Functional Integration Of Brain Networks Research Articles

Functional Brain Activation in Mild Cognitive Impairment With Defined Small Vessel Disease Burden

AbstractBackgroundVascular dysregulations and changes in functional brain network integrity play a fundamental role in the pathogenesis of dementia. While often identified in individuals with dementia, the role of small vessel disease (SVD) in the development of dementia is not completely understood yet. Previously, structural and functional brain connectivity was shown to be different between individuals with and without cerebral SVD, but a comprehensive measure of SVD has not been used consistently. We aim to analyze functional brain activation differences in mild cognitive impairment (MCI) individuals with defined SVD burden.MethodFunctional brain activation differences were analyzed in MCI individuals with absent or low (n = 34) or high (n = 34) SVD burden using data from the Parelsnoer Institute, a multicenter study involving eight Dutch medical centers. SVD burden was characterized using an ordinal scale ranging from 0 to 4 (Klarenbeek et al., 2013) considering the following markers: lacunes; microbleeds; perivascular spaces in the basal ganglia; white matter hyperintensities based on the Fazekas score. Two groups were identified: the absent or low SVD burden group with a score of 0 or 1 and the high SVD group with a score between 2 and 4. Activation differences were calculated using resting state fMRI data acquired using 3Tesla scanners and analyzed with group‐independent component analysis using the CONN toolbox.ResultActivation of two clusters in the high SVD burden group was lower than in the absent or low SVD group: the cerebellum (p‐FDR >. 001, F = 1.49) and the brainstem (p‐FDR >. 001, F = 2.79). The cerebellar cluster (4541 voxels, +20 ‐74 ‐38) consisted of the left cerebellum crus II, right cerebellum crus II, and left cerebellum lobule VIII. The brainstem cluster (218 voxels, +22 ‐28 +20) involved the right thalamus and the right caudate nucleus.ConclusionBrain activation differences between groups of individuals with MCI and absent or low or high SVD burden were found in the cerebellum and brainstem. These brain areas are mainly responsible for motor, attentional and executive functions, domains which were found in previous studies to be mostly associated with SVD markers.

Dynamic cortical and tractography atlases of proactive and reactive alpha and high-gamma activities.

Alpha waves-posterior dominant rhythms at 8-12 Hz reactive to eye opening and closure-are among the most fundamental EEG findings in clinical practice and research since Hans Berger first documented them in the early 20th century. Yet, the exact network dynamics of alpha waves in regard to eye movements remains unknown. High-gamma activity at 70-110 Hz is also reactive to eye movements and a summary measure of local cortical activation supporting sensorimotor or cognitive function. We aimed to build the first-ever brain atlases directly visualizing the network dynamics of eye movement-related alpha and high-gamma modulations, at cortical and white matter levels. We studied 28 patients (age: 5-20 years) who underwent intracranial EEG and electro-oculography recordings. We measured alpha and high-gamma modulations at 2167 electrode sites outside the seizure onset zone, interictal spike-generating areas and MRI-visible structural lesions. Dynamic tractography animated white matter streamlines modulated significantly and simultaneously beyond chance, on a millisecond scale. Before eye-closure onset, significant alpha augmentation occurred at the occipital and frontal cortices. After eye-closure onset, alpha-based functional connectivity was strengthened, while high gamma-based connectivity was weakened extensively in both intra-hemispheric and inter-hemispheric pathways involving the central visual areas. The inferior fronto-occipital fasciculus supported the strengthened alpha co-augmentation-based functional connectivity between occipital and frontal lobe regions, whereas the posterior corpus callosum supported the inter-hemispheric functional connectivity between the occipital lobes. After eye-opening offset, significant high-gamma augmentation and alpha attenuation occurred at occipital, fusiform and inferior parietal cortices. High gamma co-augmentation-based functional connectivity was strengthened, whereas alpha-based connectivity was weakened in the posterior inter-hemispheric and intra-hemispheric white matter pathways involving central and peripheral visual areas. Our results do not support the notion that eye closure-related alpha augmentation uniformly reflects feedforward or feedback rhythms propagating from lower to higher order visual cortex, or vice versa. Rather, proactive and reactive alpha waves involve extensive, distinct white matter networks that include the frontal lobe cortices, along with low- and high-order visual areas. High-gamma co-attenuation coupled to alpha co-augmentation in shared brain circuitry after eye closure supports the notion of an idling role for alpha waves during eye closure. These normative dynamic tractography atlases may improve understanding of the significance of EEG alpha waves in assessing the functional integrity of brain networks in clinical practice; they also may help elucidate the effects of eye movements on task-related brain network measures observed in cognitive neuroscience research.

Combined Cognitive Training and Vortioxetine Mitigates Age-Related Declines in Functional Brain Network Integrity

ObjectiveAge-related cognitive decline is common and potentially modifiable with cognitive training. Combining cognitive training with pro-cognitive medication offers an opportunity to modify brain networks to mitigate age-related cognitive decline. We tested the hypothesis that the efficacy of cognitive training could be amplified by combining it with vortioxetine, a pro-cognitive and pro-neuroplastic multimodal antidepressant. MethodsWe evaluated the effects of 6 months of computerized cognitive training plus vortioxetine (versus placebo) on resting state functional connectivity in older adults (age 65+) with age-related cognitive decline. We first evaluated the association of functional connectivity with age and cognitive performance (N = 66). Then we compared the effects of vortioxetine plus cognitive training versus placebo plus cognitive training on connectivity changes over the training period (n = 20). ResultsAt baseline, greater age was significantly associated with lower within-network strength and network segregation, and poorer cognitive function. Cognitive training plus vortioxetine over 6 months positively impacted the relationship between age to mean network segregation. These effects were not observed in the placebo group. In contrast, vortioxetine did not modify the relationship of age to change in mean within-network strength. Exploratory analyses identified the cingulo-opercular network as the network most affected by cognitive training plus vortioxetine. ConclusionThis preliminary study provides evidence that combining cognitive training with pro-cognitive medication may modulate the effects of aging on functional brain networks. Results indicate that for older adults experiencing age-related cognitive decline, vortioxetine has a potentially beneficial effect on the correspondence between aging and functional brain network segregation. These results await replication in a larger sample.

Improvement of cognition across a decade after stroke correlates with the integrity of functional brain networks

Background and objectiveWe recently reported improvements of working memory across 10 years post stroke among middle-aged individuals. However, the mechanisms underlying working-memory recovery are largely unknown. This study investigated the associations between long-term improvement of working memory and resting-state functional connectivity in two frontoparietal networks: the frontoparietal network and the dorsal attention network. MethodsWorking memory was repeatedly assessed by the Digit Span Backwards task in 21 persons, within 1 year after stroke onset and again 10 years post stroke onset. Brain functional connectivity was examined by resting state functional magnetic resonance imaging at the 10-year follow-up. ResultsA significant improvement of working memory was found among 21 persons after stroke (median age = 64) at the 10-year follow-up compared to the within-one-year assessment. The magnitude of performance improvement on the Digit Span Backwards task was significantly positively correlated with stronger brain connectivity in the frontoparietal network (r = 0.51, p = 0.018) measured at the 10-year follow-up only. A similar association was observed in the dorsal attention network (r = 0.43, p = 0.052) but not in a visual network (r = -0.17, p = 0.46) that served as a control network. The association between functional connectivity within the above-mentioned networks and Digit Span Backwards scores at 10-year after stroke was in the same direction but did not reach significance. ConclusionsThe present work relate stronger long-term performance improvement on the Digit Span Backwards task with higher integrity of frontoparietal network connectivity.

Improvement of Cognition Across a Decade after Stroke Correlates with the Integrity of Functional Brain Networks

Improvement of Cognition Across a Decade after Stroke Correlates with the Integrity of Functional Brain Networks

Different effects of the DRD4 genotype on intrinsic brain network connectivity strength in drug-na\xefve children with ADHD and healthy controls

The dopamine D4 receptor gene (DRD4) has been consistently reported to be associated with attention-deficit/hyperactivity disorder (ADHD). Recent studies have linked DRD4 to functional connectivity among specific brain regions. The current study aimed to compare the effects of the DRD4 genotype on functional integrity in drug-naïve ADHD children and healthy children. Resting-state functional MRI images were acquired from 49 children with ADHD and 37 healthy controls (HCs). We investigated the effects of the 2-repeat allele of DRD4 on brain network connectivity in both groups using a parameter called the degree of centrality (DC), which indexes local functional relationships across the entire brain connectome. A voxel-wise two-way ANCOVA was performed to examine the diagnosis-by-genotype interactions on DC maps. Significant diagnosis-by-genotype interactions with DC were found in the temporal lobe, including the left inferior temporal gyrus (ITG) and bilateral middle temporal gyrus (MTG) (GRF corrected at voxel level p < 0.001 and cluster level p < 0.05, two-tailed). With the further subdivision of the DC network according to anatomical distance, additional brain regions with significant interactions were found in the long-range DC network, including the left superior parietal gyrus (SPG) and right middle frontal gyrus (MFG). The post-hoc pairwise analysis found that altered network centrality related to DRD4 differed according to diagnostic status (p < 0.05). This genetic imaging study suggests that the DRD4 genotype regulates the functional integration of brain networks in children with ADHD and HCs differently. This may have important implications for our understanding of the role of DRD4 in altering functional connectivity in ADHD subjects.

NREM sleep stages specifically alter dynamical integration of large-scale brain networks.

SummaryFunctional dissociations in the brain observed during non-rapid eye movement (NREM) sleep have been associated with reduced information integration and impaired consciousness that accompany increasing sleep depth. Here, we explored the dynamical properties of large-scale functional brain networks derived from transient brain activity using functional magnetic resonance imaging. Spatial brain maps generally display significant modifications in terms of their tendency to occur across wakefulness and NREM sleep. Unexpectedly, almost all networks predominated in activity during NREM stage 2 before an abrupt loss of activity is observed in NREM stage 3. Yet, functional connectivity and mutual dependencies between these networks progressively broke down with increasing sleep depth. Thus, the efficiency of information transfer during NREM stage 2 is low despite the high attempt to communicate. Critically, our approach provides relevant data for evaluating functional brain network integrity and our findings robustly support a significant advance in our neural models of human sleep and consciousness.

Dispersion of functional gradients across the adult lifespan

Ageing is commonly associated with changes to segregation and integration of functional brain networks, but, in isolation, current network-based approaches struggle to elucidate changes across the many axes of functional organisation. However, the advent of gradient mapping techniques in neuroimaging provides a new means of studying functional organisation in a multi-dimensional connectivity space. Here, we studied ageing and behaviourally-relevant differences in a three-dimensional connectivity space using the Cambridge Centre for Ageing Neuroscience cohort (n = 643). Building on gradient mapping techniques, we developed a set of measures to quantify the dispersion within and between functional communities. We detected a strong shift of the visual network across the adult lifespan from an extreme to a more central position in the 3D gradient space. In contrast, the dispersion distance between transmodal communities (dorsal attention, ventral attention, frontoparietal and default mode) did not change. However, these communities themselves were increasingly dispersed with increasing age, reflecting more dissimilar functional connectivity profiles within each community. Increasing dispersion of frontoparietal, attention and default mode networks, in particular, were associated negatively with cognition, measured by fluid intelligence. By using a technique that explicitly captures the ordering of functional systems in a multi-dimensional hierarchical framework, we identified behaviorally-relevant age-related differences of within and between network organisation. We propose that the study of functional gradients across the adult lifespan could provide insights that may facilitate the development of new strategies to maintain cognitive ability across the lifespan in health and disease.

Functional Brain Network Connectivity Patterns Associated With Normal Cognition at Old-Age, Local β-amyloid, Tau, and APOE4

Background: Integrity of functional brain networks is closely associated with maintained cognitive performance at old age. Consistently, both carrier status of Apolipoprotein E ε4 allele (APOE4), and age-related aggregation of Alzheimer’s disease (AD) pathology result in altered brain network connectivity. The posterior cingulate and precuneus (PCP) is a node of particular interest due to its role in crucial memory processes. Moreover, the PCP is subject to the early aggregation of AD pathology. The current study aimed at characterizing brain network properties associated with unimpaired cognition in old aged adults. To determine the effects of age-related brain change and genetic risk for AD, pathological proteins β-amyloid and tau were measured by Positron-emission tomography (PET), PCP connectivity as a proxy of cognitive network integrity, and genetic risk by APOE4 carrier status.Methods: Fifty-seven cognitively unimpaired old-aged adults (MMSE = 29.20 ± 1.11; 73 ± 8.32 years) were administered 11C Pittsburgh Compound B and 18F Flutemetamol PET for assessing β-amyloid, and 18F AV-1451 PET for tau. Individual functional connectivity seed maps of the PCP were obtained by resting-state multiband BOLD functional MRI at 3-Tesla for increased temporal resolution. Voxelwise correlations between functional connectivity, β-amyloid- and tau-PET were explored by Biological Parametric Mapping (BPM).Results: Local β-amyloid was associated with increased connectivity in frontal and parietal regions of the brain. Tau was linked to increased connectivity in more spatially distributed clusters in frontal, parietal, occipital, temporal, and cerebellar regions. A positive interaction was observable for APOE4 carrier status and functional connectivity with brain regions characterized by increased local β-amyloid and tau tracer retention.Conclusions: Our data suggest an association between spatially differing connectivity systems and local β-amyloid, and tau aggregates in cognitively normal, old-aged adults, which is moderated by APOE4. Additional longitudinal studies may determine protective connectivity patterns associated with healthy aging trajectories of AD-pathology aggregation.

P.191 Subclinical obsessive-compulsive symptoms are associated with disrupted functional integrity of brain networks in healthy children

P.191 Subclinical obsessive-compulsive symptoms are associated with disrupted functional integrity of brain networks in healthy children

Disrupted brain functional networks in drug-naïve children with attention deficit hyperactivity disorder assessed using graph theory analysis.

Neuroimaging studies have revealed functional brain network abnormalities in attention deficit hyperactivity disorder (ADHD), but the results have been inconsistent, potentially related to confounding medication effects. Furthermore, specific topological alterations in functional networks and their role in behavioral inhibition dysfunction remain to be established. Resting-state functional magnetic resonance imaging was performed on 51 drug-naïve children with ADHD and 55 age-matched healthy controls. Brain functional networks were constructed by thresholding the partial correlation matrices of 90 brain regions, and graph theory was used to analyze network topological properties. The Stroop test was used to assess cognitive inhibitory abilities. Nonparametric permutation tests were used to compare the topological architectures in the two groups. Compared with healthy subjects, brain networks in ADHD patients demonstrated altered topological characteristics, including lower global (FDR q = 0.01) and local efficiency (p = 0.032, uncorrected) and a longer path length (FDR q = 0.01). Lower nodal efficiencies were found in the left inferior frontal gyrus and anterior cingulate cortex in the ADHD group (FDR both q < 0.05). Altered global and nodal topological efficiencies were associated with the severity of inhibitory cognitive control deficits and hyperactivity symptoms in ADHD (p <0 .05). Alterations in network topologies in drug-naïve ADHD patients indicate weaker small-worldization with decreased segregation and integration of functional brain networks. Deficits in the cingulo-fronto-parietal attention network were associated with inhibitory control deficits.

Interactive effects of dopamine transporter genotype and aging on resting-state functional networks.

Aging and dopamine modulation have both been independently shown to influence the functional connectivity of brain networks during rest. Dopamine modulation is known to decline during the course of aging. Previous evidence also shows that the dopamine transporter gene (DAT1) influences the re-uptake of dopamine and the anyA9 genotype of this gene is associated with higher striatal dopamine signaling. Expanding these two lines of prior research, we investigated potential interactive effects between aging and individual variations in the DAT1 gene on the modular organization of brain acvitiy during rest. The graph-theoretic metrics of modularity, betweenness centrality and participation coefficient were assessed in 41 younger (age 20–30 years) and 37 older (age 60–75 years) adults. Age differences were only observed in the participation coefficient in carriers of the anyA9 genotype of the DAT1 gene and this effect was most prominently observed in the default mode network. Furthermore, we found that individual differences in the values of the participation coefficient correlated with individual differences in fluid intelligence and a measure of executive control in the anyA9 carriers. The correlation between participation coefficient and fluid intelligence was mainly shared with age-related differences, whereas the correlation with executive control was independent of age. These findings suggest that DAT1 genotype moderates age differences in the functional integration of brain networks as well as the relation between network characteristics and cognitive abilities.

Investigating functional brain network integrity using a traditional and novel categorical scheme for neurodevelopmental disorders.

BackgroundCurrent diagnostic systems for neurodevelopmental disorders do not have clear links to underlying neurobiology, limiting their utility in identifying targeted treatments for individuals. Here, we aimed to investigate differences in functional brain network integrity between traditional diagnostic categories (autism spectrum disorder [ASD], attention-deficit/hyperactivity disorder [ADHD], typically developing [TD]) and carefully consider the impact of comorbid ASD and ADHD on functional brain network integrity in a sample adequately powered to detect large effects. We also assess the neurobiological separability of a novel, potential alternative categorical scheme based on behavioral measures of executive function.MethodFive-minute resting-state fMRI data were obtained from 168 children (128 boys, 40 girls) with ASD, ADHD, comorbid ASD and ADHD, and TD children. Independent component analysis and dual regression were used to compute within- and between-network functional connectivity metrics at the individual level.ResultsNo significant group differences in within- or between-network functional connectivity were observed between traditional diagnostic categories (ASD, ADHD, TD) even when stratified by comorbidity (ASD + ADHD, ASD, ADHD, TD). Similarly, subgroups classified by executive functioning levels showed no group differences.ConclusionsUsing clinical diagnosis and behavioral measures of executive function, no differences in functional connectivity were observed among the categories examined. Despite our limited ability to detect small- to medium-sized differences between groups, this work contributes to a growing literature suggesting that traditional diagnostic categories do not define neurobiologically separable groups. Future work is necessary to ascertain the validity of the executive function-based nosology, but current results suggest that nosologies reliant on behavioral data alone may not lead to discovery of neurobiologically distinct categories.

Disrupted Brain Functional Networks in Drug-Naïve Children with ADHD Assessed Using Graph Theory Analysis

Background: Attention Deficit Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder in childhood characterized by multiple behavioral problems and executive dysfunctions. Neuroimaging studies revealed a variety of abnormalities, but the results were inconsistent, partly owing to confounding medication effects and psychiatric comorbidities. Thus, studies of drug- naive ADHD with limited comorbidities is needed to better define disorder-related abnormalities in brain networks. Methods: Resting state functional magnetic resonance imaging was performed on 51 drug-naive ADHD patients (age 6 to 16) and 55 age-matched healthy controls. Brain functional networks were constructed by thresholding partial correlation matrices of 90 brain regions, and graph theory was used to analyze the network topological properties. The Stroop test was used to assess the cognitive inhibitory abilities in the subjects. The non-parametric permutation tests were used to compare the topological architectures in the two groups. Results: Compared with the healthy subjects, the brain networks in the ADHD patients demonstrated altered topological characteristics including lower global and local efficiency ( p=.002,.026), and longer path length (p=.002). Lower nodal efficiencies were found in the left inferior frontal gyrus and anterior cingulate cortex in the ADHD group (p<.05, corrected for the FDR). Altered global and nodal topological efficiency were associated with severity of inhibitory cognitive control deficits and hyperactivity symptoms in ADHD (p<.05). Conclusions: Alterations in network typologies in drug-naive ADHD indicate a weaker small-worldization with decreased segregation and integration of functional brain networks, notably involving a dysfunction of the cingulo-fronto-parietal attention network that was associated with inhibitory control deficits. Funding Statement: This study was supported by the National Natural Science Foundation (Grant Nos. 81621003，81761128023, 81220108013, 81227002, 81030027, 81671669, 81371536 and 81801358), the Humboldt Foundation, and the Program for Changjiang Scholars and Innovative Research Teams in Universities of China (PCSIRT, Grant No. IRT16R52). Dr. Gong would also like to acknowledge the support from his Changjiang Scholar Professorship Award of China (Award No. T2014190) and American CMB Distinguished Professorship Award (Award No. F510000/ G16916411) administered by the Institute of International Education, USA Declaration of Interests: None of the authors has conflicts of interests to report with regard to this manuscript. Ethics Approval Statement: This study was approved by the research ethics committee of West China Hospital of Sichuan University, written informed consent was obtained from the parents/guardians of all participants, and the assents were obtained from study participants prior to participation.

Corrigendum to "On the integrity of functional brain networks in schizophrenia, Parkinson's disease, and advanced age: Evidence from connectivity-based single-subject classification."

Previous whole-brain functional connectivity studies achieved successful classifications of patients and healthy controls but only offered limited specificity as to affected brain systems. Here, we examined whether the connectivity patterns of functional systems affected in schizophrenia (SCZ), Parkinson's disease (PD), or normal aging equally translate into high classification accuracies for these conditions. We compared classification performance between pre-defined networks for each group and, for any given network, between groups. Separate support vector machine classifications of 86 SCZ patients, 80 PD patients, and 95 older adults relative to their matched healthy/young controls, respectively, were performed on functional connectivity in 12 task-based, meta-analytically defined networks using 25 replications of a nested 10-fold cross-validation scheme. Classification performance of the various networks clearly differed between conditions, as those networks that best classified one disease were usually non-informative for the other. For SCZ, but not PD, emotion-processing, empathy, and cognitive action control networks distinguished patients most accurately from controls. For PD, but not SCZ, networks subserving autobiographical or semantic memory, motor execution, and theory-of-mind cognition yielded the best classifications. In contrast, young-old classification was excellent based on all networks and outperformed both clinical classifications. Our pattern-classification approach captured associations between clinical and developmental conditions and functional network integrity with a higher level of specificity than did previous whole-brain analyses. Taken together, our results support resting-state connectivity as a marker of functional dysregulation in specific networks known to be affected by SCZ and PD, while suggesting that aging affects network integrity in a more global way. Hum Brain Mapp 38:5845-5858, 2017. © 2017 Wiley Periodicals, Inc.

Network abnormalities in generalized anxiety pervade beyond the amygdala-pre-frontal cortex circuit: Insights from graph theory

Generalized anxiety disorder (GAD) has excessive anxiety and uncontrollable worry as core symptoms. Abnormal cerebral functioning underpins the expression and perhaps pathogenesis of GAD:. Studies implicate impaired communication between the amygdala and the pre-frontal cortex (PFC). Our aim was to longitudinally investigate whether such network abnormalities are spatially restricted to this circuit or if the integrity of functional brain networks is globally disrupted in GAD. We acquired resting-state functional magnetic resonance imaging data from 16 GAD patients and 16 matched controls at baseline and after 1 year. Using network modeling and graph-theory, whole-brain connectivity was characterized from local and global perspectives. Overall lower global efficiency, indicating sub-optimal brain-wide organization and integration, was present in patients with GAD compared to controls. The amygdala and midline cortices showed higher betweenness centrality, reflecting functional dominance of these brain structures. Third, lower betweenness centrality and lower degree emerged for PFC, suggesting weakened inhibitory control. Overall, network organization showed impairments consistent with neurobiological models of GAD (involving amygdala, PFC, and cingulate cortex) and further pointed to an involvement of temporal regions. Such impairments tended to progress over time and predict anxiety symptoms. A graph-analytic approach represents a powerful approach to deepen our understanding of GAD.

Do Patients Thought to Lack Consciousness Retain the Capacity for Internal as Well as External Awareness?

It is well established that some patients, who are deemed to have disorders of consciousness, remain entirely behaviorally non-responsive and are diagnosed as being in a vegetative state, yet can nevertheless demonstrate covert awareness of their external environment by modulating their brain activity, a phenomenon known as cognitive-motor dissociation. However, the extent to which these patients retain internal awareness remains unknown. To investigate the potential for internal and external awareness in patients with chronic disorders of consciousness (DoC), we asked whether the pattern of juxtaposition between the functional time-courses of the default mode (DMN) and fronto-parietal networks, shown in healthy individuals to mediate the naturally occurring dominance switching between internal and external aspects of consciousness, was present in these patients. We used a highly engaging movie by Alfred Hitchcock to drive the recruitment of the fronto-parietal networks, including the dorsal attention (DAN) and executive control (ECN) networks, and their maximal juxtaposition to the DMN in response to the complex stimulus, relative to rest and a scrambled, meaningless movie baseline condition. We tested a control group of healthy participants (N = 13/12) and two groups of patients with disorders of consciousness, one comprised of patients who demonstrated independent, neuroimaging-based evidence of covert external awareness (N = 8), and the other of those who did not (N = 8). Similarly to the healthy controls, only the group of patients with overt and, critically, covert external awareness showed significantly heightened differentiation between the DMN and the DAN in response to movie viewing relative to their resting state time-courses, which was driven by the movie's narrative. This result suggested the presence of functional integrity in the DMN and fronto-parietal networks and their relationship to one another in patients with covert external awareness. Similar to the effect in healthy controls, these networks became more strongly juxtaposed to one another in response to movie viewing relative to the baseline conditions, suggesting the potential for internal and external awareness during complex stimulus processing. Furthermore, our results suggest that naturalistic paradigms can dissociate between groups of DoC patients with and without covert awareness based on the functional integrity of brain networks.

On the integrity of functional brain networks in schizophrenia, Parkinson's disease, and advanced age: Evidence from connectivity-based single-subject classification.

Previous whole-brain functional connectivity studies achieved successful classifications of patients and healthy controls but only offered limited specificity as to affected brain systems. Here, we examined whether the connectivity patterns of functional systems affected in schizophrenia (SCZ), Parkinson's disease (PD), or normal aging equally translate into high classification accuracies for these conditions. We compared classification performance between pre-defined networks for each group and, for any given network, between groups. Separate support vector machine classifications of 86 SCZ patients, 80 PD patients, and 95 older adults relative to their matched healthy/young controls, respectively, were performed on functional connectivity in 12 task-based, meta-analytically defined networks using 25 replications of a nested 10-fold cross-validation scheme. Classification performance of the various networks clearly differed between conditions, as those networks that best classified one disease were usually non-informative for the other. For SCZ, but not PD, emotion-processing, empathy, and cognitive action control networks distinguished patients most accurately from controls. For PD, but not SCZ, networks subserving autobiographical or semantic memory, motor execution, and theory-of-mind cognition yielded the best classifications. In contrast, young-old classification was excellent based on all networks and outperformed both clinical classifications. Our pattern-classification approach captured associations between clinical and developmental conditions and functional network integrity with a higher level of specificity than did previous whole-brain analyses. Taken together, our results support resting-state connectivity as a marker of functional dysregulation in specific networks known to be affected by SCZ and PD, while suggesting that aging affects network integrity in a more global way. Hum Brain Mapp 38:5845-5858, 2017. © 2017 Wiley Periodicals, Inc.

APOE Genotype Effects on Intrinsic Brain Network Connectivity in Patients with Amnestic Mild Cognitive Impairment

Whether and how the apolipoprotein E (APOE) ε4 genotype specifically modulates brain network connectivity in patients with amnestic mild cognitive impairment (aMCI) remain largely unknown. Here, we employed resting-state (‘task-free’) functional MRI and network centrality approaches to investigate local (degree centrality, DC) and global (eigenvector centrality, EC) functional integrity in the whole-brain connectome in 156 older adults, including 66 aMCI patients (27 ε4-carriers and 39 non-carriers) and 90 healthy controls (45 ε4-carriers and 45 non-carriers). We observed diagnosis-by-genotype interactions on DC in the left superior/middle frontal gyrus, right middle temporal gyrus and cerebellum, with higher values in the ε4-carriers than non-carriers in the aMCI group. We further observed diagnosis-by-genotype interactions on EC, with higher values in the right middle temporal gyrus but lower values in the medial parts of default-mode network in the ε4-carriers than non-carriers in the aMCI group. Notably, these genotype differences in DC or EC were absent in the control group. Finally, the network connectivity DC values were negatively correlated with cognitive performance in the aMCI ε4-carriers. Our findings suggest that the APOE genotype selectively modulates the functional integration of brain networks in patients with aMCI, thus providing important insight into the gene-connectome interaction in this disease.

Is Traumatic Brain Injury Associated with Reduced Inter-Hemispheric Functional Connectivity? A Study of Large-Scale Resting State Networks following Traumatic Brain Injury.

Traumatic brain injury (TBI) often has long-term debilitating sequelae in cognitive and behavioral domains. Understanding how TBI impacts functional integrity of brain networks that underlie these domains is key to guiding future approaches to TBI rehabilitation. In the current study, we investigated the differences in inter-hemispheric functional connectivity (FC) of resting state networks (RSNs) between chronic mild-to-severe TBI patients and normal comparisons (NC), focusing on two externally oriented networks (i.e., the fronto-parietal network [FPN] and the executive control network [ECN]), one internally oriented network (i.e., the default mode network [DMN]), and one somato-motor network (SMN). Seed voxel correlation analysis revealed that TBI patients displayed significantly less FC between lateralized seeds and both homologous and non-homologous regions in the opposite hemisphere for externally oriented networks but not for DMN or SMN; conversely, TBI patients showed increased FC within regions of the DMN, especially precuneus and parahippocampal gyrus. Region of interest correlation analyses confirmed the presence of significantly higher inter-hemispheric FC in NC for the FPN (p < 0.01), and ECN (p < 0.05), but not for the DMN (p > 0.05) or SMN (p > 0.05). Further analysis revealed that performance on a neuropsychological test measuring organizational skills and visuo-spatial abilities administered to the TBI group, the Rey-Osterrieth Complex Figure Test, positively correlated with FC between the right FPN and homologous regions. Our findings suggest that distinct RSNs display specific patterns of aberrant FC following TBI; this represents a step forward in the search for biomarkers useful for early diagnosis and treatment of TBI-related cognitive impairment.