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ObjectiveTo investigate the functional correlates of recurrent secondarily generalized seizures in temporal lobe epilepsy (TLE) using task-based fMRI as a framework to test for epilepsy-specific network rearrangements. Because the thalamus modulates propagation of temporal lobe onset seizures and promotes cortical synchronization during cognition, we hypothesized that occurrence of secondarily generalized seizures, i.e., focal to bilateral tonic-clonic seizures (FBTCS), would relate to thalamic dysfunction, altered connectivity, and whole-brain network centrality.MethodsFBTCS occur in a third of patients with TLE and are a major determinant of disease severity. In this cross-sectional study, we analyzed 113 patients with drug-resistant TLE (55 left/58 right), who performed a verbal fluency fMRI task that elicited robust thalamic activation. Thirty-three patients (29%) had experienced at least one FBTCS in the year preceding the investigation. We compared patients with TLE-FBTCS to those without FBTCS via a multiscale approach, entailing analysis of statistical parametric mapping (SPM) 12–derived measures of activation, task-modulated thalamic functional connectivity (psychophysiologic interaction), and graph-theoretical metrics of centrality.ResultsIndividuals with TLE-FBTCS had less task-related activation of bilateral thalamus, with left-sided emphasis, and left hippocampus than those without FBTCS. In TLE-FBTCS, we also found greater task-related thalamotemporal and thalamomotor connectivity, and higher thalamic degree and betweenness centrality. Receiver operating characteristic curves, based on a combined thalamic functional marker, accurately discriminated individuals with and without FBTCS.ConclusionsIn TLE-FBTCS, impaired task-related thalamic recruitment coexists with enhanced thalamotemporal connectivity and whole-brain thalamic network embedding. Altered thalamic functional profiles are proposed as imaging biomarkers of active secondary generalization.

Objective: Juvenile myoclonic epilepsy (JME) is the most common genetic generalized epilepsy syndrome. Myoclonus may relate to motor system hyperexcitability and can be provoked by cognitive activities. To aid genetic mapping in complex neuropsychiatric disorders, recent research has utilized imaging intermediate phenotypes (endophenotypes). Here, we aimed to (a) characterize activation profiles of the motor system during different cognitive tasks in patients with JME and their unaffected siblings, and (b) validate those as endophenotypes of JME. / Methods: This prospective cross‐sectional investigation included 32 patients with JME, 12 unaffected siblings, and 26 controls, comparable for age, sex, handedness, language laterality, neuropsychological performance, and anxiety and depression scores. We investigated patterns of motor system activation during episodic memory encoding and verb generation functional magnetic resonance imaging (fMRI) tasks. / Results: During both tasks, patients and unaffected siblings showed increased activation of motor system areas compared to controls. Effects were more prominent during memory encoding, which entailed hand motion via joystick responses. Subgroup analyses identified stronger activation of the motor cortex in JME patients with ongoing seizures compared to seizure‐free patients. Receiver‐operating characteristic curves, based on measures of motor activation, accurately discriminated both patients with JME and their siblings from healthy controls (area under the curve: 0.75 and 0.77, for JME and a combined patient‐sibling group against controls, respectively; P < .005). / Significance: Motor system hyperactivation represents a cognitive, domain‐independent endophenotype of JME. We propose measures of motor system activation as quantitative traits for future genetic imaging studies in this syndrome.

ObjectiveTo investigate the use of muscle MRI for the differential diagnosis and as a disease progression biomarker for 2 major forms of motor neuron disorders: spinal bulbar muscular atrophy (SBMA) and amyotrophic lateral sclerosis (ALS).MethodsWe applied quantitative 3-point Dixon and semiquantitative T1-weighted and short tau inversion recovery (STIR) imaging to bulbar and lower limb muscles and performed clinical and functional assessments in ALS (n = 21) and SBMA (n = 21), alongside healthy controls (n = 16). Acquired images were analyzed for the presence of fat infiltration or edema as well as specific patterns of muscle involvement. Quantitative MRI measurements were correlated with clinical measures of disease severity in ALS and SBMA.ResultsQuantitative imaging revealed significant fat infiltration in bulbar (p < 0.001) and limb muscles in SBMA compared to controls (thigh: p < 0.001; calf: p = 0.001), identifying a characteristic pattern of muscle involvement. In ALS, semiquantitative STIR imaging detected marked hyperintensities in lower limb muscles, distinguishing ALS from SBMA and controls. Finally, MRI measurements correlated significantly with clinical scales of disease severity in both ALS and SBMA.ConclusionsOur findings show that muscle MRI differentiates between SBMA and ALS and correlates with disease severity, supporting its use as a diagnostic tool and biomarker for disease progression. This highlights the clinical utility of muscle MRI in motor neuron disorders and contributes to establish objective outcome measures, which is crucial for the development of new drugs.

OBJECTIVEThe aim of this study was to present long-term seizure outcome data in a consecutive series of patients with refractory mesial temporal lobe epilepsy primarily treated with transsylvian selective amygdalohippocampectomy (SAHE).METHODSThe authors retrospectively analyzed prospectively collected data for all patients who had undergone resective surgery for medically refractory epilepsy at their institution between July 1994 and December 2014. Seizure outcome was assessed according to the International League Against Epilepsy (ILAE) and the Engel classifications.RESULTSThe authors performed an SAHE in 158 patients (78 males, 80 females; 73 right side, 85 left side) with a mean age of 37.1 ± 10.0 years at surgery. Four patients lost to follow-up and 1 patient who committed suicide were excluded from analysis. The mean follow-up period was 9.7 years. At the last available follow-up (or before reoperation), 68 patients (44.4%) had achieved an outcome classified as ILAE Class 1a, 46 patients (30.1%) Class 1, 6 patients (3.9%) Class 2, 16 patients (10.4%) Class 3, 15 patients (9.8%) Class 4, and 2 patients (1.3%) Class 5. These outcomes correspond to Engel Class I in 78.4% of the patients, Engel Class II in 10.5%, Engel Class III in 8.5%, and Engel Class IV in 2.0%. Eleven patients underwent a second surgery (anterior temporal lobectomy) after a mean of 4.4 years from the SAHE (left side in 6 patients, right side in 5). Eight (72.7%) of these 11 patients achieved seizure freedom.The overall ILEA seizure outcome since (re)operation after a mean follow-up of 10.0 years was Class 1a in 72 patients (47.0%), Class 1 in 50 patients (32.6%), Class 2 in 7 patients (4.6%), Class 3 in 15 patients (9.8%), Class 4 in 8 patients (5.2%), and Class 5 in 1 patient (0.6%). These outcomes correspond to an Engel Class I outcome in 84.3% of the patients.CONCLUSIONSA satisfactory long-term seizure outcome following transsylvian SAHE was demonstrated in a selected group of patients with refractory temporal lobe epilepsy.

Impairment of naming function is a critical problem for temporal lobe epilepsy patients, yet the neural correlates of the disruption of temporal lobe language networks are poorly understood. Using functional MRI, we investigated the activation and task-related functional connectivity of left temporal lobe language networks and their relation to clinical naming performance and disease characteristics. We studied 59 adult patients with temporal lobe epilepsy (35 left temporal lobe epilepsy) and 32 healthy controls with auditory and visual naming functional MRI tasks. Time series of activation maxima in the left posterior inferior temporal lobe were extracted to create a psychophysiological interaction regressor for subsequent seed-based whole-brain task-related functional connectivity analyses. Correlational analyses were performed to assess the association of functional MRI activation and functional connectivity with clinical naming scores, age of onset of epilepsy, and duration of epilepsy. Auditory naming elicited activation in the left posterior inferior temporal gyrus and visual naming in the left fusiform gyrus across all groups. Activations in the left inferior temporal gyrus, left thalamus and left supplementary motor region during auditory naming as well as left fusiform activations during picture naming correlated with better clinical naming performance. Functional connectivity analyses indicated coupling of left posterior inferior temporal regions to bilateral anterior and posterior temporal lobe regions and the bilateral inferior precentral gyrus as well as contralateral occipital cortex. Stronger functional connectivity was associated with better clinical naming performance in all groups. In patients with left temporal lobe epilepsy only, functional connectivity increased with later age of onset of epilepsy and shorter disease duration. This suggests that onset of seizures early in life and prolonged disease duration lead to disrupted recruitment of temporal lobe networks ipsilateral to the seizure focus, which might account for naming deficits in temporal lobe epilepsy.

Objective To investigate the effects of sodium channel-blocking antiepileptic drugs (AEDs) on functional magnetic resonance imaging (fMRI) language network activations in patients with focal epilepsy. Methods In a retrospective study, we identified patients who were treated at the time of language fMRI scanning with either carbamazepine (CBZ; n = 42) or lamotrigine (LTG; n = 42), but not another sodium channel-blocking AED. We propensity-matched 42 patients taking levetiracetam (LEV) as "patient-controls" and included further 42 age- and gender-matched healthy controls. After controlling for age, age at onset of epilepsy, gender, and antiepileptic comedications, we compared verbal fluency fMRI activations between groups and out-of-scanner psychometric measures of verbal fluency. Results Patients on CBZ performed less well on a verbal fluency tests than those taking LTG or LEV. Compared to either LEV-treated patients or controls, patients taking CBZ showed decreased activations in left inferior frontal gyrus and patients on LTG showed abnormal deactivations in frontal and parietal default mode areas. All patient groups showed fewer activations in the putamen bilaterally compared to controls. In a post hoc analysis, out-of-scanner fluency scores correlated positively with left putamen activation. Significance Our study provides evidence of AED effects on the functional neuroanatomy of language, which might explain subtle language deficits in patients taking otherwise well-tolerated sodium channel-blocking agents. Patients on CBZ showed dysfunctional frontal activation and more pronounced impairment of performance than patients taking LTG, which was associated only with failure to deactivate task-negative networks. As previously shown for working memory, LEV treatment did not affect functional language networks.

Objective: To develop language functional MRI (fMRI) methods that accurately predict postsurgical naming decline in temporal lobe epilepsy (TLE). Methods: Forty‐six patients with TLE (25 left) and 19 controls underwent two overt fMRI paradigms (auditory naming and picture naming, both with active baseline conditions) and one covert task (verbal fluency). Clinical naming performance was assessed preoperatively and 4 months following anterior temporal lobe resection. Preoperative fMRI activations were correlated with postoperative naming decline. Individual laterality indices (LI) were calculated for temporal (auditory and picture naming) and frontal regions (verbal fluency) and were considered as predictors of naming decline in multiple regression models, along with other clinical variables (age at onset of seizures, preoperative naming scores, hippocampal volume, age). Results: In left TLE patients, activation of the left posterior inferior temporal gyrus during auditory naming and activation of left fusiform gyrus during picture naming were related to greater postoperative naming decline. Activation LI were the best individual predictors of naming decline in a multivariate regression model. For picture naming, an LI of higher than 0.34 gave 100% sensitivity and 92% specificity (positive predictive value (PPV) 91.6%). For auditory naming, a temporal lobe LI higher than 0.18 identified all patients with a clinically significant naming decline with 100% sensitivity and 58% specificity (PPV: 58.3%). No effect was seen for verbal fluency. Interpretation: Auditory and picture naming fMRI are clinically applicable to predict postoperative naming decline after left temporal lobe resection in individual patients, with picture naming being more specific.