[Show abstract][Hide abstract] ABSTRACT: To demonstrate altered N-methyl-d-aspartate (NMDA) receptor availability in patients with focal epilepsies using positron emission tomography (PET) and [(18)F]GE-179, a ligand that selectively binds to the open NMDA receptor ion channel, which is thought to be overactive in epilepsy.
Eleven patients (median age 33 years, 6 males) with known frequent interictal epileptiform discharges had an [(18)F]GE-179 PET scan, in a cross-sectional study. MRI showed a focal lesion but discordant EEG changes in two, was non-localising with multifocal EEG abnormalities in two, and was normal in the remaining seven patients who all had multifocal EEG changes. Individual patient [(18)F]GE-179 volume-of-distribution (VT) images were compared between individual patients and a group of 10 healthy controls (47 years, 7 males) using Statistical Parametric Mapping.
Individual analyses revealed a single cluster of focal VT increase in four patients; one with a single and one with multifocal MRI lesions, and two with normal MRIs. Post hoc analysis revealed that, relative to controls, patients not taking antidepressants had globally increased [(18)F]GE-179 VT (+28%; p<0.002), and the three patients taking an antidepressant drug had globally reduced [(18)F]GE-179 VT (-29%; p<0.002). There were no focal abnormalities common to the epilepsy group.
In patients with focal epilepsies, we detected primarily global increases of [(18)F]GE-179 VT consistent with increased NMDA channel activation, but reduced availability in those taking antidepressant drugs, consistent with a possible mode of action of this class of drugs. [(18)F]GE-179 PET showed focal accentuations of NMDA binding in 4 out of 11 patients, with difficult to localise and treat focal epilepsy.
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Journal of neurology, neurosurgery, and psychiatry 05/2015; 86(10). DOI:10.1136/jnnp-2014-309897 · 6.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective: We used functional MRI (fMRI) and a left-lateralizing verbal and a right-lateralizing visual-spatial working memory (WM) paradigm to investigate the effects of levetiracetam (LEV) on cognitive network activations in patients with drug-resistant temporal lobe epilepsy (TLE). Methods: In a retrospective study, we compared task-related fMRI activations and deactivations in 53 patients with left and 54 patients with right TLE treated with (59) or without (48) LEV. In patients on LEV, activation patterns were correlated with the daily LEV dose. Results: We isolated task-and syndrome-specific effects. Patients on LEV showed normaliza-tion of functional network deactivations in the right temporal lobe in right TLE during the right-lateralizing visual-spatial task and in the left temporal lobe in left TLE during the verbal task. In a post hoc analysis, a significant dose-dependent effect was demonstrated in right TLE during the visual-spatial WM task: the lower the LEV dose, the greater the abnormal right hippocampal activation. At a less stringent threshold (p , 0.05, uncorrected for multiple comparisons), a similar dose effect was observed in left TLE during the verbal task: both hippocampi were more abnormally activated in patients with lower doses, but more promi-nently on the left. Conclusions: Our findings suggest that LEV is associated with restoration of normal activation
[Show abstract][Hide abstract] ABSTRACT: Objective
Assessment of language dominance using functional magnetic resonance imaging (fMRI) is a standard tool to estimate the risk of language function decline after epilepsy surgery. Although there has been considerable research in the characterization of language networks in bilingual individuals; little is known about the clinical usefulness of language mapping in a secondary language in patients with epilepsy, and how language lateralization assessed by fMRI may differ by the use of native or a secondary language paradigms. In this study we investigate language representation in a population of nonnative English speakers to assess differences in fMRI language lateralization between the first (native) and second language (English).Methods
Sixteen nonnative English-speaking patients with focal drug-resistant epilepsy underwent language fMRI in their first (native) language (L1) and in English (L2). Differences between language maps using L1 and L2 paradigms were examined at the single subject level by comparing within-subject lateralization indexes obtained for each language. Differences at the group level were examined for each of the tasks and languages.ResultsGroup maps for the second language (English) showed overlapping areas of activation with the native language, but with larger clusters, and more bilaterally distributed than for the first language. However, at the individual level, lateralization indexes were concordant between the two languages, except for one patient with bilateral hippocampal sclerosis who was left dominant in English and showed bilateral dominance for verb generation and right dominance for verbal fluency in his native tongue.SignificanceLanguage lateralization can generally be reliably derived from fMRI tasks in a second language provided that the subject can follow the task. Subjects with greater likelihood of atypical language representation should be evaluated more carefully, using more than one language paradigm.
[Show abstract][Hide abstract] ABSTRACT: Objective:
We assessed whether display of optic radiation tractography during anterior temporal lobe resection (ATLR) for refractory temporal lobe epilepsy (TLE) can reduce the severity of postoperative visual field deficits (VFD) and increase the proportion of patients who can drive and whether correction for brain shift using intraoperative MRI (iMRI) is beneficial.
A cohort of 21 patients underwent ATLR in an iMRI suite. Preoperative tractography of the optic radiation was displayed on the navigation and operating microscope displays either without (9 patients) or with (12 patients) correction for brain shift. VFD were quantified using Goldmann perimetry and eligibility to drive was assessed by binocular Esterman perimetry 3 months after surgery. Secondary outcomes included seizure freedom and extent of hippocampal resection. The comparator was a cohort of 44 patients who underwent ATLR without iMRI.
The VFD in the contralateral superior quadrant were significantly less (p = 0.043) with iMRI guidance (0%–49.2%, median 14.5%) than without (0%–90.9%, median 24.0%). No patient in the iMRI cohort developed a VFD that precluded driving whereas 13% of the non-iMRI cohort failed to meet UK driving criteria. Outcome did not differ between iMRI guidance with and without brain shift correction. Seizure outcome and degree of hippocampal resection were unchanged.
Display of the optic radiation with image guidance reduces the severity of VFD and did not affect seizure outcome or hippocampal resection. Correction for brain shift is possible but did not further improve outcome. Future work to incorporate tractography into conventional neuronavigation systems will make the work more widely applicable.
[Show abstract][Hide abstract] ABSTRACT: Juvenile myoclonic epilepsy is a heritable idiopathic generalized epilepsy syndrome, characterized by myoclonic jerks and frequently triggered by cognitive effort. Impairment of frontal lobe cognitive functions has been reported in patients with juvenile myoclonic epilepsy and their unaffected siblings. In a recent functional magnetic resonance imaging study we reported abnormal co-activation of the motor cortex and increased functional connectivity between the motor system and prefrontal cognitive networks during a working memory paradigm, providing an underlying mechanism for cognitively triggered jerks. In this study, we used the same task in 15 unaffected siblings (10 female; age range 18-65 years, median 40) of 11 of those patients with juvenile myoclonic epilepsy (six female; age range 22-54 years, median 35) and compared functional magnetic resonance imaging activations with 20 age- and gender-matched healthy control subjects (12 female; age range 23-46 years, median 30.5). Unaffected siblings showed abnormal primary motor cortex and supplementary motor area co-activation with increasing cognitive load, as well as increased task-related functional connectivity between motor and prefrontal cognitive networks, with a similar pattern to patients (P < 0.001 uncorrected; 20-voxel threshold extent). This finding in unaffected siblings suggests that altered motor system activation and functional connectivity is not medication- or seizure-related, but represents a potential underlying mechanism for impairment of frontal lobe functions in both patients and siblings, and so constitutes an endophenotype of juvenile myoclonic epilepsy.
[Show abstract][Hide abstract] ABSTRACT: Background:
Neuronal networks involved in seizure generation, maintenance and spread of epileptic activity comprise cortico-subcortical circuits. Although epileptic foci vary in location across focal epilepsy syndromes, there is evidence for common structures in the epileptogenic networks. We recently reported evidence from functional neuroimaging for a unique area in the piriform cortex, common to focal epilepsies in humans, which might play a role in modulating seizure activity. In this study, we aimed to identify common areas of structural abnormalities in patients with frontal lobe epilepsy (FLE).
T1-weighted MRI scans of 43 FLE patients and 25 healthy controls were analysed using voxel based morphometry. Differences in regional grey matter volume were examined across the whole brain, and correlated with age at epilepsy onset, duration and frequency of seizures.
We detected areas of increased grey matter volume in the piriform cortex, amygdala and parahippocampal gyrus bilaterally, as well as left mid temporal gyrus of patients relative to controls, which did not correlate with any of the clinical variables tested. No common areas of atrophy were detected across the FLE group.
Structural abnormalities within the piriform cortex and adjacent structures of patients with FLE provide further evidence for the involvement of this area in the epileptogenic network of focal epilepsies. Lack of correlation with duration or age of onset of epilepsy suggests that this area of abnormality is not a consequence of seizure activity.
Epilepsy research 07/2014; 108(5). DOI:10.1016/j.eplepsyres.2014.03.001 · 2.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Working memory is a crucial cognitive function that is disrupted in temporal lobe epilepsy. It is unclear whether this impairment is a consequence of temporal lobe involvement in working memory processes or due to seizure spread to extratemporal eloquent cortex. Anterior temporal lobe resection controls seizures in 50-80% of patients with drug-resistant temporal lobe epilepsy and the effect of surgery on working memory are poorly understood both at a behavioural and neural level. We investigated the impact of temporal lobe resection on the efficiency and functional anatomy of working memory networks. We studied 33 patients with unilateral medial temporal lobe epilepsy (16 left) before, 3 and 12 months after anterior temporal lobe resection. Fifteen healthy control subjects were also assessed in parallel. All subjects had neuropsychological testing and performed a visuospatial working memory functional magnetic resonance imaging paradigm on these three separate occasions. Changes in activation and deactivation patterns were modelled individually and compared between groups. Changes in task performance were included as regressors of interest to assess the efficiency of changes in the networks. Left and right temporal lobe epilepsy patients were impaired on preoperative measures of working memory compared to controls. Working memory performance did not decline following left or right temporal lobe resection, but improved at 3 and 12 months following left and, to a lesser extent, following right anterior temporal lobe resection. After left anterior temporal lobe resection, improved performance correlated with greater deactivation of the left hippocampal remnant and the contralateral right hippocampus. There was a failure of increased deactivation of the left hippocampal remnant at 3 months after left temporal lobe resection compared to control subjects, which had normalized 12 months after surgery. Following right anterior temporal lobe resection there was a progressive increase of activation in the right superior parietal lobe at 3 and 12 months after surgery. There was greater deactivation of the right hippocampal remnant compared to controls between 3 and 12 months after right anterior temporal lobe resection that was associated with lesser improvement in task performance. Working memory improved after anterior temporal lobe resection, particularly following left-sided resections. Postoperative working memory was reliant on the functional capacity of the hippocampal remnant and, following left resections, the functional reserve of the right hippocampus. These data suggest that working memory following temporal lobe resection is dependent on the engagement of the posterior medial temporal lobes and eloquent cortex.
[Show abstract][Hide abstract] ABSTRACT: N-methyl d-aspartate (NMDA) ion channels play a key role in a wide range of physiologic (e.g., memory and learning tasks) and pathologic processes (e.g., excitotoxicity). To date, suitable PET markers of NMDA ion channel activity have not been available. (18)F-GE-179 is a novel radioligand that selectively binds to the open/active state of the NMDA receptor ion channel, displacing the binding of (3)H-tenocyclidine from the intrachannel binding site with an affinity of 2.4 nM. No significant binding was observed with 10 nM GE-179 at 60 other neuroreceptors, channels, or transporters. We describe the kinetic behavior of the radioligand in vivo in humans.
Nine healthy participants (6 men, 3 women; median age, 37 y) each underwent a 90-min PET scan after an intravenous injection of (18)F-GE-179. Continuous arterial blood sampling over the first 15 min was followed by discrete blood sampling over the duration of the scan. Brain radioactivity (KBq/mL) was measured in summation images created from the attenuation- and motion-corrected dynamic images. Metabolite-corrected parent plasma input functions were generated. We assessed the abilities of 1-, 2-, and 3-compartment models to kinetically describe cerebral time-activity curves using 6 bilateral regions of interest. Parametric volume-of-distribution (VT) images were generated by voxelwise rank-shaping regularization of exponential spectral analysis (RS-ESA).
A 2-brain-compartment, 4-rate-constant model best described the radioligand's kinetics in normal gray matter of subjects at rest. At 30 min after injection, 37% of plasma radioactivity represented unmetabolized (18)F-GE-179. The highest mean levels of gray matter radioactivity were seen in the putamina and peaked at 7.5 min. A significant positive correlation was observed between K1 and VT (Spearman ρ = 0.398; P = 0.003). Between-subject coefficients of variation of VT ranged between 12% and 16%. Voxelwise RS-ESA yielded similar VTs and coefficients of variation.
(18)F-GE-179 exhibits high and rapid brain extraction, with a relatively homogeneous distribution in gray matter and acceptable between-subject variability. Despite its rapid peripheral metabolism, quantification of (18)F-GE-179 VT is feasible both within regions of interest and at the voxel level. The specificity of (18)F-GE-179 binding, however, requires further characterization with in vivo studies using activation and disease models.
Journal of Nuclear Medicine 02/2014; 55(3). DOI:10.2967/jnumed.113.130641 · 6.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Anterior temporal lobe resection (ATLR) is an effective treatment for refractory temporal lobe epilepsy (TLE). Widespread abnormalities in diffusion parameters involving the ipsilateral temporal lobe white matter and extending into extratemporal white matter have been shown in cross-sectional studies in TLE. However longitudinal changes following surgery have been less well addressed. We systematically assess diffusion changes in white matter in patients with TLE in comparison to controls before surgery and look at the longitudinal changes following ATLR at two timepoints (3–4 months, 12 months) using a whole brain approach.
We find predominantly unilateral baseline changes in temporal and extratemporal structures compatible with altered myelination (reduced fractional anisotropy, increased mean and radial diffusivity). Following surgery, these changes progress in efferent tracts from the resected temporal lobe compatible with Wallerian degeneration. However more superiorly in the corona radiata, internal and external capsules and nearby tracts, changes compatible with plasticity are observed (increased fractional anisotropy and axial diffusivity, reduced radial diffusivity).
There is little progression between 3–4 months and 12 months following surgery in patients with left TLE, but the changes become more widespread in patients with right TLE suggesting that plasticity occurs more slowly in this population. The neuropsychological correlates of such plasticity should be explored further.
[Show abstract][Hide abstract] ABSTRACT: Patients with juvenile myoclonic epilepsy (JME) often present with risk-taking behavior, suggestive of frontal lobe dysfunction. Recent studies confirm functional and microstructural changes within the frontal lobes in JME. This study aimed at characterizing decision-making behavior in JME and its neuronal correlates using functional magnetic resonance imaging (fMRI).
We investigated impulsivity in 21 JME patients and 11 controls using the Iowa Gambling Task (IGT), which measures decision making under ambiguity. Performance on the IGT was correlated with activation patterns during an fMRI working memory task.
Both patients and controls learned throughout the task. Post hoc analysis revealed a greater proportion of patients with seizures than seizure-free patients having difficulties in advantageous decision making, but no difference in performance between seizure-free patients and controls. Functional imaging of working memory networks showed that overall poor IGT performance was associated with an increased activation in the dorsolateral prefrontal cortex (DLPFC) in JME patients. Impaired learning during the task and ongoing seizures were associated with bilateral medial prefrontal cortex (PFC) and presupplementary motor area, right superior frontal gyrus, and left DLPFC activation.
Our study provides evidence that patients with JME and ongoing seizures learn significantly less from previous experience. Interictal dysfunction within "normal" working memory networks, specifically, within the DLPFC and medial PFC structures, may affect their ability to learn.
[Show abstract][Hide abstract] ABSTRACT: Clinical trials of neuroprotective interventions in multiple sclerosis require outcome measures that reflect the disease pathology. Measures of neuroaxonal integrity in the anterior visual pathways are of particular interest in this context, however imaging of the optic nerve is technically challenging. We therefore developed a 3T optic nerve diffusion tensor imaging protocol incorporating fat and cerebrospinal fluid suppression and without parallel imaging. The sequence used a scheme with six diffusion-weighted directions, b=600smm-2 plus one b≈0 (b0) and 40 repetitions, averaged offline, giving an overall scan time of 30 minutes. A coronal oblique orientation was used with voxel size 1.17mmx1.17mmx4mm, We validated the sequence in 10 MS patients with a history of optic neuritis and 11 healthy controls: mean fractional anisotropy was reduced in the patients: 0.346(±0.159) versus 0.528(±0.123), p<0.001; radial diffusivity was increased: 0.940(±0.370)x10-6mm2s-1 compared to 0.670(± 0.221)x10-6mm2s-1 (p<0.01). No significant differences were seen for mean diffusivity or mean axial diffusivity.
[Show abstract][Hide abstract] ABSTRACT: To investigate cerebral grey matter (GM) abnormalities in temporal lobe epilepsy (TLE) patients who develop de novo depression following TLE surgery using voxel-based morphometry (VBM).
We retrospectively examined the pre-surgical grey matter (GM) abnormalities in 45 patients with TLE due to unilateral left-sided hippocampal sclerosis using a 1.5 T MRI scanner, which were segmented with optimised VBM parameters using SPM8 software. Grey matter maps were normalised to a sample template using DARTEL. Voxel-wise GM differences between patients that developed de novo post-surgical depression (n=6) were compared with patients with no pre- or postoperative psychiatric diagnoses (n=25), using independent samples t-tests. Analysis of covariance with age and gender as covariates was adopted for the VBM statistics; the level of statistical significance was set at p<.001, uncorrected.
Reduced preoperative GM in both the ipsilateral thalamic and orbitofrontal cortices (OFC) were significantly associated with the development of de novo depression within 4 years postoperatively. Further analyses revealed that GM atrophy of these structures was unrelated to a history or frequency of secondary generalised tonic-clonic seizures (SGTCS). We observed no differences in seizure freedom (ILAE 1 vs 2-6) or seizure recurrence (ILAE 2 vs 3-6) between the groups.
Although the development of postoperative de novo depression following TLE surgery is likely to be multi-factorial, our results suggest that ipsilateral thalamic and OFC atrophy in LTLE patients may play a modulatory role. Structural and functional abnormalities in these areas have also been implicated in primary mood disorders (1). Prospective studies with larger cohorts utilising in vivo imaging techniques are warranted to replicate these results, and further elucidate the neural correlates of de novo postoperative mood disorders.
Journal of neurology, neurosurgery, and psychiatry 09/2013; 84(9):e1. DOI:10.1136/jnnp-2013-306103.34 · 6.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Studies in rodent models of epilepsy suggest that multidrug efflux transporters at the blood-brain barrier, such as P-glycoprotein, might contribute to pharmacoresistance by reducing target-site concentrations of antiepileptic drugs. We assessed P-glycoprotein activity in vivo in patients with temporal lobe epilepsy.
We selected 16 patients with pharmacoresistant temporal lobe epilepsy who had seizures despite treatment with at least two antiepileptic drugs, eight patients who had been seizure-free on antiepileptic drugs for at least a year after 3 or more years of active temporal lobe epilepsy, and 17 healthy controls. All participants had a baseline PET scan with the P-glycoprotein substrate (R)-[(11)C]verapamil. Pharmacoresistant patients and healthy controls then received a 30-min infusion of the P-glycoprotein-inhibitor tariquidar followed by another (R)-[(11)C]verapamil PET scan 60 min later. Seizure-free patients had a second scan on the same day, but without tariquidar infusion. Voxel-by-voxel, we calculated the (R)-[(11)C]verapamil plasma-to-brain transport rate constant, K1 (mL/min/cm(3)). Low baseline K1 and attenuated K1 increases after tariquidar correspond to high P-glycoprotein activity.
Between October, 2008, and November, 2011, we completed (R)-[(11)C]verapamil PET studies in 14 pharmacoresistant patients, eight seizure-free patients, and 13 healthy controls. Voxel-based analysis revealed that pharmacoresistant patients had lower baseline K1, corresponding to higher baseline P-glycoprotein activity, than seizure-free patients in ipsilateral amygdala (0·031 vs 0·036 mL/min/cm(3); p=0·014), bilateral parahippocampus (0·032 vs 0·037; p<0·0001), fusiform gyrus (0·036 vs 0·041; p<0·0001), inferior temporal gyrus (0·035 vs 0·041; p<0·0001), and middle temporal gyrus (0·038 vs 0·044; p<0·0001). Higher P-glycoprotein activity was associated with higher seizure frequency in whole-brain grey matter (p=0·016) and the hippocampus (p=0·029). In healthy controls, we noted a 56·8% increase of whole-brain K1 after 2 mg/kg tariquidar, and 57·9% for 3 mg/kg; in patients with pharmacoresistant temporal lobe epilepsy, whole-brain K1 increased by only 21·9% for 2 mg/kg and 42·6% after 3 mg/kg. This difference in tariquidar response was most pronounced in the sclerotic hippocampus (mean 24·5% increase in patients vs mean 65% increase in healthy controls, p<0·0001).
Our results support the hypothesis that there is an association between P-glycoprotein overactivity in some regions of the brain and pharmacoresistance in temporal lobe epilepsy. If this relation is confirmed, and P-glycoprotein can be identified as a contributor to pharmacoresistance, overcoming P-glycoprotein overactivity could be investigated as a potential treatment strategy.
EU-FP7 programme (EURIPIDES number 201380).
The Lancet Neurology 06/2013; 12(8). DOI:10.1016/S1474-4422(13)70109-1 · 21.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Anterior temporal lobe resection controls seizures in 50-60% of patients with intractable temporal lobe epilepsy but may impair memory function, typically verbal memory following left, and visual memory following right anterior temporal lobe resection. Functional reorganization can occur within the ipsilateral and contralateral hemispheres. We investigated the reorganization of memory function in patients with temporal lobe epilepsy before and after left or right anterior temporal lobe resection and the efficiency of postoperative memory networks. We studied 46 patients with unilateral medial temporal lobe epilepsy (25/26 left hippocampal sclerosis, 16/20 right hippocampal sclerosis) before and after anterior temporal lobe resection on a 3 T General Electric magnetic resonance imaging scanner. All subjects had neuropsychological testing and performed a functional magnetic resonance imaging memory encoding paradigm for words, pictures and faces, testing verbal and visual memory in a single scanning session, preoperatively and again 4 months after surgery. Event-related analysis revealed that patients with left temporal lobe epilepsy had greater activation in the left posterior medial temporal lobe when successfully encoding words postoperatively than preoperatively. Greater pre- than postoperative activation in the ipsilateral posterior medial temporal lobe for encoding words correlated with better verbal memory outcome after left anterior temporal lobe resection. In contrast, greater postoperative than preoperative activation in the ipsilateral posterior medial temporal lobe correlated with worse postoperative verbal memory performance. These postoperative effects were not observed for visual memory function after right anterior temporal lobe resection. Our findings provide evidence for effective preoperative reorganization of verbal memory function to the ipsilateral posterior medial temporal lobe due to the underlying disease, suggesting that it is the capacity of the posterior remnant of the ipsilateral hippocampus rather than the functional reserve of the contralateral hippocampus that is important for maintaining verbal memory function after anterior temporal lobe resection. Early postoperative reorganization to ipsilateral posterior or contralateral medial temporal lobe structures does not underpin better performance. Additionally our results suggest that visual memory function in right temporal lobe epilepsy is affected differently by right anterior temporal lobe resection than verbal memory in left temporal lobe epilepsy.
[Show abstract][Hide abstract] ABSTRACT: Functional magnetic resonance imaging has demonstrated reorganization of memory encoding networks within the temporal lobe in temporal lobe epilepsy, but little is known of the extra-temporal networks in these patients. We investigated the temporal and extra-temporal reorganization of memory encoding networks in refractory temporal lobe epilepsy and the neural correlates of successful subsequent memory formation. We studied 44 patients with unilateral temporal lobe epilepsy and hippocampal sclerosis (24 left) and 26 healthy control subjects. All participants performed a functional magnetic resonance imaging memory encoding paradigm of faces and words with subsequent out-of-scanner recognition assessments. A blocked analysis was used to investigate activations during encoding and neural correlates of subsequent memory were investigated using an event-related analysis. Event-related activations were then correlated with out-of-scanner verbal and visual memory scores. During word encoding, control subjects activated the left prefrontal cortex and left hippocampus whereas patients with left hippocampal sclerosis showed significant additional right temporal and extra-temporal activations. Control subjects displayed subsequent verbal memory effects within left parahippocampal gyrus, left orbitofrontal cortex and fusiform gyrus whereas patients with left hippocampal sclerosis activated only right posterior hippocampus, parahippocampus and fusiform gyrus. Correlational analysis showed that patients with left hippocampal sclerosis with better verbal memory additionally activated left orbitofrontal cortex, anterior cingulate cortex and left posterior hippocampus. During face encoding, control subjects showed right lateralized prefrontal cortex and bilateral hippocampal activations. Patients with right hippocampal sclerosis showed increased temporal activations within the superior temporal gyri bilaterally and no increased extra-temporal areas of activation compared with control subjects. Control subjects showed subsequent visual memory effects within right amygdala, hippocampus, fusiform gyrus and orbitofrontal cortex. Patients with right hippocampal sclerosis showed subsequent visual memory effects within right posterior hippocampus, parahippocampal and fusiform gyri, and predominantly left hemisphere extra-temporal activations within the insula and orbitofrontal cortex. Correlational analysis showed that patients with right hippocampal sclerosis with better visual memory activated the amygdala bilaterally, right anterior parahippocampal gyrus and left insula. Right sided extra-temporal areas of reorganization observed in patients with left hippocampal sclerosis during word encoding and bilateral lateral temporal reorganization in patients with right hippocampal sclerosis during face encoding were not associated with subsequent memory formation. Reorganization within the medial temporal lobe, however, is an efficient process. The orbitofrontal cortex is critical to subsequent memory formation in control subjects and patients. Activations within anterior cingulum and insula correlated with better verbal and visual subsequent memory in patients with left and right hippocampal sclerosis, respectively, representing effective extra-temporal recruitment.
[Show abstract][Hide abstract] ABSTRACT: Purpose:
Temporal lobe epilepsy (TLE) has been considered to impair long-term memory, whilst not affecting working memory, but recent evidence suggests that working memory is compromised. Functional MRI (fMRI) studies demonstrate that working memory involves a bilateral frontoparietal network the activation of which is disrupted in hippocampal sclerosis (HS). A specific role of the hippocampus to deactivate during working memory has been proposed with this mechanism faulty in patients with HS. Structural correlates of disrupted working memory in HS have not been explored.
We studied 54 individuals with medically refractory TLE and unilateral HS (29 left) and 28 healthy controls. Subjects underwent 3T structural MRI, a visuospatial n-back fMRI paradigm and diffusion tensor imaging (DTI). Working memory capacity assessed by three span tasks (digit span backwards, gesture span, motor sequences) was combined with performance in the visuospatial paradigm to give a global working memory measure. Gray and white matter changes were investigated using voxel-based morphometry and voxel-based analysis of DTI, respectively.
Individuals with left or right HS performed less well than healthy controls on all measures of working memory. fMRI demonstrated a bilateral frontoparietal network during the working memory task with reduced activation of the right parietal lobe in both patient groups. In left HS, gray matter loss was seen in the ipsilateral hippocampus and parietal lobe, with maintenance of the gray matter volume of the contralateral parietal lobe associated with better performance. White matter integrity within the frontoparietal network, in particular the superior longitudinal fasciculus and cingulum, and the contralateral temporal lobe, was associated with working memory performance. In right HS, gray matter loss was also seen in the ipsilateral hippocampus and parietal lobe. Working memory performance correlated with the gray matter volume of both frontal lobes and white matter integrity within the frontoparietal network and contralateral temporal lobe.
Our data provide further evidence that working memory is disrupted in HS and impaired integrity of both gray and white matter is seen in functionally relevant areas. We suggest this forms the structural basis of the impairment of working memory, indicating widespread and functionally significant structural changes in patients with apparently isolated HS.
[Show abstract][Hide abstract] ABSTRACT: Working memory is a critical building block for almost all cognitive tasks, and impairment can cause significant disruption to daily life routines. We investigated the functional connectivity (FC) of the visuo-spatial working memory network in temporal lobe epilepsy and its relationship to the underlying white matter tracts emanating from the hippocampus. Fifty-two patients with unilateral hippocampal sclerosis (HS) (30 left) and 30 healthy controls underwent working memory functional MRI (fMRI) and Diffusion Tensor Imaging (DTI). Six seed regions were identified for FC analysis; 4 within a task-positive network (left and right middle frontal gyri and superior parietal lobes), and 2 within a task-negative network (left and right hippocampi). FC maps were created by extracting the time-series of the fMRI signal in each region in each subject and were used as regressors of interest for additional GLM fMRI analyses. Structural connectivity (SC) corresponding to areas to which the left and right hippocampi were connected was determined using tractography, and a mean FA for each hippocampal SC map was calculated. Both left and right HS groups showed atypical FC between task-positive and task-negative networks compared to controls. This was characterised by co-activation of the task-positive superior parietal lobe ipsilateral to the typically task-negative sclerosed hippocampus. Correlational analysis revealed stronger FC between superior parietal lobe and ipsilateral hippocampus, was associated with worse performance in each patient group. The SC of the hippocampus was associated with the intra-hemispheric FC of the superior parietal lobe, in that greater SC was associated with weaker parieto-frontal FC. The findings suggest that the segregation of the task-positive and task-negative FC networks supporting working memory in TLE is disrupted, and is associated with abnormal structural connectivity of the sclerosed hippocampus. Co-activation of parieto-temporal regions was associated with poorer working memory and this may be associated with working memory dysfunction in TLE.
[Show abstract][Hide abstract] ABSTRACT: Purpose
Topiramate (TPM) is known to cause language impairment in healthy volunteers and patients with epilepsy. We assessed the effects of TPM on functional language networks in both patients with focal epilepsies and healthy controls using functional magnetic resonance imaging (fMRI).
We obtained fMRI data in 24 controls and 35 patients with frontal lobe epilepsy using a simple verbal fluency (VF) paradigm. Eight of the 35 patients were treated with TPM in polytherapy. We compared cognitive task related activations and de-activations in patients taking TPM with patients taking other AEDs and healthy controls. In a longitudinal pilot study with VF-fMRI paradigm, we studied two patients with focal epilepsies twice, prior to starting and on stable doses of TPM, two patients twice, before and after tapering TPM completely and two healthy controls twice, before and after single doses of 200 mg TPM.
Cross sectional analyses of VF-fMRI showed a reduction in the task-related deactivation of the default mode network (DMN) in patients taking TPM. The longitudinal study corroborated these findings as both chronic administration and a single dose of TPM were associated with impaired categorical verbal fluency and disruption of task-related deactivations.
Similar neuropsychological and fMRI findings in patients and healthy controls indicate a specific effect of TPM in default mode network areas that may be essential components of the language network. Our preliminary data suggest a mechanism by which TPM impairs cognitive processing during language function and highlights the sensitivity of fMRI to detect the effects of AEDs on cognitive brain networks.
Epilepsy research 01/2013; 105(1-2). DOI:10.1016/j.eplepsyres.2012.12.007 · 2.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Malformations of cortical development (MCD), particularly focal cortical dysplasia (FCD), are a common cause of refractory epilepsy but are often invisible on structural imaging. NODDI (neurite orientation dispersion and density imaging) is an advanced diffusion imaging technique that provides additional information on tissue microstructure, including intracellular volume fraction (ICVF), a marker of neurite density.
We applied this technique in 5 patients with suspected dysplasia to show that the additional parameters are compatible with the underlying disrupted tissue microstructure and could assist in the identification of the affected area.
The consistent finding was reduced ICVF in the area of dysplasia. In one patient, an area of reduced ICVF and increased fibre dispersion was identified that was not originally seen on the structural imaging. The focal reduction in ICVF on imaging is compatible with previous iontophoretic data in surgical specimens, was more conspicuous than on other clinical or diffusion images (supported by an increased contrast-to-noise ratio) and more localised than on previous DTI studies.
NODDI may therefore assist the clinical identification and localisation of FCD in patients with epilepsy. Future studies will assess this technique in a larger cohort including MRI negative patients.
Epilepsy research 01/2013; 108(2). DOI:10.1016/j.eplepsyres.2013.11.004 · 2.02 Impact Factor