Distributed network flows generate localized category selectivity in human visual cortex.

A central goal of neuroscience is to understand how function-relevant brain activations are generated. Here we test the hypothesis that function-relevant brain activations are generated primarily by distributed network flows. We focused on visual processing in human cortex, given the long-standing literature supporting the functional relevance of brain activations in visual cortex regions exhibiting visual category selectivity. We began by using fMRI data from N = 352 human participants to identify category-specific responses in visual cortex for images of faces, places, body parts, and tools. We then systematically tested the hypothesis that distributed network flows can generate these localized visual category selective responses. This was accomplished using a recently developed approach for simulating - in a highly empirically constrained manner - the generation of task-evoked brain activations by modeling activity flowing over intrinsic brain connections. We next tested refinements to our hypothesis, focusing on how stimulus-driven network interactions initialized in V1 generate downstream visual category selectivity. We found evidence that network flows directly from V1 were sufficient for generating visual category selectivity, but that additional, globally distributed (whole-cortex) network flows increased category selectivity further. Using null network architectures we also found that each region's unique intrinsic "connectivity fingerprint" was key to the generation of category selectivity. These results generalized across regions associated with all four visual categories tested (bodies, faces, places, and tools), and provide evidence that the human brain's intrinsic network organization plays a prominent role in the generation of functionally relevant, localized responses.

Functional dysconnectivity of visual and somatomotor networks yields a simple and robust biomarker for psychosis.

People with psychosis exhibit thalamo-cortical hyperconnectivity and cortico-cortical hypoconnectivity with sensory networks, however, it remains unclear if this applies to all sensory networks, whether it arises from other illness factors, or whether such differences could form the basis of a viable biomarker. To address the foregoing, we harnessed data from the Human Connectome Early Psychosis Project and computed resting-state functional connectivity (RSFC) matrices for 54 healthy controls and 105 psychosis patients. Primary visual, secondary visual ("visual2"), auditory, and somatomotor networks were defined via a recent brain network partition. RSFC was determined for 718 regions via regularized partial correlation. Psychosis patients-both affective and non-affective-exhibited cortico-cortical hypoconnectivity and thalamo-cortical hyperconnectivity in somatomotor and visual2 networks but not in auditory or primary visual networks. When we averaged and normalized the visual2 and somatomotor network connections, and subtracted the thalamo-cortical and cortico-cortical connectivity values, a robust psychosis biomarker emerged (p = 2e-10, Hedges' g = 1.05). This "somato-visual" biomarker was present in antipsychotic-naive patients and did not depend on confounds such as psychiatric comorbidities, substance/nicotine use, stress, anxiety, or demographics. It had moderate test-retest reliability (ICC = 0.62) and could be recovered in five-minute scans. The marker could discriminate groups in leave-one-site-out cross-validation (AUC = 0.79) and improve group classification upon being added to a well-known neurocognition task. Finally, it could differentiate later-stage psychosis patients from healthy or ADHD controls in two independent data sets. These results introduce a simple and robust RSFC biomarker that can distinguish psychosis patients from controls by the early illness stages.

Correcting visual acuity beyond 20/20 improves contour element detection and integration: A cautionary tale for studies of special populations.

Contrary to popular lore, optimal visual acuity is typically better than 20/20. Could correcting acuity beyond 20/20 offer any benefit? An affirmative answer could present new confounds in studies of aging, development, psychiatric illness, neurodegenerative disorders, or any other population where refractive error might be more likely. An affirmative answer would also offer a novel explanation of inter-observer variability in visual performance. To address the question, we had individuals perform two well-studied visual tasks, once with 20/20 vision and once with optical correction, so that observers could see one line better on an eye chart. In the contour integration task, observers sought to identify the screen quadrant location of a sparsely defined (integrated) shape embedded in varying quantities of randomly oriented "noise" elements. In the collinear facilitation task, observers sought to detect a low-contrast element flanked by collinear or orthogonal high-contrast elements. In each case, displays were scaled in size to modulate element visibility and spatial frequency (4-12 cycles/deg). We found that improving acuity beyond 20/20 improved contour integration for the high spatial frequency displays. Although improving visual acuity did not affect collinear facilitation, it did improve detection of the central low-contrast target, especially at high spatial frequencies. These results, which were large in magnitude, suggest that optically correcting beyond 20/20 improves the detection and integration of contour elements, especially those that are smaller and of higher spatial frequency. Refractive blur within the normal range may confound special population studies, explain inter-observer differences, and meaningfully impact performance in low-visibility environments.

Functional dysconnectivity of visual and somatomotor networks yields a simple and robust biomarker for psychosis.

People with psychosis exhibit thalamo-cortical hyperconnectivity and cortico-cortical hypoconnectivity with sensory networks, however, it remains unclear if this applies to all sensory networks, whether it arises from other illness factors, or whether such differences could form the basis of a viable biomarker. To address the foregoing, we harnessed data from the Human Connectome Early Psychosis Project and computed resting-state functional connectivity (RSFC) matrices for 54 healthy controls and 105 psychosis patients. Primary visual, secondary visual ("visual2"), auditory, and somatomotor networks were defined via a recent brain network partition. RSFC was determined for 718 regions via regularized partial correlation. Psychosis patients- both affective and non-affective-exhibited cortico-cortical hypoconnectivity and thalamo-cortical hyperconnectivity in somatomotor and visual2 networks but not in auditory or primary visual networks. When we averaged and normalized the visual2 and somatomotor network connections, and subtracted the thalamo-cortical and cortico-cortical connectivity values, a robust psychosis biomarker emerged (p=2e-10, Hedges' g=1.05). This "somato-visual" biomarker was present in antipsychotic-naive patients and did not depend on confounds such as psychiatric comorbidities, substance/nicotine use, stress, anxiety, or demographics. It had moderate test-retest reliability (ICC=.61) and could be recovered in five-minute scans. The marker could discriminate groups in leave-one-site-out cross-validation (AUC=.79) and improve group classification upon being added to a well-known neurocognition task. Finally, it could differentiate later-stage psychosis patients from healthy or ADHD controls in two independent data sets. These results introduce a simple and robust RSFC biomarker that can distinguish psychosis patients from controls by the early illness stages.

Increased whole-brain functional heterogeneity in psychosis during rest and task.

Past work has shown that people with schizophrenia exhibit more cross-subject heterogeneity in their functional connectivity patterns. However, it remains unclear whether specific brain networks are implicated, whether common confounds could explain the results, or whether task activations might also be more heterogeneous. Unambiguously establishing the existence and extent of functional heterogeneity constitutes a first step toward understanding why it emerges and what it means clinically. METHODS: We first leveraged data from the HCP Early Psychosis project. Functional connectivity (FC) was extracted from 718 parcels via principal components regression. Networks were defined via a brain network partition (Ji et al., 2019). We also examined an independent data set with controls, later-stage schizophrenia patients, and ADHD patients during rest and during a working memory task. We quantified heterogeneity by averaging the Pearson correlation distance of each subject's FC or task activity pattern to that of every other subject of the same cohort. RESULTS: Affective and non-affective early psychosis patients exhibited more cross-subject whole-brain heterogeneity than healthy controls (ps < 0.001, Hedges' g > 0.74). Increased heterogeneity could be found in up to seven networks. In-scanner motion, medication, nicotine, and comorbidities could not explain the results. Later-stage schizophrenia patients exhibited heterogeneous connectivity patterns and task activations compared to ADHD and control subjects. Interestingly, individual connection weights, parcel-wise task activations, and network averages thereof were not more variable in patients, suggesting that heterogeneity becomes most obvious over large-scale patterns. CONCLUSION: Whole-brain cross-subject functional heterogeneity characterizes psychosis during rest and task. Developmental and pathophysiological consequences are discussed.

Poster Session: Retinal Changes Associated with Football-Related Concussions and Head Impacts.

This pilot study explored the sensitivity of retinal markers to CNS sequelae of concussive and subconcussive head hits. Three groups of college athletes were assessed at pre-season, post-season and 4-months later: Football players with a concussion history (FB+C) (n = 9), players without a concussion history (FB-C) (n = 11), and non-contact athletes (swimmers, track & field; Non-FB) (n = 12). Measures included optical coherence tomography (OCT), OCT angiography, electroretinography, and visual acuity testing. Head impacts during the season were tracked with in-helmet accelerometers. At pre-season, FB+C demonstrated thicker macular central subfields (CSF) (Hedge's g (effect size) = 1.05, p = 0.02) and retinal nerve fiber layers (RNFL) (g = 0.81, p = 0.08), relative to other athletes. Differences in CSF thickness were also observed at post-season and follow-up (gs > 1.00, ps < 0.04), reflecting their non-short-term nature. RNFL was thicker in FB+C at post-season (g = 0.93, p = 0.06) but not later. Total head impacts during the season correlated with increases in CSF thickness from baseline to follow-up only (r = -0.53, p = 0.02). High intensity head impacts in particular correlated with increases in cup-to-disc ratio at post-season and follow-up (rs > 0.53, ps < 0.03). These data suggest that concussion history is associated with retinal changes that are not short-term, and that severe head impacts are associated with acute changes whose duration is not yet known.

Dorsal attention network activity during perceptual organization is distinct in schizophrenia and predictive of cognitive disorganization.

Visual shape completion is a canonical perceptual organization process that integrates spatially distributed edge information into unified representations of objects. People with schizophrenia show difficulty in discriminating completed shapes, but the brain networks and functional connections underlying this perceptual difference remain poorly understood. Also unclear is whether brain network differences in schizophrenia occur in related illnesses or vary with illness features transdiagnostically. To address these topics, we scanned (functional magnetic resonance imaging, fMRI) people with schizophrenia, bipolar disorder, or no psychiatric illness during rest and during a task in which they discriminated configurations that formed or failed to form completed shapes (illusory and fragmented condition, respectively). Multivariate pattern differences were identified on the cortical surface using 360 predefined parcels and 12 functional networks composed of such parcels. Brain activity flow mapping was used to evaluate the likely involvement of resting-state connections for shape completion. Illusory/fragmented task activation differences ('modulations') in the dorsal attention network (DAN) could distinguish people with schizophrenia from the other groups (AUCs > .85) and could transdiagnostically predict cognitive disorganization severity. Activity flow over functional connections from the DAN could predict secondary visual network modulations in each group, except in schizophrenia. The secondary visual network was strongly and similarly modulated in each group. Task modulations were dispersed over more networks in patients compared to controls. In summary, DAN activity during visual perceptual organization is distinct in schizophrenia, symptomatically relevant, and potentially related to improper attention-related feedback into secondary visual areas.

When do contrast sensitivity deficits (or enhancements) depend on spatial frequency? Two ways to avoid spurious interactions.

Studies across a broad range of disciplines-from psychiatry to cognitive science to behavioural neuroscience-have reported on whether the magnitude of contrast sensitivity alterations in one group or condition varies with spatial frequency. Significant interactions have often gone unexplained or have been used to argue for impairments in specific processing streams. Here, we show that interactions with spatial frequency may need to be re-evaluated if the inherent skew/heteroscedasticity was not taken into account or if visual acuity could plausibly differ across groups or conditions. By re-analysing a publicly available data set, we show that-when using raw contrast sensitivity data-schizophrenia patients exhibit an apparent contrast sensitivity impairment that lessens with spatial frequency, but that when using log-transformed data or when using generalized estimating equations, this interaction reversed. The reversed interaction, but not the overall contrast sensitivity deficit, disappeared when groups were matched on visual acuity. An analysis of the contrast threshold data yielded similar results. A caveat is that matching groups on acuity is probably only defensible if acuity differences arise from non-neural factors such as optical blur. Taken together, these analyses reconcile seemingly discrepant findings in the literature and demonstrate that reporting contrast sensitivity interactions with spatial frequency requires properly accounting for visual acuity and skew/heteroscedasticity.

Visual system assessment for predicting a transition to psychosis.

The field of psychiatry is far from perfect in predicting which individuals will transition to a psychotic disorder. Here, we argue that visual system assessment can help in this regard. Such assessments have generated medium-to-large group differences with individuals prior to or near the first psychotic episode or have shown little influence of illness duration in larger samples of more chronic patients. For example, self-reported visual perceptual distortions-so-called visual basic symptoms-occur in up to 2/3rds of those with non-affective psychosis and have already longitudinally predicted an impending onset of schizophrenia. Possibly predictive psychophysical markers include enhanced contrast sensitivity, prolonged backward masking, muted collinear facilitation, reduced stereoscopic depth perception, impaired contour and shape integration, and spatially restricted exploratory eye movements. Promising brain-based markers include visual thalamo-cortical hyperconnectivity, decreased occipital gamma band power during visual detection (MEG), and reduced visually evoked occipital P1 amplitudes (EEG). Potentially predictive retinal markers include diminished cone a- and b-wave amplitudes and an attenuated photopic flicker response during electroretinography. The foregoing assessments are often well-described mechanistically, implying that their findings could readily shed light on the underlying pathophysiological changes that precede or accompany a transition to psychosis. The retinal and psychophysical assessments in particular are inexpensive, well-tolerated, easy to administer, and brief, with few inclusion/exclusion criteria. Therefore, across all major levels of analysis-from phenomenology to behavior to brain and retinal functioning-visual system assessment could complement and improve upon existing methods for predicting which individuals go on to develop a psychotic disorder.

Differences in Diffusion-Weighted Imaging and Resting-State Functional Connectivity Between Two Culturally Distinct Populations of Prairie Vole.

BACKGROUND: We used the highly prosocial prairie vole to test the hypothesis that higher-order brain structure-microarchitecture and functional connectivity (FC)-would differ between males from populations with distinctly different levels of prosocial behavior. Specifically, we studied males from Illinois (IL), which display high levels of prosocial behavior, and first generation males from Kansas dams and IL males (KI), which display the lowest level of prosocial behavior and higher aggression. Behavioral differences between these males are associated with overexpression of estrogen receptor alpha in the medial amygdala and bed nucleus of the stria terminalis and neuropeptide expression in the paraventricular nucleus. METHODS: We compared apparent diffusion coefficient, fractional anisotropy, and blood oxygen level-dependent resting-state FC between males. RESULTS: IL males displayed higher apparent diffusion coefficient in regions associated with prosocial behavior, including the bed nucleus of the stria terminalis, paraventricular nucleus, and anterior thalamic nuclei, while KI males showed higher apparent diffusion coefficient in the brainstem. KI males showed significantly higher fractional anisotropy than IL males in 26 brain regions, with the majority being in the brainstem reticular activating system. IL males showed more blood oxygen level-dependent resting-state FC between the bed nucleus of the stria terminalis, paraventricular nucleus, and medial amygdala along with other brain regions, including the hippocampus and areas associated with social and reward networks. CONCLUSIONS: Our results suggest that gray matter microarchitecture and FC may play a role the expression of prosocial behavior and that differences in other brain regions, especially the brainstem, could be involved. The differences between males suggests that this system represents a potentially valuable model system for studying emotional differences and vulnerability to stress and addiction.

Medial amygdala ERα expression influences monogamous behaviour of male prairie voles in the field.

Formation of long-term pair-bonds is a complex process, involving multiple neural circuits and is context- and experience-dependent. While laboratory studies using prairie voles have identified the involvement of several neural mechanisms, efforts to translate these findings into predictable field outcomes have been inconsistent at best. Here we test the hypothesis that inhibition of oestrogen receptor alpha (ERα) in the medial amygdala of male prairie voles would significantly increase the expression of social monogamy in the field. Prairie vole populations of equal sex ratio were established in outdoor enclosures with males bred for high levels of ERα expression and low levels of prosocial behaviour associated with social monogamy. Medial amygdala ERα expression was knocked down in half the males per population. Knockdown males displayed a greater degree of social monogamy in five of the eight behavioural indices assessed. This study demonstrates the robust nature of ERα in playing a critical role in the expression of male social monogamy in a field setting.

Activity flow underlying abnormalities in brain activations and cognition in schizophrenia.

Cognitive dysfunction is a core feature of many brain disorders, including schizophrenia (SZ), and has been linked to aberrant brain activations. However, it is unclear how these activation abnormalities emerge. We propose that aberrant flow of brain activity across functional connectivity (FC) pathways leads to altered activations that produce cognitive dysfunction in SZ. We tested this hypothesis using activity flow mapping, an approach that models the movement of task-related activity between brain regions as a function of FC. Using functional magnetic resonance imaging data from SZ individuals and healthy controls during a working memory task, we found that activity flow models accurately predict aberrant cognitive activations across multiple brain networks. Within the same framework, we simulated a connectivity-based clinical intervention, predicting specific treatments that normalized brain activations and behavior in patients. Our results suggest that dysfunctional task-evoked activity flow is a large-scale network mechanism contributing to cognitive dysfunction in SZ.

Brain network mechanisms of visual shape completion.

Visual shape completion recovers object shape, size, and number from spatially segregated edges. Despite being extensively investigated, the process's underlying brain regions, networks, and functional connections are still not well understood. To shed light on the topic, we scanned (fMRI) healthy adults during rest and during a task in which they discriminated pac-man configurations that formed or failed to form completed shapes (illusory and fragmented condition, respectively). Task activation differences (illusory-fragmented), resting-state functional connectivity, and multivariate patterns were identified on the cortical surface using 360 predefined parcels and 12 functional networks composed of such parcels. Brain activity flow mapping (ActFlow) was used to evaluate the likely involvement of resting-state connections for shape completion. We identified 36 differentially-active parcels including a posterior temporal region, PH, whose activity was consistent across 95% of observers. Significant task regions primarily occupied the secondary visual network but also incorporated the frontoparietal, dorsal attention, default mode, and cingulo-opercular networks. Each parcel's task activation difference could be modeled via its resting-state connections with the remaining parcels (r=.62, p<10-9), suggesting that such connections undergird shape completion. Functional connections from the dorsal attention network were key in modelling task activation differences in the secondary visual network. Dorsal attention and frontoparietal connections could also model activations in the remaining networks. Taken together, these results suggest that shape completion relies upon a sparsely distributed but densely interconnected network coalition that is centered in the secondary visual network, coordinated by the dorsal attention network, and inclusive of at least three other networks.

A Whole-Brain and Cross-Diagnostic Perspective on Functional Brain Network Dysfunction.

A wide variety of mental disorders have been associated with resting-state functional network alterations, which are thought to contribute to the cognitive changes underlying mental illness. These observations appear to support theories postulating large-scale disruptions of brain systems in mental illness. However, existing approaches isolate differences in network organization without putting those differences in a broad, whole-brain perspective. Using a graph distance approach-connectome-wide similarity-we found that whole-brain resting-state functional network organization is highly similar across groups of individuals with and without a variety of mental diseases. This similarity was observed across autism spectrum disorder, attention-deficit hyperactivity disorder, and schizophrenia. Nonetheless, subtle differences in network graph distance were predictive of diagnosis, suggesting that while functional connectomes differ little across health and disease, those differences are informative. These results suggest a need to reevaluate neurocognitive theories of mental illness, with a role for subtle functional brain network changes in the production of an array of mental diseases. Such small network alterations suggest the possibility that small, well-targeted alterations to brain network organization may provide meaningful improvements for a variety of mental disorders.

Breeding patterns of female prairie voles (Microtus ochrogaster) displaying alternative reproductive tactics.

Individuals of either sex may display alternative behaviors to obtain copulations, but few studies have examined the breeding patterns of females and males in populations where individuals of both sexes exhibit alternative reproductive tactics (ARTs). In prairie voles (Microtus ochrogaster), most adults are territorial, residing at a single nest site either as male-female pairs or as solitary individuals. However, some adults adopt nonterritorial, wandering tactics. During two field seasons monitoring prairie vole populations maintained in seminatural enclosures, we found evidence that females exhibiting different ARTs bred differentially with resident and wandering males. Females residing at a nest with a male bred significantly more often with a paired resident male, primarily their social partner, and significantly less often with male wanderers compared to single resident females or wandering females. These patterns were not due to chance, because paired resident females produced offspring with paired resident males significantly more than expected based on the relative abundance of these males in the population, whereas single resident females produced offspring with male wanderers significantly more than expected based on the proportion of male wanderers in the population. We did not find any evidence that multiple paternity was greater in the litters of single resident females and wanderer females even though these females lacked a male social partner to limit mating access by multiple males. This suggests that mate guarding by a female's male social partner was not the primary determinant of multiple paternity in the litters of females exhibiting different reproductive tactics. However, male ART did affect the likelihood of multiple paternity. Females that produced offspring with single resident or wanderer males had an increased likelihood of multiple paternity relative to females producing offspring with paired resident males. The results of this study show that female and male ARTs can affect breeding patterns.

Do olfactory cues from males with different avpr1a genotypes affect female mate choice in prairie voles, Microtus ochrogaster?

Multiple hypotheses have been proposed to explain female mate choice and some of the mechanisms underlying these choices. Females prairie voles display social and mating preferences for males with longer avpr1a microsatellite alleles, which provide more paternal care and exhibit less interest in novel females compared to males with shorter avpr1a microsatellite alleles. The cues females use to differentiate among males with different avpr1a genotypes are unknown, so the objective of our study was to determine if females can discriminate among males with different avpr1a genotypes using only male olfactory cues. In a laboratory choice test, females simultaneously presented with soiled bedding from a male with short versus long avpr1a microsatellite alleles showed no significant difference in the total time spent investigating each type of bedding. Nor did a greater number of females spend more time investigating soiled bedding from males with short versus long avpr1a microsatellite alleles. These findings were not influenced by female estrous status or their own avpr1a genotype. Our results suggest olfactory cues alone are insufficient to explain a female's ability to discriminate between males with different avpr1a genotypes and future research should focus on different cues or a combination of cues.