Dysregulated Cerebrospinal Fluid Proteome of Spinocerebellar Ataxia Type 2 and its Clinical Implications.

BACKGROUND: Abnormalities in ataxin-2 associated with spinocerebellar ataxia type 2 (SCA2) may lead to widespread disruptions in the proteome. This study was performed to identify dysregulated proteome in SCA2 and to explore its clinical-radiological correlations. METHODS: Cerebrospinal fluid (CSF) samples from 21 genetically confirmed SCA2 were subjected to shotgun proteome analysis using mass spectrometry (MS) and tandem mass tag (TMT)-based multiplexing. Proteins with at least 1.5-fold change in abundance were identified. Their relative abundance was measured using parallel reaction monitoring (PRM) and correlated against disease-related factors. RESULTS: Eleven proteins were significantly upregulated in SCA2. They belonged to the family of cell adhesion molecules and granins. Their fold changes showed significant clinical, genetic, and radiological correlations. CONCLUSIONS: Significant dysregulation of CSF proteome is seen in SCA2. The dysregulated protein may have potential use in clinical evaluation of patients with SCA2. © 2024 International Parkinson and Movement Disorder Society.

Childhood adversities characterize the heterogeneity in the brain pattern of individuals during neurodevelopment.

BACKGROUND: Several factors shape the neurodevelopmental trajectory. A key area of focus in neurodevelopmental research is to estimate the factors that have maximal influence on the brain and can tip the balance from typical to atypical development. METHODS: Utilizing a dissimilarity maximization algorithm on the dynamic mode decomposition (DMD) of the resting state functional MRI data, we classified subjects from the cVEDA neurodevelopmental cohort (n = 987, aged 6-23 years) into homogeneously patterned DMD (representing typical development in 809 subjects) and heterogeneously patterned DMD (indicative of atypical development in 178 subjects). RESULTS: Significant DMD differences were primarily identified in the default mode network (DMN) regions across these groups (p < 0.05, Bonferroni corrected). While the groups were comparable in cognitive performance, the atypical group had more frequent exposure to adversities and faced higher abuses (p < 0.05, Bonferroni corrected). Upon evaluating brain-behavior correlations, we found that correlation patterns between adversity and DMN dynamic modes exhibited age-dependent variations for atypical subjects, hinting at differential utilization of the DMN due to chronic adversities. CONCLUSION: Adversities (particularly abuse) maximally influence the DMN during neurodevelopment and lead to the failure in the development of a coherent DMN system. While DMN's integrity is preserved in typical development, the age-dependent variability in atypically developing individuals is contrasting. The flexibility of DMN might be a compensatory mechanism to protect an individual in an abusive environment. However, such adaptability might deprive the neural system of the faculties of normal functioning and may incur long-term effects on the psyche.

Differential patterns of functional connectivity in tremor dominant Parkinson's disease and essential tremor plus.

Tremor dominant Parkinson's disease (TDPD) and essential tremor plus (ETP) syndrome are commonly encountered tremor dominant neurological disorders. Although the basal ganglia thalamocortical (BGTC) and cerebello thalamocortical (CTC) networks are implicated in tremorogenesis, the extent of functional connectivity alterations across disorders is uncertain. This study aims to evaluate functional connectivity of the BGTC and CTC in TDPD and ETP. Resting state functional MRI was acquired for 25 patients with TDPD, ETP and 22 healthy controls (HC). Following pre-processing and denoising, seed-to-voxel based connectivity was carried out at FDR < 0.05 using ROIs belonging to the BGTC and CTC. Fahn-Tolosa-Marin tremor rating scale (FTMRS) was correlated with the average connectivity values at FDR < 0.05. Compared to HC, TDPD showed decreased connectivity between cerebellum and pre, post central gyrus. While, ETP showed decreased connectivity between pallidum and occipital cortex, precuneus, cuneus compared to HC. In comparison to ETP, TDPD showed increased connectivity between precentral gyrus, pallidum, SNc with the default mode network (DMN), and decreased connectivity between cerebellum with superior, middle frontal gyrus was observed. Tremor severity positively correlated with connectivity between SNc and DMN in TDPD, and negatively correlated with pallidal connectivity in ETP. Pattern of BGTC, CTC involvement is differential i.e., higher connectivity of the BGTC nodes in TDPD, and higher connectivity of cerebellar nodes in ETP. The interesting observation of pallidal involvement in ETP suggests the role of BGTC in the pathogenesis of ETP, and indicated similarities in concepts of tremor genesis in TDPD and ETP.

Altered cerebellar lobular volumes correlate with clinical deficits in siblings and children with ASD: evidence from toddlers.

BACKGROUND: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by impaired social and communication skills, narrow interests, and repetitive behavior. It is known that the cerebellum plays a vital role in controlling movement and gait posture. However, recently, researchers have reported that the cerebellum may also be responsible for other functions, such as social cognition, reward, anxiety, language, and executive functions. METHODS: In this study, we ascertained volumetric differences from cerebellar lobular analysis from children with ASD, ASD siblings, and typically developing healthy controls. In this cross-sectional study, a total of 30 children were recruited, including children with ASD (N = 15; mean age = 27.67 ± 5.1 months), ASD siblings (N = 6; mean age = 17.5 ± 3.79 months), and typically developing children (N = 9; mean age = 17.67 ± 3.21 months). All the MRI data was acquired under natural sleep without using any sedative medication. We performed a correlation analysis with volumetric data and developmental and behavioral measures obtained from these children. Two-way ANOVA and Pearson correlation was performed for statistical data analysis. RESULTS: We observed intriguing findings from this study, including significantly increased gray matter lobular volumes in multiple cerebellar regions including; vermis, left and right lobule I-V, right CrusII, and right VIIb and VIIIb, respectively, in children with ASD, compared to typically developing healthy controls and ASD siblings. Multiple cerebellar lobular volumes were also significantly correlated with social quotient, cognition, language, and motor scores with children with ASD, ASD siblings, and healthy controls, respectively. CONCLUSIONS: This research finding helps us understand the neurobiology of ASD and ASD-siblings, and critically advances current knowledge about the cerebellar role in ASD. However, results need to be replicated for a larger cohort from longitudinal research study in future.

Risk clustering and psychopathology from a multi-center cohort of Indian children, adolescents, and young adults.

Developmental adversities early in life are associated with later psychopathology. Clustering may be a useful approach to group multiple diverse risks together and study their relation with psychopathology. To generate risk clusters of children, adolescents, and young adults, based on adverse environmental exposure and developmental characteristics, and to examine the association of risk clusters with manifest psychopathology. Participants (n = 8300) between 6 and 23 years were recruited from seven sites in India. We administered questionnaires to elicit history of previous exposure to adverse childhood environments, family history of psychiatric disorders in first-degree relatives, and a range of antenatal and postnatal adversities. We used these variables to generate risk clusters. Mini-International Neuropsychiatric Interview-5 was administered to evaluate manifest psychopathology. Two-step cluster analysis revealed two clusters designated as high-risk cluster (HRC) and low-risk cluster (LRC), comprising 4197 (50.5%) and 4103 (49.5%) participants, respectively. HRC had higher frequencies of family history of mental illness, antenatal and neonatal risk factors, developmental delays, history of migration, and exposure to adverse childhood experiences than LRC. There were significantly higher risks of any psychiatric disorder [Relative Risk (RR) = 2.0, 95% CI 1.8-2.3], externalizing (RR = 4.8, 95% CI 3.6-6.4) and internalizing disorders (RR = 2.6, 95% CI 2.2-2.9), and suicidality (2.3, 95% CI 1.8-2.8) in HRC. Social-environmental and developmental factors could classify Indian children, adolescents and young adults into homogeneous clusters at high or low risk of psychopathology. These biopsychosocial determinants of mental health may have practice, policy and research implications for people in low- and middle-income countries.

Localisation of eloquent cortex using magnetoencephalography and its clinical implications.

OBJECTIVES: This study aimed to localise the eloquent cortex and measure evoked field (EF) parameters using magnetoencephalography in patients with epilepsy and tumours near the eloquent cortex. METHODS: A total of 41 patients (26 with drug-refractory epilepsy and 15 with tumours), with a mean age of 33 years, were recruited. Visual evoked field (VEF), auditory evoked field (AEF), sensory evoked field (SSEF), and motor-evoked field (MEF) latencies, amplitudes, and localisation were compared with those of a control population. Subgroup analyses were performed based on lobar involvement. Evoked Field parameters on the affected side were compared with those on the opposite side. The effect of distance from the lesion on nearby and distant evoked fields was evaluated. RESULTS: AEF and VEF amplitudes and latencies were reduced bilaterally (p < 0.05). Amplitude in the ipsilateral SSEF was reduced by 29.27% and 2.16% in the AEF group compared to the contralateral side (p = 0.02). In patients with temporal lobe lesions, the SSEF amplitude was reduced bilaterally (p < 0.02), and latency was prolonged compared with controls. The MEF amplitude was reduced and latency was prolonged in patients with frontal lobe lesions (p = 0.01). EF displacement was 32%, 57%, 21%, and 16% for AEF, MEF, VEF, and SSEF respectively. Patients in the epilepsy group had distant EF abnormalities. CONCLUSIONS: EF amplitude was reduced and latency was prolonged in the involved hemisphere. Distant EF amplitudes were more affected than latencies in epilepsy. Amplitude and distance from the lesion had negative correlation for all EF. EF changes indicated eloquent cortical displacement which may not be apparent on MRI.

Novel insights into the genetic profile of hereditary spastic paraplegia in India.

The Hereditary Spastic Paraplegias (HSPs) are a group of clinically and genetically heterogeneous disorders characterized by length dependent degeneration of the corticospinal tracts. Genetic data related to HSPs are limited from India. We aimed to comprehensively analyse the phenotypic characteristics and genetic basis of a large cohort of HSP from India. Patients with HSP phenotype were evaluated for their clinical features, electrophysiological and radiological abnormalities. Genetic analyses were carried out by clinical exome sequencing (n = 52) and targeted sequencing (n = 5). The cohort comprised of 57 probands (M:F 40:17, age: 3.5-49 years). Based on the phenotype, the cohort could be categorized as 'pure' (n = 15, 26.3%) and 'complicated' (n = 42, 73.7%) HSP. Brain MRI showed thin corpus callosum (n = 10), periventricular hyperintensities (n = 20), cerebral atrophy (n = 3), cerebellar atrophy (n = 3) and diffuse atrophy (n = 4). Sixty-seven variants representing 40 genes were identified including 47 novel variants. Forty-eight patients (84.2%) had variants in genes previously implicated in HSP and other spastic paraplegia syndromes (SPG genes = 24, non-SPG genes = 24); among these 13 had variations in more than one gene and 12 patients (21.0%) had variations in genes implicated in potentially treatable/modifiable metabolic disorders (MTHFR = 8, MTRR = 1, ARG1 = 2 and ABCD1 = 1). In nine patients, no genetic variants implicated in spastic paraplegia phenotype were identified. Thus, the present study from India highlights the phenotypic complexities and spectrum of genetic variations in patients with HSP including those implicated in metabolically modifiable disorders. It sets a platform for carrying out functional studies to validate the causal role of the novel variants and variants of uncertain significance.

Efficacy of pulse intravenous methylprednisolone in epileptic encephalopathy: a randomised controlled trial.

BACKGROUND: High-level evidence for using steroids in epileptic encephalopathy (EE), other than West syndrome (WS), is lacking. This study investigated the efficacy and safety of pulse intravenous methylprednisolone (IVMP) in EE other than WS. METHODS: This is an open-label evaluator-blinded randomised controlled study. Children aged 6 months or more with EE other than WS were included. Eighty children were randomised into intervention and non-intervention groups with 40 in each group. At the first visit (T1) seizure frequency, electroencephalographic (EEG) and Vineland Social Maturity Scale (VSMS) were obtained, and antiseizure medication (ASM) were optimised. After 1 month (T2), subjects were randomised to intervention (ASM+3 months IVMP pulse) or non-intervention group (only ASM) with 40 subjects in each group. They were followed up for 4 months (T3) and assessed. RESULTS: After 4 months of follow-up, 75% of patients receiving IVMP had >50% seizure reduction versus 15.4% in control group (χ2=28.29, p<0.001) (RR 4.88, 95% CI 2.29 to 10.40), median percentage change in seizure frequency (91.41% vs 10%, p<0.001), improvement in EEG (45.5% vs 9.4%, χ2=10.866, p=0.001) and social age domain of VSMS scores (Z=-3.62, p<0.001) compared with baseline. None of the patients in the intervention group had any serious side-effects. DISCUSSION: Three-month pulse IVMP therapy showed significant improvement in seizure frequency, EEG parameters and VSMS scores, with no steroid-related serious adverse effects. It can be considered as a safe and effective add on treatment in children with EE other than WS. TRIAL REGISTRATION NUMBER: CTRI/2019/02/017807.

Network alterations in eating epilepsy during resting state and during eating using Magnetoencephalography.

OBJECTIVE: Eating epilepsy presents various imaging and electrophysiological features along with various seizure triggers. As such, network changes in eating epilepsy have not been comprehensively explored. This study was conducted to illustrate resting state network changes in eating epilepsy and to study the changes in network configurations during eating. METHODS: Magnetoencephalography recordings of nineteen patients with drug-resistant eating epilepsy were compared with healthy controls during resting state. A subgroup of nine patients and 12 controls had MEG recordings during eating. Network changes were analyzed using phase lag index across 5 frequency bands [delta, theta, alpha, beta, and gamma] using clustering coefficient (CC), betweenness centrality (BC), path length (PL), modularity (Q), and small worldness (SW). RESULTS: During the resting state, PL was decreased in patients with epilepsy in the delta, theta, and gamma band. Q was lower in patients with epilepsy in the beta and gamma bands. During eating, in patients with epilepsy, PL and SW were increased in all frequency bands, and Q was decreased in the beta band and increased in the rest of the frequency bands. Patients with mixed types of seizures showed higher PL in all bands except alpha, higher Q in all bands, and higher SW in the alpha and beta bands. Node-wise changes in CC and BC implicated changes in DMN and 'eating' networks. CONCLUSION: Reflex Eating epilepsy presents with a hyperconnected network that exacerbates during eating. The cause of seizure onset and loss of consciousness in eating epilepsy might be due to aberrant network interaction between the regions of the brain involved with eating, such as the sensorimotor cortex, lateral parietal cortex, and insula with the limbic cortex and default mode network across multiple frequency bands.

Exploring immunoreactivity of TTF-1 and AVP in hypothalamic hamartoma.

INTRODUCTION: Hypothalamic hamartoma (HH) is a rare developmental disorder presenting with gelastic seizures or precocious puberty attributed to gonadotrophin-releasing hormone expression by the hamartoma. The histogenesis of HH is uncertain, and diagnosis of HH is difficult in small biopsies due to its close resemblance to normal hypothalamic nuclei. TTF-1 and arginine vasopressin (AVP) are associated with gonadotropin-releasing hormone release. MATERIALS AND METHODS: In this study, we explored the expression pattern of TTF-1 and AVP in HH and its utility, if any, in diagnosis. We reviewed the clinical, radiologic, and histopathological features of 23 HH diagnosed over the past decade at our Institute. RESULTS: The age at presentation ranged from 11 months to 34 years with gelastic seizures (82.6%), precocious puberty (17.4%), and developmental delay (8.7%) as presenting symptoms. On imaging, all the lesions (n = 9) involved the posterior and tuberal group of hypothalamic nuclei, while 5 cases involved the anterior hypothalamus. Anatomically, the lesions involved mammillary body, arcuate and periventricular nuclei. On histopathology, 52% cases revealed nodular arrangement of small neurocytic cells separated by glial stroma. TTF-1 and AVP immunoreactivity was absent in all the cases, whereas in normal hypothalamus, AVP was expressed in periventricular nuclei. CONCLUSION: Our results suggest that immunoexpression of TTF-1 is absent in HH, particularly in those arising from the posterior hypothalamus, and this can be used in small biopsies to distinguish from a normal hypothalamus as well as from posterior pituitary tumors.

The Consortium on Vulnerability to Externalizing Disorders and Addictions (c-VEDA): an accelerated longitudinal cohort of children and adolescents in India.

The global burden of disease attributable to externalizing disorders such as alcohol misuse calls urgently for effective prevention and intervention. As our current knowledge is mainly derived from high-income countries such in Europe and North-America, it is difficult to address the wider socio-cultural, psychosocial context, and genetic factors in which risk and resilience are embedded in low- and medium-income countries. c-VEDA was established as the first and largest India-based multi-site cohort investigating the vulnerabilities for the development of externalizing disorders, addictions, and other mental health problems. Using a harmonised data collection plan coordinated with multiple cohorts in China, USA, and Europe, baseline data were collected from seven study sites between November 2016 and May 2019. Nine thousand and ten participants between the ages of 6 and 23 were assessed during this time, amongst which 1278 participants underwent more intensive assessments including MRI scans. Both waves of follow-ups have started according to the accelerated cohort structure with planned missingness design. Here, we present descriptive statistics on several key domains of assessments, and the full baseline dataset will be made accessible for researchers outside the consortium in September 2019. More details can be found on our website [cveda.org].

In vivo microstructural white matter changes in early spinocerebellar ataxia 2.

OBJECTIVE: White matter (WM) integrity of Spinocerebellar ataxia 2 (SCA2) is poorly understood, more so in the early stages of SCA2. In this study, we evaluated the microstructural integrity of the WM tracts with an emphasis on the nature of in vivo pathological involvement in early SCA2. MATERIALS AND METHODS: We evaluated the MRI images of 26 genetically proven SCA2 patients with disease duration <5 years and 24 age- and gender-matched healthy controls using tract-based spatial statistics (TBSS) to identify the WM tract changes and their clinico-genetic correlates (age at onset, duration of disease, ataxia severity and CAG repeat length) using standard methodology. RESULTS: The mean age at onset and duration of disease were 28.7 ± 8.51 years and 3.5 ± 0.69 months, respectively. The mean CAG repeat length was 42.5 ± 4.6, and the ataxia severity score was 16.1 ± 4.9. Altered DTI scalars signifying degeneration was present in the bilateral anterior thalamic radiation (ATR), corticospinal tract (CST), inferior fronto-occipital fasciculus (IFOF), superior and inferior longitudinal fasciculus (SLF and ILF), uncinate fasciculus (UF), cingulum, corpus callosum (CC), forceps major and forceps minor (corrected p < .05). DTI scalars representing demyelination was seen in the superior cerebellar peduncle (SCP) and cerebellar WM. There was a significant correlation of SARA score with axial diffusivity of the bilateral cingulum, ATR, CST, forceps minor, IFOF, ILF, SLF and SCP on the right side (corrected p < .05). CONCLUSION: Extensive WM involvement is present in early SCA2. The DTI scalars indicate degeneration and demyelination and may have clinical implications.

EEG-based P300 in mesial temporal lobe epilepsy and its correlation with cognitive functions: A case-control study.

OBJECTIVE: P300 is an event-related potential, being explored as an objective tool to assess cognition. This study aimed to investigate the characteristics of auditory and visual P300 in patients with TLE having unilateral HS using electroencephalography (EEG) and to study its correlation with cognition. METHODS: This is a cross-sectional case-control study, where P300 characteristics in thirty patients with unilateral hippocampal sclerosis with refractory epilepsy were compared with fifteen age-, gender-, and years of education-matched healthy controls (M: F-10:5, mean age-28 ±â€¯4.76 years). Among patients, 15 belonged to the right HS group (M: F-9:6, age at onset-12.92 ±â€¯10.22 years, duration of epilepsy-16.67 ±â€¯9.38 years) and 15 to the left HS group (M: F-8:7, age at onset-10.62 ±â€¯7.18 years, duration of epilepsy-15.53 ±â€¯10.14 years). All subjects underwent EEG-based auditory and visual oddball tasks and cognitive assessment. The P300 latencies (in milliseconds) as well as amplitudes (in microvolts) were predicted in EEG and were correlated with cognitive scores. Source localization of P300 was performed with the CLARA algorithm. RESULTS: The auditory P300 latencies in controls, right HS, and left HS were 323.93 ±â€¯40.28, 351.06 ±â€¯47.23, and 328.80 ±â€¯36.03, respectively (p = 0.18) and its amplitudes were 2.3040 ±â€¯1.46, 2.77 ±â€¯1.19, and 2.68 ±â€¯1.78, respectively (p = 0.48). Visual P300 latencies in controls, right HS, and left HS were 365.87 ±â€¯47.37, 359.67 ±â€¯64.45, and 376.00 ±â€¯60.06, respectively (p = 0.51) and its amplitudes were 3.93 ±â€¯2.28, 2.09 ±â€¯1.45, and 3.56 ±â€¯1.74, respectively (p = 0.014). Further, when compared to the control group the cognitive scores were lower in the patient group (p < 0.05). SIGNIFICANCE: In comparison to the controls, patients with right HS recorded lesser amplitude on visual P300 and lower scores on cognitive tests. P300 and cognitive parameters exhibited varied relationship. P300 could be a complementary objective tool to assess cognition in patients with TLE.

Posterior Quadrant Disconnection for Childhood Onset Sub-Hemispheric Posterior Head Region Epilepsy: Indications in an Indian Cohort and Outcome.

BACKGROUND: Posterior quadrant disconnection (PQD) is an under-utilized surgical technique in the management of refractory epilepsy. There is a dearth of data pertinent to post-PQD seizure outcomes. METHODS: This retrospective study analyzed patients with drug-resistant childhood-onset epilepsy who underwent PQD at our center from 2009 to 2018. The clinical, imaging, and electrophysiological data were reviewed. The seizure outcome was noted from the latest follow-up in all patients. RESULTS: Fifteen patients underwent PQD, with a mean age at onset of epilepsy of 3.3 ± 4.6 years. All patients had seizure onset in childhood with focal onset of seizures, and in addition, 5 had multiple seizure types. All cases underwent presurgical workup with MRI, video-EEG, psychometry, while PET/MEG was done if required. Engel Ia and ILAE I outcomes were considered to be favorable. The histology of the specimen showed 9 patients (60%) had gliosis, 4 (26.7%) had focal cortical dysplasia (FCD), while 1 patient had nodular heterotopia and another had polymicrogyria-pachygyria complex. Postoperative follow-up was available in 14 cases. One patient was lost to follow-up. Mean follow-up duration for the cohort was 45 + 24 months. At last, follow-up (n = 14), 66.7% (10 cases) had favorable outcome (Engel Ia). At the end of 1-year follow-up, up to 73% (n = 11) of the patients were seizure-free. Four patients developed transient hemiparesis after surgery which improved completely by 3-6 months. CONCLUSIONS: Gliosis was more common etiology requiring PQD in our series than Western series, where FCD was more common. PQD is a safe and effective surgical modality in childhood-onset epilepsy with posterior head region epileptogenic focus.

A series of five population-specific Indian brain templates and atlases spanning ages 6-60 years.

Anatomical brain templates are commonly used as references in neurological MRI studies, for bringing data into a common space for group-level statistics and coordinate reporting. Given the inherent variability in brain morphology across age and geography, it is important to have templates that are as representative as possible for both age and population. A representative-template increases the accuracy of alignment, decreases distortions as well as potential biases in final coordinate reports. In this study, we developed and validated a new set of T1w Indian brain templates (IBT) from a large number of brain scans (total n = 466) acquired across different locations and multiple 3T MRI scanners in India. A new tool in AFNI, make_template_dask.py, was created to efficiently make five age-specific IBTs (ages 6-60 years) as well as maximum probability map (MPM) atlases for each template; for each age-group's template-atlas pair, there is both a "population-average" and a "typical" version. Validation experiments on an independent Indian structural and functional-MRI dataset show the appropriateness of IBTs for spatial normalization of Indian brains. The results indicate significant structural differences when comparing the IBTs and MNI template, with these differences being maximal along the Anterior-Posterior and Inferior-Superior axes, but minimal Left-Right. For each age-group, the MPM brain atlases provide reasonably good representation of the native-space volumes in the IBT space, except in a few regions with high intersubject variability. These findings provide evidence to support the use of age and population-specific templates in human brain mapping studies.

Magnetoencephalography imaging of high frequency oscillations strengthens presurgical localization and outcome prediction.

In patients with medically refractory epilepsy, resective surgery is the mainstay of therapy to achieve seizure freedom. However, ∼20-50% of cases have intractable seizures post-surgery due to the imprecise determination of epileptogenic zone. Recent intracranial studies suggest that high frequency oscillations between 80 and 200 Hz could serve as one of the consistent epileptogenicity biomarkers for localization of the epileptogenic zone. However, these high frequency oscillations are not adopted in the clinical setting because of difficult non-invasive detection. Here, we investigated non-invasive detection and localization of high frequency oscillations and its clinical utility in accurate pre-surgical assessment and post-surgical outcome prediction. We prospectively recruited 52 patients with medically refractory epilepsy who underwent standard pre-surgical workup including magnetoencephalography (MEG) followed by resective surgery after determination of the epileptogenic zone. The post-surgical outcome was assessed after 22.14 ± 10.05 months. Interictal epileptic spikes were expertly identified, and interictal epileptic oscillations across the neural activity frequency spectrum from 8 to 200 Hz were localized using adaptive spatial filtering methods. Localization results were compared with epileptogenic zone and resected cortex for congruence assessment and validated against the clinical outcome. The concordance rate of high frequency oscillations sources (80-200 Hz) with the presumed epileptogenic zone and the resected cortex were 75.0% and 78.8%, respectively, which is superior to that of other frequency bands and standard dipole fitting methods. High frequency oscillation sources corresponding with the resected cortex, had the best sensitivity of 78.0%, positive predictive value of 100% and an accuracy of 78.84% to predict the patient's surgical outcome, among all other frequency bands. If high frequency oscillation sources were spatially congruent with resected cortex, patients had an odds ratio of 5.67 and 82.4% probability of achieving a favourable surgical outcome. If high frequency oscillations sources were discordant with the epileptogenic zone or resection area, patient has an odds ratio of 0.18 and only 14.3% probability of achieving good outcome, and mostly tended to have an unfavourable outcome (χ2 = 5.22; P = 0.02; φ = -0.317). In receiver operating characteristic curve analyses, only sources of high-frequency oscillations demonstrated the best sensitivity and specificity profile in determining the patient's surgical outcome with area under the curve of 0.76, whereas other frequency bands indicate a poor predictive performance. Our study is the first non-invasive study to detect high frequency oscillations, address the efficacy of high frequency oscillations over the different neural oscillatory frequencies, localize them and clinically validate them with the post-surgical outcome in patients with medically refractory epilepsy. The evidence presented in the current study supports the fact that HFOs might significantly improve the presurgical assessment, and post-surgical outcome prediction, where it could widely be used in a clinical setting as a non-invasive biomarker.

Synthesis, 18F-radiolabeling and apoptosis inducing studies of novel 4, 7-disubstituted coumarins.

In present study, a new series of 4, 7-disubstituted coumarin derivatives (7a-y) have been synthesized as galectin-1 targeting apoptosis inducing agents and evaluated for their in vitro cytotoxic potentials against a panel of selected human cancer cell lines namely, Brest (MCF7), Ovarian (SKOV3), Prostate (PC-3 & DU145) and normal embryonic kidney (HEK293T) cells, using MTT assay. Most of the compounds exhibited potent growth inhibitory action against the treated cancer cell lines with an IC50 range of 10-30 µM. Compound 7q exhibited a significant growth inhibition against prostate cancer (PC-3 & DU145) cell lines with an IC50 value of 7.45 ± 0.03 µM, 8.95 ± 0.17 µM respectively. Further, the target compound 7q was radiolabeled with fluorine-18 [18F] to be used as a novel PET radiotracer for imaging of tumors via targeting galectin-1, using appropriate reaction conditions in the GE Tracer-lab FX2N synthesis module. The purification of the [18F] radiolabeled compound [18F]-7q was successfully achieved with 60% ethanol. The radiochemical purity was>85% and residual solvent limits of DMF was 65 ± 3 ppm as analysed by HPLC, TLC & GC analytical methods. The apoptosis studies confirm the inhibition of cell proliferation with morphological changes like cell shrinkage, blebbing and cell wall deformation, increasing the ROS levels, and loss of mitochondrial membrane potential by Acridine orange/Ethidium bromide staining, Hoechst-33342 staining, H2DCFDA staining, annexin V-FITC/PI, and JC-1 staining methods. In flow cytometric analysis, 7q selectively arrested the sub-G1 phase of the cell cycle in a dose-dependent manner. In Gal-1 ELISA studies, compound 7q efficiently reduced the levels of Gal-1 protein in dose-dependent manner with an IC50 value of 100 µM. The binding constant (Ka) of 7q with Gal-1 was observed as 1.3 × 104 M-1 by fluorescence spectroscopy. The molecular docking studies clearly showed possible interactions and the pharmacokinetic (ADMET) properties of compound 7q with Gal-1. Hence, the novel 4, 7-disubstituted coumarins could be a potential cytotoxic and PET imaging agents via Gal-1.

Consortium on Vulnerability to Externalizing Disorders and Addictions (cVEDA): A developmental cohort study protocol.

BACKGROUND: Low and middle-income countries like India with a large youth population experience a different environment from that of high-income countries. The Consortium on Vulnerability to Externalizing Disorders and Addictions (cVEDA), based in India, aims to examine environmental influences on genomic variations, neurodevelopmental trajectories and vulnerability to psychopathology, with a focus on externalizing disorders. METHODS: cVEDA is a longitudinal cohort study, with planned missingness design for yearly follow-up. Participants have been recruited from multi-site tertiary care mental health settings, local communities, schools and colleges. 10,000 individuals between 6 and 23 years of age, of all genders, representing five geographically, ethnically, and socio-culturally distinct regions in India, and exposures to variations in early life adversity (psychosocial, nutritional, toxic exposures, slum-habitats, socio-political conflicts, urban/rural living, mental illness in the family) have been assessed using age-appropriate instruments to capture socio-demographic information, temperament, environmental exposures, parenting, psychiatric morbidity, and neuropsychological functioning. Blood/saliva and urine samples have been collected for genetic, epigenetic and toxicological (heavy metals, volatile organic compounds) studies. Structural (T1, T2, DTI) and functional (resting state fMRI) MRI brain scans have been performed on approximately 15% of the individuals. All data and biological samples are maintained in a databank and biobank, respectively. DISCUSSION: The cVEDA has established the largest neurodevelopmental database in India, comparable to global datasets, with detailed environmental characterization. This should permit identification of environmental and genetic vulnerabilities to psychopathology within a developmental framework. Neuroimaging and neuropsychological data from this study are already yielding insights on brain growth and maturation patterns.

Machine learning identifies "rsfMRI epilepsy networks" in temporal lobe epilepsy.

OBJECTIVES: Experimental models have provided compelling evidence for the existence of neural networks in temporal lobe epilepsy (TLE). To identify and validate the possible existence of resting-state "epilepsy networks," we used machine learning methods on resting-state functional magnetic resonance imaging (rsfMRI) data from 42 individuals with TLE. METHODS: Probabilistic independent component analysis (PICA) was applied to rsfMRI data from 132 subjects (42 TLE patients + 90 healthy controls) and 88 independent components (ICs) were obtained following standard procedures. Elastic net-selected features were used as inputs to support vector machine (SVM). The strengths of the top 10 networks were correlated with clinical features to obtain "rsfMRI epilepsy networks." RESULTS: SVM could classify individuals with epilepsy with 97.5% accuracy (sensitivity = 100%, specificity = 94.4%). Ten networks with the highest ranking were found in the frontal, perisylvian, cingulo-insular, posterior-quadrant, thalamic, cerebello-thalamic, and temporo-thalamic regions. The posterior-quadrant, cerebello-thalamic, thalamic, medial-visual, and perisylvian networks revealed significant correlation (r > 0.40) with age at onset of seizures, the frequency of seizures, duration of illness, and a number of anti-epileptic drugs. CONCLUSIONS: IC-derived rsfMRI networks contain epilepsy-related networks and machine learning methods are useful in identifying these networks in vivo. Increased network strength with disease progression in these "rsfMRI epilepsy networks" could reflect epileptogenesis in TLE. KEY POINTS: • ICA of resting-state fMRI carries disease-specific information about epilepsy. • Machine learning can classify these components with 97.5% accuracy. • "Subject-specific epilepsy networks" could quantify "epileptogenesis" in vivo.

Altered brain cortical maturation is found in adolescents with a family history of alcoholism.

Substance-naïve offspring from high-density alcohol use disorder (AUD) families exhibit altered subcortical brain volumes structurally and altered executive-functioning and emotion-processing functionally, compared with their peers. However, there is a dearth of literature exploring alterations of cortical thickness (CTh) in this population. T1-weighted structural brain MRI was acquired in 75 substance-naïve male offspring of treatment-seeking early onset (<25 years) AUD patients with high familial loading of AUDs (≥2 affected relatives) (FHP) and 65 age-matched substance-naïve male controls with negative family history from the community. Surface-based CTh reconstruction was done using FreeSurfer. Univariate general linear models were implemented at each vertex using SurfStat, controlling for age (linear and quadratic effects), and head size, to examine the main effect of familial AUD risk on CTh and its relationship with externalizing symptom score (ESS). A Johnson-Neyman procedure revealed that the main effect of familial AUD risk on CTh was seen during adolescence, where the FHP group had thicker cortices involving bilateral precentral gyri, left caudal middle frontal gyrus (MFG), bilateral temporo-parietal junction, left inferior-frontal gyrus and right inferior-temporal gyrus. Thicker cortices in left MFG and inferior-parietal lobule were also associated with greater ESS within both groups. More importantly, these group differences diminished with age by young adulthood. Familial AUD risk is associated with age-related differences in maturation of several higher order association cortices that are critical to ongoing development in executive function, emotion regulation and social cognition during adolescence. Early supportive intervention for a delay in alcohol initiation during this critical phase may be crucial for this at-risk population.