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Objective: Memory is one of the most sensitive markers of cognitive compromise in people with new‐onset epilepsy. Nonetheless, around half of these cases score within the normal range on standard memory testing. Here we explore whether memory retention at a 1‐week delay reveals otherwise undetected memory compromise in such individuals, and how it relates to subjective memory complaints and mood. Methods: Using a prospective design, 38 adults with new‐onset epilepsy underwent baseline memory screening via telephone using an abbreviated Rey Auditory Verbal Learning Test (RAVLT). Psychological screening occurred via online questionnaires. One week later, without forewarning, participants completed three follow‐up memory tasks. Of particular focus, we explored longer‐term memory performances and forgetting trajectories in those individuals (n = 23) who demonstrated normal memory performances (scores >10th percentile) at baseline (30‐min delay). Outcomes were compared to 32 healthy controls, matched for age, sex, and education. Results: As a group, people with epilepsy performed worse than controls on all memory measures, with 44 percent impaired at baseline testing. Of those unimpaired at baseline, the rate and volume of information loss over 1 week was significantly greater than for controls. Contextual memory performance at 1 week was also significantly poorer for people with epilepsy. At the individual level, the prevalence of impaired forgetting was not significantly different between patients and controls. Subjective memory complaints were not related to any objective tests but were strongly related to self‐reported mood and anxiety symptoms. Significance: People with new‐onset epilepsy show reduced memory at short and extended intervals. For those showing normal memory at baseline, information does appear to be forgotten more quickly than in healthy controls, though the effect is not large. The findings indicate that while extended delay memory testing is not essential in all new epilepsy cases, it could provide useful information for particular individuals. Plain Language Statement: Memory problems are common in people with epilepsy shortly after seizure onset, however, many individuals still show normal memory performances on standard neuropsychological testing. Through testing memory at an extended timepoint (1 week), our study found that on average, these individuals showed a slightly quicker rate of forgetting over a 1‐week period than people without a brain condition. Self‐reported memory complaints in people with new epilepsy were unrelated to their actual memory skills on testing at short and long timepoints but were rather linked to lower mood and quality of life. [ABSTRACT FROM AUTHOR]

Objective: Neuropsychological comorbidities found in chronic epilepsy have also been reported earlier in the disease course. However, recurrent seizures, antiseizure medication (ASM), and adjustment to a chronic diagnosis remain potential confounds of this literature. It thus remains unclear whether these comorbidities are primary or secondary attributes of epilepsy. To capture individuals as close to disease onset as possible, we studied the cognitive and psychological functioning in adults after their first seizure, yet prior to epilepsy diagnosis and treatment. Methods: Using a telehealth‐based prospective design, we screened cognition, mood, and anxiety symptoms in adult patients referred to a First Seizure Clinic (FSC), who were over 18 years, English‐speaking and not taking ASM. We screened cognition via telephone, and psychological symptoms via online questionnaires, all prior to the patients' diagnostic evaluation. Data were collected on 32 individuals subsequently diagnosed with epilepsy at the FSC, and 30 healthy controls from the community, who were matched to the epilepsy group for age, gender, and education. Results: A multivariate analysis of variance revealed that the groups differed significantly on combined cognitive measures with a large effect size (F[1,56] = 5.75, p < 0.001, η2 = 0.45). Post‐hoc analyses showed that performances on measures of verbal memory, working memory, and executive functions were significantly worse for the newly diagnosed epilepsy group than controls. The epilepsy group also exhibited higher rates of clinically significant depressive and anxiety symptoms. Significance: Cognitive and psychological dysfunction is prevalent in people with epilepsy as early as the first seizure event, before the influence of diagnosis, ASM and recurrent seizures. Their neuropsychological profile parallels that seen in chronic epilepsy, showing that this dysfunction is already present at the very onset of the disease. The current study demonstrates the viability of telehealth neuropsychological screening for all new epilepsy cases. Plain Language Statement: The results of this study show, using telephone‐based cognitive assessment and online questionnaires, that people with newly diagnosed epilepsy can experience problems with their thinking and memory skills, and low mood and anxiety, as early as after their first seizure. These issues are apparent at the very beginning of the disease, before an epilepsy diagnosis is made and before antiseizure medication is commenced, which suggests that they are due to the underlying brain disturbance, rather than the secondary effects of seizures, treatment, or lifestyle changes. Telehealth‐screening of thinking skills and mental health for all new epilepsy cases is recommended to promote early management of such problems. [ABSTRACT FROM AUTHOR]

Objective: Epilepsy is a common and serious neurological disorder. This cross‐sectional analysis addresses the burden of epilepsy at different stages of the disease. Methods: This pilot study is embedded within the Australian Epilepsy Project (AEP), aiming to provide epilepsy support through a national network of dedicated sites. For this analysis, adults aged 18–65 years with first unprovoked seizure (FUS), newly diagnosed epilepsy (NDE), or drug‐resistant epilepsy (DRE) were recruited between February–August 2022. Baseline clinicodemographic data were collected from the participants who completed questionnaires to assess their quality of life (QOLIE‐31, EQ‐5D‐5L), work productivity (Work Productivity and Activity Impairment [WPAI]), and care needs. Univariate analysis and multivariate regression was performed. Results: 172 participants formed the study cohort (median age 34, interquartile range [IQR]: 26–45), comprising FUS (n = 44), NDE (n = 53), and DRE (n = 75). Mean QOLIE‐31 score was 56 (standard deviation [SD] ± 18) and median EQ‐5D‐5L score was 0.77 (IQR: 0.56–0.92). QOLIE‐31 but not EQ‐5D‐5L scores were significantly lower in the DRE group compared to FUS and NDE groups (p < 0.001). Overall, 64.5% of participants participated in paid work, with fewer DRE (52.0%) compared with FUS (76.7%) and NDE (72.5%) (p < 0.001). Compared to those not in paid employment, those in paid employment had significantly higher quality of life scores (p < 0.001). Almost 5.8% of participants required formal care (median 20 h/week, IQR: 12–55) and 17.7% required informal care (median 16 h/week, IQR: 7–101). Significance: Epilepsy is associated with a large burden in terms of quality of life, productivity and care needs. Plain Language Summary: This is a pilot study from the Australian Epilepsy Project (AEP). It reports health economic data for adults of working age who live with epilepsy. It found that people with focal drug‐resistant epilepsy had lower quality of life scores and were less likely to participate in paid employment compared to people with new diagnosis epilepsy. This study provides important local data regarding the burden of epilepsy and will help researchers in the future to measure the impact of the AEP on important personal and societal health economic outcomes. [ABSTRACT FROM AUTHOR]

Objective: Visual assessment of magnetic resonance imaging (MRI) from the Human Epilepsy Project 1 (HEP1) found 18% of participants had atrophic brain changes relative to age without known etiology. Here, we identify the underlying factors related to brain volume differences in people with focal epilepsy enrolled in HEP1. Methods: Enrollment data for participants with complete records and brain MRIs were analyzed, including 391 participants aged 12–60 years. HEP1 excluded developmental or cognitive delay with intelligence quotient <70, and participants reported any formal learning disability diagnoses, repeated grades, and remediation. Prediagnostic seizures were quantified by semiology, frequency, and duration. T1‐weighted brain MRIs were analyzed using Sequence Adaptive Multimodal Segmentation (FreeSurfer v7.2), from which a brain tissue volume to intracranial volume ratio was derived and compared to clinically relevant participant characteristics. Results: Brain tissue volume changes observable on visual analyses were quantified, and a brain tissue volume to intracranial volume ratio was derived to compare with clinically relevant variables. Learning difficulties were associated with decreased brain tissue volume to intracranial volume, with a ratio reduction of.005 for each learning difficulty reported (95% confidence interval [CI] = −.007 to −.002, p =.0003). Each 10‐year increase in age at MRI was associated with a ratio reduction of.006 (95% CI = −.007 to −.005, p <.0001). For male participants, the ratio was.011 less than for female participants (95% CI = −.014 to −.007, p <.0001). There were no effects from seizures, employment, education, seizure semiology, or temporal lobe electroencephalographic abnormalities. Significance: This study shows lower brain tissue volume to intracranial volume in people with newly treated focal epilepsy and learning difficulties, suggesting developmental factors are an important marker of brain pathology related to neuroanatomical changes in focal epilepsy. Like the general population, there were also independent associations between brain volume, age, and sex in the study population. [ABSTRACT FROM AUTHOR]

Improved quality of life (QoL) is an important outcome goal following epilepsy surgery. This study aims to quantify change in QoL for adults with drug‐resistant epilepsy (DRE) who undergo epilepsy surgery, and to explore clinicodemographic factors associated with these changes. We conducted a systematic review and meta‐analysis using Medline, Embase, and Cochrane Central Register of Controlled Trials. All studies reporting pre‐ and post‐epilepsy surgery QoL scores in adults with DRE via validated instruments were included. Meta‐analysis assessed the postsurgery change in QoL. Meta‐regression assessed the effect of postoperative seizure outcomes on postoperative QoL as well as change in pre‐ and postoperative QoL scores. A total of 3774 titles and abstracts were reviewed, and ultimately 16 studies, comprising 1182 unique patients, were included. Quality of Life in Epilepsy Inventory–31 item (QOLIE‐31) meta‐analysis included six studies, and QOLIE‐89 meta‐analysis included four studies. Postoperative change in raw score was 20.5 for QOLIE‐31 (95% confidence interval [CI] = 10.9–30.1, I2 = 95.5) and 12.1 for QOLIE‐89 (95% CI = 8.0–16.1, I2 = 55.0%). This corresponds to clinically meaningful QOL improvements. Meta‐regression demonstrated a higher postoperative QOLIE‐31 score as well as change in pre‐ and postoperative QOLIE‐31 score among studies of cohorts with higher proportions of patients with favorable seizure outcomes. At an individual study level, preoperative absence of mood disorders, better preoperative cognition, fewer trials of antiseizure medications before surgery, high levels of conscientiousness and openness to experience at the baseline, engagement in paid employment before and after surgery, and not being on antidepressants following surgery were associated with improved postoperative QoL. This study demonstrates the potential for epilepsy surgery to provide clinically meaningful improvements in QoL, as well as identifies clinicodemographic factors associated with this outcome. Limitations include substantial heterogeneity between individual studies and high risk of bias. [ABSTRACT FROM AUTHOR]

Magnetoencephalography with optically pumped magnometers (OPM‐MEG) is an emerging and novel, cost‐effective wearable system that can simultaneously record neuronal activity with high temporal resolution ("when" neuronal activity occurs) and spatial resolution ("where" neuronal activity occurs). This paper will first outline recent methodological advances in OPM‐MEG compared to conventional superconducting quantum interference device (SQUID)‐MEG before discussing how OPM‐MEG can become a valuable and noninvasive clinical support tool in epilepsy surgery evaluation. Although OPM‐MEG and SQUID‐MEG share similar data features, OPM‐MEG is a wearable design that fits children and adults, and it is also robust to head motion within a magnetically shielded room. This means that OPM‐MEG can potentially extend the application of MEG into the neurobiology of severe childhood epilepsies with intellectual disabilities (e.g., epileptic encephalopathies) without sedation. It is worth noting that most OPM‐MEG sensors are heated, which may become an issue with large OPM sensor arrays (OPM‐MEG currently has fewer sensors than SQUID‐MEG). Future implementation of triaxial sensors may alleviate the need for large OPM sensor arrays. OPM‐MEG designs allowing both awake and sleep recording are essential for potential long‐term epilepsy monitoring. [ABSTRACT FROM AUTHOR]

Objectives: An important but understudied benefit of resective epilepsy surgery is improvement in productivity; that is, people's ability to contribute to society through participation in the workforce and in unpaid roles such as carer duties. Here, we aimed to evaluate productivity in adults with drug‐resistant epilepsy (DRE) pre‐ and post‐resective epilepsy surgery, and to explore the factors that positively influence productivity outcomes. Methods: We conducted a systematic review and meta‐analysis using four electronic databases: Medline (Ovid), EMBASE (Ovid), EBM Reviews ‐ Cochrane Central Register of Controlled Trials (CENTRAL), and Cochrane Library. All studies over the past 30 years reporting on pre‐ and post‐resective epilepsy surgical outcomes in adults with DRE were eligible for inclusion. Meta‐analysis was performed to assess the post‐surgery change in employment outcomes. Results: A total of 1005 titles and abstracts were reviewed. Seventeen studies, comprising 2056 unique patients, were suitable for the final quantitative synthesis and meta‐analysis. Resective epilepsy surgery resulted in a 22% improvement in overall productivity (95% confidence interval [CI]: 1.07–1.40). The factors associated with increased post‐surgery employment risk ratios were lower pre‐surgical employment in the workforce (relative risk ratio [RRR] =0.34; 95% CI: 0.15–0.74), shorter follow‐up duration (RRR = 0.95; 95% CI: 0.90–0.99), and lower mean age at time of surgery (RRR= 0.97; 95% CI: 0.94–0.99). The risk of bias of the included studies was assessed using Risk Of Bias In Non‐randomised Studies ‐ of Interventions and was low for most variables except "measurement of exposure." Significance: There is clear evidence that resective surgery in eligible surgical DRE patients results in improved productivity. Future work may include implementing a standardized method for collecting and reporting productivity in epilepsy cohorts and focusing on ways to reprioritize health care resource allocation to allow suitable candidates to access surgery earlier. This will ultimately benefit individuals with DRE, their families, our communities, and the wider health care system. [ABSTRACT FROM AUTHOR]

Objective: We use the dynamic electroencephalography–functional magnetic resonance imaging (EEG‐fMRI) method to incorporate variability in the amplitude and field of the interictal epileptic discharges (IEDs) into the fMRI analysis. We ask whether IED variability analysis can (a) identify additional activated brain regions during the course of IEDs, not seen in standard analysis; and (b) demonstrate the origin and spread of epileptic activity. We explore whether these functional changes recapitulate the structural connections and propagation of epileptic activity during seizures. Methods: Seventeen patients with focal epilepsy and at least 30 IEDs of a single type during simultaneous EEG‐fMRI were studied. IED variability and EEG source imaging (ESI) analysis extracted time‐varying dynamic changes. General linear modeling (GLM) generated static functional maps. Dynamic maps were compared to static functional maps. The dynamic sequence from IED variability was compared to the ESI results. In a subset of patients, we investigated structural connections between active brain regions using diffusion‐based fiber tractography. Results: IED variability distinguished the origin of epileptic activity from its propagation in 15 of 17 (88%) patients. This included two cases where no result was obtained from the standard GLM analysis. In both of these cases, IED variability revealed activation in line with the presumed epileptic focus. Two cases showed no result from either method. Both had very high spike rates associated with dysplasia in the postcentral gyrus. In all 15 cases with dynamic activation, the observed dynamics were concordant with ESI. Fiber tractography identified specific white matter pathways between brain regions that were active at IED onset and propagation. Significance: Dynamic techniques involving IED variability can provide additional power for EEG‐fMRI analysis, compared to standard analysis, revealing additional biologically plausible information in cases with no result from the standard analysis and gives insight into the origin and spread of IEDs. [ABSTRACT FROM AUTHOR]

Objective: The aim of this report is to present our clinical experience of electroencephalography–functional magnetic resonance imaging (EEG‐fMRI) in localizing the epileptogenic focus, and to evaluate the clinical impact and challenges associated with the use of EEG‐fMRI in pharmacoresistant focal epilepsy. Methods: We identified EEG‐fMRI studies (n = 118) in people with focal epilepsy performed at our center from 2003 to 2018. Participants were referred from our Comprehensive Epilepsy Program in an exploratory research effort to address often difficult clinical questions, due to complex and difficult‐to‐localize epilepsy. We assessed the success of each study, the clinical utility of the result, and when surgery was performed, the postoperative outcome. Results: Overall, 50% of EEG‐fMRI studies were successful, meaning that data were of good quality and interictal epileptiform discharges were recorded. With an altered recruitment strategy since 2012 with increased inclusion of patients who were inpatients for video‐EEG monitoring, we found that this patients in this selected group were more likely to have epileptic discharges detected during EEG‐fMRI (96% of inpatients vs 29% of outpatients, P<.0001). To date, 48% (57 of 118) of patients have undergone epilepsy surgery. In 10 cases (17% of the 59 successful studies) the EEG‐fMRI result had a "critical impact" on the surgical decision. These patients were difficult to localize because of subtle abnormalities, apparently normal MRI, or extensive structural abnormalities. All 10 had a good seizure outcome at 1 year after surgery (mean follow‐up 6.5 years). Significance: EEG‐fMRI results can assist identification of the epileptogenic focus in otherwise difficult‐to‐localize cases of pharmacoresistant focal epilepsy. Surgery determined largely by localization from the EEG‐fMRI result can lead to good seizure outcomes. A limitation of this study is its retrospective design with nonconsecutive recruitment. Prospective clinical trials with well‐defined inclusion criteria are needed to determine the overall benefit of EEG‐fMRI for preoperative localization and postoperative outcome in focal epilepsy. [ABSTRACT FROM AUTHOR]

Structural magnetic resonance imaging (MRI) is of fundamental importance to the diagnosis and treatment of epilepsy, particularly when surgery is being considered. Despite previous recommendations and guidelines, practices for the use of MRI are variable worldwide and may not harness the full potential of recent technological advances for the benefit of people with epilepsy. The International League Against Epilepsy Diagnostic Methods Commission has thus charged the 2013‐2017 Neuroimaging Task Force to develop a set of recommendations addressing the following questions: (1) Who should have an MRI? (2) What are the minimum requirements for an MRI epilepsy protocol? (3) How should magnetic resonance (MR) images be evaluated? (4) How to optimize lesion detection? These recommendations target clinicians in established epilepsy centers and neurologists in general/district hospitals. They endorse routine structural imaging in new onset generalized and focal epilepsy alike and describe the range of situations when detailed assessment is indicated. The Neuroimaging Task Force identified a set of sequences, with three‐dimensional acquisitions at its core, the harmonized neuroimaging of epilepsy structural sequences—HARNESS‐MRI protocol. As these sequences are available on most MR scanners, the HARNESS‐MRI protocol is generalizable, regardless of the clinical setting and country. The Neuroimaging Task Force also endorses the use of computer‐aided image postprocessing methods to provide an objective account of an individual's brain anatomy and pathology. By discussing the breadth and depth of scope of MRI, this report emphasizes the unique role of this noninvasive investigation in the care of people with epilepsy. [ABSTRACT FROM AUTHOR]

Summary: Epilepsy is among the most common chronic neurologic disorders, with 30%‐40% of patients having seizures despite antiepileptic drug treatment. The advent of brain imaging and network analyses has greatly improved the understanding of this condition. In particular, developments in magnetic resonance imaging (MRI) have provided measures for the noninvasive characterization and detection of lesions causing epilepsy. MRI techniques can probe structural and functional connectivity, and network analyses have shaped our understanding of whole‐brain anomalies associated with focal epilepsies. This review considers the progress made by neuroimaging and connectomics in the study of drug‐resistant epilepsies due to focal substrates, particularly temporal lobe epilepsy related to mesiotemporal sclerosis and extratemporal lobe epilepsies associated with malformations of cortical development. In these disorders, there is evidence of widespread disturbances of structural and functional connectivity that may contribute to the clinical and cognitive prognosis of individual patients. It is hoped that studying the interplay between macroscale network anomalies and lesional profiles will improve our understanding of focal epilepsies and assist treatment choices. [ABSTRACT FROM AUTHOR]

Summary: The aim of this study was to investigate upper airway anatomy in quadriplegics with obstructive sleep apnea. Fifty subjects were recruited from three hospitals in Australia: people with quadriplegia due to spinal cord injury and obstructive sleep apnea (n = 11), able‐bodied people with obstructive sleep apnea (n = 18), and healthy, able‐bodied controls (n = 19). All underwent 3‐Tesla magnetic resonance imaging of their upper airway. A subgroup (n = 34) received a topical vasoconstrictor, phenylephrine and post‐phenylephrine magnetic resonance imaging. Mixed‐model analysis indicated no significant differences in total airway lumen volume between the three groups (P = 0.086). Spinal cord injury–obstructive sleep apnea subjects had a significantly larger volume of soft palate (P = 0.020) and retroglossal lateral pharyngeal walls (P = 0.043) than able‐bodied controls. Able‐bodied–obstructive sleep apnea subjects had a smaller mandible volume than spinal cord injury–obstructive sleep apnea subjects and able‐bodied control subjects (P = 0.036). No differences were seen in airway length between groups when controlling for height (P = 0.055). There was a marginal increase in velopharyngeal volume across groups post‐phenylephrine (P = 0.050), and post hoc testing indicated the difference was confined to the able‐bodied–obstructive sleep apnea group (P < 0.001). No other upper airway structures showed significant changes with phenylephrine administration. In conclusion, people with obstructive sleep apnea and quadriplegia do not have a structurally smaller airway than able‐bodied subjects. They did, however, have greater volumes of soft palate and lateral pharyngeal walls, possibly due to greater neck fat deposition. The acute response to upper airway topical vasoconstriction was not enhanced in those with obstructive sleep apnea and quadriplegia. Changes in upper airway anatomy likely contribute to the high incidence in obstructive sleep apnea in quadriplegic subjects. [ABSTRACT FROM AUTHOR]

Abstract: Objective: The dominant model of cognitive impairment in focal epilepsy has emphasised structural bases for cognitive deficits. Current theories of cognition in the healthy brain emphasise the importance of the reweighting of brain network interactions in support of task performance. Here, we explore the hypothesis that cognitive deficits in epilepsy arise through abnormalities of dynamic functional network interactions. Method: We studied 19 healthy controls and 37 temporal lobe epilepsy (TLE) patients, using a behavioural measure of verbal fluency (the Controlled Oral Word Association Test) and an fMRI verbal fluency paradigm (Orthographic Lexical Retrieval). Results: Behaviourally, verbal fluency was significantly impaired in TLE. Psychophysiological interaction analyses of the fMRI data, which capture state‐dependent changes in network connectivity, revealed reduced task‐dependent modulations of connectivity from left superior medial frontal cortex to left middle frontal gyrus in TLE patients. Individual differences in verbal fluency among TLE cases was correlated with task‐dependent changes in connectivity from left posterior cingulate to left superior medial frontal cortex, and from left superior medial frontal cortex to a range of right predominant brain areas. Interpretation: These data reveal that the typical pattern of task‐driven shifts in network connectivity is not observed in TLE. Our observations go beyond simple structure‐function associations and suggest that failure of network flexibility can be an important contributor to cognitive impairment in epilepsy. [ABSTRACT FROM AUTHOR]

Objective To identify abnormal thalamocortical circuits in the severe epilepsy of Lennox-Gastaut syndrome ( LGS) that may explain the shared electroclinical phenotype and provide potential treatment targets. Methods Twenty patients with a diagnosis of LGS (mean age = 28.5 years) and 26 healthy controls (mean age = 27.6 years) were compared using task-free functional magnetic resonance imaging ( MRI). The thalamus was parcellated according to functional connectivity with 10 cortical networks derived using group-level independent component analysis. For each cortical network, we assessed between-group differences in thalamic functional connectivity strength using nonparametric permutation-based tests. Anatomical locations were identified by quantifying spatial overlap with a histologically informed thalamic MRI atlas. Results In both groups, posterior thalamic regions showed functional connectivity with visual, auditory, and sensorimotor networks, whereas anterior, medial, and dorsal thalamic regions were connected with networks of distributed association cortex (including the default-mode, anterior-salience, and executive-control networks). Four cortical networks (left and right executive-control network; ventral and dorsal default-mode network) showed significantly enhanced thalamic functional connectivity strength in patients relative to controls. Abnormal connectivity was maximal in mediodorsal and ventrolateral thalamic nuclei. Significance Specific thalamocortical circuits are affected in LGS. Functional connectivity is abnormally enhanced between the mediodorsal and ventrolateral thalamus and the default-mode and executive-control networks, thalamocortical circuits that normally support diverse cognitive processes. In contrast, thalamic regions connecting with primary and sensory cortical networks appear to be less affected. Our previous neuroimaging studies show that epileptic activity in LGS is expressed via the default-mode and executive-control networks. Results of the present study suggest that the mediodorsal and ventrolateral thalamus may be candidate targets for modulating abnormal network behavior underlying LGS, potentially via emerging thalamic neurostimulation therapies. [ABSTRACT FROM AUTHOR]

Simultaneous scalp EEG-fMRI recording is a noninvasive neuroimaging technique for combining electrophysiological and hemodynamic aspects of brain function. Despite the time-varying nature of both measurements, their relationship is usually considered as time-invariant. The aim of this study was to detect direct associations between scalp-recorded EEG and regional changes of hemodynamic brain connectivity in focal epilepsy through a time-frequency paradigm. To do so, we developed a voxel-wise framework that analyses wavelet coherence between dynamic regional phase synchrony (DRePS, calculated from fMRI) and band amplitude fluctuation (BAF) of a target EEG electrode with dominant interictal epileptiform discharges (IEDs). As a proof of concept, we applied this framework to seven patients with focal epilepsy. The analysis produced patient-specific spatial maps of DRePS-BAF coupling, which highlight regions with a strong link between EEG power and local fMRI connectivity. Although we observed DRePS-BAF coupling proximate to the suspected seizure onset zone in some patients, our results suggest that DRePS-BAF is more likely to identify wider 'epileptic networks'. We also compared DRePS-BAF with standard EEG-fMRI analysis based on general linear modelling (GLM). There was, in general, little overlap between the DRePS-BAF maps and GLM maps. However, in some subjects the spatial clusters revealed by these two analyses appeared to be adjacent, particularly in medial posterior cortices. Our findings suggest that (1) there is a strong time-varying relationship between local fMRI connectivity and interictal EEG power in focal epilepsy, and (2) that DRePS-BAF reflect different aspects of epileptic network activity than standard EEG-fMRI analysis. These two techniques, therefore, appear to be complementary. Hum Brain Mapp 38:5356-5374, 2017. © 2017 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

We previously observed that adults with Lennox-Gastaut syndrome ( LGS) show abnormal functional connectivity among cognitive networks, suggesting that this may contribute to impaired cognition. Herein we report network reorganization following seizure remission in a child with LGS who underwent functional magnetic resonance imaging ( fMRI) before and after resection of a cortical dysplasia. Concurrent electroencephalography ( EEG) was acquired during presurgical fMRI. Presurgical and postsurgical functional connectivity were compared using (1) graph theoretical analyses of small-world network organization and node-wise strength; and (2) seed-based analyses of connectivity within and between five functional networks. To explore the specificity of these postsurgical network changes, connectivity was further compared to nine children with LGS who did not undergo surgery. The presurgical EEG- fMRI revealed diffuse activation of association cortex during interictal discharges. Following surgery and seizure control, functional connectivity showed increased small-world organization, stronger connectivity in subcortical structures, and greater within-network integration/between-network segregation. These changes suggest network improvement, and diverged sharply from the comparison group of nonoperated children. Following surgery, this child with LGS achieved seizure control and showed extensive reorganization of networks that underpin cognition. This case illustrates that the epileptic process of LGS can directly contribute to abnormal network organization, and that this network disruption may be reversible. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether genetics, underlying pathology, or repeated seizures contribute to atrophy in specific white matter tracts.Methods: Medically refractory unilateral temporal lobe epilepsy (TLE) with hippocampal sclerosis (HS-TLE, n = 26) was studied as an archetype of focal epilepsy, using fixel-based analysis of diffusion-weighted imaging. A genetic effect was assessed in first-degree relatives of HS-TLE subjects who did not have epilepsy themselves (HS-1°Rel; n = 26). The role of disease process was uncovered by comparing HS-TLE to unilateral TLE with normal clinical magnetic resonance imaging (MRI-neg TLE; n = 26, matched for seizure severity). The effect of focal seizures was inferred from lateralized atrophy common to both HS-TLE and MRI-neg TLE, in comparison to healthy controls (n = 76).Results: HS-1 °Rel had bilaterally small hippocampi, but no focal white matter atrophy was detected, indicating a limited effect of genetics. HS-TLE subjects had lateralized atrophy of most temporal lobe tracts, and hippocampal volumes in HS-TLE correlated with parahippocampal cingulum and anterior commissure atrophy, indicating an effect of the underlying pathology. Ipsilateral atrophy of the tapetum, uncinate, and inferior fronto-occipital fasciculus was found in both HS-TLE and MRI-neg TLE, suggesting a common lateralized effect of focal seizures. Both epilepsy groups had bilateral atrophy of the dorsal cingulum and corpus callosum fibers, which we interpret as a consequence of bilateral insults (potentially generalized seizures and/or medications).Interpretation: Underlying pathology, repeated focal seizures, and global insults each contribute to atrophy in specific tracts. Genetic factors make less of a contribution in this cohort. A multifactorial model of white matter atrophy in focal epilepsy is proposed. Ann Neurol 2017;81:240-250. [ABSTRACT FROM AUTHOR]

Objective There is considerable difficulty in diagnosing hippocampal malrotation ( HIMAL), with different criteria of variable reliability. Here we assess qualitative and quantitative criteria in HIMAL diagnosis and explore the role of HIMAL in magnetic resonance imaging ( MRI)-negative temporal lobe epilepsy ( TLE). Methods We studied the MRI of 155 adult patients with MRI-negative TLE and 103 healthy volunteers, and we asked (1) what are the qualitative and quantitative features that allow a reliable diagnosis of HIMAL, (2) how common is HIMAL in a normal control population, and (3) is HIMAL congruent with the epileptogenic side in MRI-negative TLE. Results We found that the features that are most correlated with the expert diagnosis of HIMAL are hippocampal shape change with hippocampal diameter ratio > 0.8, lack of normal lateral convex margin, and a deep dominant inferior temporal sulcus ( DITS) with DITS height ratio > 0.6. In a blinded analysis, a consensus diagnosis of unilateral or bilateral HIMAL was made in 25 of 103 controls (24.3% of people, 14.6% of hippocampi-14 left, six right, 10 bilateral) that did not differ from 155 lesion-negative TLE patients where 25 had HIMAL (16.1% of patients, 11.6% of hippocampi-12 left, two right, 11 bilateral). Of the 12 with left HIMAL only, 9 had seizures arising from the left temporal lobe, whereas 3 had right-sided seizures. Of the two with right HIMAL only, both had seizures arising from the left temporal lobe. Significance HIMAL is an anatomic variant commonly found in controls. HIMAL is also an incidental nonpathologic finding in adult MRI-negative TLE and should not influence surgical decision making. [ABSTRACT FROM AUTHOR]

Objective In patients with Lennox-Gastaut syndrome ( LGS), recurrent epileptic activity is thought to contribute to impaired cognition (epileptic encephalopathy). Using concurrent electroencephalography-functional magnetic resonance imaging ( EEG- fMRI), we recently showed that epileptiform discharges in LGS recruit large-scale networks that normally support key cognitive processes. In LGS, given that epileptic activity engages cognitive networks, and cognition is pervasively impaired, we hypothesized that cognitive network interactions in LGS are persistently abnormal. Methods We studied 15 LGS patients (mean age ± 1 standard deviation [SD] = 28.7 ± 10.6 years) and 17 healthy controls (mean age ± 1 SD = 27.6 ± 6.6 years) using task-free EEG- fMRI. Four networks of interest (default-mode, dorsal attention, executive control, and anterior salience) were defined using group-level independent components analysis ( ICA). Functional connectivity within and between networks was determined for each subject, and then LGS network interactions were compared to network behavior in the control group. To test whether group differences were present in periods without scalp-detectable epileptiform discharges (i.e., persistent), we separately assessed discharge-affected and discharge-unaffected epochs in six patients with sufficient data for this analysis. Results In LGS, cognitive networks showed (1) reduced within-network integration, including weaker connectivity within the default-mode network, and (2) impaired between-network segregation, including stronger connectivity between the default-mode and dorsal attention networks. Abnormal interactions were present during fMRI periods with and without discharges, indicating that impaired network behavior may endure during periods without scalp-detectable epileptic activity. Significance In LGS, cognitive network interactions are persistently abnormal. Given that cognition typically worsens with the onset of LGS, and may improve after seizure control, our findings are consistent with the hypothesis that the epileptic process in LGS may initiate and perhaps sustain abnormal network behavior. We propose that epileptic encephalopathy may be a consequence of persistently disrupted cognitive network interactions. [ABSTRACT FROM AUTHOR]

Dynamic functional brain connectivity analysis is a fast expanding field in computational neuroscience research with the promise of elucidating brain network interactions. Sliding temporal window based approaches are commonly used in order to explore dynamic behavior of brain networks in task-free functional magnetic resonance imaging (fMRI) data. However, the low effective temporal resolution of sliding window methods fail to capture the full dynamics of brain activity at each time point. These also require subjective decisions regarding window size and window overlap. In this study, we introduce dynamic regional phase synchrony (DRePS), a novel analysis approach that measures mean local instantaneous phase coherence within adjacent fMRI voxels. We evaluate the DRePS framework on simulated data showing that the proposed measure is able to estimate synchrony at higher temporal resolution than sliding windows of local connectivity. We applied DRePS analysis to task-free fMRI data of 20 control subjects, revealing ultra-slow dynamics of local connectivity in different brain areas. Spatial clustering based on the DRePS feature time series reveals biologically congruent local phase synchrony networks (LPSNs). Taken together, our results demonstrate three main findings. Firstly, DRePS has increased temporal sensitivity compared to sliding window correlation analysis in capturing locally synchronous events. Secondly, DRePS of task-free fMRI reveals ultra-slow fluctuations of ∼0.002-0.02 Hz. Lastly, LPSNs provide plausible spatial information about time-varying brain local phase synchrony. With the DRePS method, we introduce a framework for interrogating brain local connectivity, which can potentially provide biomarkers of human brain function in health and disease. Hum Brain Mapp 37:1970-1985, 2016. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Polymicrogyria is a significant malformation of cortical development with a high incidence of epilepsy and cognitive deficits. Graph theoretic analysis is a useful approach to studying network organization in brain disorders. In this study, we used task-free functional magnetic resonance imaging ( fMRI) data from four patients with polymicrogyria and refractory epilepsy. Gray matter masks from structural MRI data were parcellated into 1,024 network nodes. Functional 'connectomes' were obtained based on fMRI time series between the parcellated network nodes; network analysis was conducted using clustering coefficient, path length, node degree, and participation coefficient. These graph metrics were compared between nodes within polymicrogyric cortex and normal brain tissue in contralateral homologous cortical regions. Polymicrogyric nodes showed significantly increased clustering coefficient and characteristic path length. This is the first study using functional connectivity analysis in polymicrogyria-our results indicate a shift toward a regular network topology in polymicrogyric nodes. Regularized network topology has been demonstrated previously in patients with focal epilepsy and during focal seizures. Thus, we postulate that these network alterations predispose to seizures and may be relevant to cognitive deficits in patients with polymicrogyria. [ABSTRACT FROM AUTHOR]

Changes in hardware or image-processing settings are a common issue for large multicenter studies. To pool MRI data acquired under these changed conditions, it is necessary to demonstrate that the changes do not affect MRI-based measurements. In these circumstances, classical inference testing is inappropriate because it is designed to detect differences, not prove similarity. We used a method known as statistical equivalence testing to address this limitation. Equivalence testing was carried out on 3 datasets: (1) cortical thickness and automated hippocampal volume estimates obtained from healthy individuals imaged using different multichannel head coils; (2) manual hippocampal volumetry obtained using two readers; and (3) corpus callosum area estimates obtained using an automated method with manual cleanup carried out by two readers. Equivalence testing was carried out using the "two one-sided tests" (TOST) approach. Power analyses of the TOST were used to estimate sample sizes required for well-powered equivalence testing analyses. Mean and standard deviation estimates from the automated hippocampal volume dataset were used to carry out an example power analysis. Cortical thickness values were found to be equivalent over 61% of the cortex when different head coils were used (q < .05, false discovery rate correction). Automated hippocampal volume estimates obtained using the same two coils were statistically equivalent (TOST P = 4.28 × 10(-15) ). Manual hippocampal volume estimates obtained using two readers were not statistically equivalent (TOST P = .97). The use of different readers to carry out limited correction of automated corpus callosum segmentations yielded equivalent area estimates (TOST P = 1.28 × 10(-14) ). Power analysis of simulated and automated hippocampal volume data demonstrated that the equivalence margin affects the number of subjects required for well-powered equivalence tests. We have presented a statistical method for determining if morphometric measures obtained under variable conditions can be pooled. The equivalence testing technique is applicable for analyses in which experimental conditions vary over the course of the study. [ABSTRACT FROM AUTHOR]

Objective Lennox-Gastaut syndrome, and the similar but less tightly defined Lennox-Gastaut phenotype, describe patients with severe epilepsy, generalized epileptic discharges, and variable intellectual disability. Our previous functional neuroimaging studies suggest that abnormal diffuse association network activity underlies the epileptic discharges of this clinical phenotype. Herein we use a data-driven multivariate approach to determine the spatial changes in local and global networks of patients with severe epilepsy of the Lennox-Gastaut phenotype. Methods We studied 9 adult patients and 14 controls. In 20 min of task-free blood oxygen level-dependent functional magnetic resonance imaging data, two metrics of functional connectivity were studied: Regional homogeneity or local connectivity, a measure of concordance between each voxel to a focal cluster of adjacent voxels; and eigenvector centrality, a global connectivity estimate designed to detect important neural hubs. Multivariate pattern analysis of these data in a machine-learning framework was used to identify spatial features that classified disease subjects. Results Multivariate pattern analysis was 95.7% accurate in classifying subjects for both local and global connectivity measures (22/23 subjects correctly classified). Maximal discriminating features were the following: increased local connectivity in frontoinsular and intraparietal areas; increased global connectivity in posterior association areas; decreased local connectivity in sensory (visual and auditory) and medial frontal cortices; and decreased global connectivity in the cingulate cortex, striatum, hippocampus, and pons. Significance Using a data-driven analysis method in task-free functional magnetic resonance imaging, we show increased connectivity in critical areas of association cortex and decreased connectivity in primary cortex. This supports previous findings of a critical role for these association cortical regions as a final common pathway in generating the Lennox-Gastaut phenotype. Abnormal function of these areas is likely to be important in explaining the intellectual problems characteristic of this disorder. [ABSTRACT FROM AUTHOR]

Whole-exome sequencing of two brothers with drug-resistant, early-onset, focal epilepsy secondary to extensive type IIA focal cortical dysplasia identified a paternally inherited, nonsense variant of DEPDC5 (c.C1663T, p.Arg555*). This variant has previously been reported to cause familial focal epilepsy with variable foci in patients with normal brain imaging. Immunostaining of resected brain tissue from both brothers demonstrated mammalian target of rapamycin ( mTOR) activation. This report shows the histopathological features of cortical dysplasia associated with a DEPDC5 mutation, confirms mTOR dysregulation in the malformed tissue and expands the spectrum of neurological manifestations of DEPDC5 mutations to include severe phenotypes with large areas of cortical malformation. [ABSTRACT FROM AUTHOR]

Objective Childhood absence epilepsy ( CAE) is a childhood-onset generalized epilepsy. Recent fMRI studies have suggested that frontal cortex activity occurs before thalamic involvement in epileptic discharges suggesting that frontal cortex may play an important role in childhood absence seizures. Neurocognitive deficits can persist after resolution of the epilepsy. We investigate whether structural connectivity changes are present in the brains of CAE patients in young adulthood. Methods Cortical thickness measurements were obtained for 30 subjects with CAE (mean age 21 ± 2 years) and 56 healthy controls (mean age 24 ± 4) and regressed for age, sex, and total intracranial volume ( TIV). Structural connectivity was evaluated by measuring the correlation between average cortical thicknesses in 915 regions over the brain. Maps of connectivity strength were then obtained for both groups. Results When compared to controls, the CAE group shows overall increased 'connectivity' with focal increased connection strength in anterior regions including; the anterior cingulate and the insula and superior temporal gyrus bilaterally; the right orbito-frontal and supramarginal regions; and the left entorhinal cortex. Decreased connection strength in the CAE group was found in the left occipital lobe, with a similar trend in right occipital lobe. Interpretation Brains in young adults whose CAE was resolved had abnormal structural connectivity. Our findings suggest that frontal regions correlate most with cortical thickness throughout the brain in CAE patients, whereas occipital regions correlate most in well matched normal controls. We interpret this as evidence of a developmental difference in CAE that emphasizes these frontal lobe regions, perhaps driven by frontal lobe epileptiform activity. [ABSTRACT FROM AUTHOR]

Objectives: Autobiographic memory encompasses the encoding and retrieval of episodes, people, and places encountered in everyday life. It can be impaired in both epilepsy and frontal lobe damage. Here, we performed an initial investigation of how autobiographic memory is impacted by chronic frontal lobe epilepsy (FLE) together with its underlying pathology. Method: We prospectively studied a series of nine consecutive patients with medically refractory FLE, relative to 24 matched healthy controls. Seven of the nine patients had frontal lobe structural abnormalities. Episodic and semantic autobiographic memory functioning was profiled, and factors associated with impaired autobiographic memory were identified among epileptologic, neuroimaging, neuropsychiatric, and cognitive variables including auditory-verbal and visual memory, and the executive function of cognitive control. Results: Results showed that the FLE group experienced significantly higher rates of autobiographic memory and mood disturbance (p < 0.001), with detailed assessment of individual patients revealing two profiles of impairment, primarily characterized by cognitive or mood disturbance. Five of the patients (56%) exhibited significant episodic autobiographic memory deficits, whereas in three of these, knowledge of semantic autobiographic facts was preserved. Four of them also had reduced cognitive control. Mood disorder was largely unrelated to poor autobiographic memory. In contrast, the four cases with preserved autobiographic memory were notable for their past or current depressive symptoms. Significance: These findings provide preliminary data that frontal lobe seizure activity with its underlying pathology may selectively disrupt large-scale cognitive or affective networks, giving rise to different neurobehavioral profiles that may be used to inform clinical management. [ABSTRACT FROM AUTHOR]

Objective Lennox-Gastaut syndrome ( LGS) is a severe epilepsy phenotype with characteristic electroclinical features despite diverse etiologies. We previously found common cerebral networks involved during slow spike-and-wave ( SSW) and generalized paroxysmal fast activity ( PFA), characteristic interictal discharges. Some patients have a Lennox-Gastaut-like phenotype and cortical lesions. We wished to explore the interaction between cerebral networks and lesions in this group. Methods 3 Tesla electroencephalography-functional magnetic resonance imaging ( EEG-f MRI) on six subjects with Lennox-Gastaut phenotype and a structural lesion. Timings of SSW and PFA events were used in an event-related fMRI analysis, and to estimate the time course of the hemodynamic response from key regions. Results (1) PFA-robust fMRI signal increases were observed in frontal and parietal association cortical areas, thalamus, and pons, with simultaneous increases in both 'attention' and resting-state (default mode) networks, a highly unusual pattern. (2) SSW showed mixed increased and decreased fMRI activity, with preevent increases in association cortex and thalamus, and then prominent postevent reduction. There was decreased fMRI activity in primary cortical areas. (3) Lesion-variable fMRI increases were observed during PFA and SSW discharges. Three subjects who proceeded to lesionectomy are >1 year seizure-free. Significance We conceptualize Lennox-Gastaut phenotype as a being a network epilepsy, where key cerebral networks become autonomously unstable. Epileptiform activity in Lennox-Gastaut phenotype, and by implication in LGS, appears to be amplified and expressed through association cortical areas, possibly because the attention and default-mode networks are widely interconnected, fundamental brain networks. Seizure freedom in the subjects who proceeded to lesionectomy suggests that cortical lesions are able to establish and maintain this abnormal unstable network behavior. LGS may be considered a secondary network epilepsy because the unifying epileptic manifestations of the disorder, including PFA and SSW, reflect network dysfunction, rather than the specific initiating process. A PowerPoint slide summarizing this article is available for download in the Supporting Information section . [ABSTRACT FROM AUTHOR]

Objective Studies of focal epilepsy have revealed abnormalities of language organization; however, little attention has been paid to disorders of reading in this group. We hypothesized that language functional magnetic resonance imaging ( fMRI) would reveal differences in language organization between focal epilepsy patients with and without reading difficulties. Methods We conducted language fMRI studies of 10 focal epilepsy patients with reading difficulties, 34 focal epilepsy patients without reading difficulties, and 42 healthy controls. Results We defined regions of interests on the basis of activation patterns on an orthographic lexical retrieval task. Comparison of activations within these ROIs on a second Noun-Verb task revealed epilepsy-related effects (relative to healthy controls: reduced activation in left inferior frontal cortex), as well as greater activation in the right temporooccipital cortex specific to the reading difficulty group. Significance These findings identify a focal epilepsy effect in the left frontal region (present in patients with and without reading difficulties), and a functional abnormality specific to the reading difficulty group localized to right temporooccipital cortex-a region implicated in lexicosemantic processing. Our observations suggest a failure of left hemisphere specialization among focal epilepsy patients with reading difficulties. A PowerPoint slide summarizing this article is available for download in the Supporting Information section . [ABSTRACT FROM AUTHOR]

Focal cortical dysplasia is a common cortical malformation and an important cause of epilepsy. There is evidence for shared molecular mechanisms underlying cortical dysplasia, ganglioglioma, hemimegalencephaly, and dysembryoplastic neuroepithelial tumor. However, there are no familial reports of typical cortical dysplasia or co-occurrence of cortical dysplasia and related lesions within the same pedigree. We report the clinical, imaging, and histologic features of six pedigrees with familial cortical dysplasia and related lesions. Twelve patients from six pedigrees were ascertained from pediatric and adult epilepsy centers, eleven of whom underwent epilepsy surgery. Pedigree data, clinical information, neuroimaging findings, and histopathologic features are presented. The families comprise brothers with focal cortical dysplasia, a male and his sister with focal cortical dysplasia, a female with focal cortical dysplasia and her brother with hemimegalencephaly, a female with focal cortical dysplasia and her female first cousin with ganglioglioma, a female with focal cortical dysplasia and her male cousin with dysembryoplastic neuroepithelial tumor, and a female and her nephew with focal cortical dysplasia. This series shows that focal cortical dysplasia can be familial and provides clinical evidence suggesting that cortical dysplasia, hemimegalencephaly, ganglioglioma, and dysembryoplastic neuroepithelial tumors may share common genetic determinants. A PowerPoint slide summarizing this article is available for download in the Supporting Information section . [ABSTRACT FROM AUTHOR]

Purpose Lennox- Gastaut syndrome ( LGS) is a severe epileptic disorder with characteristic electroclinical features but diverse etiologies. The shared electroclinical characteristics suggest that common cerebral networks are involved in generating seizures. We sought to reveal these networks by comparing ictal and interictal single-photon emission computed tomography ( SPECT). Methods We identified 10 ictal-interictal SPECT pairs from seven patients with LGS (median age 11 years; range 1-38) who were studied during video electroencephalography ( EEG)-confirmed tonic seizures. We performed a voxel-wise comparison of ictal and interictal SPECT studies across the group. The evolution of blood flow changes was explored by examining early and late injection groups. Key Findings Median duration of tonic seizures was 10 s (range 6-29 s), and injection latency from seizure offset was −8 to 48 s. In the early injection group (<10 s; three studies), there was hyperperfusion over pons and cerebellar hemispheres (p < 0.05 cluster corrected family wise error), and hypoperfusion bilaterally over the pericentral region, with a trend toward hyperperfusion over bilateral superior and middle frontal gyri, and lateral parietal cortex. In the late injection group, there was hyperperfusion over midline and lateral cerebellar regions, with hypoperfusion widely over bilateral frontal regions. Significance This study suggests that the tonic seizures of LGS result from activity in a network, containing bilateral frontal and parietal association areas and the pons. We postulate that tonic seizures recruit the corticoreticular system, which connects frontal attentional areas to the pontine reticular formation, and is normally responsible for postural tone and orienting behavior. [ABSTRACT FROM AUTHOR]

Introduction: Cortical thickness mapping is a widely used method for the analysis of neuroanatomical differences between subject groups. We applied power analysis methods over a range of image processing parameters to derive a model that allows researchers to calculate the number of subjects required to ensure a well-powered cross-sectional cortical thickness study. Methods: 0.9-mm isotropic T1-weighted 3D MPRAGE MRI scans from 98 controls (53 females, age 29.1 ± 9.7 years) were processed using Freesurfer 5.0. Power analyses were carried out using vertex-wise variance estimates from the coregistered cortical thickness maps, systematically varying processing parameters. A genetic programming approach was used to derive a model describing the relationship between sample size and processing parameters. The model was validated on four Alzheimer's Disease Neuroimaging Initiative control datasets (mean 126.5 subjects/site, age 76.6 ± 5.0 years). Results: Approximately 50 subjects per group are required to detect a 0.25-mm thickness difference; less than 10 subjects per group are required for differences of 1 mm (two-sided test, 10 mm smoothing, α = 0.05). Sample size estimates were heterogeneous over the cortical surface. The model yielded sample size predictions within 2-6% of that determined experimentally using independent data from four other datasets. Fitting parameters of the model to data from each site reduced the estimation error to less than 2%. Conclusions: The derived model provides a simple tool for researchers to calculate how many subjects should be included in a well-powered cortical thickness analysis. Hum Brain Mapp 34:3000-3009, 2013. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The thalamus is one of the most important brain structures, with strong connections between subcortical and cortical areas of the brain. Most of the incoming information to the cortex passes through the thalamus. Accurate identification of substructures of the thalamus is therefore of great importance for the understanding of human brain connectivity. Direct visualization of thalamic substructures, however, is not easily achieved with currently available magnetic resonance imaging (MRI), including ultra-high field MRI such as 7.0T, mainly due to the limited contrast between the relevant structures. Recently, improvements in ultra-high field 7.0T MRI have opened the possibility of observing thalamic substructures by well-adjusted high-resolution T1-weighted imaging. Moreover, the recently developed super-resolution track-density imaging (TDI) technique, based on results from whole-brain fiber-tracking, produces images with sub-millimeter resolution. These two methods enable us to show markedly improved anatomical detail of the substructures of the thalamus, including their detailed locations and directionality. In this study, we demonstrate the role of TDI for the visualization of the substructures of the thalamic nuclei, and relate these images to T1-weighted imaging at 7.0T MRI. Hum Brain Mapp 34:2538-2548, 2013. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Summary: The ILAE 2010 report does not classify focal seizures and instead uses “descriptors” to distinguish focal seizures with versus without impaired consciousness. Below, we recall a recent informal conversation that took place while traveling a back road in Australia (true story), discussing problems with the old terms as well as new biological and practical evidence separating events formerly known as complex partial versus simple partial seizures. Impaired level of consciousness is a core distinguishing feature of focal seizures, which arises from established physiological mechanisms and can be readily determined based on behavior in most cases. After some debate, we arrive at succinct terms compatible with the old as well as the new ILAE classification report: Focal Impaired Consciousness Seizures (FICS), and Focal Aware Conscious Seizures (FACS). We hope that this discussion will bring impaired consciousness off the back roads of epilepsy classification, and provide useful names for these two very common seizure types. [ABSTRACT FROM AUTHOR]

Purpose The aim of this study was to provide better spatiotemporal description of the brain activity observed during generalized spike-and-wave ( GSW) discharges. Simultaneous electroencephalography and functional magnetic resonance imaging (EEG-fMRI) studies of these epileptiform events have shown regional differences in the timing of f MRI signal changes, which suggests activities within multiple interacting networks rather than a single unified network. Methods EEG- fMRI recordings from eight patients with childhood absence epilepsy ( CAE) were studied using event-related independent components analysis ( eICA). This technique separates the f MRI signal changes observed during GSW discharges into different spatial components, each showing different event-related timing. Unlike standard independent components analysis (ICA), which is applied to the entire f MRI time series, the e ICA method is applied only to the event-related time courses at each voxel, which means that only a small number of components are generated that are all explicitly related to the event of interest. Key Findings Six e ICA components were identified, representing distinct GSW-related subnetworks. Activations were detected in a number of brain regions, including the striatum, which have not previously been reported in association with GSW in CAE patients. Significance The e ICA results support previous findings that the earliest activity associated with GSW may be in posterior cortical regions and provide new evidence that the thalamostriate network may play a more important role in the generation of GSW than suggested by previous studies. [ABSTRACT FROM AUTHOR]

The benign occipital epilepsies of childhood include Panayiotopoulos and Gastaut syndromes; a third syndrome, idiopathic photosensitive occipital epilepsy may also begin in childhood or adolescence. We describe siblings with occipital epilepsy characterized by refractory, frequent, brief visual seizures and normal magnetic resonance imaging ( MRI). Electroencephalography ( EEG) with functional MRI (fMRI) supports localization of interictal epileptiform activity to the occipital lobes. Our hypothesis is that the siblings share a genetic focal epilepsy arising from a localized occipital network. Although they share many features of Gastaut syndrome, their refractory ongoing seizures in adolescence is unusual and likely due to underlying genetic determinants. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to assess long-term seizure outcome and risk factors for seizure recurrence in a cohort of patients who have undergone extratemporal resection for management of refractory seizures. Methods: Eighty-one patients underwent extratemporal resection at Austin Health, Melbourne, Australia (1991-2004). Seizure recurrence was any postoperative disabling seizure (complex partial seizure [CPS] ± secondary generalization). Multivariate Cox proportional hazards regression models examined potential preoperative and perioperative risk factors and the risk associated with early postoperative seizures (≤28 days postsurgery). The change between preoperative and postoperative seizure frequency was also measured. Key Findings: Median follow-up was 10.3 years (range 1-17.7). The probabilities of freedom from disabling seizures (on or off antiepileptic medication) were 40.7% (95% confidence interval [CI] 30-51) at 1 month, 23.5% (95% CI 15-33) at 1 year, and 14.7% (95% CI 8-23) at 5 years postoperative. Reduction of disabling seizures to at least 20% of preoperative frequency was attained by 57% of patients at 5 postoperative years. Of the preoperative/perioperative factors, focal cortical dysplasia (FCD) type 1 (hazard ratio [HR] 1.90, 95% CI 1.08-3.34, p = 0.025) and incomplete resection (HR 1.71, 95% CI 1.06-2.76, p = 0.028) were independent recurrence risks. After surgery, an early postoperative seizure was the only factor associated with higher risk (HR 4.28 [2.42-7.57], p = 0.00). Significance: Distinction between subtypes of focal cortical dysplasia, which can be made using magnetic resonance imaging (MRI) criteria, may be useful for preoperative prognostication. Early seizures after surgery are not benign and may be markers of factors that contribute to seizure recurrence. Most patients achieve substantial reduction in seizure frequency. Further study of the significance of this reduction in terms of surgical 'success' or otherwise is required. [ABSTRACT FROM AUTHOR]

Vocal singing (singing with lyrics) shares features common to music and language but it is not clear to what extent they use the same brain systems, particularly at the higher cortical level, and how this varies with expertise. Twenty-six participants of varying singing ability performed two functional imaging tasks. The first examined covert generative language using orthographic lexical retrieval while the second required covert vocal singing of a well-known song. The neural networks subserving covert vocal singing and language were found to be proximally located, and their extent of cortical overlap varied with singing expertise. Nonexpert singers showed greater engagement of their language network during vocal singing, likely accounting for their less tuneful performance. In contrast, expert singers showed a more unilateral pattern of activation associated with reduced engagement of the right frontal lobe. The findings indicate that singing expertise promotes independence from the language network with decoupling producing more tuneful performance. This means that the age-old singing practice of 'finding your singing voice' may be neurologically mediated by changing how strongly singing is coupled to the language system. Hum Brain Mapp, 2011. © 2010 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Hippocampal sclerosis (HS) is the most common pathologic finding in intractable temporal lobe epilepsy (TLE). In many patients, HS is accompanied by an extrahippocampal lesion (EHL). We sought to assess the lobar distribution and side of EHLs in relation to HS in a large consecutive series of patients presenting to our epilepsy surgery program. The inclusion criterion was the presence of both definite HS and an unequivocal EHL on magnetic resonance imaging (MRI) studies in patients evaluated for potential epilepsy surgery at our tertiary epilepsy center. Fifty-eight patients were identified over a 7-year period. This represented about one-third of all patients with HS. The mean age was 32 years (SD 18.4), and the mean age of seizure onset 13 years (SD 16.4). Fifty-four percent of the EHLs could be classified as acquired and 36% as developmental. In 98% of patients HS was found on the same side as EHL. Our findings support the hypothesis that HS may be a secondary event from seizures generated initially by another focal lesion. However, HS and EHL may also originate from the same insult to the brain. [ABSTRACT FROM AUTHOR]

To determine if constraint-induced movement therapy (CIMT) is more effective than bimanual training (BIM) in improving upper limb activity outcomes for children with congenital hemiplegia in a matched-pairs randomized trial. Sixty-three children (mean age 10.2, SD 2.7, range 5-16y; 33 males, 30 females), 16 in Manual Ability Classification System level I, 46 level II, and 1 level III and 16 in Gross Motor Function Classification level I, 47 level II) were randomly allocated to either CIMT or BIM group day camps (60 hours over 10 days). The Melbourne Assessment of Unilateral Upper Limb Function assessed unimanual capacity of the impaired limb and Assisting Hand Assessment evaluated bimanual coordination at baseline, 3 and 26 weeks, scored by blinded raters. After concealed random allocation, there was no baseline difference between groups. CIMT had superior outcomes compared with BIM for unimanual capacity at 26 weeks (estimated mean difference [EMD] 4.4, 95% confidence interval [CI] 2.2-6.7; p<0.001). There was no other significant difference between groups post-intervention. Both groups demonstrated significant improvements in bimanual performance at 3 weeks, with gains maintained by BIM at 26 weeks (EMD 2.3; 95% CI 0.6-4.0; p=0.008). Overall, there were only small differences between the two training approaches. CIMT yielded greater changes in unimanual capacity of the impaired upper limb compared with BIM. Results generally reflect specificity of practice, with CIMT improving unimanual capacity and BIM improving bimanual performance. Considerable inter-individual variation in response to either intervention was evident. Future research should consider serial sequencing unimanual then BIM approaches to optimize upper limb outcomes for children with congenital hemiplegia. [ABSTRACT FROM AUTHOR]

We used transcranial magnetic stimulation (TMS) to investigate whether there were any characteristic cortical excitability changes in progressive myoclonic epilepsy (PME) compared to juvenile myoclonic epilepsy (JME). Six patients with PME were studied. Motor threshold (MT) at rest and recovery curve analysis using paired-pulse stimulation at a number of interstimulus intervals (ISIs) was determined. Results were compared to those of 9 patients with chronic refractory JME and 10 with chronic well-controlled JME. PME showed a marked increase in cortical excitability at all the long ISIs (p < 0.01), compared to refractory JME (effect sizes ranging from 1.4 to 1.9) and well-controlled JME (effect sizes ranging from 2.0 to 2.4). Significant differences at the short ISIs 2-5 ms were seen only on comparison with the well-controlled group (p < 0.05, effect size 0.6, 0.7). There were no significant differences in MTs of PME compared to either JME groups. Our findings demonstrate specific differences in cortical excitability using TMS between PME and those with JME, particularly at long latencies in the paired-pulse paradigm, implicating a role for γ-aminobutyric acid (GABA)B-mediated networks. [ABSTRACT FROM AUTHOR]

Epilepsy due to encephaloceles of the temporal pole may be an under recognized, treatable cause of refractory temporal lobe epilepsy (TLE). We describe three adult patients initially labeled 'lesion negative' TLE. In all, video-electroencephalography (EEG) revealed ictal theta in the left temporal region and positron emission tomography (PET) showed temporal lobe hypometabolism, but neuropsychology revealed preserved verbal memory. Close inspection of structural magnetic resonance imaging (MRI) suggested subtle abnormalities at the tip of the left temporal lobe. High resolution computed tomography (CT) confirmed bony defects in the inner table of the skull. 3T MRI with fine coronal and sagittal slices indicated cerebrospinal fluid (CSF) and brain tissue protruding into the defects. All proceeded to resection of the temporal tip and became seizure free. Patients with 'lesion negative' TLE should have careful review of images covering the temporal pole. If encephalocele is suspected, further imaging with high-resolution CT and MRI can be helpful. Temporal polar resection, sparing mesial structures, appears to be curative. [ABSTRACT FROM AUTHOR]

Temporal lobe epilepsy (TLE) is not a unitary electroclinical imaging syndrome. We asked if seizures arising from the parahippocampal-inferior temporal (PIT) region differ from those associated with hippocampal sclerosis (HS). The electroclinical features of 22 patients with HS and 14 patients with lesions in the PIT region who underwent epilepsy surgery and were seizure free for at least 2 years postoperatively were analyzed retrospectively. Patients with PIT lesions had a higher frequency of hypermotor and bilateral features and a lower frequency of behavioral arrest at the onset of seizure compared to cases with HS, suggesting that TLE originating in the PIT area can mimic frontal lobe epilepsy or contralateral mesial TLE. [ABSTRACT FROM AUTHOR]

Assessment of language dominance with functional magnetic resonance imaging (fMRI) and neuropsychological evaluation is often used prior to epilepsy surgery. This study explores whether language lateralization and cognitive performance are systematically related in young patients with focal epilepsy. Language fMRI and neuropsychological data (language, visuospatial functions, and memory) of 40 patients (7–18 years of age) with unilateral, refractory focal epilepsy in temporal and/or frontal areas of the left (n = 23) or right hemisphere (n = 17) were analyzed. fMRI data of 18 healthy controls (7–18 years) served as a normative sample. A laterality index was computed to determine the lateralization of activation in three regions of interest (frontal, parietal, and temporal). Atypical language lateralization was demonstrated in 12 (30%) of 40 patients. A correlation between language lateralization and verbal memory performance occurred in patients with left-sided epilepsy over all three regions of interest, with bilateral or right-sided language lateralization being correlated with better verbal memory performance (Word Pairs Recall: frontal r = −0.4, p = 0.016; parietal r = −0.4, p = 0.043; temporal r = −0.4, p = 0.041). Verbal memory performance made the largest contribution to language lateralization, whereas handedness and side of seizures did not contribute to the variance in language lateralization. This finding reflects the association between neocortical language and hippocampal memory regions in patients with left-sided epilepsy. Atypical language lateralization is advantageous for verbal memory performance, presumably a result of transfer of verbal memory function. In children with focal epilepsy, verbal memory performance provides a better idea of language lateralization than handedness and side of epilepsy and lesion. [ABSTRACT FROM AUTHOR]

Objective Approximately 30% of patients with newly diagnosed epilepsy do not respond to antiepileptic drugs (AEDs), but this is not predictable. We used transcranial magnetic stimulation to determine the effect of AEDs on cortical excitability in patients with epilepsy and correlated this with a successful response to treatment. Methods Ninety-nine drug-naïve patients with newly diagnosed epilepsy (55 idiopathic generalized epilepsy, 44 focal epilepsy) were evaluated. Motor threshold and cortical excitability on recovery curve analysis were measured before and 4 to 16 weeks after starting medication. After 1 year of treatment, 43 of 55 idiopathic generalized epilepsy and 26 of 44 focal epilepsy patients were seizure free. Results A decrease in cortical excitability occurred in the seizure-free group as indicated by an increase in motor threshold ( p < 0.05) and intracortical inhibition on recovery curve analysis, maximum at the 250-millisecond interstimulus interval ( p < 0.01) compared with pretreatment values. These changes were not present in the group with ongoing seizures. Interpretation Seizure freedom is marked by a reduction in transcranial magnetic stimulation measures of cortical excitability, evident shortly after beginning therapy. This virtual normalization of cortical excitability occurred regardless of the seizure characteristics or AED used. Failure to show this response to AED treatment may be valuable as an early predictor of pharmacoresistance in individual patients. ANN NEUROL 2010;67:64-73 [ABSTRACT FROM AUTHOR]

Lesion-negative refractory partial epilepsy is a major challenge in the assessment of patients for potential surgery. Finding a potential epileptogenic lesion simplifies assessment and is associated with good outcome. Here we describe imaging features of subtle parahippocampal dysplasia in five cases that were initially assessed as having imaging-negative frontal or temporal lobe epilepsy. We analyzed the clinical and imaging features of five patients with seizures from the parahippocampal region. Five patients had subtle but distinctive magnetic resonance imaging (MRI) abnormalities in the parahippocampal gyrus. This was a unilateral signal abnormality in the parahippocampal white matter extending into gray matter on heavily T1- and T2-weighted images with relative preservation of the gray–white matter boundary on T1-weighted volume sequences. Only one of these patients had typical electroclinical unilateral temporal lobe epilepsy (TLE); one mimicked frontal lobe epilepsy, two showed bitemporal seizures, and one had unlocalized partial seizures. All have had surgery; four are seizure-free (one has occasional auras only, follow-up 6 months to 10 years), and one has a >50% seizure reduction. Histopathologic evaluation suggested dysplastic features in the surgical specimens in all. In patients with lesion-negative partial epilepsy with frontal or temporal semiology, or in cases with apparent bitemporal seizures, subtle parahippocampal abnormalities should be carefully excluded. Recognizing the MRI findings of an abnormal parahippocampal gyrus can lead to successful surgery without invasive monitoring, despite apparently incongruent electroclinical features. [ABSTRACT FROM AUTHOR]

Quantitative measurement of hippocampal volume using structural magnetic resonance imaging (MRI) is a valuable tool for detection and lateralization of mesial temporal lobe epilepsy with hippocampal sclerosis (mTLE). We compare two automated hippocampal volume methodologies and manual hippocampal volumetry to determine which technique is most sensitive for the detection of hippocampal atrophy in mTLE. We acquired a three-dimensional (3D) volumetric sequence in 10 patients with left-lateralized mTLE and 10 age-matched controls. Hippocampal volumes were measured manually, and using the software packages Freesurfer and FSL-FIRST. The sensitivities of the techniques were compared by determining the effect size for average volume reduction in patients with mTLE compared to controls. The volumes and spatial overlap of the automated and manual segmentations were also compared. Significant volume reduction in affected hippocampi in mTLE compared to controls was detected by manual hippocampal volume measurement (p < 0.01, effect size 33.2%), Freesurfer (p < 0.01, effect size 20.8%), and FSL-FIRST (p < 0.01, effect size 13.6%) after correction for brain volume. Freesurfer correlated reasonably (r = 0.74, p << 0.01) with this manual segmentation and FSL-FIRST relatively poorly (r = 0.47, p << 0.01). The spatial overlap between manual and automated segmentation was reduced in affected hippocampi, suggesting the accuracy of automated segmentation is reduced in pathologic brains. Expert manual hippocampal volumetry is more sensitive than both automated methods for the detection of hippocampal atrophy associated with mTLE. In our study Freesurfer was the most sensitive to hippocampal atrophy in mTLE and could be used if expert manual segmentation is not available. [ABSTRACT FROM AUTHOR]

Benign childhood epilepsy with centrotemporal spikes (BECTS) is the most common epilepsy syndrome of childhood and can be associated with language difficulties. The exact profile of these difficulties and their neurofunctional underpinnings, however, are not yet clear. To further understand the impact of the BECTS syndrome on language, we assessed language performance using standard neuropsychological measures, and patterns of language lateralization using functional magnetic resonance imaging (fMRI) in children with typical BECTS (n = 20) and healthy controls (n = 20). The fMRI analyses revealed that language-related activation was less lateralized to the left hemisphere in anterior brain regions in the patients relative to the control group. This finding was consistent with decreased performance in the BECTS group compared to the control group on the neuropsychological measure most dependent on the integrity of anterior aspects of the language axis, namely, sentence production. The converging lines of evidence from the neuropsychological and activation methodologies support the view that BECTS is associated with language difficulties that are regional, and anterior, in nature. [ABSTRACT FROM AUTHOR]

Purpose: Patients with refractory temporal lobe epilepsy (refractory TLE) often have hippocampal sclerosis (HS). However, some HS patients have less-severe, drug-responsive epilepsy (mild TLE). We investigated the pattern of MR changes in these two HS groups. Methods: We acquired a 3D volumetric sequence, T2 relaxation times (T2) and proton MR spectroscopy (MRS) in 41 HS patients (24 refractory TLE, 17 mild TLE) and 60 controls. Hippocampal volumes were measured bilaterally. T2 was measured in the hippocampus, amygdala, thalamus, in the white matter of the anterior temporal lobe (ATL), and in the frontal lobe. The temporal lobe MRS established concentrations of N-acetylaspartate (NAA), choline, creatine, myoinositol and glutamine/glutamate. Results: The degree of hippocampal volume loss and hippocampal T2 increase was not different between the two HS groups. However, in refractory TLE, the T2 signal in the ipsilateral ATL was increased, and the ipsilateral NAA concentration was reduced (p ≤ 0.05). Conclusions: In this group of HS patients, the degree of HS was not related to the clinical course, possibly reflecting the common cause of epilepsy. In contrast, refractory TLE patients had pronounced white matter changes and metabolite disturbance in the ipsilateral temporal lobe. These abnormalities may indicate the refractory nature of the epilepsy. [ABSTRACT FROM AUTHOR]

Background: Malformations of cortical development can cause epileptiform activity and myoclonic jerks, yet EEG correlates of jerks can be difficult to obtain. Methods: We studied a woman who had frequent episodes of persistent right-foot jerking since childhood. Ictal and interictal EEG had shown no localizing epileptiform activity. Functional imaging experiments were performed with concurrent video monitoring to document the timing of foot jerks. These studies mapped brain regions controlling voluntary right- and left-foot movements, and spontaneous right-foot jerks. Results: High-resolution structural MR imaging revealed a dysplastic gyrus extending anteriorly off the left central sulcus. Event-related analysis of spontaneous jerks revealed prominent activation of the left precentral gyrus (right-foot motor area), bilateral medial frontal regions (supplementary motor area), and the dysplastic gyrus. Hemodynamic response modeling to foot jerks revealed the hemodynamic response peaked earlier in the dysplastic cortex and SMA regions than in the foot area. Discussion: Event-related fMRI in a patient with spontaneous and induced epileptic foot jerks revealed brain regions active during jerks. The results of this analysis allowed us to tailor subsequent intracerebral recordings. Analysis of the timing of the hemodynamic response showed certain brain regions with an earlier rise in BOLD signal, suggesting a possible initiating role, or different hemodynamic response functions. Hemodynamic response timing should be considered carefully when interpreting event-related studies of epileptiform activity. [ABSTRACT FROM AUTHOR]