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Purpose: To investigate whether different genetic mutations observed in children with global developmental delay (GD) are associated with unique patterns of the arcuate fasciculus dysmorphology., Materials and Methods: Six children with GD (age: 36.8 ± 14.1 months, 5 boys) having mutations in MID1, CDK4, SFRP1, EN2, RXRG-GLRB, or MECP2, and five children with typical development (TD, age: 38.5 ± 20.5 months, 4 boys) underwent a 3 Tesla MRI including diffusion weighted imaging (DWI). Five language pathway segments in the left hemisphere, "C 1 : Broca's to Wernicke's area," "C 2 : Broca's to premotor area," "C 3 : premotor to Wernicke's area," "C 4 : Wernicke's to inferior parietal area," and "C 5 : premotor to inferior parietal area" were objectively identified using the DWI "maximum a posteriori probability" classifier., Results: Affinity propagation clustering analysis found that three arcuate pathway segments, C 1,2,4 , of MID1, CDK4, EN2, and MECP2 had a similar pattern of volume ratio while those of SFRP1 and RXRG-GLRB had a heterogeneous pattern of volume ratio (net similarity = -0.01). Using receiver operating characteristic curve analysis, the fiber ratios of C 1,2,4 showed a high probability to discriminate between GD and TD, yielding an accuracy of 0.91, 0.91, 1.00, respectively. The fiber volumes of C 1 and C 4 showed a strong correlation with expressive language (R 2  = 0.6019; P-value = 0.033) and receptive language (R 2  = 0.6379; P-value = 0.028), respectively., Conclusion: The findings of the present study provide preliminary evidence to suggest that different segments of the arcuate fasciculus are formed under the regulation of different genes which, when mutated, may result in developmental delay. J. Magn. Reson. Imaging 2016;44:1504-1512., (© 2016 International Society for Magnetic Resonance in Medicine.)

To determine brain plasticity changes due to resective epilepsy surgery in children, we performed a longitudinal connectome analysis on the pattern of axonal connectivity in the contralateral hemisphere. Pre- and postoperative diffusion tensor imaging (DTI) data were acquired from 35 children with intractable focal epilepsy. A total of 54 brain regions of interest (ROIs) were generated in the hemisphere contralateral to the resection. Within a 54 × 54 connectivity matrix, a pairwise connectivity score was calculated for each connection between two ROIs, based on the DTI fiber streamline number in each connection. A permuted Spearman's ρ-rank analysis was used to identify specific inter-regional connections showing a significant association between the postoperative change of connectivity score and clinical variables. Nineteen connections in the contralateral hemisphere showed postoperative increases in the strength of connectivity. Postoperative increase in connectivity between insular-inferior frontal operculum regions as well as that between superior frontal orbital and mid frontal orbital regions were both significantly associated with a larger surgical resection volume (ρ > +0.40) and a younger patient age (ρ > -0.34). These increases were more robust in patients with frontal resection and in those achieving seizure freedom. Neuropsychological evaluation on subsets of patients revealed that such increases in connectivity were associated with preserved or improved cognitive functions such as visual memory and planning. Resective epilepsy surgery may lead to increased contralateral axonal connectivity in children with focal epilepsy. Our data lead to a hypothesis that such increased connectivity may be an imaging marker of postoperative brain plasticity to compensate for cognitive function. Hum Brain Mapp 37:3946-3956, 2016. © 2016 Wiley Periodicals, Inc., Competing Interests: The authors declare no conflicts of interest., (© 2016 Wiley Periodicals, Inc.)

Purpose: We evaluated if cortical thickness measures were associated with surgical outcome in patients with non-lesional neocortical epilepsy., Methods: Twenty-one young patients (age: 2.4-19.7years) with epilepsy of neocortical origin and normal MRI underwent two-stage epilepsy surgery with subdural EEG monitoring. Cortical thickness was measured on presurgical volumetric MRI using the FreeSurfer software. The prognostic value of hemispheric and lobar/regional cortical thickness measures for 1-year and 2-year post-surgical seizure outcome has been analyzed., Results: At one-year follow-up, 14 patients (67%) were seizure-free. Hemispheric and frontal lobe cortical thickness showed no/minimal asymmetry in seizure-free patients but thinner cortex ipsilateral to the seizure focus in those with recurrent seizures (p=0.02). More robust differences were found in patients≥6years of age (p=0.006 for frontal asymmetries), whose cortical thickness asymmetries remained prognostic for 2-year post-surgical outcome (p=0.007). By using an optimal cutoff threshold based on a receiver operating characteristic analysis, mean hemispheric asymmetry predicted one-year seizure freedom with 93% sensitivity and 71% specificity in the whole group, and with 100% sensitivity and 92% specificity in patients≥6years of age., Conclusion: In patients with neocortical epilepsy and normal MRI, neocortical thinning in the epileptic hemisphere, particularly in frontal cortex, is associated with poor surgical outcome. Although these results require validation in a larger cohort prospectively, these data suggest that presurgical evaluation of cortical thickness may assist in identification of patients at high risk for surgical failure., Competing Interests: None., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Sturge-Weber syndrome is often accompanied by seizures and neurocognitive deterioration, although previous studies have suggested that early functional brain reorganization may diminish the cognitive sequelae in some children with unilateral Sturge-Weber syndrome. The "rules" governing these plasticity mechanisms are poorly understood. In this study, we evaluated longitudinal changes of cognitive functioning (intelligence quotient [IQ]) and assessed the performance of clinical, electroencephalography (EEG), and magnetic resonance imaging (MRI) variables for predicting IQ in children with Sturge-Weber syndrome., Methods: Thirty-three young children (mean age: 3.3 years at baseline) with unilateral Sturge-Weber syndrome underwent MRI, scalp EEG, and neuropsychology evaluation twice, with a median follow-up of 2 years. None of the children had epilepsy surgery. Longitudinal IQ changes were calculated. Seizure variables, interictal EEG abnormalities, and extent and location of MRI brain involvement were correlated with IQ assessed at follow-up., Results: Global IQ showed a highly variable course with both increases and decreases over time. Lower IQ at baseline was associated with interval IQ increase. In univariate analyses, lower outcome IQ was associated with baseline EEG abnormalities (P < 0.001), young age at seizure onset (P = 0.001), high seizure frequency (P = 0.02), and early frontal-lobe involvement on MRI (P = 0.01). In multivariate analysis, EEG abnormalities at baseline remained a robust, independent predictor of outcome IQ., Conclusions: The early trajectory of cognitive changes in children with unilateral Sturge-Weber syndrome is highly variable; children with improving IQ likely undergo effective unimpeded functional reorganization. Early onset, frequent seizures, and interictal epileptiform abnormalities on EEG likely interfere with this process resulting in poor cognitive functions. Future studies assessing interventions should target this high-risk subgroup to optimize cognitive outcome in Sturge-Weber syndrome., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The use of gonadotropin-releasing hormone analogs has been reported in the treatment of gelastic seizures and precocious puberty associated with hypothalamic hamartomas, but not in other seizure types without hypothalamic hamartoma. We describe a 7.5 year-old girl whose seizures subsided after gonadotropin-releasing hormone analog implant, administered for precocious puberty., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Prevalence of autism spectrum disorders has increased over recent years, however, little is known about the identification and management of autism spectrum disorder in Africa. This report summarizes a workshop on autism spectrum disorder in Africa under the auspices of the International Child Neurology Association and the African Child Neurology Association through guided presentations and working group reports, focusing on identification, diagnosis, management, and community support. A total of 47 delegates participated from 14 African countries. Although there was a huge variability in services across the countries represented, numbers of specialists assessing and managing autism spectrum disorder was small relative to populations served. Strategies were proposed to improve identification, diagnosis, management and support delivery for individuals with autism spectrum disorder across Africa in these culturally diverse, low-resource settings. Emphasis on raising public awareness through community engagement and improving access to information and training in autism spectrum disorder. Special considerations for the cultural, linguistic, and socioeconomic factors within Africa are discussed., (© The Author(s) 2016.)

Background and Purpose: Pure speech delay is a common developmental disorder which, according to some estimates, affects 5%-8% of the population. Speech delay may not only be an isolated condition but also can be part of a broader condition such as global developmental delay. The present study investigated whether diffusion tensor imaging tractography-based connectome can differentiate global developmental delay from speech delay in young children., Materials and Methods: Twelve children with pure speech delay (39.1 ± 20.9 months of age, 9 boys), 14 children with global developmental delay (39.3 ± 18.2 months of age, 12 boys), and 10 children with typical development (38.5 ± 20.5 months of age, 7 boys) underwent 3T DTI. For each subject, whole-brain connectome analysis was performed by using 116 cortical ROIs. The following network metrics were measured at individual regions: strength (number of the shortest paths), efficiency (measures of global and local integration), cluster coefficient (a measure of local aggregation), and betweeness (a measure of centrality)., Results: Compared with typical development, global and local efficiency were significantly reduced in both global developmental delay and speech delay (P < .0001). The nodal strength of the cognitive network is reduced in global developmental delay, whereas the nodal strength of the language network is reduced in speech delay. This finding resulted in a high accuracy of >83% ± 4% to discriminate global developmental delay from speech delay., Conclusions: The network abnormalities identified in the present study may underlie the neurocognitive and behavioral consequences commonly identified in children with global developmental delay and speech delay. Further validation studies in larger samples are required., (© 2016 by American Journal of Neuroradiology.)

Background: Sturge-Weber syndrome (SWS) is strongly associated with epilepsy. Brain tissue studies have suggested that epileptic activity in SWS is driven by glutamatergic synaptic activity. Here, we used proton magnetic resonance spectroscopic imaging (MRSI) to test if glutamate (GLU) concentrations are increased in the affected hemisphere and if such increases are associated with severity of epilepsy in children with SWS. We also studied the metabolic correlates of MRSI abnormalities, using glucose positron emission tomography (PET) imaging., Methods: 3T MRI and glucose PET were performed in 10 children (age: 7-78 months) with unilateral SWS and a history of epilepsy. MRSI data were acquired from the affected (ipsilateral) and non-affected (contralateral) hemispheres. GLU, N-acetyl-aspartate (NAA) and creatine (Cr) were quantified in multiple voxels; GLU/Cr and NAA/Cr ratios were calculated and compared to seizure frequency as well as glucose PET findings., Results: The highest GLU/Cr ratios were found in the affected hemisphere in all children except one with severe atrophy. The maximum ipsilateral/contralateral GLU/Cr ratios ranged between 1.0 and 2.5 (mean: 1.6). Mean ipsilateral/contralateral GLU/Cr ratios were highest in the youngest children and showed a strong positive correlation with clinical seizure frequency scores assessed at the time of the scan (r=0.88, p=0.001) and also at follow-up (up to 1 year, r=0.80, p=0.009). GLU increases in the affected hemisphere coincided with areas showing current or previous increases of glucose metabolism on PET in 5 children. NAA/Cr ratios showed no association with clinical seizure frequency., Conclusions: Increased glutamate concentrations in the affected hemisphere, measured by MRSI, are common in young children with unilateral SWS and are associated with frequent seizures. The findings lend support to the role of excess glutamate in SWS-associated epilepsy., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Tuberous sclerosis complex (TSC) is a multisystem genetic disorder caused by mutations in the TSC1 and TSC2 genes. Over 80% of TSC patients are affected by epilepsy, but the molecular events contributing to seizures in TSC are not well understood. Recent reports have demonstrated that the brain is enriched with microRNA activity, and they are critical in neural development and function. However, little is known about the role of microRNAs in TSC. Here, we report the characterization of aberrant microRNA activity in cortical tubers resected from 5 TSC patients surgically treated for medically intractable epilepsy. By comparing epileptogenic tubers with adjacent nontuber tissue, we identified a set of 4 coordinately overexpressed microRNAs (miRs 23a, 34a, 34b*, 532-5p). We used quantitative liquid chromatography-tandem mass spectrometry (LC-MS/MS) proteomic profiling to investigate the combined effect of the 4 microRNAs on target proteins. The proportion of repressed proteins among the predicted targets was significantly greater than in the overall proteome and was highly enriched for proteins involved in synaptic signal transmission. Among the combinatorial targets were TSC1, coding for the protein hamartin, and several epilepsy risk genes. We found decreased levels of hamartin in epileptogenic tubers and confirmed targeting of the TSC1 3' UTR by miRs-23a and 34a., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objectives: To determine safety and efficacy of the 5HT1A serotonin partial agonist buspirone on core autism and associated features in children with autism spectrum disorder (ASD)., Study Design: Children 2-6 years of age with ASD (N = 166) were randomized to receive placebo or 2.5 or 5.0 mg of buspirone twice daily. The primary objective was to evaluate the effects of 24 weeks of buspirone on the Autism Diagnostic Observation Schedule (ADOS) Composite Total Score. Secondary objectives included evaluating the effects of buspirone on social competence, repetitive behaviors, language, sensory dysfunction, and anxiety and to assess side effects. Positron emission tomography measures of tryptophan metabolism and blood serotonin concentrations were assessed as predictors of buspirone efficacy., Results: There was no difference in the ADOS Composite Total Score between baseline and 24 weeks among the 3 treatment groups (P = .400); however, the ADOS Restricted and Repetitive Behavior score showed a time-by-treatment effect (P = .006); the 2.5-mg buspirone group showed significant improvement (P = .003), whereas placebo and 5.0-mg buspirone groups showed no change. Children in the 2.5-mg buspirone group were more likely to improve if they had fewer foci of increased brain tryptophan metabolism on positron emission tomography (P = .018) or if they showed normal levels of blood serotonin (P = .044). Adverse events did not differ significantly among treatment groups., Conclusions: Treatment with 2.5 mg of buspirone in young children with ASD might be a useful adjunct therapy to target restrictive and repetitive behaviors in conjunction with behavioral interventions., Trial Registration: ClinicalTrials.gov: NCT00873509., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The karyotype 49, XXXXY is one of the most severe forms of chromosome aneuploidy and is characterized clinically by developmental delay and profound language impairment, particularly involving expressive language functions. We describe the neurocognitive profile and structural anatomy of language pathway in a 2-year-old boy with 49, XXXXY syndrome with expressive aphasia., Methods: Retrospective chart review of the patient was performed. We characterized the language deficits using neuropsychologic testing. We further studied the language pathways using diffusion tensor imaging analytical technique., Results: The neurocognitive profile of the patient showed relative weakness of expressive language skills compared with other domains. Diffusion tensor imaging analysis demonstrated a poorly developed frontal aslant tract, a weak indirect segment of arcuate fasciculus, and normally developed direct segment of arcuate fasciculus. The frontal aslant tract is a novel pathway that connects the Broca's area with the anterior cingulate and presupplementary motor area and plays a role in the "motor stream" of language., Conclusion: A poorly developed frontal aslant tract may underlie the expressive language deficits and provide some insight into the role of X chromosome in modulating the development of language tracts., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: We reviewed our experience of surgery for epileptic spasms (ES) with or without history of infantile spasms., Methods: Data were reviewed from 65 (33 male) patients with ES who underwent surgery between 1993 and 2014; palliative cases were excluded., Results: Mean age at surgery was 5.1 (range 0.2-19) years, with mean postsurgical follow-up of 45.3 (6-120) months. Mean number of anticonvulsants used preoperatively was 4.2 (2-8), which decreased to 1.2 (0-4) postoperatively (p < 0.0001). Total hemispherectomy was the most commonly performed surgery (n = 20), followed by subtotal hemispherectomy (n = 17), multilobar resection (n = 13), lobectomy (n = 7), tuberectomy (n = 6), and lobectomy + tuberectomy (n = 2), with International League Against Epilepsy (ILAE) class I outcome in 20, 10, 7, 6, 3, and 0 patients, respectively (total 46/65 (71%); 22 off medication). Shorter duration of epilepsy (p = 0.022) and presence of magnetic resonance imaging (MRI) lesion (p = 0.026) were independently associated with class I outcome. Of 34 patients operated <3 years after seizure onset, 30 (88%) achieved class I outcome. Thirty-seven (79%) of 47 patients with lesional MRI had class-I outcome, whereas 9 (50%) of 18 with normal MRI had class I outcome. Positron emission tomography (PET) scan was abnormal in almost all patients [61 (97%) of 63 with lateralizing/localizing findings in 56 (92%) of 61 patients, thus helping in surgical decision making and guiding subdural grid placements, particularly in patients with nonlesional MRI. Fifteen patients had postoperative complications, mostly minor., Significance: Curative epilepsy surgery in ES patients, with or without history of infantile spasms, is best accomplished at an early age and in those patients with lesional abnormalities on MRI with electroencephalography (EEG) concordance. Good outcomes can be achieved even when there is no MRI lesion but positive PET localization., (Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.)

Purpose: To examine whether an objective segmenation of corticospinal tract (CST) associated with hand and leg movements can be used to detect central motor weakness in the corresponding extremities in a pediatric population., Material and Methods: This retrospective study included diffusion tensor imaging (DTI) of 25 children with central paresis affecting at least one limb (age: 9.0±4.2years, 15 boys, 5/13/7 children with left/right/both hemispheric lesions including ischemia, cyst, and gliosis), as well as 42 pediatric control subjects with no motor dysfunction (age: 9.0±5.5years, 21 boys, 31 healthy/11 non-lesional epilepsy children). Leg- and hand-related CST pathways were segmented using DTI-maximum a posteriori (DTI-MAP) classification. The resulting CST volumes were then divided by total supratentorial white matter volume, resulting in a marker called "normalized streamline volume ratio (NSVR)" to quantify the degree of axonal loss in separate CST pathways associated with leg and hand motor functions. A receiver operating characteristic curve was applied to measure the accuracy of this marker to identify extremities with motor weakness., Results: NSVR values of hand/leg CST selectively achieved the following values of accuracy/sensitivity/specificity: 0.84/0.84/0.57, 0.82/0.81/0.55, 0.78/0.75/0.55, 0.79/0.81/0.54 at a cut-off of 0.03/0.03/0.03/0.02 for right hand CST, left hand CST, right leg CST, and left leg CST, respectively. Motor weakness of hand and leg was most likely present at the cut-off values of hand and leg NSVR (i.e., 0.029/0.028/0.025/0.020 for left-hand/right-hand/left-leg/right-leg). The control group showed a moderate age-related increase in absolute CST volumes and a biphasic age-related variation of the normalized CST volumes, which were lacking in the paretic children., Conclusions: This study demonstrates that DTI-MAP classification may provide a new imaging tool to quantify axonal loss in children with central motor dysfunction. Using this technique, we found that early-life brain lesions affect the maturational trajectory of the primary motor pathway which may be used as an effective marker to facilitate evidence-based treatment of paretic children., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Mutations in ATP1A3 cause Alternating Hemiplegia of Childhood (AHC) by disrupting function of the neuronal Na+/K+ ATPase. Published studies to date indicate 2 recurrent mutations, D801N and E815K, and a more severe phenotype in the E815K cohort. We performed mutation analysis and retrospective genotype-phenotype correlations in all eligible patients with AHC enrolled in the US AHC Foundation registry from 1997-2012. Clinical data were abstracted from standardized caregivers' questionnaires and medical records and confirmed by expert clinicians. We identified ATP1A3 mutations by Sanger and whole genome sequencing, and compared phenotypes within and between 4 groups of subjects, those with D801N, E815K, other ATP1A3 or no ATP1A3 mutations. We identified heterozygous ATP1A3 mutations in 154 of 187 (82%) AHC patients. Of 34 unique mutations, 31 (91%) are missense, and 16 (47%) had not been previously reported. Concordant with prior studies, more than 2/3 of all mutations are clusteredin exons 17 and 18. Of 143 simplex occurrences, 58 had D801N (40%), 38 had E815K(26%) and 11 had G947R (8%) mutations [corrected].Patients with an E815K mutation demonstrate an earlier age of onset, more severe motor impairment and a higher prevalence of status epilepticus. This study further expands the number and spectrum of ATP1A3 mutations associated with AHC and confirms a more deleterious effect of the E815K mutation on selected neurologic outcomes. However, the complexity of the disorder and the extensive phenotypic variability among subgroups merits caution and emphasizes the need for further studies.

We applied PET scanning with (11)C-[R]-PK11195 (PK) to evaluate neuroinflammatory changes in basal ganglia and thalamus in children with clinically diagnosed pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) and Tourette syndrome. Seventeen children with PANDAS (mean age: 11.4 ± 2.6 years; 13 males), 12 with Tourette syndrome (mean age: 11.0 ± 3.0 years; 10 males), and 15 normal adults (mean age: 28.7 ± 7.9 years; 8 males) underwent dynamic PK PET imaging and binding potential, a measure of ligand-TSPO receptor (expressed by activated microglia) binding, was calculated for basal ganglia and thalamus. Binding potential values, suggesting underlying activated microglia-mediated neuroinflammation, were found to be increased in bilateral caudate and bilateral lentiform nucleus in the PANDAS group and in bilateral caudate nuclei only in the Tourette syndrome group, compared to control group. These differences in the pattern and extent of neuroinflammation also signify a possible difference in pathophysiological etiology between PANDAS and Tourette syndrome patients., (© The Author(s) 2014.)

Background: Diffusion tensor imaging (DTI) has expanded our knowledge of corticospinal tract (CST) anatomy and development. However, previous developmental DTI studies assessed the CST as a whole, overlooking potential differences in development of its components related to control of the upper and lower extremities. The present cross-sectional study investigated age-related changes, side and gender differences in streamline volume of the leg- and hand-related segments of the CST in children., Subjects and Methods: DTI data of 31 children (1-14 years; mean age: 6±4 years; 17 girls) with normal conventional MRI were analyzed. Leg- and hand-related CST streamline volumes were quantified separately, using a recently validated novel tractography approach. CST streamline volumes on both sides were compared between genders and correlated with age., Results: Higher absolute streamline volumes were found in the left leg-related CST compared to the right (p=0.001) without a gender effect (p=0.4), whereas no differences were found in the absolute hand-related CST volumes (p>0.4). CST leg-related streamline volumes, normalized to hemispheric white matter volumes, declined with age in the right hemisphere only (R=-.51; p=0.004). Absolute leg-related CST streamline volumes showed similar, but slightly weaker correlations. Hand-related absolute or normalized CST streamline volumes showed no age-related variations on either side., Conclusion: These results suggest differential development of CST segments controlling hand vs. leg movements. Asymmetric volume changes in the lower limb motor pathway may be secondary to gradually strengthening left hemispheric dominance and is consistent with previous data suggesting that footedness is a better predictor of hemispheric lateralization than handedness., (Copyright © 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Purpose: To determine the relation between glucose metabolic changes of the primary visual cortex, structural abnormalities of the corresponding visual tracts, and visual symptoms in children with Sturge-Weber syndrome (SWS)., Materials and Methods: In 10 children with unilateral SWS (ages 1.5-5.5 years), a region-of-interest analysis was applied in the bilateral medial occipital cortex on positron emission tomography (PET) and used to track diffusion-weighted imaging (DWI) streamlines corresponding to the central visual pathway. Normalized streamline volumes of individual SWS patients were compared with values from age-matched control groups as well as correlated with normalized glucose uptakes and visual field deficit., Results: Lower glucose uptake and lower corresponding streamline volumes were detected in the affected occipital lobe in 9/10 patients, as compared to the contralateral side. Seven of these 9 patients had visual field deficit and normal or decreased streamline volumes on the unaffected side. The two other children had no visual symptoms and showed high contralateral visual streamline volumes. There was a positive correlation between the normalized ratios on DWI and PET, indicating that lower glucose metabolism was associated with lower streamline volume in the affected hemisphere (R = 0.70, P = 0.024)., Conclusion: We demonstrated that 18F-flurodeoxyglucose (FDG)-PET combined with DWI tractography can detect both brain damage on the side of the lesion and contralateral plasticity in children with early occipital lesions., (© 2014 Wiley Periodicals, Inc.)

Background: Post-traumatic epilepsy after a traumatic brain injury occurs in 10%-20% of children. Unfortunately, a biomarker that could provide prognostic information about both post-traumatic epilepsy and cognitive development is lacking. In this first of a series of studies, we have reviewed and analyzed clinical variables in children following traumatic brain injury to understand the epidemiologic and clinical characteristics of post-traumatic epilepsy in our urban population., Methods: We performed a retrospective electronic chart review of patients who had suffered traumatic brain injury and subsequently evaluated at Children's Hospital of Michigan from 2002 to 2012. Various epidemiologic and clinical variables were analyzed., Results: Patients who had severe traumatic brain injury and post-traumatic epilepsy had an abnormal acute head computed tomography. These patients had increased number of different seizure types, increased risk of intractability of epilepsy, and were on multiple antiepileptic drugs. Hypomotor seizure was the most common seizure type in these patients. There was a high prevalence of patients who suffered nonaccidental trauma, all of whom had severe traumatic brain injury., Conclusions: This study demonstrates a need for biomarkers in children following traumatic brain injury to reliably evaluate the risk of post-traumatic epilepsy., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: To examine whether diffusion-weighted imaging (DWI) tractography can detect multiple white matter pathways connected to language cortices, we employed a maximum a posteriori probability (MAP) classification method, which has been recently validated for the corticospinal tract., Methods: DWI was performed in 12 normally developing children and 17 children with intractable focal epilepsy who underwent subsequent two-stage epilepsy surgery with intracranial functional mapping. First, whole-brain DWI tractography was performed to identify unique pathways originating from Broca's area, premotor area, and Wernicke's area on functional magnetic resonance imaging (fMRI) of normal children and intracranial electrical stimulation mapping (ESM) of children with epilepsy. Group averaging of these pathways based on fMRI was performed to construct the probability maps of language areas in standard MRI space. These maps were finally used to design a DWI-MAP classifier, which can automatically sort individual fibers originating from fMRI language areas as well as ESM language areas., Results: In normally developing children, the DWI-MAP classifier predicted language-activation areas on fMRI with up to 77% accuracy. In children with focal epilepsy, the DWI-MAP classifier also showed high accuracy (up to 82%) for the fibers terminating in proximity to essential language areas determined by ESM. Decreased volumes in DWI-MAP-defined pathways after epilepsy surgery were associated with postoperative language deficits., Significance: This study encourages further investigations to determine if DWI-MAP analysis can serve as a noninvasive diagnostic tool during pediatric presurgical planning by estimating not only the location of essential language cortices, but also the underlying fibers connecting these cortical areas., (Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.)

Objective: Cortical resections in epilepsy surgery tend to be larger in children, compared to adults, partly due to underlying pathology. Some children show unilateral multifocal seizure onsets involving much of the hemisphere. If there were a significant hemiparesis present, hemispherectomy would be the procedure of choice. Otherwise, it is preferable to spare the primary sensorimotor cortex. We report the results of "subtotal" hemispherectomy in 23 children., Methods: All children (ages 1 year and 4 months to 14 years and 2 months) were operated on between 2001 and 2013 at Children's Hospital of Michigan (Detroit). Patients were evaluated with scalp video-electroencephalography (EEG), magnetic resonance imaging (MRI), (18) F-fluorodeoxyglucose-positron emission tomography (FDG-PET) scans, and neuropsychological assessments when applicable. Subsequently, each case was discussed in a multidisciplinary epilepsy surgery conference, and a consensus was reached pertaining to candidacy for surgery and optimum surgical approach. The actual extent of resection was based on the results from subdural electrocorticography (ECoG) monitoring. The surgical outcome is based on International League Against Epilepsy (ILAE) classification (class 1-6)., Results: Among the 23 patients, 11 had epileptic spasms as their major seizure type; these were associated with focal seizures in 3 children. MRI showed focal abnormalities in 12 children. FDG-PET was abnormal in all but one subject. All except two children underwent chronic subdural ECoG. Multiple subpial transections were performed over the sensorimotor cortex in three subjects. On histopathology, various malformations were seen in 9 subjects; the remainder showed gliosis alone (n = 12), porencephaly (n = 1), and gliosis with microglial activation (n = 1). Follow-up ranged from 13 to 157 months (mean = 65 months). Outcomes consisted of class 1 (n = 17, 74%), class 2 (n = 2), class 3 (n = 1), class 4 (n = 1), and class 5 (n = 2)., Significance: Extensive unilateral resections sparing only sensorimotor cortex can be performed with excellent results in seizure control. Even with the presence of widespread unilateral epileptogenicity or anatomic/functional imaging abnormalities, complete hemispherectomy can often be avoided, particularly when there is little hemiparesis., (Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.)

The high energetic costs of human brain development have been hypothesized to explain distinctive human traits, including exceptionally slow and protracted preadult growth. Although widely assumed to constrain life-history evolution, the metabolic requirements of the growing human brain are unknown. We combined previously collected PET and MRI data to calculate the human brain's glucose use from birth to adulthood, which we compare with body growth rate. We evaluate the strength of brain-body metabolic trade-offs using the ratios of brain glucose uptake to the body's resting metabolic rate (RMR) and daily energy requirements (DER) expressed in glucose-gram equivalents (glucosermr% and glucoseder%). We find that glucosermr% and glucoseder% do not peak at birth (52.5% and 59.8% of RMR, or 35.4% and 38.7% of DER, for males and females, respectively), when relative brain size is largest, but rather in childhood (66.3% and 65.0% of RMR and 43.3% and 43.8% of DER). Body-weight growth (dw/dt) and both glucosermr% and glucoseder% are strongly, inversely related: soon after birth, increases in brain glucose demand are accompanied by proportionate decreases in dw/dt. Ages of peak brain glucose demand and lowest dw/dt co-occur and subsequent developmental declines in brain metabolism are matched by proportionate increases in dw/dt until puberty. The finding that human brain glucose demands peak during childhood, and evidence that brain metabolism and body growth rate covary inversely across development, support the hypothesis that the high costs of human brain development require compensatory slowing of body growth rate.

The multistep preparation of (11)C-levetiracetam ((11)C-LEV) was carried out by a one-pot radiosynthesis with 8.3 ± 1.6% (n = 8) radiochemical yield in 50 ± 5.0 min. Briefly, the propionaldehyde was converted to propan-1-imine in situ as labeling precursor by incubation with ammonia. Without further separation, the imine was reacted with (11)C-HCN to form (11)C-aminonitrile. This crude was then reacted with 4-chlorobutyryl chloride and followed by hydrolysis to yield (11)C-LEV after purification by chiral high-performance liquid chromatography (HPLC). Both the radiochemical and enantiomeric purities of (11)C-LEV were >98%.

Children with tuberous sclerosis complex, Sturge-Weber syndrome, and Rasmussen encephalitis all have complex but differing needs in the process of transition/transfer to adult care. All three may be associated with long-term normal intelligence or a varying degree of intellectual disability. In tuberous sclerosis complex, the emphasis of care in adulthood shifts from seizure control and developmental issues to renal and psychiatric disease and other issues. In Sturge-Weber syndrome, the emphasis shifts from seizure control and rehabilitation to management of disability and migraine. In Rasmussen encephalitis, transition may be particularly complex for those with adolescent onset. Those successfully operated on for childhood onset have a static problem and the potential to do well in life., (Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.)

As a new tool to quantify primary motor pathways and predict postoperative motor deficits in children with focal epilepsy, the present study utilized a maximum a posteriori probability (MAP) classification of diffusion weighted imaging (DWI) tractography combined with Kalman filter. DWI was performed in 31 children with intractable focal epilepsy who underwent epilepsy surgery. Three primary motor pathways associated with "finger," "leg," and "face" were classified using DWI-MAP classifier and compared with the results of invasive electrical stimulation mapping (ESM) via receiver operating characteristic (ROC) curve analysis. The Kalman filter analysis was performed to generate a model to determine the probability of postoperative motor deficits as a function of the proximity between the resection margin and the finger motor pathway. The ROC curve analysis showed that the DWI-MAP achieves high accuracy up to 89% (finger), 88% (leg), 89% (face), in detecting the three motor areas within 20 mm, compared with ESM. Moreover, postoperative reduction of the fiber count of finger pathway was associated with postoperative motor deficits involving the hand. The prediction model revealed an accuracy of 92% in avoiding postoperative deficits if the distance between the resection margin and the finger motor pathway seen on preoperative DWI tractography was 19.5 mm. This study provides evidence that the DWI-MAP combined with Kalman filter can effectively identify the locations of cortical motor areas even in patients whose motor areas are difficult to identify using ESM, and also can serve as a reliable predictor for motor deficits following epilepsy surgery., (Copyright © 2013 Wiley Periodicals, Inc.)

The human neocortex is characterized by protracted developmental intervals of synaptogenesis and myelination, which allow for an extended period of learning. The molecular basis of these and other postnatal developmental changes in the human cerebral cortex remain incompletely understood. Recently, a new large class of mammalian genes, encoding nonmessenger, long nonprotein-coding ribonucleic acid (lncRNA) molecules has been discovered. Although their function remains uncertain, numerous lncRNAs have primate-specific sequences and/or show evidence of rapid, lineage-specific evolution, making them potentially relevant to the evolution of unique human neural properties. To examine the hypothesis that lncRNA expression varies with age, potentially paralleling known developmental trends in synaptogenesis, myelination, and energetics, we quantified levels of nearly 6000 lncRNAs in 36 surgically resected human neocortical samples (primarily derived from temporal cortex) spanning infancy to adulthood. Our analysis identified 8 lncRNA genes with distinct developmental expression patterns. These lncRNA genes contained anthropoid-specific exons, as well as splice sites and polyadenylation signals that resided in primate-specific sequences. To our knowledge, our study is the first to describe developmental expression profiles of lncRNA in surgically resected in vivo human brain tissue. Future analysis of the functional relevance of these transcripts to neural development and energy metabolism is warranted.

Background: Reorganization of the corticospinal tract after early damage can limit motor deficit. In this study, we explored patterns of structural corticospinal tract reorganization in children with Sturge-Weber syndrome., Methods: Five children (age 1.5-7 years) with motor deficit resulting from unilateral Sturge-Weber syndrome were studied prospectively and longitudinally (1-2 years follow-up). Corticospinal tract segments belonging to hand and leg movements were separated and their volume was measured by diffusion tensor imaging tractography using a recently validated method. Corticospinal tract segmental volumes were normalized and compared between the Sturge-Weber syndrome children and age-matched healthy controls. Volume changes during follow-up were also compared with clinical motor symptoms., Results: In the Sturge-Weber syndrome children, hand-related (but not leg-related) corticospinal tract volumes were consistently decreased in the affected cerebral hemisphere at baseline. At follow-up, two distinct patterns of hand corticospinal tract volume changes emerged. (1) Two children with extensive frontal lobe damage showed a corticospinal tract volume decrease in the lesional hemisphere and a concomitant increase in the nonlesional (contralateral) hemisphere. These children developed good hand grasp but no fine motor skills. (2) The three other children, with relative sparing of the frontal lobe, showed an interval increase of the normalized hand corticospinal tract volume in the affected hemisphere; these children showed no gross motor deficit at follow-up., Conclusions: Diffusion tensor imaging tractography can detect differential abnormalities in the hand corticospinal tract segment both ipsi- and contralateral to the lesion. Interval increase in the corticospinal tract hand segment suggests structural reorganization, whose pattern may determine clinical motor outcome and could guide strategies for early motor intervention., (Copyright © 2014 Elsevier Inc. All rights reserved.)

This study utilized diffusion tensor imaging fiber tractography to examine the miscrostructural integrity of limbic and paralimbic white matter tracts in 36 children (age M = 124 months) with histories of early deprivation, raised from birth in orphanages and subsequently adopted into the United States, compared to 16 age-matched typically developing children. We found increased mean diffusivity bilaterally in the arcuate fasciculus and increased mean diffusivity and reduced fractional anisotropy bilaterally in the uncinate fasciculus and cingulum in children with early deprivation. Microstructural integrity of the left arcuate fasciculus and right cingulum was related to language and behavioral functioning, respectively. White matter abnormalities were also associated with length of deprivation and time in the adoptive home. Our findings suggest that white matter pathways, connecting limbic and paralimbic brain regions is abnormal in children with histories of early deprivation, with some pathways appearing more susceptible to early deprivation than others.

Postmortem neuropathology studies report reduced number and size of Purkinje cells (PC) in a majority of cerebellar specimens from persons diagnosed with autism spectrum disorders (ASD). We used diffusion weighted MRI tractography to investigate whether structural changes associated with reduced number and size of PC, could be detected in vivo by measuring streamlines connecting the posterior-lateral region of the cerebellar cortex to the dentate nucleus using an independent component analysis with a ball and stick model. Seed regions were identified in the cerebellar cortex, and streamlines were identified to two sorting regions, the dorsal dentate nucleus (DDN) and the ventral dentate nucleus (VDN), and probability of connection and measures of directional coherence for these streamlines were calculated. Tractography was performed in 14 typically developing children (TD) and 15 children with diagnoses of ASD. Decreased numbers of streamlines were found in the children with ASD in the pathway connecting cerebellar cortex to the right VDN (p-value = 0.015). Reduced fractional anisotropy (FA) values were observed in pathways connecting the cerebellar cortex to the right DDN (p-value = 0.008), the right VDN (p-value = 0.010) and left VDN (p-value = 0.020) in children with ASD compared to the TD group. In an analysis of single subjects, reduced FA in the pathway connecting cerebellar cortex to the right VDN was found in 73% of the children in the ASD group using a threshold of 3 standard errors of the TD group. The detection of diffusion changes in cerebellum may provide an in vivo biomarker of Purkinje cell pathology in children with ASD.

Children who have experienced deprivation as a result of orphanage care during early development are at increased risk for a number of cognitive, emotional, and social difficulties (MacLean, 2003). This study examined the neuropsychological and behavioral profile of internationally adopted children with language difficulties, one of the most common cognitive challenges (Behen et al., 2008). In addition to neuropsychological testing, fMRI was utilized to examine activation patterns during expressive fluency and receptive language tasks. In comparison to internationally adopted children without language difficulties and nonadopted controls, participants with language difficulty had worse performance on tasks of verbal memory and reasoning, academic skills, and working memory. Behaviorally, all internationally adopted participants, regardless of language ability, had more parent-reported hyperactivity and impulsivity compared with controls. The fMRI tasks revealed reduced activation in traditional language areas in participants with language difficulty. The impact of early adverse experience on later development is discussed.

Following unilateral cerebral injury, several patterns of cerebellar metabolism have been noted on positron emission tomography (PET); these changes have been attributed both to the distant diaschisis as well as to reorganizational changes within the cerebellum. We used diffusion tensor magnetic resonance imaging (MRI) to study 14 children who had undergone cerebral hemispherectomy because of intractable epilepsy and compared them with those from 17 controls. In 10 children who had preoperative and postoperative scans, a paired comparison was performed. Our findings showed significantly higher fractional anisotropy values in corticopontocerebellar pathways postoperatively compared to preoperatively. When compared to controls, we found a higher rate of age-related fractional anisotropy changes of corticopontocerebellar pathways in the postoperative scans. Our results indicate reorganizational changes in the contralateral (intact) corticopontocerebellar pathway and the cerebellar white matter. These changes likely contribute to the far better motor outcomes seen in children compared to adults sustaining such cortical injuries.

Purpose: To explore whether diffusion-weighted imaging (DWI) can localize specific segments of primary motor areas in children with Sturge-Weber syndrome (SWS), this study investigated the corticospinal tract (CST) between precentral gyrus (PCG) and posterior limb of internal capsule (PIC)., Materials and Methods: DWI was performed on 32 healthy children and seven children with unilateral SWS affecting the sensorimotor area variably. A hierarchical dendrogram was applied to find PCG-segments uniquely connected to PIC-segments. The resulting PCG-clusters were used to image primary motor pathways in DWI and find metabolic abnormalities of primary motor areas in positron emission tomography (PET) scans., Results: In healthy children, five PCG-clusters were found to have unique CST courses, corresponding to CST segments of mouth/lip, fingers, and leg/ankle primary motor areas determined by functional magnetic resonance imaging (fMRI). In children with SWS, reduced streamlines in these PCG clusters were highly correlated with glucose-hypometabolism on PET (R(2) = 0.2312, P = 0.0032). Impaired CST segment corresponding to finger movements correlated with severity of hand motor deficit., Conclusion: The presented method can detect impaired CST segments corresponding to specific motor functions in young children who cannot cooperate for fMRI. This approach can be clinically useful for a noninvasive presurgical evaluation of cortical motor areas in such children., (Copyright © 2013 Wiley Periodicals, Inc.)

PET and SPECT can play an important role in the evaluation of various epileptic syndromes, particularly those with unknown causes, by revealing various underlying abnormalities that may not be fully appreciated from MR imaging studies. In some cases, PET and SPECT provide crucial data that guide surgical resections of the epileptogenic zone for medically refractory epilepsy. In other cases, these neuroimaging modalities preclude a surgical option and can guide genetic studies. Longitudinal PET and SPECT studies may increase our understanding of the etiopathogenesis of epilepsy syndromes and provide a clearer picture of the natural history of neurologic progression.

In this study, we examined whether topologic network analysis, using resting state functional magnetic resonance imaging (MRI), can detect abnormalities of functional brain connectivity in children with unilateral brain injury due to Sturge-Weber syndrome. Three children with Sturge-Weber syndrome (ages 1, 3, and 10 years) underwent structural and resting state functional MRI, glucose metabolism positron emission tomography (PET), and neurocognitive evaluation. Eight different resting state networks were compared between the affected and unaffected hemispheres by quantitatively accessing communication efficiency measures. Significantly reduced efficiency values were found in all 3 patients. Visual network deficiency was present in both children with a visual field defect; frontal network abnormalities were associated with fine motor impairment. Location of network abnormalities corresponded to and, in some cases, extended beyond structural MRI and glucose PET abnormalities. The presented approach can detect early functional abnormalities of specific brain networks in children with Sturge-Weber syndrome.

Epilepsy is one of the most common yet diverse neurologic disorders, affecting almost 1%-2% of the population. Presently, radionuclide imaging such as PET and SPECT is not used in the primary diagnosis or evaluation of recent-onset epilepsy. However, it can play a unique and important role in certain specific situations, such as in noninvasive presurgical localization of epileptogenic brain regions in intractable-seizure patients being considered for epilepsy surgery. Radionuclide imaging can be particularly useful if MR imaging is either negative for lesions or shows several lesions of which only 1 or 2 are suspected to be epileptogenic and if electroencephalogram changes are equivocal or discordant with the structural imaging. Similarly, PET and SPECT can also be useful for evaluating the functional integrity of the rest of the brain and may provide useful information on the possible pathogenesis of the neurocognitive and behavioral abnormalities frequently observed in these patients.

The authors tested the hypothesis that de novo copy number variations (CNVs) implicated in known genomic disorders ("pathogenic CNVs") are significant predisposing factors of infantile spasms. The authors performed a genome-wide analysis of single-nucleotide polymorphism genotyping microarray data to identify the role of de novo/known pathogenic large CNVs in 13 trios of children affected by infantile spasms. A rare, large (4.8 Mb) de novo duplication was detected in the 15q11-13 region of 1 patient. In addition, 3 known pathogenic CNVs (present in the patient as well as 1 of the parents) were detected in total. In 1 patient, a known pathogenic deletion was detected in the region of 2q32.3. Similarly, in 1 other patient, 2 known pathogenic deletions in the regions of 16p11.2 and Xp22.13 (containing CDKL5) were detected. These findings suggest that some specific pathogenic CNVs predispose to infantile spasms and may be associated with different phenotypes.

Objectives: This was an observational study done on a large cohort of patients with tuberous sclerosis complex (TSC) to determine whether i) the presence of α-[(11)C]-methyl-l-tryptophan (AMT) hotspots is related to the duration of seizure intractability, ii) the presence of AMT hotspots is related to specific TSC gene mutations, and iii) there is concordance between areas with an AMT hotspot and seizure lateralization/localization on scalp EEG., Methods: One hundred ninety-one patients (mean age: 6.7 years; median: 5 years; range: 3 months to 37 years) with TSC and intractable epilepsy were included. All patients underwent AMT-PET scan. AMT uptake in each tuber and normal-appearing cortex was measured and correlated with clinical, scalp EEG, and, if available, electrocorticographic data., Results: The longer the duration of seizure intractability, the greater the number of AMT hotspots (r = 0.2; p = 0.03). AMT hotspots were seen in both TSC1 and TSC2. There was excellent agreement in seizure focus lateralization between ictal scalp EEG and AMT-PET (Cohen κ 0.94) in 68 of 95 patients in whom both ictal video-EEG and AMT-PET showed lateralizing findings; in 28 of 68 patients (41%), AMT was more localizing. Furthermore, AMT-PET was localizing in 10 of 17 patients (58%) with nonlateralized ictal EEG., Conclusion: AMT-PET, when used together with video-EEG, provides additional lateralization/localization data, regardless of TSC mutation. The duration of seizure intractability may predict the multiplicity of areas with AMT hotspots.

Purpose: As an alternative tool to identify cortical motor areas for planning surgical resection in children with focal epilepsy, the present study proposed a maximum a posteriori probability (MAP) classification of corticospinal tract (CST) visualized by diffusion MR tractography., Methods: Diffusion-weighted imaging (DWI) was performed in 17 normally developing children and 20 children with focal epilepsy. An independent component analysis tractography combined with ball-stick model was performed to identify unique CST pathways originating from mouth/lip, finger, and leg areas determined by functional magnetic resonance imaging (fMRI) in healthy children and electrical stimulation mapping (ESM) in children with epilepsy. Group analyses were performed to construct stereotaxic probability maps of primary motor pathways connecting precentral gyrus and posterior limb of internal capsule, and then utilized to design a novel MAP classifier that can sort individual CST fibers associated with three classes of interest: mouth/lip, fingers, and leg. A systematic leave-one-out approach was applied to train an optimal classifier. A match was considered to occur if classified fibers contacted or surrounded true areas localized by fMRI and ESM., Key Findings: It was found that the DWI-MAP provided high accuracy for the CST fibers terminating in proximity to the localization of fMRI/ESM: 78%/77% for mouth/lip, 77%/76% for fingers, 78%/86% for leg (contact), and 93%/89% for mouth/lip, 91%/89% for fingers, and 92%/88% for leg (surrounded within 2 cm)., Significance: This study provides preliminary evidence that in the absence of fMRI and ESM data, the DWI-MAP approach can effectively retrieve the locations of cortical motor areas and underlying CST courses for planning epilepsy surgery., (Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.)

The independent component analysis (ICA) tractography method has improved the ability to isolate intravoxel crossing fibers; however, the accuracy of ICA is limited in cases with voxels in local clusters lacking sufficient numbers of fibers with the same orientations. To overcome this limitation, the ICA was combined with a ball-stick model (BSM) ["ICA+BSM"]. An ICA approach is applied to identify crossing fiber components in voxels of small cluster, which are maximally independent in orientation. The eigenvectors of these components are numerically optimized via the subsequent BSM procedure. Simulation studies for two or three crossing fibers demonstrate that ICA+BSM overcomes the limitation of the original ICA method by refining regional ICA solutions in diffusion measurement of a single voxel. It shows 2°-5° of angular errors to isolate two or three fibers, providing a better recovery of simulated fibers compared with ICA alone. Human studies show that ICA+BSM achieves high anatomical correspondence of corticospinal tracts compared with postmortem corticospinal histology, yielding 92.2% true positive detection including both lateral and medial projections, compared with 84.1% for ICA alone. This study demonstrates that the intravoxel crossing fiber problem in clinical diffusion MRI may be sorted out more efficiently by combining ICA with BSM., (© 2012 Wiley Periodicals, Inc.)

Background: Genetic mutations play a crucial role in the etiology of cryptogenic infantile spasms, but the cause is still unknown in a significant proportion of patients. Whole exome sequencing technology shows great promise in identifying genetic causes of infantile spasms., Methods: In this study whole exome sequencing was performed with 2-deoxy-2-((18)F)fluoro-d-glucose positron emission tomography scan of an infant boy with infantile spasms. Exome sequencing was also performed in the parents to identify any de novo mutations., Results: The positron emission tomography scan showed a pattern of bilateral symmetric temporal lobe glucose hypometabolism. A total of 8171 nonsynonymous variants were identified in the child. Despite the large number of nonsynonymous variants, there was only a single de novo missense mutation in SCN2A in the child (NCBI hg19 assembly, position: Chr2:166234116, K1422E). Subsequent Sanger sequencing confirmed the de novo status of this variant. This mutation has never been reported in 6500 individuals of the exome variant server database. Similarly, this variant is not reported in the Online Mendelian Inheritance in Man Database or the Human Gene Mutation Database. It has previously been shown that SCN2A mutations are associated with hippocampal hyperexcitability. Therefore, this study indicates that infantile spasms and bitemporal hypometabolism in this patient might have been caused by hippocampal hyperexcitability due to SCN2A mutation., Conclusions: The simultaneous presence of an SCN2A mutation and bitemporal hypometabolism in this patient with infantile spasms suggests a plausible hippocampal origin. However, additional mechanistic and clinical studies are required to validate this link., (Copyright © 2013 Elsevier Inc. All rights reserved.)

New-onset refractory status epilepticus (NORSE) has high morbidity and mortality. The authors describe the successful surgical treatment of a 56-year-old man presenting with NORSE. Magnetic resonance imaging showed a left temporal lobe lesion suspicious for a low-grade tumor, while PET imaging with the alpha[(11)C]methyl-L-tryptophan (AMT) radiotracer showed increased cortical uptake extending beyond this lesion and partly overlapping with epileptogenic cortex mapped by chronic intracranial electroencephalographic monitoring. Resection of the epileptic focus resulted in long-term seizure freedom, and the nonresected portion of the PET-documented abnormality normalized. Histopathology showed reactive gliosis and inflammatory markers in the AMT-PET-positive cortex. Molecular imaging of neuroinflammation can be instrumental in the management of NORSE by guiding placement of intracranial electrodes or assessing the extent and severity of inflammation for antiinflammatory interventions.

Flumazenil is a specific, reversibly bound antagonist at benzodiazepine binding sites of gamma-aminobutyric acid A receptors; these sites can be imaged using positron emission tomography with 11C-flumazenil. We reported an exponential decline of flumazenil volume of distribution (proportional to receptor binding) of gamma-aminobutyric acid A receptors in children 2 to 17 years. Six newborns (33.3-46.7 weeks' postconception) were studied. All had experienced epileptic seizures and undergone 60-minute dynamic 11C-flumazenil-positron emission tomography imaging after injection of 0.4 mCi/kg of 11C-flumazenil. All newborns were scanned during their natural sleep. Binding potential (indicating flumazenil receptor binding) was calculated using Logan-plot analysis. Visual and quantitative analyses showed highest receptor binding in the amygdala-hippocampus region, sensory-motor cortex, thalamus, brainstem and basal ganglia, in that order. Cerebellum and most of the cerebral cortex showed relatively low binding. This is the first demonstration of gamma-aminobutyric acid A receptor binding in human neonates and is strikingly different from that in older children/adults, showing a programmed pattern of expression. The ontogeny data of flumazenil receptor binding from children may contribute to understanding regional differences in synaptic plasticity and improve rational therapeutic use of drugs acting at the gamma-aminobutyric acid A receptor in the pediatric population., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objectives: Human brain development follows a unique pattern characterized by a prolonged period of postnatal growth and reorganization, and a postnatal peak in glucose utilization. The molecular processes underlying these developmental changes are poorly characterized. The objectives of this study were to determine developmental trajectories of gene expression and to examine the evolutionary history of genes differentially expressed as a function of age., Methods: We used microarrays to determine age-related patterns of mRNA expression in human cerebral cortical samples ranging from infancy to adulthood. In contrast to previous developmental gene expression studies of human neocortex that relied on postmortem tissue, we measured mRNA expression from the nondiseased margins of surgically resected tissue. We used regression models designed to identify transcripts that followed significant linear or curvilinear functions of age and used population genetics techniques to examine the evolution of these genes., Results: We identified 40 transcripts with significant age-related trajectories in expression. Ten genes have documented roles in nervous system development and energy metabolism, others are novel candidates in brain development. Sixteen transcripts showed similar patterns of expression, characterized by decreasing expression during childhood. Comparative genomic analyses revealed that the regulatory regions of three genes have evidence of adaptive evolution in recent human evolution., Conclusions: These findings provide evidence that a subset of genes expressed in the human cerebral cortex broadly mirror developmental patterns of cortical glucose consumption. Whether there is a causal relationship between gene expression and glucose utilization remains to be determined., (Copyright © 2013 Wiley Periodicals, Inc.)

Purpose: Microstructural alterations seen in the epileptic cortex have been implicated as a cause and also result of multiple seizure activity. In the present study, we evaluated water diffusion changes at different cortical thickness fractions and in the underlying white matter of the epileptic cortex and compared them with electrographically normal cortex and also with corresponding cortical regions of healthy controls., Methods: We selected 18 children with normal magnetic resonance imaging (MRI) who underwent two-stage epilepsy surgery to control seizures of neocortical origin, and compared their MR images with those of 18 age-matched healthy controls. First, delineation of the gray-white and gray-pial intersection surfaces was performed on high-resolution volumetric T1 MR images. Using the delineated surfaces as reference, diffusion values were measured at different cortical thickness fractions and in the underlying white matter at various depths, using diffusion tensor imaging (DTI). Cortical regions representing seizure onset and electrographically normal cortex were differentiated by electrocorticography in the epilepsy patients., Key Findings: We observed different patterns of diffusion abnormalities in both the seizure onset and electrographically normal cortical regions when compared to healthy controls. In the seizure-onset regions, a marked increase in diffusivity was noted in the cortical gray matter, and this increase was most pronounced in the outer fraction of the gray matter. Similarly, increased diffusivity was noted in the white matter underlying the epileptic cortex. The electrographically normal cortex, in contrast, showed decreased diffusivity in inner and middle cortical fractions compared to the controls. The white matter underlying the electrographically normal cortex did not show any difference in diffusivity between the children with epilepsy and controls. Finally, both the cortical gray matter and the underlying white matter regions showed decreased anisotropy in epileptic as well as electrographically normal regions when compared to controls., Significance: Our results suggest specific patterns of diffusion changes in the cortical fractions and the underlying white matter of the epileptic region compared to electrographically normal and normal control regions. The abnormal increase in diffusivity of the superficial cortex might be associated with microstructural abnormalities commonly seen in layers II through IV of epileptic cortex. Such combined use of a high-resolution structural image to extract the laminar diffusion values, which are highly sensitive to microstructural alterations, could be of clinical value in localizing epileptogenic cortex., (Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.)

Among various neuroimaging techniques used for the evaluation of children with intractable epilepsy, positron emission tomography (PET) employing various PET tracers plays a very important role, especially in localizing areas of focal cortical dysplasia. This is particularly important in infants, where incomplete myelination may limit the structural information provided by MRI. In children with tuberous sclerosis, PET can differentiate between epileptogenic and nonepileptogenic tubers, previously not thought to be possible with neuroimaging. PET may reveal cortical or subcortical abnormalities in various epilepsy syndromes, such as infantile spasms and Landau-Kleffner syndrome. Various other applications of PET have included the investigation of epileptic networks, secondary epileptic foci, dual pathology, and neuroinflammation. Finally, PET can also be used to evaluate various cognitive processes and their underlying neurological substrates and can help in addressing the issue of brain plasticity and reorganization, related to epilepsy., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Neuropathological studies have demonstrated decreased Purkinje cells in cerebellar cortex and changes in the dentate nucleus of the cerebellum, the projection target for the Purkinje cells, in autistic spectrum disorders (ASD). The dentatorubrothalamic tract is formed by efferents from the dentate nucleus projecting toward the red nucleus with axon collaterals to this nucleus and continuing to innervate the ventral lateral and ventral anterior nuclei of the thalamus. In the current study, we assessed whether the dentatorubrothalamic tract is altered in ASD using Q-ball imaging (QBI). The QBI tractography was performed in 13 children with high functioning ASD (HFA), 11 children with low functioning ASD (LFA), and 14 typically developing children (TD). Regions of interest in dentate nucleus and red nucleus in both hemispheres were objectively placed to sort bilateral dorsal-rostral (DR), dorsal-caudal (DC), ventral-rostral (VR), and ventral-caudal (VC) portions of the dentatorubrothalamic pathway. Group differences in fractional anisotropy (FA), axial diffusivity, radial diffusivity, and fiber volume of individual pathways were analyzed. Significantly reduced FA was found in children with LFA and HFA, compared to the TD group in tracts originating in all four subdivisions of the right dentate nucleus. Tract-based morphometry (TBM) analysis demonstrated significant reductions of FA in caudal midbrain (p<0.0001), dorsal-caudal dentate (p=0.0013), and ventral-caudal dentate (p=0.0061) on the right in the LFA group. The FA values in TBM segments of right VR and VC pathways were significantly correlated with communication skills in the combined HFA/LFA group, while there was a significant correlation found between TBM segments of right DR pathway and daily living skills (r=0.76; p=0.004). Decreased white matter integrity in dorsal portions of the dentatorubrothalamic tract may be related to motor features in ASD, while changes in the ventral portions are related more to communication behavior.