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Objective: Neuroimaging studies in children with ADHD indicate that their brain exhibits an atypical functional connectivity pattern characterized by increased local connectivity and decreased distant connectivity. We aim to evaluate if the local and distant distribution of functional connectivity is also altered in adult samples with ADHD who have never received medication before. Methods: We compared local and distant functional connectivity between 31 medication-naïve adults with ADHD and 31 healthy controls and tested whether this pattern was associated with symptoms severity scores. Results: ADHD sample showed increased local connectivity in the dACC and the SFG and decreased local connectivity in the PCC. Conclusion: Results parallel those obtained in children samples suggesting a deficient integration within the DMN and segregation between DMN, FPN, and VAN. These results are consistent with the three main frameworks that explain ADHD: the neurodevelopmental delay hypothesis, the DMN interference hypothesis and multi-network models.

Investment decisions rely on perceptions from external stimuli along with the integration of inner brain-body signals, all of which are shaped by experience. As experience is capable of molding both the structure and function of the human brain, we have used a novel neuroimaging connectomic-genetic approach to investigate the influence of investment work experience on brain anatomy. We found that senior investors display higher gray matter volume and increased structural brain connectivity in dopamine-related pathways, as well as a set of genes functionally associated with adrenaline and noradrenaline biosynthesis (SLC6A3, TH and SLC18A2), which is seemingly involved in reward processing and bodily stress responses during financial trading. These results suggest the key role of catecholamines in the way senior investors harness their emotions while raising bodily awareness as they grow in investment maturity.

Recent studies of creative cognition have revealed interactions between functional brain networks involved in the generation of novel ideas; however, the neural basis of creativity is highly complex and presents a great challenge in the field of cognitive neuroscience, partly because of ambiguity around how to assess creativity. We applied a novel computational method of verbal creativity assessment—semantic distance—and performed weighted degree functional connectivity analyses to explore how individual differences in assembly of resting-state networks are associated with this objective creativity assessment. To measure creative performance, a sample of healthy adults ( n = 175) completed a battery of divergent thinking (DT) tasks, in which they were asked to think of unusual uses for everyday objects. Computational semantic models were applied to calculate the semantic distance between objects and responses to obtain an objective measure of DT performance. All participants underwent resting-state imaging, from which we computed voxel-wise connectivity matrices between all gray matter voxels. A linear regression analysis was applied between DT and weighted degree of the connectivity matrices. Our analysis revealed a significant connectivity decrease in the visual-temporal and parietal regions, in relation to increased levels of DT. Link-level analyses showed higher local connectivity within visual regions was associated with lower DT, whereas projections from the precuneus to the right inferior occipital and temporal cortex were positively associated with DT. Our results demonstrate differential patterns of resting-state connectivity associated with individual creative thinking ability, extending past work using a new application to automatically assess creativity via semantic distance.

Objective Impaired multisensory integration in autism spectrum disorder (ASD) may arise from functional dysconnectivity among brain systems. Our study examines the functional connectivity integration between primary modal sensory regions and heteromodal processing cortex in ASD, and whether abnormalities in network integration relate to clinical severity. Method We studied a sample of 55 high-functioning ASD and 64 healthy control (HC) male children and adolescents (total n = 119, age range 7−18 years). Stepwise functional connectivity analysis (SFC) was applied to resting state functional magnetic resonance images (rsfMRI) to characterize the connectivity paths that link primary sensory cortices to higher-order brain cognitive functional circuits and to relate alterations in functional connectivity integration with three clinical scales: Social Communication Questionnaire, Social Responsiveness Scale, and Vineland Adaptive Behavior Scales. Results HC displayed typical functional connectivity transitions from primary sensory systems to association areas, but the ASD group showed altered patterns of multimodal sensory integration to heteromodal systems. Specifically, compared to the HC group, the ASD group showed the following: (1) hyperconnectivity in the visual cortex at initial link step distances; (2) hyperconnectivity between sensory unimodal regions and regions of the default mode network; and (3) hypoconnectivity between sensory unimodal regions and areas of the fronto-parietal and attentional networks. These patterns of hyper- and hypoconnectivity were associated with increased clinical severity in ASD. Conclusion Networkwise reorganization in high-functioning ASD individuals affects strategic regions of unimodal-to-heteromodal cortical integration predicting clinical severity. In addition, SFC analysis appears to be a promising approach for studying the neural pathophysiology of multisensory integration deficits in ASD.

Functional neurological (conversion) disorder (FND) is a neuropsychiatric condition whereby individuals present with sensorimotor symptoms incompatible with other neurological disorders. Early-life maltreatment (ELM) is a risk factor for developing FND, yet few studies have investigated brain network-trauma relationships in this population. In this neuroimaging-gene expression study, we used two graph theory approaches to elucidate ELM subtype effects on resting-state functional connectivity architecture in 30 patients with motor FND. Twenty-one individuals with comparable depression, anxiety, and ELM scores were used as psychiatric controls. Thereafter, we compared trauma endophenotypes in FND with regional differences in transcriptional gene expression as measured by the Allen Human Brain Atlas (AHBA). In FND patients only, we found that early-life physical abuse severity, and to a lesser extent physical neglect, correlated with corticolimbic weighted-degree functional connectivity. Connectivity profiles influenced by physical abuse occurred in limbic (amygdalar-hippocampal), paralimbic (cingulo-insular and ventromedial prefrontal), and cognitive control (ventrolateral prefrontal) areas, as well as in sensorimotor and visual cortices. These findings held adjusting for individual differences in depression/anxiety, PTSD, and motor phenotypes. In FND, physical abuse also correlated with amygdala and insula coupling to motor cortices. In exploratory analyses, physical abuse correlated connectivity maps overlapped with the AHBA spatial expression of three gene clusters: (i) neuronal morphogenesis and synaptic transmission genes in limbic/paralimbic areas; (ii) locomotory behavior and neuronal generation genes in left-lateralized structures; and (iii) nervous system development and cell motility genes in right-lateralized structures. These circuit-specific architectural profiles related to individual differences in childhood physical abuse burden advance our understanding of the pathophysiology of FND.

Background:The correlations between apolipoprotein epsilon 4 (APOE4) status and regional amyloid, tau, and cortical thickness in cognitively normal elderly are not fully understood. Our cross-sectional study aimed to compare regional amyloid/tau burden, and cortical thickness according to APOE4 carrier status and assess correlations between APOE4 and Alzheimer’s disease (AD)-related biomarker burdens.Methods:We analyzed 185 cognitively normal participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Participants aged 55–90 with normal cognitive function were divided into amyloid ꞵ-positive (Aß+) APOE4 carriers (group 1, n=27), Aß+ APOE4 non-carriers (group 2, n=29), and Aß- normal controls (group 0, n=129). We compared amyloid depositions, tau depositions, and cortical thickness among the 3 groups and assessed correlations between APOE4 existence and imaging biomarkers adjusted for age and sex. Results:The participants in group 2 were older than those in the other groups. The regional amyloid/tau standardized uptake value ratios (SUVRs) did not differ between groups 1 and 2, but the amyloid/tau SUVRs in most regions were numerically higher (especially in the younger (Conclusions:We identified that the presence of APOE4 allele might be more highly associated with amyloid deposition than with other AD-related biomarkers such as tau or cortical thickness, especially in the younger group below 70 in cognitively normal elderly.

The human brain is composed of functional networks that have a modular topology, where brain regions are organized into communities that form internally dense (segregated) and externally sparse (integrated) subnetworks that underlie higher-order cognitive functioning. It is hypothesized that amyloid-β and tau pathology in preclinical Alzheimer’s disease (AD) spread through functional networks, disrupting neural communication that results in cognitive dysfunction. We used high-resolution (voxel-level) graph-based network analyses to test whether in vivo amyloid-β and tau burden was associated with the segregation and integration of brain functional connections, and episodic memory, in cognitively unimpaired Presenilin-1 E280A carriers who are expected to develop early-onset AD dementia in ∼13 y on average. Compared to noncarriers, mutation carriers exhibited less functional segregation and integration in posterior default-mode network (DMN) regions, particularly the precuneus, and in the retrospenial cortex, which has been shown to link medial temporal regions and cortical regions of the DMN. Mutation carriers also showed greater functional segregation and integration in regions connected to the salience network, including the striatum and thalamus. Greater tau burden was associated with lower segregated and integrated functional connectivity of DMN regions, particularly the precuneus and medial prefrontal cortex. In turn, greater tau pathology was related to higher segregated and integrated functional connectivity in the retrospenial cortex and the anterior cingulate cortex, a hub of the salience network. These findings enlighten our understanding of how AD-related pathology distinctly alters the brain’s functional architecture in the preclinical stage, possibly contributing to pathology propagation and ultimately resulting in dementia.

Small vessel disease (SVD) is a disorder that causes vascular lesions in the entire parenchyma of the human brain. At present, it is not well known how primary and secondary damage interact to give rise to the complex scenario of white matter (WM) and grey matter (GM) lesions. Using novel cross-sectional and longitudinal connectomic approaches, we unveil the bidirectional nature of GM and WM changes, that is, primary cortical neurodegeneration that leads to secondary alterations in vascular border zones, and WM lesions that lead to secondary neurodegeneration in cortical projecting areas. We found this GM-WM interaction to be essential for executive cognitive performance. Moreover, we also observed that the interlocked degeneration of GM and WM over time associates with prototypical expression levels of genes potentially linked to SVD. Among these connectomic-genetic intersections, we found that the Androgen Receptor (AR) protein coding gene, is a particularly central candidate gene that might confer key vulnerability for brain lesion development in SVD. In conclusion, this study advances in the understanding of the bidirectional relationships between GM and WM lesions, primary and secondary vascular neurodegeneration, and sheds light on the biological mechanisms which underlie the genetic signatures of SVD.

Highlights • In this study we characterized in vivo large-scale propagation pathways of α-synuclein pathology and identified different patterns of functional connectivity disruptions in PD patients at different stages of the disease. • Our results identified key genetic signatures of large-scale PD pathology, highlighting their contribution to focal neuronal vulnerability to disease progression. • Our results pave the way toward better accounting for the brain networks complexity and mechanisms underlying distinct spatial vulnerability to PD pathology, thus informing early diagnosis and future novel therapeutic strategies., The genetic traits that underlie vulnerability to neuronal damage across specific brain circuits in Parkinson’s disease (PD) remain to be elucidated. In this study, we characterized the brain topological intersection between propagating connectivity networks in controls and PD participants and gene expression patterns across the human cortex – such as the SNCA gene. We observed that brain connectivity originated from PD-related pathology epicenters in the brainstem recapitulated the anatomical distribution of alpha-synuclein histopathology in postmortem data. We also discovered that the gene set most related to cortical propagation patterns of PD-related pathology was primarily involved in microtubule cellular components. Thus, this study sheds light on new avenues for enhancing detection of PD neuronal vulnerability via an evaluation of in vivo connectivity trajectories across the human brain and successful integration of neuroimaging-genetic strategies.

[(18)F]AV-1451 (aka (18)F-Flortaucipir, [(18)F]T807) was developed for positron-emission tomography (PET) imaging of paired helical filaments of hyperphosphorylated tau, which are of interest in a range of neuropathologies, including traumatic brain injury (TBI). Magnetic resonance imaging (MRI) techniques like diffusion tensor imaging (DTI) and resting state functional connectivity assess structural and functional characteristics of the brain, complementing the molecular information that can be obtained by PET. The goal herein was to explore the utility of such multi-modal imaging in a case series based on a population of TBI subjects. This study probes the interrelationship between tau deposition, white matter integrity, and gray matter functional connectivity across the spectrum of TBI. Nineteen subjects (11 controls, five former contact sports athletes, one automotive accident, and two with military-related injury) underwent [(18)F]AV-1451 PET and magnetic resonance scanning procedures. [(18)F]AV-1451 distribution volume ratio (DVR) was estimated using the Logan method and the cerebellum as a reference region. Diffusion tractography images and fractional anisotropy (FA) images were generated using diffusion toolkit and FSL. Resting-state functional MRI (fMRI) analysis was based on a graph theory metric, namely weighted degree centrality. TBI subjects showed greater heterogeneity in [(18)F]AV-1451 DVR when compared with control subjects. In a subset of TBI subjects, areas with high [(18)F]AV-1451 binding corresponded with increased FA and diminished white matter tract density in DTI. Functional MRI results exhibited an increase in functional connectivity, particularly among local connections, in the areas where tau aggregates were more prevalent. In a case series of a diverse group of TBI subjects, brain regions with elevated tau burden exhibited increased functional connectivity as well as decreased white matter integrity. These findings portray molecular, microstructural, and functional corollaries of TBI that spatially coincide and can be measured in the living human brain using noninvasive neuroimaging techniques.

ObjectiveSome individuals with functional neurological disorder (FND) exhibit motor and affective disturbances, along with limbic hyper-reactivity and enhanced motor-limbic connectivity. Given that the multimodal integration network (insula, dorsal cingulate, temporoparietal junction (TPJ)) is implicated in convergent sensorimotor, affective and interoceptive processing, we hypothesised that patients with FND would exhibit altered motor and amygdalar resting-state propagation to this network. Patient-reported symptom severity and clinical outcome were also hypothesised to map onto multimodal integration areas.MethodsBetween-group differences in primary motor and amygdalar nuclei (laterobasal, centromedial) were examined using graph-theory stepwise functional connectivity (SFC) in 30 patients with motor FND compared with 30 healthy controls. Within-group analyses correlated functional propagation profiles with symptom severity and prospectively collected 6-month outcomes as measured by the Screening for Somatoform Symptoms Conversion Disorder subscale and Patient Health Questionnaire-15 composite score. Findings were clusterwise corrected for multiple comparisons.ResultsCompared with controls, patients with FND exhibited increased SFC from motor regions to the bilateral posterior insula, TPJ, middle cingulate cortex and putamen. From the right laterobasal amygdala, the FND cohort showed enhanced connectivity to the left anterior insula, periaqueductal grey and hypothalamus among other areas. In within-group analyses, symptom severity correlated with enhanced SFC from the left anterior insula to the right anterior insula and TPJ; increased SFC from the left centromedial amygdala to the right anterior insula correlated with clinical improvement. Within-group associations held controlling for depression, anxiety and antidepressant use.ConclusionsThese neuroimaging findings suggest potential candidate neurocircuit pathways in the pathophysiology of FND.

Purpose of review The prevalence of new public datasets of brain-wide and single-cell transcriptome data has created new opportunities to link neuroimaging findings with genetic data. The aim of this study is to present the different methodological approaches that have been used to combine this data. Recent findings Drawing from various sources of open access data, several studies have been able to correlate neuroimaging maps with spatial distribution of brain expression. These efforts have enabled researchers to identify functional annotations of related genes, identify specific cell types related to brain phenotypes, study the expression of genes across life span and highlight the importance of selected brain genes in disease genetic networks. Summary New transcriptome datasets and methodological approaches complement current neuroimaging work and will be crucial to improve our understanding of the biological mechanism that underlies many neurological conditions.

Previous investigations have used global graph theory measures in order to disentangle the complexity of the neural reorganizations occurring in cocaine use disorder (CUD). However, how these global topological alterations map into individual brain network areas remains unknown. In this study, we used resting state functional magnetic resonance imaging (fMRI) data to investigate node-level topological dysfunctions in CUD. The sample was composed of 32 individuals with CUD and 32 healthy controls, matched in age, years of education and intellectual functioning. Graph theory measures of optimal connectivity distance, node strength, nodal efficiency and clustering coefficient were estimated in each participant using voxel-wise functional connectivity connectomes. CUD individuals as compared with healthy controls showed higher optimal connectivity distances in ventral striatum, insula, cerebellum, temporal cortex, lateral orbitofrontal cortex, middle frontal cortex and left hippocampus. Furthermore, clinical measures quantifying severity of dependence were positively related with optimal connectivity distances in the right rolandic operculum and the right lateral orbitofrontal cortex, whereas length of abstinence was negatively associated with optimal connectivity distances in the right temporal pole and the left insula. Our results reveal a topological distancing of cognitive and affective related areas in addiction, suggesting an overall reduction in the communication capacity of these regions. Funding for open access charge: CRUE-Universitat Jaume I This research was supported by grant 040/2011 from Spanish National Drug Strategy, Ministerio de Sanidad y Consumo to ABL. JAV was supported by a predoctoral graduate programme grant (National FPU). MPG and AMP were supported by a postdoctoral graduate programme grant (postdoc-UJI). VC was supported by grant PID2019-105077RJ-I00 from Ministerio de Ciencia, Innovación y Universidades.

Amyloid‐beta (Aβ) plaques and tau neurofibrillary tangles are pathological hallmarks of Alzheimer's disease (AD); their contribution to neurodegeneration and clinical manifestations are critical in understanding preclinical AD. At present, the mechanisms related to Aβ and tau pathogenesis leading to cognitive decline in older adults remain largely unknown. Here, we examined graph theory‐based positron emission tomography (PET) analytical approaches, within and between tau and Aβ PET modalities, and tested the effects on cognitive changes in cognitively normal older adults (CN). Particularly, we focused on the network interdigitations of Aβ and tau deposits, along with cognitive test scores in CN at both baseline and 2‐year follow‐up (FU). We found highly significant Aβ‐tau network integrations in AD vulnerable areas, as well as significant associations between those Aβ‐tau interdigitations and general cognitive impairment in CN at baseline and FU. Our findings suggest a distinctive contribution of interlinking network relationships between Aβ and tau deposits in heteromodal areas of the human brain. They support a network‐based interaction between Aβ and tau accumulations as a key factor for cognitive deterioration in CN prior to dementia., We examined network interaction patterns within single positron emission tomography (PET) modality, such as Aß‐to‐Aß or Tau‐to‐Tau correlations, and between different PET modalities, such as Aß‐to‐Tau or Tau‐to‐Aß, at high‐resolution (voxel‐level) in cognitively normal older adults (CN), using a graph theory‐based analysis. We observed that the PET uptakes derived from Aß‐to‐Tau interdigitations were significantly associated with Alzheimer's Disease Assessment Scale‐Cognitive Subscale in AD vulnerable brain areas, a finding confirmed by our longitudinal investigation. Therefore, our work suggests the preceding contribution of network interactions between Aß and tau deposits to explain initial cognitive changes in CN prior to the conversion of dementia.

Altres ajuts: National Institutes of Health (R01AG061811, R01AG061445); Ministerio de Educación, Cultura y Deporte (Estancias de movilidad en el extranjero "José Castillejo" para jóvenes doctores. Convocatoria 2017); Generalitat Valenciana. The relationship between human brain connectomics and genetic evolutionary traits remains elusive due to the inherent challenges in combining complex associations within cerebral tissue. In this study, insights are provided about the relationship between connectomics, gene expression and divergent evolutionary pathways from non-human primates to humans. Using in vivo human brain resting-state data, we detected two co-existing idiosyncratic functional systems: the segregation network, in charge of module specialization, and the integration network, responsible for information flow. Their topology was approximated to whole-brain genetic expression (Allen Human Brain Atlas) and the co-localization patterns yielded that neuron communication functionalities-linked to Neuron Projection-were overrepresented cell traits. Homologue-orthologue comparisons using dN/dS-ratios bridged the gap between neurogenetic outcomes and biological data, summarizing the known evolutionary divergent pathways within the Homo Sapiens lineage. Evidence suggests that a crosstalk between functional specialization and information flow reflects putative biological qualities of brain architecture, such as neurite cellular functions like axonal or dendrite processes, hypothesized to have been selectively conserved in the species through positive selection. These findings expand our understanding of human brain function and unveil aspects of our cognitive trajectory in relation to our simian ancestors previously left unexplored.

Highlights • Utilized graph theory to study mGluR5 networks in FCD patients. • Global reductions were observed in mGluR5 network efficiency and resilience. • Epilepsy duration was associated with network efficiency in hub regions. • Focal epileptogenic lesions may progressively reduce whole brain network integration., To determine the extent of metabotropic glutamate receptor type 5 (mGluR5) network abnormalities associated with focal cortical dysplasia (FCD), we performed graph theoretical analysis of [11C]ABP688 PET binding potentials (BPND), which allows for quantification of mGluR5 availability. Undirected graphs were constructed for the entire cortex in 17 FCD patients and 33 healthy controls using inter-regional similarity of [11C]ABP688 BPND. We assessed group differences in network integration between healthy controls and the ipsilateral and contralateral hemispheres of FCD patients. Compared to healthy controls, FCD patients showed reduced network efficiency and reduced small-world connectivity. The mGluR5 network of FCD patients was also less resilient to targeted removal of high centrality nodes, suggesting a less integrated network organization. In highly efficient hub nodes of FCD patients, we observed a significant negative correlation between local efficiency and duration of epilepsy only in the contralateral hemisphere, suggesting that some nodes may be more vulnerable to persistent epileptic activity. Our study provides the first in vivo evidence for a widespread reduction in cortical mGluR5 network integration in FCD patients. In addition, we find that ongoing epileptic activity may alter chemoarchitectural brain organization resulting in reduced efficiency in distant regions that are essential for network integration.

Aim To delineate the neurogenetic profiles of brain degeneration patterns in myotonic dystrophy type I (DM1). Methods In two cohorts of DM1 patients, brain maps of volume loss (VL) and neuropsychological deficits (NDs) were intersected to large-scale transcriptome maps provided by the Allen Human Brain Atlas (AHBA). For validation, neuropathological and RNA analyses were performed in a small series of DM1 brain samples. Results Twofold: (1) From a list of preselected hypothesis-driven genes, confirmatory analyses found that three genes play a major role in brain degeneration: dystrophin (DMD), alpha-synuclein (SNCA) and the microtubule-associated protein tau (MAPT). Neuropathological analyses confirmed a highly heterogeneous Tau-pathology in DM1, different to the one in Alzheimer's disease. (2) Exploratory analyses revealed gene clusters enriched for key biological processes in the central nervous system, such as synaptic vesicle recycling, localization, endocytosis and exocytosis, and the serotonin and dopamine neurotransmitter pathways. RNA analyses confirmed synaptic vesicle dysfunction. Conclusions The combination of large-scale transcriptome interactions with brain imaging and cognitive function sheds light on the neurobiological mechanisms of brain degeneration in DM1 that might help define future therapeutic strategies and research into this condition. We wish to thank Prof. Virginia Arechavala for providing us with an updated list of relevant genes in DM1, some of which were considered in our study. J.M.C. is funded by Ikerbasque: The Basque Foundation for Science and from the Ministerio de Economia, Industria y Competitividad (Spain) and FEDER (grant DPI2016-79874-R), and from the Department of Economic and Infrastructure Development of the Basque Country (Elkartek Program, KK-2018/00032 and KK-2018/00090). A.L. d. M. was founded by the Institute of Health Carlos III co-founded by Fondo Europeo de Desarrollo Regional-FEDER (grant PI17/01841), CIBERNED (grant 609), and La Caixa Foundation (grant HR17-00268). A. S. was founded by the Institute of Health Carlos III co-founded by Fondo Europeo de Desarrollo Regional-FEDER (grant PI17/01231), and the Basque Government (grant SAIO08-PE08BF01). A. J.M was partially funded by Euskampus Fundazioa and a predoctoral grant from the Basque Government (PRE_2019_1_ 0070). G.L. was founded by a predoctoral grant from the Basque Government (PRE_2016_1_0187). I.F. was founded from `la Caixa' Foundation under the agreement LCF/PR/HR19/52160007 and was also supported by the Ministry of Economy and Competiveness, Institute of Health Carlos III (co-funded by European Regional Development Fund, ERDF, a way to build Europe): FIS PI17/000809.

Individual differences in humans are driven by unique brain structural and functional profiles, presumably mediated in part through differential cortical gene expression. However, the relationships between cortical gene expression profiles and individual differences in large-scale neural network organization remain poorly understood. In this study, we aimed to investigate whether the magnitude of sequence alterations in regional cortical genes mapped onto brain areas with high degree of functional connectivity variability across individuals. First, human genetic expression data from the Allen Brain Atlas was used to identify protein-coding genes associated with cortical areas, which delineated the regional genetic signature of specific cortical areas based on sequence alteration profiles. Thereafter, we identified brain regions that manifested high degrees of individual variability by using test-retest functional connectivity magnetic resonance imaging and graph-theory analyses in healthy subjects. We found that rates of genetic sequence alterations shared a distinct spatial topography with cortical regions exhibiting individualized (highly-variable) connectivity profiles. Interestingly, gene expression profiles of brain regions with highly individualized connectivity patterns and elevated number of sequence alterations are devoted to neuropeptide-signaling-pathways and chemical-synaptic-transmission. Our findings support that genetic sequence alterations may underlie important aspects of brain connectome individualities in humans.Significance Statement: The neurobiological underpinnings of our individuality as humans are still an unsolved question. Although the notion that genetic variation drives an individual’s brain organization has been previously postulated, specific links between neural connectivity and gene expression profiles have remained elusive. In this study, we identified the magnitude of population-based sequence alterations in discrete cortical regions and compared them to the brain topological distribution of functional connectivity variability across an independent human sample. We discovered that brain regions with high degree of connectional individuality are defined by increased rates of genetic sequence alterations; these findings specifically implicated genes involved in neuropeptide-signaling pathways and chemical-synaptic transmission. These observations support that genetic sequence alterations may underlie important aspects of the emergence of the brain individuality across humans.

Introduction: Amyloid positron emission tomography (PET) data are commonly expressed as binary measures of cortical deposition. However, not all individuals with high cortical amyloid will experience rapid cognitive decline. Motivated by postmortem data, we evaluated a three-stage PET classification: low cortical; high cortical, low striatal; and high cortical, high striatal amyloid; hypothesizing this model could better reflect Alzheimer's dementia progression than a model based only on cortical measures. Methods: We classified PET data from 1433 participants (646 normal, 574 mild cognitive impairment, and 213 AD), explored the successive involvement of cortex and striatum using 3-year follow-up PET data, and evaluated the associations between PET stages, hippocampal volumes, and cognition. Results: Follow-up data indicated that PET detects amyloid first in cortex and then in striatum. Our three-category staging including striatum better predicted hippocampal volumes and subsequent cognition than a three-category staging including only cortical amyloid. Discussion: PET can evaluate amyloid expansion from cortex to subcortex. Using striatal signal as a marker of advanced amyloidosis may increase predictive power in Alzheimer's dementia research. (C) 2018 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer's Association.

Training‐induced neuroplasticity has been described in athletes' population. However, it remains largely unknown how regular training and sports proficiency modifies neuronal circuits in the human brain. In this study, we used voxel‐based morphometry and stepwise functional connectivity (SFC) analyses to uncover connectivity changes in the functional stream architecture in student‐athletes at early stages of sensorimotor skill training. Thirty‐two second‐year student‐athletes whose major was little‐ball sports and thirty‐four nonathlete controls were recruited for the study. We found that athletes showed greater gray matter volume in the right sensorimotor area, the limbic lobe, and the anterior lobe of the cerebellum. Furthermore, SFC analysis demonstrated that athletes displayed significantly smaller optimal connectivity distance from those seed regions to the dorsal attention network (DAN) and larger optimal connectivity distance to the default mode network (DMN) compared to controls. The Attention Network Test showed that the reaction time of the orienting attention subnetwork was positively correlated with SFC between the seeds and the DAN, while negatively correlated with SFC between the seeds and the DMN. Our findings suggest that neuroplastic adaptations on functional connectivity streams after motor skill training may enable novel information flow from specific areas of the cortex toward distributed networks such as the DAN and the DMN. This could potentially regulate the focus of external and internal attention synchronously in athletes, and consequently accelerate the reaction time of orienting attention in athletes.

Animal models of Alzheimer's disease have suggested that tau pathology propagation, facilitated by amyloid pathology, may occur along connected pathways. To investigate these ideas in humans, we combined amyloid scans with longitudinal data on white matter connectivity, hippocampal volume, tau positron emission tomography and memory performance in 256 cognitively healthy older individuals. Lower baseline hippocampal volume was associated with increased mean diffusivity of the connecting hippocampal cingulum bundle (HCB). HCB diffusivity predicted tau accumulation in the downstream-connected posterior cingulate cortex in amyloid-positive but not in amyloid-negative individuals. Furthermore, HCB diffusivity predicted memory decline in amyloid-positive individuals with high posterior cingulate cortex tau binding. Our results provide in vivo evidence that higher amyloid pathology strengthens the association between HCB diffusivity and tau accumulation in the downstream posterior cingulate cortex and facilitates memory decline. This confirms amyloid's crucial role in potentiating neural vulnerability and memory decline marking the onset of preclinical Alzheimer's disease.

The dynamic architecture of the human brain has been consistently observed. However, there is still limited modeling work to elucidate how neuronal circuits are hierarchically and flexibly organized in functional systems. Here we proposed a reachable probability approach based on non-homogeneous Markov chains, to characterize all possible connectivity flows and the hierarchical structure of brain functional systems at the dynamic level. We proved at the theoretical level the convergence of the functional brain network system, and demonstrated that this approach is able to detect network steady states across connectivity structure, particularly in areas of the default mode network. We further explored the dynamically hierarchical functional organization centered at the primary sensory cortices. We observed smaller optimal reachable steps to their local functional regions, and differentiated patterns in larger optimal reachable steps for primary perceptual modalities. The reachable paths with the largest and second largest transition probabilities between primary sensory seeds via multisensory integration regions were also tracked to explore the flexibility and plasticity of the multisensory integration. The present work provides a novel approach to depict both the stable and flexible hierarchical connectivity organization of the human brain.

Cerebrovascular abnormality is linked to Alzheimer’s disease and related dementias (ADRDs). ApoE-Ɛ4 (APOE4) is known to play a critical role in neurovascular dysfunction, however current medical imaging technologies are limited in quantification. This cross-sectional study tested the feasibility of a recently established imaging modality, quantitative ultra-short time-to-echo contrast-enhanced magnetic resonance imaging (QUTE-CE MRI), to identify small vessel abnormality early in development of human APOE4 knock-in female rat (TGRA8960) animal model. At 8 months, 48.3% of the brain volume was found to have significant signal increase (75/173 anatomically segmented regions; q

Amyloid positron emission tomography (PET) imaging is a valuable tool for research and diagnosis in Alzheimer’s disease (AD). Partial volume effects caused by the limited spatial resolution of PET scanners degrades the quantitative accuracy of PET image. In this study, we have applied a method to evaluate the impact of a joint-entropy based partial volume correction (PVC) technique on brain networks learned from a clinical dataset of AV-45 PET image and compare network properties of both uncorrected and corrected image-based brain networks. We also analyzed the region-wise SUVRs of both uncorrected and corrected images. We further performed classification tests on different groups using the same set of algorithms with same parameter settings. PVC has sometimes been avoided due to increased noise sensitivity in image registration and segmentation, however, our results indicate that appropriate PVC may enhance the brain network structure analysis for AD progression and improve classification performance.

Objective Affective symptoms influence health status (health-related quality of life) in functional neurological disorder (FND), and the salience network is implicated in the pathophysiology of FND and mood/anxiety disorders. We hypothesised that self-reported health status and affective symptoms would map onto salience network regions and that patients with FND would show decreased insular volumes compared with controls. Methods This voxel-based morphometry study investigated volumetric differences in 26 patients with FND (21 women, 5 men; mean age=40.3±11.5) compared with 27 healthy controls (22 women, 5 men; mean age=40.5±10.8). Post hoc analyses stratified patients with FND by mental and physical health scores (Short Form Health Survey-36). Within-group analyses investigated associations with mental health, physical health, trait anxiety and depression in patients with FND. Results There were no volumetric differences between the complete FND cohort and controls. In stratified analyses, however, patients with FND reporting the most severe physical health impairments showed reduced left anterior insular volume compared with controls. In within-group analyses, impaired mental health and elevated trait anxiety were associated with increased right amygdalar volumes in patients with FND. The relationship between amygdalar volume and mental health, driven by emotional well-being deficits and role limitations due to emotional problems, was independent of sensorimotor functional neurological symptom severity and motor FND subtype. In secondary within-group analyses, increased periaqueductal grey volume was associated with role limitations due to emotional problems. Impaired physical functioning correlated with decreased left anterior insular volumes. Conclusions These findings support roles for several regions of the salience network in the pathophysiology of FND.

Tau pathology has been associated with neuronal loss at autopsy, but the temporal evolution of tau pathology and atrophy remains unclear. Here, we investigate the association between cross-sectional AV-1451-PET as a marker of tau pathology and cortical thickness cross-sectionally. We also investigated retrospective rates of cortical thinning over the three years preceding the AV-1451 scan in a clinically normal cohort of 103 older adults from the Harvard Aging Brain Study. Tau measurements were Geometric Transfer Matrix partial volume corrected standardized uptake value ratios (SUVRs) with a cerebellar gray reference region. Thirty-four FreeSurfer-defined cortical regions of interest (ROIs) were used for both thickness and AV-1451 in each hemisphere, with seven additional volumetric ROIs. We examined "local" relationships between AV-1451 and cortical thickness in the same ROI, as well as inferior temporal AV-1451 and all thickness ROIs. All models included baseline age and sex, both interacting with time in retrospective longitudinal models, as covariates. Cross-sectional models controlled for the number of days between the two scans. Cross-sectional local comparisons revealed significant associations between elevated AV-1451 and thinner cortical ROIs predominantly in temporal regions, while analyses associating inferior temporal AV-1451 with all cortical ROIs showed a widespread pattern of significant relationships, which was strongest in temporal and parietal cortices. In our retrospective longitudinal analyses, we saw significant relationships in temporal and parietal regions. Significant local relationships were seen in right superior temporal, middle temporal, temporal pole, and fusiform, as well as the left cuneus and banks of the left superior temporal sulcus. Significant relationships between inferior temporal AV-1451 and faster thinning were observed in right temporal regions (middle temporal and fusiform) and bilateral parahippocampal cortices. We observed significant negative relationships between local and inferior temporal AV-1451 signal and both cross-sectional cortical thickness and rates of thinning in lateral and medial temporal regions. This is an important early step toward elucidating the relationship between tau pathology and retrospective longitudinal atrophy in aging and preclinical AD.

Functional connectivity (FC) analysis has revealed stable and reproducible features of brain network organization, as well as their variations across individuals. Here, we localize network markers of individual variability in FC and track their dynamical expression across time. First, we determine the minimal set of network components required to identify individual subjects. Among specific resting-state networks, we find that the FC pattern of the frontoparietal network allows for the most reliable identification of individuals. Looking across the whole brain, an optimization approach designed to identify a minimal node set converges on distributed portions of the frontoparietal system. Second, we track the expression of these network markers across time. We find that the FC fingerprint is most clearly expressed at times when FC patterns exhibit low modularity. In summary, our study reveals distributed network markers of individual variability that are localized in both space and time.

Introduction Misfolded tau and amyloid β (Aβ) proteins progressively accumulate in the human brain, causing altered neuronal function and neurodegeneration. This study sought to investigate whether the wide spectrum of functional reorganization in aging brains of cognitively normal individuals relates to specific pathological patterns of tau and Aβ deposits. Methods We used functional connectivity neuroimaging and in vivo tau and Aβ positron emission tomography scans to study cortical spatial relationships between imaging modalities. Results We found that a negative association between tau and functional connectivity combined with a positive association between Aβ and functional connectivity is the most frequent cortical pattern among elderly subjects. Moreover, we found specific brain areas that interrelate hypoconnectivity and hyperconnectivity regions. Discussion Our findings have critical implications to understanding how the two main elements of Alzheimer's disease–related pathology affect the aging brain and how they cause alterations in large-scale neuronal circuits.

Background Neurosurgical intervention studies have provided direct evidence that the ventral striatum/nucleus accumbens (NAc) mediates symptoms of obsessive-compulsive disorder (OCD), yet meta-analysis of functional neuroimaging studies using symptom provocation revealed no striatal activation differences, and the existing studies reporting hyperactivity found abnormalities in dorsal but not ventral striatal subdivisions. Resting-state neuroimaging evidence holds that corticostriatal areas are more connected both locally and to distant regions, but the functional inferences to be drawn from these altered network characteristics regarding the present experience of OCD symptoms remain limited. Methods The present study tested whether symptom provocation induces abnormally high striatal network connectivity using two independent datasets of unmedicated patients with OCD. One study (14 patients, 14 matched controls) required passive viewing of OC-related, emotionally aversive and neutral pictures, the other (21 patients, 21 controls) involved self-referential evaluation of the same picture types, as well as distraction from these stimuli (engagement in a simple task). Results Heightened local connectivity of the dorsal striatum occurred during passive viewing of briefly presented OC-related pictures in patients, however group differences were also observed in a neutral control condition. In contrast, distracted symptom provocation selectively yielded local connectivity differences of the ventral striatum, as heightened NAc connectivity to its immediate neighborhood was exclusively observed when OC-related pictures were accompanied by concurrent task demands. Limitations Small samples sizes. Conclusions In moderately affected patients with OCD, symptom provocation induces a discrete, condition-specific network abnormality anchored in NAc, the location targeted by deep brain stimulation for refractory patients with OCD.

Visuomotor impairments characterize numerous neurological disorders and neurogenetic syndromes, such as autism spectrum disorder (ASD) and Dravet, Fragile X, Prader–Willi, Turner, and Williams syndromes. Despite recent advances in systems neuroscience, the biological basis underlying visuomotor functional impairments associated with these clinical conditions is poorly understood. In this study, we used neuroimaging connectomic approaches to map the visuomotor integration (VMI) system in the human brain and investigated the topology approximation of the VMI network to the Allen Human Brain Atlas, a whole-brain transcriptome-wide atlas of cortical genetic expression. We found the genetic expression of four genes—TBR1, SCN1A, MAGEL2, and CACNB4—to be prominently associated with visuomotor integrators in the human cortex. TBR1 gene transcripts, an ASD gene whose expression is related to neural development of the cortex and the hippocampus, showed a central spatial allocation within the VMI system. Our findings delineate gene expression traits underlying the VMI system in the human cortex, where specific genes, such as TBR1, are likely to play a central role in its neuronal organization, as well as on specific phenotypes of neurogenetic syndromes.

Judgments of learning (JOL) pertain to introspective metamemory processes evaluating how well information is learned. Using a functional magnetic resonance imaging (fMRI) task, we investigated the neural substrates of JOL predictions in a group of 105 cognitively unimpaired older adults from the Harvard Aging Brain Study. Associations of JOL performance and its neural correlates with amyloid-β (Aβ) and tau pathology, two proteinopathies associated with Alzheimer’s disease (AD) and aging, were also examined. We found that trials judged as learned well relative to trials judged as learned less well (high JOL > low JOL) engaged the ventromedial prefrontal cortex and precuneus, among other midline regions, in addition to bilateral hippocampi. In this cohort of older adults, greater levels of entorhinal tau deposition were associated with overestimation of memory performance and with lower fMRI signal in midline regions during predicted memory success. No associations with Aβ were found. The findings suggest that tau pathology in unimpaired older adults may play a role in altered metamemory processes. We discuss our findings in light of the hypothesis that JOLs are partially dependent on a process involving attempts to retrieve a correct answer from memory, as well as implications for clinical research investigating unawareness of memory performance (i.e., anosognosia) in patients with AD dementia.

Alzheimer's disease (AD) is associated with brain network dysfunction. Network-based investigations of brain connectivity have mainly focused on alterations in the strength of connectivity; however, the network breakdown in AD spectrum is a complex scenario in which multiple pathways of connectivity are affected. To integrate connectivity changes that occur under AD-related conditions, here we developed a novel metric that computes the connectivity distance between cortical regions at the voxel level (or nodes). We studied 114 individuals with mild cognitive impairment, 24 with AD, and 27 healthy controls. Results showed that areas of the default mode network, salience network, and frontoparietal network display a remarkable network separation, or greater connectivity distances, from the rest of the brain. Furthermore, this greater connectivity distance was associated with lower global cognition. Overall, the investigation of AD-related changes in paths and distances of connectivity provides a novel framework for characterizing subjects with cognitive impairment; a framework that integrates the overall network topology changes of the brain and avoids biases toward unreferenced connectivity effects. This research was supported by a grant from the National Institutes of Health (NIH) (grant No. R01AG061445 and R01AG061811) (K23-EB019023 to J. Sepulcre).

Objective: To characterize the progression of brain structural abnormalities in adults with pediatric and adult/late onset DM1, as well as to examine the potential predictive markers of such progression. Methods: 21 DM1 patients (pediatric onset: N = 9; adult/late onset: N = 12) and 18 healthy controls (HC) were assessed longitudinally over 9.17 years through brain MRI. Additionally, patients underwent neuropsychological, genetic, and muscular impairment assessment. Inter-group comparisons of total and voxel-level regional brain volume were conducted through Voxel Based Morphometry (VBM); cross-sectionally and longitudinally, analyzing the associations between brain changes and demographic, clinical, and cognitive outcomes. Results: The percentage of GM loss did not significantly differ in any of the groups compared with HC and when assessed independently, adult/late DM1 patients and their HC group suffered a significant loss in WM volume. Regional VBM analyses revealed subcortical GM damage in both DM1 groups, evolving to frontal regions in the pediatric onset patients. Muscular impairment and the outcomes of certain neuropsychological tests were significantly associated with follow-up GM damage, while visuoconstruction, attention, and executive function tests showed sensitivity to WM degeneration over time. Interpretation: Distinct patterns of brain atrophy and its progression over time in pediatric and adult/late onset DM1 patients are suggested. Results indicate a possible neurodevelopmental origin of the brain abnormalities in DM1, along with the possible existence of an additional neurodegenerative process. Fronto-subcortical networks appear to be involved in the disease progression at young adulthood in pediatric onset DM1 patients. The involvement of a multimodal integration network in DM1 is discussed. This study was supported by funding from the Institute of Health Carlos III co‐founded by Fondo Europeo de Desarrollo Regional‐FEDER [grant numbers PI17/01231 and PI17/01841], CIBERNED (grant number: 609) and the Basque Government [SAIO08‐PE08BF01]. G. Labayru was supported by a predoctoral grant from the Basque Government [PRE_2016_1_0187]. A. Jiménez‐Marín was supported by a predoctoral grant from the Basque Government [PRE_2019_1_0070].

The neurobiological underpinnings of stuttering, a speech disorder characterized by disrupted speech fluency, remain unclear. While recent developments in the field have afforded researchers the ability to pinpoint several genetic profiles associated with stuttering, how these specific genetic backgrounds impact neuronal circuits and how they generate or facilitate the emergence of stuttered speech remains unknown. In this study, we identified the large-scale cortical network that characterizes stuttering using functional connectivity MRI and graph theory. We performed a spatial similarity analysis that examines whether the topology of the stuttering cortical network intersects with genetic expression levels of previously reported genes for stuttering from the protein-coding transcriptome data of the Allen Human Brain Atlas. We found that GNPTG – a gene involved in the mannose-6-phosphate lysosomal targeting pathways – was significantly co-localized with the stuttering cortical network. An enrichment analysis demonstrated that the genes identified with the stuttering cortical network shared a significantly overrepresented biological functionality of Neurofilament Cytoskeleton Organization (NEFH, NEFL and INA). The relationship between lysosomal pathways, cytoskeleton organization, and stuttering, was investigated by comparing the genetic interactome between GNPTG and the neurofilament genes implicated in the current study. We found that genes of the interactome network, including CDK5, SNCA, and ACTB, act as functional links between lysosomal and neurofilament genes. These findings support the notion that stuttering is due to a lysosomal dysfunction, which has deleterious effects on the neurofilament organization of the speech neuronal circuits. They help to elucidate the intriguing, unsolved link between lysosomal mutations and the presence of stuttering., This work has been partially supported by the National Institutes of Health grants K23EB019023 (JS), (NIBIB) 2T32EB013180-06 (LOT), R01DC011277 (SC), and Post-Doctoral Fellowship Program from the Basque Country Government (ID).

Highlights • Predominance of white matter impairment in DM1 is questioned. • Age poses vulnerability to grey matter loss in specific areas in DM1. • White matter alterations in DM1 may be developmental. • Muscular and genetic features are associated with brain abnormalities in DM1. • Neuropsychology is an unspecific but strong predictor of gray matter damage in DM1., Background Myotonic Dystrophy type 1 (DM1) is a slowly progressive myopathy characterized by varying multisystemic involvement. Several cerebral features such as brain atrophy, ventricular enlargement, and white matter lesions (WMLs) have frequently been described. The aim of this study is to investigate the structural organization of the brain that defines the disease through multimodal imaging analysis, and to analyze the relation between structural cerebral changes and DM1 clinical and neuropsychological profiles. Method 31 DM1 patients and 57 healthy controls underwent an MRI scan protocol, including T1, T2 and DTI. Global gray matter (GM), global white matter (WM), and voxel-level Voxel Based Morphometry (VBM) and voxel-level microstructural WM abnormalities through Diffusion Tensor Imaging (DTI) were assessed through group comparisons and linear regression analysis with age, degree of muscular impairment (MIRS score), CTG expansion size and neuropsychological outcomes from a comprehensive assessment. Results Compared with healthy controls, DM1 patients showed a reduction in both global GM and WM volume; and further regional GM decrease in specific primary sensory, multi-sensory and association cortical regions. Fractional anisotropy (FA) was reduced in both total brain and regional analysis, being most marked in frontal, paralimbic, temporal cortex, and subcortical regions. Higher ratings on muscular impairment and longer CTG expansion sizes predicted a greater volume decrease in GM and lower FA values. Age predicted global GM reduction, specifically in parietal regions. At the cognitive level, the DM1 group showed significant negative correlations between IQ estimate, visuoconstructive and executive neuropsychological scores and both global and regional volume decrease, mainly distributed in the frontal, parietal and subcortical regions. Conclusions In this study, we describe the structural brain signatures that delineate the involvement of the CNS in DM1. We show that specific sensory and multi-sensory — as well as frontal cortical areas — display potential vulnerability associated with the hypothesized neurodegenerative nature of DM1 brain abnormalities.

Highlights • Decreased meta-memory processing is related to tauopathy. • No association was found with amyloid pathology. • Decreased meta-memory may be a sensitive clinical indicator of AD pathophysiology in the pre-symptomatic phase., The ability to accurately judge memory efficiency (meta-memory monitoring) for newly learned (episodic) information, is decreased in older adults and even worse in Alzheimer's disease (AD), whereas no differences have been found for semantic meta-memory. The pathological substrates of this phenomenon are poorly understood. Here, we examine the association between meta-memory monitoring for episodic and semantic information to the two major proteinopathies in AD: amyloid (Aβ) and tau pathology in a group of cognitively unimpaired older adults. All participants underwent multi-tracer PET and meta-memory monitoring was assessed using a feeling-of-knowing (FOK) task for non-famous (episodic) and famous (semantic) face-name pairs. Whole brain voxel-wise correlations between meta-memory and PET data were conducted (controlling for memory), as well as confirmatory region-of-interest analyses. Participants had reduced episodic FOK compared to semantic FOK. Decreased episodic FOK was related to tauopathy in the medial temporal lobe regions, including the entorhinal cortex and temporal pole, whereas decreased semantic FOK was related to increased tau in regions associated with the semantic knowledge network. No association was found with Aβ-pathology. Alterations in the ability to accurately judge memory efficiency (in the absence of memory decline) may be a sensitive clinical indicator of AD pathophysiology in the pre-symptomatic phase.

Individuals with body dysmorphic disorder (BDD) and obsessive-compulsive disorder (OCD) are categorized within the same major diagnostic group and both show regional brain hyperactivity in the orbitofrontal cortex (OFC) and the basal ganglia during symptom provocation. While recent studies revealed that degree connectivity of these areas is abnormally high in OCD and positively correlates with symptom severity, no study has investigated degree connectivity in BDD. We used functional magnetic resonance imaging (fMRI) to compare the local and distant degree of functional connectivity in all brain areas between 28 unmedicated BDD participants and 28 demographically matched healthy controls during a face-processing task. Correlational analyses tested for associations between degree connectivity and symptom severity assessed by the BDD version of the Yale-Brown obsessive-compulsive scale (BDD-Y-BOCS). Reduced local amygdalar connectivity was found in participants with BDD. No differences in distant connectivity were found. BDD-Y-BOCS scores significantly correlated with the local connectivity of the posterior-lateral OFC, and distant connectivity of the posterior-lateral and post-central OFC, respectively. These findings represent preliminary evidence that individuals with BDD exhibit brain-behavioral associations related to obsessive thoughts and compulsive behaviors that are highly similar to correlations previously found in OCD, further underscoring their related pathophysiology. This relationship could be further elucidated through investigation of resting-state functional connectivity in BDD, ideally in direct comparison with OCD and other obsessive-compulsive and related disorders.

Neuroimaging studies indicate that children with attention-deficit/hyperactivity disorder (ADHD) present alterations in several functional networks of the sensation-to-cognition spectrum. These alterations include functional overconnectivity within sensory regions and underconnectivity between sensory regions and neural hubs supporting higher order cognitive functions. Today, it is unknown whether this same pattern of alterations persists in adult patients with ADHD who had never been medicated for their condition. The aim of the present study was to assess whether medication-naïve adults with ADHD presented alterations in functional networks of the sensation-to-cognition spectrum. Thirty-one medication-naïve adults with ADHD and twenty-two healthy adults underwent resting-state functional magnetic resonance imaging (rs-fMRI). Stepwise functional connectivity (SFC) was used to characterize the pattern of functional connectivity between sensory seed regions and the rest of the brain at direct, short, intermediate, and long functional connectivity distances, thus covering the continuum from the sensory input to the neural hubs supporting higher order cognitive functions. As compared to controls, adults with ADHD presented increased SFC degree within primary sensory regions and decreased SFC degree between sensory seeds and higher order integration nodes. In addition, they exhibited decreased connectivity degree between sensory seeds and regions of the default-mode network. Consistently, the higher the score in clinical severity scales the lower connectivity degree between seed regions and the default mode network. The authors thank the volunteers who generously contributed to this research. This work was supported by the Ministerio de Economía y Competitividad research grant (SAF2012‐32362) and the Instituto de Salud Carlos III (Miguel Servet Type I (CP16/00096), AES Grant (PI17/00064), and P‐FIS Grant (FI18/00255)).

Amyloid deposition and neurofibrillary degeneration in Alzheimer's disease specifically affect discrete neuronal systems, but the underlying mechanisms that render some brain regions more vulnerable to Alzheimer's disease pathology than others remain largely unknown. Here we studied molecular properties underlying these distinct regional vulnerabilities by analysing Alzheimer's disease-typical neuroimaging patterns of amyloid deposition and neurodegeneration in relation to regional gene expression profiles of the human brain. Graded patterns of brain-wide vulnerability to amyloid deposition and neurodegeneration in Alzheimer's disease were estimated by contrasting multimodal amyloid-sensitive PET and structural MRI data between patients with Alzheimer's disease dementia (n = 76) and healthy controls (n = 126) enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Regional gene expression profiles were derived from brain-wide microarray measurements provided by the Allen brain atlas of the adult human brain transcriptome. In a hypothesis-driven analysis focusing on the genes coding for the amyloid precursor (APP) and tau proteins (MAPT), regional expression levels of APP were positively correlated with the severity of regional amyloid deposition (r = 0.44, P = 0.009), but not neurodegeneration (r = 0.01, P = 0.96), whereas the opposite pattern was observed for MAPT (neurodegeneration: r = 0.46, P = 0.006; amyloid: r = 0.08, P = 0.65). Using explorative gene set enrichment analysis, amyloid-vulnerable regions were found to be characterized by relatively low expression levels of gene sets implicated in protein synthesis and mitochondrial respiration. By contrast, neurodegeneration-vulnerable regions were characterized by relatively high expression levels of gene sets broadly implicated in neural plasticity, with biological functions ranging from neurite outgrowth and synaptic contact over intracellular signalling cascades to proteoglycan metabolism. At the individual gene level this data-driven analysis further corroborated the association between neurodegeneration and MAPT expression, and additionally identified associations with known tau kinases (CDK5, MAPK1/ERK2) alongside components of their intracellular (Ras-ERK) activation pathways. Sensitivity analyses showed that these pathology-specific imaging-genetic associations were largely robust against changes in some of the methodological parameters, including variation in the brain donor sample used for estimating regional gene expression profiles, and local variations in the Alzheimer's disease-typical imaging patterns when these were derived from an independent patient cohort (BioFINDER study). These findings highlight that the regionally selective vulnerability to Alzheimer's disease pathology relates to specific molecular-functional properties of the affected neural systems, and that the implicated biochemical pathways largely differ for amyloid accumulation versus neurodegeneration. The data provide novel insights into the complex pathophysiological mechanisms of Alzheimer's disease and point to pathology-specific treatment targets that warrant further exploration in independent studies.

Background Insecure attachment and maladaptive coping are important predisposing vulnerabilities for Functional Neurological Disorders (FND)/Conversion Disorder, yet no prior structural neuroimaging studies have investigated biomarkers associated with these risk factors in FND populations. This magnetic resonance imaging study examined cortical thickness and subcortical volumes associated with self-reported attachment and coping styles in patients with FND. We hypothesized that insecure attachment and maladaptive coping would relate to limbic-paralimbic structural alterations. Methods FreeSurfer cortical thickness and subcortical volumetric analyses were performed in 26 patients with motor FND (21 women; 5 men) and 27 healthy controls (22 women; 5 men). For between-group comparisons, patients with FND were stratified by Relationship Scales Questionnaire, Ways of Coping Scale-Revised, and Connor-Davidson Resilience Scale scores. Within-group analyses were also performed in patients with FND. All analyses were performed in the complete cohort and separately in women only to evaluate for gender-specific effects. Cortical thickness analyses were whole-brain corrected at the cluster-wise level; subcortical analyses were Bonferroni corrected. Results In women with FND, dismissing attachment correlated with reduced left parahippocampal cortical thickness. Confrontive coping was associated with reduced right hippocampal volume, while accepting responsibility positively correlated with right precentral gyrus cortical thickness. These findings held adjusting for anti-depressant use. All FND-related findings were within the normal range when compared to healthy women. Conclusion These observations connect individual-differences in limbic-paralimbic and premotor structures to attachment and coping styles in FND. The relationship between parahippocampal thickness and dismissing attachment may indicate aberrant social-emotional and contextual appraisal in women with FND.

Tau and amyloid beta (Aβ) proteins accumulate along neuronal circuits in Alzheimer’s disease. Unraveling the genetic background for the regional vulnerability of these proteinopathies can help in understanding the mechanisms of pathology progression. To that end, we developed a novel graph theory approach and used it to investigate the intersection of longitudinal Aβ and tau positron emission tomography imaging of healthy adult individuals and the genetic transcriptome of the Allen Human Brain Atlas. We identified distinctive pathways for tau and Aβ accumulation, of which the tau pathways correlated with cognitive levels. We found that tau propagation and Aβ propagation patterns were associated with a common genetic profile related to lipid metabolism, in which APOE played a central role, whereas the tau-specific genetic profile was classified as ‘axon related’ and the Aβ profile as ‘dendrite related’. This study reveals distinct genetic profiles that may confer vulnerability to tau and Aβ in vivo propagation in the human brain. Cross-sectional and longitudinal PET imaging of amyloid beta and tau in the human brain is combined with gene expression profiles to define the interactions between Alzheimer’s disease-related pathology propagation and brain-region-specific vulnerability.

This is a pre-print of an article published in [ Brain Imaging and Behavior. The final authenticated version is available online at: https://doi.org/10.1007/s11682-018-9993-y Brain plasticity occurs over the course of the human lifetime. Learning and training modify our neuronal synapses and adapt our brain activity, from priming effects in modal areas to higher-order changes in the association cortex. The current state of the art suggests that learning and training effects might induce large-scale brain connectivity changes. Here, we used task-fMRI data and graph-based approaches to study the immediate brain changes in functional connections associated with training on a visual search task, and the individual differences in learning were studied by means of brain-behavior correlations. In a previous work, we found that trained participants improved their response speed on a visual search task by 31%, whereas the control group hardly changed. In the present study, we showed that trained individuals changed regional connections (local links) in cortical areas devoted to the specific visual search processes and to areas that support information integration, and largely modified distributed connections (distant links) linking primary visual areas to specific attentional and cognitive control areas. In addition, we found that the individuals with the most enhanced connectivity in the dorsolateral prefrontal cortex performed the task faster after training. The observed behavioral and brain connectivity findings expand our understanding of large-scale dynamic readjustment of the human brain after learning experiences.

Experimental and modeling work of neural activity has described recurrent and attractor dynamic patterns in cerebral microcircuits. However, it is still poorly understood whether similar dynamic principles exist or can be generalizable to the large-scale level. Here, we applied dynamic graph theory-based analyses to evaluate the dynamic streams of whole-brain functional connectivity over time across cognitive states. Dynamic connectivity in local networks is located in attentional areas during tasks and primary sensory areas during rest states, and dynamic connectivity in distributed networks converges in the default mode network (DMN) in both task and rest states. Importantly, we find that distinctive dynamic connectivity patterns are spatially associated with Allen Human Brain Atlas genetic transcription levels of synaptic long-term potentiation and long-term depression-related genes. Our findings support the neurobiological basis of large-scale attractor-like dynamics in the heteromodal cortex within the DMN, irrespective of cognitive state. This work has been partially supported by the National Institutes of Health (NIH) grant K23EB019023 (to J.S.), Postdoctoral Fellowship Program from the Basque Country Government and Bizkaia Talent (to I.D.).

Importance Abnormal accumulation of tau and amyloid-β (Aβ) proteins in the human brain are 2 pathologic hallmarks of Alzheimer disease (AD). Because pathologic processes begin decades before the onset of the clinical manifestations, the study of the cortical distribution of early-stage pathologic alterations is critical in understanding the underpinnings of the disease. Objectives To identify the in vivo brain spatial distributions of tau and Aβ deposits in a sample of cognitively normal participants in the Harvard Aging Brain Study, determine spatial patterns of pathologic alterations, and provide means for improved individual in vivo staging. Design, Setting, and Participants Eighty-eight individuals from the general community underwent flortaucipir 18 T807 ( 18 F-T807) and carbon 11–labeled Pittsburgh Compound B ( 11 C-PiB) positron emission tomographic (PET) imaging. A voxel-level hierarchical clustering approach was used to obtain the main clustering partitions corresponding to the cortical distribution maps of 18 F-T807 and 11 C-PiB. Hierarchical relationships between areas of distinctive pathologic deposits were then studied. Using cerebellar gray reference, 18 F-T807 data were expressed as standardized uptake value ratio, and 11 C-PiB were given as distribution volume ratio. Main Outcomes and Measures Main in vivo and hierarchically organized tau and Aβ deposits in the elderly brain. Results Of the 88 study participants, 39 (44%) were men, with a mean (SD) age of 76.2 (6.2) years. The tau and Aβ maps both displayed optimal cortical partitions at 4 clusters. The tau deposits were grouped in the temporal lobe, distributed in heteromodal areas, medial and visual regions, and primary somatomotor cortex; the Aβ deposits were clustered in the heteromodal areas and rather patchy in distributed regions involving the primary cortices, medial structures, and temporal areas. Moreover, tau deposits in the temporal lobe and distributed heteromodal areas were tightly nested. Conclusions and Relevance Tau and Aβ deposits in the elderly brain generally display well-defined hierarchical cortical relationships as well as overlaps between the principal clusters of both pathologic alterations in the heteromodal association regions. These findings represent systematic, large-scale mechanisms of early AD pathology.

Previous studies have associated Attention‐Deficit/Hyperactivity Disorder (ADHD) with a maturational lag of brain functional networks. Functional connectivity of the human brain changes from primarily local to more distant connectivity patterns during typical development. Under the maturational lag hypothesis, we expect children with ADHD to exhibit increased local connectivity and decreased distant connectivity compared with neurotypically developing (ND) children. We applied a graph‐theory method to compute local and distant connectivity levels and cross‐sectionally compared them in a sample of 120 children with ADHD and 120 age‐matched ND children (age range = 7–17 years). In addition, we measured if potential group differences in local and distant connectivity were stable across the age range considered. Finally, we assessed the clinical relevance of observed group differences by correlating the connectivity levels and ADHD symptoms severity separately for each group. Children with ADHD exhibited more local connectivity than age‐matched ND children in multiple brain regions, mainly overlapping with default mode, fronto‐parietal and ventral attentional functional networks (p

Alzheimer's disease (AD) is a neurological disorder that creates neurodegenerative changes at several structural and functional levels in human brain tissue. The fractal dimension (FD) is a quantitative parameter that characterizes the morphometric variability of the human brain. In this study, we investigate spherical harmonic-based FD (SHFD), thickness, and local gyrification index (LGI) to assess whether they identify cortical surface abnormalities toward the conversion to AD. We study 33 AD patients, 122 mild cognitive impairment (MCI) patients (50 MCI converters and 29 MCI nonconverters), and 32 healthy controls (HC). SHFD, thickness, and LGI methodology allowed us to perform not only global level but also local level assessments in each cortical surface vertex. First, we found that global SHFD decreased in AD and future MCI converters compared to HC, and in MCI converters compared to MCI nonconverters. Second, we found that local white matter SHFD was reduced in AD compared to HC and MCI mainly in medial temporal lobe. Third, local white-matter SHFD was significantly reduced in MCI converters compared to MCI nonconverters in distributed areas, including the medial frontal lobe. Thickness and LGI metrics presented a reduction in AD compared to HC. Thickness was significantly reduced in MCI converters compared to healthy controls in entorhinal cortex and lateral temporal. In summary, SHFD was the only surface measure showing differences between MCI individuals that will convert or remain stable in the next 4 years. We suggest that SHFD may be an optimal complement to thickness loss analysis in monitoring longitudinal changes in preclinical and clinical stages of AD. Hum Brain Mapp 38:5905-5918, 2017. © 2017 Wiley Periodicals, Inc.

Objective Adverse early-life events are predisposing factors for functional neurological disorder (FND) and post-traumatic stress disorder (PTSD). Cingulo-insular regions are implicated in the biology of both conditions and are sites of stress-mediated neuroplasticity. We hypothesised that functional neurological symptoms and the magnitude of childhood abuse would be associated with overlapping anterior cingulate cortex (ACC) and insular volumetric reductions, and that FND and PTSD symptoms would map onto distinct cingulo-insular areas. Methods This within-group voxel-based morphometry study probes volumetric associations with self-report measures of functional neurological symptoms, adverse life events and PTSD symptoms in 23 mixed-gender FND patients. Separate secondary analyses were also performed in the subset of 18 women with FND to account for gender-specific effects. Results Across the entire cohort, there were no statistically significant volumetric associations with self-report measures of functional neurological symptom severity or childhood abuse. In women with FND, however, parallel inverse associations were observed between left anterior insular volume and functional neurological symptoms as measured by the Patient Health Questionnaire-15 and the Screening for Somatoform Symptoms Conversion Disorder subscale. Similar inverse relationships were also appreciated between childhood abuse burden and left anterior insular volume. Across all subjects, PTSD symptom severity was inversely associated with dorsal ACC volume, and the magnitude of lifetime adverse events was inversely associated with left hippocampal volume. Conclusions This study reveals distinct cingulo-insular alterations for FND and PTSD symptoms and may advance our understanding of FND. Potential biological convergence between stress-related neuroplasticity, functional neurological symptoms and reduced insular volume was identified.

Importance Previous postmortem studies have long demonstrated that neurofibrillary tangles made of hyperphosphorylated tau proteins are closely associated with Alzheimer disease clinical phenotype and neurodegeneration pattern. Validating these associations in vivo will lead to new diagnostic tools for Alzheimer disease and better understanding of its neurobiology. Objective To examine whether topographical distribution and severity of hyperphosphorylated tau pathologic findings measured by fluorine 18–labeled AV-1451 ([ 18 F]AV-1451) positron emission tomographic (PET) imaging are linked with clinical phenotype and cortical atrophy in patients with Alzheimer disease. Design, Setting, and Participants This observational case series, conducted from July 1, 2012, to July 30, 2015, in an outpatient referral center for patients with neurodegenerative diseases, included 6 patients: 3 with typical amnesic Alzheimer disease and 3 with atypical variants (posterior cortical atrophy, logopenic variant primary progressive aphasia, and corticobasal syndrome). Patients underwent [ 18 F]AV-1451 PET imaging to measure tau burden, carbon 11–labeled Pittsburgh Compound B ([ 11 C]PiB) PET imaging to measure amyloid burden, and structural magnetic resonance imaging to measure cortical thickness. Seventy-seven age-matched controls with normal cognitive function also underwent structural magnetic resonance imaging but not tau or amyloid PET imaging. Main Outcomes and Measures Tau burden, amyloid burden, and cortical thickness. Results In all 6 patients (3 women and 3 men; mean age 61.8 years), the underlying clinical phenotype was associated with the regional distribution of the [ 18 F]AV-1451 signal. Furthermore, within 68 cortical regions of interest measured from each patient, the magnitude of cortical atrophy was strongly correlated with the magnitude of [ 18 F]AV-1451 binding (3 patients with amnesic Alzheimer disease, r = –0.82; P r = –0.70; P r = –0.58; P r = –0.51; P r = –0.63; P r = –0.70; P 11 C]PiB binding. Conclusions and Relevance These findings provide further in vivo evidence that distribution of the [ 18 F]AV-1451 signal as seen on results of PET imaging is a valid marker of clinical symptoms and neurodegeneration. By localizing and quantifying hyperphosphorylated tau in vivo, results of tau PET imaging will likely serve as a key biomarker that links a specific type of molecular Alzheimer disease neuropathologic condition with clinically significant neurodegeneration, which will likely catalyze additional efforts to develop disease-modifying therapeutics.

BackgroundAlthough neurobiological models of obsessive–compulsive disorder (OCD) traditionally emphasise the central role of corticostriatal brain regions, studies of default mode network integrity have garnered increasing interest, but have produced conflicting results.AimsTo resolve these discrepant findings by examining the integrity of default mode network subsystems in OCD.MethodComparison of seed-based resting-state functional connectivity of 11 default mode network components between 46 patients with OCD and 46 controls using functional magnetic resonance imaging.ResultsSignificantly reduced connectivity within the dorsal medial prefrontal cortex self subsystem was identified in the OCD group, and remained significant after controlling for medication status and life-time history of affective disorders. Further, greater connectivity between the self subsystem and salience and attention networks was observed.ConclusionsResults indicate that people with OCD show abnormalities in a neural system previously associated with self-referential processing in healthy individuals, and suggest the need for examination of dynamic interactions between this default mode network subsystem and other large-scale networks in this disorder.

Sensory comprehension and motor production of language symbols form the basis of human speech. Classical neuroanatomy has pointed to Wernicke's and Broca's areas as playing important roles in the integration of these 2 functions. However, recent studies have proposed that more direct pathways may exist between auditory input and motor output, bypassing Wernicke's and Broca's areas. We used functional network analyses to investigate potential auditory-motor (A-M) couplings between language-related cortices. We found that operculum parietale (OP) interconnectivity in region OP4 seems to play a critical role in the A-M integration of the brain. This finding supports a novel landscape in the functional neuroarchitecture that sustains language in humans.