Functional connector hubs in the cerebellum.

Accumulating evidence from anatomical and neuroimaging studies suggests that the cerebellum is engaged in a variety of motor and cognitive tasks. Given its various functions, a key question is whether the cerebellum also plays an important role in the brain's integrative functions. Here, we hypothesize the existence of connector regions, also known as connector hubs, where multiple resting state networks converged in the cerebellum. To verify this, we employed a recently developed voxel-level network measure called functional connectivity overlap ratio (FCOR), which could be used to quantify the spatial extent of a region's connection to several large-scale cortical networks. Using resting state functional MRI data from 101 healthy participants, cerebellar FCOR maps were constructed and used to identify the locations of connector hubs in the cerebellum. Results showed that a number of cerebellar regions exhibited strong connectivity with multiple functional networks, verifying our hypothesis. These highly connected regions were located in the posterior cerebellum, especially in lobules VI, VII, and IX, and mainly connected to the core neurocognitive networks such as default mode and executive control networks. Regions associated with the sensorimotor network were also localized in lobule V, VI, and VIII, albeit in small clusters. These cerebellar connector hubs may play an essential role in the processing of information across the core neurocognitive networks.

Fiber-specific white matter analysis reflects upper motor neuron impairment in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: To clarify the relationship between fiber-specific white matter changes in amyotrophic lateral sclerosis (ALS) and clinical signs of upper motor neuron (UMN) involvement, we performed a fixel-based analysis (FBA), a novel framework for diffusion-weighted imaging analysis. METHODS: We enrolled 96 participants, including 48 nonfamilial ALS patients and 48 age- and sex-matched healthy controls (HCs), in this study and conducted whole-brain FBA and voxel-based morphometry analysis. We compared the fiber density (FD), fiber morphology (fiber cross-section [FC]), and a combined index of FD and FC (FDC) between the ALS and HC groups. We performed a tract-of-interest analysis to extract FD values across the significant regions in the whole-brain analysis. Then, we evaluated the associations between FD values and clinical variables. RESULTS: The bilateral corticospinal tracts (CSTs) and the corpus callosum (CC) showed reduced FD and FDC in ALS patients compared with HCs (p < 0.05, familywise error-corrected), and the comparison of FCs revealed no region that was significantly different from another. Voxel-based morphometry showed cortical volume reduction in the regions, including the primary motor area. Clinical scores showed correlations with FD values in the CSTs (UMN score: rho = -0.530, p < 0.001; central motor conduction time [CMCT] in the upper limb: rho = -0.474, p = 0.008; disease duration: rho = -0.383, p = 0.007; ALS Functional Rating Scale-Revised: rho = 0.340, p = 0.018). In addition, patients whose CMCT was not calculated due to unevoked waves also showed FD reduction in the CSTs. CONCLUSIONS: Our findings suggest that FD values in the CST estimated via FBA can be potentially used in evaluating UMN impairments.

Involvement of brain structures in childhood epilepsy with centrotemporal spikes.

BACKGROUND: We aimed to investigate electroencephalography (EEG)-functional magnetic resonance imaging (fMRI) findings to elucidate the interictal epileptiform discharge (IED)-related functional alterations in deep brain structures and the neocortex in childhood epilepsy with centrotemporal spikes (CECTS). METHODS: Ten children with CECTS (median age 8.2 years), referred to our hospital within a year of onset, were eligible for inclusion. They underwent EEG-fMRI recording during sleep. Llongitudinal evaluations, including medical examinations, intelligence tests, and questionnaires about developmental disabilities, were performed. The initial evaluation was performed at the same time as the EEG-fMRI, and the second evaluation was performed over 2 years after the initial evaluation. RESULTS: Three children were unable to maintain sleep during the EEG-fMRI recording, and the remaining seven children were eligible for further assessment. All patients showed unilateral-dominant centrotemporal spikes during scans. One patient had only positive hemodynamic responses, while the others had both positive and negative hemodynamic responses. All patients showed IED-related hemodynamic responses in the bilateral neocortex. For deep brain structures, IED-related hemodynamic responses were observed in the cingulate gyrus (n = 4), basal ganglia (n = 3), thalamus (n = 2), and default mode network (n = 1). Seizure frequencies at the second evaluation were infrequent or absent, and the longitudinal results of intelligence tests and questionnaires were within normal ranges. CONCLUSIONS: We demonstrated that IEDs affect broad brain areas, including deep brain structures such as the cingulate gyrus, basal ganglia, and thalamus. Deep brain structures may play an important role in the pathophysiology of CECTS.

Identifying the brain's connector hubs at the voxel level using functional connectivity overlap ratio.

Neuroimaging studies have shown that the brain is functionally organized into several large-scale brain networks. Within these networks are regions that are widely connected to several other regions within and/or outside the network. Regions that connect to several other networks, known as connector hubs, are believed to be crucial for information transfer and between-network communication within the brain. To identify regions with high between-network connectivity at the voxel level, we introduced a novel metric called functional connectivity overlap ratio (FCOR), which quantifies the spatial extent of a region's connection to a given network. Using resting state functional magnetic resonance imaging data, FCOR maps were generated for several well-known large-scale resting state networks (RSNs) and used to examine the relevant associations among different RSNs, identify connector hub regions in the cerebral cortex, and elucidate the hierarchical functional organization of the brain. Constructed FCOR maps revealed a strong association among the core neurocognitive networks (default mode, salience, and executive control) as well as among primary processing networks (sensorimotor, auditory, and visual). Prominent connector hubs were identified in the bilateral middle frontal gyrus, posterior cingulate, lateral parietal, middle temporal, dorsal anterior cingulate, and anterior insula, among others, regions mostly associated with the core neurocognitive networks. Finally, clustering the whole brain using FCOR features yielded a topological organization that arranges brain regions into a hierarchy of information processing systems with the primary processing systems at one end and the heteromodal systems comprising connector hubs at the other end.

Changes in white matter fiber density and morphology across the adult lifespan: A cross-sectional fixel-based analysis.

White matter (WM) fiber bundles change dynamically with age. These changes could be driven by alterations in axonal diameter, axonal density, and myelin content. In this study, we applied a novel fixel-based analysis (FBA) framework to examine these changes throughout the adult lifespan. Using diffusion-weighted images from a cohort of 293 healthy volunteers (89 males/204 females) from ages 21 to 86 years old, we performed FBA to analyze age-related changes in microscopic fiber density (FD) and macroscopic fiber morphology (fiber cross section [FC]). Our results showed significant and widespread age-related alterations in FD and FC across the whole brain. Interestingly, some fiber bundles such as the anterior thalamic radiation, corpus callosum, and superior longitudinal fasciculus only showed significant negative relationship with age in FD values, but not in FC. On the other hand, some segments of the cerebello-thalamo-cortical pathway only showed significant negative relationship with age in FC, but not in FD. Analysis at the tract-level also showed that major fiber tract groups predominantly distributed in the frontal lobe (cingulum, forceps minor) exhibited greater vulnerability to the aging process than the others. Differences in FC and the combined measure of FD and cross section values observed between sexes were mostly driven by differences in brain sizes although male participants tended to exhibit steeper negative linear relationship with age in FD as compared to female participants. Overall, these findings provide further insights into the structural changes the brain's WM undergoes due to the aging process.

Alterations in Cognition-Related Cerebello-Cerebral Networks in Multiple System Atrophy.

We aimed to elucidate the effect of cerebellar degeneration in relation to cognition in multiple system atrophy (MSA). Thirty-two patients diagnosed with probable MSA and 32 age- and gender-matched healthy controls (HCs) were enrolled. We conducted voxel-based morphometry (VBM) for anatomical images and independent component analysis (ICA), dual-regression analysis, and seed-based analysis for functional images with voxel-wise gray matter correction. In the MSA group, a widespread cerebellar volume loss was observed. ICA and dual-regression analysis showed lower functional connectivity (FC) in the left executive control and salience networks in regions located in the cerebellum. Seed-based analysis using the identified cerebellar regions as seeds showed extensive disruptions in cerebello-cerebral networks. Global cognitive scores correlated with the FC values between the right lobules VI/crus I and the medial prefrontal/anterior cingulate cortices and between the same region and the amygdala/parahippocampal gyrus. Our study indicates that cerebellar degeneration in MSA causes segregation of cerebellar-cerebral networks. Furthermore, the cognitive deficits in MSA may be driven by decreased cerebello-prefrontal and cerebello-amygdaloid functional connections.

Tau Accumulation and Network Breakdown in Alzheimer's Disease.

Misfolded and aggregated tau and amyloid ß (Aß) proteins are the pathological hallmarks of Alzheimer's disease (AD). These aberrant proteins lose their physiological roles, acquire neurotoxicity, and propagate across neural systems. Despite the growing understanding of the molecular pathophysiology, the relationship among molecular alterations, pathological changes, and dementia onset and progression remain to be elucidated. Connectivity is an exclusive characteristic of the brain, and the integrity and segregation of the functional and anatomical networks are crucial for normal functioning. Interestingly, a lot of magnetic resonance imaging (MRI) studies have demonstrated successive structural and functional disconnection among brain regions supporting the idea that AD is a disconnection syndrome. Recent several studies using the combination of cutting-edge Aß and tau PET tracers integrated by data-driven statistical methods, resting-state functional MRI, and diffusion tensor imaging have shed light on the spatial distribution pattern of tau retention as well the relationship between tau retention and functional/structural network disruption in AD. Regional retention of tau PET traces is associated with gray matter changes, structural network disruption, and cognitive function tests. The tau retention will mainly spread along with cognition-related resting state networks and be more common in the network hubs which exhibit many strong interconnections with other regions within the network as well as without the networks. Mainly, precuneus and posterior cingulate gyrus are commonly involved and can be the critical nodes associated with clinically manifested dementia from the normal cognitive state.

An unbiased data-driven age-related structural brain parcellation for the identification of intrinsic brain volume changes over the adult lifespan.

This study aims to elucidate age-related intrinsic brain volume changes over the adult lifespan using an unbiased data-driven structural brain parcellation. Anatomical brain images from a cohort of 293 healthy volunteers ranging in age from 21 to 86 years were analyzed using independent component analysis (ICA). ICA-based parcellation identified 192 component images, of which 174 (90.6%) showed a significant negative correlation with age and with some components being more vulnerable to aging effects than others. Seven components demonstrated a convex slope with aging; 3 components had an inverted U-shaped trajectory, and 4 had a U-shaped trajectory. Linear combination of 86 components provided reliable prediction of chronological age with a mean absolute prediction error of approximately 7.2 years. Structural co-variation analysis showed strong interhemispheric, short-distance positive correlations and long-distance, inter-lobar negative correlations. Estimated network measures either exhibited a U- or an inverted U-shaped relationship with age, with the vertex occurring at approximately 45-50 years. Overall, these findings could contribute to our knowledge about healthy brain aging and could help provide a framework to distinguish the normal aging processes from that associated with age-related neurodegenerative diseases.

Structural MRI correlates of amyotrophic lateral sclerosis progression.

PURPOSE: Amyotrophic lateral sclerosis (ALS) presents with varying degrees of brain degeneration that can extend beyond the corticospinal tract (CST). Furthermore, the clinical course and progression of ALS varies widely. Brain degeneration detected using structural MRI could reflect disease progression. SUBJECTS AND METHODS: On study registration, 3-Tesla volumetric MRI and diffusion tensor imaging scans were obtained at baseline in 38 healthy controls and 67 patients with sporadic ALS. Patients had Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) scores of ≥36 and did not have the chromosome 9, open reading frame 72 repeat expansion. Six months later, changes in ALSFRS-R (ΔALSFRS-R) scores were calculated and patients were grouped into three categories, namely, patients with slow progression with ΔALSFRS-R scores ≤3 (n=19), intermediate progression with ΔALSFRS-R scores =4, 5 and 6 (n=36) and rapid progression with ΔALSFRS-R scores ≥7 (n=12). We analysed voxel-based morphometry and tract-based spatial statistics among these subgroups and controls. RESULTS: In comparison with controls, patients with ALS showed grey matter atrophy and decreased fractional anisotropy beyond the motor cortex and CST, especially in the frontotemporal lobes and basal ganglia. Moreover, the degree of change was highly proportional to ΔALSFRS-R at the 6-month assessment. CONCLUSION: A more rapid disease progression and poorer functional decline were associated with greater involvement of the extra-motor cortex and basal ganglia, suggesting that the spatial extent of brain involvement can be an indicator of the progression in ALS.

Longitudinal brain changes in Parkinson's disease with severe olfactory deficit.

INTRODUCTION: Olfactory dysfunction and REM sleep behavior disorder (RBD) are associated with distinct cognitive trajectories in the course of Parkinson's disease (PD). The underlying neurobiology for this relationship remains unclear but may involve distinct patterns of neurodegeneration. This study aimed to examine longitudinal cortical atrophy and thinning in early-stage PD with severe olfactory deficit (anosmia) without and with concurrent probable RBD. METHODS: Longitudinal MRI data over four years of 134 de novo PD and 49 healthy controls (HC) from the Parkinson Progression Marker Initiative (PPMI) cohort were analyzed using a linear mixed-effects model. Patients were categorized into those with anosmia by the University of Pennsylvania Smell Identification Test (UPSIT) score ≤ 18 (AO+) and those without (UPSIT score > 18, AO-). The AO+ group was further subdivided into AO+ with probable RBD (AO+RBD+) and without (AO+RBD-) for subanalysis. RESULTS: Compared to subjects without baseline anosmia, the AO+ group exhibited greater longitudinal declines in both volume and thickness in the bilateral parahippocampal gyri and right transverse temporal gyrus. Patients with concurrent anosmia and RBD showed more extensive longitudinal declines in cortical volume and thickness, involving additional brain regions including the bilateral precuneus, left inferior temporal gyrus, right paracentral gyrus, and right precentral gyrus. CONCLUSIONS: The atrophy/thinning patterns in early-stage PD with severe olfactory dysfunction include regions that are critical for cognitive function and could provide a structural basis for previously reported associations between severe olfactory deficit and cognitive decline in PD. Concurrent RBD might enhance the dynamics of cortical changes.

Cognitive dysfunction in de novo Parkinson disease: Remitting vs. progressive cognitive impairment.

INTRODUCTION: Parkinson's disease (PD) exhibits divergent cognitive trajectories; however, the factors contributing to these variations remain elusive. This study aimed to examine the clinical features of patients with different long-term cognitive trajectories in de novo PD over a five-year follow-up. METHODS: We analyzed 258 patients who completed every annual evaluation for five years. According to the Montreal Cognitive Assessment (MoCA) scores, we classified patients into three groups: cognitively normal (n = 118, CN), remitting MoCA decline (n = 74, RMD), and progressive MoCA decline (n = 66, PMD). RESULTS: The RMD group was associated with lower olfactory scores (Odds Ratio (OR) = 0.958, p = 0.040), whereas PMD was associated with higher depression scores (OR = 1.158, p = 0.045), probable RBD (OR = 3.169, p = 0.002), older age (OR = 1.132, p < 0.001) and lower educational attainment (OR = 0.828, p = 0.004). PMD had higher neurofilament light chain protein values than CN and RMD (p = 0.006, 0.015, respectively). Longitudinally, PMD showed a greater decline in all cognitive scores and hippocampus volumes (p = 0.004). Meanwhile, RMD exhibited intermediate cognitive and volumetric trajectories between CN and PMD and displayed worse score changes in memory tasks than CN. CONCLUSIONS: While PMD exhibited known risk factors for cognitive impairment, along with worse cognitive performance and hippocampal volume decline, RMD displayed baseline lower olfactory scores and intermediate cognitive and hippocampal volume decline between the two groups. These findings suggest individuals in RMD may still be at risk for cognitive deficits. However, further long-term follow-up data are needed to unravel the determinants and dynamics of cognitive functions.

Cerebellar and thalamic connector hubs facilitate the involvement of visual and cognitive networks in essential tremor.

INTRODUCTION: Connector hubs are specialized brain regions that connect multiple brain networks and therefore have the potential to affect the functions of multiple systems. This study aims to examine the involvement of connector hub regions in essential tremor. METHODS: We examined whole-brain functional connectivity alterations across multiple brain networks in 27 patients with essential tremor and 27 age- and sex-matched healthy controls to identify affected hub regions using a network metric called functional connectivity overlap ratio estimated from resting-state functional MRI. We also evaluated the relationships of affected hubs with cognitive and tremor scores in all patients and with motor function improvement scores in 15 patients who underwent postoperative follow-up evaluations after focused ultrasound thalamotomy. RESULTS: We have identified affected connector hubs in the cerebellum and thalamus. Specifically, the dentate nucleus in the cerebellum and the dorsomedial thalamus exhibited more extensive connections with the sensorimotor network in patients. Moreover, the connections of the thalamic pulvinar with the visual network were also significantly widespread in the patient group. The connections of these connector hub regions with cognitive networks were negatively associated (FDR q < 0.05) with cognitive, tremor, and motor function improvement scores. CONCLUSION: In patients with essential tremor, connector hub regions within the cerebellum and thalamus exhibited widespread functional connections with sensorimotor and visual networks, leading to alternative pathways outside the classical tremor axis. Their connections with cognitive networks also affect patients' cognitive function.

＜Editors' Choice＞ Pattern of THK 5351 retention in normal aging involves core regions of resting state networks associated with higher cognitive function.

We aimed to elucidate the distribution pattern of the positron emission tomography probe [18F]THK 5351, a marker for astrogliosis and tau accumulation, in healthy aging. We also assessed the relationship between THK5351 retention and resting state networks. We enrolled 62 healthy participants in this study. All participants underwent magnetic resonance imaging/positron emission tomography scanning consisting of T1-weighted images, resting state functional magnetic resonance imaging, Pittsburgh Compound-B and THK positron emission tomography. The preprocessed THK images were entered into a scaled subprofile modeling/principal component analysis to extract THK distribution patterns. Using the most significant THK pattern, we generated regions of interest, and performed seed-based functional connectivity analyses. We also evaluated the functional connectivity overlap ratio to identify regions with high between-network connectivity. The most significant THK distributions were observed in the medial prefrontal cortex and bilateral putamen. The seed regions of interest in the medial prefrontal cortex had a functional connectivity map that significantly overlapped with regions of the dorsal default mode network. The seed regions of interest in the putamen showed strong overlap with the basal ganglia and anterior salience networks. The functional connectivity overlap ratio also showed that three peak regions had the characteristics of connector hubs. We have identified an age-related spatial distribution of THK in the medial prefrontal cortex and basal ganglia in normal aging. Interestingly, the distribution's peaks are located in regions of connector hubs that are strongly connected to large-scale resting state networks associated with higher cognitive function.

Magnetic resonance-guided focused ultrasound thalamotomy restored distinctive resting-state networks in patients with essential tremor.

OBJECTIVE: Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy ameliorates symptoms in patients with essential tremor (ET). How this treatment affects canonical brain networks has not been elucidated. The purpose of this study was to clarify changes of brain networks after MRgFUS thalamotomy in ET patients by analyzing resting-state networks (RSNs). METHODS: Fifteen patients with ET were included in this study. Left MRgFUS thalamotomy was performed in all cases, and MR images, including resting-state functional MRI (rsfMRI), were taken before and after surgery. MR images of 15 age- and sex-matched healthy controls (HCs) were also used for analysis. Using rsfMRI data, canonical RSNs were extracted by performing dual regression analysis, and the functional connectivity (FC) within respective networks was compared among pre-MRgFUS patients, post-MRgFUS patients, and HCs. The severity of tremor was evaluated using the Clinical Rating Scale for Tremor (CRST) score pre- and postoperatively, and its correlation with RSNs was examined. RESULTS: Preoperatively, ET patients showed a significant decrease in FC in the sensorimotor network (SMN), primary visual network (VN), and visuospatial network (VSN) compared with HCs. The decrease in FC in the SMN correlated with the severity of tremor. After MRgFUS thalamotomy, ET patients still exhibited a significant decrease in FC in a small area of the SMN, but they exhibited an increase in the cerebellar network (CN). In comparison between pre- and post-MRgFUS patients, the FC in the SMN and the VSN significantly increased after treatment. Quantitative evaluation of the FCs in these three groups showed that the SMN and VSN increased postoperatively and demonstrated a trend toward those of HCs. CONCLUSIONS: The SMN and CN, which are considered to be associated with the cerebello-thalamo-cortical loop, exhibited increased connectivity after MRgFUS thalamotomy. In addition, the FC of the visual network, which declined in ET patients compared with HCs, tended to normalize postoperatively. This could be related to the hypothesis that visual feedback is involved in tremor severity in ET patients. Overall, the analysis of the RSNs by rsfMRI reflected the pathophysiology with the intervention of MRgFUS thalamotomy in ET patients and demonstrated a possibility of a biomarker for successful treatment.

Involvement of cerebellar and subcortical connector hubs in schizophrenia.

BACKGROUND: Schizophrenia is considered a brain connectivity disorder in which functional integration within the brain fails. Central to the brain's integrative function are connector hubs, brain regions characterized by strong connections with multiple networks. Given their critical role in functional integration, we hypothesized that connector hubs, including those located in the cerebellum and subcortical regions, are severely impaired in patients with schizophrenia. METHODS: We identified brain voxels with significant connectivity alterations in patients with schizophrenia (n = 76; men = 43) compared to healthy controls (n = 80; men = 43) across multiple large-scale resting state networks (RSNs) using a network metric called functional connectivity overlap ratio (FCOR). From these voxels, candidate connector hubs were identified and verified using seed-based connectivity analysis. RESULTS: We found that most networks exhibited connectivity alterations in the patient group. Specifically, connectivity with the basal ganglia and high visual networks was severely affected over widespread brain areas in patients, affecting subcortical and cerebellar regions and the regions involved in visual and sensorimotor processing. Furthermore, we identified critical connector hubs in the cerebellum, midbrain, thalamus, insula, and calcarine with connectivity to multiple RSNs affected in the patients. FCOR values of these regions were also associated with clinical data and could classify patient and control groups with > 80 % accuracy. CONCLUSIONS: These findings highlight the critical role of connector hubs, particularly those in the cerebellum and subcortical regions, in the pathophysiology of schizophrenia and the potential role of FCOR as a clinical biomarker for the disorder.

Multitier Network Analysis Using Resting-state Functional MRI for Epilepsy Surgery.

Resting-state functional MRI (rs-fMRI) has been utilized to visualize large-scale brain networks. We evaluated the usefulness of multitier network analysis using rs-fMRI in patients with focal epilepsy. Structural and rs-fMRI data were retrospectively evaluated in 20 cases with medically refractory focal epilepsy, who subsequently underwent surgery. First, structural changes were examined using voxel-based morphometry analysis. Second, alterations in large-scale networks were evaluated using dual-regression analysis. Third, changes in cortical hubs were analyzed and the relationship between aberrant hubs and the epileptogenic zone (EZ) was evaluated. Finally, the relationship between the hubs and the default mode network (DMN) was examined using spectral dynamic causal modeling (spDCM). Dual-regression analysis revealed significant decrease in functional connectivity in several networks including DMN in patients, although no structural difference was seen between groups. Aberrant cortical hubs were observed in and around the EZ (EZ hubs) in 85% of the patients, and a strong degree of EZ hubs correlated to good seizure outcomes postoperatively. In spDCM analysis, facilitation was often seen from the EZ hub to the contralateral side, while inhibition was seen from the EZ hub to nodes of the DMN. Some cognition-related networks were impaired in patients with focal epilepsy. The EZ hub appeared in the vicinity of EZ facilitating connections to distant regions in the early phase, which may eventually generate secondary focus, while inhibiting connections to the DMN, which may cause cognitive deterioration. Our results demonstrate pathological network alterations in epilepsy and suggest that earlier surgical intervention may be more effective.

Connectivity impairment of cerebellar and sensorimotor connector hubs in Parkinson's disease.

Cognitive and movement processes involved integration of several large-scale brain networks. Central to these integrative processes are connector hubs, brain regions characterized by strong connections with multiple networks. Growing evidence suggests that many neurodegenerative and psychiatric disorders are associated with connector hub dysfunctions. Using a network metric called functional connectivity overlap ratio, we investigated connector hub alterations in Parkinson's disease. Resting-state functional MRI data from 99 patients (male/female = 44/55) and 99 age- and sex-matched healthy controls (male/female = 39/60) participating in our cross-sectional study were used in the analysis. We have identified two sets of connector hubs, mainly located in the sensorimotor cortex and cerebellum, with significant connectivity alterations with multiple resting-state networks. Sensorimotor connector hubs have impaired connections primarily with primary processing (sensorimotor, visual), visuospatial, and basal ganglia networks, whereas cerebellar connector hubs have impaired connections with basal ganglia and executive control networks. These connectivity alterations correlated with patients' motor symptoms. Specifically, values of the functional connectivity overlap ratio of the cerebellar connector hubs were associated with tremor score, whereas that of the sensorimotor connector hubs with postural instability and gait disturbance score, suggesting potential association of each set of connector hubs with the disorder's two predominant forms, the akinesia/rigidity and resting tremor subtypes. In addition, values of the functional connectivity overlap ratio of the sensorimotor connector hubs were highly predictive in classifying patients from controls with an accuracy of 75.76%. These findings suggest that, together with the basal ganglia, cerebellar and sensorimotor connector hubs are significantly involved in Parkinson's disease with their connectivity dysfunction potentially driving the clinical manifestations typically observed in this disorder.

Reproducibility of functional connectivity metrics estimated from resting-state functional MRI with differences in days, coils, and global signal regression.

In multisite studies, differences in imaging acquisition systems could affect the reproducibility of the results when examining changes in brain function using resting-state functional magnetic resonance imaging (rs-fMRI). This is also important for longitudinal studies, in which changes in equipment settings can occur. This study examined the reproducibility of functional connectivity (FC) metrics estimated from rs-fMRI data acquired using scanner receiver coils with different numbers of channels. This study involved 80 rs-fMRI datasets from 20 healthy volunteers scanned in two independent imaging sessions using both 12- and 32-channel coils for each session. We used independent component analysis (ICA) to evaluate the FC of canonical resting-state networks (RSNs) and graph theory to calculate several whole-brain network metrics. The effect of global signal regression (GSR) as a preprocessing step was also considered. Comparisons within and between receiver coils were performed. Irrespective of the GSR, RSNs derived from rs-fMRI data acquired using the same receiver coil were reproducible, but not from different receiver coils. However, both the GSR and the channel count of the receiver coil have discernible effects on the reproducibility of network metrics estimated using whole-brain network analysis. The data acquired using the 32-channel coil tended to have better reproducibility than those acquired using the 12-channel coil. Our findings suggest that the reproducibility of FC metrics estimated from rs-fMRI data acquired using different receiver coils showed some level of dependence on the preprocessing method and the type of analysis performed.

Reserve and Maintenance in the Aging Brain: A Longitudinal Study of Healthy Older Adults.

The aging brain undergoes structural changes even in very healthy individuals. Quantifying these changes could help disentangle pathologic changes from those associated with the normal human aging process. Using longitudinal magnetic resonance imaging (MRI) data from 227 carefully selected healthy human cohort with age ranging from 50 to 80 years old at baseline scan, we quantified age-related volumetric changes in the brain of healthy human older adults. Longitudinally, the rates of tissue loss in total gray matter (GM) and white matter (WM) were 2497.5 and 2579.8 mm3 per year, respectively. Across the whole brain, the rates of GM decline varied with regions in the frontal and parietal lobes having faster rates of decline, whereas some regions in the occipital and temporal lobes appeared relatively preserved. In contrast, cross-sectional changes were mainly observed in the temporal-occipital regions. Similar longitudinal atrophic changes were also observed in subcortical regions including thalamus, hippocampus, putamen, and caudate, whereas the pallidum showed an increasing volume with age. Overall, regions maturing late in development (frontal, parietal) are more vulnerable to longitudinal decline, whereas those that fully mature in the early stage (temporal, occipital) are mainly affected by cross-sectional changes in healthy older cohort. This may suggest that, for a successful healthy aging, the former needs to be maximally developed at an earlier age to compensate for the longitudinal decline later in life and the latter to remain relatively preserved even in old age, consistent with both concepts of reserve and brain maintenance.