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Brain : a Journal of Neurology Mar 2024Dopaminergic dysfunction in the basal ganglia, particularly in the posterior putamen, is often viewed as the primary pathological mechanism behind motor slowing (i.e....
Dopaminergic dysfunction in the basal ganglia, particularly in the posterior putamen, is often viewed as the primary pathological mechanism behind motor slowing (i.e. bradykinesia) in Parkinson's disease. However, striatal dopamine loss fails to account for interindividual differences in motor phenotype and rate of decline, implying that the expression of motor symptoms depends on additional mechanisms, some of which may be compensatory in nature. Building on observations of increased motor-related activity in the parieto-premotor cortex of Parkinson patients, we tested the hypothesis that interindividual differences in clinical severity are determined by compensatory cortical mechanisms and not just by basal ganglia dysfunction. Using functional MRI, we measured variability in motor- and selection-related brain activity during a visuomotor task in 353 patients with Parkinson's disease (≤5 years disease duration) and 60 healthy controls. In this task, we manipulated action selection demand by varying the number of possible actions that individuals could choose from. Clinical variability was characterized in two ways. First, patients were categorized into three previously validated, discrete clinical subtypes that are hypothesized to reflect distinct routes of α-synuclein propagation: diffuse-malignant (n = 42), intermediate (n = 128) or mild motor-predominant (n = 150). Second, we used the scores of bradykinesia severity and cognitive performance across the entire sample as continuous measures. Patients showed motor slowing (longer response times) and reduced motor-related activity in the basal ganglia compared with controls. However, basal ganglia activity did not differ between clinical subtypes and was not associated with clinical scores. This indicates a limited role for striatal dysfunction in shaping interindividual differences in clinical severity. Consistent with our hypothesis, we observed enhanced action selection-related activity in the parieto-premotor cortex of patients with a mild-motor predominant subtype, both compared to patients with a diffuse-malignant subtype and controls. Furthermore, increased parieto-premotor activity was related to lower bradykinesia severity and better cognitive performance, which points to a compensatory role. We conclude that parieto-premotor compensation, rather than basal ganglia dysfunction, shapes interindividual variability in symptom severity in Parkinson's disease. Future interventions may focus on maintaining and enhancing compensatory cortical mechanisms, rather than only attempting to normalize basal ganglia dysfunction.
Topics: Humans; Parkinson Disease; Hypokinesia; Basal Ganglia; Corpus Striatum; Dopamine; Putamen
PubMed: 37757883
DOI: 10.1093/brain/awad325 -
NeuroImage. Clinical 2022Perinatal stroke affects millions of children and results in lifelong disability. Two forms prevail: arterial ischemic stroke (AIS), and periventricular venous...
INTRODUCTION
Perinatal stroke affects millions of children and results in lifelong disability. Two forms prevail: arterial ischemic stroke (AIS), and periventricular venous infarction (PVI). With such focal damage early in life, neural structures may reorganize during development to determine clinical function, particularly in the contralesional hemisphere. Such processes are increasingly understood in the motor system, however, the role of the basal ganglia, a group of subcortical nuclei that are critical to movement, behaviour, and learning, remain relatively unexplored. Perinatal strokes that directly damage the basal ganglia have been associated with worse motor outcomes, but how developmental plasticity affects bilateral basal ganglia structure is unknown. We hypothesized that children with perinatal stroke have alterations in bilateral basal ganglia volumes, the degree of which correlates with clinical motor function.
METHODS
Children with AIS or PVI, and controls, aged 6-19 years, were recruited from a population-based cohort. MRIs were acquired on a 3 T GE MR750w scanner. High-resolution T1-weighted images (166 slices, 1 mm isotropic voxels) underwent manual segmentations of bilateral caudate and putamen. Extracted volumes were corrected for total intracranial volume. A structure volume ratio quantified hemispheric asymmetry of caudate and putamen (non-dominant/dominant hemisphere structure volume) with ratios closer to 1 reflecting a greater degree of symmetry between structures. Participants were additionally dichotomized by volume ratios into two groups, those with values above the group mean (0.8) and those below. Motor function was assessed using the Assisting Hand Assessment (AHA) and the Box and Blocks test in affected (BBTA) and unaffected (BBTU) hands. Group differences in volumes were explored using Kruskal-Wallis tests, and interhemispheric differences using Wilcoxon. Partial Spearman correlations explored associations between volumes and motor function (factoring out age, and whole-brain white matter volume, a proxy for lesion extent).
RESULTS
In the dominant (non-lesioned) hemisphere, volumes were larger in AIS compared to PVI for both the caudate (p < 0.05) and putamen (p < 0.01) but comparable between stroke groups and controls. Non-dominant (lesioned) hemisphere volumes were larger for controls than AIS for the putamen (p < 0.05), and for the caudate in PVI (p = 0.001). Interhemispheric differences showed greater dominant hemisphere volumes for the putamen in controls (p < 0.01), for both the caudate (p < 0.01) and putamen (p < 0.001) in AIS, and for the caudate (p = 0.01) in PVI. Motor scores did not differ between AIS and PVI thus groups were combined to increase statistical power. Better motor scores were associated with larger non-dominant putamen volumes (BBTA: r = 0.40, p = 0.011), and larger putamen volume ratios (BBTA: r = 0.52, p < 0.001, AHA: r = 0.43, p < 0.01). For those with relatively symmetrical putamen volume ratios (ratio > group mean of 0.8), age was positively correlated with BBTA (r = 0.54, p < 0.01) and BBTU (r = 0.69, p < 0.001). For those with more asymmetrical putamen volume ratios, associations with motor function and age were not seen (BBTA: r = 0.21, p = 0.40, BBTU: r = 0.37, p = 0.13).
CONCLUSION
Specific perinatal stroke lesions affect different elements of basal ganglia development. PVI primarily affected the caudate, while AIS primarily affected the putamen. Putamen volumes in the lesioned hemisphere are associated with clinical motor function. The basal ganglia should be included in evolving models of developmental plasticity after perinatal stroke.
Topics: Basal Ganglia; Child; Female; Hand; Humans; Magnetic Resonance Imaging; Pregnancy; Putamen; Stroke
PubMed: 36002972
DOI: 10.1016/j.nicl.2022.103143 -
Movement Disorders : Official Journal... Jan 2022Dopamine transporter single photon-emission computed tomography (DAT-SPECT) is the strongest risk factor for phenoconversion in patients with idiopathic rapid eye...
BACKGROUND
Dopamine transporter single photon-emission computed tomography (DAT-SPECT) is the strongest risk factor for phenoconversion in patients with idiopathic rapid eye movement (REM)-sleep behavior disorder (iRBD). However, it might be used as a second-line stratification tool in clinical trials, because it is expensive and mini-invasive.
OBJECTIVE
Aim of the study is to investigate whether other cost-effective and non-invasive biomarkers may be proposed as first-line stratification tools.
METHODS
Forty-seven consecutive iRBD patients (68.53 ± 7.16 years, 40 males) underwent baseline clinical and neuropsychological assessment, olfaction test, resting electroencephalogram (EEG), and DAT-SPECT. All patients underwent 6 month-based clinical follow-up to investigate the emergence of parkinsonism and/or dementia. Survival analysis and Cox regression were used to estimate conversion risk.
RESULTS
Seventeen patients developed an overt synucleinopathy (eight Parkinsonism and nine dementia) 32.8 ± 22 months after diagnosis. The strongest risk factors were putamen specific to non-displaceable binding ratio (SBR) (hazard ratio [HR], 7.3), attention/working memory cognitive function (NPS-AT/WM) (HR, 5.9), EEG occipital mean frequency (HR, 2.7) and clinical motor assessment (HR, 2.3). On multivariate Cox-regression analysis, only putamen SBR and NPS-AT/WM significantly contributed to the model (HR, 6.2, 95% confidence interval [CI], 1.9-19.8). At post-hoc analysis, the trail-making test B (TMT-B) was the single most efficient first-line stratification tool that allowed to reduce the number of eligible subjects to 76.6% (sensitivity 1, specificity 0.37). Combining TMT-B and DAT-SPECT further reduced the sample to 66% (sensitivity 0.88, specificity 0.47).
CONCLUSION
The TMT-B seems to be a cost-effective and efficient first-line screening tool, to be used to select patients that deserve DAT-SPECT as second-line screening tool for disease-modifying clinical trials. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Aged; Female; Humans; Male; Middle Aged; Parkinsonian Disorders; Putamen; REM Sleep Behavior Disorder; Synucleinopathies; Tomography, Emission-Computed, Single-Photon
PubMed: 34533239
DOI: 10.1002/mds.28785 -
Psychoneuroendocrinology Feb 2022Acute stress is associated with a shift from goal-directed to habitual behavior. This stress-induced preference for habitual behavior has been suggested as a potential...
Acute stress is associated with a shift from goal-directed to habitual behavior. This stress-induced preference for habitual behavior has been suggested as a potential mechanism by which binge eating disorder (BED) patients succumb to eating large amounts of high-caloric foods in an uncontrolled manner (i.e., binge episodes). While in healthy subjects the balance between goal-directed and habitual behavior is subserved by the anterior cingulate cortex (ACC), insular cortex, orbitofrontal cortex (OFC), anterior caudate nucleus, and posterior putamen, the brain mechanism that underlies this (possibly amplified) stress-induced behavioral shift in BED patients is currently unknown. In the current study, 76 participants (38 BED, 38 healthy controls (HCs)) learned six stimulus-response-outcome associations in a well-established instrumental learning task. Subsequently, three outcomes were selectively devalued, after which participants underwent either a stress induction procedure (Maastricht Acute Stress Test; MAST) or a no-stress control procedure. Next, the balance between goal-directed and habitual behavior was assessed during functional magnetic resonance imaging. Findings show that the balance between goal-directed and habitual behavior was associated with activity in the ACC, insula, and OFC in no-stress HCs. Although stress and BED did not modulate the balance between goal-directed and habitual behavior, BED participants displayed a smaller difference in putamen activation between trials probing goal-directed and habitual behavior compared with HCs when using a ROI approach. We conclude that putamen activity differences between BED and HC could reflect changes in monitoring of response accuracy or reward value, albeit perhaps not sufficiently to induce a measurable shift from goal-directed to habitual behavior. Future research could clarify potential boundary conditions of stress-induced shifts in instrumental behavior in BED patients.
Topics: Binge-Eating Disorder; Conditioning, Operant; Goals; Humans; Motivation; Putamen
PubMed: 34839081
DOI: 10.1016/j.psyneuen.2021.105596 -
NeuroImage Jul 2021A wide homology between human and macaque striatum is often assumed as in both the striatum is involved in cognition, emotion and executive functions. However,... (Comparative Study)
Comparative Study
A wide homology between human and macaque striatum is often assumed as in both the striatum is involved in cognition, emotion and executive functions. However, differences in functional and structural organization between human and macaque striatum may reveal evolutionary divergence and shed light on human vulnerability to neuropsychiatric diseases. For instance, dopaminergic dysfunction of the human striatum is considered to be a pathophysiological underpinning of different disorders, such as Parkinson's disease (PD) and schizophrenia (SCZ). Previous investigations have found a wide similarity in structural connectivity of the striatum between human and macaque, leaving the cross-species comparison of its functional organization unknown. In this study, resting-state functional connectivity (RSFC) derived striatal parcels were compared based on their homologous cortico-striatal connectivity. The goal here was to identify striatal parcels whose connectivity is human-specific compared to macaque parcels. Functional parcellation revealed that the human striatum was split into dorsal, dorsomedial, and rostral caudate and ventral, central, and caudal putamen, while the macaque striatum was divided into dorsal, and rostral caudate and rostral, and caudal putamen. Cross-species comparison indicated dissimilar cortico-striatal RSFC of the topographically similar dorsal caudate. We probed clinical relevance of the striatal clusters by examining differences in their cortico-striatal RSFC and gray matter (GM) volume between patients (with PD and SCZ) and healthy controls. We found abnormal RSFC not only between dorsal caudate, but also between rostral caudate, ventral, central and caudal putamen and widespread cortical regions for both PD and SCZ patients. Also, we observed significant structural atrophy in rostral caudate, ventral and central putamen for both PD and SCZ while atrophy in the dorsal caudate was specific to PD. Taken together, our cross-species comparative results revealed shared and human-specific RSFC of different striatal clusters reinforcing the complex organization and function of the striatum. In addition, we provided a testable hypothesis that abnormalities in a region with human-specific connectivity, i.e., dorsal caudate, might be associated with neuropsychiatric disorders.
Topics: Adult; Aged; Animals; Caudate Nucleus; Cerebral Cortex; Connectome; Datasets as Topic; Female; Humans; Macaca; Magnetic Resonance Imaging; Male; Middle Aged; Nerve Net; Parkinson Disease; Putamen; Schizophrenia; Species Specificity; Young Adult
PubMed: 33819611
DOI: 10.1016/j.neuroimage.2021.118006 -
NeuroImage. Clinical 2017Recent neuroimaging findings have highlighted the impact of premature birth on subcortical development and morphological changes in the deep grey nuclei and ventricular...
Recent neuroimaging findings have highlighted the impact of premature birth on subcortical development and morphological changes in the deep grey nuclei and ventricular system. To help characterize subcortical microstructural changes in preterm neonates, we recently implemented a multivariate tensor-based method (mTBM). This method allows to precisely measure local surface deformation of brain structures in infants. Here, we investigated ventricular abnormalities and their spatial relationships with surrounding subcortical structures in preterm neonates. We performed regional group comparisons on the surface morphometry and relative position of the lateral ventricles between 19 full-term and 17 preterm born neonates at term-equivalent age. Furthermore, a relative pose analysis was used to detect individual differences in translation, rotation, and scale of a given brain structure with respect to an average. Our mTBM results revealed broad areas of alterations on the frontal horn and body of the left ventricle, and narrower areas of differences on the temporal horn of the right ventricle. A significant shift in the rotation of the left ventricle was also found in preterm neonates. Furthermore, we located significant correlations between morphology and pose parameters of the lateral ventricles and that of the putamen and thalamus. These results show that regional abnormalities on the surface and pose of the ventricles are also associated with alterations on the putamen and thalamus. The complementarity of the information provided by the surface and pose analysis may help to identify abnormal white and grey matter growth, hinting toward a pattern of neural and cellular dysmaturation.
Topics: Female; Humans; Infant, Newborn; Infant, Premature; Lateral Ventricles; Magnetic Resonance Imaging; Male; Prospective Studies; Putamen; Thalamus
PubMed: 28649491
DOI: 10.1016/j.nicl.2017.05.025 -
Aging Cell Jul 2023Age is a major risk factor for neurodegenerative diseases. Shortening of leucocyte telomeres with advancing age, arguably a measure of "biological" age, is a known...
Age is a major risk factor for neurodegenerative diseases. Shortening of leucocyte telomeres with advancing age, arguably a measure of "biological" age, is a known phenomenon and epidemiologically correlated with age-related disease. The main mechanism of telomere shortening is cell division, rendering telomere length in post-mitotic cells presumably stable. Longitudinal measurement of human brain telomere length is not feasible, and cross-sectional cortical brain samples so far indicated no attrition with age. Hence, age-related changes in telomere length in the brain and the association between telomere length and neurodegenerative diseases remain unknown. Here, we demonstrate that mean telomere length in the putamen, a part of the basal ganglia, physiologically shortens with age, like leukocyte telomeres. This was achieved by using matched brain and leukocyte-rich spleen samples from 98 post-mortem healthy human donors. Using spleen telomeres as a reference, we further found that mean telomere length was brain region-specific, as telomeres in the putamen were significantly shorter than in the cerebellum. Expression analyses of genes involved in telomere length regulation and oxidative phosphorylation revealed that both region- and age-dependent expression pattern corresponded with region-dependent telomere length dynamics. Collectively, our results indicate that mean telomere length in the human putamen physiologically shortens with advancing age and that both local and temporal gene expression dynamics correlate with this, pointing at a potential mechanism for the selective, age-related vulnerability of the nigro-striatal network.
Topics: Humans; Putamen; Cross-Sectional Studies; Telomere Shortening; Risk Factors; Telomere
PubMed: 37129365
DOI: 10.1111/acel.13861 -
The American Journal of Psychiatry Jan 2023Cortical-subcortical hyperconnectivity related to affective-behavioral integration and cortical network hypoconnectivity related to cognitive control have been... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Cortical-subcortical hyperconnectivity related to affective-behavioral integration and cortical network hypoconnectivity related to cognitive control have been demonstrated in obsessive-compulsive disorder (OCD); the study objective was to examine whether these connectivity patterns predict treatment response.
METHODS
Adolescents (ages 12-17) and adults (ages 24-45) were randomly assigned to 12 sessions of exposure and response prevention (ERP) or stress management therapy (SMT), an active control. Before treatment, resting-state connectivity of ventromedial prefrontal cortical (vmPFC), cingulo-opercular, frontoparietal, and subcortical regions was assessed with functional MRI. OCD severity was assessed with the Yale-Brown Obsessive Compulsive Scale before, during, and after treatment. Usable fMRI and longitudinal symptom data were obtained from 116 patients (68 female; 54 adolescents; 60 medicated).
RESULTS
ERP produced greater decreases in symptom scores than SMT. ERP was selectively associated with less vmPFC-subcortical (caudate and thalamus) connectivity in both age groups and primarily in unmedicated participants. Greater symptom improvement with both ERP and SMT was associated with greater cognitive-control (cingulo-opercular and frontoparietal) and subcortical (putamen) connectivity across age groups. Developmental specificity was observed across ERP and SMT treatments, such that greater improvements with ERP than SMT were associated with greater frontoparietal-subcortical (nucleus accumbens) connectivity in adolescents but greater connectivity between frontoparietal regions in adults. Comparison of response-predictive connections revealed no significant differences compared with a matched healthy control group.
CONCLUSIONS
The results suggest that less vmPFC-subcortical connectivity related to affect-influenced behavior may be important for ERP engagement, whereas greater cognitive-control and motor circuit connectivity may generally facilitate response to psychotherapy. Finally, neural predictors of treatment response may differ by age.
Topics: Humans; Adult; Female; Adolescent; Child; Young Adult; Middle Aged; Prefrontal Cortex; Psychotherapy; Nucleus Accumbens; Putamen; Obsessive-Compulsive Disorder; Magnetic Resonance Imaging; Brain Mapping
PubMed: 36475374
DOI: 10.1176/appi.ajp.21111173 -
Human Brain Mapping Jan 2022To identify neuroimaging biomarkers of alcohol dependence (AD) from structural magnetic resonance imaging, it may be useful to develop classification models that are... (Meta-Analysis)
Meta-Analysis
To identify neuroimaging biomarkers of alcohol dependence (AD) from structural magnetic resonance imaging, it may be useful to develop classification models that are explicitly generalizable to unseen sites and populations. This problem was explored in a mega-analysis of previously published datasets from 2,034 AD and comparison participants spanning 27 sites curated by the ENIGMA Addiction Working Group. Data were grouped into a training set used for internal validation including 1,652 participants (692 AD, 24 sites), and a test set used for external validation with 382 participants (146 AD, 3 sites). An exploratory data analysis was first conducted, followed by an evolutionary search based feature selection to site generalizable and high performing subsets of brain measurements. Exploratory data analysis revealed that inclusion of case- and control-only sites led to the inadvertent learning of site-effects. Cross validation methods that do not properly account for site can drastically overestimate results. Evolutionary-based feature selection leveraging leave-one-site-out cross-validation, to combat unintentional learning, identified cortical thickness in the left superior frontal gyrus and right lateral orbitofrontal cortex, cortical surface area in the right transverse temporal gyrus, and left putamen volume as final features. Ridge regression restricted to these features yielded a test-set area under the receiver operating characteristic curve of 0.768. These findings evaluate strategies for handling multi-site data with varied underlying class distributions and identify potential biomarkers for individuals with current AD.
Topics: Alcoholism; Cerebral Cortex; Humans; Machine Learning; Magnetic Resonance Imaging; Multicenter Studies as Topic; Neuroimaging; Putamen; Reproducibility of Results
PubMed: 33064342
DOI: 10.1002/hbm.25248 -
Minerva Medica Dec 2023
Topics: Humans; Putamen; Punctures
PubMed: 37293891
DOI: 10.23736/S0026-4806.23.08662-7