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Thalamic abnormality in temporal lobe epilepsy (TLE) is well known from imaging studies, but evidence is lacking regarding connectivity profiles of the thalamus and their involvement in the disease process. We used a novel multisequence magnetic resonance imaging (MRI) protocol to elucidate the relationship between mesial temporal and thalamic pathology in TLE.For 23 patients with TLE and 23 healthy controls, we performed T1 -weighted (for analysis of tissue structure), diffusion tensor imaging (tissue connectivity), and T1 and T2 relaxation (tissue integrity) MRI across the whole brain. We used connectivity-based segmentation to determine connectivity patterns of thalamus to ipsilateral cortical regions (occipital, parietal, prefrontal, postcentral, precentral, and temporal). We subsequently determined volumes, mean tractography streamlines, and mean T1 and T2 relaxometry values for each thalamic segment preferentially connecting to a given cortical region, and of the hippocampus and entorhinal cortex.As expected, patients had significant volume reduction and increased T2 relaxation time in ipsilateral hippocampus and entorhinal cortex. There was bilateral volume loss, mean streamline reduction, and T2 increase of the thalamic segment preferentially connected to temporal lobe, corresponding to anterior, dorsomedial, and pulvinar thalamic regions, with no evidence of significant change in any other thalamic segments. Left and right thalamotemporal segment volume and T2 were significantly correlated with volume and T2 of ipsilateral (epileptogenic), but not contralateral (nonepileptogenic), mesial temporal structures.These convergent and robust data indicate that thalamic abnormality in TLE is restricted to the area of the thalamus that is preferentially connected to the epileptogenic temporal lobe. The degree of thalamic pathology is related to the extent of mesial temporal lobe damage in TLE.

Primary sensory and motor areas of the cerebral cortex contain organised maps of the body. These maps appear to reorganise after damage to the peripheral parts of the sensory or motor systems, so that the cortical representation of undamaged structures expands at the expense of the damaged parts. Several studies in animals have suggested that decreased activity of the inhibitory GABAergic neurones is responsible for driving these changes. However, whether similar mechanisms sustain the effects in the longer term in humans is unknown. The present study addressed this question by examining reorganisation of sensorimotor areas of cortex in six unilateral upper limb amputees several years after the initial injury. We measured two independent indices of GABAergic function. Volumes of distribution of GABA(A) receptors were determined from 11C-flumazenil binding measured with positron emission tomography (PET). The strength of inhibition in the motor cortex was measured with paired-pulse transcranial magnetic stimulation. In the six amputees taken as a whole and compared with 24 normal subjects, there was a highly significant increase in 11C-flumazenil binding in the upper limb region of primary sensorimotor cortex bilaterally and in medial frontal cortex of the hemisphere contralateral to the amputation. Surprisingly, however, there was no change in the time course or strength of intra-cortical inhibition in the motor cortex of the amputees compared with matched control subjects. The increased 11C-flumazenil binding may reflect up-regulation of GABA(A) receptors to compensate for a decrease in the GABA content or activity of inhibitory neurones. Up-regulation of GABA(A) receptors may also indicate that long-term changes require stabilisation of cortical organisation.

BACKGROUND/AIMS—To measure cerebral benzodiazepine receptor binding using 11C-flumazenil positron emission tomography in patients with stable chronic hepatic encephalopathy, who were also characterised by proton magnetic resonance spectroscopy. METHODS—Six abstinent patients of mean age 61 years with alcohol related cirrhosis and grade I-II hepatic encephalopathy and 11 matched healthy volunteers were studied. Each patient's encephalopathy was defined according to clinical, psychometric, electroencephalographic, and magnetic resonance spectroscopy criteria. Using positron emission tomography, the brain volume of distribution of 11C-flumazenil was obtained; this reflects benzodiazepine receptor availability. Proton magnetic resonance spectra were acquired at 1.5 T using a multivoxel technique; peak area ratios were calculated for choline, glutamine/glutamate, N-acetylaspartate, and creatine resonances. RESULTS—The mean volume of distribution of 11C-flumazenil was significantly higher in the cortex, cerebellum, and the basal ganglia in the patients compared with controls (p

Studies in animals implicate endogenous release of opioid peptides as a mechanism for terminating partial and generalised seizures. To localise dynamic changes in opioid neurotransmission associated with partial seizures and higher cognitive function, we investigated the release of endogenous opioids in patients with reading-induced seizures compared with healthy controls.Five patients who had reading epilepsy and six controls had 11C-diprenorphine (DPN) positron-emission-tomography (PET) scans while reading a string of symbols (baseline) or a scientific paper (activation). Statistical parametric mapping was used to find areas with differences in opioid-receptor binding.On activation scans mean 11C-DPN binding to opioid receptors was significantly lower (p0.05 corrected for multiple non-independent comparisons) in the left parieto-temporo-occipital cortex (Brodmann area 37) in reading-epilepsy patients compared with controls.These findings suggest that opioid-like substances are involved in the termination of reading-induced seizures.

Malformations of cortical development (MCD) are an important aetiology of localization-related epilepsy. Previous MRI and [11C]flumazenil PET studies have demonstrated widespread structural and neuroreceptor abnormalities beyond the region of MCD that is visually apparent on MRI. We investigated the ability of brain regions affected by MCD to participate in normal cognitive and motor tasks and compared the responses seen in such patients with those in normal subjects. We studied five patients known to have MCD affecting the occipital region and seven normal subjects using H2 (15)O PET whilst they were performing a visual attention task. We also studied five right-handed patients known to have MCD affecting the left frontal lobe and seven right-handed normal subjects, using H2 (15)O PET whilst they were performing a motor learning task with the right hand. The patient and normal control data were examined using statistical parametric mapping to determine the ability of the brain region affected by MCD to participate in the task and also to detect evidence for atypical organization of cortical function in association with the MCD. Eight of the ten patients with MCD showed significant alteration of relative regional cerebral blood flow during the task compared with 'rest' in the affected brain region. These regions included focally dysgenetic cortex, the cortex lining schizencephalic clefts, heterotopic bands, subependymal grey matter heterotopia, and the cortex overlying band and subependymal heterotopia. In addition there was a significant alteration in the overall activation pattern in five patients compared with the normal control groups; in all five patients this atypical organization involved regions of cortex that appeared entirely normal on MRI. We conclude that regions of MCD may participate in normal cognitive functions but widespread cortical atypical organization may be seen. These findings have implications for surgical planning in any such patients.

By using [ 11 C]flumaxenil-positron emission tomography ([ 11 C]FMZ-PET, we have previously shown that reductions of central benzodiazepine receptors (cBZRs) are restricted to the hippocampus in mesial temporal lobe epilepsy (mTLE) caused by unilateral hippocampal sclerosis (HS). Receptor autoradiographic studies on resected hippocampal specimens from the same patients demonstrated loss of cBZRs that was over and above loss of neurons in the CA1 subregion. Here, we report the first direct comparison of in vivo cBZR binding with [ 11 C]FMZPET and ex vivo binding using [ 3 H]FMZ autoradiography. We applied a magnetic resonance imaging-based method for partial volume effect correction to the PET images of [ 11 C]FMZ volume of distribution ([ ll c]FMZ V d ) obtained in 10 patients with refractory mTLE due to unilateral, histologically verified HS. Saturation autoradiography was performed on the hippocampal specimens obtained from the same patients, allowing calculation of receptor availability ([ 3 H]FMZ B max ). After correction for partial volume elect, [ 11 C]FMZ V d in the body of the epileptogenic hippocampus was reduced by a mean of 42.1% compared with normal controls. [ 3 H]FMZ B max , determined autoradiographically from the same hippocampal tissue, was reduced by a mean of 42.7% compared with control hippocampi. Absolute in vivo and ex vivo measurements of cBZR binding for the body of the hippocampus were significantly correlated in each individual. Our study demonstrates that reduction of available cBZR on remaining neurons in HS can be reliably detected in vivo by using [ 11 C]FMZPET after correction for partial volume effect.

Summary: Purpose: Previous [11C]flumazenil (FMZ) positron emission tomography (PET) investigations in patients with idiopathic generalized epilepsy (IGE) have demonstrated nonsignificant global cortical decreases in central benzodiazepine γ-aminobutyric acid, (GABAA) receptor (cBZR) binding or focal decreases in the thalamus and increases in the cerebellar nuclei with no changes in cerebral cortex. We previously reported lower [11C]FMZ binding in cerebral cortex of IGE patients treated with valproate (VPA) than in cerebral cortex of controls. We now report high-resolution three-dimensional [11C]FMZ PET studies in a larger number of subjects using an improved method to detect differences in cBZR between IGE patients and controls and a more powerful longitudinal design to determine the functional effect of VPA. Methods: We compared parametric images of [11C]FMZ volume of distribution (FMZVD) in 10 IGE patients before and after addition of VPA and in 20 normal subjects. Results: Mean FMZVD was significantly higher in the cerebral cortex (11%, p = 0.009), thalamus (14%, p = 0.018), and cerebellum (15%, p = 0.027) of the 10 IGE patients as compared with that of 20 normal controls. Using statistical parametric mapping, no significant areas of focal abnormality of FMZVD were detected. Addition of VPA was not associated with a significant change in mean FMZVD in any brain area. Conclusions: Our finding of increased FMZVD in IGE could reflect microdysgenesis or a state of cortical hyperexcitability. Our data suggest that short-term VPA therapy does not affect the number of available cBZR in patients with IGE.

Purpose: Liver enzyme inducing antiepileptic drugs (LEI AEDs) have adverse effects on bone metabolism but it is unclear whether this translates into increased fracture risk. This population based cohort study aimed to evaluate whether treatment with LEI AEDs is associated with increased risk of fracture in people with active epilepsy.Methods: The cohort included patients diagnosed with epilepsy and prescribed AEDs while registered at a GPRD general practice during 1993-2008. The hazard ratio with current use of LEI AEDs for fracture at any site and hip fracture was estimated using Cox proportional hazards models.Results: There were 7356 fractures (788 hip fractures) in 63 259 participants. In women, the adjusted hazard ratio with use of LEI AEDs was 1.22 for fracture (95% Cl 1.12-1.34; p Conclusions: LEI AEDs may increase the risk of fracture in people with epilepsy. In patients at high risk of osteoporotic fracture alternative AED therapy may be appropriate. Further information is urgently needed on the safety of valproate and newer AEDs and on strategies to maintain bone health in people who need to be treated with LEI. (C) 2012 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Previous imaging studies using C-11-flumazenil in patients with mesial temporal lobe epilepsy and neocortical partial seizure disorders have found focal decreases in gamma-aminobutyric acid type A/benzodiazepine receptor binding. These studies used subjective visual assessment and a region of interest approach to quantitation. We performed three-dimensional, C-11-flumazenil positron emission tomography in 12 patients with cortical dysgenesis identified by high-resolution volumetric magnetic resonance imaging and in 26 normal subjects. Spectral analysis was used to produce a parametric image of C-11-flumazenil volume of distribution for each subject. Using volumetric normalization and statistical parametric mapping, we compared the entire brain volume of each patient with the brains of the normal group to produce maps of regions of abnormal C-11-flumazenil binding which were then rendered into the volumetric magnetic resonance images. This allowed a correlation of structure and function to be made. Of the 12 patients, 10 showed at least one region of abnormal C-11-flumazenil binding; the abnormal regions were frequently more extensive than were the lesions seen with magnetic resonance imaging. C-11-Flumazenil binding abnormalities were frequently seen in regions of cortex that had a normal magnetic resonance appearance. Lesions were characterized by increases in gamma-aminobutyric acid type A/benzodiazepine receptor availability, and by the decreases found in previous studies. These findings have implications for the neurobiology of seizure disorders associated with cortical dysgenesis and for the management of such patients if surgery is contemplated.

We objectively delineated the extent of abnormalities in central benzodiazepine receptor (cBZR) binding using [11C]flumazenil (FMZ)-PET and high resolution volumetric MRI in 12 patients with mesial temporal lobe epilepsy (mTLE) associated with unilateral hippocampal sclerosis, who underwent presurgical evaluation and subsequent temporal lobe surgery. We compared parametric 3D-images of regional cerebral [11C]FMZ volume of distribution (Vd) obtained from individuals and groups of patients with [11C]FMZ-Vd from a group of 17 healthy controls using statistical parametric mapping (SPM). The [12C]FMZ-Vd was significantly reduced (P < 0.001) in the affected hippocampus in the group of 12 patients with unilateral hippocampal sclerosis. Analysis of individual patients reflected the group finding and there was no significant abnormality of cBZR binding outside the hippocampus in any patient. We conclude that SPM is an useful objective method for detecting changes in regional cerebral [11C]FMZ binding and that in patients with mTLE and unilateral hippocampal sclerosis reduction of cBZR binding is restricted to the area of hippocampal sclerosis with no abnormalities being detected in the temporal neocortex or elsewhere in the neocortex.

Juvenile myoclonic epilepsy is the most common idiopathic generalized epilepsy, characterized by frequent myoclonic jerks, generalized tonic-clonic seizures and, less commonly, absences. Neuropsychological and, less consistently, anatomical studies have indicated frontal lobe dysfunction in the disease. Given its presumed thalamo–cortical basis, we investigated thalamo–cortical structural connectivity, as measured by diffusion tensor imaging, in a cohort of 28 participants with juvenile myoclonic epilepsy and detected changes in an anterior thalamo–cortical bundle compared with healthy control subjects. We then investigated task-modulated functional connectivity from the anterior thalamic region identified using functional magnetic resonance imaging in a task consistently shown to be impaired in this group, phonemic verbal fluency. We demonstrate an alteration in task-modulated connectivity in a region of frontal cortex directly connected to the thalamus via the same anatomical bundle, and overlapping with the supplementary motor area. Further, we show that the degree of abnormal connectivity is related to disease severity in those with active seizures. By integrating methods examining structural and effective interregional connectivity, these results provide convincing evidence for abnormalities in a specific thalamo–cortical circuit, with reduced structural and task-induced functional connectivity, which may underlie the functional abnormalities in this idiopathic epilepsy.

Idiopathic (genetic) generalised epilepsy (IGE) is assumed to have a complex genetic aetiology, and is characterised by generalised spike-wave (GSW) discharges on EEG. Rodent models of GSW implicate thalamocortical mechanisms. Human imaging with simultaneous EEG-fMRI shows an extended network of cortical and subcortical regions engaged during GSW discharges. Therefore it is possible that inherited characteristics of extended cortical–subcortical brain networks are a component of the mechanism of IGE. In theoretical work, we have shown that the tendency of a connected network of simulated brain regions to generate highly synchronised discharges is dependent on the topological structure of the network. We hypothesised that the topology of brain networks is abnormal in IGE, and that the abnormal topology predisposes to seizure onset. Therefore, we investigated functionally connected brain networks derived from EEG, in a group of patients with IGE, their unaffected relatives, and healthy controls. Our data showed that the topological structure of networks based on EEG data is abnormal in IGE and some of these abnormalities were also present in unaffected relatives. Furthermore, using a model to estimate the tendency for these networks to initiate seizures, we found elevated seizure tendency in patients. The implications of these findings will be discussed.

PURPOSE: Focal epilepsies are often associated with structural and functional changes that may extend beyond the area of seizure onset. In this study we investigated the functional anatomy of memory in patients with frontal lobe epilepsy (FLE), focusing on the local and remote effects of FLE on the networks supporting memory encoding. METHODS: We studied 32 patients with drug-resistant FLE and 18 controls using a functional magnetic resonance imaging (fMRI) memory encoding paradigm. KEY FINDINGS: During encoding of stimuli, patients with FLE recruited more widely distributed areas than healthy controls, in particular within the frontal lobe contralateral to the seizure onset. Normal memory performance was associated with increased recruitment of frontal areas, and conversely a poor performance was associated with an absence of this increased recruitment and decreased activation in mesial temporal lobe areas. SIGNIFICANCE: In patients with FLE, recruitment of wider areas, particularly in the contralateral frontal lobe, appears to be an effective compensatory mechanism to maintain memory function. Impaired hippocampal activation is relatively rare and, in turn, associated with poor recognition memory.

The longstanding dichotomy between the concepts of "focal" and "primary generalized" epilepsy has become increasingly blurred, raising fundamental questions about the nature of ictal onset in localized brain regions versus large-scale brain networks. We hypothesize that whether an EEG discharge appears focal or generalized is driven by the pattern of connections in brain networks, irrespective of the presence of focal brain abnormality. Using a computational model of a simple "brain" consisting of four regions and the connections between them, we explored the effects of altering connectivity structure versus the effects of introducing an "abnormal" brain region, and the interactions between these factors. Computer simulations demonstrated that electroencephalography (EEG) discharges representing either generalized or focal seizures arose purely as a consequence of subtle changes in network structure, without the requirement for any localized pathologic brain region. Furthermore we found that introducing a pathologic region gave rise to focal, secondary generalized, or primary generalized seizures depending on the network structure. Counterintuitively, we found that decreasing connectivity between regions of the brain increased the frequency of seizure-like activity. Our findings may enlighten current controversies surrounding the concepts of focal and generalized epilepsy, and help to explain recent observations in genetic animal models and human epilepsies, where loss of white matter pathways was associated with the occurrence of seizures.

Objectives: Juvenile myoclonic epilepsy (JME) is characterized by myoclonic jerks of the upper limbs, often triggered by cognitive stressors. Here we aim to reconcile this particular seizure phenotype with the known frontal lobe type neuropsychological profile, photosensitivity, hyperexcitable motor cortex, and recent advanced imaging studies that identified abnormal functional connectivity of the motor cortex and supplementary motor area (SMA). Methods: We acquired fMRI and diffusion tensor imaging (DTI) in a cohort of 29 patients with JME and 28 healthy control subjects. We used fMRI to determine functional connectivity and DTI-based region parcellation and voxel-wise comparison of probabilistic tractography data to assess the structural connectivity profiles of the mesial frontal lobe. Results: Patients with JME showed alterations of mesial frontal connectivity with increased structural connectivity between the prefrontal cognitive cortex and motor cortex. We found a positive correlation between DTI and fMRI-based measures of structural and functional connectivity: the greater the structural connectivity between these 2 regions, the greater the observed functional connectivity of corresponding areas. Furthermore, connectivity was reduced between prefrontal and frontopolar regions and increased between the occipital cortex and the SMA. Conclusion: The observed alterations in microstructural connectivity of the mesial frontal region may represent the anatomic basis for cognitive triggering of motor seizures in JME. Changes in the mesial frontal connectivity profile provide an explanatory framework for several other clinical observations in JME and may be the link between seizure semiology, neurophysiology, neuropsychology, and imaging findings in JME.

Highlights ► The neuronal firing patterns during interictal epileptiform discharges (IEDs) and after single pulse electrical stimulation (SPES) can be described as burst-only, suppression-only, burst–suppression or no-change. ► Similar neuronal firing patterns can be observed during IEDs and after SPES. ► IEDs and responses to SPES appear to activate similar and generic cortical mechanisms, which may explain transient cognitive impairment., Objective To describe neuronal firing patterns observed during human spontaneous interictal epileptiform discharges (IEDs) and responses to single pulse electrical stimulation (SPES). Methods Activity of single neurons was recorded during IEDs and after SPES in 11 consecutive patients assessed with depth EEG electrodes and attached microelectrodes. Results A total of 66 neurons were recorded during IEDs and 151 during SPES. We have found essentially similar patterns of neuronal firing during IEDs and after SPES, namely: (a) a burst of high frequency firing lasting less than 100 ms (in 39% and 25% of local neurons, respectively for IED and SPES); (b) a period of suppression in firing lasting around 100–1300 ms (in 19% and 14%, respectively); (c) a burst followed by suppression (in 10% and 12%, respectively); (d) no-change (in 32% and 50%, respectively). Conclusions The similarities in neuronal firing patterns associated with IEDs and SPES suggest that, although both phenomena are initiated differently, they result in the activation of a common cortical mechanism, probably initiated by brief synchronised burst firing in some cells followed by long inhibition. Significance The findings provide direct in vivo human evidence to further comprehend the pathophysiology of human focal epilepsy.

We report findings concerning the relationship between electroencephalography (EEG) frequency during spike-and-wave discharges (SWDs) and response to treatment in 21 patients with idiopathic generalized epilepsy (IGE). We studied patients whose EEG contained SWDs lasting at least 4 s. Among these patients, two groups could be distinguished on the basis of a subtle difference in EEG frequency during the first 2 s of the burst. The two groups differed markedly in their clinical response to medication, with the group becoming seizure-free during the next 1-2 years showing a spike-wave onset frequency of3.2 Hz, and those not seizure-free3.2 Hz (p = 0.0034, sensitivity 75% and specificity 92%). Given this strong effect in a relatively small group, further work is needed to clarify the predictive value of this frequency measure for clinical outcomes in absence epilepsies.

Juvenile myoclonic epilepsy is the most frequent idiopathic generalized epilepsy syndrome. It is characterized by predominant myoclonic jerks of upper limbs, often provoked by cognitive activities, and typically responsive to treatment with sodium valproate. Neurophysiological, neuropsychological and imaging studies in juvenile myoclonic epilepsy have consistently pointed towards subtle abnormalities in the medial frontal lobes. Using functional magnetic resonance imaging with an executive frontal lobe paradigm, we investigated cortical activation patterns and interaction between cortical regions in 30 patients with juvenile myoclonic epilepsy and 26 healthy controls. With increasing cognitive demand, patients showed increasing coactivation of the primary motor cortex and supplementary motor area. This effect was stronger in patients still suffering from seizures, and was not seen in healthy controls. Patients with juvenile myoclonic epilepsy showed increased functional connectivity between the motor system and frontoparietal cognitive networks. Furthermore, we found impaired deactivation of the default mode network during cognitive tasks with persistent activation in medial frontal and central regions in patients. Coactivation in the motor cortex and supplementary motor area with increasing cognitive load and increased functional coupling between the motor system and cognitive networks provide an explanation how cognitive effort can cause myoclonic jerks in juvenile myoclonic epilepsy. The supplementary motor area represents the anatomical link between these two functional systems, and our findings may be the functional correlate of previously described structural abnormalities in the medial frontal lobe in juvenile myoclonic epilepsy. © 2011 The Author. Wellcome Trust (Project Grant No 079474); The Big Lottery Fund, Wolfson Trust and the Epilepsy Society (ES MRI scanner). Part of this work was undertaken at University College London Hospitals who received a proportion of funding from the NIHR, Biomedical Research Centres funding scheme.

Although the frontal lobes contain a large proportion of the total cerebral cortex in human brain, the epilepsies arising in this region are less studied and less well characterised than epilepsies arising in the mesial temporal lobe. Detailed studies of seizure semiology have identified a number of patterns of frontal lobe seizure, but with inconsistency across studies, and with limited evidence that specific patterns arise in specific discrete frontal lobe regions. In contrast to mesial temporal lobe epilepsy, there is no consistent pattern of cognitive impairment seen in patients with frontal lobe epilepsy, although some evidence exists to support the notion that cognitive function may be impaired. Given the rich interconnectivity between frontal lobes and many other brain regions, it is not surprising to find functional deficits in the frontal lobes in patients with epilepsy arising in other sites; this is best studied in patients with temporal lobe epilepsy. Current concepts in epilepsy suggest that epilepsies hitherto regarded as idiopathic generalised (rather than focal) may in fact have a focal origin of seizure activity; this may be supported by increasing evidence for focal structural and functional frontal lobe abnormalities in idiopathic generalised epilepsies.

Subtle structural abnormalities of frontal lobe gray and white matter have been described in cryptogenic frontal lobe and idiopathic generalized epilepsies. The supplementary motor area (SMA) has a role in motor control, and its involvement during frontal lobe epileptic seizures is characterized by a typical asymmetric tonic posturing. Moreover, motor networks are dysfunctional in juvenile myoclonic epilepsy (JME). We tested the hypothesis that SMA structural connectivity is altered in focal frontal lobe epilepsy (FLE) and JME compared to healthy controls.Diffusion tensor imaging (DTI) and probabilistic tractography were used to map the structural connectivity of the SMA, defined by motor functional magnetic resonance imaging (MRI), in 15 patients with JME, 36 patients with FLE, and 18 healthy controls.Structural connectivity of the SMA was significantly reduced in JME compared to controls (reduced fractional anisotropy and increased mean diffusivity). In FLE there was no significant difference compared to controls, and in all groups there was stronger connectivity in the left hemisphere (higher fractional anisotropy) compared to the right. There was no difference in SMA connectivity between patients with medial or lateral frontal lobe epileptic foci.Reduced white matter connectivity is the structural correlate of functional frontal lobe abnormalities in JME. In FLE, the structural connectivity of the SMA was preserved, suggesting a robust motor network that is not compromised by longstanding epilepsy involving the medial frontal lobes.

Reliable identification of thalamic nuclei is required to improve positioning of electrodes in Deep Brain Stimulation (DBS), and to allow the role of individual thalamic nuclei in health and disease to be fully investigated. In this work, a previously proposed method for identifying sub-regions within the thalamus based on differences in their T1 and T2 values is explored in detail. The effect on the segmentation of T1 and T2 dependence weighted against priors for spatial position and extent was investigated. When T1 and T2 dependence was highly weighted, good distinction between identified regions was obtained in T1/T2 feature-space, but no contiguous anatomically distinct regions were identified within the thalamus. Incorporating spatial priors was necessary to ensure anatomically distinct regions were defined. Optimal values for segmentation parameters were obtained by assessing performance on a 'synthetic thalamus'. Using these optimum input parameters, within- and between-subjects reproducibility was assessed. Good reproducibility was obtained when six regions were specified to be identified in the thalamus. The six regions identified were similar in the majority of the normal subject group. However, intriguingly these regions were different from those obtained in the same subjects using a well-known connectivity-based segmentation technique. This method shows promise to identify intrathalamic structures on the basis of T1 and T2 signal. A comprehensive characterisation of thalamic nuclei may require a fully multi-modal approach.

Our working hypothesis is that constant inter-pulse interval (IPI) electrical stimulation (ES) would resonate with endogenous epileptogenic reverberating circuits, favoring seizure, while random inter-interval ES protocol would promote desynchronization of such neural networks, interfering with the abnormal recruitment of neural structures. Male Wistar rats were stereotaxically implanted with a monopolar ES carbon-fiber electrode (minimizing fMRI artifact) in the amygdala. A 7T fMRI scanner was used to evaluate brain activity during ES, fixed four pulses per second ratio, using either a periodic IPI (ES-P) or random IPI (non-periodic ES-NP) stimulation paradigm. Appropriate imaging protocols were used to compare baseline BOLD (blood oxygen level dependent) MRI with scans during ES. A second series of experiments, both without stimuli and under the same ES paradigms, were evaluated during continuous infusion of pentylenetetrazole (PTZ, 4mg/ml/min) through an i.v. catheter. Our results show that temporal lobe activation during ES-P or ES-NP did not present any statistical differences during ES. However, during PTZ infusion, PTZ-P facilitated recruitment of the temporal lobe ipsilateral to ES while PTZ-NP showed significantly less activation ipsilateral to ES and, in turn, less inter-hemispheric differences. Altogether, our results support the hypothesis of reverberating circuits being synchronized by ES-P and desynchronized by ES-NP. Time-coded low frequency stimulation may be an interesting alternative treatment for patients with refractory epilepsy.

Reliable identification of thalamic nuclei is required to improve targeting of electrodes used in Deep Brain Stimulation (DBS), and for exploring the role of thalamus in health and disease. A previously described method using probabilistic tractography to segment the thalamus based on connections to cortical target regions was implemented. Both within- and between-subject reproducibility were quantitatively assessed by the overlap of the resulting segmentations; the effect of two different numbers of target regions (6 and 31) on reproducibility of the segmentation results was also investigated. Very high reproducibility was observed when a single dataset was processed multiple times using different starting conditions. Thalamic segmentation was also very reproducible when multiple datasets from the same subject were processed using six cortical target regions. Within-subject reproducibility was reduced when the number of target regions was increased, particularly in medial and posterior regions of the thalamus. A large degree of overlap in segmentation results from different subjects was obtained, particularly in thalamic regions classified as connecting to frontal, parietal, temporal and pre-central cortical target regions.

In this article, we present a method for tracking changes in curvature of limit cycle solutions that arise due to inflection points. In keeping with previous literature, we term these changes false bifurcations, as they appear to be bifurcations when considering a Poincare section that is tangent to the solution, but in actual fact the deformation of the solution occurs smoothly as a parameter is varied. These types of solutions arise commonly in electroencephalogram models of absence seizures and correspond to the formation of spikes in these models. Tracking these transitions in parameter space allows regions to be defined corresponding to different types of spike and wave dynamics, that may be of use in clinical neuroscience as a means to classify different subtypes of the more general syndrome.

In this paper we describe how an ordinary differential equation model of corticothalamic interactions may be obtained from a more general system of delay differential equations. We demonstrate that transitions to epileptic dynamics via changes in system parameters are qualitatively the same as in the original model with delay, as well as demonstrating that the onset of epileptic activity may arise due to regions of bistability. Hence, the model presents in one unique framework, two competing theories for the genesis of epileptiform activity. Similarities between model transitions and clinical data are presented and we argue that statistics obtained from, and a parameter estimation of this model may be a potential means of classifying and predicting the onset and offset of seizure activity.

IntroductionIt is unknown why over one-third of patients with mesial temporal lobe epilepsy (mTLE) and hippocampal sclerosis (HS) continue to experience seizures despite temporal lobe surgery. We investigated the relationship between hippocampal internal architecture (HIA) on preoperative MRI, and postoperative seizure outcome in patients with refractory mTLE and HS.MethodsHIA was assessed on preoperative T2-STIR MR images using a published scoring system1 for 79 patients undergoing evaluation at University Hospital Bonn, Germany. Patients underwent amygdalohippocampectomy and received postoperative outcome assessment using the International League Against Epilepsy (ILAE) classification. Hippocampal volumes were obtained using 3D T1-weighted images. Quantitative histopathological assessment was performed on resected hippocampal specimens.ResultsNo significant differences in ipsilateral or contralateral HIA ratings, or HIA score asymmetry, were found between patients rendered seizure free (ILAE I) compared to those continuing to experience postoperative seizures (ILAE II-VI). HIA significantly correlated with neuronal density in CA3 and CA4 in the pathologic hippocampus, and hippocampal volumes bilaterally. There was no significant correlation between HIA and clinical variables.ConclusionAlthough valuable in determining seizure laterality, HIA does not predict postoperative outcome.AcknowledgementsThis work was supported by a UK MRC grant awarded to SSK (Grant Number: MR/K023152/1). References:1Ver Hoef 2013

Objective Our overall aim is to evaluate the clinical and cost effectiveness of specifically adapted Cognitive Behavioural Therapy (CBT) (plus Standardised Medical Care – SMC) in comparison to SMC alone for outpatients with dissociative seizures (DS), within a pragmatic, multi-centre UK-based RCT. This will redress the limited evidence base for psychotherapy in this patient group. Method Adults with DS but without currently active epilepsy will receive their diagnosis and information from a neurologist/epilepsy specialist and their seizure occurrence will be monitored. Three months post diagnosis they will be reviewed by a psychiatrist with interest and expertise in DS who will represent the diagnosis and deliver an information leaflet. Those continuing to experience DS in the previous 8 weeks and meeting other inclusion criteria will, if willing, be consented, undergo baseline assessments and be randomised to receive either 12 sessions of CBT (plus a booster session) as well as SMC or SMC alone. We aim to randomise 298 patients (149 to each arm). DS frequency will be monitored fortnightly and follow-ups will occur at 6 and 12 months post randomisation. An intention to treat analysis will evaluate effectiveness in outcomes relating to seizure frequency severity and freedom, mood and psychological state, quality of life and health service use. A qualitative study will investigate participants’ experiences of the interventions and barriers to participation that might affect subsequent implementation in the NHS. Results Multiple sites in England, Wales and Scotland have been enlisted. Recruitment in neurology clinics has commenced. Training for service user advisors, research workers and CBT therapists has been delivered. Conclusion The design and progress will be described. This is the largest planned trial for patients with DS to date. See ISRCTN05681227 for further details. FUNDING: NIHR HTA reference 12/26/01.

Graph theory has evolved into a useful tool for studying complex brain networks inferred from a variety of measures of neural activity, including fMRI, DTI, MEG and EEG. In the study of neurological disorders, recent work has discovered differences in the structure of graphs inferred from patient and control cohorts. However, most of these studies pursue a purely observational approach; identifying correlations between properties of graphs and the cohort which they describe, without consideration of the underlying mechanisms. To move beyond this necessitates the development of computational modeling approaches to appropriately interpret network interactions and the alterations in brain dynamics they permit, which in the field of complexity sciences is known as dynamics on networks. In this study we describe the development and application of this framework using modular networks of Kuramoto oscillators. We use this framework to understand functional networks inferred from resting state EEG recordings of a cohort of 35 adults with heterogeneous idiopathic generalized epilepsies and 40 healthy adult controls. Taking emergent synchrony across the global network as a proxy for seizures, our study finds that the critical strength of coupling required to synchronize the global network is significantly decreased for the epilepsy cohort for functional networks inferred from both theta (3–6 Hz) and low-alpha (6–9 Hz) bands. We further identify left frontal regions as a potential driver of seizure activity within these networks. We also explore the ability of our method to identify individuals with epilepsy, observing up to 80 predictive power through use of receiver operating characteristic analysis. Collectively these findings demonstrate that a computer model based analysis of routine clinical EEG provides significant additional information beyond standard clinical interpretation, which should ultimately enable a more appropriate mechanistic stratification of people with epilepsy leading to improved diagnostics and therapeutics., Author Summary In this paper we show that within modular networks (that is, networks with multiple scales of connections), two distinct mechanisms may drive the emergence of synchrony at the global level. We term the first of these mechanisms “network-driven synchrony”, which is characterized by the presence of cycles within the macroscopic network. The second mechanism we term “node-driven”, which is characterized by the ability of an individual node (or nodes) to drive synchrony across the rest of the network, due to the hierarchical structure of the macroscopic network. By applying this framework to routine clinically collected resting state data from people with idiopathic generalized epilepsy and from age matched healthy controls, we demonstrate that functional networks of people with epilepsy have a significantly enhanced capacity to synchronize than those of people without epilepsy. This finding suggests a critical role for the connectivity structure of large-scale networks in the tendency to have seizures. Further, by deriving a mathematical equation for the global synchrony of the network, we make it computationally tractable to analyze data in close to real time. This gives our method potential to be used within the clinic as a diagnostic aid for clinicians treating neurological disease.

Emotional visual stimuli evoke enhanced responses in the visual cortex. To test whether this reflects modulatory influences from the amygdala on sensory processing, we used event-related functional magnetic resonance imaging (fMRI) in human patients with medial temporal lobe sclerosis. Twenty-six patients with lesions in the amygdala, the hippocampus or both, plus 13 matched healthy controls, were shown pictures of fearful or neutral faces in task-releant or task-irrelevant positions on the display. All subjects showed increased fusiform cortex activation when the faces were in task-relevant positions. Both healthy individuals and those with hippocampal damage showed increased activation in the fusiform and occipital cortex when they were shown fearful faces, but this was not the case for individuals with damage to the amygdala, even though visual areas were structurally intact. The distant influence of the amygdala was also evidenced by the parametric relationship between amygdala damage and the level of emotional activation in the fusiform cortex. Our data show that combining the fMRI and lesion approaches can help reveal the source of functional modulatory influences between distant but interconnected brain regions.

Lesion-deficit studies have provided evidence for a functional dissociation between the left medial temporal lobe (MTL) mediating verbal memory encoding and right MTL mediating non-verbal memory encoding. While a small number of functional MRI studies have demonstrated similar findings, none has looked specifically for material-specific lateralization using subsequent memory effects. In addition, in many fMRI studies, encoding activity has been located in posterior MTL structures, at odds with lesion-deficit and positron emission tomography (PET) evidence. In this study, we used an event-related fMRI memory encoding paradigm to demonstrate a material-specific lateralization of encoding in the medial temporal lobes of ten healthy control subjects. Activation was left-lateralized for word encoding, bilateral for picture encoding, and right-lateralized for face encoding. Secondly, we demonstrated the locations of activations revealed using an event-related analysis to be more anterior than those revealed using a blocked analysis of the same data. This suggests that anterior MTL structures underlie memory encoding as judged by subsequent memory effects, and that more posterior activity detected in other fMRI studies is related to deficiencies of blocked designs in the analysis of memory encoding.

We have studied patients with variable degrees of left hippocampal and amygdala pathology who performed a verbal encoding task during functional magnetic resonance imaging (fMRI) to assess the impact of pathology on emotional-memory performance and encoding-evoked activity. The severity of left hippocampal pathology predicted memory performance for neutral and emotional items alike, whereas the severity of amygdala pathology predicted memory performance for emotional items alone. Encoding-related hippocampal activity for successfully remembered emotional items correlated with the degree of left amygdala pathology. Conversely, amygdala-evoked activity with respect to subsequently remembered emotional items correlated with the degree of left hippocampal pathology. Our data indicate a reciprocal dependence between amygdala and hippocampus during the encoding of emotional memories.

In 20-30% of potential surgical candidates with refractory focal epilepsy, standard MRI does not identify the cause. gamma-Aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the brain. [(11)C]Flumazenil (FMZ) PET images most subtypes of GABA(A) receptors, present on most neurons. We investigated [(11)C]FMZ binding in grey and white matter in 16 normal controls and in 44 patients with refractory neocortical focal epilepsy and normal optimal MRI. Fourteen patients had unilateral frontal lobe epilepsy, five occipital lobe epilepsy (OLE), six parietal lobe epilepsy (PLE) and 19 neocortical epilepsy that was not clearly lobar. Parametric images of FMZ volume of distribution (FMZ-V(d)) were computed. Statistical parametric mapping (SPM99) with explicit masking, including the white matter, was used to analyse individual patients and groups. Thirty-three of the 44 patients showed focal abnormal FMZ-V(d); increases in 16, decreases in eight, and both increases and decreases in nine. In seven patients, the increases in FMZ binding were periventricular, in locations normally seen in periventricular nodular heterotopia on MRI. There were frontal and parietal increases in FMZ binding in grey and white matter in the PLE group and decreases in the cingulate gyrus in the OLE group. FMZ binding increases, particularly periventricular increases, were a prominent feature of MRI-negative focal epilepsies and may represent neuronal migration disturbances.

Objectives: To implement and validate the use of coronal dual echo T2 maps for the measurement of T2 relaxation time of the amygdala (AT2) as a rapid and reproducible method for identifying amygdala abnormality. Methods: 20 healthy subjects and 25 patients with known hippocampal sclerosis (HS) were studied using a dual echo CSE sequence on a 1.5T MRI GE scanner. The T2 relaxation time of the amygdala was calculated and measured using a previously validated method. Results: The mean control AT2 was 88.1 ms (SD 2 ms). The coefficient of reliability was good at 6.3% test-retest and 7.4% inter-rater. The upper limit of normal AT2 was 92 ms. AT2 was abnormal ipsilaterally in six, and bilaterally in three, of 20 patients with unilateral HS. Two of five patients with bilateral HS had unilateral abnormal AT2. Conclusion: Reliable T2 measurements can be obtained in the amygdala, and may be useful in the detection of amygdala abnormality.

We present a region template and a protocol for transforming that template to define anatomical volumes of interest (VOIs) in the human brain without operator intervention, based on software contained in the SPM99 package (Statistical Parametric Mapping, Wellcome Department of Cognitive Neurology, London, UK). We used an MRI of a reference brain to create an anatomical template of 41 VOIs, covering the entire brain, that can be spatially transformed to fit individual brain scans. Modified software allows for the reslicing and adaptation of the tranformed template to any type of coregistered functional data. Individually defined VOIs can be added. We present an assessment of the necessary spatial transformations and compare results obtained for scans acquired in two different orientations. To evaluate the spatial transformations, 11 landmarks distributed throughout the brain were chosen. Euclidean distances between repeat samples at each landmark were averaged across all landmarks to give a mean difference of 1.3 ± 1.0 mm. Average Euclidean distances between landmarks (MRI:transformed template) were 8.1 ± 3.7 mm in anterior‐posterior commissure (ACPC) and 7.6 ± 3.7 mm in temporal lobe (TL) orientation. In this study, we use [(11)C]‐flumazenil‐(FMZ‐)PET as an example for the application of the region template. Thirty‐four healthy volunteers were scanned, 21 in standard ACPC orientation, 13 in TL orientation. All had high resolution MRI and FMZ‐PET. The average coefficient of variation (CV) of FMZ binding for cortical regions was 0.15, comparable with CVs from manually defined VOIs. FMZ binding was significantly different in 6/19 anatomical areas in the control groups obtained in the different orientations, probably due to anisotropic voxel dimensions. This new template allows for the reliable and fast definition of multiple VOIs. It can be used for different imaging modalities and in different orientations. It is necessary that imaging data for groups compared are acquired in the same orientation. Hum. Brain Mapping 15:165–174, 2002. © 2002 Wiley‐Liss, Inc.

Background Teaching people with epilepsy to identify and manage seizure triggers, implement strategies to remember to take antiepileptic drugs, implement precautions to minimize risks during seizures, tell others what to do during a seizure and learn what to do during recovery may lead to better self-management. No teaching programme exists for adults with epilepsy in the United Kingdom although a number of surveys have shown patients want more information. Methods/Design This is a multicentre, pragmatic, parallel group randomised controlled trial to evaluate the effectiveness and cost-effectiveness of a two-day Self-Management education for epILEpsy (SMILE (UK)), which was originally developed in Germany (MOSES). Four hundred and twenty eight adult patients who attended specialist epilepsy outpatient clinics at 15 NHS participating sites in the previous 12 months, and who fulfil other eligibility criteria will be randomised to receive the intervention (SMILE (UK) course with treatment as usual- TAU) or to have TAU only (control). The primary outcome is the effect on patient reported quality of life (QoL). Secondary outcomes are seizure frequency and psychological distress (anxiety and depression), perceived impact of epilepsy, adherence to medication, management of adverse effects from medication, and improved self-efficacy in management (mastery/control) of epilepsy. Within the trial there will be a nested qualitative study to explore users’ views of the intervention, including barriers to participation and the perceived benefits of the intervention. The cost-effectiveness of the intervention will also be assessed. Discussion This study will provide quantitative and qualitative evidence of the impact of a structured self management programme on quality of life and other aspects of clinical and cost effectiveness in adults with poorly controlled epilepsy. Trial registration Current Controlled Trials: ISRCTN57937389.