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Proceedings of the National Academy of... Jan 2021The human striatum can be subdivided into the caudate, putamen, and nucleus accumbens (NAc). Each of these structures have some overlapping and some distinct functions...
The human striatum can be subdivided into the caudate, putamen, and nucleus accumbens (NAc). Each of these structures have some overlapping and some distinct functions related to motor control, cognitive processing, motivation, and reward. Previously, we used a "time-of-death" approach to identify diurnal rhythms in RNA transcripts in human cortical regions. Here, we identify molecular rhythms across the three striatal subregions collected from postmortem human brain tissue in subjects without psychiatric or neurological disorders. Core circadian clock genes are rhythmic across all three regions and show strong phase concordance across regions. However, the putamen contains a much larger number of significantly rhythmic transcripts than the other two regions. Moreover, there are many differences in pathways that are rhythmic across regions. Strikingly, the top rhythmic transcripts in NAc (but not the other regions) are predominantly small nucleolar RNAs and long noncoding RNAs, suggesting that a completely different mechanism might be used for the regulation of diurnal rhythms in translation and/or RNA processing in the NAc versus the other regions. Further, although the NAc and putamen are generally in phase with regard to timing of expression rhythms, the NAc and caudate, and caudate and putamen, have several clusters of discordant rhythmic transcripts, suggesting a temporal wave of specific cellular processes across the striatum. Taken together, these studies reveal distinct transcriptome rhythms across the human striatum and are an important step in helping to understand the normal function of diurnal rhythms in these regions and how disruption could lead to pathology.
Topics: Brain; Circadian Clocks; Circadian Rhythm; Humans; Nucleus Accumbens; Putamen; Transcriptome; Ventral Striatum
PubMed: 33372142
DOI: 10.1073/pnas.2016150118 -
Journal of Affective Disorders Dec 2022Apathy is a common non-motor symptom in Parkinson's disease (PD), yet the neural mechanism remains unknown. It has been reported that the lateralization of dopamine...
BACKGROUND
Apathy is a common non-motor symptom in Parkinson's disease (PD), yet the neural mechanism remains unknown. It has been reported that the lateralization of dopamine levels is correlated with apathetic symptoms. We aimed to ascertain the role of lateralization in the neuropathogenesis of apathy in PD.
METHODS
Twenty-six apathetic PD patients (PD-A), twenty-seven nonapathetic PD patients (PD-NA), and twenty-three healthy controls (HCs) were recruited. All subjects underwent T1-weighted and resting state functional MRI scanning during OFF medication state. Voxel-mirrored Homotopic Connectivity (VMHC) and asymmetry voxel-based morphometry (asymmetry VBM) analysis were applied to detect the synchrony of homotopic connections between hemispheres and grey matter asymmetry index.
RESULTS
Compared with both PD-NA and HCs groups, the PD-A group showed excessively decreased z-VMHC values in the nucleus accumbens (NAcc) and putamen. Additionally, both PD subgroups exhibited decreased z-VMHC values in the cerebellum lobule VIII compared with controls. However, no corresponding alteration in grey matter asymmetry index was found. Further, a negative correlation between the z-VMHC values of the NAcc and the Apathy Scale (AS) was confirmed in the PD-A group. Meanwhile, the same relationship was also confirmed between the putamen and AS. Notably, ROC curve analyses uncovered that the z-VMHC values of the NAcc and putamen could be a potential neuroimaging feature discerning apathetic PD patient, respectively.
LIMITATIONS
This is a cross-sectional study.
CONCLUSION
Our findings demonstrated that the asymmetric functional connectivity in the mesocorticolimbic and nigrostriatal systems might induce the pathophysiological mechanisms of apathy in PD.
Topics: Apathy; Brain Mapping; Cross-Sectional Studies; Dopamine; Humans; Magnetic Resonance Imaging; Parkinson Disease
PubMed: 36096372
DOI: 10.1016/j.jad.2022.09.006 -
CNS Neuroscience & Therapeutics Feb 2020Impairment of basal ganglia (BG)-thalamo-cortical circuit causes various symptoms of Parkinson's disease (PD). We investigated the functional connectivity (FC) patterns...
OBJECTIVE
Impairment of basal ganglia (BG)-thalamo-cortical circuit causes various symptoms of Parkinson's disease (PD). We investigated the functional connectivity (FC) patterns of putamen among PD subtypes and healthy control (HC) and explored their clinical significance.
METHODS
A total of 16 patients with tremor-dominant (TD) PD, 23 patients with postural instability and gait difficulty-dominant (PIGD) PD, and 31 HC that underwent functional magnetic resonance imaging were observed. Voxel-wise FC analysis was performed by computing correlation between bilateral putamen and other voxels within the brain. Correlation analysis was performed between FC strength and clinical symptoms.
RESULTS
Compared with PIGD group, TD group showed increased FC between left putamen and right cerebellum lobule VI and cerebellum crus I, then we compared the cerebellum FC difference among the three groups. The cerebellum lobule VI FC difference was mainly involved in motor related cortex, and the cerebellum crus I FC difference was related to cognition areas. While compared with HC, TD and PIGD groups both had significant FC difference brain areas correlated with motor and cognition symptoms. The connectively of putamen and right cerebellum lobules VI and I showed positive correlation with tremor and Montreal Cognitive Assessment degree of scores, respectively. The connectivity of putamen and sensorimotor cortex had negative correlation with PIGD scores.
CONCLUSIONS
The altered connectivity of BG-cortical circuit in patients with PD was related to PIGD symptoms. Motor and cognitive impairments declined slower in patients with TD PD, which may be related to increased functional connectivity between putamen and cerebellum.
Topics: Aged; Cerebellum; Cognition Disorders; Female; Gait Disorders, Neurologic; Humans; Magnetic Resonance Imaging; Male; Mental Status and Dementia Tests; Middle Aged; Motor Cortex; Neural Pathways; Parkinson Disease; Putamen; Tremor
PubMed: 31730272
DOI: 10.1111/cns.13259 -
The Journal of Neuropsychiatry and... 2021Persistent fatigue is common among military servicemembers returning from deployment, especially those with a history of mild traumatic brain injury (mTBI). The purpose...
OBJECTIVE
Persistent fatigue is common among military servicemembers returning from deployment, especially those with a history of mild traumatic brain injury (mTBI). The purpose of this study was to characterize fatigue following deployment using the Multidimensional Fatigue Inventory (MFI), a multidimensional self-report instrument. The study was developed to test the hypothesis that if fatigue involves disrupted effort/reward processing, this should manifest as altered basal ganglia functional connectivity as observed in other amotivational states.
METHODS
Twenty-eight current and former servicemembers were recruited and completed the MFI. All 28 participants had a history of at least one mTBI during deployment. Twenty-six participants underwent resting-state functional MRI. To test the hypothesis that fatigue was associated with basal ganglia functional connectivity, the investigators measured correlations between MFI subscale scores and the functional connectivity of the left and right caudate, the putamen, and the globus pallidus with the rest of the brain, adjusting for the presence of depression.
RESULTS
The investigators found a significant correlation between functional connectivity of the left putamen and bilateral superior frontal gyri and mental fatigue scores. No correlations with the other MFI subscales survived multiple comparisons correction.
CONCLUSIONS
This exploratory study suggests that mental fatigue in military servicemembers with a history of deployment with at least one mTBI may be related to increased striatal-prefrontal functional connectivity, independent of depression. A finding of effort/reward mismatch may guide future treatment approaches.
Topics: Adult; Basal Ganglia; Brain; Brain Concussion; Fatigue; Female; Humans; Magnetic Resonance Imaging; Male; Military Deployment; Prefrontal Cortex; Putamen; Self Report; Surveys and Questionnaires
PubMed: 34392692
DOI: 10.1176/appi.neuropsych.20100255 -
Cells Aug 2020Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons from the substantia nigra (SN) that project to the dorsal striatum (caudate-putamen). To...
Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons from the substantia nigra (SN) that project to the dorsal striatum (caudate-putamen). To better understand the molecular mechanisms underlying PD, we performed combined lipid profiling and RNA sequencing of SN and putamen samples from PD patients and age-matched controls. SN lipid analysis pointed to a neuroinflammatory component and included elevated levels of the endosomal lipid Bis (Monoacylglycero)Phosphate 42:8, while two of the three depleted putamen lipids were saturated sphingomyelin species. Remarkably, we observed gender-related differences in the SN and putamen lipid profiles. Transcriptome analysis revealed that the top-enriched pathways among the 354 differentially expressed genes (DEGs) in the SN were "protein folding" and "neurotransmitter transport", and among the 261 DEGs from putamen "synapse organization". Furthermore, we identified pathways, e.g., "glutamate signaling", and genes, encoding, e.g., an angiotensin receptor subtype or a proprotein convertase, that have not been previously linked to PD. The identification of 33 genes that were common among the SN and putamen DEGs, which included the α-synuclein paralog β-synuclein, may contribute to the understanding of general PD mechanisms. Thus, our proof-of-concept data highlights new genes, pathways and lipids that have not been explored before in the context of PD.
Topics: Aged; Aged, 80 and over; Female; Gene Expression Profiling; Humans; Lipids; Male; Parkinson Disease; Putamen; Substantia Nigra
PubMed: 32858884
DOI: 10.3390/cells9091966 -
NeuroImage. Clinical 2022Compulsive behaviors in obsessive-compulsive disorder (OCD) have been suggested to result from an imbalance in cortico-striatal connectivity. However, the nature of this...
BACKGROUND
Compulsive behaviors in obsessive-compulsive disorder (OCD) have been suggested to result from an imbalance in cortico-striatal connectivity. However, the nature of this impairment, the relative involvement of different striatal areas, their imbalance in genetically related but unimpaired individuals, and their relationship with cognitive dysfunction in OCD patients, remain unknown.
METHODS
In the current study, striatal (i.e., caudate and putamen) whole-brain connectivity was computed in a sample of OCD patients (OCD, n = 62), unaffected first-degree relatives (UFDR, n = 53) and healthy controls (HC, n = 73) by ROI-based resting-state functional magnetic resonance imaging (rs-fMRI). A behavioral task switch paradigm outside of the scanner was also performed to measure cognitive flexibility in OCD patients.
RESULTS
There were significantly increased strengths (Z-transformed Pearson correlation coefficient) in caudate connectivity in OCD patients. A significant correlation between the two types of connectivity strengths in the relevant regions was observed only in the OCD patient group. Furthermore, the caudate connectivity of patients was negatively associated with their task-switch performance.
CONCLUSIONS
The imbalance between the caudate and putamen connectivity, arising from the abnormal increase of caudate activity, may serve as a clinical characteristic for obsessive-compulsive disorder.
Topics: Brain Mapping; Corpus Striatum; Humans; Magnetic Resonance Imaging; Neural Pathways; Obsessive-Compulsive Disorder; Putamen
PubMed: 35717885
DOI: 10.1016/j.nicl.2022.103083 -
Parkinsonism & Related Disorders Apr 2021Microstructural integrity of the middle cerebellar peduncle (MCP) and the putamen captured by diffusion-tensor imaging (DTI) is differentially affected in the...
INTRODUCTION
Microstructural integrity of the middle cerebellar peduncle (MCP) and the putamen captured by diffusion-tensor imaging (DTI) is differentially affected in the parkinsonian and cerebellar variants of multiple system atrophy (MSA-P, MSA-C) compared to Parkinson's disease (PD). The current study applied DTI and tractography in order to 1) characterize the distribution of DTI metrics along the tracts of the MCP and from the putamen in MSA variants, and 2) evaluate the usefulness of combining these measures for the differential diagnosis of MSA-P against PD in the clinical setting.
METHODS
Twenty-nine MSA patients (MSA-C, n = 10; MSA-P, n = 19), with a mean disease duration of 2.8 ± 1.7 years, 19 PD patients, and 27 healthy controls (HC) were included in the study. Automatized tractography with a masking procedure was employed to isolate the MCP tracts. DTI measures along the tracts of the MCP and within the putamen were acquired and jointly used to classify MSA vs. PD, and MSA-P vs. PD. Putamen volume was additionally tested as classification feature in post hoc analyses.
RESULTS
DTI measures within the MCP and putamen showed significant alterations in MSA variants compared to HC and PD. Classification accuracy for MSA vs. PD and MSA-P vs PD using diffusion measures was 91.7% and 89.5%, respectively. When replacing the putaminal DTI measure by a normalized measure of putamen volume classification accuracy improved to 95.8% and 94.7%, respectively.
CONCLUSION
Multimodal information from MCP tractography and putamen volume yields excellent diagnostic accuracy to discriminate between early-to-moderately advanced patients with MSA and PD.
Topics: Aged; Diagnosis, Differential; Diffusion Tensor Imaging; Female; Humans; Male; Middle Aged; Middle Cerebellar Peduncle; Multiple System Atrophy; Parkinson Disease; Putamen; Sensitivity and Specificity
PubMed: 33713904
DOI: 10.1016/j.parkreldis.2021.02.027 -
Molecular Therapy : the Journal of the... Dec 2022Direct putaminal infusion of adeno-associated virus vector (serotype 2) (AAV2) containing the human glial cell line-derived neurotrophic factor (GDNF) transgene was...
Direct putaminal infusion of adeno-associated virus vector (serotype 2) (AAV2) containing the human glial cell line-derived neurotrophic factor (GDNF) transgene was studied in a phase I clinical trial of participants with advanced Parkinson's disease (PD). Convection-enhanced delivery of AAV2-GDNF with a surrogate imaging tracer (gadoteridol) was used to track infusate distribution during real-time intraoperative magnetic resonance imaging (iMRI). Pre-, intra-, and serial postoperative (up to 5 years after infusion) MRI were analyzed in 13 participants with PD treated with bilateral putaminal co-infusions (52 infusions in total) of AAV2-GDNF and gadoteridol (infusion volume, 450 mL per putamen). Real-time iMRI confirmed infusion cannula placement, anatomic quantification of volumetric perfusion within the putamen, and direct visualization of off-target leakage or cannula reflux (which permitted corresponding infusion rate/cannula adjustments). Serial post-treatment MRI assessment (n = 13) demonstrated no evidence of cerebral parenchyma toxicity in the corresponding regions of AAV2-GDNF and gadoteridol co-infusion or surrounding regions over long-term follow-up. Direct confirmation of key intraoperative safety and efficacy parameters underscores the safety and tissue targeting value of real-time imaging with co-infused gadoteridol and putative therapeutic agents (i.e., AAV2-GDNF). This delivery-imaging platform enhances safety, permits delivery personalization, improves therapeutic distribution, and facilitates assessment of efficacy and dosing effect.
Topics: Humans; Parkinson Disease; Magnetic Resonance Imaging
PubMed: 35957524
DOI: 10.1016/j.ymthe.2022.08.003 -
BMC Neurology Mar 2021To explore the correlation between the volume of putamen and brain cognitive impairment in patients with HIV and to predict the feasibility of early-stage HIV brain...
BACKGROUND
To explore the correlation between the volume of putamen and brain cognitive impairment in patients with HIV and to predict the feasibility of early-stage HIV brain cognitive impairment through radiomics.
METHOD
Retrospective selection of 90 patients with HIV infection, including 36 asymptomatic neurocognitive impairment (ANI) patients and 54 pre-clinical ANI patients in Beijing YouAn Hospital. All patients received comprehensive neuropsychological assessment and MRI scanning. 3D Slicer software was used to acquire volume of interest (VOI) and radiomics features. Clinical variables and volume of putamen were compared between patients with ANI and pre-clinical ANI. The Kruskal Wallis test was used to analysis multiple comparisons between groups. The relationship between cognitive scores and VOI was compared using linear regression. For radiomics, principal component analysis (PCA) was used to reduce model overfitting and calculations and then a support vector machine (SVM) was used to build a binary classification model. For model performance evaluation, we used an accuracy, sensitivity, specificity and receiver operating characteristic curve (ROC).
RESULT
There were no significant differences in clinical variables between ANI group and pre-clinical-ANI group (P>0.05). The volume of bilateral putamen was significantly different between AHI group and pre-clinical group (P<0.05), but there was only a trend in the left putamen between ANI-treatment group and pre-clinical treatment group(P = 0.063). Reduced cognitive scores in Verbal Fluency, Attention/Working Memory, Executive Functioning, memory and Speed of Information Processing were negatively correlated with the increased VOI (P<0.05), but the correlation was relatively low. In diagnosing the ANI from pre-clinical ANI, the mean area under the ROC curves (AUC) were 0.85 ± 0.22, the mean sensitivity and specificity were 63.12 ± 5.51 and 94.25% ± 3.08%.
CONCLUSION
The volumes of putamen in patients with ANI may be larger than patients with pre-clinical ANI, the change of the volume of the putamen may have a certain process; there is a relationship between putamen and cognitive impairment, but the exact mechanism is unclear. Radiomics may be a useful tool for predicting early stage HAND in patients with HIV.
Topics: AIDS Dementia Complex; Adult; Brain; Cognitive Dysfunction; Female; Humans; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Putamen; Radiographic Image Interpretation, Computer-Assisted; Retrospective Studies
PubMed: 33750319
DOI: 10.1186/s12883-021-02114-x -
American Journal of Medical Genetics.... Jun 2020Individuals with attention deficit hyperactivity disorder (ADHD) show gray matter volume (GMV) reduction in the putamen. KTN1 variants may regulate kinectin 1 expression...
Individuals with attention deficit hyperactivity disorder (ADHD) show gray matter volume (GMV) reduction in the putamen. KTN1 variants may regulate kinectin 1 expression in the putamen and influence putamen structure and function. We aim to test the hypothesis that the KTN1 variants may represent a genetic risk factor of ADHD. Two independent family-based Caucasian samples were analyzed, including 922 parent-child trios (a total of 2,757 subjects with 924 ADHD children) and 735 parent-child trios (a total of 1,383 subjects with 613 ADHD children). The association between ADHD and a total of 143 KTN1 SNPs was analyzed in the first sample, and the nominally-significant (p < .05) risk SNPs were classified into independent haplotype blocks. All SNPs, including imputed SNPs within these blocks, and haplotypes across each block, were explored for replication of associations in both samples. The potential biological functions of all risk SNPs were predicted using a series of bioinformatics analyses, their regulatory effects on the putamen volumes were tested, and the KTN1 mRNA expression was examined in three independent human putamen tissue samples. We found that fifteen SNPs were nominally associated with ADHD (p < .05) in the first sample, and three of them remained significant even after correction for multiple testing (1.3 × 10 ≤ p ≤ 1.2 × 10 ; α = 2.5 × 10 ). These 15 risk SNPs were located in five haplotype blocks, and 13 SNPs within four of these blocks were associated with ADHD in the second sample. Six haplotypes within these blocks were also significantly (1.2 × 10 ≤ p ≤ .009) associated with ADHD in these samples. These risk variants were located in disease-related transposons and/or transcription-related functional regions. Major alleles of these risk variants significantly increased putamen volumes. Finally, KTN1 mRNA was significantly expressed in putamen across three independent cohorts. We concluded that the KTN1 variants were significantly associated with ADHD. KTN1 may play a functional role in the development of ADHD.
Topics: Adolescent; Alleles; Attention Deficit Disorder with Hyperactivity; Child; Computational Biology; Family Health; Female; Genetic Predisposition to Disease; Genetic Variation; Genotype; Gray Matter; Haplotypes; Humans; Male; Membrane Proteins; Polymorphism, Single Nucleotide; Putamen; Risk
PubMed: 32190980
DOI: 10.1002/ajmg.b.32782