Age-related decrease of functional connectivity additional to gray matter atrophy in a network for movement initiation

The relationship between age-related changes in brain structural connectivity (SC) and functional connectivity (FC) with cognition is not well understood. Furthermore, it is not clear whether cognition is represented via a similar spatial pattern of FC and SC or instead is mapped by distinct sets of distributed connectivity patterns. To this end, we used a longitudinal, within-subject, multimodal approach aiming to combine brain data from diffusion-weighted MRI (DW-MRI), and functional MRI (fMRI) with behavioral evaluation, to better understand how changes in FC and SC correlate with changes in cognition in a sample of older adults. FC and SC measures were derived from the multimodal scans acquired at two time points. Change in FC and SC was correlated with 13 behavioral measures of cognitive function using Partial Least Squares Correlation (PLSC). Two of the measures indicate an age-related change in cognition and the rest indicate baseline cognitive performance. FC and SC—cognition correlations were expressed across several cognitive measures, and numerous structural and functional cortical connections, mainly cingulo-opercular, dorsolateral prefrontal, somatosensory and motor, and temporo-parieto-occipital, contributed both positively and negatively to the brain-behavior relationship. Whole-brain FC and SC captured distinct and independent connections related to the cognitive measures. Overall, we examined age-related function-structure associations of the brain in a comprehensive and integrated manner, using a multimodal approach. We pointed out the behavioral relevance of age-related changes in FC and SC. Taken together, our results highlight that the heterogeneity in distributed FC and SC connectivity patterns provide unique information about the variable nature of healthy cognitive aging.

Previous studies have reported significant changes in functional connectivity among various brain networks following sleep restriction. The cerebellum plays an important role in information processing for motor control and provides this information to higher-order networks. However, little is known regarding how sleep deprivation influences functional connectivity between the cerebellum and the cerebral cortex in humans. The present study aimed to investigate the changes in cerebellar functional connectivity induced by sleep deprivation, and their relationship with psychomotor vigilance. A total of 52 healthy men underwent resting-state functional magnetic resonance imaging before and after 36 h of total sleep deprivation. Functional connectivity was evaluated using region of interest (ROI)-to-ROI analyses, using 26 cerebellar ROIs as seed regions. Psychomotor vigilance was assessed using the psychomotor vigilance test (PVT). Decreased functional connectivity was observed between cerebellar seed regions and the bilateral postcentral, left inferior frontal, left superior medial frontal, and right middle temporal gyri. In contrast, increased functional connectivity was observed between the cerebellum and the bilateral caudate. Furthermore, decrease in functional connectivity between the cerebellum and the postcentral gyrus was negatively correlated with increase in PVT reaction times, while increase in functional connectivity between the cerebellum and the bilateral caudate was positively correlated with increase in PVT reaction times. These results imply that altered cerebellar functional connectivity is associated with impairment in psychomotor vigilance induced by sleep deprivation.

BackgroundPatients with amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD) show functional and structural connectivity alterations in the default mode network (DMN) while cerebrovascular disease (CeVD) shows functional and structural connectivity changes in the executive control network (ECN). Such disruptions are associated with memory and executive function impairment, respectively. Concurrent AD and CeVD pathology is associated with a higher rate of cognitive decline and differential neurodegenerative patterns. Together, such findings are likely reflective of different underlying pathology in AD with and without CeVD. However, few studies have examined the effect of CeVD on network functional connectivity (task-free functional magnetic resonance imaging (fMRI)) and structural connectivity (diffusion MRI) of the DMN and ECN in aMCI and AD using a hypothesis-driven multiple seed-based approach.MethodsWe examined functional and structural connectivity network changes in 39 aMCI, 50 aMCI+CeVD, 47 AD, 47 AD+CeVD, and 65 healthy controls (HCs) and their associations with cognitive impairment in the executive/attention and memory domains.ResultsWe demonstrate divergent DMN and ECN functional connectivity changes in CeVD and non-CeVD subjects. Compared with controls, intra-DMN hippocampal functional connectivity reductions were observed in both AD and AD+CeVD, while intra-DMN parietal and medial prefrontal-parietal functional connectivity was higher in AD+CeVD and aMCI+CeVD, but lower in AD. Intra-ECN frontal functional connectivity increases and fronto-parietal functional connectivity decreases occurred in CeVD but not non-CeVD subjects. Such functional connectivity alterations were related with cognitive impairment in a dissociative manner: intra-DMN functional connectivity changes were associated with worse cognition primarily in non-CeVD groups, while intra-ECN functional connectivity changes were associated with worse cognition primarily in CeVD groups. Additionally, CeVD and non-CeVD groups showed overlapping and distinct alterations in inter-network DMN-ECN functional connectivity depending on disease severity. In contrast to functional connectivity, CeVD groups had greater network structural connectivity damage compared with non-CeVD groups in both aMCI and AD patients. Network structural connectivity damage was associated with worse cognition.ConclusionsWe demonstrate differential functional and structural network changes between aMCI and AD patients with and without CeVD through diverging and deleterious network-based degeneration underlying domain-specific cognitive impairment.

Brain-computer interface (BCI) technology is being incorporated into new stroke rehabilitation devices, but little is known about brain changes associated with its use. We collected anatomical and functional MRI of nine stroke patients with persistent upper extremity motor impairment before, during, and after therapy using a BCI system. Subjects were asked to perform finger tapping of the impaired hand during fMRI. Action Research Arm Test (ARAT), 9-Hole Peg Test (9-HPT), and Stroke Impact Scale (SIS) domains of Hand Function (HF) and Activities of Daily Living (ADL) were also assessed. Group-level analyses examined changes in whole-brain task-based functional connectivity (FC) to seed regions in the motor network observed during and after BCI therapy. Whole-brain FC analyses seeded in each thalamus showed FC increases from baseline at mid-therapy and post-therapy (p < 0.05). Changes in FC between seeds at both the network and the connection levels were examined for correlations with changes in behavioral measures. Average motor network FC was increased post-therapy, and changes in average network FC correlated (p < 0.05) with changes in performance on ARAT (R2 = 0.21), 9-HPT (R2 = 0.41), SIS HF (R2 = 0.27), and SIS ADL (R2 = 0.40). Multiple individual connections within the motor network were found to correlate in change from baseline with changes in behavioral measures. Many of these connections involved the thalamus, with change in each of four behavioral measures significantly correlating with change from baseline FC of at least one thalamic connection. These preliminary results show changes in FC that occur with the administration of rehabilitative therapy using a BCI system. The correlations noted between changes in FC measures and changes in behavioral outcomes indicate that both adaptive and maladaptive changes in FC may develop with this therapy and also suggest a brain-behavior relationship that may be stimulated by the neuromodulatory component of BCI therapy.

Autism spectrum disorder (ASD) is associated with disruption of local- and long-range functional connectivity (FC). The direction of those changes in FC (increase or decrease), however, is inconsistent across studies. Further, age-dependent changes of distance-specific FC in ASD remain unclear. In this study, we used resting-state functional magnetic resonance imaging data from sixty-four typical controls (TC) and sixty-four patients with ASD, whom we further classified into child (<11 years), adolescent (11–18 years) and adult cohorts (>18 years). Functional connectivity (FC) analysis was conducted at voxel level. We employed a three-way analysis of covariance on FC to conduct statistical analyses. Results revealed that patients with ASD had lower FC than TC in cerebellum, fusiform gyrus, inferior occipital gyrus and posterior inferior temporal gyrus. Significant diagnosis-by-distance interaction was observed in ASD patients with reduced short-range and long-range FC in posterior cingulate cortex and medial prefrontal cortex. Importantly, we found significant diagnosis-by-age-by-distance interaction in orbitofrontal cortex with short-range FC being lower in autistic children, but –to a less extent– higher in autistic adults. Our findings suggest a major role of connection length in development changes of FC in ASD. We hope our study will facilitate deeper understanding of the neural mechanisms underlying ASD.

ObjectivesThe distribution of pathology in neurodegenerative disease can be predicted by the organizational characteristics of white matter in healthy brains. However, we have very little evidence for the impact these pathological changes have on brain function. Understanding any such link between structure and function is critical for understanding how underlying brain pathology influences the progressive behavioral changes associated with neurodegeneration. Here, we demonstrate such a link between structure and function in individuals with premanifest Huntington's.MethodsUsing diffusion tractography and resting state functional magnetic resonance imaging to characterize white matter organization and functional connectivity, we investigate whether characteristic patterns of white matter organization in the healthy human brain shape the changes in functional coupling between brain regions in premanifest Huntington's disease.ResultsWe find changes in functional connectivity in premanifest Huntington's disease that link directly to underlying patterns of white matter organization in healthy brains. Specifically, brain areas with strong structural connectivity show decreases in functional connectivity in premanifest Huntington's disease relative to controls, while regions with weak structural connectivity show increases in functional connectivity. Furthermore, we identify a pattern of dissociation in the strongest functional connections between anterior and posterior brain regions such that anterior functional connectivity increases in strength in premanifest Huntington's disease, while posterior functional connectivity decreases.InterpretationOur findings demonstrate that organizational principles of white matter underlie changes in functional connectivity in premanifest Huntington's disease. Furthermore, we demonstrate functional antero–posterior dissociation that is in keeping with the caudo–rostral gradient of striatal pathology in HD.

During growth and aging, the role of the hippocampus in memory depends on its interactions with related brain regions. Particularly, two subregions, anterior hippocampus (aHipp) and posterior hippocampus (pHipp), play different and critical roles in memory processing. However, age-related changes of hippocampus subregions on structure and function are still unclear. Here, we investigated age-related structural and functional characteristics of 106 participants (7-85 years old) in resting state based on fractional anisotropy (FA) and functional connectivity (FC) in aHipp and pHipp in the lifespan. The correlation between FA and FC was also explored to identify the coupling. Furthermore, the Wechsler Abbreviated Scale of Intelligence (WASI) was used to explore the relationship between cognitive ability and hippocampal changes. Results showed that there was functional separation and integration in aHipp and pHipp, and the number of functional connections in pHipp was more than that in aHipp across the lifespan. The age-related FC changes showed four different trends (U-shaped/inverted U-shaped/linear upward/linear downward). And around the age of 40 was a critical period for transformation. Then, FA analyses indicated that all effects of age on the hippocampal structures were nonlinear, and the white matter integrity of pHipp was higher than that of aHipp. In the functional-structural coupling, we found that the age-related FA of the right aHipp (aHipp.R) was negatively related to the FC. Finally, through the WASI, we found that the age-related FA of the left aHipp (aHipp.L) was positively correlated with verbal IQ (VERB) and vocabulary comprehension (VOCAB.T), the FA of aHipp.R was only positively correlated with VERB, and the FA of the left pHipp (pHipp.L) was only positively correlated with VOCAB.T. These FC and FA results supported that age-related normal memory changes were closely related to the hippocampus subregions. We also provided empirical evidence that memory ability was altered with the hippocampus, and its efficiency tended to decline after age 40.

We aimed to investigate whether cognitive deficits and structural and functional connectivity changes can be detected before symptom onset in a large cohort of carriers of microtubule-associated protein tau and progranulin mutations. In this case-control study, 75 healthy individuals (aged 20-70 years) with 50% risk for frontotemporal dementia (FTD) underwent DNA screening, neuropsychological assessment, and structural and functional MRI. We used voxel-based morphometry and tract-based spatial statistics for voxelwise analyses of gray matter volume and diffusion tensor imaging measures. Using resting-state fMRI scans, we assessed whole-brain functional connectivity to frontoinsula, anterior midcingulate cortex (aMCC), and posterior cingulate cortex. Although carriers (n = 37) and noncarriers (n = 38) had similar neuropsychological performance, worse performance on Stroop III, Ekman faces, and Happé cartoons correlated with higher age in carriers, but not controls. Reduced fractional anisotropy and increased radial diffusivity throughout frontotemporal white matter tracts were found in carriers and correlated with higher age. Reductions in functional aMCC connectivity were found in carriers compared with controls, and connectivity between frontoinsula and aMCC seeds and several brain regions significantly decreased with higher age in carriers but not controls. We found no significant differences or age correlations in posterior cingulate cortex connectivity. No differences in regional gray matter volume were found. This study convincingly demonstrates that alterations in structural and functional connectivity develop before the first symptoms of FTD arise. These findings suggest that diffusion tensor imaging and resting-state fMRI may have the potential to become sensitive biomarkers for early FTD in future clinical trials.

Understanding the relationship between functional connectivity (FC) of higher-order neurocognitive networks and age-related cognitive decline is a complex and evolving field of research. Decreases in FC have been associated with cognitive decline in persons with Alzheimer's disease and related dementias (ADRD). However, the contributions of FC have been less straightforward in typical cognitive aging. Some investigations suggest relatively robust FC within neurocognitive networks differentiates unusually successful cognitive aging from average aging, while others do not. Methodologic limitations in data processing and varying definitions of 'successful aging' may have contributed to the inconsistent results to date. The current study seeks to address previous limitations by optimized MRI methods to examine FC in the well-established SuperAging phenotype, defined by age and cognitive performance as individuals 80 and older with episodic memory performance equal to or better than 50-to-60-year-olds. Within- and between-network FC of large-scale neurocognitive networks were compared between 24 SuperAgers and 16 cognitively average older-aged control (OACs) with stable cognitive profiles using resting-state functional MRI (rs-fMRI) from a single visit. Group classification was determined based on measures of episodic memory, executive functioning, verbal fluency and picture naming. Inclusion criteria required stable cognitive status across two visits. First, we investigated the FC within and between seven resting-state networks from a common atlas parcellation. A separate index of network segregation was also compared between groups. Second, we investigated the FC between six subcomponents of the default mode network (DMN), the neurocognitive network commonly associated with memory performance and disrupted in persons with ADRD. For each analysis, FCs were compared across groups using two-sample independent t-tests and corrected for multiple comparisons. There were no significant between-group differences in demographic characteristics including age, sex and education. At the group-level, within-network FC, between-network FC, and segregation measurements of seven large-scale networks, including subcomponents of the DMN, were not a primary differentiator between cognitively average aging and SuperAging phenotypes. Thus, FC within or between large-scale networks does not appear to be a primary driver of the exceptional memory performance observed in SuperAgers. These results have relevance for differentiating the role of FC changes associated with cognitive aging from those associated with ADRD.

Changes in regional cerebral blood flow and functional connectivity in the cholinergic pathway associated with cognitive performance in subjects with mild Alzheimer's disease after 12-week donepezil treatment

The effect of tDCS on functional connectivity in primary progressive aphasia

Objective To study the resting-state functional connectivity(FC) changes of anterior cingulate cortex(ACC) and amygdala in adolescent patients with medication-naive first-episode major depressive disorder(MDD). Methods Medication-naive first-episode MDD adolescents(n=30) and pair-wise matched healthy controls(HCs, n=29) underwent resting-state functional magnetic resonance images(fMRI). To study whether there were different in FC changes between amygdala and ACC and whole brain regions, and whether abnormal FC was related to clinical characteristics. Results Compared with HCs, the adolescent MDD patients showed decreased FC between the left amygdala and right thalamus(MNI x, y, z: 15, -21, 18)(t=-2.85)and increased FC between the left amygdala and the bilateral temporal middle gyrus, left occipital gyrus, right medial prefrontal cortex(MPFC)(MNI x, y, z: 9, 66, 15)(t=2.80). The right amygdale showed decreased FC with bilateral middle frontal gyrus, left caudate(MNI x, y, z: -15, -9, 21)(t=-2.53), right thalamus(MNI x, y, z: 12, -36, 12)(t=-3.01), right cerebellum(MNI x, y, z: 3, -84, -33)(t=-2.45) and increased FC with right temporal middle gyrus, right MPFC(MNI x, y, z: 6, 69, 12)(t=2.41). The left ACC showed decreased FC with left cerebellum(MNI x, y, z: 12, -87, -24)(t=-2.36), left frontal inferior triangle gyrus, right frontal inferior orbital gyrus and increased FC with right frontal middle orbital gyrus.The right ACC showed decreased FC with left caudate(MNI x, y, z: -15, 21, 6)(t=-2.29), right temporal middle gyrus, right MPFC(MNI x, y, z: 9, 54, 36)(t=-2.29), right frontal inferior orbital gyrus, right angular(MNI x, y, z: 45, -51, 21)(t=-3.01), left dorsolateral prefrontal cortex(MNI x, y, z: -21, 33, 36)(t=-2.61). The increased FC between the left amygdale and bilateral temporal middle gyrus showed positive correlation with the score of HAMD(r=0.50, P<0.05; r=0.45, P<0.05). And the FC between the right amygdale and right middle frontal gyrus was positive correlation with duration of disease(r=0.63, P<0.05). Conclusion There is widespread FC disorder in amygdala and ACC in adolescents patients with first-episode depression.Abnormal FC changes may be the neuropathological mechanism of depression. Key words: Adolescent major depressive disorder; Resting-state fMRI; Functional connectivity; Amygdala; Anterior cingulated cortex

Changes in functional connectivity related to direct training and generalization effects of a word finding treatment in chronic aphasia

Functional connectivity (FC) is crucial for the execution of functional activities and the progression of diseases. From a functional perspective, changes in subthalamic nucleus (STN)-based FC and network properties across lifespan and their effectiveness in predicting age require further investigation. The STN-based atlas was constructed using neuroimaging data from 1060 healthy participants. Based on this atlas, the FC and brain network properties were quantified subsequently. Both linear and non-linear changes in FC and network properties with aging, and relationships across brain regions were analyzed with generalized additive model (GAM). Connectome-based predictive modeling (CPM) was used to evaluate the performance of FC in predicting age, while computational lesion analysis was utilized to identify the FC with significant contributions to model performance. The STN-based atlas mainly involved bilateral sensory, motor, and sensory-motor integration cortices, subcortical nuclei, and cerebellar crus I and II. Global network properties were declined with aging (all P ​< ​0.05). Significant non-linear age-related changes were identified in regional network properties of bilateral M1 and right STN (all P ​< ​0.05). There were non-linear negative relationships between bilateral M1, and between right M1 and right STN (all P ​< ​0.05). The FC within motor cortex, and between limbic areas and subcortical nuclei, significantly contributed to the performance of CPM. Therefore, from a functional perspective, dynamic changes in FC and network properties across the lifespan were highlighted, particularly within motor-related circuits. This provides valuable insights into neural mechanisms underlying motor dysfunction during aging and informs circuit-based neuromodulation strategies.

Parkinson's disease (PD) is characterized by degenerative changes of nigral dopamine neurons, resulting in the dopaminergic denervation of the striatum. Resting state networks studies have demonstrated that dopamine modulates distinct network connectivity patterns in both a linear and a nonlinear fashion, but quantitative analyses of dopamine-dependent functional connectivity secondary to PD pathology were less informative. In the present study, we performed a correlation analysis between striatal dopamine levels assessed quantitatively by FP-CIT positron emission tomography imaging and resting-state functional connectivity in 23 drug naïve de novo patients with PD to elucidate dopamine-dependent functional networks. The major finding is that the patterns of dopamine-dependent positive functional connectivity varied depending on the location of striatal seeds. Dopamine-dependent functional connectivity with the caudate predominantly overlay pericentral cortical areas, whereas dopamine-dependent structures functionally connected with the posterior putamen predominantly involved cerebellar areas. The dorsolateral frontal area overlapped as a dopamine-dependent cortical region that was positively connected with the anterior and posterior putamen. On the other hand, cortical areas where functional connectivity from the posterior cingulate was negatively correlated with dopaminergic status in the posterior putamen were localized in the left anterior prefrontal area and the parietal area. Additionally, functional connectivity between the anterior putamen and mesiofrontal areas was negatively coupled with striatal dopamine levels. The present study demonstrated that dopamine-dependent functional network connectivity secondary to PD pathology mainly exhibits a consistent pattern, albeit with some variation. These patterns may reflect the diverse effects of dopaminergic medication on parkinsonian-related motor and cognitive performance.