Neuroimaging epicenters as potential sites of onset of the neuroanatomical pathology in schizophrenia.

Schizophrenia lacks a clear definition at the neuroanatomical level, capturing the sites of origin and progress of this disorder. Using a network-theory approach called epicenter mapping on cross-sectional magnetic resonance imaging from 1124 individuals with schizophrenia, we identified the most likely "source of origin" of the structural pathology. Our results suggest that the Broca's area and adjacent frontoinsular cortex may be the epicenters of neuroanatomical pathophysiology in schizophrenia. These epicenters can predict an individual's response to treatment for psychosis. In addition, cross-diagnostic similarities based on epicenter mapping over of 4000 individuals diagnosed with neurological, neurodevelopmental, or psychiatric disorders appear to be limited. When present, these similarities are restricted to bipolar disorder, major depressive disorder, and obsessive-compulsive disorder. We provide a comprehensive framework linking schizophrenia-specific epicenters to multiple levels of neurobiology, including cognitive processes, neurotransmitter receptors and transporters, and human brain gene expression. Epicenter mapping may be a reliable tool for identifying the potential onset sites of neural pathophysiology in schizophrenia.

The aging trajectories of brain functional hierarchy and its impact on cognition across the adult lifespan.

Introduction: The hierarchical network architecture of the human brain, pivotal to cognition and behavior, can be explored via gradient analysis using restingstate functional MRI data. Although it has been employed to understand brain development and disorders, the impact of aging on this hierarchical architecture and its link to cognitive decline remains elusive. Methods: This study utilized resting-state functional MRI data from 350 healthy adults (aged 20-85) to investigate the functional hierarchical network using connectome gradient analysis with a cross-age sliding window approach. Gradient-related metrics were estimated and correlated with age to evaluate trajectory of gradient changes across lifespan. Results: The principal gradient (unimodal-to-transmodal) demonstrated a significant non-linear relationship with age, whereas the secondary gradient (visual-to-somatomotor) showed a simple linear decreasing pattern. Among the principal gradient, significant age-related changes were observed in the somatomotor, dorsal attention, limbic and default mode networks. The changes in the gradient scores of both the somatomotor and frontal-parietal networks were associated with greater working memory and visuospatial ability. Gender differences were found in global gradient metrics and gradient scores of somatomotor and default mode networks in the principal gradient, with no interaction with age effect. Discussion: Our study delves into the aging trajectories of functional connectome gradient and its cognitive impact across the adult lifespan, providing insights for future research into the biological underpinnings of brain function and pathological models of atypical aging processes.

The connectivity of the human frontal pole cortex, and a theory of its involvement in exploit versus explore.

The frontal pole is implicated in humans in whether to exploit resources versus explore alternatives. Effective connectivity, functional connectivity, and tractography were measured between six human frontal pole regions and for comparison 13 dorsolateral and dorsal prefrontal cortex regions, and the 360 cortical regions in the Human Connectome Project Multi-modal-parcellation atlas in 171 HCP participants. The frontal pole regions have effective connectivity with Dorsolateral Prefrontal Cortex regions, the Dorsal Prefrontal Cortex, both implicated in working memory; and with the orbitofrontal and anterior cingulate cortex reward/non-reward system. There is also connectivity with temporal lobe, inferior parietal, and posterior cingulate regions. Given this new connectivity evidence, and evidence from activations and damage, it is proposed that the frontal pole cortex contains autoassociation attractor networks that are normally stable in a short-term memory state, and maintain stability in the other prefrontal networks during stable exploitation of goals and strategies. However, if an input from the orbitofrontal or anterior cingulate cortex that expected reward, non-reward, or punishment is received, this destabilizes the frontal pole and thereby other prefrontal networks to enable exploration of competing alternative goals and strategies. The frontal pole connectivity with reward systems may be key in exploit versus explore.

Changes in microstructural similarity of hippocampal subfield circuits in pathological cognitive aging.

The hippocampal networks support multiple cognitive functions and may have biological roles and functions in pathological cognitive aging (PCA) and its associated diseases, which have not been explored. In the current study, a total of 116 older adults with 39 normal controls (NC) (mean age: 52.3 ± 13.64 years; 16 females), 39 mild cognitive impairment (MCI) (mean age: 68.15 ± 9.28 years, 14 females), and 38 dementia (mean age: 73.82 ± 8.06 years, 8 females) were included. The within-hippocampal subfields and the cortico-hippocampal circuits were assessed via a micro-structural similarity network approach using T1w/T2w ratio and regional gray matter tissue probability maps, respectively. An analysis of covariance was conducted to identify between-group differences in structural similarities among hippocampal subfields. The partial correlation analyses were performed to associate changes in micro-structural similarities with cognitive performance in the three groups, controlling the effect of age, sex, education, and cerebral small-vessel disease. Compared with the NC, an altered T1w/T2w ratio similarity between left CA3 and left subiculum was observed in the mild cognitive impairment (MCI) and dementia. The left CA3 was the most impaired region correlated with deteriorated cognitive performance. Using these regions as seeds for GM similarity comparisons between hippocampal subfields and cortical regions, group differences were observed primarily between the left subiculum and several cortical regions. By utilizing T1w/T2w ratio as a proxy measure for myelin content, our data suggest that the imbalanced synaptic weights within hippocampal CA3 provide a substrate to explain the abnormal firing characteristics of hippocampal neurons in PCA. Furthermore, our work depicts specific brain structural characteristics of normal and pathological cognitive aging and suggests a potential mechanism for cognitive aging heterogeneity.

Dopaminergic-related Anatomical Pattern of Dorsal Striatum in Schizophrenia.

Striatal dopaminergic overactivity was hypothesized as the core pathophysiology of schizophrenia. However, morphological alterations of striatum in schizophrenia remains exclusive, largely because brain regional heterogeneity limited traditional group-mean based approach. Leveraging third-party brain maps of neurotransmitter and cognition behaviours, we developed a pattern-based representation feature score (ReFS) to investigate structural spatial pattern variation in schizophrenia. Structural ReFS of subcortical regions, particularly the striatum, were linked to schizophrenia diagnosis, symptom severity, and genetic susceptibility. Dopaminergic-ReFS of striatum was increased in schizophrenia patients and reliably reproduced across 13 datasets. The pattern-based ReFS effectively captured the shared genetic pathways underlying both schizophrenia and striatum. The results provide convergent, multimodal suggest the central role of striatal spatial patterns in schizophrenia psychopathologies and and open new avenues to develop individualized treatments for psychotic disorders.

Functional connectome through the human life span.

The functional connectome of the human brain represents the fundamental network architecture of functional interdependence in brain activity, but its normative growth trajectory across the life course remains unknown. Here, we aggregate the largest, quality-controlled multimodal neuroimaging dataset from 119 global sites, including 33,809 task-free fMRI and structural MRI scans from 32,328 individuals ranging in age from 32 postmenstrual weeks to 80 years. Lifespan growth charts of the connectome are quantified at the whole cortex, system, and regional levels using generalized additive models for location, scale, and shape. We report critical inflection points in the non-linear growth trajectories of the whole-brain functional connectome, particularly peaking in the fourth decade of life. Having established the first fine-grained, lifespan-spanning suite of system-level brain atlases, we generate person-specific parcellation maps and further show distinct maturation timelines for functional segregation within different subsystems. We identify a spatiotemporal gradient axis that governs the life-course growth of regional connectivity, transitioning from primary sensory cortices to higher-order association regions. Using the connectome-based normative model, we demonstrate substantial individual heterogeneities at the network level in patients with autism spectrum disorder and patients with major depressive disorder. Our findings shed light on the life-course evolution of the functional connectome and serve as a normative reference for quantifying individual variation in patients with neurological and psychiatric disorders.

Structure-function coupling in white matter uncovers the abnormal brain connectivity in Schizophrenia.

Schizophrenia is characterized by dysconnectivity syndrome. Evidence of widespread impairment of structural and functional integration has been demonstrated in schizophrenia. Although white matter (WM) microstructural abnormalities have been commonly reported in schizophrenia, the dysfunction of WM as well as the relationship between structure and function in WM remains uncertain. In this study, we proposed a novel structure-function coupling measurement to reflect neuronal information transfer, which combined spatial-temporal correlations of functional signals with diffusion tensor orientations in the WM circuit from functional and diffusion magnetic resonance images (MRI). By analyzing MRI data from 75 individuals with schizophrenia (SZ) and 89 healthy volunteers (HV), the associations between structure and function in WM regions in schizophrenia were examined. Randomized validation of the measurement was performed in the HV group to confirm the capacity of the neural signal transferring along the WM tracts, referring to quantifying the association between structure and function. Compared to HV, SZ showed a widespread decrease in the structure-function coupling within WM regions, involving the corticospinal tract and the superior longitudinal fasciculus. Additionally, the structure-function coupling in the WM tracts was found to be significantly correlated with psychotic symptoms and illness duration in schizophrenia, suggesting that abnormal signal transfer of neuronal fiber pathways could be a potential mechanism of the neuropathology of schizophrenia. This work supports the dysconnectivity hypothesis of schizophrenia from the aspect of circuit function, and highlights the critical role of WM networks in the pathophysiology of schizophrenia.

Mapping Neurophysiological Subtypes of Major Depressive Disorder Using Normative Models of the Functional Connectome.

BACKGROUND: Major depressive disorder (MDD) is a highly heterogeneous disorder that typically emerges in adolescence and can occur throughout adulthood. Studies aimed at quantitatively uncovering the heterogeneity of individual functional connectome abnormalities in MDD and identifying reproducibly distinct neurophysiological MDD subtypes across the lifespan, which could provide promising insights for precise diagnosis and treatment prediction, are still lacking. METHODS: Leveraging resting-state functional magnetic resonance imaging data from 1148 patients with MDD and 1079 healthy control participants (ages 11-93), we conducted the largest multisite analysis to date for neurophysiological MDD subtyping. First, we characterized typical lifespan trajectories of functional connectivity strength based on the normative model and quantitatively mapped the heterogeneous individual deviations among patients with MDD. Then, we identified neurobiological MDD subtypes using an unsupervised clustering algorithm and evaluated intersite reproducibility. Finally, we validated the subtype differences in baseline clinical variables and longitudinal treatment predictive capacity. RESULTS: Our findings indicated great intersubject heterogeneity in the spatial distribution and severity of functional connectome deviations among patients with MDD, which inspired the identification of 2 reproducible neurophysiological subtypes. Subtype 1 showed severe deviations, with positive deviations in the default mode, limbic, and subcortical areas and negative deviations in the sensorimotor and attention areas. Subtype 2 showed a moderate but converse deviation pattern. More importantly, subtype differences were observed in depressive item scores and the predictive ability of baseline deviations for antidepressant treatment outcomes. CONCLUSIONS: These findings shed light on our understanding of different neurobiological mechanisms underlying the clinical heterogeneity of MDD and are essential for developing personalized treatments for this disorder.

Resting-state functional connectivity of the raphe nuclei in major depressive Disorder: A Multi-site study.

Accumulating evidence showed that major depressive disorder (MDD) is characterized by a dysfunction of serotonin neurotransmission. Raphe nuclei are the sources of most serotonergic neurons that project throughout the brain. Incorporating measurements of activity within the raphe nuclei into the analysis of connectivity characteristics may contribute to understanding how neurotransmitter synthesized centers are involved in thepathogenesisof MDD. Here, we analyzed the resting-state functional magnetic resonance imaging (RS-fMRI) dataset from 1,148 MDD patients and 1,079 healthy individuals recruited across nine centers. A seed-based analysis with the dorsal raphe and median raphe nuclei was performed to explore the functional connectivity (FC) alterations. Compared to controls, for dorsal raphe, the significantly decreased FC linking with the right precuneus and median cingulate cortex were found; for median raphe, the increased FC linking with right superior cerebellum (lobules V/VI) was found in MDD patients. In further exploratory analyzes, MDD-related connectivity alterations in dorsal and median raphe nuclei in different clinical factors remained highly similar to the main findings, indicating these abnormal connectivities are a disease-related alteration. Our study highlights a functional dysconnection pattern of raphe nuclei in MDD with multi-site big data. These findings help improve our understanding of the pathophysiology of depression and provide evidence of the theoretical foundation for the development of novel pharmacotherapies.

Convergence of the arcuate fasciculus and third branch of the superior longitudinal fasciculus with direct cortical stimulation-induced speech arrest area in the anterior ventral precentral gyrus.

OBJECTIVE: The objective was to identify the correspondence between the anterior terminations of the arcuate fasciculus (AF) and third branch of the superior longitudinal fasciculus (SLF-III) and the intraoperative direct cortical electrical stimulation (DCS)-induced speech arrest area. METHODS: The authors retrospectively screened 75 glioma patients (group 1) who received intraoperative DCS mapping in the left dominant frontal cortex. To minimize the influence of tumors or edema, we subsequently selected 26 patients (group 2) with glioma or edema not affecting Broca's area, the ventral precentral gyrus (vPCG), and the subcortical pathways to generate DCS functional maps and to construct the anterior terminations of AF and SLF-III with tractography. Next, a grid-by-grid pairwise comparison was performed between the fiber terminations and the DCS-induced speech arrest sites to calculate Cohen's kappa coefficient (κ) in both groups 1 and 2. Finally, the authors also demonstrated the distribution of the AF/SLF-III anterior projection maps obtained in 192 healthy participants (group 3) and subsequently correlated these with the speech arrest sites in group 2 to examine their validity in predicting speech output area. RESULTS: The authors found that speech arrest sites were substantially consistent with SLF-III anterior terminations (group 1, κ = 0.64 ± 0.03; group 2, κ = 0.73 ± 0.05) and moderately consistent with AF (group 1, κ = 0.51 ± 0.03; group 2, κ = 0.49 ± 0.05) and AF/SLF-III complex (group 1, κ = 0.54 ± 0.03; group 2, κ = 0.56 ± 0.05) terminations (all p < 0.0001). The DCS speech arrest sites of the group 2 patients mainly (85.1%) emerged at the anterior bank of the vPCG (vPCGa). In group 3, both terminations of AF and SLF-III converged onto the vPCGa, and their terminations well predicted the DCS speech output area of group 2 (AF, area under the curve [AUC] 86.5%; SLF-III, AUC 79.0%; AF/SLF-III complex, AUC 86.7%). CONCLUSIONS: This study supports the key role of the left vPCGa as the speech output node by showing convergence between speech output mapping and anterior AF/SLF-III connectivity in the vPCGa. These findings may contribute to the understanding of speech networks and could have clinical implications in preoperative surgical planning.

Integrated diffusion image operator (iDIO): A pipeline for automated configuration and processing of diffusion MRI data.

The preprocessing of diffusion magnetic resonance imaging (dMRI) data involve numerous steps, including the corrections for head motion, susceptibility distortion, low signal-to-noise ratio, and signal drifting. Researchers or clinical practitioners often need to configure different preprocessing steps depending on disparate image acquisition schemes, which increases the technical threshold for dMRI analysis for nonexpert users. This could cause disparities in data processing approaches and thus hinder the comparability between studies. To make the dMRI data processing steps transparent and adapt to various dMRI acquisition schemes for researchers, we propose a semi-automated pipeline tool for dMRI named integrated diffusion image operator or iDIO. This pipeline integrates features from a wide range of advanced dMRI software tools and targets at providing a one-click solution for dMRI data analysis, via adaptive configuration for a set of suggested processing steps based on the image header of the input data. Additionally, the pipeline provides options for post-processing, such as estimation of diffusion tensor metrics and whole-brain tractography-based connectomes reconstruction using common brain atlases. The iDIO pipeline also outputs an easy-to-interpret quality control report to facilitate users to assess the data quality. To keep the transparency of data processing, the execution log and all the intermediate images produced in the iDIO's workflow are accessible. The goal of iDIO is to reduce the barriers for clinical or nonspecialist users to adopt the state-of-art dMRI processing steps.

Frequency-resolved connectome alterations in major depressive disorder: A multisite resting fMRI study.

BACKGROUND: Functional connectome studies have revealed widespread connectivity alterations in major depressive disorder (MDD). However, the low frequency bandpass filtering (0.01-0.08 Hz or 0.01-0.1 Hz) in most studies have impeded our understanding on whether and how these alterations are affected by frequency of interest. METHODS: Here, we performed frequency-resolved (0.01-0.06 Hz, 0.06-0.16 Hz and 0.16-0.24 Hz) connectome analyses using a large-sample resting-state functional MRI dataset of 1002 MDD patients and 924 healthy controls from seven independent centers. RESULTS: We reported significant frequency-dependent connectome alterations in MDD in left inferior parietal, inferior temporal, precentral, and fusiform cortices and bilateral precuneus. These frequency-dependent connectome alterations are mainly derived by abnormalities of medium- and long-distance connections and are brain network-dependent. Moreover, the connectome alteration of left precuneus in high frequency band (0.16-0.24 Hz) is significantly associated with illness duration. LIMITATIONS: Multisite harmonization model only removed linear site effects. Neurobiological underpinning of alterations in higher frequency (0.16-0.24 Hz) should be further examined by combining fMRI data with respiration, heartbeat and blood flow recordings in future studies. CONCLUSIONS: These results highlight the frequency-dependency of connectome alterations in MDD and the benefit of examining connectome alteration in MDD under a wider frequency band.

Short-term Medication Effects on Brain Functional Activity and Network Architecture in First-Episode psychosis: a longitudinal fMRI study.

The effect of antipsychotic medications is critical for the long-term outcome of symptoms and functions during first-episode psychosis (FEP). However, how brain functions respond to the antipsychotic treatment in the early stage of psychosis and its underlying neural mechanisms remain unclear. In this study, we explored the cross-sectional and longitudinal changes of regional homogeneity (ReHo), whole-brain functional connectivity, and network topological properties via resting-state functional magnetic resonance images. Thirty-two drug-naïve FEP patients and 30 matched healthy volunteers (HV) were included, where 23 patients were re-visited with effective responses after two months of antipsychotic treatment. Compared to HV, drug-naive patients demonstrated significantly different patterns of functional connectivity involving the right thalamus. These functional alterations mainly involved decreased ReHo, increased nodal efficiency in the right thalamus, and increased thalamic-sensorimotor-frontoparietal connectivity. In the follow-up analysis, patients after treatment showed reduced ReHo and nodal clustering in visual networks, as well as disturbances of visual-somatomotor and hippocampus-superior frontal gyrus connectivity. The longitudinal changes of ReHo in the visual cortex were associated with an improvement in general psychotic symptoms. This study provides new evidence regarding alterations in brain function linked to schizophrenia onset and affected by antipsychotic medications. Moreover, our results demonstrated that the functional alterations at baseline were not fully modulated by antipsychotic medications, suggesting that antipsychotic medications may reduce psychotic symptoms but limit the effects in regions involved in disease pathophysiology.

Multiple cortical visual streams in humans.

The effective connectivity between 55 visual cortical regions and 360 cortical regions was measured in 171 HCP participants using the HCP-MMP atlas, and complemented with functional connectivity and diffusion tractography. A Ventrolateral Visual "What" Stream for object and face recognition projects hierarchically to the inferior temporal visual cortex, which projects to the orbitofrontal cortex for reward value and emotion, and to the hippocampal memory system. A Ventromedial Visual "Where" Stream for scene representations connects to the parahippocampal gyrus and hippocampus. An Inferior STS (superior temporal sulcus) cortex Semantic Stream receives from the Ventrolateral Visual Stream, from visual inferior parietal PGi, and from the ventromedial-prefrontal reward system and connects to language systems. A Dorsal Visual Stream connects via V2 and V3A to MT+ Complex regions (including MT and MST), which connect to intraparietal regions (including LIP, VIP and MIP) involved in visual motion and actions in space. It performs coordinate transforms for idiothetic update of Ventromedial Stream scene representations. A Superior STS cortex Semantic Stream receives visual inputs from the Inferior STS Visual Stream, PGi, and STV, and auditory inputs from A5, is activated by face expression, motion and vocalization, and is important in social behaviour, and connects to language systems.

The human posterior parietal cortex: effective connectome, and its relation to function.

The effective connectivity between 21 regions in the human posterior parietal cortex, and 360 cortical regions was measured in 171 Human Connectome Project (HCP) participants using the HCP atlas, and complemented with functional connectivity and diffusion tractography. Intraparietal areas LIP, VIP, MIP, and AIP have connectivity from early cortical visual regions, and to visuomotor regions such as the frontal eye fields, consistent with functions in eye saccades and tracking. Five superior parietal area 7 regions receive from similar areas and from the intraparietal areas, but also receive somatosensory inputs and connect with premotor areas including area 6, consistent with functions in performing actions to reach for, grasp, and manipulate objects. In the anterior inferior parietal cortex, PFop, PFt, and PFcm are mainly somatosensory, and PF in addition receives visuo-motor and visual object information, and is implicated in multimodal shape and body image representations. In the posterior inferior parietal cortex, PFm and PGs combine visuo-motor, visual object, and reward input and connect with the hippocampal system. PGi in addition provides a route to motion-related superior temporal sulcus regions involved in social interactions. PGp has connectivity with intraparietal regions involved in coordinate transforms and may be involved in idiothetic update of hippocampal visual scene representations.

Human amygdala compared to orbitofrontal cortex connectivity, and emotion.

The amygdala and orbitofrontal cortex have been implicated in emotion. To understand these regions better in humans, their effective connectivity with 360 cortical regions was measured in 171 humans from the Human Connectome Project, and complemented with functional connectivity and diffusion tractography. The human amygdala has effective connectivity from few cortical regions compared to the orbitofrontal cortex: primarily from auditory cortex A5 and the related superior temporal gyrus and temporal pole regions; the piriform (olfactory) cortex; the lateral orbitofrontal cortex 47m; somatosensory cortex; the hippocampus, entorhinal cortex, perirhinal cortex, and parahippocampal TF; and from the cholinergic nucleus basalis. The amygdala has effective connectivity to the hippocampus, entorhinal and perirhinal cortex; to the temporal pole; and to the lateral orbitofrontal cortex. The orbitofrontal cortex has effective connectivity from gustatory, olfactory, and temporal visual, auditory and pole cortex, and to the pregenual anterior and posterior cingulate cortex, hippocampal system, and prefrontal cortex, and provides for rewards and punishers to be used in reported emotions, and memory and navigation to goals. Given the paucity of amygdalo-neocortical connectivity in humans, it is proposed that the human amygdala is involved primarily in autonomic and conditioned responses via brainstem connectivity, rather than in reported (declarative) emotion.

Auditory cortical connectivity in humans.

To understand auditory cortical processing, the effective connectivity between 15 auditory cortical regions and 360 cortical regions was measured in 171 Human Connectome Project participants, and complemented with functional connectivity and diffusion tractography. 1. A hierarchy of auditory cortical processing was identified from Core regions (including A1) to Belt regions LBelt, MBelt, and 52; then to PBelt; and then to HCP A4. 2. A4 has connectivity to anterior temporal lobe TA2, and to HCP A5, which connects to dorsal-bank superior temporal sulcus (STS) regions STGa, STSda, and STSdp. These STS regions also receive visual inputs about moving faces and objects, which are combined with auditory information to help implement multimodal object identification, such as who is speaking, and what is being said. Consistent with this being a "what" ventral auditory stream, these STS regions then have effective connectivity to TPOJ1, STV, PSL, TGv, TGd, and PGi, which are language-related semantic regions connecting to Broca's area, especially BA45. 3. A4 and A5 also have effective connectivity to MT and MST, which connect to superior parietal regions forming a dorsal auditory "where" stream involved in actions in space. Connections of PBelt, A4, and A5 with BA44 may form a language-related dorsal stream.

Sex disparity of cerebral white matter hyperintensity in the hypertensive elderly: The Shanghai Changfeng study.

White matter hyperintensity (WMH) is associated with vascular hemodynamic alterations and reflects white matter injury. To date, the sex difference of tract-specific WMH and the relationship between high blood pressure (BP) and tract-specific WMH remain unclear. We recruited 515 subjects from the Shanghai Changfeng study (range 53-89 years, mean age 67.33 years). Systolic and diastolic blood pressure (SBP and DBP) were collected and used to calculate pulse pressure (PP). Magnetic resonance T1 and T2 FLAIR images were acquired to measure WMH and calculate WMH index. The ANCOVA test was performed to test the difference between sexes, and the linear regression model was used to examine the associations between BP and WMH index. Men showed higher WMH index than women in all white matter tracts (p < .001, respectively) except for the bilateral superior longitudinal fasciculus (SLF) and its left temporal part (tSLF). High SBP and PP was associated with a lower WMH index on the left corticospinal tract (CST), SLF, tSLF and right cingulum in hippocampus (p ≤ .001, respectively) in women, while high DBP was associated with a higher WMH index on the bilateral CST (left p < .001; right p = .001), left inferior longitudinal fasciculus (p < .001) and inferior fronto-occipital fasciculus (p = .002) in men. Men tend to have more WMH compared to women. A high SBP/PP relates to a lower WMH burden in women. This suggests that women could benefit from higher blood pressure in older age.

Prefrontal and somatosensory-motor cortex effective connectivity in humans.

Effective connectivity, functional connectivity, and tractography were measured between 57 cortical frontal and somatosensory regions and the 360 cortical regions in the Human Connectome Project (HCP) multimodal parcellation atlas for 171 HCP participants. A ventral somatosensory stream connects from 3b and 3a via 1 and 2 and then via opercular and frontal opercular regions to the insula, which then connects to inferior parietal PF regions. This stream is implicated in "what"-related somatosensory processing of objects and of the body and in combining with visual inputs in PF. A dorsal "action" somatosensory stream connects from 3b and 3a via 1 and 2 to parietal area 5 and then 7. Inferior prefrontal regions have connectivity with the inferior temporal visual cortex and orbitofrontal cortex, are implicated in working memory for "what" processing streams, and provide connectivity to language systems, including 44, 45, 47l, TPOJ1, and superior temporal visual area. The dorsolateral prefrontal cortex regions that include area 46 have connectivity with parietal area 7 and somatosensory inferior parietal regions and are implicated in working memory for actions and planning. The dorsal prefrontal regions, including 8Ad and 8Av, have connectivity with visual regions of the inferior parietal cortex, including PGs and PGi, and are implicated in visual and auditory top-down attention.

The human posterior cingulate, retrosplenial, and medial parietal cortex effective connectome, and implications for memory and navigation.

The human posterior cingulate, retrosplenial, and medial parietal cortex are involved in memory and navigation. The functional anatomy underlying these cognitive functions was investigated by measuring the effective connectivity of these Posterior Cingulate Division (PCD) regions in the Human Connectome Project-MMP1 atlas in 171 HCP participants, and complemented with functional connectivity and diffusion tractography. First, the postero-ventral parts of the PCD (31pd, 31pv, 7m, d23ab, and v23ab) have effective connectivity with the temporal pole, inferior temporal visual cortex, cortex in the superior temporal sulcus implicated in auditory and semantic processing, with the reward-related vmPFC and pregenual anterior cingulate cortex, with the inferior parietal cortex, and with the hippocampal system. This connectivity implicates it in hippocampal episodic memory, providing routes for "what," reward and semantic schema-related information to access the hippocampus. Second, the antero-dorsal parts of the PCD (especially 31a and 23d, PCV, and also RSC) have connectivity with early visual cortical areas including those that represent spatial scenes, with the superior parietal cortex, with the pregenual anterior cingulate cortex, and with the hippocampal system. This connectivity implicates it in the "where" component for hippocampal episodic memory and for spatial navigation. The dorsal-transitional-visual (DVT) and ProStriate regions where the retrosplenial scene area is located have connectivity from early visual cortical areas to the parahippocampal scene area, providing a ventromedial route for spatial scene information to reach the hippocampus. These connectivities provide important routes for "what," reward, and "where" scene-related information for human hippocampal episodic memory and navigation. The midcingulate cortex provides a route from the anterior dorsal parts of the PCD and the supracallosal part of the anterior cingulate cortex to premotor regions.