Cortical-subcortical Connectivity Research Articles

Individualized morphological covariation network aberrance associated with seizure relapse after antiseizure medication withdrawal.

This study intents to detect graphical network features associated with seizure relapse following antiseizure medication (ASM) withdrawal. Twenty-four patients remaining seizure-free (SF-group) and 22 experiencing seizure relapse (SR-group) following ASM withdrawal as well as 46 matched healthy participants (Control) were included. Individualized morphological similarity network was constructed using T1-weighted images, and graphic metrics were compared between groups. Relative to the Control, the SF-group exhibited lower local efficiency, while the SR-group displayed lower global and local efficiency and longer characteristic path length. Both patient groups displayed reduced centrality in certain subcortical and cortical nodes than the Control, with a more pronounced reduction in the SR-group. Additionally, the SR-group exhibited lower centrality of the right pallidum than the SF-group. Decreased subcortical-cortical connectivity was found in both patient groups than the Control, with a more extensive decrease in the SR-group. Furthermore, an edge connecting the right pallidum and left middle temporal gyrus exhibited decreased connectivity in the SR-group than in the SF-group. A weaker small-worldization network upon medication withdrawal, potentially underpinned by node decentralization and subcortical-cortical decoupling, may elevate the risk of seizure relapse.

Distributed associations among white matter hyperintensities and structural brain networks with fluid cognition in healthy aging

White matter hyperintensities (WMHs) are associated with age-related cognitive impairment and increased risk of Alzheimer’s disease. However, the manner by which WMHs contribute to cognitive impairment is unclear. Using a combination of predictive modeling and network neuroscience, we investigated the relationship between structural white matter connectivity and age, fluid cognition, and WMHs in 68 healthy adults (18–78 years). Consistent with previous work, WMHs were increased in older adults and exhibited a strong negative association with fluid cognition. Extending previous work, using predictive modeling, we demonstrated that age, WMHs, and fluid cognition were jointly associated with widespread alterations in structural connectivity. Subcortical-cortical connections between the thalamus/basal ganglia and frontal and parietal regions of the default mode and frontoparietal networks were most prominent. At the network level, both age and WMHs were negatively associated with network density and communicability, and positively associated with modularity. Spatially, WMHs were most prominent in arterial zones served by the middle cerebral artery and associated lenticulostriate branches that supply subcortical regions. Finally, WMHs overlapped with all major white matter tracts, most prominently in tracts that facilitate subcortical-cortical communication and are implicated in fluid cognition, including the anterior thalamic-radiations and forceps minor. Finally, results of mediation analyses suggest that whole-brain WMH load influences age-related decline in fluid cognition. Thus, across multiple levels of analysis, we showed that WMHs were increased in older adults and associated with altered structural white matter connectivity and network topology involving subcortical-cortical pathways critical for fluid cognition.

Selectively predicting the onset of ADHD, oppositional defiant disorder, and conduct disorder in early adolescence with high accuracy.

The externalizing disorders of attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and conduct disorder (CD) are common in adolescence and are strong predictors of adult psychopathology. While treatable, substantial diagnostic overlap complicates intervention planning. Understanding which factors predict the onset of each disorder and disambiguating their different predictors is of substantial translational interest. We analyzed 5,777 multimodal candidate predictors from children aged 9-10 years and their parents in the ABCD cohort to predict the future onset of ADHD, ODD, and CD at 2-year follow-up. We used deep learning optimized with an innovative AI algorithm to jointly optimize model training, perform automated feature selection, and construct individual-level predictions of illness onset and all prevailing cases at 11-12 years and examined relative predictive performance when candidate predictors were restricted to only neural metrics. Multimodal models achieved ~86-97% accuracy, 0.919-0.996 AUROC, and ~82-97% precision and recall in testing in held-out, unseen data. In neural-only models, predictive performance dropped substantially but nonetheless achieved accuracy and AUROC of ~80%. Parent aggressive and externalizing traits uniquely differentiated the onset of ODD, while structural MRI metrics in the limbic system were specific to CD. Psychosocial measures of sleep disorders, parent mental health and behavioral traits, and school performance proved valuable across all disorders. In neural-only models, structural and functional MRI metrics in subcortical regions and cortical-subcortical connectivity were emphasized. Overall, we identified a strong correlation between accuracy and final predictor importance. Deep learning optimized with AI can generate highly accurate individual-level predictions of the onset of early adolescent externalizing disorders using multimodal features. While externalizing disorders are frequently co-morbid in adolescents, certain predictors were specific to the onset of ODD or CD vs. ADHD. To our knowledge, this is the first machine learning study to predict the onset of all three major adolescent externalizing disorders with the same design and participant cohort to enable direct comparisons, analyze >200 multimodal features, and include many types of neuroimaging metrics. Future study to test our observations in external validation data will help further test the generalizability of these findings.

Screen Media Use Affects Subcortical Structures, Resting-State Functional Connectivity, and Mental Health Problems in Early Adolescence.

The association between excessive screen media use and mental health problems has attracted widespread attention. The literature to date has neglected the biological mechanisms underlying such a relationship and failed to distinguish between different types of screen media activities. A sample from the Adolescent Brain and Cognitive Development study was used in the present study to elucidate the longitudinal associations between specific types of screen media use, brain development, and diverse mental health problems. The results showed that different types of screen media use have differentiated associations with mental health problems, subcortical volume, and cortical-subcortical connectivity. Specifically, more passive media use was associated with increased rule-breaking behavior, while more video game playing was associated with increased withdrawn/depressed symptoms. In addition, more social media use was associated with a reduced volume of the hippocampus, caudate, and thalamus proper. More research is needed to examine the differential effects of screen media use on neurodevelopmental processes and mental health problems across adolescence.

Disrupted functional connectivity of the striatum in patients with diffuse axonal injury: a resting-state functional MRI study.

Diffuse axonal injury (DAI) disrupts the integrity of white matter microstructure and affects brain functional connectivity, resulting in persistent cognitive, behavioral and affective deficits. Mounting evidence suggests that altered cortical-subcortical connectivity is a major contributor to cognitive dysfunction. The functional integrity of the striatum is particularly vulnerable to DAI, but has received less attention. This study aimed to investigate the alteration patterns of striatal subdivision functional connectivity. Twenty-six patients with DAI and 27 healthy controls underwent resting-state fMRI scans on a 3.0 T scanner. We assessed striatal subdivision functional connectivity using a seed-based analysis in DAI. Furthermore, a partial correlation was used to measure its clinical association. Compared to controls, patients with DAI showed decreased functional connectivity between the right inferior ventral striatum and right inferior frontal gyrus, as well as the right inferior parietal lobule, between the left inferior ventral striatum and right inferior frontal gyrus, between the right superior ventral striatum and bilateral cerebellar posterior lobe, between the bilateral dorsal caudal putamen and right anterior cingulate gyrus, and between the right dorsal caudal putamen and right inferior parietal lobule. Moreover, decreased functional connectivity was observed between the left dorsal caudate and the right cerebellar posterior lobe, while increased functional connectivity was found between the left dorsal caudate and right inferior parietal lobule. Correlation analyses showed that regions with functional connectivity differences in the DAI group correlated with multiple clinical scoring scales, including cognition, motor function, agitated behavior, and anxiety disorders. These findings suggest that abnormalities in cortico-striatal and cerebellar-striatal functional connectivity are observed in patients with DAI, enriching our understanding of the neuropathological mechanisms of post-injury cognitive disorders and providing potential neuroimaging markers for the diagnosis and treatment of DAI.

Caudolenticular gray bridges of the brain: A magnetic resonance imaging study.

The caudolenticular (or transcapsular) gray bridges (CLGBs) connect the caudate nucleus (CN) and putamen across the internal capsule. The CLGBs function as the main efferent terminus from premotor and supplementary motor area cortex to the basal ganglia (BG). We conjectured if inherent variations in numbers and sizes of CLGBs could contribute to abnormal cortical-subcortical connectivity in Parkinson's disease (PD), a neurodegenerative disorder featuring a hindrance of BG processing. However, there are no literature accounts of normative anatomy and morphometry of CLGBs. We therefore retrospectively analyzed axial and coronal 3T fast spoiled gradient-echo magnetic resonance images (MRIs) of 34 healthy individuals for bilateral CLGBs symmetry, their numbers, dimensions of thickest and longest bridge, and axial surface areas of CN head and putamen. We calculated Evans' index (EI) to account for any brain atrophy. We statistically tested associations between sex or age and measured dependent variables, and linear correlations between all measured variables (significance at p < 0.05). Study subjects were F:M=23:11 with mean age 49.9 years. All EI's were normal (<0.3). All but three CLGBs were bilaterally symmetrical with a mean 7.4 CLGBs per side. Mean CLGBs thickness and lengths were 1.0 and 4.6 mm, respectively; CN head and putamen areas were 205and 382.0 mm2 , respectively. Females had thicker CLGBs (p=0.02) but we found no significant interactions between sex or age and measured dependent variables, and no correlations between CN head or putamen areas and CLGBs dimensions. These normative MRI dimensions of the CLGBs will help guide future studies on the possible role of CLGBs morphometry in PD predisposition.

A Postsynaptic Density Immediate Early Gene-Based Connectome Analysis of Acute NMDAR Blockade and Reversal Effect of Antipsychotic Administration.

Although antipsychotics' mechanisms of action have been thoroughly investigated, they have not been fully elucidated at the network level. We tested the hypothesis that acute pre-treatment with ketamine (KET) and administration of asenapine (ASE) would modulate the functional connectivity of brain areas relevant to the pathophysiology of schizophrenia, based on transcript levels of Homer1a, an immediate early gene encoding a key molecule of the dendritic spine. Sprague-Dawley rats (n = 20) were assigned to KET (30 mg/kg) or vehicle (VEH). Each pre-treatment group (n = 10) was randomly split into two arms, receiving ASE (0.3 mg/kg), or VEH. Homer1a mRNA levels were evaluated by in situ hybridization in 33 regions of interest (ROIs). We computed all possible pairwise Pearson correlations and generated a network for each treatment group. Acute KET challenge was associated with negative correlations between the medial portion of cingulate cortex/indusium griseum and other ROIs, not detectable in other treatment groups. KET/ASE group showed significantly higher inter-correlations between medial cingulate cortex/indusium griseum and lateral putamen, the upper lip of the primary somatosensory cortex, septal area nuclei, and claustrum, in comparison to the KET/VEH network. ASE exposure was associated with changes in subcortical-cortical connectivity and an increase in centrality measures of the cingulate cortex and lateral septal nuclei. In conclusion, ASE was found to finely regulate brain connectivity by modelling the synaptic architecture and restoring a functional pattern of interregional co-activation.

Abnormal Static and Dynamic Functional Connectivity in Left and Right Temporal Lobe Epilepsy.

ObjectiveTemporal lobe epilepsy (TLE) can be conceptualized as a network disease. However, the network characteristics in lateralization remain controversial.MethodsIn this study, resting-state functional MRI scans were acquired from 53 TLE patients [22 with left-side TLE (LTLE) and 31 with right-side TLE (RTLE)] and 37 matched healthy controls. We focused on the characteristics of static and dynamic functional connectivity, including static connectivity patterns and topological properties, as well as temporal properties of the dynamic connectivity state and the variability of the dynamic connectivity and network topological organization. Correlation analyses were conducted between abnormal static and dynamic properties and cognitive performances.ResultsThe static functional connectivity analysis presented a significantly decreased cortical-cortical connectivity pattern and increased subcortical-cortical connectivity pattern in RTLE. The global-level network in RTLE showed a significant decrease in global efficiency. The dynamic functional connectivity analysis revealed that RTLE patients exhibited aberrant connectivity states, as well as increased variability in the subcortical-cortical connectivity. The global-level network in RTLE revealed increased variance in global efficiency and local efficiency. The static or dynamic functional connectivity in LTLE did not show any significant abnormalities. The altered dynamic properties were associated with worsening cognitive performance in language and conceptual thinking by the TLE patients.ConclusionOur findings demonstrated the presence of abnormalities in the static and dynamic functional connectivity of TLE patients. RTLE patients exhibited more pronounced aberrant connectivity patterns and topological properties, which might represent a mechanism for reconfiguration of brain networks in RTLE patients. These observations extended our understanding of the pathophysiological network mechanisms of TLE.

Altered Thalamocortical Connectivity in 6-Week-Old Infants at High Familial Risk for Autism Spectrum Disorder.

Converging evidence from neuroimaging studies has revealed altered connectivity in cortical-subcortical networks in youth and adults with autism spectrum disorder (ASD). Comparatively little is known about the development of cortical-subcortical connectivity in infancy, before the emergence of overt ASD symptomatology. Here, we examined early functional and structural connectivity of thalamocortical networks in infants at high familial risk for ASD (HR) and low-risk controls (LR). Resting-state functional connectivity and diffusion tensor imaging data were acquired in 52 6-week-old infants. Functional connectivity was examined between 6 cortical seeds-prefrontal, motor, somatosensory, temporal, parietal, and occipital regions-and bilateral thalamus. We found significant thalamic-prefrontal underconnectivity, as well as thalamic-occipital and thalamic-motor overconnectivity in HR infants, relative to LR infants. Subsequent structural connectivity analyses also revealed atypical white matter integrity in thalamic-occipital tracts in HR infants, compared with LR infants. Notably, aberrant connectivity indices at 6weeks predicted atypical social development between 9 and 36months of age, as assessed with eye-tracking and diagnostic measures. These findings indicate that thalamocortical connectivity is disrupted at both the functional and structural level in HR infants as early as 6 weeks of age, providing a possible early marker of risk for ASD.

Subtle Roles of Down Syndrome Cell Adhesion Molecules in Embryonic Forebrain Development and Neuronal Migration.

Down Syndrome (DS) Cell Adhesion Molecules (DSCAMs) are transmembrane proteins of the immunoglobulin superfamily. Human DSCAM is located within the DS critical region of chromosome 21 (duplicated in Down Syndrome patients), and mutations or copy-number variations of this gene have also been associated to Fragile X syndrome, intellectual disability, autism, and bipolar disorder. The DSCAM paralogue DSCAM-like 1 (DSCAML1) maps to chromosome 11q23, implicated in the development of Jacobsen and Tourette syndromes. Additionally, a spontaneous mouse DSCAM deletion leads to motor coordination defects and seizures. Previous research has revealed roles for DSCAMs in several neurodevelopmental processes, including synaptogenesis, dendritic self-avoidance, cell sorting, axon growth and branching. However, their functions in embryonic mammalian forebrain development have yet to be completely elucidated. In this study, we revealed highly dynamic spatiotemporal patterns of Dscam and Dscaml1 expression in definite cortical layers of the embryonic mouse brain, as well as in structures and ganglionic eminence-derived neural populations within the embryonic subpallium. However, an in-depth histological analysis of cortical development, ventral forebrain morphogenesis, cortical interneuron migration, and cortical-subcortical connectivity formation processes in Dscam and Dscaml1 knockout mice (Dscamdel17 and Dscaml1GT) at several embryonic stages indicated that constitutive loss of Dscam and Dscaml1 does not affect these developmental events in a significant manner. Given that several Dscam- and Dscaml1-linked neurodevelopmental disorders are associated to chromosomal region duplication events, we furthermore sought to examine the neurodevelopmental effects of Dscam and Dscaml1 gain of function (GOF). In vitro, ex vivo, and in vivo GOF negatively impacted neural migration processes important to cortical development, and affected the morphology of maturing neurons. Overall, these findings contribute to existing knowledge on the molecular etiology of human neurodevelopmental disorders by elucidating how dosage variations of genes encoding adhesive cues can disrupt cell-cell or cell-environment interactions crucial for neuronal migration.

Disrupted Subcortical-Cortical Connections in a Phonological but Not Semantic Task in Chinese Children With Dyslexia.

Reading disability has been considered as a disconnection syndrome. Recently, an increasing number of studies have emphasized the role of subcortical regions in reading. However, the majority of research on reading disability has focused on the connections amongst brain regions within the classic cortical reading network. Here, we used graph theoretical analysis to investigate whether subcortical regions serve as hubs (regions highly connected with other brain regions) during reading both in Chinese children with reading disability (N = 15, age ranging from 11.03 to 13.08 years) and in age-matched typically developing children (N = 16, age ranging from 11.17 to 12.75 years) using a visual rhyming judgment task and a visual meaning judgment task. We found that the bilateral thalami were the unique hubs for typically developing children across both tasks. Additionally, subcortical regions (right putamen, left pallidum) were also unique hubs for typically developing children but only in the rhyming task. Among these subcortical hub regions, the left pallidum showed reduced connectivity with inferior frontal regions in the rhyming judgment but not semantic task in reading disabled compared with typically developing children. These results suggest that subcortical-cortical disconnection, which may be particularly relevant to the phonological and phonology-related learning process, may be associated with Chinese reading disability.

Afferent-efferent connectivity between auditory brainstem and cortex accounts for poorer speech-in-noise comprehension in older adults

Speech-in-noise (SIN) comprehension deficits in older adults have been linked to changes in both subcortical and cortical auditory evoked responses. However, older adults' difficulty understanding SIN may also be related to an imbalance in signal transmission (i.e., functional connectivity) between brainstem and auditory cortices. By modeling high-density scalp recordings of speech-evoked responses with sources in brainstem (BS) and bilateral primary auditory cortices (PAC), we show that beyond attenuating neural activity, hearing loss in older adults compromises the transmission of speech information between subcortical and early cortical hubs of the speech network. We found that the strength of afferent BS→PAC neural signaling (but not the reverse efferent flow; PAC→BS) varied with mild declines in hearing acuity and this “bottom-up” functional connectivity robustly predicted older adults’ performance in a SIN identification task. Connectivity was also a better predictor of SIN processing than unitary subcortical or cortical responses alone. Our neuroimaging findings suggest that in older adults (i) mild hearing loss differentially reduces neural output at several stages of auditory processing (PAC > BS), (ii) subcortical-cortical connectivity is more sensitive to peripheral hearing loss than top-down (cortical-subcortical) control, and (iii) reduced functional connectivity in afferent auditory pathways plays a significant role in SIN comprehension problems.

A three‐wave longitudinal study of subcortical–cortical resting‐state connectivity in adolescence: Testing age‐ and puberty‐related changes

Adolescence is the transitional period between childhood and adulthood, characterized by substantial changes in reward‐driven behavior. Although reward‐driven behavior is supported by subcortical‐medial prefrontal cortex (PFC) connectivity, the development of these circuits is not well understood. Particularly, while puberty has been hypothesized to accelerate organization and activation of functional neural circuits, the relationship between age, sex, pubertal change, and functional connectivity has hardly been studied. Here, we present an analysis of resting‐state functional connectivity between subcortical structures and the medial PFC, in 661 scans of 273 participants between 8 and 29 years, using a three‐wave longitudinal design. Generalized additive mixed model procedures were used to assess the effects of age, sex, and self‐reported pubertal status on connectivity between subcortical structures (nucleus accumbens, caudate, putamen, hippocampus, and amygdala) and cortical medial structures (dorsal anterior cingulate, ventral anterior cingulate, subcallosal cortex, frontal medial cortex). We observed an age‐related strengthening of subcortico‐subcortical and cortico‐cortical connectivity. Subcortical–cortical connectivity, such as, between the nucleus accumbens—frontal medial cortex, and the caudate—dorsal anterior cingulate cortex, however, weakened across age. Model‐based comparisons revealed that for specific connections pubertal development described developmental change better than chronological age. This was particularly the case for changes in subcortical–cortical connectivity and distinctively for boys and girls. Together, these findings indicate changes in functional network strengthening with pubertal development. These changes in functional connectivity may maximize the neural efficiency of interregional communication and set the stage for further inquiry of biological factors driving adolescent functional connectivity changes.

Dynamic-flip-angle ECG-gating with nuisance signal regression improves resting-state BOLD functional connectivity mapping by reducing cardiogenic noise.

To investigate an ECG-gated dynamic-flip-angle BOLD sequence with improved robustness against cardiogenic noise in resting-state fMRI. ECG-gating minimizes the cardiogenic noise but introduces T1 -dependent signal variation, which is minimized by combination of a dynamic-flip-angle technique and retrospective nuisance signal regression (NSR) using signals of white matter, CSF, and global average. The technique was studied with simulations in a wide range of T1 and B1 fields and phantom imaging with pre-programmed TR variations. Resting-state fMRI of 20 healthy subjects was acquired with non-gated BOLD (NG), ECG-gated constant-flip-angle BOLD (GCFA), ECG-gated BOLD with retrospective T1 -correction (GRC), and ECG-gated dynamic-flip-angle BOLD (GDFA), all processed by the same NSR method. GDFA was compared to alternative methods over temporal SNR (tSNR), seed-based connectivity, and whole-brain voxelwise connectivity based on intrinsic connectivity distribution (ICD). A previous large-cohort data set (N = 100) was used as a connectivity gold standard. Simulations and phantom imaging show substantial reduction of the T1 -dependent signal variation with GDFA alone, and further reduction with NSR. The resting-state study shows improved tSNR in the basal brain, comparing GDFA to NG, after both processed with NSR. Furthermore, GDFA significantly improved subcortical-subcortical and cortical-subcortical connectivity for several representative seeds and significantly improved ICD in the brainstem, thalamus, striatum, and prefrontal cortex, compared to the other 3 approaches. GDFA with NSR improves mapping of the resting-state functional connectivity of the basal-brain regions by reducing cardiogenic noise.

Thalamocortical Hyperconnectivity and Amygdala-Cortical Hypoconnectivity in Male Patients With Autism Spectrum Disorder.

Background: Analyses of resting-state functional magnetic resonance imaging (rs-fMRI) have been performed to investigate pathophysiological changes in the brains of patients with autism spectrum disorder (ASD) relative to typically developing controls (CTLs). However, the results of these previous studies, which have reported mixed patterns of hypo- and hyperconnectivity, are controversial, likely due to the small sample sizes and limited age range of included participants. Methods: To overcome this issue, we analyzed multisite neuroimaging data from a large sample (n = 626) of male participants aged between 5 and 29 years (mean age = 13 years). The rs-fMRI data were preprocessed using SPM12 and DPARSF software, and signal changes in 90 brain regions were extracted. Multiple linear regression was used to exclude the effect of site differences in connectivity data. Subcortical–cortical connectivity was computed using connectivities in the hippocampus, amygdala, caudate nucleus, putamen, pallidum, and thalamus. Eighty-eight connectivities in each structure were compared between patients with ASD and CTLs using multiple linear regression with group, age, and age × group interactions, head movement parameters, and overall connectivity as variables. Results: After correcting for multiple comparisons, patients in the ASD group exhibited significant increases in connectivity between the thalamus and 19 cortical regions distributed throughout the fronto-parietal lobes, including the temporo-parietal junction and posterior cingulate cortices. In addition, there were significant decreases in connectivity between the amygdala and six cortical regions. The mean effect size of hyperconnectivity (0.25) was greater than that for hypoconnectivity (0.08). No other subcortical structures showed significant group differences. A group-by-age interaction was observed for connectivity between the thalamus and motor-somatosensory areas. Conclusions: These results demonstrate that pathophysiological changes associated with ASD are more likely related to thalamocortical hyperconnectivity than to amygdala-cortical hypoconnectivity. Future studies should examine full sets of clinical and behavioral symptoms in combination with functional connectivity to explore possible biomarkers for ASD.

Altered Functional Connectivity of Amygdala with the Fronto-Limbic-Striatal Circuit in Temporal Lobe Lesion as a Proposed Mechanism for Poststroke Depression.

Poststroke depression (PSD) is an important complication that affects stroke rehabilitation. Abnormal cortical-subcortical connectivity may be associated with the development of PSD. However, few studies have focused on the emotional network of PSD in the temporal lobe lesions. The aim of is study was to investigate amygdala-cortical functional connectivity (FC) in the temporal lobe in individuals with and without PSD. Twenty-three patients with PSD and 21 stroke patients without depression were recruited to undergo functional magnetic imaging scanning. In stroke patients with depression, the left amygdala had increased FC with the bilateral precuneus and right orbital frontal lobe but decreased FC with the right putamen. The right amygdala had increased FC with the right temporal pole, right rectus gyrus, and left orbital frontal lobe but decreased FC with the right primary sensory area (S1). Correlative analyses revealed that the amygdala's FCs with the right orbital frontal lobe, right insular cortex, and right cingulate cortex were correlated with the Hamilton Depression Rating Scale score. The current study identified mood affected through the fronto-limbic-striatal circuit in PSD. Hyperconnectivity between the amygdala, default mode network, and salience network might be related to depressive symptoms, which may provide novel insight into the underlying neuropathologic mechanisms of PSD in temporal lobe lesions.

Neural cell adhesion molecule Negr1 deficiency in mouse results in structural brain endophenotypes and behavioral deviations related to psychiatric disorders

Neuronal growth regulator 1 (NEGR1) belongs to the immunoglobulin (IgLON) superfamily of cell adhesion molecules involved in cortical layering. Recent functional and genomic studies implicate the role of NEGR1 in a wide spectrum of psychiatric disorders, such as major depression, schizophrenia and autism. Here, we investigated the impact of Negr1 deficiency on brain morphology, neuronal properties and social behavior of mice. In situ hybridization shows Negr1 expression in the brain nuclei which are central modulators of cortical-subcortical connectivity such as the island of Calleja and the reticular nucleus of thalamus. Brain morphological analysis revealed neuroanatomical abnormalities in Negr1−/− mice, including enlargement of ventricles and decrease in the volume of the whole brain, corpus callosum, globus pallidus and hippocampus. Furthermore, decreased number of parvalbumin-positive inhibitory interneurons was evident in Negr1−/− hippocampi. Behaviorally, Negr1−/− mice displayed hyperactivity in social interactions and impairments in social hierarchy. Finally, Negr1 deficiency resulted in disrupted neurite sprouting during neuritogenesis. Our results provide evidence that NEGR1 is required for balancing the ratio of excitatory/inhibitory neurons and proper formation of brain structures, which is prerequisite for adaptive behavioral profiles. Therefore, Negr1−/− mice have a high potential to provide new insights into the neural mechanisms of neuropsychiatric disorders.

Anatomical distance affects cortical-subcortical connectivity in first-episode, drug-naive somatization disorder

BackgroundBrain structural and functional alterations in the cortical-subcortical circuits have been observed in somatization disorder (SD). However, whether and how anatomical distance affects the cortical-subcortical connectivity in SD remain unclear. This study aims to examine whether anatomical distance affects the cortical-subcortical in first-episode, drug-naive SD. MethodsTwenty-five first-episode, drug-naive patients with SD and twenty-eight healthy controls were recruited for a resting-state scan. Regional functional connectivity strength (FCS) was calculated for each voxel in the brain, which was further divided into short- and long-range FCSs. Correlation analyses were conducted between abnormal FCS and clinical/cognitive variables in the patients. ResultsCompared with the controls, the patients showed increased short-range positive FCS (spFCS) in the right superior frontal gyrus (SFG) and decreased spFCS in the left pallidum, and increased long-range positive FCS (lpFCS) in the left middle frontal gyrus and right inferior temporal gyrus (ITG). Positive correlations were observed between the spFCS values in the right SFG and Eysenck Personality Questionnaire psychoticism scores (r=0.441, p=0.027, uncorrected) and between the lpFCS values in the right ITG and scores of digit symbol-coding of Wechsler Adult Intelligence Scale (r=0.416, p=0.039, uncorrected) in the patients ConclusionsThe patients exhibited increased spFCS/lpFCS in the cortical regions and decreased spFCS in the subcortical regions. The left pallidum is first reported here to show decreased spFCS in SD. The present results suggest that abnormal cortical-subcortical circuits may play an important role in SD neurobiology.

Abnormal sensorimotor integration correlates with cognitive profile in vascular parkinsonism

IntroductionVascular parkinsonism is a syndrome that develops as a result of cerebrovascular disease. Although several studies on clinical features and neuroimaging have been published, little is known about its pathophysiology. Our aim was to study sensorimotor integration using transcranial magnetic stimulation in this condition and to correlate the potential abnormalities in this technique with the cognitive profile of these patients. MethodsWe studied 11 vascular parkinsonism patients and 13 controls. We applied transcranial magnetic stimulation to investigate sensorimotor inhibition and sensorimotor plasticity and we performed extensive neuropsychological examinations. ResultsVascular parkinsonism patients showed reduced short latency afferent inhibition and lack of long term potentiation-like plasticity after paired associative stimulation protocol. Correlations were found in these patients between short latency afferent inhibition and sensorimotor plasticity with verbal memory tests. ConclusionsOur neurophysiological findings suggest deficiencies of a variety of receptors and signalling systems in vascular parkinsonism, including cortical glutamatergic and cholinergic synapses, which may be a consequence of the disruption of subcortical-cortical connections caused by vascular lesions. The correlations found suggest that these neurotransmitter systems may be involved in the processes of cognitive decline in these patients.

Changes in cortico-subcortical and subcortico-subcortical connectivity impact cognitive control to emotional cues across development

The capacity to suppress inappropriate thoughts, emotions and actions in favor of appropriate ones shows marked changes throughout childhood and adolescence. Most research has focused on pre-frontal circuit development to explain these changes. Yet, subcortical circuitry involving the amygdala and ventral striatum (VS) has been shown to modulate cue-triggered motivated behaviors in rodents. The nature of the interaction between these two subcortical regions in humans is less well understood, especially during development when there appears to be heightened sensitivity to emotional cues. In the current study, we tested how task-based cortico-subcortical and subcortico-subcortical functional connectivity in 155 participants ages from 5 to 32 impacted cognitive control performance on an emotional go/nogo task. Functional connectivity between the amygdala and VS was inversely correlated with age and predicted cognitive control to emotional cues, when controlling for performance to neutral cues. In contrast, increased medial pre-frontal-amygdala connectivity was associated with better cognitive control to emotional cues and this cortical-subcortical connectivity mediated the association between amygdala-VS connectivity and emotional cognitive control. These findings suggest a dissociation in how subcortical-subcortical and cortical-subcortical connectivity impact cognitive control across development.