Correlation between structural and functional connectivity impairment in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, characterized by progressive loss of motor function. While the pathogenesis of ALS remains largely unknown, imaging studies of the brain should lead to more insight into structural and functional disease effects on the brain network, which may provide valuable information on the underlying disease process. This study investigates the correlation between changes in structural connectivity (SC) and functional connectivity (FC) of the brain network in ALS. Structural reconstructions of the brain network, derived from diffusion weighted imaging (DWI), were obtained from 64 patients and 27 healthy controls. Functional interactions between brain regions were derived from resting‐state fMRI. Our results show that (i) the most structurally affected connections considerably overlap with the most functionally impaired connections, (ii) direct connections of the motor cortex are both structurally and functionally more affected than connections at greater topological distance from the motor cortex, and (iii) there is a strong positive correlation between changes in SC and FC averaged per brain region (r = 0.44, P < 0.0001). Our findings indicate that structural and functional network degeneration in ALS is coupled, suggesting the pathogenic process affects both SC and FC of the brain, with the most prominent effects in SC. Hum Brain Mapp 35:4386–4395, 2014. © 2014 The Authors. Human Brain Mapping Published by Wiley Periodicals, Inc.     

Functionally linked resting‐state networks reflect the underlying structural connectivity architecture of the human brain

During rest, multiple cortical brain regions are functionally linked forming resting‐state networks. This high level of functional connectivity within resting‐state networks suggests the existence of direct neuroanatomical connections between these functionally linked brain regions to facilitate the ongoing interregional neuronal communication. White matter tracts are the structural highways of our brain, enabling information to travel quickly from one brain region to another region. In this study, we examined both the functional and structural connections of the human brain in a group of 26 healthy subjects, combining 3 Tesla resting‐state functional magnetic resonance imaging time‐series with diffusion tensor imaging scans. Nine consistently found functionally linked resting‐state networks were retrieved from the resting‐state data. The diffusion tensor imaging scans were used to reconstruct the white matter pathways between the functionally linked brain areas of these resting‐state networks. Our results show that well‐known anatomical white matter tracts interconnect at least eight of the nine commonly found resting‐state networks, including the default mode network, the core network, primary motor and visual network, and two lateralized parietal‐frontal networks. Our results suggest that the functionally linked resting‐state networks reflect the underlying structural connectivity architecture of the human brain. Hum Brain Mapp 2009. © 2009 Wiley‐Liss, Inc.     

White matter structural network abnormalities underlie executive dysfunction in amyotrophic lateral sclerosis

Research in amyotrophic lateral sclerosis (ALS) suggests that executive dysfunction, a prevalent cognitive feature of the disease, is associated with abnormal structural connectivity and white matter integrity. In this exploratory study, we investigated the white matter constructs of executive dysfunction, and attempted to detect structural abnormalities specific to cognitively impaired ALS patients. Eighteen ALS patients and 22 age and education matched healthy controls underwent magnetic resonance imaging on a 4.7 Tesla scanner and completed neuropsychometric testing. ALS patients were categorized into ALS cognitively impaired (ALSci, n = 9) and ALS cognitively competent (ALScc, n = 5) groups. Tract‐based spatial statistics and connectomics were used to compare white matter integrity and structural connectivity of ALSci and ALScc patients. Executive function performance was correlated with white matter FA and network metrics within the ALS group. Executive function performance in the ALS group correlated with global and local network properties, as well as FA, in regions throughout the brain, with a high predilection for the frontal lobe. ALSci patients displayed altered local connectivity and structural integrity in these same frontal regions that correlated with executive dysfunction. Our results suggest that executive dysfunction in ALS is related to frontal network disconnectivity, which potentially mediates domain‐specific, or generalized cognitive impairment, depending on the degree of global network disruption. Furthermore, reported co‐localization of decreased network connectivity and diminished white matter integrity suggests white matter pathology underlies this topological disruption. We conclude that executive dysfunction in ALSci is associated with frontal and global network disconnectivity, underlined by diminished white matter integrity. Hum Brain Mapp 38:1249–1268, 2017. © 2016 Wiley Periodicals, Inc.     

Relationship between white matter connectivity loss and cortical thinning in cerebral amyloid angiopathy

Patients with cerebral amyloid angiopathy (CAA) show loss of white matter connectivity and cortical thinning on MRI, primarily in posterior brain regions. Here we examined whether a potential causal relationship exists between these markers of subcortical and cortical brain injury by examining whether changes in cortical thickness progress in tandem with changes in their underlying connections. Thirty‐one patients with probable CAA with brain MRI at two time points were included (follow‐up time: 1.3 ± 0.4 years). Brain networks were reconstructed using diffusion MRI‐based fiber tractography. Of each network node, we calculated the change in fractional anisotropy‐weighted connectivity strength over time and the change in cortical thickness. The association between change in connectivity strength and cortical thickness was assessed with (hierarchical) linear regression models. Our results showed that decline in posterior network connectivity over time was strongly related to thinning of the occipital cortex (β = 0.65 (0.35–0.94), P < 0.001), but not to thinning of the other posterior or frontal cortices. However, at the level of individual network nodes, we found no association between connectivity strength and cortical thinning of the corresponding node (β = 0.009 ± 0.04, P = 0.80). Associations were independent of age, sex, and other brain MRI markers of CAA. To conclude, CAA patients with greater progressive loss of posterior white matter connectivity also have greater progression of occipital cortical thinning, but our results do not support a direct causal relationship between them. The association can be better explained by a shared underlying mechanism, which may form a potential target for future treatments. Hum Brain Mapp 38:3723–3731, 2017. © 2017 Wiley Periodicals, Inc.     

Structural and functional connectivity of the human brain in autism spectrum disorders and attention‐deficit/hyperactivity disorder: A rich club‐organization study

Attention‐deficit/hyperactive disorder (ADHD) and autism spectrum disorders (ASD) are two of the most common and vexing neurodevelopmental disorders among children. Although the two disorders share many behavioral and neuropsychological characteristics, most MRI studies examine only one of the disorders at a time. Using graph theory combined with structural and functional connectivity, we examined the large‐scale network organization among three groups of children: a group with ADHD (8–12 years, n = 20), a group with ASD (7–13 years, n = 16), and typically developing controls (TD) (8–12 years, n = 20). We apply the concept of the rich‐club organization, whereby central, highly connected hub regions are also highly connected to themselves. We examine the brain into two different network domains: (1) inside a rich‐club network phenomena and (2) outside a rich‐club network phenomena. The ASD and ADHD groups had markedly different patterns of rich club and non rich‐club connections in both functional and structural data. The ASD group exhibited higher connectivity in structural and functional networks but only inside the rich‐club networks. These findings were replicated using the autism brain imaging data exchange dataset with ASD (n = 85) and TD (n = 101). The ADHD group exhibited a lower generalized fractional anisotropy and functional connectivity inside the rich‐club networks, but a higher number of axonal fibers and correlation coefficient values outside the rich club. Despite some shared biological features and frequent comorbity, these data suggest ADHD and ASD exhibit distinct large‐scale connectivity patterns in middle childhood. Hum Brain Mapp 35:6032–6048, 2014. © 2014 Wiley Periodicals, Inc.     

Structural and functional underconnectivity as a negative predictor for language in autism

The development of language, social interaction, and communicative skills are remarkably different in the child with autism spectrum disorder (ASD). Atypical brain connectivity has frequently been reported in this patient population. However, the interplay between their brain connectivity and language performance remains largely understudied. Using diffusion tensor imaging tractography and resting‐state fMRI, the authors explored the structural and functional connectivity of the language network and its relation to the language profile in a group of healthy control subjects (N = 25) and a group of children with ASD (N = 17). The authors hypothesized that in children with ASD, a neural connectivity deficit of the language network can be related to the observed abnormal language function. They found an absence of the right‐hemispheric arcuate fascicle (AF) in 28% (7/25) of the healthy control children and in 59% (10/17) of the children with ASD. In contrast to healthy control children, the absence of the right‐hemispheric AF in children with autism was related to a lower language performance as indicated by a lower verbal IQ, lower scores on the Peabody Picture Vocabulary Test, and lower language scores on the Dutch version of the Clinical Evaluation of Language Fundamentals (CELF‐4NL). In addition, through iterative fMRI data analyses, the language impairment of children with ASD could be linked to a marked loss of intrahemispheric functional connectivity between inferior frontal and superior temporal regions, known as the cortical language network. Both structural and functional underconnectivity patterns coincide and are related to an abnormal language function in children with ASD. Hum Brain Mapp 35:3602–3615, 2014. © 2013 Wiley Periodicals, Inc .     

Disruption of rich club organisation in cerebral small vessel disease

Cerebral small vessel disease (SVD) is an important cause of vascular cognitive impairment. Recent studies have demonstrated that structural connectivity of brain networks in SVD is disrupted. However, little is known about the extent and location of the reduced connectivity in SVD. Here they investigate the rich club organisation—a set of highly connected and interconnected regions—and investigate whether there is preferential rich club disruption in SVD. Diffusion tensor imaging (DTI) and cognitive assessment were performed in a discovery sample of SVD patients (n = 115) and healthy control subjects (n = 50). Results were replicated in an independent dataset (49 SVD with confluent WMH cases and 108 SVD controls) with SVD patients having a similar SVD phenotype to that of the discovery cases. Rich club organisation was examined in structural networks derived from DTI followed by deterministic tractography. Structural networks in SVD patients were less dense with lower network strength and efficiency. Reduced connectivity was found in SVD, which was preferentially located in the connectivity between the rich club nodes rather than in the feeder and peripheral connections, a finding confirmed in both datasets. In discovery dataset, lower rich club connectivity was associated with lower scores on psychomotor speed (β = 0.29, P < 0.001) and executive functions (β = 0.20, P = 0.009). These results suggest that SVD is characterized by abnormal connectivity between rich club hubs in SVD and provide evidence that abnormal rich club organisation might contribute to the development of cognitive impairment in SVD. Hum Brain Mapp 38:1751–1766, 2017. © 2017 Wiley Periodicals, Inc.     

Patterned functional network disruption in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease primarily affecting motor function, with additional evidence of extensive nonmotor involvement. Despite increasing recognition of the disease as a multisystem network disorder characterised by impaired connectivity, the precise neuroelectric characteristics of impaired cortical communication remain to be fully elucidated. Here, we characterise changes in functional connectivity using beamformer source analysis on resting‐state electroencephalography recordings from 74 ALS patients and 47 age‐matched healthy controls. Spatiospectral characteristics of network changes in the ALS patient group were quantified by spectral power, amplitude envelope correlation (co‐modulation) and imaginary coherence (synchrony). We show patterns of decreased spectral power in the occipital and temporal (δ‐ to β‐band), lateral/orbitofrontal (δ‐ to θ‐band) and sensorimotor (β‐band) regions of the brain in patients with ALS. Furthermore, we show increased co‐modulation of neural oscillations in the central and posterior (δ‐, θ‐ and γ_l‐band) and frontal (δ‐ and γ_l‐band) regions, as well as decreased synchrony in the temporal and frontal (δ‐ to β‐band) and sensorimotor (β‐band) regions. Factorisation of these complex connectivity patterns reveals a distinct disruption of both motor and nonmotor networks. The observed changes in connectivity correlated with structural MRI changes, functional motor scores and cognitive scores. Characteristic patterned changes of cortical function in ALS signify widespread disease‐associated network disruption, pointing to extensive dysfunction of both motor and cognitive networks. These statistically robust findings, that correlate with clinical scores, provide a strong rationale for further development as biomarkers of network disruption for future clinical trials.     

Cortical disconnection of the ipsilesional primary motor cortex is associated with gait speed and upper extremity motor impairment in chronic left hemispheric stroke

Advances in neuroimaging have enabled the mapping of white matter connections across the entire brain, allowing for a more thorough examination of the extent of white matter disconnection after stroke. To assess how cortical disconnection contributes to motor impairments, we examined the relationship between structural brain connectivity and upper and lower extremity motor function in individuals with chronic stroke. Forty‐three participants [mean age: 59.7 (±11.2) years; time poststroke: 64.4 (±58.8) months] underwent clinical motor assessments and MRI scanning. Nonparametric correlation analyses were performed to examine the relationship between structural connectivity amid a subsection of the motor network and upper/lower extremity motor function. Standard multiple linear regression analyses were performed to examine the relationship between cortical necrosis and disconnection of three main cortical areas of motor control [primary motor cortex (M1), premotor cortex (PMC), and supplementary motor area (SMA)] and motor function. Anatomical connectivity between ipsilesional M1/SMA and the (1) cerebral peduncle, (2) thalamus, and (3) red nucleus were significantly correlated with upper and lower extremity motor performance (P ≤ 0.003). M1–M1 interhemispheric connectivity was also significantly correlated with gross manual dexterity of the affected upper extremity (P = 0.001). Regression models with M1 lesion load and M1 disconnection (adjusted for time poststroke) explained a significant amount of variance in upper extremity motor performance (R² = 0.36–0.46) and gait speed (R² = 0.46), with M1 disconnection an independent predictor of motor performance. Cortical disconnection, especially of ipsilesional M1, could significantly contribute to variability seen in locomotor and upper extremity motor function and recovery in chronic stroke. Hum Brain Mapp 39:120–132, 2018. © 2017 Wiley Periodicals, Inc.     

COMT genotype affects brain white matter pathways in attention‐deficit/hyperactivity disorder

Increased dopamine availability may be associated with impaired structural maturation of brain white matter connectivity. This study aimed to derive a comprehensive, whole‐brain characterization of large‐scale axonal connectivity differences in attention‐deficit/hyperactivity disorder (ADHD) associated with catechol‐O‐methyltransferase gene (COMT) Val158Met polymorphism. Using diffusion tensor imaging, whole‐brain tractography, and an imaging connectomics approach, we characterized altered white matter connectivity in youth with ADHD who were COMT Val‐homozygous (N = 29) compared with those who were Met‐carriers (N = 29). Additionally, we examined whether dopamine transporter gene (DAT1) and dopamine D4 receptor gene (DRD4) polymorphisms were associated with white matter differences. Level of attention was assessed using the continuous performance test before and after an 8‐week open‐label trial of methylphenidate (MPH). A network of white matter connections linking 18 different brain regions was significantly weakened in youth with ADHD who were COMT Met‐carriers compared to those who were Val‐homozygous (P < 0.05, family‐wise error‐corrected). A measure of white matter integrity, fractional anisotropy, was correlated with impaired pretreatment performance in continuous performance test omission errors and response time variability, as well as with improvement in continuous performance test response time variability after MPH treatment. Altered white matter connectivity was exclusively based on COMT genotypes, and was not evident in DAT1 or DRD4. We demonstrated that white matter connectivity in youth with ADHD is associated with COMT Val158Met genotypes. The present findings suggest that different layers of dopamine‐related genes and interindividual variability in the genetic polymorphisms should be taken into account when investigating the human connectome. Hum Brain Mapp, 36:367–377, 2015. © 2014 Wiley Periodicals, Inc.     

Rich club analysis in the Alzheimer's disease connectome reveals a relatively undisturbed structural core network

Diffusion imaging can assess the white matter connections within the brain, revealing how neural pathways break down in Alzheimer's disease (AD). We analyzed 3‐Tesla whole‐brain diffusion‐weighted images from 202 participants scanned by the Alzheimer's Disease Neuroimaging Initiative–50 healthy controls, 110 with mild cognitive impairment (MCI) and 42 AD patients. From whole‐brain tractography, we reconstructed structural brain connectivity networks to map connections between cortical regions. We tested whether AD disrupts the “rich club” – a network property where high‐degree network nodes are more interconnected than expected by chance. We calculated the rich club properties at a range of degree thresholds, as well as other network topology measures including global degree, clustering coefficient, path length, and efficiency. Network disruptions predominated in the low‐degree regions of the connectome in patients, relative to controls. The other metrics also showed alterations, suggesting a distinctive pattern of disruption in AD, less pronounced in MCI, targeting global brain connectivity, and focusing on more remotely connected nodes rather than the central core of the network. AD involves severely reduced structural connectivity; our step‐wise rich club coefficients analyze points to disruptions predominantly in the peripheral network components; other modalities of data are needed to know if this indicates impaired communication among non rich club regions. The highly connected core was relatively preserved, offering new evidence on the neural basis of progressive risk for cognitive decline. Hum Brain Mapp 36:3087–3103, 2015. © 2015 Wiley Periodicals, Inc.     

Structural and functional magnetic resonance imaging correlates of motor network dysfunction in primary progressive multiple sclerosis

We combined functional magnetic resonance imaging (fMRI) and diffusion tensor tractography to investigate the functional and structural substrates of motor network dysfunction in patients with primary progressive multiple sclerosis (PPMS). In 15 right‐handed PPMS patients and 15 age‐matched healthy controls, we acquired diffusion tensor magnetic resonance imaging and fMRI during the performance of a simple motor task. Tractography was used to calculate diffusion tensor‐derived measures of the corpus callosum, the corticospinal tract, the optic radiation, the fronto‐occipital fasciculus, and the inferior longitudinal fasciculus. Analyses of fMRI activations and functional connectivity were performed using statistical parametric mapping (cluster threshold of P = 0.001, and extent cluster threshold of 10 voxels for comparison of activations; P < 0.05, family‐wise error corrected for functional connectivity). As compared with controls, PPMS patients had more significant activations of the left postcentral gyrus, left secondary sensorimotor area, left parahippocampal gyrus, left cerebellum, right primary sensorimotor cortex (SMC), right basal ganglia, right insula, right cingulum, and cuneus bilaterally. As compared with PPMS patients, controls had increased functional connectivity between the left primary SMC and the ipsilateral inferior frontal gyrus. Conversely, PPMS patients showed increased functional connectivity between the left primary SMC and the right cuneus. Moderate correlations were found between functional activations and damage to the tracts studied (r‐values between 0.82 and 0.84; P < 0.001). These results suggest that, as compared with healthy controls, PPMS patients show increased activations and abnormal functional connectivity measures in several areas of the sensorimotor network. Such changes are correlated with the structural damage to the white matter fiber bundles connecting these regions.     

Small vessel disease and cognitive impairment: The relevance of central network connections

Central brain network connections greatly contribute to overall network efficiency. Here we examined whether small vessel disease (SVD) related white matter alterations in central brain network connections have a greater impact on executive functioning than alterations in non‐central brain network connections. Brain networks were reconstructed from diffusion‐weighted MRI scans in 72 individuals (75 ± 8 years) with cognitive impairment and SVD on MRI. The centrality of white matter connections in the network was defined using graph theory. The association between the fractional anisotropy (FA) of central versus non‐central connections, executive functioning, and markers of SVD was evaluated with linear regression and mediation analysis. Lower FA in central network connections was more strongly associated with impairment in executive functioning than FA in non‐central network connections (r = 0.41 vs. r = 0.27; P < 0.05). Results were consistent across varying thresholds to define the central subnetwork (>50%–10% connections). Higher SVD burden was associated with lower FA in central as well as non‐central network connections. However, only central network FA mediated the relationship between white matter hyperintensity volume and executive functioning [change in regression coefficient after mediation (95% CI): ?0.15 (?0.35 to ?0.02)]. The mediation effect was not observed for FA alterations in non‐central network connections [?0.03 (?0.19 to 0.04)]. These findings suggest that the centrality of network connections, and thus their contribution to global network efficiency, appears to be relevant for understanding the relationship between SVD and cognitive impairment. Hum Brain Mapp 37:2446–2454, 2016. © 2016 Wiley Periodicals, Inc .     

Functional–structural relationship in large‐scale brain networks of patients with end stage renal disease after kidney transplantation: A longitudinal study

It is unclear how the brain network changed after kidney transplantation (KT). We explored the patterns of large‐scale complex network after KT in end‐stage renal disease (ESRD) patients with resting‐state functional MRI (rs‐fMRI) and diffusion tensor imaging (DTI). Twenty‐one ESRD patients (14 men; mean age, 31.5 ± 9.9 years) scheduled for KT and 17 age‐ and gender‐matched healthy controls (HC) (8 men; mean age, 28.9 ± 7.2 years) were enrolled in this study. Each participant underwent rs‐fMRI and DTI scans in three time points (pre‐KT, 1 and 6 months after KT [for ESRD]). Graph theory analysis was used to characterize the topological properties by using functional and structural network connectivities intergroup correlation analysis was performed between functional/structural MR indexes and clinical markers. Compared with HC, pre‐KT ESRD patients showed an altered topological organization in both functional and structural networks. Compared with pre‐KT, increased node degree and node efficiency were observed for both functional and structural networks at 1 month after KT (all p < .05), which were further increased at 6 months after KT (p < .05). Both functional and structural networks did not recover completely at 6 months after KT (all p < .05). The patients showed an increased functional–structural connectivity coupling at 1 month after KT compared with HC (p = .041). A trend of progressive recovery of functional and structural connectivity networks was observed in ERSD patients after KT, which did not recover to the normal levels even in 6 months after KT. The study results underlie cognitive function recovery in ESRD patients following KT in the neuropathophysiological perspective.     

Basal ganglia‐cortical structural connectivity in Huntington's disease

Huntington's disease is an incurable neurodegenerative disease caused by inheritance of an expanded cytosine‐adenine‐guanine (CAG) trinucleotide repeat within the Huntingtin gene. Extensive volume loss and altered diffusion metrics in the basal ganglia, cortex and white matter are seen when patients with Huntington's disease (HD) undergo structural imaging, suggesting that changes in basal ganglia‐cortical structural connectivity occur. The aims of this study were to characterise altered patterns of basal ganglia‐cortical structural connectivity with high anatomical precision in premanifest and early manifest HD, and to identify associations between structural connectivity and genetic or clinical markers of HD. 3‐Tesla diffusion tensor magnetic resonance images were acquired from 14 early manifest HD subjects, 17 premanifest HD subjects and 18 controls. Voxel‐based analyses of probabilistic tractography were used to quantify basal ganglia‐cortical structural connections. Canonical variate analysis was used to demonstrate disease‐associated patterns of altered connectivity and to test for associations between connectivity and genetic and clinical markers of HD; this is the first study in which such analyses have been used. Widespread changes were seen in basal ganglia‐cortical structural connectivity in early manifest HD subjects; this has relevance for development of therapies targeting the striatum. Premanifest HD subjects had a pattern of connectivity more similar to that of controls, suggesting progressive change in connections over time. Associations between structural connectivity patterns and motor and cognitive markers of disease severity were present in early manifest subjects. Our data suggest the clinical phenotype in manifest HD may be at least partly a result of altered connectivity. Hum Brain Mapp 36:1728–1740, 2015. © 2015 Wiley Periodicals, Inc .     

Brain network analysis reveals affected connectome structure in bipolar I disorder

The notion that healthy brain function emerges from coordinated neural activity constrained by the brain's network of anatomical connections—i.e., the connectome—suggests that alterations in the connectome's wiring pattern may underlie brain disorders. Corroborating this hypothesis, studies in schizophrenia are indicative of altered connectome architecture including reduced communication efficiency, disruptions of central brain hubs, and affected “rich club” organization. Whether similar deficits are present in bipolar disorder is currently unknown. This study examines structural connectome topology in 216 bipolar I disorder patients as compared to 144 healthy controls, focusing in particular on central regions (i.e., brain hubs) and connections (i.e., rich club connections, interhemispheric connections) of the brain's network. We find that bipolar I disorder patients exhibit reduced global efficiency (?4.4%, P =0.002) and that this deficit relates (r = 0.56, P < 0.001) to reduced connectivity strength of interhemispheric connections (?13.0%, P = 0.001). Bipolar disorder patients were found not to show predominant alterations in the strength of brain hub connections in general, or of connections spanning brain hubs (i.e., “rich club” connections) in particular (all P > 0.1). These findings highlight a role for aberrant brain network architecture in bipolar I disorder with reduced global efficiency in association with disruptions in interhemispheric connectivity, while the central “rich club” system appears not to be particularly affected. Hum Brain Mapp 37:122–134, 2016. © 2015 Wiley Periodicals, Inc.     

Role of testosterone and Y chromosome genes for the masculinization of the human brain

Women with complete androgen insensitivity syndrome (CAIS) have a male (46,XY) karyotype but no functional androgen receptors. Their condition, therefore, offers a unique model for studying testosterone effects on cerebral sex dimorphism. We present MRI data from 16 women with CAIS and 32 male (46,XY) and 32 female (46,XX) controls. Methods: FreeSurfer software was employed to measure cortical thickness and subcortical structural volumes. Axonal connections, indexed by fractional anisotropy, (FA) were measured with diffusion tensor imaging, and functional connectivity with resting state fMRI. Results: Compared to men, CAIS women displayed a “female” pattern by having thicker parietal and occipital cortices, lower FA values in the right corticospinal, superior and inferior longitudinal tracts, and corpus callosum. Their functional connectivity from the amygdala to the medial prefrontal cortex, was stronger and amygdala‐connections to the motor cortex weaker than in control men. CAIS and control women also showed stronger posterior cingulate and precuneus connections in the default mode network. Thickness of the motor cortex, the caudate volume, and the FA in the callosal body followed, however, a “male” pattern. Conclusion: Altogether, these data suggest that testosterone modulates the microstructure of somatosensory and visual cortices and their axonal connections to the frontal cortex. Testosterone also influenced functional connections from the amygdala, whereas the motor cortex could, in agreement with our previous reports, be moderated by processes linked to X‐chromosome gene dosage. These data raise the question about other genetic factors masculinizing the human brain than the SRY gene and testosterone. Hum Brain Mapp 38:1801–1814, 2017. © 2017 Wiley Periodicals, Inc.     

A combined diffusion‐weighted and electroencephalography study on age‐related differences in connectivity in the motor network during bimanual performance

We studied the relationship between age‐related differences in inter‐ and intra‐hemispheric structural and functional connectivity in the bilateral motor network. Our focus was on the correlation between connectivity and declined motor performance in older adults. Structural and functional connectivity were estimated using diffusion weighted imaging and resting‐state electro‐encephalography, respectively. A total of 48 young and older healthy participants were measured. In addition, motor performances were assessed using bimanual coordination tasks. To pre‐select regions‐of‐interest (ROIs), a neural model was adopted that accounts for intra‐hemispheric functional connectivity between dorsal premotor area (PMd) and primary motor cortex (M1) and inter‐hemispheric connections between left and right M1 (M1_L and M1_R). Functional connectivity was determined via the weighted phase‐lag index (wPLI) in the source‐reconstructed beta activity during rest. We quantified structural connectivity using kurtosis anisotropy (KA) values of tracts derived from diffusion tensor‐based fiber tractography between the aforementioned areas. In the group of older adults, wPLI values between M1_L–M1_R were negatively associated with the quality of bimanual motor performance. The additional association between wPLI values of PMd_L––M1_L and PMd_R–M1_L supports that functional connectivity with the left hemisphere mediated (bimanual) motor control in older adults. The correlational analysis between the selected structural and functional connections revealed a strong association between wPLI values in the left intra‐hemispheric PMd_L–M1_L pathway and KA values in M1_L–M1_R and PMd_R–M1_L pathways in the group of older adults. This suggests that weaker structural connections in older adults correlate with stronger functional connectivity and, hence, poorer motor performance.     

Variability of structurally constrained and unconstrained functional connectivity in schizophrenia

Spatial variation in connectivity is an integral aspect of the brain's architecture. In the absence of this variability, the brain may act as a single homogenous entity without regional specialization. In this study, we investigate the variability in functional links categorized on the basis of the presence of direct structural paths (primary) or indirect paths mediated by one (secondary) or more (tertiary) brain regions ascertained by diffusion tensor imaging. We quantified the variability in functional connectivity using an unbiased estimate of unpredictability (functional connectivity entropy) in a neuropsychiatric disorder where structure‐function relationship is considered to be abnormal; 34 patients with schizophrenia and 32 healthy controls underwent DTI and resting state functional MRI scans. Less than one‐third (27.4% in patients, 27.85% in controls) of functional links between brain regions were regarded as direct primary links on the basis of DTI tractography, while the rest were secondary or tertiary. The most significant changes in the distribution of functional connectivity in schizophrenia occur in indirect tertiary paths with no direct axonal linkage in both early (P = 0.0002, d = 1.46) and late (P = 1 × 10^?17, d = 4.66) stages of schizophrenia, and are not altered by the severity of symptoms, suggesting that this is an invariant feature of this illness. Unlike those with early stage illness, patients with chronic illness show some additional reduction in the distribution of connectivity among functional links that have direct structural paths (P = 0.08, d = 0.44). Our findings address a critical gap in the literature linking structure and function in schizophrenia, and demonstrate for the first time that the abnormal state of functional connectivity preferentially affects structurally unconstrained links in schizophrenia. It also raises the question of a continuum of dysconnectivity ranging from less direct (structurally unconstrained) to more direct (structurally constrained) brain pathways underlying the progressive clinical staging and persistence of schizophrenia. Hum Brain Mapp 36:4529–4538, 2015. © 2015 The Authors. Human Brain Mapping Published by Wiley Periodicals, Inc.