Objective Functional magnetic resonance imaging is sensitive to the variation in language network patterns. Large populations are needed to rigorously assess atypical patterns, which, even in neurological populations, are a minority. Methods We studied 220 patients with focal epilepsy and 118 healthy volunteers who performed an auditory description decision task. We compared a data-driven hierarchical clustering approach to the commonly used a priori laterality index (LI) threshold (LI < 0.20 as atypical) to classify language patterns within frontal and temporal regions of interest. We explored (n = 128) whether IQ varied with different language activation patterns. Results The rate of atypical language among healthy volunteers (2.5%) and patients (24.5%) agreed with previous studies; however, we found 6 patterns of atypical language: a symmetrically bilateral, 2 unilaterally crossed, and 3 right dominant patterns. There was high agreement between classification methods, yet the cluster analysis revealed novel correlations with clinical features. Beyond the established association of left-handedness, early seizure onset, and vascular pathology with atypical language, cluster analysis identified an association of handedness with frontal lateralization, early seizure onset with temporal lateralization, and left hemisphere focus with a unilateral right pattern. Intelligence quotient was not significantly different among patterns. Interpretation Language dominance is a continuum; however, our results demonstrate meaningful thresholds in classifying laterality. Atypical language patterns are less frequent but more variable than typical language patterns, posing challenges for accurate presurgical planning. Language dominance should be assessed on a regional rather than hemispheric basis, and clinical characteristics should inform evaluation of atypical language dominance. Reorganization of language is not uniformly detrimental to language functioning.

IMPORTANCE Neuroinflammation may play a role in epilepsy. Translocator protein 18 kDa (TSPO), a biomarker of neuroinflammation, is overexpressed on activated microglia and reactive astrocytes. A preliminary positron emission tomographic (PET) imaging study using carbon 11 ([ 11 C])-labeled PBR28 in patients with temporal lobe epilepsy (TLE) found increased TSPO ipsilateral to seizure foci. Full quantitation of TSPO in vivo is needed to detect widespread inflammation in the epileptic brain. OBJECTIVES To determine whether patients with TLE have widespread TSPO overexpression using [ 11 C]PBR28 PET imaging, and to replicate relative ipsilateral TSPO increases in patients with TLE using [ 11 C]PBR28 and another TSPO radioligand, [ 11 C]DPA-713. DESIGN, SETTING, AND PARTICIPANTS In a cohort study from March 2009 through September 2013 at the Clinical Epilepsy Section of the National Institute of Neurological Disorders and Stroke, participants underwent brain PET and a subset had concurrent arterial sampling. Twenty-three patients with TLE and 11 age-matched controls were scanned with [ 11 C]PBR28, and 8 patients and 7 controls were scanned with [ 11 C]DPA-713. Patients with TLE had unilateral temporal seizure foci based on ictal electroencephalography and structural magnetic resonance imaging. Participants with homozygous low-affinity TSPO binding were excluded. MAIN OUTCOMES AND MEASURESThe [ 11 C]PBR28 distribution volume (V T ) corrected for free fraction (f P ) was measured in patients with TLE and controls using FreeSurfer software and T1-weighted magnetic resonance imaging for anatomical localization of bilateral temporal and extratemporal regions. Side-to-side asymmetry in patients with TLE was calculated as the ratio of ipsilateral to contralateral [ 11 C]PBR28 and [ 11 C]DPA-713 standardized uptake values from temporal regions.RESULTS The [ 11 C]PBR28 V T to f p ratio was higher in patients with TLE than in controls for all ipsilateral temporal regions (27%-42%; P < .05) and in contralateral hippocampus, amygdala, and temporal pole (approximately 30%-32%; P < .05). Individually, 12 patients, 10 with mesial temporal sclerosis, had asymmetrically increased hippocampal [ 11 C]PBR28 uptake exceeding the 95% confidence interval of the controls. Binding of [ 11 C]PBR28 was increased significantly in thalamus. Relative [ 11 C]PBR28 and [ 11 C]DPA-713 uptakes were higher ipsilateral than contralateral to seizure foci in patients with TLE ([ 11 C]PBR28: 2%-6%; [ 11 C]DPA-713: 4%-9%). Asymmetry of [ 11 C]DPA-713 was greater than that of [ 11 C]PBR28 (F = 29.4; P = .001).CONCLUSIONS AND RELEVANCE Binding of TSPO is increased both ipsilateral and contralateral to seizure foci in patients with TLE, suggesting ongoing inflammation. Anti-inflammatory therapy may play a role in treating drug-resistant epilepsy.

Animal studies and clinical observations suggest that epilepsy is associated with inflammation. Translocator protein (TSPO) (18 kDa), a marker of inflammation, is increased in vitro in surgical samples from patients with temporal lobe epilepsy. TSPO can be measured in the living human brain with PET and the novel radioligand 11C-PBR28. In this study, we sought to determine whether in vivo expression of TSPO is increased ipsilateral to the seizure focus in patients with temporal lobe epilepsy. Methods Sixteen patients with unilateral temporal lobe epilepsy and 30 healthy subjects were studied with 11C-PBR28 PET and MRI. Uptake of radioactivity after injection of 11C-PBR28 was measured from regions of interest drawn bilaterally onto MR images. Brain uptake from ipsilateral and contralateral hemispheres was compared using a paired-samples t test. Results We found that brain uptake was higher ipsilateral to the seizure focus in the hippocampus, parahippocampal gyrus, amygdala, fusiform gyrus, and choroid plexus but not in other brain regions. This asymmetry was more pronounced in patients with hippocampal sclerosis than in those without. Conclusion We found increased uptake of radioactivity after injection of 11C-PBR28 ipsilateral to the seizure focus in patients with temporal lobe epilepsy, suggesting increased expression of TSPO. Studies in larger samples are required to confirm this finding and determine the clinical utility of imaging TSPO in temporal lobe epilepsy.

Objective: Succinic semialdehyde dehydrogenase (SSADH) deficiency is an autosomal recessive disorder of GABA metabolism characterized by elevated levels of GABA and gammahydroxybutyric acid. Clinical findings include intellectual impairment, hypotonia, hyporeflexia, hallucinations, autistic behaviors, and seizures. Autoradiographic labeling and slice electrophysiology studies in the murine model demonstrate use-dependent downregulation of GABA(A) receptors. We studied GABA(A) receptor activity in human SSADH deficiency utiliz- Succinic semialdehyde dehydrogenase (SSADH) deficiency, also called 4-hydroxybutyric aciduria (McKusick 279180) and aldehyde dehydrogenase 5a1 (Aldh5a1), is an autosomal recessive disorder. About 350 patients are known, with about 85% under 18, making this the most prevalent pediatric neurotransmitter disorder. 1 In the absence of SSADH, transamination of GABA to succinic semialdehyde is followed by its conversion to 4-hydroxybutryic acid (gamma-hydroxybutyric acid, or GHB), leading to CNS GABA and ␥-hydroxy butyrate (GHB) accumulation.2 Major clinical manifestations include developmental delay, hypotonia, ataxia, and seizures. Hyperkinetic behavior, aggression, self-injurious behaviors, and hallucinations have also been described; EEG abnormalities include generalized and focal epileptiform discharges, photosensitivity, and background slowing.

Since long interval intracortical inhibition and cortical silent period are thought to reflect GABA(B) receptor-mediated inhibitory circuits, our results point to a particularly GABA(B)-ergic motor cortex dysfunction in patients with SSADH deficiency. This human phenotype is consistent with the proposed mechanism of use-dependent downregulation of postsynaptic GABA(B) receptors in SSADH deficiency animal models. Additionally, the results suggest autoinhibition of GABAergic neurons. This first demonstration of altered GABA(B)-ergic function in patients with SSADH deficiency may help to explain clinical features of the disease, and suggest pathophysiologic mechanisms in other neurotransmitter-related disorders.

SUMMARYBackground: Positron emission tomography (PET) with 18 F-fluorodeoxyglucose (FDG) shows widespread hypometabolism even in temporal lobe epilepsy (TLE) patients with mesial temporal foci.

Objective: To study 5-HT transport and 5-HT 1A receptors in temporal lobe epilepsy (TLE) and depression. Conclusions: Our study showed increased [ Methods11 C]DASB asymmetry in insula and fusiform gyrus, and relatively reduced transporter activity, in subjects with both TLE and depression, as compared to subjects with TLE alone, implying reduced reuptake and thus increased synaptic 5-HT availability. This finding may represent a compensatory mechanism for 5-HT 1A receptor loss. Altered serotonergic mechanisms have an important role in TLE and concomitant depression. Serotonin (5-HT) exerts antiseizure effects in experimental models mediated by 5-HT 1A receptors, by hyperpolarizing hippocampal CA3 membranes.1 Some antiepileptic drugs (AEDs) may exert antiseizure effects by blocking 5-HT reuptake. 2PET studies showed reduced 5-HT 1A receptor binding ipsilateral to temporal lobe epilepsy (TLE) foci.3-5 Not due to hippocampal atrophy, reductions are more pronounced in seizure onset than secondary spread regions. 5,6 Epidemiologic and clinical data support relationships between epilepsy and depression, one of the most common epilepsy comorbidities.7 A history of depression increases risk for later epilepsy development.8 Otherwise healthy patients with major depressive disorders (MDD) may have limbic 5-HT 1A receptor binding reductions.9-11 5-HT 1A receptor PET studies in patients with both TLE and depression showed additional binding alterations compared to TLE alone.

Objective FMRI activation of the mesial temporal lobe (MTL) may be important for epilepsy surgical planning. We examined MTL activation and lateralization during language fMRI in children and adults with focal epilepsy. Methods 142 controls and patients with left hemisphere focal epilepsy (Pediatric: epilepsy, n = 17, mean age = 9.9 ± 2.0; controls, n = 48; mean age = 9.1 ± 2.6; Adult: epilepsy, n = 20, mean age = 26.7 ± 5.8; controls, n = 57, mean age = 26.2 ± 7.5) underwent 3T fMRI using a language task (auditory description decision task). Image processing and analyses were conducted in SPM8; ROIs included MTL, Broca’s area, and Wernicke’s area. We assessed group and individual MTL activation, and examined degree of lateralization. Results Patients and controls (pediatric and adult) demonstrated group and individual MTL activation during language fMRI. MTL activation was left lateralized for adults but less so in children (p’s < 0.005). Patients did not differ from controls in either age group. Stronger left-lateralized MTL activation was related to older age (p = 0.02). Language lateralization (Broca’s and Wernicke’s) predicted 19% of the variance in MTL lateralization for adults (p = 0.001), but not children. Significance Language fMRI may be used to elicit group and individual MTL activation. The developmental difference in MTL lateralization and its association with language lateralization suggests a developmental shift in lateralization of MTL function, with increased left lateralization across the age span. This shift may help explain why children have better memory outcomes following resection compared to adults.