The functional role of the basal ganglia (BG) in the gating of suitable motor responses to the cortex is well established. Growing evidence supports an analogous role of the BG during working memory ...encoding, a task phase in which the “input-gating” of relevant materials (or filtering of irrelevant information) is an important mechanism supporting cognitive capacity and the updating of working memory buffers. One important aspect of stimulus relevance is the novelty of working memory items, a quality that is understudied with respect to its effects on corticostriatal function and connectivity. To this end, we used functional magnetic resonance imaging (fMRI) in 74 healthy volunteers performing an established Sternberg working memory task with different task phases (encoding vs. retrieval) and degrees of stimulus familiarity (novel vs. previously trained). Activation analyses demonstrated a highly significant engagement of the anterior striatum, in particular during the encoding of novel working memory items. Dynamic causal modeling (DCM) of corticostriatal circuit connectivity identified a selective positive modulatory influence of novelty encoding on the connection from the dorsolateral prefrontal cortex (DLPFC) to the anterior striatum. These data extend prior research by further underscoring the relevance of the BG for human cognitive function and provide a mechanistic account of the DLPFC as a plausible top-down regulatory element of striatal function that may facilitate the “input-gating” of novel working memory materials.
Physical activity substantially improves well-being and mental health, but the underlying brain processes remain unclear. Most research concerns exercise, although the majority of everyday human ...behaviors, such as walking or stair climbing, are nonexercise activities. Combining neuroimaging with ecological assessment of activity and GPS-triggered smartphone diaries, we show a specific association of nonexercise activity with energy in two independent samples mediated by the subgenual part of the anterior cingulate cortex (sgACC), a key emotion regulatory site. Furthermore, energy predicted a range of mental health metrics. sgACC volume moderated humans' emotional gain from nonexercise activity in real life: Individuals with low sgACC volume, a risk factor for depression, felt less energized when inactive but benefited more from periods of high nonexercise activity. This suggests an everyday life mechanism affecting affective well-being in the general population and, if substantiated in patient samples, a risk and resilience process for mood disorders.
Graph theoretical functional magnetic resonance imaging (fMRI) studies have demonstrated that brain networks reorganize significantly during motor skill acquisition, yet the associations between ...motor learning ability, brain network features, and the underlying biological mechanisms remain unclear. In the current study, we applied a visually guided sequential pinch force learning task and graph theoretical analyses to investigate the associations between short-term motor learning ability and resting-state brain network metrics in 60 healthy subjects. We further probed the test-retest reliability (
= 26) and potential effects of the
-methyl-
-aspartate (NMDA) antagonist ketamine (
= 19) in independent healthy volunteers. Our results show that the improvement of motor performance after short-term training was positively correlated with small-worldness (
= 0.032) and global efficiency (
= 0.025), whereas negatively correlated with characteristic path length (
= 0.014) and transitivity (
= 0.025). In addition, using network-based statistics (NBS), we identified a learning ability–associated (
= 0.037) and ketamine-susceptible (
= 0.027) cerebellar-cortical network with fair to good reliability (intraclass correlation coefficient ICC > 0.7) and higher functional connectivity in better learners. Our results provide new evidence for the association of intrinsic brain network features with motor learning and suggest a role of NMDA-related glutamatergic processes in learning-associated subnetworks.
Learning a new motor skill prompts immediate reconfigurations of distributed brain networks followed by adaptive changes in intrinsic brain circuits related to synaptic plasticity. Here, we identify global brain network properties and a cerebellar-cortical functional subnetwork that are both significantly associated with motor learning ability in a previously trained visuomotor task in humans. We further show that the associated functional subnetwork connectivity but not the global brain network properties are susceptible to ketamine. Our findings suggest a distinct functional role for learning-related global versus local network metrics and support the idea of a preferential susceptibility of learning-associated subnetworks to
-methyl-
-aspartate antagonist and plasticity-related consolidation effects.
•A third of the amyotrophic lateral sclerosis patients exhibited T2-weighted hyperintensity of the Corticospinal Tract (ALS CST+).•ALS CST+patients showed equivalent ALSFRS-R score and disease ...progression rate with the ALS CST- patients.•The Amplitude of Low-Frequency Fluctuation (ALFF) and Functional Connectivity (FC) of the premotor areas displayed “HC>ALS CST+ > ALS CST-” group differences. Significant associations between the premotor ALFF and FC were identified with ALSFRS-R and disease duration in the ALS CST- group, but no the ALS CST+group.•All results indicate that the ALS CST+group showed functional compensation of the premotor areas.•The current study indicates neurologists may consider different interventions for ALS patients with clear-visible CST hyperintensity on T2-weighted images during clinical routine examination.
Nearly half of the amyotrophic lateral sclerosis (ALS) patients showed hyperintensity of the corticospinal tract (CST+), yet whether brain functional pattern differs between CST+and CST- patients remains obscure. In the current study, 19 ALS CST+, 41 ALS CST- patients and 37 healthy controls (HC) underwent resting state fMRI scans. We estimated local activity and connectivity patterns via the Amplitude of Low Frequency Fluctuations (ALFF) and the Network-Based Statistic (NBS) approaches respectively. The ALS CST+patients did not differ from the CST- patients in amyotrophic lateral sclerosis functional rating scale revised (ALSFRS-R) score and disease duration. ALFF of the superior frontal gyrus (SFG) and the inferior frontal gyrus pars opercularis (OIFG) were highest in the HC and lowest in the ALS CST- patients, resulting in significant group differences (PFWE<0.05). NBS analysis revealed a frontal network consisting of connections between SFG, OIFG, orbital frontal gyrus, middle cingulate cortex and the basal ganglia, which exhibited HC>ALS CST+ > ALS CST- group differences (PFWE=0.037) as well. The ALFF of the OIFG was significantly correlated with ALSFRS-R (R=0.34, P=0.028) and mean connectivity of the frontal network was trend-wise significantly correlated with disease duration (R=-0.31, P=0.052) in the ALS CST- patients. However, these correlations were insignificant in ALS CST+patients (P values > 0.8). In conclusion, The ALS CST+patients exhibited different patterns of baseline functional activity and connectivity in the frontal cortex which may indicate a functional compensatory effect.
The huge heterogeneity of the disease progression rate may cause inconsistent findings between local activity and functional connectivity of the primary sensorimotor area (PSMA) in amyotrophic ...lateral sclerosis (ALS). For illustration of this hypothesis, resting‐state fMRI (RS‐fMRI) data were collected and analyzed on 38 “definite” or “probable” ALS patients (19 fast and 19 slow, cut off median = 0.41) and 37 matched healthy controls. Amplitude of low frequency fluctuations (ALFFs) and functional connectivity strength (FCS) were analyzed within the PSMA. There was a decreased ALFF (pFDR <.05) and FCS (p = .022) in all ALS patients. The two metrics shared about 50% of variance (R = .7) and both showed significant positive correlation with ALS Functional Rating Scale‐Revised (ALSFRS‐R) in the fast (p values <.034) but not in the slow progression groups. Interestingly, when regressing out the ALFF, the PSMA network FCS, especially the inter‐hemisphere FCS, showed negative correlation with the ALSFRS‐R score in the slow (R = −.54, p = .026) but not the fast progression group. In summary, the current results suggest that RS‐fMRI local activity and network functional connectivity accounts for the severity differently in the slow and fast progression ALS patients.
(1) The decreased ALFF could account for the severity (ALSFRS‐R score) in the fast progression group but not for slow progression group; (2) The network FCS, especially the inter‐hemisphere FCS, showed both pathophysiological effect (i.e., decreased FCS) and a compensatory effect (i.e., negative correlation with severity when the covariate ALFF was regressed out) in the slow progression group, but not in the fast group.
Invasive electrophysiological recordings in patients with Parkinson's disease (PD) are extremely difficult for cross-sectional comparisons with healthy controls. Noninvasive approaches for ...identifying information flow between the motor area and the subthalamic nucleus (STN) are critical for evaluation of treatment strategy. We aimed to investigate the direction of the cortical-STN hyperdirect pathway using simultaneous 18F-FDG-PET/functional magnetic resonance imaging (fMRI). Data were acquired during resting state on 34 PD patients and 25 controls. The ratio of standard uptake value for PET images and the STN functional connectivity (FC) maps for fMRI data were generated. The metabolic connectivity mapping (MCM) approach that combines PET and fMRI data was used to evaluate the direction of the connectivity. Results showed that PD patients exhibited both increased FDG uptake and STN-FC in the sensorimotor area (PFDR < 0.05). MCM analysis showed higher cortical-STN MCM value in the PD group (F = 6.63, P = 0.013) in the left precentral gyrus. There was a high spatial overlap between the increased glucose metabolism and increased STN-FC in the sensorimotor area in PD. The MCM approach further revealed an exaggerated cortical input to the STN in PD, supporting the precentral gyrus as a target for treatment such as the repetitive transcranial magnetic stimulation.
Abstract
Gene expression plays a critical role in the pathogenesis of Parkinson's disease (PD). How gene expression profiles are correlated with functional‐metabolic architecture remains obscure. We ...enrolled 34 PD patients and 25 age‐and‐sex‐matched healthy controls for simultaneous
18
F‐FDG‐PET/functional MRI scanning during resting state. We investigated the functional gradients and the ratio of standard uptake value. Principal component analysis was used to further combine the functional gradients and glucose metabolism into functional‐metabolic architecture. Using partial least squares (PLS) regression, we introduced the transcriptomic data from the Allen Institute of Brain Sciences to identify gene expression patterns underlying the affected functional‐metabolic architecture in PD. Between‐group comparisons revealed significantly higher gradient variation in the visual, somatomotor, dorsal attention, frontoparietal, default mode, and subcortical network (
p
FDR
< .048) in PD. Increased FDG‐uptake was found in the somatomotor and ventral attention network while decreased FDG‐uptake was found in the visual network (
p
FDR
< .008). Spatial correlation analysis showed consistently affected patterns of functional gradients and metabolism (
p
= 2.47 × 10
−8
). PLS analysis and gene ontological analyses further revealed that genes were mainly enriched for metabolic, catabolic, cellular response to ions, and regulation of DNA transcription and RNA biosynthesis. In conclusion, our study provided genetic pathological mechanism to explain imaging‐defined brain functional‐metabolic architecture of PD.
Abstract
Increased glucose metabolism and decreased low-frequency fluctuation have been consistently reported in the motor area of Parkinson’s disease (PD). The reason for such seeming paradox is ...unclear. Here, we enrolled 34 PD patients and 25 healthy controls (HCs) for hybrid PET/fMRI scan (PET/fMRI(discovery) dataset). In addition, 2 replication datasets, namely fMRI(validation-1) and fMRI(validation-2) dataset, were also included. We computed ratio of standard uptake value (SUVr) to measure FDG-uptake. The amplitude of low-frequency fluctuations (ALFF) for the following 4 frequency bands was calculated: slow-5, slow-4, slow-3, and slow-2. We obtained a significant group-by-frequency interaction effect of ALFF in the paracentral lobule/supplementary motor area (PFWE = 0.003) and the right sensorimotor area (PFWE < 0.001) in the PET/fMRI(discovery) dataset, which could be replicated using fMRI(validation-1) and fMRI(validation-2) datasets (PFWE < 0.05). In detail, HCs exhibited power law-like fluctuation pattern, but PD patients did not. Correlation analyses further revealed significant associations between ALFF and FDG-uptake in HCs (P-values < 0.031), but not in PD (P-values > 0.28). Taken together, this study identified a fluctuation shift over frequency effect in PD patients, which further disassociated with glucose metabolism in the motor cortex.
Neurodegeneration of the substantia nigra affects putamen activity in Parkinson's disease (PD), yet in vivo evidence of how the substantia nigra modulates putamen glucose metabolism in humans is ...missing. We aimed to investigate how substantia nigra modulates the putamen glucose metabolism using a cross‐sectional design. Resting‐state fMRI, susceptibility‐weighted imaging, and 18F‐fluorodeoxyglucose‐PET (FDG‐PET) data were acquired. Forty‐two PD patients and 25 healthy controls (HCs) were recruited for simultaneous PET/MRI scanning. The main measurements of the current study were R2* images representing iron deposition (28 PD and 25 HCs), standardized uptake value ratio (SUVr) images representing FDG‐uptake (33 PD and 25 HCs), and resting state functional connectivity maps from resting state fMRI (34 PD and 25 HCs). An interaction term based on the general linear model was used to investigate the joint modulation effect of nigral iron deposition and nigral‐putamen functional connectivity on putamen FDG‐uptake. Compared with HCs, we found increased iron deposition in the substantia nigra (p = .007), increased FDG‐uptake in the putamen (left: PFWE < 0.001; right: PFWE < 0.001), and decreased functional connectivity between the substantia nigra and the anterior putamen (left PFWE < 0.001, right: PFWE = 0.007). We then identified significant interaction effect of nigral iron deposition and nigral‐putamen connectivity on FDG‐uptake in the putamen (p = .004). The current study demonstrated joint modulation effect of the substantia nigra iron deposition and nigral‐putamen functional connectivity on putamen glucose metabolic distribution, thereby revealing in vivo pathological mechanism of nigrostriatal neurodegeneration of PD.
Compared to healthy controls, Parkinson's disease patients exhibited increased iron deposition in the substantia nigra, increased putamen FDG‐uptake and decreased nigral‐putamen FC. Nigral iron deposition and FC can jointly modulate putamen glucose metabolism.
IMPORTANCE: Schizophrenia is a severe mental disorder in which epigenetic mechanisms may contribute to illness risk. Epigenetic profiles can be derived from blood cells, but to our knowledge, it is ...unknown whether these predict established brain alterations associated with schizophrenia. OBJECTIVE: To identify an epigenetic signature (quantified as polymethylation score PMS) of schizophrenia using machine learning applied to genome-wide blood DNA-methylation data; evaluate whether differences in blood-derived PMS are mirrored in data from postmortem brain samples; test whether the PMS is associated with alterations of dorsolateral prefrontal cortex hippocampal (DLPFC-HC) connectivity during working memory in healthy controls (HC); explore the association between interactions between polygenic and epigenetic risk with DLPFC-HC connectivity; and test the specificity of the signature compared with other serious psychiatric disorders. DESIGN, SETTING, AND PARTICIPANTS: In this case-control study conducted from 2008 to 2018 in sites in Germany, the United Kingdom, the United States, and Australia, blood DNA-methylation data from 2230 whole-blood samples from 6 independent cohorts comprising HC (1238 55.5%) and participants with schizophrenia (803 36.0%), bipolar disorder (39 1.7%), major depressive disorder 35 1.6%), and autism (27 1.2%), and first-degree relatives of all patient groups (88 3.9%) were analyzed. DNA-methylation data were further explored from 244 postmortem DLPFC samples from 136 HC and 108 patients with schizophrenia. Neuroimaging and genome-wide association data were available for 393 HC. The latter data was used to calculate a polygenic risk score (PRS) for schizophrenia. The data were analyzed in 2019. MAIN OUTCOMES AND MEASURES: The accuracy of schizophrenia control classification based on machine learning using epigenetic data; association of schizophrenia PMS scores with DLPFC-HC connectivity; and association of the interaction between PRS and PMS with DLPFC-HC connectivity. RESULTS: This study included 7488 participants (4395 men 58.7%), of whom 3158 (2230 men 70.6%) received a diagnosis of schizophrenia. The PMS signature was associated with schizophrenia across 3 independent data sets (area under the curve AUC from 0.69 to 0.78; P value from 0.049 to 1.24 × 10−7) and data from postmortem DLPFC samples (AUC = 0.63; P = 1.42 × 10−4), but not with major depressive disorder (AUC = 0.51; P = .16), autism (AUC = 0.53; P = .66), or bipolar disorder (AUC = 0.58; P = .21). Pathways contributing most to the classification included synaptic processes. Healthy controls with schizophrenia-like PMS showed significantly altered DLPFC-HC connectivity (validation methylation/magnetic resonance imaging, t < −3.81; P for familywise error, <.04; validation magnetic resonance imaging, t < −3.54; P for familywise error, <.02), mirroring the lack of functional decoupling in schizophrenia. There was no significant association of the interaction between PMS and PRS with DLPFC-HC connectivity (P > .19). CONCLUSIONS AND RELEVANCE: We identified a reproducible blood DNA-methylation signature specific for schizophrenia that was correlated with altered functional DLPFC-HC coupling during working memory and mapped to methylation differences found in DLPFC postmortem samples. This indicates a possible epigenetic contribution to a schizophrenia intermediate phenotype and suggests that PMS could be of interest to be studied in the context of multimodal biomarkers for disease stratification and treatment personalization.
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