Human striatal association megaclusters.

The striatum receives projections from multiple regions of the cerebral cortex consistent with the role of the basal ganglia in diverse motor, affective, and cognitive functions. Within the striatum, the caudate receives projections from association cortex, including multiple distinct regions of prefrontal cortex. Building on recent insights about the details of how juxtaposed cortical networks are specialized for distinct aspects of higher-order cognition, we revisited caudate organization using within-individual precision neuroimaging initially in two intensively scanned individuals (each scanned 31 times). Results revealed that the caudate has side-by-side regions that are coupled to at least five distinct distributed association networks, paralleling the organization observed in the cerebral cortex. We refer to these spatial groupings of regions as striatal association megaclusters. Correlation maps from closely juxtaposed seed regions placed within the megaclusters recapitulated the five distinct cortical networks, including their multiple spatially distributed regions. Striatal association megaclusters were explored in 15 additional participants (each scanned at least 8 times), finding that their presence generalizes to new participants. Analysis of the laterality of the regions within the megaclusters further revealed that they possess asymmetries paralleling their cortical counterparts. For example, caudate regions linked to the language network were left lateralized. These results extend the general notion of parallel specialized basal ganglia circuits with the additional discovery that, even within the caudate, there is fine-grained separation of multiple distinct higher-order networks that reflects the organization and lateralization found in the cerebral cortex.NEW & NOTEWORTHY An individualized precision neuroimaging approach reveals juxtaposed zones of the caudate that are coupled with five distinct networks in association cortex. The organization of these caudate zones recapitulates organization observed in the cerebral cortex and extends the notion of specialized basal ganglia circuits.

Organization of the human cerebral cortex estimated within individuals: networks, global topography, and function.

The cerebral cortex is populated by specialized regions that are organized into networks. Here we estimated networks from functional MRI (fMRI) data in intensively sampled participants. The procedure was developed in two participants (scanned 31 times) and then prospectively applied to 15 participants (scanned 8-11 times). Analysis of the networks revealed a global organization. Locally organized first-order sensory and motor networks were surrounded by spatially adjacent second-order networks that linked to distant regions. Third-order networks possessed regions distributed widely throughout association cortex. Regions of distinct third-order networks displayed side-by-side juxtapositions with a pattern that repeated across multiple cortical zones. We refer to these as supra-areal association megaclusters (SAAMs). Within each SAAM, two candidate control regions were adjacent to three separate domain-specialized regions. Response properties were explored with task data. The somatomotor and visual networks responded to body movements and visual stimulation, respectively. Second-order networks responded to transients in an oddball detection task, consistent with a role in orienting to salient events. The third-order networks, including distinct regions within each SAAM, showed two levels of functional specialization. Regions linked to candidate control networks responded to working memory load across multiple stimulus domains. The remaining regions dissociated across language, social, and spatial/episodic processing domains. These results suggest that progressively higher-order networks nest outward from primary sensory and motor cortices. Within the apex zones of association cortex, there is specialization that repeatedly divides domain-flexible from domain-specialized regions. We discuss implications of these findings, including how repeating organizational motifs may emerge during development.NEW & NOTEWORTHY The organization of cerebral networks was estimated within individuals with intensive, repeat sampling of fMRI data. A hierarchical organization emerged in each individual that delineated first-, second-, and third-order cortical networks. Regions of distinct third-order association networks consistently exhibited side-by-side juxtapositions that repeated across multiple cortical zones, with clear and robust functional specialization among the embedded regions.

The brain's default network: updated anatomy, physiology and evolving insights.

Discoveries over the past two decades demonstrate that regions distributed throughout the association cortex, often called the default network, are suppressed during tasks that demand external attention and are active during remembering, envisioning the future and making social inferences. This Review describes progress in understanding the organization and function of networks embedded within these association regions. Detailed high-resolution analyses of single individuals suggest that the default network is not a single network, as historically described, but instead comprises multiple interwoven networks. The multiple networks share a common organizational motif (also evident in marmoset and macaque anatomical circuits) that might support a general class of processing function dependent on internally constructed rather than externally constrained representations, with each separate interwoven network specialized for a distinct processing domain. Direct neuronal recordings in humans and monkeys reveal evidence for competitive relationships between the internally and externally oriented networks. Findings from rodent studies suggest that the thalamus might be essential to controlling which networks are engaged through specialized thalamic reticular neurons, including antagonistic subpopulations. These association networks (and presumably thalamocortical circuits) are expanded in humans and might be particularly vulnerable to dysregulation implicated in mental illness.

Graded Variation in T1w/T2w Ratio during Adolescence: Measurement, Caveats, and Implications for Development of Cortical Myelin.

Adolescence is characterized by the maturation of cortical microstructure and connectivity supporting complex cognition and behavior. Axonal myelination influences brain connectivity during development by enhancing neural signaling speed and inhibiting plasticity. However, the maturational timing of cortical myelination during human adolescence remains poorly understood. Here, we take advantage of recent advances in high-resolution cortical T1w/T2w mapping methods, including principled correction of B1+ transmit field effects, using data from the Human Connectome Project in Development (HCP-D; N = 628, ages 8-21). We characterize microstructural changes relevant to myelination by estimating age-related differences in T1w/T2w throughout the cerebral neocortex from childhood to early adulthood. We apply Bayesian spline models and clustering analysis to demonstrate graded variation in age-dependent cortical T1w/T2w differences that are correlated with the sensorimotor-association (S-A) axis of cortical organization reported by others. In sensorimotor areas, T1w/T2w ratio measures start at high levels at early ages, increase at a fast pace, and decelerate at later ages (18-21). In intermediate multimodal areas along the S-A axis, T1w/T2w starts at intermediate levels and increases linearly at an intermediate pace. In transmodal/paralimbic association areas, T1w/T2w starts at low levels and increases linearly at the slowest pace. These data provide evidence for graded variation of the T1w/T2w ratio along the S-A axis that may reflect cortical myelination changes during adolescence underlying the development of complex information processing and psychological functioning. We discuss the implications of these results as well as caveats in interpreting magnetic resonance imaging (MRI)-based estimates of myelination.SIGNIFICANCE STATEMENT Myelin is a lipid membrane that is essential to healthy brain function. Myelin wraps axons to increase neural signaling speed, enabling complex neuronal functioning underlying learning and cognition. Here, we characterize the developmental timing of myelination across the cerebral cortex during adolescence using a noninvasive proxy measure, T1w/T2w mapping. Our results provide new evidence demonstrating graded variation across the cortex in the timing of T1w/T2w changes during adolescence, with rapid T1w/T2w increases in lower-order sensory areas and gradual T1w/T2w increases in higher-order association areas. This spatial pattern of microstructural brain development closely parallels the sensorimotor-to-association axis of cortical organization and plasticity during ontogeny.

Brain morphometry in older adults with and without dementia using extremely rapid structural scans.

T1-weighted structural MRI is widely used to measure brain morphometry (e.g., cortical thickness and subcortical volumes). Accelerated scans as fast as one minute or less are now available but it is unclear if they are adequate for quantitative morphometry. Here we compared the measurement properties of a widely adopted 1.0 mm resolution scan from the Alzheimer's Disease Neuroimaging Initiative (ADNI = 5'12'') with two variants of highly accelerated 1.0 mm scans (compressed-sensing, CSx6 = 1'12''; and wave-controlled aliasing in parallel imaging, WAVEx9 = 1'09'') in a test-retest study of 37 older adults aged 54 to 86 (including 19 individuals diagnosed with a neurodegenerative dementia). Rapid scans produced highly reliable morphometric measures that largely matched the quality of morphometrics derived from the ADNI scan. Regions of lower reliability and relative divergence between ADNI and rapid scan alternatives tended to occur in midline regions and regions with susceptibility-induced artifacts. Critically, the rapid scans yielded morphometric measures similar to the ADNI scan in regions of high atrophy. The results converge to suggest that, for many current uses, extremely rapid scans can replace longer scans. As a final test, we explored the possibility of a 0'49'' 1.2 mm CSx6 structural scan, which also showed promise. Rapid structural scans may benefit MRI studies by shortening the scan session and reducing cost, minimizing opportunity for movement, creating room for additional scan sequences, and allowing for the repetition of structural scans to increase precision of the estimates.

Side-by-side regions in dorsolateral prefrontal cortex estimated within the individual respond differentially to domain-specific and domain-flexible processes.

A recurring debate concerns whether regions of primate prefrontal cortex (PFC) support domain-flexible or domain-specific processes. Here we tested the hypothesis with functional MRI (fMRI) that side-by-side PFC regions, within distinct parallel association networks, differentially support domain-flexible and domain-specialized processing. Individuals (N = 9) were intensively sampled, and all effects were estimated within their own idiosyncratic anatomy. Within each individual, we identified PFC regions linked to distinct networks, including a dorsolateral PFC (DLPFC) region coupled to the medial temporal lobe (MTL) and an extended region associated with the canonical multiple-demand network. We further identified an inferior PFC region coupled to the language network. Exploration in separate task data, collected within the same individuals, revealed a robust functional triple dissociation. The DLPFC region linked to the MTL was recruited during remembering and imagining the future, distinct from juxtaposed regions that were modulated in a domain-flexible manner during working memory. The inferior PFC region linked to the language network was recruited during sentence processing. Detailed analysis of the trial-level responses further revealed that the DLPFC region linked to the MTL specifically tracked processes associated with scene construction. These results suggest that the DLPFC possesses a domain-specialized region that is small and easily confused with nearby (larger) regions associated with cognitive control. The newly described region is domain specialized for functions traditionally associated with the MTL. We discuss the implications of these findings in relation to convergent anatomical analysis in the monkey.NEW & NOTEWORTHY Competing hypotheses link regions of prefrontal cortex (PFC) to domain-flexible or domain-specific processes. Here, using a precision neuroimaging approach, we identify a domain-specialized region in dorsolateral PFC, coupled to the medial temporal lobe and recruited for scene construction. This region is juxtaposed to, but distinct from, broader PFC regions recruited flexibly for cognitive control. Region distinctions align with broader network differences, suggesting that PFC regions gain dissociable processing properties via segregated anatomical projections.

Functional specialization of parallel distributed networks revealed by analysis of trial-to-trial variation in processing demands.

Multiple large-scale networks populate human association cortex. Here, we explored the functional properties of these networks by exploiting trial-to-trial variation in component-processing demands. In two behavioral studies (n = 136 and n = 238), participants quantified strategies used to solve individual task trials that spanned remembering, imagining future scenarios, and various control trials. These trials were also all scanned in an independent sample of functional MRI participants (n = 10), each with sufficient data to precisely define within-individual networks. Stable latent factors varied across trials and correlated with trial-level functional responses selectively across networks. One network linked to parahippocampal cortex, labeled Default Network A (DN-A), tracked scene construction, including for control trials that possessed minimal episodic memory demands. To the degree, a trial encouraged participants to construct a mental scene with imagery and awareness about spatial locations of objects or places, the response in DN-A increased. The juxtaposed Default Network B (DN-B) showed no such response but varied in relation to social processing demands. Another adjacent network, labeled Frontoparietal Network B (FPN-B), robustly correlated with trial difficulty. These results support that DN-A and DN-B are specialized networks differentially supporting information processing within spatial and social domains. Both networks are dissociable from a closely juxtaposed domain-general control network that tracks cognitive effort.NEW & NOTEWORTHY Tasks shown to differentially recruit parallel association networks are multifaceted, leaving open questions about network processes. Here, examining trial-to-trial network response properties in relation to trial traits reveals new insights into network functions. In particular, processes linked to scene construction selectively recruit a distributed network with links to parahippocampal and retrosplenial cortices, including during trials designed not to rely on the personal past. Adjacent networks show distinct patterns, providing novel evidence of functional specialization.

A third somatomotor representation in the human cerebellum.

Seminal neurophysiological studies in the 1940s discovered two somatomotor maps in the cerebellum-an inverted anterior lobe map and an upright posterior lobe map. Both maps have been confirmed in the human using noninvasive neuroimaging with additional hints of a third map within and near to the cerebellar vermis. Here, we sought direct evidence for the third somatomotor map by using intensive, repeated functional MRI (fMRI) scanning of individuals performing movements across multiple body parts (tongue, hands, glutes, and feet). An initial discovery sample (n = 4, 4 sessions per individual including 576 separate blocks of body movements) yielded evidence for the two established cerebellar somatomotor maps, as well as evidence for a third discontinuous foot representation within the vermis. When the left versus right foot movements were directly contrasted, the third representation could be clearly distinguished from the second representation in multiple individuals. Functional connectivity from seed regions in the third somatomotor representation confirmed anatomically specific connectivity with the cerebral cortex, paralleling the patterns observed for the two well-established maps. All results were prospectively replicated in an independent dataset with new individuals (n = 4). These collective findings provide direct support for a third somatomotor representation in the vermis of the cerebellum that may be part of a third map. We discuss the relations of this candidate third map to the broader topography of the cerebellum as well as its implications for understanding the specific organization of the human cerebellar vermis where distinct zones appear functionally specialized for somatomotor and visual domains.NEW & NOTEWORTHY A third somatomotor representation exists in the vermis of the human cerebellum. Evidence for this elusive representation arises specifically from mapping the foot. Separate foot representations distinguish the third from the nearby second somatomotor representation. A third somatomotor representation in the posterior vermis supports a large-scale organization hypothesis in which the cerebellum possesses three sets of roughly homotopic representations of the full cerebrum.

Cortical thickness across the lifespan: Data from 17,075 healthy individuals aged 3-90 years.

Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3-90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes.

Mega-analysis methods in ENIGMA: The experience of the generalized anxiety disorder working group.

The ENIGMA group on Generalized Anxiety Disorder (ENIGMA-Anxiety/GAD) is part of a broader effort to investigate anxiety disorders using imaging and genetic data across multiple sites worldwide. The group is actively conducting a mega-analysis of a large number of brain structural scans. In this process, the group was confronted with many methodological challenges related to study planning and implementation, between-country transfer of subject-level data, quality control of a considerable amount of imaging data, and choices related to statistical methods and efficient use of resources. This report summarizes the background information and rationale for the various methodological decisions, as well as the approach taken to implement them. The goal is to document the approach and help guide other research groups working with large brain imaging data sets as they develop their own analytic pipelines for mega-analyses.

Subcortical volumes across the lifespan: Data from 18,605 healthy individuals aged 3-90 years.

Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine age-related trajectories inferred from cross-sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3-90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter-individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age-related morphometric patterns.

Heterogeneity of Cerebral White Matter Lesions and Clinical Correlates in Older Adults.

BACKGROUND AND PURPOSE: Cerebral white matter signal abnormalities (WMSAs) are a significant radiological marker associated with brain and vascular aging. However, understanding their clinical impact is limited because of their pathobiological heterogeneity. We determined whether use of robust reliable automated procedures can distinguish WMSA classes with different clinical consequences. METHODS: Data from generally healthy participants aged >50 years with moderate or greater WMSA were selected from the Human Connectome Project-Aging (n=130). WMSAs were segmented on T1 imaging. Features extracted from WMSA included total and regional volume, number of discontinuous clusters, size of noncontiguous lesion, contrast of lesion intensity relative to surrounding normal appearing tissue using a fully automated procedure. Hierarchical clustering was used to classify individuals into distinct classes of WMSA. Radiological and clinical variability was evaluated across the individual WMSA classes. RESULTS: Class I was characterized by multiple, small, lower-contrast lesions predominantly in the deep WM; class II by large, confluent lesions in the periventricular WM; and class III by higher-contrast lesions restricted to the juxtaventricular WM. Class II was associated with lower myelin content than the other 2 classes. Class II was more prevalent in older subjects and was associated with a higher prevalence of hypertension and lower physical activity levels. Poor sleep quality was associated with a greater risk of class I. CONCLUSIONS: We classified heterogeneous subsets of cerebral white matter lesions into distinct classes that have different clinical risk factors. This new method for identifying classes of WMSA will be important in understanding the underlying pathophysiology and in determining the impact on clinical outcomes.

Characterizing cerebral hemodynamics across the adult lifespan with arterial spin labeling MRI data from the Human Connectome Project-Aging.

Arterial spin labeling (ASL) magnetic resonance imaging (MRI) has become a popular approach for studying cerebral hemodynamics in a range of disorders and has recently been included as part of the Human Connectome Project-Aging (HCP-A). Due to the high spatial resolution and multiple post-labeling delays, ASL data from HCP-A holds promise for localization of hemodynamic signals not only in gray matter but also in white matter. However, gleaning information about white matter hemodynamics with ASL is challenging due in part to longer blood arrival times in white matter compared to gray matter. In this work, we present an analytical approach for deriving measures of cerebral blood flow (CBF) and arterial transit times (ATT) from the ASL data from HCP-A and report on gray and white matter hemodynamics in a large cohort (n = 234) of typically aging adults (age 36-90 years). Pseudo-continuous ASL data were acquired with labeling duration = 1500 ms and five post-labeling delays = 200 ms, 700 ms, 1200, 1700 ms, and 2200 ms. ATT values were first calculated on a voxel-wise basis through normalized cross-correlation analysis of the acquired signal time course in that voxel and an expected time course based on an acquisition-specific Bloch simulation. CBF values were calculated using a two-compartment model and with age-appropriate blood water longitudinal relaxation times. Using this approach, we found that white matter CBF reduces (ρ = 0.39) and white matter ATT elongates (ρ = 0.42) with increasing age (p < 0.001). In addition, CBF is lower and ATTs are longer in white matter compared to gray matter across the adult lifespan (Wilcoxon signed-rank tests; p < 0.001). We also found sex differences with females exhibiting shorter white matter ATTs than males, independently of age (Wilcoxon rank-sum test; p < 0.001). Finally, we have shown that CBF and ATT values are spatially heterogeneous, with significant differences in cortical versus subcortical gray matter and juxtacortical versus periventricular white matter. These results serve as a characterization of normative physiology across the human lifespan against which hemodynamic impairment due to cerebrovascular or neurodegenerative diseases could be compared in future studies.

The detailed organization of the human cerebellum estimated by intrinsic functional connectivity within the individual.

Distinct regions of the cerebellum connect to separate regions of the cerebral cortex forming a complex topography. Although cerebellar organization has been examined in group-averaged data, study of individuals provides an opportunity to discover features that emerge at a higher spatial resolution. Here, functional connectivity MRI was used to examine the cerebellum of two intensively sampled individuals (each scanned 31 times). Connectivity to somatomotor cortex showed the expected crossed laterality and topography of the body maps. A surprising discovery was connectivity to the primary visual cortex along the vermis with evidence for representation of the central field. Within the hemispheres, each individual displayed a hierarchical progression from the inverted anterior lobe somatomotor map through to higher-order association zones. The hierarchy ended at Crus I/II and then progressed in reverse order through to the upright somatomotor map in the posterior lobe. Evidence for a third set of networks was found in the most posterior extent of the cerebellum. Detailed analysis of the higher-order association networks revealed robust representations of two distinct networks linked to the default network, multiple networks linked to cognitive control, as well as a separate representation of a language network. Although idiosyncratic spatial details emerged between subjects, each network could be detected in both individuals, and seed regions placed within the cerebellum recapitulated the full extent of the spatially specific cerebral networks. The observation of multiple networks in juxtaposed regions at the Crus I/II apex confirms the importance of this zone to higher-order cognitive function and reveals new organizational details.NEW & NOTEWORTHY Stable, within-individual maps of cerebellar organization reveal orderly macroscale representations of the cerebral cortex with local juxtaposed zones representing distinct networks. In addition, individuals reveal idiosyncratic organizational features.

Dedifferentiation of caudate functional connectivity and striatal dopamine transporter density predict memory change in normal aging.

Age-related changes in striatal function are potentially important for predicting declining memory performance over the adult life span. Here, we used fMRI to measure functional connectivity of caudate subfields with large-scale association networks and positron emission tomography to measure striatal dopamine transporter (DAT) density in 51 older adults (age 65-86 years) who received annual cognitive testing for up to 7 years (mean = 5.59, range 2-7 years). Analyses showed that cortical-caudate functional connectivity was less differentiated in older compared with younger adults (n = 63, age 18-32 years). Unlike in younger adults, the central lateral caudate was less strongly coupled with the frontal parietal control network in older adults. Older adults also showed less "decoupling" of the caudate from other networks, including areas of the default network (DN) and the hippocampal complex. Contrary to expectations, less decoupling between caudate and the DN was not associated with an age-related reduction of striatal DAT, suggesting that neurobiological changes in the cortex may drive dedifferentiation of cortical-caudate connectivity. Reduction of specificity in functional coupling between caudate and regions of the DN predicted memory decline over subsequent years at older ages. The age-related reduction in striatal DAT density also predicted memory decline, suggesting that a relation between striatal functions and memory decline in aging is multifaceted. Collectively, the study provides evidence highlighting the association of age-related differences in striatal function to memory decline in normal aging.

Situating the left-lateralized language network in the broader organization of multiple specialized large-scale distributed networks.

Using procedures optimized to explore network organization within the individual, the topography of a candidate language network was characterized and situated within the broader context of adjacent networks. The candidate network was first identified using functional connectivity and replicated across individuals, acquisition tasks, and analytical methods. In addition to classical language regions near the perisylvian cortex and temporal pole, regions were also observed in dorsal posterior cingulate, midcingulate, and anterior superior frontal and inferior temporal cortex. The candidate network was selectively activated when processing meaningful (as contrasted with nonword) sentences, whereas spatially adjacent networks showed minimal or even decreased activity. Results were replicated and triplicated across two prospectively acquired cohorts. Examined in relation to adjacent networks, the topography of the language network was found to parallel the motif of other association networks, including the transmodal association networks linked to theory of mind and episodic remembering (often collectively called the default network). The several networks contained juxtaposed regions in multiple association zones. Outside of these juxtaposed higher-order networks, we further noted a distinct frontotemporal network situated between language regions and a frontal orofacial motor region and a temporal auditory region. A possibility is that these functionally related sensorimotor regions might anchor specialization of neighboring association regions that develop into a language network. What is most striking is that the canonical language network appears to be just one of multiple similarly organized, differentially specialized distributed networks that populate the evolutionarily expanded zones of human association cortex.NEW & NOTEWORTHY This research shows that a language network can be identified within individuals using functional connectivity. Organizational details reveal that the language network shares a common spatial motif with other association networks, including default and frontoparietal control networks. The language network is activated by language task demands, whereas closely juxtaposed networks are not, suggesting that similarly organized but differentially specialized distributed networks populate association cortex.

Parallel distributed networks dissociate episodic and social functions within the individual.

Association cortex is organized into large-scale distributed networks. One such network, the default network (DN), is linked to diverse forms of internal mentation, opening debate about whether shared or distinct anatomy supports multiple forms of cognition. Using within-individual analysis procedures that preserve idiosyncratic anatomical details, we probed whether multiple tasks from two domains, episodic projection and theory of mind (ToM), rely on the same or distinct networks. In an initial experiment (6 subjects, each scanned 4 times), we found evidence that episodic projection and ToM tasks activate separate regions distributed throughout the cortex, with adjacent regions in parietal, temporal, prefrontal, and midline zones. These distinctions were predicted by the hypothesis that the DN comprises two parallel, interdigitated networks. One network, linked to parahippocampal cortex (PHC), is preferentially recruited during episodic projection, including both remembering and imagining the future. A second juxtaposed network, which includes the temporoparietal junction (TPJ), is differentially engaged during multiple forms of ToM. In two prospectively acquired independent experiments, we replicated and triplicated the dissociation (each with 6 subjects scanned 4 times). Furthermore, the dissociation was found in all zones when analyzed independently, including robustly in midline regions previously described as hubs. The TPJ-linked network is interwoven with the PHC-linked network across the cortex, making clear why it is difficult to fully resolve the two networks in group-averaged or lower-resolution data. These results refine our understanding of the functional-anatomical organization of association cortex and raise fundamental questions about how specialization might arise in parallel, juxtaposed association networks.NEW & NOTEWORTHY Two distributed, interdigitated networks exist within the bounds of the canonical default network. Here we used repeated scanning of individuals, across three independent samples, to provide evidence that tasks requiring episodic projection or theory of mind differentially recruit the two networks across multiple cortical zones. The two distributed networks thus appear to preferentially subserve distinct functions.

Increased amygdala-visual cortex connectivity in youth with persecutory ideation.

BACKGROUND: Subclinical delusional ideas, including persecutory beliefs, in otherwise healthy individuals are heritable symptoms associated with increased risk for psychotic illness, possibly representing an expression of one end of a continuum of psychosis severity. The identification of variation in brain function associated with these symptoms may provide insights about the neurobiology of delusions in clinical psychosis. METHODS: A resting-state functional magnetic resonance imaging scan was collected from 131 young adults with a wide range of severity of subclinical delusional beliefs, including persecutory ideas. Because of evidence for a key role of the amygdala in fear and paranoia, resting-state functional connectivity of the amygdala was measured. RESULTS: Connectivity between the amygdala and early visual cortical areas, including striate cortex (V1), was found to be significantly greater in participants with high (n = 43) v. low (n = 44) numbers of delusional beliefs, particularly in those who showed persistence of those beliefs. Similarly, across the full sample, the number of and distress associated with delusional beliefs were positively correlated with the strength of amygdala-visual cortex connectivity. Moreover, further analyses revealed that these effects were driven by those who endorsed persecutory beliefs. CONCLUSIONS: These findings are consistent with the hypothesis that aberrant assignments of threat to sensory stimuli may lead to the downstream development of delusional ideas. Taken together with prior findings of disrupted sensory-limbic coupling in psychosis, these results suggest that altered amygdala-visual cortex connectivity could represent a marker of psychosis-related pathophysiology across a continuum of symptom severity.

Global White Matter Diffusion Characteristics Predict Longitudinal Cognitive Change Independently of Amyloid Status in Clinically Normal Older Adults.

White matter degradation has been proposed as one possible explanation for age-related cognitive decline. In the present study, we examined 2 main questions: 1) Do diffusion characteristics predict longitudinal change in cognition independently or synergistically with amyloid status? 2) Are the effects of diffusion characteristics on longitudinal cognitive change tract-specific or global in nature? Cognitive domains of executive function, episodic memory, and processing speed were measured annually (mean follow-up = 3.93 ± 1.25 years). Diffusion tensor imaging and Pittsburgh Compound-B positron emission tomography were performed at baseline in 265 clinically normal older adults (aged 63-90). Tract-specific diffusion was measured as the mean fractional anisotropy (FA) for 9 major white matter tracts. Global diffusion was measured as the mean FA across the 9 white matter tracts. Linear mixed models demonstrated independent, rather than synergistic, effects of global FA and amyloid status on cognitive decline. After controlling for amyloid status, lower global FA was associated with worse longitudinal performance in episodic memory and processing speed, but not executive function. After accounting for global FA, none of the individual tracts predicted a significant change in cognitive performance. These findings suggest that global, rather than tract-specific, diffusion characteristics predict longitudinal cognitive decline independently of amyloid status.

Heritability analysis with repeat measurements and its application to resting-state functional connectivity.

Heritability, defined as the proportion of phenotypic variation attributable to genetic variation, provides important information about the genetic basis of a trait. Existing heritability analysis methods do not discriminate between stable effects (e.g., due to the subject's unique environment) and transient effects, such as measurement error. This can lead to misleading assessments, particularly when comparing the heritability of traits that exhibit different levels of reliability. Here, we present a linear mixed effects model to conduct heritability analyses that explicitly accounts for intrasubject fluctuations (e.g., due to measurement noise or biological transients) using repeat measurements. We apply the proposed strategy to the analysis of resting-state fMRI measurements-a prototypic data modality that exhibits variable levels of test-retest reliability across space. Our results reveal that the stable components of functional connectivity within and across well-established large-scale brain networks can be considerably heritable. Furthermore, we demonstrate that dissociating intra- and intersubject variation can reveal genetic influence on a phenotype that is not fully captured by conventional heritability analyses.