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Annals of Neurology Feb 2022Randomized clinical trials have shown that aerobic exercise attenuates motor symptom progression in Parkinson's disease, but the underlying neural mechanisms are... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Randomized clinical trials have shown that aerobic exercise attenuates motor symptom progression in Parkinson's disease, but the underlying neural mechanisms are unclear. Here, we investigated how aerobic exercise influences disease-related functional and structural changes in the corticostriatal sensorimotor network, which is involved in the emergence of motor deficits in Parkinson's disease. Additionally, we explored effects of aerobic exercise on tissue integrity of the substantia nigra, and on behavioral and cerebral indices of cognitive control.
METHODS
The Park-in-Shape trial is a single-center, double-blind randomized controlled trial in 130 Parkinson's disease patients who were randomly assigned (1:1 ratio) to aerobic exercise (stationary home trainer) or stretching (active control) interventions (duration = 6 months). An unselected subset from this trial (exercise, n = 25; stretching, n = 31) underwent resting-state functional and structural magnetic resonance imaging (MRI), and an oculomotor cognitive control task (pro- and antisaccades), at baseline and at 6-month follow-up.
RESULTS
Aerobic exercise, but not stretching, led to increased functional connectivity of the anterior putamen with the sensorimotor cortex relative to the posterior putamen. Behaviorally, aerobic exercise also improved cognitive control. Furthermore, aerobic exercise increased functional connectivity in the right frontoparietal network, proportionally to fitness improvements, and it reduced global brain atrophy.
INTERPRETATION
MRI, clinical, and behavioral results converge toward the conclusion that aerobic exercise stabilizes disease progression in the corticostriatal sensorimotor network and enhances cognitive performance. ANN NEUROL 2022;91:203-216.
Topics: Aged; Behavior; Brain; Cognition; Double-Blind Method; Exercise; Exercise Therapy; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Nerve Net; Parkinson Disease; Prospective Studies; Psychomotor Performance; Putamen; Sensorimotor Cortex; Substantia Nigra
PubMed: 34951063
DOI: 10.1002/ana.26291 -
Nature Oct 2018The genetic architecture of brain structure and function is largely unknown. To investigate this, we carried out genome-wide association studies of 3,144 functional and...
The genetic architecture of brain structure and function is largely unknown. To investigate this, we carried out genome-wide association studies of 3,144 functional and structural brain imaging phenotypes from UK Biobank (discovery dataset 8,428 subjects). Here we show that many of these phenotypes are heritable. We identify 148 clusters of associations between single nucleotide polymorphisms and imaging phenotypes that replicate at P < 0.05, when we would expect 21 to replicate by chance. Notable significant, interpretable associations include: iron transport and storage genes, related to magnetic susceptibility of subcortical brain tissue; extracellular matrix and epidermal growth factor genes, associated with white matter micro-structure and lesions; genes that regulate mid-line axon development, associated with organization of the pontine crossing tract; and overall 17 genes involved in development, pathway signalling and plasticity. Our results provide insights into the genetic architecture of the brain that are relevant to neurological and psychiatric disorders, brain development and ageing.
Topics: Aging; Biological Specimen Banks; Brain; Datasets as Topic; Epidermal Growth Factor; Extracellular Matrix; Female; Genome-Wide Association Study; Heredity; Humans; Iron; Male; Neuroimaging; Neuronal Plasticity; Phenotype; Polymorphism, Single Nucleotide; Putamen; Signal Transduction; United Kingdom; White Matter
PubMed: 30305740
DOI: 10.1038/s41586-018-0571-7 -
Brain : a Journal of Neurology Feb 2024While Parkinson's disease remains clinically defined by cardinal motor symptoms resulting from nigrostriatal degeneration, it is now appreciated that the disease...
While Parkinson's disease remains clinically defined by cardinal motor symptoms resulting from nigrostriatal degeneration, it is now appreciated that the disease commonly consists of multiple pathologies, but it is unclear where these co-pathologies occur early in disease and whether they are responsible for the nigrostriatal degeneration. For the past number of years, we have been studying a well-characterized cohort of subjects with motor impairment that we have termed mild motor deficits. Motor deficits were determined on a modified and validated Unified Parkinson's Disease Rating Scale III but were insufficient in degree to diagnose Parkinson's disease. However, in our past studies, cases in this cohort had a selection bias, as both a clinical syndrome in between no motor deficits and Parkinson's disease, plus nigral Lewy pathology as defined post-mortem, were required for inclusion. Therefore, in the current study, we only based inclusion on the presence of a clinical phenotype with mild motor impairment insufficient to diagnose Parkinson's disease. Then, we divided this group further based upon whether or not subjects had a synucleinopathy in the nigrostriatal system. Here we demonstrate that loss of nigral dopaminergic neurons, loss of putamenal dopaminergic innervation and loss of the tyrosine hydroxylase-phenotype in the substantia nigra and putamen occur equally in mild motor deficit groups with and without nigral alpha-synuclein aggregates. Indeed, the common feature of these two groups is that both have similar degrees of AT8 positive phosphorylated tau, a pathology not seen in the nigrostriatal system of age-matched controls. These findings were confirmed with early (tau Ser208 phosphorylation) and late (tau Ser396/Ser404 phosphorylation) tau markers. This suggests that the initiation of nigrostriatal dopaminergic neurodegeneration occurs independently of alpha-synuclein aggregation and can be tau mediated.
Topics: Humans; Parkinson Disease; alpha-Synuclein; Parkinsonian Disorders; Synucleinopathies; Putamen; Substantia Nigra; Dopamine
PubMed: 38006313
DOI: 10.1093/brain/awad388 -
Journal of Psychopharmacology (Oxford,... Dec 2022Previous magnetic resonance imaging studies in regular cannabis users report altered grey matter volume (GMV) in brain regions, including the prefrontal cortex (PFC),...
BACKGROUND
Previous magnetic resonance imaging studies in regular cannabis users report altered grey matter volume (GMV) in brain regions, including the prefrontal cortex (PFC), putamen and hippocampus. However, most studies have tended to recruit recreational users with high levels of cannabis use, and have not controlled for the possible confounding effects of tobacco use. We attempt to address these limitations in the present study.
METHODS
We acquired volumetric images in sex, age and IQ-matched groups of (1) regular Cannabis users who also smoke Tobacco cigarettes ('CT'; = 33), (2) non-cannabis-using Tobacco cigarette smokers ('T'; = 19) and (3) non-cannabis/tobacco-using Controls ('C'; = 35). GMV in bilateral PFC, putamen and hippocampal regions was compared across groups. We also examined the associations between GMV differences and levels of cannabis and tobacco use, measures of intellectual function, and of depression, anxiety and stress.
RESULTS
Relative to controls, both CT and T groups showed lower GMV in the left inferior frontal gyrus, and greater GMV in the putamen. In addition, lower GMV in the right frontal pole in the CT group (but not the T group) was associated with lifetime cannabis use, but not with cigarette use.
CONCLUSIONS
Regular cannabis users who also smoked tobacco cigarettes showed altered GMV patterns relative to controls. However, a similar pattern of GMV differences was also seen between regular tobacco users that did not use cannabis. Further research is needed to disentangle the effects of cannabis and tobacco use on brain structure.
Topics: Gray Matter; Nicotiana; Cannabis; Putamen; Prefrontal Cortex; Magnetic Resonance Imaging
PubMed: 36112825
DOI: 10.1177/02698811221117523 -
Journal of Neurochemistry Mar 2020The dorsal striatum coordinates input-output processing of numerous functions including those related to motor activity, motivation, and learning. Considerable...
Old neurochemical markers, new functional directions?: An Editorial for 'Distinct gradients of various neurotransmitter markers in caudate nucleus and putamen of the human brain' on page 650.
The dorsal striatum coordinates input-output processing of numerous functions including those related to motor activity, motivation, and learning. Considerable anatomical and biochemical heterogeneity across striatal subregions has long been known to result in distinct functional outcomes, and for imbalances in these pathways to contribute to many complex disorders. Here we highlight the study of Hörtnagl et al. (2019) who utilize precision dissection of human caudate nucleus and putamen for detailed measurement of major neurochemical markers to address the question of anatomical heterogeneity of neurotransmitter distribution and turnover in these regions. The findings identify gradients of neurotransmitter markers in rostro-caudal, dorso-lateral, and anterior-posterior directions with a precision that has not been previously determined in humans. Correlative analyses of the results also suggest tentative links between content of various neurotransmitters in specific subregions, raising the intriguing possibility that neurotransmitter quantity in one territory may correlate with the quantity of the same or different transmitter from another territory. This suggests the presence of a functional anatomy over extensive brain regions and networks that can be studied through multiple correlative analyses, and identify a possible basis for a new approach for postmortem analysis of neurotransmitter distribution and function.
Topics: Aged; Biomarkers; Caudate Nucleus; Female; Humans; Male; Neurotransmitter Agents; Postmortem Changes; Putamen
PubMed: 31917872
DOI: 10.1111/jnc.14929 -
Cerebral Cortex (New York, N.Y. : 1991) Jul 2022Striatal loci are connected to both the ipsilateral and contralateral frontal cortex. Normative quantitation of the dissimilarity between striatal loci's hemispheric...
Striatal loci are connected to both the ipsilateral and contralateral frontal cortex. Normative quantitation of the dissimilarity between striatal loci's hemispheric connection profiles and its spatial variance across the striatum, and assessment of how interindividual differences relate to function, stands to further the understanding of the role of corticostriatal circuits in lateralized functions and the role of abnormal corticostriatal laterality in neurodevelopmental and other neuropsychiatric disorders. A resting-state functional connectivity fingerprinting approach (n = 261) identified "laterality hotspots"-loci whose profiles of connectivity with ipsilateral and contralateral frontal cortex were disproportionately dissimilar-in the right rostral ventral putamen, left rostral central caudate, and bilateral caudal ventral caudate. Findings were replicated in an independent sample and were robust to both preprocessing choices and the choice of cortical atlas used for parcellation definitions. Across subjects, greater rightward connectional laterality at the right ventral putamen hotspot and greater leftward connectional laterality at the left rostral caudate hotspot were associated with higher performance on tasks engaging lateralized functions (i.e., response inhibition and language, respectively). In sum, we find robust and reproducible evidence for striatal loci with disproportionately lateralized connectivity profiles where interindividual differences in laterality magnitude are associated with behavioral capacities on lateralized functions.
Topics: Brain Mapping; Corpus Striatum; Functional Laterality; Humans; Magnetic Resonance Imaging; Neural Pathways; Putamen
PubMed: 34727171
DOI: 10.1093/cercor/bhab392 -
Biological Psychiatry Dec 2022The putamen has been implicated in depressive disorders, but how its structure and function increase depression risk is not clearly understood. Here, we examined how...
BACKGROUND
The putamen has been implicated in depressive disorders, but how its structure and function increase depression risk is not clearly understood. Here, we examined how putamen volume, neuronal density, and mood-modulated functional activity relate to family history and prospective course of depression.
METHODS
The study includes 115 second- and third-generation offspring at high or low risk for depression based on the presence or absence of major depressive disorder in the first generation. Offspring were followed longitudinally using semistructured clinical interviews blinded to their familial risk; putamen structure, neuronal integrity, and functional activation were indexed by structural magnetic resonance imaging (MRI), proton magnetic resonance spectroscopy (N-acetylaspartate/creatine ratio), and functional MRI activity modulated by valence and arousal components of a mood induction task, respectively.
RESULTS
After adjusting for covariates, the high-risk individuals had lower putamen volume (standardized betas, β- = -0.17, β- = -0.15, ps = .002), N-acetylaspartate/creatine ratio (β-= -0.40, β-= -0.37, ps < .0001), and activation modulated by valence (β- = -0.22, β- = -0.27, ps < .05) than low-risk individuals. Volume differences were greater at younger ages, and N-acetylaspartate/creatine ratio differences were greater at older ages. Lower putamen volume also predicted major depressive disorder episodes up to 8 years after the scan (β- = -0.72, p = .013; β- = -0.83, p = .037). Magnetic resonance spectroscopy and task functional MRI measures were modestly correlated (0.27 ≤ r ≤ 0.33).
CONCLUSIONS
Findings demonstrate abnormalities in putamen structure and function in individuals at high risk for major depressive disorder. Future studies should focus on this region as a potential biomarker for depressive illness, noting meanwhile that differences attributable to family history may peak at different ages based on which MRI modality is being used to assay them.
Topics: Humans; Putamen; Depressive Disorder, Major; Creatine; Depression; Genetic Predisposition to Disease; Prospective Studies; Magnetic Resonance Imaging; Multimodal Imaging
PubMed: 36038379
DOI: 10.1016/j.biopsych.2022.06.035 -
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 -
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 -
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