of the paraventricular, paratenial, interanteromedial, intermediodorsal, and central medial nuclei facilitated PTZ myoclonic and clonic seizures and also produced sedation. These effects on seizure thresholds were attributable both to a lower PTZ threshold dose for initiation of electroencephalographic (EEG) seizure activity and to an increased probability of this EEG activity being expressed as behavioral seizures. Midline injections located more posteriorly in the thalamus also inhibited tonic seizures. Muscimol injections placed laterally, dorsally, or ventrally to this midline thalamic region had much less effect on behavior or seizures. In contrast, GVG injections in the anterior medial thalamus elevated the threshold for all PTZ seizure types and for associated EEG seizure activity but had little effect on spontaneous behavior. These findings demonstrate the existence of an important seizure regulatory system in the midline of the thalamus and a direct anatomic link between the mechanisms for regulating arousal and seizure production which may help explain the association between sleep and seizure facilitation in humans.(ABSTRACT TRUNCATED AT 250 WORDS)     

Thalamic midline cell populations projecting to the nucleus accumbens, amygdala, and hippocampus in the rat.

The organization of the thalamic midline efferents to the amygdaloid complex, hippocampal formation, and nucleus accumbens was investigated in the rat by means of multiple retrograde fluorescent tracing. The present findings indicate that these connections derive from separate cell populations of the thalamic midline, with a low degree of divergent collateralization upon more than one of the targets examined. The neural populations projecting to the amygdala, hippocampus, or accumbens are highly intermingled throughout the thalamic midline, but display some topographical prevalence. Midline thalamo-hippocampal cells are concentrated in the nucleus reuniens; thalamo-accumbens neurons prevail in the ventral portion of the paraventricular nucleus, and in the central medial nucleus. Thalamo-amygdaloid cells display a topographical prevalence in the rostral third of the thalamic midline and are concentrated in the dorsal part of the paraventricular nucleus and in the medial part of the nucleus reuniens. Both dorsally in the paraventricular nucleus and ventrally in the nucleus reuniens, thalamo-amygdaloid cells are located closer to the ependymal lining than the neurons projecting to the hippocampus or nucleus accumbens. Further, thalamo-amygdaloid cells, especially in the paraventricular nucleus, extend their dendritic processes in the vicinity of the ependymal lining, where they arborize profusely. These features indicate a close topographical relationship of neurons projecting to the amygdala with ependymal cells. The fairly discrete origin of midline outputs to the amygdala, hippocampus, and accumbens indicates that the flow of information is conveyed through separate channels from the thalamic midline to limbic and limbic-related targets. Together with the literature on the limbic afferents to the thalamus, these findings emphasize the relationships between the thalamus and the limbic system subserved by parallel input-output routes. However, because of the overlap of the projection cell populations, the thalamic midline may represent a locus of interaction among neurons connected with different parts of the limbic system. The functional implications of these findings are discussed in relation to the "nonspecific" thalamic system, as well as to the circuits involved in memory formation.     

Epilepsy: a review of selected clinical syndromes and advances in basic science.

Epilepsy is a common neurologic disorder that manifests in diverse ways. There are numerous seizure types and numerous mechanisms by which the brain generates seizures. The two hallmarks of seizure generation are hyperexcitability of neurons and hypersynchrony of neural circuits. A large variety of mechanisms alters the balance between excitation and inhibition to predispose a local or widespread region of the brain to hyperexcitability and hypersynchrony. This review discusses five clinical syndromes that have seizures as a prominent manifestation. These five syndromes differ markedly in their etiologies and clinical features, and were selected for discussion because the seizures are generated at a different 'level' of neural dysfunction in each case: (1) mutation of a specific family of ion (potassium) channels in benign familial neonatal convulsions; (2) deficiency of the protein that transports glucose into the CNS in Glut-1 deficiency; (3) aberrantly formed local neural circuits in focal cortical dysplasia; (4) synaptic reorganization of limbic circuitry in temporal lobe epilepsy; and (5) abnormal thalamocortical circuit function in childhood absence epilepsy. Despite this diversity of clinical phenotype and mechanism, these syndromes are informative as to how pathophysiological processes converge to produce brain hyperexcitability and seizures.     

Why does surgery fail to cure limbic epilepsy? Seizure functional anatomy may hold the answer

Surgery for the mesial temporal lobe epilepsy syndrome is highly effective in controlling seizures in as many as 80% of the patients who undergo this procedure. However, the majority of the patients with successful operations still require medications to control their seizures. Only a small minority are able to stop medications and remain seizure free, patients who would be considered cured. Why are so few patients cured by this procedure? The answer may lie in the relation of the critical seizure circuits to the tissue that is actually resected. In this paper we will discuss two hypotheses for the functional anatomy of limbic epilepsy in light of what is known about the pathology and physiology of limbic epilepsy. Combining the clinical and scientific observations with these constructs for seizure initiation may lead us to a better understanding of this particular epilepsy syndrome as well as to more effective surgical approaches.     

Thalamic kindling: electrical stimulation of the lateral geniculate nucleus produces photosensitive grand mal seizures

Kindling is traditionally viewed as a chronic, focal epilepsy model which consistently induces complex partial seizures from limbic structures in animals. This study revealed that primary or exceedingly rapid secondary generalized seizures could also be kindled when stimulation was applied to the lateral geniculate nucleus, a thalamic region involved in sleep regulation and possibly also photosensitive epilepsy. Two experiments were conducted in cats. Experiment 1 compared the development of generalized tonic-clonic convulsions and associated sleep disorders following electrical stimulation of the lateral geniculate nucleus (N = 4) and the amygdala (N = 4). Experiment 2 described the effects of intermittent light stimulation on seizure thresholds in both groups. Three primary findings distinguished the epileptogenic process in those two brain regions. First, generalized electroencephalographic and clinical seizures accompanied the first afterdischarge obtained with thalamic stimulation. In contrast, focal seizures with secondary generalization appeared during a 3- to 4-week period of afterdischarge elicitations from the amygdala. Second, amygdala-kindled cats showed fewer sleep spindles during slow-wave sleep whereas cats kindled in the lateral geniculate nucleus had abnormal sleep spindles approaching spike wave-like activity. Third, only the latter cats showed reduced seizure thresholds in response to photic stimulation. Based on the anatomic substrates involved, the clinical and electrographic profiles observed during kindling and the type of sleep disturbance shown, we concluded that lateral geniculate nucleus kindling may represent primary generalized epilepsy, possibly of a photosensitive nature; alternatively, the rapid propagation of abnormal discharge was also consistent with the important role of the thalamus in secondary seizure generalization.     

Effect of stage 2 kindling on local cerebral blood flow rates in rats with genetic absence epilepsy

Purpose:   Genetic absence epilepsy rats from Strasbourg (GAERS) are resistant to the progression of kindling seizures. We studied local cerebral blood flow (LCBF) changes in brain regions involved in seizures in both GAERS and nonepileptic rats (NEC) to map the differences that may be related to the resistance to kindling.
Methods:   Electrodes were implanted in the amygdala of adult NEC and GAERS male rats, which were stimulated to reach stage 2. Quantitative autoradiographic measurements of LCBF were performed by the [¹⁴C]-iodoantipyrine ([¹⁴C]IAP) autoradiographic technique allowing the precise mapping of regional perfusion changes. LCBF rates were measured bilaterally in 43 brain regions. The tracer infusion lasted for 60 s and started at 15 s before seizure induction.
Results:   Rates of LCBF increased in stimulated GAERS and NEC groups compared to nonstimulated controls. The LCBF increase in stimulated GAERS was larger and more widespread than that observed in stimulated NEC. The LCBF increase in the somatosensory cortex, ventrobasal and anterior thalamic nuclei, hypothalamus, subthalamic nucleus, piriform, entorhinal and perirhinal cortex, amygdala, CA2 region of hippocampus, and substantia nigra was statistically significantly larger in stimulated GAERS compared to stimulated NEC rats.
Conclusion:   The results show that more brain regions are activated by kindling stimulation in GAERS. This widespread activation in GAERS involves the somatosensory cortex and thalamus, which are both known to be involved in the expression of absence seizures as well as numerous limbic regions thought not to play a role in the expression of absence seizures, suggesting an interaction between corticothalamocortical and limbic circuitries.     

Coupling of Cortical and Thalamic Ictal Activity in Human Partial Epilepsy: Demonstration by Functional Magnetic Resonance Imaging

Summary: Purpose: To localize metabolic coupling between a cortical seizure focus and other brain regions by using functional magnetic resonance imaging (fMRI) data of ictal events obtained in a patient with frequent partial seizures involving his right face.
Methods: Cross-correlation analysis was used to examine time-dependent alterations in regional signal intensity that correlated with signal-intensity changes from a well-characterized cortical seizure focus in a patient with frequent partial seizures.
Results: Signal changes in the left ventrolateral thalamus showed a high degree of temporal correlation with signal changes in the left frontal cortical seizure focus, demonstrating close corticothalamic coupling of metabolism.
Conclusions: A significant role for thalamocortical interactions in the pathophysiology of epilepsy has been suggested by studies in animal models and human patients. This finding provides further support for the integral involvement of the thalamus in human focal epilepsy and underscores the potential for identifying neuronal networks by using cross-correlation analysis of fMRI data.     

应用Fluoro-Jade C评价匹罗卡品模型丘脑神经变性

目的 应用Fluoro-Jade C(FJC)染色方法 观察小鼠匹罗卡品癫(癎)模型丘脑神经元变性情况,以了解丘脑结构在慢性颞叶癫痫发生中的病理变化和癫(癎)反复发作的神经学基础.方法 以盐酸匹罗卡品腹腔注射(220 mg/kg)制备小鼠癫痼持续状态模型.脑组织切片经FJC染色后.荧光显微镜下观察FJC阳性细胞形态和在丘脑的整体分布情况.结果 匹罗卡品模型组小鼠FJC阳性细胞呈神经元形态,丘脑结构损害呈连续性.功能不同的丘脑核其细胞损害程度有所不同.结论 采用FJC染色技术观察匹罗卡品癫(癎)持续状态小鼠模型丘脑神经元变性情况,有利于更好地理解颞叶癫(癎)的中枢神经系统长期病理变化和自发性反复发作机制.     

Chronic anterior thalamus stimulation for intractable epilepsy

PURPOSE: A significant number of patients with epilepsy remain poorly controlled despite antiepileptic medication (AED) treatment and are not eligible for resective surgery. Novel therapeutic methods are required to decrease seizure burden in this population. Several observations have indicated that the anterior thalamic region plays an important role in the maintenance and propagation of seizures. We investigated neuromodulation of the anterior thalamus by using deep-brain stimulation (DBS) in patients with intractable seizures. METHODS: Five patients with medically refractory epilepsy underwent stereotactic placement of and received stimulation through bilateral DBS electrodes in the anterior thalamus. RESULTS: Treatment showed a statistically significant decrease in seizure frequency, with a mean reduction of 54% (mean follow-up, 15 months). Two of the patients had a seizure reduction of > or =75%. No adverse effects were observed after DBS electrode insertion or stimulation. Unexpectedly, the observed benefits did not differ between stimulation-on and stimulation-off periods. CONCLUSIONS: DBS of the anterior thalamus is a safe procedure and possibly effective in patients with medically resistant seizures.     

Single-pulse stimulation of cerebellar nuclei stops epileptic thalamic activity

BackgroundEpileptic (absence) seizures in the cerebral cortex can be stopped by pharmacological and optogenetic stimulation of the cerebellar nuclei (CN) neurons that innervate the thalamus. However, it is unclear how such stimulation can modify underlying thalamo-cortical oscillations.HypothesisHere we tested whether rhythmic synchronized thalamo-cortical activity during absence seizures can be desynchronized by single-pulse optogenetic stimulation of CN neurons to stop seizure activity.MethodsWe performed simultaneous thalamic single-cell and electrocorticographical recordings in awake tottering mice, a genetic model of absence epilepsy, to investigate the rhythmicity and synchronicity. Furthermore, we tested interictally the impact of single-pulse optogenetic CN stimulation on thalamic and cortical recordings.ResultsWe show that thalamic firing is highly rhythmic and synchronized with cortical spike-and-wave discharges during absence seizures and that this phase-locked activity can be desynchronized upon single-pulse optogenetic stimulation of CN neurons. Notably, this stimulation of CN neurons was more effective in stopping seizures than direct, focal stimulation of groups of afferents innervating the thalamus. During interictal periods, CN stimulation evoked reliable but heterogeneous responses in thalamic cells in that they could show an increase or decrease in firing rate at various latencies, bi-phasic responses with an initial excitatory and subsequent inhibitory response, or no response at all.ConclusionOur data indicate that stimulation of CN neurons and their fibers in thalamus evokes differential effects in its downstream pathways and desynchronizes phase-locked thalamic neuronal firing during seizures, revealing a neurobiological mechanism that may explain how cerebellar stimulation can stop seizures.     

Arousal and Consciousness in Focal Seizures

Impaired consciousness during seizures severely affects quality of life for people with epilepsy but the mechanisms are just beginning to be understood. Consciousness is thought to involve large-scale brain networks, so it is puzzling that focal seizures often impair consciousness. Recent work investigating focal temporal lobe or limbic seizures in human patients and experimental animal models suggests that impaired consciousness is caused by active inhibition of subcortical arousal mechanisms. Focal limbic seizures exhibit decreased neuronal firing in brainstem, basal forebrain, and thalamic arousal networks, and cortical arousal can be restored when subcortical arousal circuits are stimulated during seizures. These findings open the possibility of restoring arousal and consciousness therapeutically during and following seizures by thalamic neurostimulation. When seizures cannot be stopped by existing treatments, targeted subcortical stimulation may improve arousal and consciousness, leading to improved safety and better psychosocial function for people with epilepsy.