The importance of covert memory consolidation in schizophrenia: Dysfunctional network profiles of the hippocampus and the dorsolateral prefrontal cortex.

Altered brain network profiles in schizophrenia (SCZ) during memory consolidation are typically observed during task-active periods such as encoding or retrieval. However active processes are also sub served by covert periods of memory consolidation. These periods are active in that they allow memories to be recapitulated even in the absence of overt sensorimotor processing. It is plausible that regions central to memory formation like the dlPFC and the hippocampus, exert network signatures during covert periods. Are these signatures altered in patients? The question is clinically relevant because real world learning and memory is facilitated by covert processing, and may be impaired in schizophrenia. Here, we compared network signatures of the dlPFC and the hippocampus during covert periods of a learning and memory task. Because behavioral proficiency increased non-linearly, functional connectivity of the dlPFC and hippocampus [psychophysiological interaction (PPI)] was estimated for each of the Early (linear increases in performance) and Late (asymptotic performance) covert periods. During Early periods, we observed hypo-modulation by the hippocampus but hyper-modulation by dlPFC. Conversely, during Late periods, we observed hypo-modulation by both the dlPFC and the hippocampus. We stitch these results into a conceptual model of network deficits during covert periods of memory consolidation.

Blunted brain responses to neutral faces in healthy first-degree relatives of patients with schizophrenia: an image-based fMRI meta-analysis.

Schizophrenia is characterized by the misattribution of emotional significance to neutral faces, accompanied by overactivations of the limbic system. To understand the disorder's genetic and environmental contributors, investigating healthy first-degree relatives is crucial. However, inconsistent findings exist regarding their ability to recognize neutral faces, with limited research exploring the cerebral correlates of neutral face processing in this population. Thus, we here investigated brain responses to neutral face processing in healthy first-degree relatives through an image-based meta-analysis of functional magnetic resonance imaging studies. We included unthresholded group-level T-maps from 5 studies comprising a total of 120 first-degree relatives and 150 healthy controls. In sensitivity analyses, we ran a combined image- and coordinate-based meta-analysis including 7 studies (157 first-degree relatives, 207 healthy controls) aiming at testing the robustness of the results in a larger sample of studies. Our findings revealed a pattern of decreased brain responses to neutral faces in relatives compared with healthy controls, particularly in limbic areas such as the bilateral amygdala, hippocampus, and insula. The same pattern was observed in sensitivity analyses. These results contrast with the overactivations observed in patients, potentially suggesting that this trait could serve as a protective factor in healthy relatives. However, further research is necessary to test this hypothesis.

Abnormal Oculomotor Corollary Discharge Signaling as a Trans-diagnostic Mechanism of Psychosis.

BACKGROUND AND HYPOTHESIS: Corollary discharge (CD) signals are "copies" of motor signals sent to sensory areas to predict the corresponding input. They are a posited mechanism enabling one to distinguish actions generated by oneself vs external forces. Consequently, altered CD is a hypothesized mechanism for agency disturbances in psychosis. Previous studies have shown a decreased influence of CD signals on visual perception in individuals with schizophrenia-particularly in those with more severe positive symptoms. We therefore hypothesized that altered CD may be a trans-diagnostic mechanism of psychosis. STUDY DESIGN: We examined oculomotor CD (using the blanking task) in 49 participants with schizophrenia or schizoaffective disorder (SZ), 36 bipolar participants with psychosis (BPP), and 40 healthy controls (HC). Participants made a saccade to a visual target. Upon saccade initiation, the target disappeared and reappeared at a horizontally displaced position. Participants indicated the direction of displacement. With intact CD, participants can make accurate perceptual judgements. Otherwise, participants may use saccade landing site as a proxy of pre-saccadic target to inform perception. Thus, multi-level modeling was used to examine the influence of target displacement and saccade landing site on displacement judgements. STUDY RESULTS: SZ and BPP were equally less sensitive to target displacement than HC. Moreover, regardless of diagnosis, SZ and BPP with more severe positive symptoms were more likely to rely on saccade landing site. CONCLUSIONS: These results suggest that altered CD may be a trans-diagnostic mechanism of psychosis.

Topological Data Analysis Captures Task-Driven fMRI Profiles in Individual Participants: A Classification Pipeline Based on Persistence.

BOLD-based fMRI is the most widely used method for studying brain function. The BOLD signal while valuable, is beset with unique vulnerabilities. The most notable of these is the modest signal to noise ratio, and the relatively low temporal and spatial resolution. However, the high dimensional complexity of the BOLD signal also presents unique opportunities for functional discovery. Topological Data Analyses (TDA), a branch of mathematics optimized to search for specific classes of structure within high dimensional data may provide particularly valuable applications. In this investigation, we acquired fMRI data in the anterior cingulate cortex (ACC) using a basic motor control paradigm. Then, for each participant and each of three task conditions, fMRI signals in the ACC were summarized using two methods: a) TDA based methods of persistent homology and persistence landscapes and b) non-TDA based methods using a standard vectorization scheme. Finally, using machine learning (with support vector classifiers), classification accuracy of TDA and non-TDA vectorized data was tested across participants. In each participant, TDA-based classification out-performed the non-TDA based counterpart, suggesting that our TDA analytic pipeline better characterized task- and condition-induced structure in fMRI data in the ACC. Our results emphasize the value of TDA in characterizing task- and condition-induced structure in regional fMRI signals. In addition to providing our analytical tools for other users to emulate, we also discuss the unique role that TDA-based methods can play in the study of individual differences in the structure of functional brain signals in the healthy and the clinical brain.

Aberrant Effective Connectivity During Eye Gaze Processing Is Linked to Social Functioning and Symptoms in Schizophrenia.

BACKGROUND: Patients with schizophrenia show abnormal gaze processing, which is associated with social dysfunction. These abnormalities are related to aberrant connectivity among brain regions that are associated with visual processing, social cognition, and cognitive control. In this study, we investigated 1) how effective connectivity during gaze processing is disrupted in schizophrenia and 2) how this may contribute to social dysfunction and clinical symptoms. METHODS: Thirty-nine patients with schizophrenia/schizoaffective disorder (SZ) and 33 healthy control participants completed an eye gaze processing task during functional magnetic resonance imaging. Participants viewed faces with different gaze angles and performed explicit and implicit gaze processing. Four brain regions-the secondary visual cortex, posterior superior temporal sulcus, inferior parietal lobule, and posterior medial frontal cortex-were identified as nodes for dynamic causal modeling analysis. RESULTS: Both the SZ and healthy control groups showed similar model structures for general gaze processing. Explicit gaze discrimination led to changes in effective connectivity, including stronger excitatory, bottom-up connections from the secondary visual cortex to the posterior superior temporal sulcus and inferior parietal lobule and inhibitory, top-down connections from the posterior medial frontal cortex to the secondary visual cortex. Group differences in top-down modulation from the posterior medial frontal cortex to the posterior superior temporal sulcus and inferior parietal lobule were noted, such that these inhibitory connections were attenuated in the healthy control group but further strengthened in the SZ group. Connectivity was associated with social dysfunction and symptom severity. CONCLUSIONS: The SZ group showed notably stronger top-down inhibition during explicit gaze discrimination, which was associated with more social dysfunction but less severe symptoms among patients. These findings help pinpoint neural mechanisms of aberrant gaze processing and may serve as future targets for interventions that combine neuromodulation with social cognitive training.

Learning without contingencies: A loss of synergy between memory and reward circuits in schizophrenia.

Motivational deficits in schizophrenia may interact with foundational cognitive processes including learning and memory to induce impaired cognitive proficiency. If such a loss of synergy exists, it is likely to be underpinned by a loss of synchrony between the brains learning and reward sub-networks. Moreover, this loss should be observed even during tasks devoid of explicit reward contingencies given that such tasks are better models of real world performance than those with artificial contingencies. Here we applied undirected functional connectivity (uFC) analyses to fMRI data acquired while participants engaged in an associative learning task without contingencies or feedback. uFC was estimated and inter-group differences (between schizophrenia patients and controls, n = 54 total, n = 28 patients) were assessed within and between reward (VTA and NAcc) and learning/memory (Basal Ganglia, DPFC, Hippocampus, Parahippocampus, Occipital Lobe) sub-networks. The task paradigm itself alternated between Encoding, Consolidation, and Retrieval conditions, and uFC differences were quantified for each of the conditions. Significantly reduced uFC dominated the connectivity profiles of patients across all conditions. More pertinent to our motivations, these reductions were observed within and across classes of sub-networks (reward-related and learning/memory related). We suggest that disrupted functional connectivity between reward and learning sub-networks may drive many of the performance deficits that characterize schizophrenia. Thus, cognitive deficits in schizophrenia may in fact be underpinned by a loss of synergy between reward-sensitivity and cognitive processes.

Depth and hierarchies in the predictive brain: From reaction to action.

The human brain is a prediction device, a view widely accepted in neuroscience. Prediction is a rational and efficient response that relies on the brain's ability to create and employ generative models to optimize actions over unpredictable time horizons. We argue that extant predictive frameworks while compelling, have not explicitly accounted for the following: (a) The brain's generative models must incorporate predictive depth (i.e., rely on degrees of abstraction to enable predictions over different time horizons); (b) The brain's implementation scheme to account for varying predictive depth relies on dynamic predictive hierarchies formed using the brain's functional networks. We show that these hierarchies incorporate the ascending processes (driven by reaction), and the descending processes (related to prediction), eventually driving action. Because they are dynamically formed, predictive hierarchies allow the brain to address predictive challenges in virtually any domain. By way of application, we explain how this framework can be applied to heretofore poorly understood processes of human behavioral thermoregulation. Although mammalian thermoregulation has been closely tied to deep brain structures engaged in autonomic control such as the hypothalamus, this narrow conception does not translate well to humans. In addition to profound differences in evolutionary history, the human brain is bestowed with substantially increased functional complexity (that itself emerged from evolutionary differences). We argue that behavioral thermoregulation in humans is possible because, (a) ascending signals shaped by homeostatic sub-networks, interject with (b) descending signals related to prediction (implemented in interoceptive and executive sub-networks) and action (implemented in executive sub-networks). These sub-networks cumulatively form a predictive hierarchy for human thermoregulation, potentiating a range of viable responses to known and unknown thermoregulatory challenges. We suggest that our proposed extensions to the predictive framework provide a set of generalizable principles that can further illuminate the many facets of the predictive brain. This article is categorized under: Neuroscience > Behavior Philosophy > Action Psychology > Prediction.

The topology, stability, and instability of learning-induced brain network repertoires in schizophrenia.

There is a paucity of graph theoretic methods applied to task-based data in schizophrenia (SCZ). Tasks are useful for modulating brain network dynamics, and topology. Understanding how changes in task conditions impact inter-group differences in topology can elucidate unstable network characteristics in SCZ. Here, in a group of patients and healthy controls (n = 59 total, 32 SCZ), we used an associative learning task with four distinct conditions (Memory Formation, Post-Encoding Consolidation, Memory Retrieval, and Post-Retrieval Consolidation) to induce network dynamics. From the acquired fMRI time series data, betweenness centrality (BC), a metric of a node's integrative value was used to summarize network topology in each condition. Patients showed (a) differences in BC across multiple nodes and conditions; (b) decreased BC in more integrative nodes, but increased BC in less integrative nodes; (c) discordant node ranks in each of the conditions; and (d) complex patterns of stability and instability of node ranks across conditions. These analyses reveal that task conditions induce highly variegated patterns of network dys-organization in SCZ. We suggest that the dys-connection syndrome that is schizophrenia, is a contextually evoked process, and that the tools of network neuroscience should be oriented toward elucidating the limits of this dys-connection.

Neurobehavioral indices of gaze perception are associated with social cognition across schizophrenia patients and healthy controls.

BACKGROUND: Gaze perception is a basic building block of social cognition, which is impaired in schizophrenia (SZ) and contributes to functional outcomes. Few studies, however, have investigated neural underpinnings of gaze perception and their relation to social cognition. We address this gap. METHOD: We recruited 77 SZ patients and 71 healthy controls, who completed various social-cognition tasks. During functional magnetic resonance imaging, participants (62 SZ, 54 controls) completed a gaze-perception task, where they judged whether faces with varying gaze angles were self-directed or averted; as a control condition, participants identified stimulus gender. Activation estimates were extracted based on (a) task versus baseline, (b) gaze-perception versus gender-identification, (c) parametric modulation by perception of stimuli as self-directed versus averted, and (d) parametric modulation by stimulus gaze angle. We used latent variable analysis to test associations among diagnostic group, brain activation, gaze perception, and social cognition. RESULTS: Preferential activation to gaze perception was observed throughout dorsomedial prefrontal cortex, superior temporal sulcus, and insula. Activation was modulated by stimulus gaze angle and perception of stimuli as self-directed versus averted. More precise gaze perception and higher task-related activation were associated with better social cognition. Patients with SZ showed hyperactivation within left pre-/postcentral gyrus, which was associated with more precise gaze perception and fewer symptoms and thus may be a compensatory mechanism. CONCLUSIONS: Neural and behavioral indices of gaze perception were related to social cognition, across patients and controls. This suggests gaze perception is an important perceptual building block for more complex social cognition. Results are discussed in the context of dimensional psychopathology and clinical heterogeneity. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Regularities in vertical saccadic metrics: new insights, and future perspectives.

Introduction: Asymmetries in processing by the healthy brain demonstrate regularities that facilitate the modeling of brain operations. The goal of the present study was to determine asymmetries in saccadic metrics during visual exploration, devoid of confounding clutter in the visual field. Methods: Twenty healthy adults searched for a small, low-contrast gaze-contingent target on a blank computer screen. The target was visible, only if eye fixation was within a 5 deg. by 5 deg. area of the target's location. Results: Replicating previously-reported asymmetries, repeated measures contrast analyses indicated that up-directed saccades were executed earlier, were smaller in amplitude, and had greater probability than down-directed saccades. Given that saccade velocities are confounded by saccade amplitudes, it was also useful to investigate saccade kinematics of visual exploration, as a function of vertical saccade direction. Saccade kinematics were modeled for each participant, as a square root relationship between average saccade velocity (i.e., average velocity between launching and landing of a saccade) and corresponding saccade amplitude (Velocity = S*[Saccade Amplitude]0.5). A comparison of the vertical scaling parameter (S) for up- and down-directed saccades showed that up-directed saccades tended to be slower than down-directed ones. Discussion: To motivate future research, an ecological theory of asymmetric pre-saccadic inhibition was presented to explain the collection of vertical saccadic regularities. For example, given that the theory proposes strong inhibition for the releasing of reflexive down-directed prosaccades (cued by an attracting peripheral target below eye fixation), and weak inhibition for the releasing of up-directed prosaccades (cued by an attracting peripheral target above eye fixation), a prediction for future studies is longer reaction times for vertical anti-saccade cues above eye fixation. Finally, the present study with healthy individuals demonstrates a rationale for further study of vertical saccades in psychiatric disorders, as bio-markers for brain pathology.

Basal glutamate in the hippocampus and the dorsolateral prefrontal cortex in schizophrenia: Relationships to cognitive proficiency investigated with structural equation modelling.

OBJECTIVES: Schizophrenia is characterised by deficits across multiple cognitive domains and altered glutamate related neuroplasticity. The purpose was to investigate whether glutamate deficits are related to cognition in schizophrenia, and whether glutamate-cognition relationships are different between schizophrenia and controls. METHODS: Magnetic resonance spectroscopy (MRS) at 3 Tesla was acquired from the dorsolateral prefrontal cortex (dlPFC) and hippocampus in 44 schizophrenia participants and 39 controls during passive viewing visual task. Cognitive performance (working memory, episodic memory, and processing speed) was assessed on a separate session. Group differences in neurochemistry and mediation/moderation effects using structural equation modelling (SEM) were investigated. RESULTS: Schizophrenia participants showed lower hippocampal glutamate (p = .0044) and myo-Inositol (p = .023) levels, and non-significant dlPFC levels. Schizophrenia participants also demonstrated poorer cognitive performance (p < .0032). SEM-analyses demonstrated no mediation or moderation effects, however, an opposing dlPFC glutamate-processing speed association between groups was observed. CONCLUSIONS: Hippocampal glutamate deficits in schizophrenia participants are consistent with evidence of reduced neuropil density. Moreover, SEM analyses indicated that hippocampal glutamate deficits in schizophrenia participants as measured during a passive state were not driven by poorer cognitive ability. We suggest that functional MRS may provide a better framework for investigating glutamate-cognition relationships in schizophrenia.

Are Brain Responses to Emotion a Reliable Endophenotype of Schizophrenia? An Image-Based Functional Magnetic Resonance Imaging Meta-analysis.

BACKGROUND: Impaired emotion processing constitutes a key dimension of schizophrenia and a possible endophenotype of this illness. Empirical studies consistently report poorer emotion recognition performance in patients with schizophrenia as well as in individuals at enhanced risk of schizophrenia. Functional magnetic resonance imaging studies also report consistent patterns of abnormal brain activation in response to emotional stimuli in patients, in particular, decreased amygdala activation. In contrast, brain-level abnormalities in at-risk individuals are more elusive. We address this gap using an image-based meta-analysis of the functional magnetic resonance imaging literature. METHODS: Functional magnetic resonance imaging studies investigating brain responses to negative emotional stimuli and reporting a comparison between at-risk individuals and healthy control subjects were identified. Frequentist and Bayesian voxelwise meta-analyses were performed separately, by implementing a random-effect model with unthresholded group-level T-maps from individual studies as input. RESULTS: In total, 17 studies with a cumulative total of 677 at-risk individuals and 805 healthy control subjects were included. Frequentist analyses did not reveal significant differences between at-risk individuals and healthy control subjects. Similar results were observed with Bayesian analyses, which provided strong evidence for the absence of meaningful brain activation differences across the entire brain. Region of interest analyses specifically focusing on the amygdala confirmed the lack of group differences in this region. CONCLUSIONS: These results suggest that brain activation patterns in response to emotional stimuli are unlikely to constitute a reliable endophenotype of schizophrenia. We suggest that future studies instead focus on impaired functional connectivity as an alternative and promising endophenotype.

Magnocellular and parvocellular contributions to brain network dysfunction during learning and memory: Implications for schizophrenia.

Memory deficits are core features of schizophrenia, and a central aim in biological psychiatry is to identify the etiology of these deficits. Scrutiny is naturally focused on the dorsolateral prefrontal cortex and the hippocampal cortices, given these structures' roles in memory and learning. The fronto-hippocampal framework is valuable but restrictive. Network-based underpinnings of learning and memory are substantially diverse and include interactions between hetero-modal and early sensory networks. Thus, a loss of fidelity in sensory information may impact memorial and cognitive processing in higher-order brain sub-networks, becoming a sensory source for learning and memory deficits. In this overview, we suggest that impairments in magno- and parvo-cellular visual pathways result in degraded inputs to core learning and memory networks. The ascending cascade of aberrant neural events significantly contributes to learning and memory deficits in schizophrenia. We outline the network bases of these effects, and suggest that any network perspectives of dysfunction in schizophrenia must assess the impact of impaired perceptual contributions. Finally, we speculate on how this framework enriches the space of biomarkers and expands intervention strategies to ameliorate this prototypical disconnection syndrome.

Inefficient white matter activity in Schizophrenia evoked during intra and inter-hemispheric communication.

Intensive cognitive tasks induce inefficient regional and network responses in schizophrenia (SCZ). fMRI-based studies have naturally focused on gray matter, but appropriately titrated visuo-motor integration tasks reliably activate inter- and intra-hemispheric white matter pathways. Such tasks can assess network inefficiency without demanding intensive cognitive effort. Here, we provide the first application of this framework to the study of white matter functional responses in SCZ. Event-related fMRI data were acquired from 28 patients (nine females, mean age 43.3, ±11.7) and 28 age- and gender-comparable controls (nine females, mean age 42.1 ± 10.1), using the Poffenberger paradigm, a rapid visual detection task used to induce intra- (ipsi-lateral visual and motor cortex) or inter-hemispheric (contra-lateral visual and motor cortex) transfer. fMRI data were pre- and post-processed to reliably isolate activations in white matter, using probabilistic tractography-based white matter tracts. For intra- and inter-hemispheric transfer conditions, SCZ evinced hyper-activations in longitudinal and transverse white matter tracts, with hyper-activation in sub-regions of the corpus callosum primarily observed during inter-hemispheric transfer. Evidence for the functional inefficiency of white matter was observed in conjunction with small (~50 ms) but significant increases in response times. Functional inefficiencies in SCZ are (1) observable in white matter, with the degree of inefficiency contextually related to task-conditions, and (2) are evoked by simple detection tasks without intense cognitive processing. These cumulative results while expanding our understanding of this dys-connection syndrome, also extend the search of biomarkers beyond the traditional realm of fMRI studies of gray matter.

Sustained attention induces altered effective connectivity of the ascending thalamo-cortical relay in obsessive-compulsive disorder.

Abnormal function of the thalamo-cortical relay is considered a hallmark of obsessive-compulsive disorder (OCD) and aberrant network interactions may underpin many of the clinical and cognitive symptoms that characterize the disorder. Several statistical approaches have been applied to in vivo fMRI data to support the general loss of thalamo-cortical connectivity in OCD. However, (a) few studies have assessed the contextual constraints under which abnormal network interactions arise or (b) have used methods of effective connectivity to understand abnormal network interactions. Effective connectivity is a particularly valuable method as it describes the putative causal influences that brain regions exert over each other, as opposed to the largely statistical consistencies captured in functional connectivity techniques. Here, using dynamic causal modeling (DCM), we evaluated how attention demand induced inter-group differences (HC ≠ OCD) in effective connectivity within a motivated thalamo-cortical network. Of interest was whether these effects were observed on the ascending thalamo-cortical relay, essential for the sensory innervation of the cortex. fMRI time series data from sixty-two participants (OCD, 30; HC, 32) collected using an established sustained attention task were submitted to a space of 162 competing models. Across the space, models distinguished between competing hypotheses of thalamo-cortical interactions. Bayesian model selection (BMS) identified marginally differing likely generative model architectures in OCD and HC groups. Bayesian model averaging (BMA), was used to weight connectivity parameter estimates across all models, with each parameter weighted by each model's posterior probability, thus providing more stable estimates of effective connectivity. Inferential statistical analyses of estimated parameters revealed two principal results: (1) Significantly reduced intrinsic connectivity of the V1 → SPC pathway in OCD, suggested connective weakness in the early constituents of the dorsal visual pathway; (2) More pertinent with the discovery possibilities afforded by DCM, sustained attention in OCD patients induced significantly reduced contextual modulation of the ascending relay from the thalamus to the prefrontal cortex. These results form an important complement to our understanding of the contextual bases of thalamo-cortical network deficits in OCD, emphasizing vulnerability of the ascending relay.

Effective connectivity of brain networks controlling human thermoregulation.

Homeostatic centers in the mammalian brainstem are critical in responding to thermal challenges. These centers play a prominent role in human thermoregulation, but humans also respond to thermal challenges through behavior modification. Behavioral modifications are presumably sub served by interactions between the brainstem and interoceptive, cognitive and affective elements in human brain networks. Prior evidence suggests that interoceptive regions such as the insula, and cognitive/affective regions such as the orbitofrontal cortex and anterior cingulate cortex are crucial. Here we used dynamic causal modeling (DCM) to discover likely generative network architectures and estimate changes in the effective connectivity between nodes in a hierarchically organized thermoregulatory network (homeostatic-interoceptive-cognitive/affective). fMRI data were acquired while participants (N = 20) were subjected to a controlled whole body thermal challenge that alternatingly evoked sympathetic and parasympathetic responses. Using a competitive modeling framework (ten competing modeling architectures), we demonstrated that sympathetic responses (evoked by whole-body cooling) resulted in more complex network interactions along two ascending pathways: (i) homeostatic interoceptive and (ii) homeostatic cognitive/affective. Analyses of estimated connectivity coefficients demonstrated that sympathetic responses evoked greater network connectivity in key pathways compared to parasympathetic responses. These results reveal putative mechanisms by which human thermoregulatory networks evince a high degree of contextual sensitivity to thermoregulatory challenges. The patterns of the discovered interactions also reveal how information propagation from homeostatic regions to both interoceptive and cognitive/affective regions sub serves the behavioral repertoire that is an important aspect of thermoregulatory defense in humans.

From mathematics to medicine: A practical primer on topological data analysis (TDA) and the development of related analytic tools for the functional discovery of latent structure in fMRI data.

fMRI is the preeminent method for collecting signals from the human brain in vivo, for using these signals in the service of functional discovery, and relating these discoveries to anatomical structure. Numerous computational and mathematical techniques have been deployed to extract information from the fMRI signal. Yet, the application of Topological Data Analyses (TDA) remain limited to certain sub-areas such as connectomics (that is, with summarized versions of fMRI data). While connectomics is a natural and important area of application of TDA, applications of TDA in the service of extracting structure from the (non-summarized) fMRI data itself are heretofore nonexistent. "Structure" within fMRI data is determined by dynamic fluctuations in spatially distributed signals over time, and TDA is well positioned to help researchers better characterize mass dynamics of the signal by rigorously capturing shape within it. To accurately motivate this idea, we a) survey an established method in TDA ("persistent homology") to reveal and describe how complex structures can be extracted from data sets generally, and b) describe how persistent homology can be applied specifically to fMRI data. We provide explanations for some of the mathematical underpinnings of TDA (with expository figures), building ideas in the following sequence: a) fMRI researchers can and should use TDA to extract structure from their data; b) this extraction serves an important role in the endeavor of functional discovery, and c) TDA approaches can complement other established approaches toward fMRI analyses (for which we provide examples). We also provide detailed applications of TDA to fMRI data collected using established paradigms, and offer our software pipeline for readers interested in emulating our methods. This working overview is both an inter-disciplinary synthesis of ideas (to draw researchers in TDA and fMRI toward each other) and a detailed description of methods that can motivate collaborative research.

Ocular measures during associative learning predict recall accuracy.

The ability to form associations between stimuli and commit those associations to memory is a cornerstone of human cognition. Dopamine and noradrenaline are critical neuromodulators implicated in a range of cognitive functions, including learning and memory. Eye blink rate (EBR) and pupil diameter have been shown to index dopaminergic and noradrenergic activity. Here, we examined how these ocular measures relate to accuracy in a paired-associate learning task where participants (N = 73) learned consistent object-location associations over eight trials consisting of pre-trial fixation, encoding, delay, and retrieval epochs. In order to examine how within-subject changes and between-subject changes in ocular metrics related to accuracy, we mean centered individual metric values on each trial based on within-person and across-subject means for each epoch. Within-participant variation in EBR was positively related to accuracy in both encoding and delay epochs: faster EBR within the individual predicted better retrieval. Differences in EBR across participants was negatively related to accuracy in the encoding epoch and in early trials of the pre-trial fixation: faster EBR, relative to other subjects, predicted poorer retrieval. Visual scanning behavior in pre-trial fixation and delay epochs was also positively related to accuracy in early trials: more scanning predicted better retrieval. We found no relationship between pupil diameter and accuracy. These results provide novel evidence supporting the utility of ocular metrics in illuminating cognitive and neurobiological mechanisms of paired-associate learning.

Stimulus valence, episodic memory, and the priming of brain activation profiles in borderline personality disorder.

BACKGROUND: Borderline personality disorder (BPD) is characterized by instability in affective regulation that can result in a loss of cognitive control. Triggers may be neuronal responses to emotionally valenced context and/or stimuli. 'Neuronal priming' indexes the familiarity of stimuli, and may capture the obligatory effects of affective valence on the brain's processing system, and how such valence mediates responses to the repeated presentation of stimuli. We investigated the effects of affective valence of stimuli on neuronal priming (i.e. changes in activation to repeated presentation of stimuli), and if these effects distinguished BPD patients from controls. METHODS: Forty BPD subjects and 25 control subjects (age range: 18-44) participated in an episodic memory task during fMRI. Stimuli were presented in alternating epochs of encoding (six images of positive, negative, and neutral valence) and recognition (six images for 'old' v. 'new' recognition). Analyses focused on inter-group differences in the change in activation to repeated stimuli (presented during Encoding and Recognition). RESULTS: Relative to controls, BPD showed greater priming (generally greater decrease from encoding to recognition) for negatively valenced stimuli. Conversely, BPD showed less priming for positively valenced stimuli (generally greater increase from encoding to recognition). CONCLUSION: Plausibly, the relative familiarity of negative valence to patients with BPD exerts an influence on obligatory responses to repeated stimuli leading to repetition priming of neuronal profiles. The specific effects of valence on memory and/or attention, and consequently on priming can inform the understanding of mechanisms of altered salience for affective stimuli in BPD.

Sexual Regional Dimorphism of Post-Adolescent and Middle Age Brain Maturation. A Multi-center 3T MRI Study.

Sex-related differences are tied into neurodevelopmental and lifespan processes, beginning early in the perinatal and developmental phases and continue into adulthood. The present study was designed to investigate sexual dimorphism of changes in gray matter (GM) volume in post-adolescence, with a focus on early and middle-adulthood using a structural magnetic resonance imaging (MRI) dataset of healthy controls from the European Network on Psychosis, Affective disorders and Cognitive Trajectory (ENPACT). Three hundred and seventy three subjects underwent a 3.0 T MRI session across four European Centers. Age by sex effects on GM volumes were investigated using voxel-based morphometry (VBM) and the Automated Anatomical Labeling atlas regions (ROI). Females and males showed overlapping and non-overlapping patterns of GM volume changes during aging. Overlapping age-related changes emerged in bilateral frontal and temporal cortices, insula and thalamus. Both VBM and ROI analyses revealed non-overlapping changes in multiple regions, including cerebellum and vermis, bilateral mid frontal, mid occipital cortices, left inferior temporal and precentral gyri. These findings highlight the importance of accounting for sex differences in cross-sectional analyses, not only in the study of normative changes, but particularly in the context of psychiatric and neurologic disorders, wherein sex effects may be confounded with disease-related changes.