Connectome reorganization associated with temporal lobe pathology and its surgical resection.

Network neuroscience offers a unique framework to understand the organizational principles of the human brain. Despite recent progress, our understanding of how the brain is modulated by focal lesions remains incomplete. Resection of the temporal lobe is the most effective treatment to control seizures in pharmaco-resistant temporal lobe epilepsy (TLE), making this syndrome a powerful model to study lesional effects on network organization in young and middle-aged adults. Here, we assessed the downstream consequences of a focal lesion and its surgical resection on the brain's structural connectome, and explored how this reorganization relates to clinical variables at the individual patient level. We included adults with pharmaco-resistant TLE (n = 37) who underwent anterior temporal lobectomy between two imaging time points, as well as age- and sex-matched healthy controls who underwent comparable imaging (n = 31). Core to our analysis was the projection of high-dimensional structural connectome data-derived from diffusion MRI tractography from each subject-into lower-dimensional gradients. We then compared connectome gradients in patients relative to controls before surgery, tracked surgically-induced connectome reconfiguration from pre- to postoperative time points, and examined associations to patient-specific clinical and imaging phenotypes. Before surgery, individuals with TLE presented with marked connectome changes in bilateral temporo-parietal regions, reflecting an increased segregation of the ipsilateral anterior temporal lobe from the rest of the brain. Surgery-induced connectome reorganization was localized to this temporo-parietal subnetwork, but primarily involved postoperative integration of contralateral regions with the rest of the brain. Using a partial least-squares analysis, we uncovered a latent clinical imaging signature underlying this pre- to postoperative connectome reorganization, showing that patients who displayed postoperative integration in bilateral fronto-occipital cortices also had greater preoperative ipsilateral hippocampal atrophy, lower seizure frequency and secondarily generalized seizures. Our results bridge the effects of focal brain lesions and their surgical resections with large-scale network reorganization and interindividual clinical variability, thus offering new avenues to examine the fundamental malleability of the human brain.

Cortical morphometric vulnerability to generalised epilepsy reflects chromosome- and cell type-specific transcriptomic signatures.

AIMS: Generalised epilepsy is thought to involve distributed brain networks. However, the molecular and cellular factors that render different brain regions more vulnerable to epileptogenesis remain largely unknown. We aimed to investigate epilepsy-related morphometric similarity network (MSN) abnormalities at the macroscale level and their relationships with microscale gene expressions at the microscale level. METHODS: We compared the MSN of genetic generalised epilepsy with generalised tonic-clonic seizure patients (GGE-GTCS, n = 101) to demographically matched healthy controls (HC, n = 150). Cortical MSNs were estimated by combining seven morphometric features derived from structural magnetic resonance imaging for each individual. Regional gene expression profiles were derived from brain-wide microarray measurements provided by the Allen Human Brain Atlas. RESULTS: GGE-GTCS patients exhibited decreased regional MSNs in primary motor, prefrontal and temporal regions and increases in occipital, insular and posterior cingulate cortices, when compared with the HC. These case-control neuroimaging differences were validated using split-half analyses and were not affected by medication or drug response effects. When assessing associations with gene expression, genes associated with GGE-GTCS-related MSN differences were enriched in several biological processes, including 'synapse organisation', 'neurotransmitter transport' pathways and excitatory/inhibitory neuronal cell types. Collectively, the GGE-GTCS-related cortical vulnerabilities were associated with chromosomes 4, 5, 11 and 16 and were dispersed bottom-up at the cellular, pathway and disease levels, which contributed to epileptogenesis, suggesting diverse neurobiologically relevant enrichments in GGE-GTCS. CONCLUSIONS: By bridging the gaps between transcriptional signatures and in vivo neuroimaging, we highlighted the importance of using MSN abnormalities of the human brain in GGE-GTCS patients to investigate disease-relevant genes and biological processes.

Cortico-striato-thalamo-cerebellar networks of structural covariance underlying different epilepsy syndromes associated with generalized tonic-clonic seizures.

Generalized tonic-clonic seizures (GTCS) are the severest and most remarkable clinical expressions of human epilepsy. Cortical, subcortical, and cerebellar structures, organized with different network patterns, underlying the pathophysiological substrates of genetic associated epilepsy with GTCS (GE-GTCS) and focal epilepsy associated with focal to bilateral tonic-clonic seizure (FE-FBTS). Structural covariance analysis can delineate the features of epilepsy network related with long-term effects from seizure. Morphometric MRI data of 111 patients with GE-GTCS, 111 patients with FE-FBTS and 111 healthy controls were studied. Cortico-striato-thalao-cerebellar networks of structural covariance within the gray matter were constructed using a Winner-take-all strategy with five cortical parcellations. Comparisons of structural covariance networks were conducted using permutation tests, and module effects of disease duration on networks were conducted using GLM model. Both patient groups showed increased connectivity of structural covariance relative to controls, mainly within the striatum and thalamus, and mostly correlated with the frontal, motor, and somatosensory cortices. Connectivity changes increased as a function of epilepsy durations. FE-FBTS showed more intensive and extensive gray matter changes with volumetric loss and connectivity increment than GE-GTCS. Our findings implicated cortico-striato-thalamo-cerebellar network changes at a large temporal scale in GTCS, with FE-FBTS showing more severe network disruption. The study contributed novel imaging evidence for understanding the different epilepsy syndromes associated with generalized seizures.

Decreased functional connectivity of hippocampal subregions and methylation of the NR3C1 gene in Han Chinese adults who lost their only child.

BACKGROUND: Losing one's only child is a major traumatic life event that may lead to post-traumatic stress disorder (PTSD); however, the underlying mechanisms of its psychological consequences remain poorly understood. Here, we investigated subregional hippocampal functional connectivity (FC) networks based on resting-state functional magnetic resonance imaging and the deoxyribonucleic acid methylation of the human glucocorticoid receptor gene (NR3C1) in adults who had lost their only child. METHODS: A total of 144 Han Chinese adults who had lost their only child (51 adults with PTSD and 93 non-PTSD adults [trauma-exposed controls]) and 50 controls without trauma exposure were included in this fMRI study (age: 40-67 years). FCs between hippocampal subdivisions (four regions in each hemisphere: cornu ammonis1 [CA1], CA2, CA3, and dentate gyrus [DG]) and methylation levels of the NR3C1 gene were compared among the three groups. RESULTS: Trauma-exposed adults, regardless of PTSD diagnosis, had weaker positive FC between the left hippocampal CA1, left DG, and the posterior cingulate cortex, and weaker negative FC between the right CA1, right DG, and several frontal gyri, relative to healthy controls. Compared to non-PTSD adults, PTSD adults showed decreased negative FC between the right CA1 region and the right middle/inferior frontal gyri (MFG/IFG), and decreased negative FC between the right DG and the right superior frontal gyrus and left MFG. Both trauma-exposed groups showed lower methylation levels of the NR3C1 gene. CONCLUSIONS: Adults who had lost their only child may experience disrupted hippocampal network connectivity and NR3C1 methylation status, regardless of whether they have developed PTSD.

Functional connectome contractions in temporal lobe epilepsy: Microstructural underpinnings and predictors of surgical outcome.

OBJECTIVE: Temporal lobe epilepsy (TLE) is the most common drug-resistant epilepsy in adults. Although it is commonly related to hippocampal pathology, increasing evidence suggests structural changes beyond the mesiotemporal lobe. Functional anomalies and their link to underlying structural alterations, however, remain incompletely understood. METHODS: We studied 30 drug-resistant TLE patients and 57 healthy controls using multimodal magnetic resonance imaging (MRI) analyses. All patients had histologically verified hippocampal sclerosis and underwent postoperative imaging to outline the extent of their surgical resection. Our analysis leveraged a novel resting-state functional MRI framework that parameterizes functional connectivity distance, consolidating topological and physical properties of macroscale brain networks. Functional findings were integrated with morphological and microstructural metrics, and utility for surgical outcome prediction was assessed using machine learning techniques. RESULTS: Compared to controls, TLE patients showed connectivity distance reductions in temporoinsular and prefrontal networks, indicating topological segregation of functional networks. Testing for morphological and microstructural associations, we observed that functional connectivity contractions occurred independently from TLE-related cortical atrophy but were mediated by microstructural changes in the underlying white matter. Following our imaging study, all patients underwent an anterior temporal lobectomy as a treatment of their seizures, and postsurgical seizure outcome was determined at a follow-up at least 1 year after surgery. Using a regularized supervised machine learning paradigm with fivefold cross-validation, we demonstrated that patient-specific functional anomalies predicted postsurgical seizure outcome with 76 ± 4% accuracy, outperforming classifiers operating on clinical and structural imaging features. SIGNIFICANCE: Our findings suggest connectivity distance contractions as a macroscale substrate of TLE. Functional topological isolation may represent a microstructurally mediated network mechanism that tilts the balance toward epileptogenesis in affected networks and that may assist in patient-specific surgical prognostication.

Similarity and diversity of spontaneous brain activity in functional dyspepsia subtypes.

BACKGROUND: Functional dyspepsia (FD) subtypes may differ in terms of pathophysiology, but the underlying mechanisms remain poorly understood. PURPOSE: To explore spontaneous brain activity in two main FD subtypes, namely epigastric pain syndrome (EPS) and postprandial distress syndrome (PDS), using the amplitude of low-frequency fluctuation (ALFF). MATERIAL AND METHODS: Thirty-one FD patients (18 EPS and 13 PDS) and 22 matched healthy controls (HC) underwent resting-state functional MRI scanning. Spontaneous brain activity was evaluated by measuring the ALFF and then compared among the EPS, PDS, and HC groups with ANOVA test. Pearson correlation analysis was performed between the ALFF values and clinical indices. RESULTS: Compared to healthy controls, both EPS and PDS patients had increased ALFF in the bilateral precentral/postcentral gyri, insula, and thalami. Furthermore, only the EPS patients displayed increased ALFF in the right middle and inferior frontal gyri, and only the PDS patients showed increased ALFF in the left posterior cingulate cortex (PCC). The ALFF values in the left thalamus were positively correlated with the sleep disturbance in EPS patients, and the ALFF values in the right precentral/postcentral gyri showed a positive correlation with the symptom score in PDS patients. CONCLUSION: EPS and PDS had similarities of higher spontaneous brain activity in the primary motor/sensory areas and homeostatic-afferent network regions, and differences in the prefrontal region and PCC, providing evidence to suggest the similarity and diversity of pathophysiology in FD subtypes.

Disturbed effective connectivity patterns in an intrinsic triple network model are associated with posttraumatic stress disorder.

BACKGROUND: Disturbance of the triple network model was recently proposed to be associated with the occurrence of posttraumatic stress disorder (PTSD) symptoms. Based on resting-state dynamic causal modeling (rs-DCM) analysis, we investigated the neurobiological model at a neuronal level along with potential neuroimaging biomarkers for identifying individuals with PTSD. METHODS: We recruited survivors of a devastating typhoon including 27 PTSD patients, 33 trauma-exposed controls (TECs), and 30 healthy controls without trauma exposure. All subjects underwent resting-state functional magnetic resonance imaging. Independent components analysis was used to identify triple networks. Detailed effective connectivity patterns were estimated by rs-DCM analysis. Spearman correlation analysis was performed on aberrant DCM parameters with clinical assessment results relevant to PTSD diagnosis. We also carried out step-wise binary logistic regression and receiver operating characteristic curve (ROC) analysis to confirm the capacity of altered effective connectivity parameters to distinguish PTSD patients. RESULTS: Within the executive control network, enhanced positive connectivity from the left posterior parietal cortex to the left dorsolateral prefrontal cortex was correlated with intrusion symptoms and showed good performance (area under the receiver operating characteristic curve = 0.879) in detecting PTSD patients. In the salience network, we observed a decreased causal flow from the right amygdala to the right insula and a lower transit value for the right amygdala in PTSD patients relative to TECs. CONCLUSION: Altered effective connectivity patterns in the triple network may reflect the occurrence of PTSD symptoms, providing a potential biomarker for detecting patients. Our findings shed new insight into the neural pathophysiology of PTSD.

Pathological factors contributing to crossed cerebellar diaschisis in cerebral gliomas: a study combining perfusion, diffusion, and structural MR imaging.

PURPOSE: To investigate imaging features of crossed cerebellar diaschisis (CCD) in cerebral gliomas, and its underlying pathophysiological mechanisms. METHODS: Thirty-three pre-surgical patients with cerebral gliomas and 33 healthy controls underwent arterial spin-labeling, diffusion tensor imaging, and high-resolution T1-weighted imaging using MRI, in order to estimate cerebral blood flow (CBF), white matter integrity, and lesion volume, respectively. Asymmetry indices of CBF in the cerebellum were used for evaluating the level of CCD in the patients. These indices were correlated with clinical variables (lesion size and position, tumor histological grade, and CBF asymmetry) and diffusion tensor imaging parameters (fractional anisotropy and number of fibers in the cortico-ponto-cerebellar pathway and across the cerebral hemispheres), respectively. RESULTS: The patients showed decreased CBF in the cerebellar hemisphere contralateral to the supratentorial tumor, and increased CBF asymmetry in the cerebellum (both P < 0.05). CCD levels in high-grade gliomas were higher than those of low-grade gliomas (P < 0.05). CCD levels were negatively correlated with the size of the supratentorial lesions, and positively correlated with FA asymmetry in the cerebral fibers (both P < 0.05). CONCLUSIONS: CCD in cerebral gliomas was specifically associated with tumor histological grade, lesion size, and white matter impairments in the hemisphere ipsilateral to the tumor. The findings implicated that observing CCD might have potential for assisting grading diagnosis of cerebral gliomas.

Dynamic Network Analysis Reveals Altered Temporal Variability in Brain Regions after Stroke: A Longitudinal Resting-State fMRI Study.

Recent fMRI studies have demonstrated that resting-state functional connectivity (FC) is of nonstationarity. Temporal variability of FC reflects the dynamic nature of brain activity. Exploring temporal variability of FC offers a new approach to investigate reorganization and integration of brain networks after stroke. Here, we examined longitudinal alterations of FC temporal variability in brain networks after stroke. Nineteen stroke patients underwent resting fMRI scans across the acute stage (within-one-week after stroke), subacute stage (within-two-weeks after stroke), and early chronic stage (3-4 months after stroke). Nineteen age- and sex-matched healthy individuals were enrolled. Compared with the controls, stroke patients exhibited reduced regional temporal variability during the acute stages, which was recovered at the following two stages. Compared with the acute stage, the subacute stage exhibited increased temporal variability in the primary motor, auditory, and visual cortices. Across the three stages, the temporal variability in the ipsilesional precentral gyrus (PreCG) was increased first and then reduced. Increased temporal variability in the ipsilesional PreCG from the acute stage to the subacute stage was correlated with motor recovery from the acute stage to the early chronic stage. Our results demonstrated that temporal variability of brain network might be a potential tool for evaluating and predicting motor recovery after stroke.

Male-specific behavioral and transcriptomic changes in aging C. elegans neurons.

Aging is a complex biological process with sexually dimorphic aspects. Although cognitive aging of Caenorhabditis elegans hermaphrodites has been studied, less is known about cognitive decline in males. We found that cognitive aging has both sex-shared and sex-dimorphic characteristics, and we identified neuron-specific age-associated sex-differential targets. In addition to sex-shared neuronal aging genes, males differentially downregulate mitochondrial metabolic genes and upregulate GPCR genes with age, while the X chromosome exhibits increased gene expression in hermaphrodites and altered dosage compensation complex expression with age, indicating possible X chromosome dysregulation that contributes to sexual dimorphism in cognitive aging. Finally, the sex-differentially expressed gene hrg-7, an aspartic-type endopeptidase, regulates male cognitive aging but does not affect hermaphrodites' behaviors. These results suggest that males and hermaphrodites exhibit different age-related neuronal changes. This study will strengthen our understanding of sex-specific vulnerability and resilience and identify pathways to target with treatments that could benefit both sexes.

The neuron-specific IIS/FOXO transcriptome in aged animals reveals regulatory mechanisms of cognitive aging.

Cognitive decline is a significant health concern in our aging society. Here, we used the model organism C. elegans to investigate the impact of the IIS/FOXO pathway on age-related cognitive decline. The daf-2 Insulin/IGF-1 receptor mutant exhibits a significant extension of learning and memory span with age compared to wild-type worms, an effect that is dependent on the DAF-16 transcription factor. To identify possible mechanisms by which aging daf-2 mutants maintain learning and memory with age while wild-type worms lose neuronal function, we carried out neuron-specific transcriptomic analysis in aged animals. We observed downregulation of neuronal genes and upregulation of transcriptional regulation genes in aging wild-type neurons. By contrast, IIS/FOXO pathway mutants exhibit distinct neuronal transcriptomic alterations in response to cognitive aging, including upregulation of stress response genes and downregulation of specific insulin signaling genes. We tested the roles of significantly transcriptionally-changed genes in regulating cognitive functions, identifying novel regulators of learning and memory. In addition to other mechanistic insights, a comparison of the aged vs young daf-2 neuronal transcriptome revealed that a new set of potentially neuroprotective genes is upregulated; instead of simply mimicking a young state, daf-2 may enhance neuronal resilience to accumulation of harm and take a more active approach to combat aging. These findings suggest a potential mechanism for regulating cognitive function with age and offer insights into novel therapeutic targets for age-related cognitive decline.

Adult Single-nucleus Neuronal Transcriptomes of Insulin Signaling Mutants Reveal Regulators of Behavior and Learning.

The insulin/insulin-like signaling (IIS) pathway regulates many of C. elegans' adult functions, including learning and memory 1 . While whole-worm and tissue-specific transcriptomic analyses have identified IIS targets 2,3 , a higher-resolution single-cell approach is required to identify changes that confer neuron-specific improvements in the long-lived insulin receptor mutant, daf-2 . To understand how behaviors that are controlled by a small number of neurons change in daf-2 mutants, we used the deep resolution of single-nucleus RNA sequencing to define each neuron type's transcriptome in adult wild-type and daf-2 mutants. First, we found surprising differences between wild-type L4 larval neurons and young adult neurons in chemoreceptor expression, synaptic genes, and learning and memory genes. These Day 1 adult neuron transcriptomes allowed us to identify adult AWC-specific regulators of chemosensory function and to predict neuron-to-neuron peptide/receptor pairs. We then identified gene expression changes that correlate with daf-2's improved cognitive functions, particularly in the AWC sensory neuron that controls learning and associative memory 4 , and used behavioral assays to test their roles in cognitive function. Combining deep single-neuron transcriptomics, genetic manipulation, and behavioral analyses enabled us to identify genes that may function in a single adult neuron to control behavior, including conserved genes that function in learning and memory. One-Sentence Summary: Single-nucleus sequencing of adult wild-type and daf-2 C. elegans neurons reveals functionally relevant transcriptional changes, including regulators of chemosensation, learning, and memory.

Atypical connectome topography and signal flow in temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) is the most common pharmaco-resistant epilepsy in adults. While primarily associated with mesiotemporal pathology, recent evidence suggests that brain alterations in TLE extend beyond the paralimbic epicenter and impact macroscale function and cognitive functions, particularly memory. Using connectome-wide manifold learning and generative models of effective connectivity, we examined functional topography and directional signal flow patterns between large-scale neural circuits in TLE at rest. Studying a multisite cohort of 95 patients with TLE and 95 healthy controls, we observed atypical functional topographies in the former group, characterized by reduced differentiation between sensory and transmodal association cortices, with most marked effects in bilateral temporo-limbic and ventromedial prefrontal cortices. These findings were consistent across all study sites, present in left and right lateralized patients, and validated in a subgroup of patients with histopathological validation of mesiotemporal sclerosis and post-surgical seizure freedom. Moreover, they were replicated in an independent cohort of 30 TLE patients and 40 healthy controls. Further analyses demonstrated that reduced differentiation related to decreased functional signal flow into and out of temporolimbic cortical systems and other brain networks. Parallel analyses of structural and diffusion-weighted MRI data revealed that topographic alterations were independent of TLE-related cortical thinning but partially mediated by white matter microstructural changes that radiated away from paralimbic circuits. Finally, we found a strong association between the degree of functional alterations and behavioral markers of memory dysfunction. Our work illustrates the complex landscape of macroscale functional imbalances in TLE, which can serve as intermediate markers bridging microstructural changes and cognitive impairment.

Persistent neuroinflammation of the right insular cortex in children with juvenile idiopathic arthritis: a proton MRS study.

OBJECTIVE: The aim of this study of children with juvenile idiopathic arthritis (JIA) was to use proton magnetic resonance spectroscopy (1H-MRS) to compare the levels of five neurometabolites in the right and left insular cortexes of subjects in three groups: JIA-active, JIA-inactive, and healthy controls (HCs). METHODS: Two inflammation markers and five psychometric scores were determined. 1H-MRS was used to measure the levels of total N-acetylaspartate (NAA), total choline (Cho), myo-inositol (mI), and glutamate (Glu), and the complex of glutamine and glutamate (Glx) relative to total creatine (tCr) in the right and left insular cortexes of participants. RESULTS: Intra-group comparisons indicated that each group had higher levels of NAA/tCr, Glu/tCr, Glx/tCr, and mI/tCr in the right insula, and higher levels of Cho/tCr in the left insula. Inter-group comparisons of the right insula indicated that the JIA-active and JIA-inactive groups had higher levels of Cho/tCr than the HC group, but none of the other inter-group differences were statistically significant. The score of the Sleep Disturbance Scale for Children (SDCD) had an inverse correlation with the level of Cho/tCr in the right insular cortex of patients in the JIA-inactive group. CONCLUSIONS: Relative to the HC group, the right insular cortex of subjects in the JIA-active and the JIA-inactive groups had greater levels of Cho/tCr, suggesting increased inflammation in this region. The Cho/tCr level in the right insular cortex had an inverse correlation with SDCD score in the JIA-inactive group. Key Points • Healthy controls and JIA patients had higher levels of tNAA/tCr, Glu/tCr, Glx/tCr, and mI/tCr in the right insula, and higher levels of Cho/tCr in the left insula. • A greater level of Cho/tCr in the right insula of JIA-active and JIA-inactive patients indicated neuroinflammation in this region. • The Cho/tCr level in the right insular cortex had an inverse correlation with SDCD score in the JIA-inactive group.

Neuronal activation of Gαq EGL-30/GNAQ late in life rejuvenates cognition across species.

Loss of cognitive function with age is devastating. EGL-30/GNAQ and Gαq signaling pathways are highly conserved between C. elegans and mammals, and murine Gnaq is enriched in hippocampal neurons and declines with age. We found that activation of EGL-30 in aged worms triples memory span, and GNAQ gain of function significantly improved memory in aged mice: GNAQ(gf) in hippocampal neurons of 24-month-old mice (equivalent to 70- to 80-year-old humans) rescued age-related impairments in well-being and memory. Single-nucleus RNA sequencing revealed increased expression of genes regulating synaptic function, axon guidance, and memory in GNAQ-treated mice, and worm orthologs of these genes were required for long-term memory extension in worms. These experiments demonstrate that C. elegans is a powerful model to identify mammalian regulators of memory, leading to the identification of a pathway that improves memory in extremely old mice. To our knowledge, this is the oldest age at which an intervention has improved age-related cognitive decline.

Atypical connectome topography and signal flow in temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) is one of the most common pharmaco-resistant epilepsies in adults. While hippocampal pathology is the hallmark of this condition, emerging evidence indicates that brain alterations extend beyond the mesiotemporal epicenter and affect macroscale brain function and cognition. We studied macroscale functional reorganization in TLE, explored structural substrates, and examined cognitive associations. We investigated a multisite cohort of 95 patients with pharmaco-resistant TLE and 95 healthy controls using state-of-the-art multimodal 3T magnetic resonance imaging (MRI). We quantified macroscale functional topographic organization using connectome dimensionality reduction techniques and estimated directional functional flow using generative models of effective connectivity. We observed atypical functional topographies in patients with TLE relative to controls, manifesting as reduced functional differentiation between sensory/motor networks and transmodal systems such as the default mode network, with peak alterations in bilateral temporal and ventromedial prefrontal cortices. TLE-related topographic changes were consistent in all three included sites and reflected reductions in hierarchical flow patterns between cortical systems. Integration of parallel multimodal MRI data indicated that these findings were independent of TLE-related cortical grey matter atrophy, but mediated by microstructural alterations in the superficial white matter immediately beneath the cortex. The magnitude of functional perturbations was robustly associated with behavioral markers of memory function. Overall, this work provides converging evidence for macroscale functional imbalances, contributing microstructural alterations, and their associations with cognitive dysfunction in TLE.

Control of spinal motor neuron terminal differentiation through sustained Hoxc8 gene activity.

Spinal motor neurons (MNs) constitute cellular substrates for several movement disorders. Although their early development has received much attention, how spinal MNs become and remain terminally differentiated is poorly understood. Here, we determined the transcriptome of mouse MNs located at the brachial domain of the spinal cord at embryonic and postnatal stages. We identified novel transcription factors (TFs) and terminal differentiation genes (e.g. ion channels, neurotransmitter receptors, adhesion molecules) with continuous expression in MNs. Interestingly, genes encoding homeodomain TFs (e.g. HOX, LIM), previously implicated in early MN development, continue to be expressed postnatally, suggesting later functions. To test this idea, we inactivated Hoxc8 at successive stages of mouse MN development and observed motor deficits. Our in vivo findings suggest that Hoxc8 is not only required to establish, but also maintain expression of several MN terminal differentiation markers. Data from in vitro generated MNs indicate Hoxc8 acts directly and is sufficient to induce expression of terminal differentiation genes. Our findings dovetail recent observations in Caenorhabditis elegans MNs, pointing toward an evolutionarily conserved role for Hox in neuronal terminal differentiation.

The Brain Structural-Functional Vulnerability in Drug-Naive Children With Juvenile Idiopathic Arthritis: Insights From the Hippocampus.

Objective: Leveraging an integrative multimodal MRI paradigm to elaborate on the hippocampus-derived structural and functional changes in children and adolescents with juvenile idiopathic arthritis (JIA) and to explore potential correlations within the "joint-inflammation-brain" axis during the period of central neural system (CNS) development. Methods: Twenty-one patients with JIA all completed the multimodal MRI scanning, laboratory tests, and neuropsychological assessments; meanwhile, 23 matched controls were recruited. We then harnessed the spherical harmonics with a point distribution model (SPHARM-PDM) and the ROI-to-voxel functional connectivity (FC) to measure the hippocampal shape and hippocampo-cortical FC patterns. Correlation analysis was performed to explore the potential links in neuroimaging features with disease-related indices. Results: Compared to controls, JIA patients only presented an atrophic tendency in the posterior part of the bilateral hippocampus. The hippocampo-cortical FC revealed the between-group divergences mainly located at the pain matrix, striatum, and temporal lobe. Remarkably, the enhanced FC between the right hippocampus and postcentral cortex is positively correlated with the disability index, while the weakened FC of right anterior hippocampus with right insula and that of left posterior hippocampus with left superior temporal gyrus was inversely related to the erythrocyte sedimentation rate and anxiety status, separately. Conclusion: As with macroscopic damages, the altered functional-connectome patterns of the hippocampus in JIA patients might be more sensitive to detect the early neuropathological changes. Moreover, the functional disturbances were demonstrated associated with the physical disability, inflammation, and emotional status. These findings may enlighten us on the underlying neuropathological mechanism of CNS comorbidities in JIA.

Influence of epileptogenic region on brain structural changes in Rolandic epilepsy.

To investigate the influence of epileptogenic cortex (Rolandic areas) with executive functions in Rolandic epilepsy using structural covariance analysis of structural magnetic resonance imaging (MRI). Structural MRI data of drug-naive patients with Rolandic epilepsy (n = 70) and typically developing children as healthy controls (n = 83) were analyzed using voxel-based morphometry. Gray matter volumes in the patients were compared with those of healthy controls, and were further correlated with epilepsy duration and cognitive score of executive function, respectively. By applying Granger causal analysis to the sequenced morphometric data according to disease progression information, causal network of structural covariance was constructed to assess the causal influence of structural changes from Rolandic cortices to the regions engaging executive function in the patients. Compared with healthy controls, epilepsy patients showed increased gray matter volume in the Rolandic regions, and also the regions engaging in executive function. Covariance network analyses showed that along with disease progression, the Rolandic regions imposed positive causal influence on the regions engaging in executive function. In the patients with Rolandic epilepsy, epileptogenic regions have causal influence on the structural changes in the regions of executive function, implicating damaging effects of Rolandic epilepsy on human brain.

Evidence of persistent glial cell dysfunction in the anterior cingulate cortex of juvenile idiopathic arthritis children: a proton MRS study.

BACKGROUND: This study aims to investigate whether the neurometabolites of the anterior cingulate cortex (ACC) were distinct in patients with active and inactive juvenile idiopathic arthritis (JIA) using the proton magnetic resonance spectroscopy. METHODS: We measured the levels of total N-acetylaspartate (tNAA), choline (Cho), myo-inositol (ml), glutamate (Glu) and the complex of glutamate and glutamine (Glx) relative to total creatine (tCr) in ACC of each participant. RESULTS: Compared with the healthy controls, a significant decrease of total Cho/tCr and Glx/tCr ratio in ACC occurred in active and inactive JIA group. The tCho/Cr level was negatively associated with the serum level of ESR in active JIA patients. There was no difference in NAA/tCr ratio among the three groups, which may imply that no neuron and axonal losses occurred in either active or inactive JIA patients. CONCLUSIONS: The abnormal neurometabolites in tCho/tCr and Glx/tCr in ACC may indicate that persistent dysfunction of glial cell, while neither neuron nor axonal losses occurred in active and inactive JIA patients.