Anterior Cerebellum Research Articles

Altered local and matrix functional connectivity in depressed essential tremor patients

BackgroundDepression in essential tremor (ET) has been constantly studied and reported, while the associated brain activity changes remain unclear. Recently, regional homogeneity (ReHo), a voxel-wise local functional connectivity (FC) analysis of resting-state functional magnetic resonance imaging, has provided a promising way to observe spontaneous brain activity.MethodsLocal FC analyses were performed in forty-one depressed ET patients, 49 non-depressed ET patients and 43 healthy controls (HCs), and then matrix FC and clinical depression severity correlation analyses were further performed to reveal spontaneous neural activity changes in depressed ET patients.ResultsCompared with the non-depressed ET patients, the depressed ET patients showed decreased ReHo in the bilateral cerebellum lobules IX, and increased ReHo in the bilateral anterior cingulate cortices and middle prefrontal cortices. Twenty-five significant changes of ReHo clusters were observed in the depressed ET patients compared with the HCs, and matrix FC analysis further revealed that inter-ROI FC differences were also observed in the frontal-cerebellar-anterior cingulate cortex pathway. Correlation analyses showed that clinical depression severity was positively correlated with the inter-ROI FC values between the anterior cingulate cortex and bilateral middle prefrontal cortices and was negatively correlated with the inter-ROI FC values of the anterior cingulate cortex and bilateral cerebellum lobules IX.ConclusionOur findings revealed local and inter-ROI FC differences in frontal-cerebellar-anterior cingulate cortex circuits in depressed ET patients, and among these regions, the cerebellum lobules IX, middle prefrontal cortices and anterior cingulate cortices could function as pathogenic structures underlying depression in ET patients.

Hyperactivation of Posterior Default Mode Network During Self-Referential Processing in Children at Familial High-Risk for Psychosis.

Patients with schizophrenia spectrum disorders show disturbances in self-referential processing and associated neural circuits including the default mode network (DMN). These disturbances may precede the onset of psychosis and may underlie early social and emotional problems. In this study, we examined self-referential processing in a group of children (7–12 years) at familial high risk (FHR) for psychosis (N = 17), compared to an age and sex-matched group of healthy control (HC) children (N = 20). The participants were presented with a list of adjectives and asked to indicate whether or not the adjectives described them (self-reference condition) and whether the adjectives described a good or bad trait (semantic condition). Three participants were excluded due to chance-level performance on the semantic task, leaving N = 15 FHR and N = 19 HC for final analysis. Functional MRI (fMRI) was used to measure brain activation during self-referential vs. semantic processing. Internalizing and externalizing problems were assessed with the Child Behavior Checklist (CBCL). Evaluating main effects of task (self > semantic) showed activation of medial prefrontal cortex in HC and precuneus/posterior cingulate cortex (PCC) in FHR. Group-comparison yielded significant results for the FHR > HC contrast, showing two clusters of hyperactivation in precuneus/ PCC (p = 0.004) and anterior cerebellum / temporo-occipital cortex (p = 0.009). Greater precuneus/PCC activation was found to correlate with greater CBCL internalizing (r = 0.60, p = 0.032) and total (r = 0.69, p = 0.009) problems. In all, this study shows hyperactivity of posterior DMN during self-referential processing in pre-adolescent FHR children. This finding posits DMN-related disturbances in self-processing as a developmental brain abnormality associated with familial risk factors that predates not just psychosis, but also the prodromal stage. Moreover, our results suggest that early disturbances in self-referential processing may be related to internalizing problems in at-risk children.

Associations Between Brain Gray Matter Volumes and Adipose Tissue Metabolism in Healthy Adults.

Gray matter (GM) volume in different brain loci has been shown to vary in obesity and diabetes, and elevated fasting plasma nonesterified fatty acid (NEFA) levels have been suggested as one potential mechanism. The hypothesis presented in this study is that brown adipose tissue (BAT) activity may correlate with GM volume in areas negatively associated with obesity and diabetes. A total of 36 healthy patients (M/F: 12/24, age 39.7 ± 9.4 years, BMI 27.5 ± 5.6 kg/m2 ) were imaged with positron emission tomography using fatty acid analog [18 F]FTHA to measure NEFA uptake and with [15 O]H2 O to measure perfusion during cold exposure, at room temperature during fasting, or during a postprandial state. A 2-hour hyperinsulinemic euglycemic clamp was performed to measure whole-body insulin sensitivity (M value, mean 7.6 ± 3.9 mg/kg/min). T1-weighted magnetic resonance imaging at 1.5 T was performed on all patients. BAT NEFA uptake was associated directly with GM volume in anterior cerebellum and occipital lobe (P ≤ 0.04) when adjusted for age, gender, and intra-abdominal fat volume and with anterior cerebellum, limbic lobe, and temporal lobe GM volumes when adjusted for M value. BAT NEFA metabolism may participate in protection from cognitive degeneration associated with cardiometabolic risk factors, such as central obesity and insulin resistance. Potential causal relationships between BAT activity and GM volumes remain to be examined.

Use of Functional MRI to Assess Effects of Deep Brain Stimulation Frequency Changes on Brain Activation in Parkinson Disease.

Models have been developed for predicting ideal contact and amplitude for subthalamic nucleus (STN) deep brain stimulation (DBS) for Parkinson disease (PD). Pulse-width is generally varied to modulate the size of the energy field produced. Effects of varying frequency in humans have not been systematically evaluated. To examine how altered frequencies affect blood oxygen level-dependent activation in PD. PD subjects with optimized DBS programming underwent functional magnetic resonance imaging (fMRI). Frequency was altered and fMRI scans/Unified Parkinson Disease Rating Scale motor subunit (UPDRS-III) scores were obtained. Analysis using DBS-OFF data was used to determine which regions were activated during DBS-ON. Peak activity utilizing T-values was obtained and compared. At clinically optimized settings (n=14 subjects), thalamic, globus pallidum externa (GPe), and posterior cerebellum activation were present. Activation levels significantly decreased in the thalamus, anterior cerebellum, and the GPe when frequency was decreased (P <.001). Primary somatosensory cortex activation levels significantly decreased when frequency was increased by 30Hz, but not 60Hz. Sex, age, disease/DBS duration, and bilaterality did not significantly affect the data. Retrospective analysis of fMRI activation patterns predicted optimal frequency in 11/14 subjects. We show the first data with fMRI of STN DBS-ON while synchronizing cycling with magnetic resonance scanning. At clinically optimized settings, an fMRI signature of thalamic, GPe, and posterior cerebellum activation was seen. Reducing frequency significantly decreased thalamic, GPe, and anterior cerebellum activation. Current standard-of-care programming can take up to 6 mo using UPDRS-III testing alone. We provide preliminary evidence that using fMRI signature of frequency may have clinical utility and feasibility.

Effects of aging on brain networks during swallowing: general linear model and independent component analyses

Swallowing disorders occur more frequently in older adults. However, the effects of the aging process on neural activation when swallowing are unclear. We aimed to identify neural regions activated during swallowing and evaluate changes in neural activation and neural networks with aging. Using a general linear model (GLM) and independent component (IC) analyses, blood oxygen level-dependent (BOLD) signals were observed in the lateral precentral gyrus, postcentral gyrus, anterior insular cortices, supramarginal gyri, and medial frontal gyrus during swallowing. The right thalamus and anterior cingulate gyri were found to be active areas by GLM and IC analyses, respectively. In the correlational analyses, age was negatively correlated with BOLD signals of the lateral precentral gyri, postcentral gyri, and insular cortices in swallowing tasks. Additionally, correlation analyses between ICs of all participants and age revealed negative correlations in the right supramarginal gyrus, both anterior cingulate cortices, putamen, and cerebellum. In the network analysis, the BOLD signal positively correlated with age in the default mode network (DMN), and was negatively correlated in the lateral precentral gyri, postcentral gyri, and insular cortices. The amplitude of low-frequency fluctuations was significantly decreased in the DMN and increased in swallowing-related areas during swallowing tasks. These results suggest that aging has negative effects on the activation of swallowing-related regions and task-induced deactivation of the DMN. These changes may be used to detect early functional decline during swallowing.

Sarcomatoid Carcinoma of the Transverse Colon With Extremely Aggressive Brain Metastases

Introduction Sarcomatoid carcinoma (SC) is a rare subtype of malignant neoplasm with a poor prognosis that involves both carcinomatous and sarcomatous components. Although it may develop in various organs, SC in the large intestine has rarely been reported. It is not rare for patients with SC to have distant metastasis, reflecting its highly aggressive oncologic features, but cases with brain metastasis on initial visit are rare. In this report, we described a case of SC in the transverse colon with brain metastases whose initial symptom was neurological disorder, and reviewed 31 reported cases of SC. Case presentation A 70-year-old man was admitted to our hospital with the chief complaints of gait disorder and severe dizziness. Head magnetic resonance imaging revealed tumor masses in the anterior lobe and cerebellum. A large tumor in the transverse colon was detected by colonoscopy and abdominal enhanced computed tomography (CT), and was diagnosed as undifferentiated adenocarcinoma by histology. Laparoscopic extended right hemicolectomy was performed to remove the obstruction, and the resected specimens revealed an invasive tumor consisting of a mixture of carcinomatous and sarcomatous components. According to the immunopathological study, the patient was diagnosed with SC. The clinical course was extremely aggressive, and the patient died on the 28th postoperative day because of disease progression. Conclusion To the best of our knowledge, this is the first case of SC in the transverse colon with a neurological disorder derived from brain metastases. This experience may contribute to the guidance regarding proper therapeutic options for SC.

Aberrant Hippocampal Network Connectivity Is Associated With Neurocognitive Dysfunction in Patients With Moderate and Severe Obstructive Sleep Apnea.

Objectives: This work aims to explore the changes of functional connectivity (FC) within the hippocampus network in patients with moderate and severe obstructive sleep apnea (OSA) and its correlation with neurocognitive dysfunction to explore the potential neurophysiological mechanism.Methods: A total of 32 treatment-naïve patients with moderate or severe OSA and 26 healthy controls (HCs), matched in age, gender, and education, underwent the evaluations of Epworth Sleep Scale, neurocognitive function, full-night polysomnography, and resting-state functional magnetic resonance imaging. The FC map of the hippocampus to other brain areas was compared among 15 OSA patients and 15 HCs with little head motion. Finally, the correlation between hippocampus FC strength and respiratory sleep parameters and neurocognitive assessments was analyzed.Results: Compared with HCs, the right hippocampus showed a significantly decreased FC with the bilateral insular lobe, right thalamus, and right anterior cingulate gyrus (ACG) and an increased FC with the right superior and middle temporal gyrus, left posterior cingulate gyrus, and left angular gyrus in the patients with OSA. The left hippocampus presented a significantly decreased FC with the left anterior cerebellum in patients with OSA. In addition, the aberrant right hippocampal FC with the right ACG was significantly correlated with disease severity and disrupted sleep architecture in the OSA group. Furthermore, after adjusting the related confounding factors, the FC strength between the right hippocampus, right insular lobe, and right thalamus was positively associated with the scores of Stroop Color–Word Test (SCWT) or Hopkins Verbal Learning Test—Revised (HVLT-R), while the FC between the right hippocampus and the right middle temporal gyrus was negatively correlated with the scores of HVLT-R. The right hippocampus FC with right superior temporal gyrus, left angular gyrus, and ACG were all negatively related to the scores of the symbol coding test (r = −0.642, p = 0.045; r = −0.638, p = 0.047; r = −0.753, p = 0.012), respectively. The FC between the left hippocampal and the left anterior cerebellar lobe showed a positive relationship with the scores of HVLT-R (r = 0.757, p = 0.011) and CPT-3D (r = −0.801, p = 0.005).Conclusion: The hippocampus presented abnormal FC with the cerebral and cerebellar regions extensively in OSA, and the correlation between abnormal hippocampal network FC and neurocognitive dysfunction in OSA suggests a promising insight to explore the potential biomarker and pathophysiologic mechanism of neurocognitive dysfunction of OSA.

NREM sleep stages specifically alter dynamical integration of large-scale brain networks.

SummaryFunctional dissociations in the brain observed during non-rapid eye movement (NREM) sleep have been associated with reduced information integration and impaired consciousness that accompany increasing sleep depth. Here, we explored the dynamical properties of large-scale functional brain networks derived from transient brain activity using functional magnetic resonance imaging. Spatial brain maps generally display significant modifications in terms of their tendency to occur across wakefulness and NREM sleep. Unexpectedly, almost all networks predominated in activity during NREM stage 2 before an abrupt loss of activity is observed in NREM stage 3. Yet, functional connectivity and mutual dependencies between these networks progressively broke down with increasing sleep depth. Thus, the efficiency of information transfer during NREM stage 2 is low despite the high attempt to communicate. Critically, our approach provides relevant data for evaluating functional brain network integrity and our findings robustly support a significant advance in our neural models of human sleep and consciousness.

Exploring the effect of type 2 diabetes on brain structure and cerebral perfusion in patients with early Alzheimer’s disease

AbstractBackgroundPast research has shown that Alzheimer’s Disease (AD) can have a significant detrimental effect on the cerebrovascular system. Previous work has also indicated that type 2 diabetes mellitus (T2DM), along with being a risk factor for AD, shares certain similarities with AD in terms of the mechanisms affecting the cerebrovascular system. Hence, comorbid T2DM in AD could cause additional cardiovascular burden that may cause further damage to brain structure and function than that seen in AD.MethodThe current study compares 54 patients across the AD spectrum with and without T2DM (with 27 patients in each group). Voxel based morphometry was used to determine volumetric differences in grey matter using T1‐weighted magnetic resonance images. To assess whether these volumetric differences were associated with a reduction in cerebral blood flow, arterial spin labelling (ASL) was used to measure cerebral perfusion.ResultsPatients with T2DM had smaller grey matter volume compared to patients without T2DM in the anterior caudate nucleus and posterior cerebellum in the right hemisphere. Perfusion deficits mirrored the regional volumetric abnormalities, along with additional hypoperfusion observed in the right parahippocampal gyrus. These differences were also associated with deficits in cognitive function.ConclusionsMicrovascular and macrovascular complications seen in the AD patients with comorbid T2DM could therefore contribute toward the negative effects exerted on cerebral perfusion that could potentially contribute toward the structural deficits observed. Furthermore, the right lateralised effects seen in the present study could arise due to the characteristic trajectory of the arteries supplying the brain. With the increasing prevalence of cardiovascular risk factors such as T2DM combined with the rise in numbers of people living with AD, the additional cardiovascular burden caused by such risk factors may be a crucial tipping point toward conversion to AD dementia from prodromal stages. This is one of the first studies to show that the additional cerebrovascular burden resulting from comorbid T2DM in AD can result in worse structural and perfusion deficits using multi‐modal neuroimaging and that these deficits can be associated with clinical presentations.

The handwriting brain in middle childhood.

While the brain network supporting handwriting has previously been defined in adults, its organization in children has never been investigated. We compared the handwriting network of 23 adults and 42 children (8- to 11-year-old). Participants were instructed to write the alphabet, the days of the week, and to draw loops while being scanned. The handwriting network previously described in adults (five key regions: left dorsal premotor cortex, superior parietal lobule (SPL), fusiform and inferior frontal gyri, and right cerebellum) was also strongly activated in children. The right precentral gyrus and the right anterior cerebellum were more strongly activated in adults than in children, while the left fusiform gyrus (FuG) was more strongly activated in children than in adults. Finally, we found that, contrary to adults, children recruited prefrontal regions to complete the writing task. This constitutes the first comparative investigation of the neural correlates of writing in children and adults. Our results suggest that the network supporting handwriting is already established in middle childhood. They also highlight the major role of prefrontal regions in learning this complex skill and the importance of right precentral regions and cerebellum in the performance of automated handwriting.

Structural Brain Imaging Phenotypes of Mild Cognitive Impairment (MCI) and Alzheimer's Disease (AD) Found by Hierarchical Clustering.

A hierarchical clustering algorithm was applied to magnetic resonance images (MRI) of a cohort of 751 subjects having a mild cognitive impairment (MCI), 282 subjects having received Alzheimer's disease (AD) diagnosis, and 428 normal controls (NC). MRIs were preprocessed to gray matter density maps and registered to a stereotactic space. By first rendering the gray matter density maps comparable by regressing out age, gender, and years of education, and then performing the hierarchical clustering, we found clusters displaying structural features of typical AD, cortically-driven atypical AD, limbic-predominant AD, and early-onset AD (EOAD). Among these clusters, EOAD subjects displayed marked cortical gray matter atrophy and atrophy of the precuneus. Furthermore, EOAD subjects had the highest progression rates as measured with ADAS slopes during the longitudinal follow-up of 36 months. Striking heterogeneities in brain atrophy patterns were observed with MCI subjects. We found clusters of stable MCI, clusters of diffuse brain atrophy with fast progression, and MCI subjects displaying similar atrophy patterns as the typical or atypical AD subjects. Bidirectional differences in structural phenotypes were found with MCI subjects involving the anterior cerebellum and the frontal cortex. The diversity of the MCI subjects suggests that the structural phenotypes of MCI subjects would deserve a more detailed investigation with a significantly larger cohort. Our results demonstrate that the hierarchical agglomerative clustering method is an efficient tool in dividing a cohort of subjects with gray matter atrophy into coherent clusters manifesting different structural phenotypes.

Evidence for an effector-independent action system from people born without hands

Many parts of the visuomotor system guide daily hand actions, like reaching for and grasping objects. Do these regions depend exclusively on the hand as a specific body part whose movement they guide, or are they organized for the reaching task per se, for any body part used as an effector? To address this question, we conducted a neuroimaging study with people born without upper limbs-individuals with dysplasia-who use the feet to act, as they and typically developed controls performed reaching and grasping actions with their dominant effector. Individuals with dysplasia have no prior experience acting with hands, allowing us to control for hand motor imagery when acting with another effector (i.e., foot). Primary sensorimotor cortices showed selectivity for the hand in controls and foot in individuals with dysplasia. Importantly, we found a preference based on action type (reaching/grasping) regardless of the effector used in the association sensorimotor cortex, in the left intraparietal sulcus and dorsal premotor cortex, as well as in the basal ganglia and anterior cerebellum. These areas also showed differential response patterns between action types for both groups. Intermediate areas along a posterior-anterior gradient in the left dorsal premotor cortex gradually transitioned from selectivity based on the body part to selectivity based on the action type. These findings indicate that some visuomotor association areas are organized based on abstract action functions independent of specific sensorimotor parameters, paralleling sensory feature-independence in visual and auditory cortices in people born blind and deaf. Together, they suggest association cortices across action and perception may support specific computations, abstracted from low-level sensorimotor elements.

Grey matter abnormalities in first-episode mania: A systematic review and meta-analysis of voxel-based morphometry studies.

It has been proposed that different stages of bipolar disorder may be underpinned by distinct neurobiological substrates. However, structural neuroimaging studies in early stages of the illness are limited by small sample sizes yielding inconsistent findings. The purpose of this systematic review and meta-analysis, therefore, was to identify regional grey matter volume (GMV) changes that are consistently associated with first episode of mania (FEM). Following PRISMA guidelines, we conducted a systematic search of the literature to identify Voxel-Based Morphometry (VBM) studies in FEM patients compared with healthy individuals. We then conducted a voxel-wise meta-analysis using Seed-based d-Mapping technique. Finally, we performed univariate meta-regression analyses to explore the potential effects of moderator variables including age, gender, and percentage of lithium users on GMV alterations. We identified 15 VBM studies and included 12 studies in the meta-analysis. Four studies found no regional differences in GM volumes while other 11 studies reported volume changes in frontal and temporal regions as well as anterior cingulate cortex (ACC), cerebellum and basal ganglia. The meta-analysis revealed a single cluster of GMV reduction in bilateral pregenual ACC in patients with FEM compared to healthy individuals (P<.001). The Egger's test showed no evidence of publication bias at peak voxel level (P=.447). Meta-regression analyses revealed no significant effects of moderators evaluated. Structural brain changes are evident in the early stages of bipolar disorder. GMV reduction in bilateral pregenual ACC is the most consistent finding in VBM studies of FEM.

Altered Capicua expression drives regional Purkinje neuron vulnerability through ion channel gene dysregulation in spinocerebellar ataxia type 1.

Selective neuronal vulnerability in neurodegenerative disease is poorly understood. Using the ATXN1[82Q] model of spinocerebellar ataxia type 1 (SCA1), we explored the hypothesis that regional differences in Purkinje neuron degeneration could provide novel insights into selective vulnerability. ATXN1[82Q] Purkinje neurons from the anterior cerebellum were found to degenerate earlier than those from the nodular zone, and this early degeneration was associated with selective dysregulation of ion channel transcripts and altered Purkinje neuron spiking. Efforts to understand the basis for selective dysregulation of channel transcripts revealed modestly increased expression of the ATXN1 co-repressor Capicua (Cic) in anterior cerebellar Purkinje neurons. Importantly, disrupting the association between ATXN1 and Cic rescued the levels of these ion channel transcripts, and lentiviral overexpression of Cic in the nodular zone accelerated both aberrant Purkinje neuron spiking and neurodegeneration. These findings reinforce the central role for Cic in SCA1 cerebellar pathophysiology and suggest that only modest reductions in Cic are needed to have profound therapeutic impact in SCA1.

Hippocampus plays a role in speech feedback processing

There is increasing evidence that the hippocampus is involved in language production and verbal communication, although little is known about its possible role. According to one view, hippocampus contributes semantic memory to spoken language. Alternatively, hippocampus is involved in the processing the (mis)match between expected sensory consequences of speaking and the perceived speech feedback. In the current study, we re-analysed functional magnetic resonance (fMRI) data of two overt picture-naming studies to test whether hippocampus is involved in speech production and, if so, whether the results can distinguish between a “pure memory” versus a “prediction” account of hippocampal involvement. In both studies, participants overtly named pictures during scanning while hearing their own speech feedback unimpededly or impaired by a superimposed noise mask. Results showed decreased hippocampal activity when speech feedback was impaired, compared to when feedback was unimpeded. Further, we found increased functional coupling between auditory cortex and hippocampus during unimpeded speech feedback, compared to impaired feedback. Finally, we found significant functional coupling between a hippocampal/supplementary motor area (SMA) interaction term and auditory cortex, anterior cingulate cortex and cerebellum during overt picture naming, but not during listening to one's own pre-recorded voice. These findings indicate that hippocampus plays a role in speech production that is in accordance with a “prediction” view of hippocampal functioning.

Nonlinear engagement of action observation network underlying action anticipation in players with different levels of expertise.

The goal of this study was to reconcile inconsistency of neural engagement underlying action anticipation between experts and nonexperts, as well as between correct and incorrect anticipations. Therefore, we asked novice, intermediate, and skilled baseball batters (N, IB, and SB) to anticipate their swing decisions in response to pitching videos of a strike or ball, using functional magnetic resonance imaging. Behavioral results confirmed the effect of expertise that is generally shown in a linear fashion. Imaging results instead revealed a nonlinear relationship between expertise level and the evoked response amplitude of nodes within the action observation network. The relationship was best captured by an inverted U‐shaped quadratic response profile across the three groups such that IB exhibited higher activation than did both SB and N. These empirical findings extend the framework of predictive coding as well as of neural efficiency in anticipating the action of others, and they might be associated with the underlying process to interpret the goal of the observed action and prepare one's own response. Furthermore, the right anterior cerebellum showed different levels of activation for correct and incorrect anticipations in all groups, adding novel evidence of its subtle involvement in anticipation processes irrespective of expertise status.

Mosaic Analysis with Double Markers reveals IGF1R function in granule cell progenitors during cerebellar development

During cerebellar development, granule cell progenitors (GCPs) proliferate exponentially for a fixed period, promoted by paracrine mitogenic factor Sonic Hedgehog (Shh) secreted from Purkinje cells (PCs). Dysregulation of Shh signaling leads to uncontrolled GCP proliferation and medulloblastoma. Serendipitously our previous work discovered insulin-like growth factor 1 (IGF1) as another key driver for medulloblastoma, which led to the current investigation into the role of IGF1 in GCPs during normal development. While the IGF1R conditional knockout model revealed GCP defects in anterior cerebellum, the posterior cerebellum was mostly intact, likely owing to incomplete excision of floxed alleles. To circumvent this hurdle, we enlisted a mouse genetic system called Mosaic Analysis of Double Markers (MADM), which sporadically generates homozygous null cells unequivocally labeled with GFP and their wildtype sibling cells labeled with RFP, enabling phenotypic analysis at single-cell resolution. Using MADM, we found that loss of IGF1R resulted in a 10-fold reduction of GCs in both anterior and posterior cerebellum; and that hindered S phase entry and increased cell cycle exit collectively led to this phenotype. Genetic interaction studies showed that IGF1 signaling prevents GCP cell cycle exit at least partially through suppressing the level of p27kip1, a negative regulator of cell cycle. Finally, we found that IGF1 is produced by PCs in a temporally regulated fashion: it is highly expressed early in development when GCPs proliferate exponentially, then gradually decline as GCPs commit to cell cycle exit. Taken together, our studies reveal IGF1 as a paracrine factor that positively regulates GCP cell cycle in cooperation with Shh, through dampening the level of p27 to prevent precocious cell cycle exit. Our work not only showcases the power of phenotypic analysis by the MADM system but also provides an excellent example of multi-factorial regulation of robust developmental programs.

Neuroanatomical Substrates and Predictors of Response to Capsulotomy in Intractable Obsessive-Compulsive Disorder

BackgroundAnterior capsulotomy that surgically targets fiber tracts connecting prefrontal cortex and subcortical nuclei is a therapeutic option for a subgroup of patients with treatment-refractory obsessive-compulsive disorder. The goal of this study was to investigate neural correlates to anterior capsulotomy and find predictors of clinical improvement following this procedure. MethodsStructural and diffusion imaging data and clinical evaluation were acquired from 31 patients with refractory obsessive-compulsive disorder who underwent anterior capsulotomy. Of the 31 patients, 16 were clinical responders defined by a ≥35% reduction in the Yale-Brown Obsessive Compulsive Scale scores. Analysis of variance was applied on 2 levels (surgery and response) to examine alterations of gray matter volume and fiber tract integrity (measured by generalized fractional anisotropy). The correlation between preoperative data and clinical response was further investigated. ResultsAfter surgery, generalized fractional anisotropy was significantly decreased in the bilateral anterior limb of the internal capsule and anterior thalamic radiation, accompanied by a decrease in gray matter volume in the prefrontal cortex, anterior cingulate cortex, striatum, thalamus, and cerebellum. Moreover, atrophy of the right caudate was greater in responders than in nonresponders, which correlated with alteration in Yale-Brown Obsessive Compulsive Scale score. In addition, preoperative gray matter volume in the right inferior frontal gyrus and generalized fractional anisotropy in the left superior longitudinal fasciculus and right cingulum predicted improved response. More anterior location of the lesion area predicted better clinical response. ConclusionsThese results demonstrate that reduced volume of the right caudate might be associated with therapeutic response of capsulotomy and might offer a potential predictor of treatment outcome and a guide for lesion site.

Correlations Among mRNA Expression Levels of ATP7A, Serum Ceruloplasmin Levels, and Neuronal Metabolism in Unmedicated Major Depressive Disorder.

BackgroundPrevious studies have found that elevated copper levels induce oxidation, which correlates with the occurrence of major depressive disorder (MDD). However, the mechanism of abnormal cerebral metabolism of MDD patients remains ambiguous. The main function of the enzyme ATPase copper-transporting alpha (ATP7A) is to transport copper across the membrane to retain copper homeostasis, which is closely associated with the onset of mental disorders and cognitive impairment. However, less is known regarding the association of ATP7A expression in MDD patients.MethodsA total of 31 MDD patients and 21 healthy controls were recruited in the present study. Proton magnetic resonance spectroscopy was used to assess the concentration levels of N-acetylaspartate, choline (Cho), and creatine (Cr) in brain regions of interest, including prefrontal white matter (PWM), anterior cingulate cortex (ACC), thalamus, lentiform nucleus, and cerebellum. The mRNA expression levels of ATP7A were measured using polymerase chain reaction (SYBR Green method). The correlations between mRNA expression levels of ATP7A and/or ceruloplasmin levels and neuronal biochemical metabolite ratio in the brain regions of interest were evaluated.ResultsThe decline in the mRNA expression levels of ATP7A and the increase in ceruloplasmin levels exhibited a significant correlation in MDD patients. In addition, negative correlations were noted between the decline in mRNA expression levels of ATP7A and the increased Cho/Cr ratios of the left PWM, right PWM, and right ACC in MDD patients. A positive correlation between elevated ceruloplasmin levels and increased Cho/Cr ratio of the left PWM was noted in MDD patients.ConclusionsThe findings suggested that the decline in the mRNA expression levels of ATP7A and the elevated ceruloplasmin levels induced oxidation that led to the disturbance of neuronal metabolism in the brain, which played important roles in the pathophysiology of MDD. The decline in the mRNA expression levels of ATP7A and the elevated ceruloplasmin levels affected neuronal membrane metabolic impairment in the left PWM, right PWM, and right ACC of MDD patients.

T163. STRUCTURAL AND CONNECTIVITY CHANGES IN THE CEREBELLUM CONTRIBUTE TO EXPERIENCING AUDITORY VERBAL HALLUCINATIONS

BackgroundAuditory verbal hallucinations (AVH) have been explained in the context of the forward model, giving the cerebellum a prominent role. However, research utilizing multiple neuroimaging modalities has rendered results on the specificity of cerebellar contribution to AVH unclear.MethodsTo examine the reliability and regional specificity of cerebellar changes in AVH, a systematic search of electronic databases through October 2019 was conducted to identify neuroimaging studies of the cerebellum in psychotic patients or nonclinical participants reporting AVH, focusing on structural MRI, diffusion tensor imaging, and resting state functional connectivity studies. Twenty-two studies were selected, including 892 participants with AVH (792 psychotic patients; 100 at-risk subjects) and 775 healthy controls. Activation likelihood estimate analysis (ALE) examined the reported coordinates for reduced volume, fractional anisotropy (FA) or connectivity (control participants > participants with AVH) and increased volume, FA or connectivity (participants with AVH > control participants). The consistency of cerebellar changes and their relationship with sociodemographic and clinical measures were meta-analyzed.ResultsThe ALE meta-analysis revealed changes in both anterior and posterior cerebellar lobes, with opposite patterns: whereas decreased volume or connectivity was identified in the right anterior cerebellum (lobule IV/V), increased volume or connectivity was identified in the bilateral posterior cerebellum (Crus I and II). A random-effects model with small sample corrections identified consistent changes in both volume and functional connectivity of the cerebellum in participants with AVH (g = .84; SE = .24, 95% CI [.33, 1.34]), which were enhanced in Crus I (g = 1.52, SE = .28, p = .006, 95% CI [.73, 2.31]) but not moderated by age, sex, medication, or illness duration.DiscussionThe ALE meta-analysis confirms cerebellar structural and connectivity changes in psychotic and nonclinical participants reporting AVH. These changes may contribute to AVH due to altered sensory feedback and consequently to erratic prediction as described by the forward model. The current findings also indicate that not all cerebellar regions are equally affected by AVH: the most pronounced changes were observed in Crus I. Specifically, altered communication between Crus I and neocortical network nodes, including the prefrontal cortex, may contribute to ineffective cognitive control in AVH, leading to external misattributions of auditory feedback and a reduced sense of control over events in the environment.