Excessive interstitial free-water in cortical gray matter preceding accelerated volume changes in individuals at clinical high risk for psychosis.

Recent studies show that accelerated cortical gray matter (GM) volume reduction seen in anatomical MRI can help distinguish between individuals at clinical high risk (CHR) for psychosis who will develop psychosis and those who will not. This reduction is suggested to represent atypical developmental or degenerative changes accompanying an accumulation of microstructural changes, such as decreased spine density and dendritic arborization. Detecting the microstructural sources of these changes before they accumulate into volume loss is crucial. Our study aimed to detect these microstructural GM alterations using diffusion MRI (dMRI). We tested for baseline and longitudinal group differences in anatomical and dMRI data from 160 individuals at CHR and 96 healthy controls (HC) acquired in a single imaging site. Of the CHR individuals, 33 developed psychosis (CHR-P), while 127 did not (CHR-NP). Among all participants, longitudinal data was available for 45 HCs, 17 CHR-P, and 66 CHR-NP. Eight cortical lobes were examined for GM volume and GM microstructure. A novel dMRI measure, interstitial free water (iFW), was used to quantify GM microstructure by eliminating cerebrospinal fluid contribution. Additionally, we assessed whether these measures differentiated the CHR-P from the CHR-NP. In addition, for completeness, we also investigated changes in cortical thickness and in white matter (WM) microstructure. At baseline the CHR group had significantly higher iFW than HC in the prefrontal, temporal, parietal, and occipital lobes, while volume was reduced only in the temporal lobe. Neither iFW nor volume differentiated between the CHR-P and CHR-NP groups at baseline. However, in many brain areas, the CHR-P group demonstrated significantly accelerated changes (iFW increase and volume reduction) with time than the CHR-NP group. Cortical thickness provided similar results as volume, and there were no significant changes in WM microstructure. Our results demonstrate that microstructural GM changes in individuals at CHR have a wider extent than volumetric changes or microstructural WM changes, and they predate the acceleration of brain changes that occur around psychosis onset. Microstructural GM changes, as reflected by the increased iFW, are thus an early pathology at the prodromal stage of psychosis that may be useful for a better mechanistic understanding of psychosis development.

Multimodal 7T imaging reveals enhanced functional coupling between salience and frontoparietal networks in young adult tobacco cigarette smokers.

Tobacco cigarette smoking is associated with disrupted brain network dynamics in resting brain networks including the Salience (SN) and Fronto parietal (FPN). Unified multimodal methods [Resting state connectivity analysis, Diffusion Tensor Imaging (DTI), neurite orientation dispersion and density imaging (NODDI), and cortical thickness analysis] were employed to test the hypothesis that the impact of cigarette smoking on the balance among these networks is due to alterations in white matter connectivity, microstructural architecture, functional connectivity and cortical thickness (CT) and that these metrics define fundamental differences between people who smoke and nonsmokers. Multimodal analyses of previously collected 7 Tesla MRI data via the Human Connectome Project were performed on 22 people who smoke (average number of daily cigarettes was 10 ± 5) and 22 age- and sex-matched nonsmoking controls. First, functional connectivity analysis was used to examine SN-FPN-DMN interactions between people who smoke and nonsmokers. The anatomy of these networks was then assessed using DTI and CT analyses while microstructural architecture of WM was analyzed using the NODDI toolbox. Seed-based connectivity analysis revealed significantly enhanced within network [p = 0.001 FDR corrected] and between network functional coupling of the salience and R-frontoparietal networks in people who smoke [p = 0.004 FDR corrected]. The network connectivity was lateralized to the right hemisphere. Whole brain diffusion analysis revealed no significant differences between people who smoke and nonsmokers in Fractional Anisotropy, Mean diffusivity and in neurite orienting and density. There were also no significant differences in CT in the hubs of these networks. Our results demonstrate that tobacco cigarette smoking is associated with enhanced functional connectivity, but anatomy is largely intact in young adults. Whether this enhanced connectivity is pre-existing, transient or permanent is not known. The observed enhanced connectivity in resting state networks may contribute to the maintenance of smoking frequency.

Targeting the superior temporal gyrus with real-time fMRI neurofeedback: A pilot study of the indirect effects on self-referential processes in schizophrenia.

BACKGROUND: Individuals with schizophrenia (SZ) and auditory hallucinations (AHs) display a distorted sense of self and self-other boundaries. Alterations of activity in midline cortical structures such as the prefrontal cortex (mPFC) and anterior cingulate cortex (ACC) during self-reference as well as in the superior temporal gyrus (STG) have been proposed as neuromarkers of SZ and AHs. METHODS: In this randomized, participant-blinded, sham-controlled trial, 22 adults (18 males) with SZ spectrum disorders (SZ or schizoaffective disorder) and frequent medication-resistant AHs received one session of real-time fMRI neurofeedback (NFB) either from the STG (n = 11; experimental group) or motor cortex (n = 11; control group). During NFB, participants were instructed to upregulate their STG activity by attending to pre-recorded sentences spoken in their own voice and downregulate it by ignoring unfamiliar voices. Before and after NFB, participants completed a self-reference task where they evaluated if trait adjectives referred to themselves (self condition), Abraham Lincoln (other condition), or whether adjectives had a positive valence (semantic condition). FMRI activation analyses of self-reference task data tested between-group changes after NFB (self>semantic, post>pre-NFB, experimental>control). Analyses were pre-masked within a self-reference network. RESULTS: Activation analyses revealed significantly (p < 0.001) greater activation increase in the experimental, compared to the control group, after NFB within anterior regions of the self-reference network (mPFC, ACC, superior frontal cortex). CONCLUSIONS: STG-NFB was associated with activity increase in the mPFC, ACC, and superior frontal cortex during self-reference. Modulating the STG is associated with activation changes in other, not-directly targeted, regions subserving higher-level cognitive processes associated with self-referential processes and AHs psychopathology in SZ. CLINICALTRIALS: GOV: Rt-fMRI Neurofeedback and AH in Schizophrenia; https://clinicaltrials.gov/study/NCT03504579.

Neuroimaging for precision medicine in psychiatry.

Although the lifetime burden due to mental disorders is increasing, we lack tools for more precise diagnosing and treating prevalent and disabling disorders such as major depressive disorder. We lack strategies for selecting among available treatments or expediting access to new treatment options. This critical review concentrates on functional neuroimaging as a modality of measurement for precision psychiatry, focusing on major depressive and anxiety disorders. We begin by outlining evidence for the use of functional neuroimaging to stratify the heterogeneity of these disorders, based on underlying circuit dysfunction. We then review the current landscape of how functional neuroimaging-derived circuit predictors can predict treatment outcomes and clinical trajectories in depression and anxiety. Future directions for advancing clinically appliable neuroimaging measures are considered. We conclude by considering the opportunities and challenges of translating neuroimaging measures into practice. As an illustration, we highlight one approach for quantifying brain circuit function at an individual level, which could serve as a model for clinical translation.

Physical activity-related individual differences in functional human connectome are linked to fluid intelligence in older adults.

The study examined resting state functional connectivity (rs-FC) associated with moderate-to-vigorous physical activity (MV-PA), sedentary time (ST), TV viewing, computer use, and their relationship to cognitive performance in older adults. We used pre-intervention data from 119 participants from the Fit & Active Seniors trial. Multivariate pattern analysis revealed two seeds associated with MV-PA: right superior frontal gyrus (SFG; spanning frontoparietal [FPN] and ventral attention networks [VAN]) and right precentral (PrG) and postcentral gyri (PoG) of the somatosensory network (SN). A positive correlation between the right SFG seed and a cluster spanning default mode (DMN), dorsal attention (DAN), FPN, and visual networks (VIS) was linked to higher fluid intelligence, as was FC between the right PrG/PoG seed and a cluster in VIS. No significant rs-FC patterns associated with ST, TV viewing, or computer use were found. Our findings suggest that greater functional integration within networks implementing top-down control and within those supporting visuospatial abilities, paired with segregation between networks critical and those not critical to top-down control, may help promote cognitive reserve in more physically active seniors.

Connectome predictive modeling of trait mindfulness.

Introduction: Trait mindfulness refers to one's disposition or tendency to pay attention to their experiences in the present moment, in a non-judgmental and accepting way. Trait mindfulness has been robustly associated with positive mental health outcomes, but its neural underpinnings are poorly understood. Prior resting-state fMRI studies have associated trait mindfulness with within- and between-network connectivity of the default-mode (DMN), fronto-parietal (FPN), and salience networks. However, it is unclear how generalizable the findings are, how they relate to different components of trait mindfulness, and how other networks and brain areas may be involved. Methods: To address these gaps, we conducted the largest resting-state fMRI study of trait mindfulness to-date, consisting of a pre-registered connectome predictive modeling analysis in 367 adults across three samples collected at different sites. Results: In the model-training dataset, we did not find connections that predicted overall trait mindfulness, but we identified neural models of two mindfulness subscales, Acting with Awareness and Non-judging. Models included both positive networks (sets of pairwise connections that positively predicted mindfulness with increasing connectivity) and negative networks, which showed the inverse relationship. The Acting with Awareness and Non-judging positive network models showed distinct network representations involving FPN and DMN, respectively. The negative network models, which overlapped significantly across subscales, involved connections across the whole brain with prominent involvement of somatomotor, visual and DMN networks. Only the negative networks generalized to predict subscale scores out-of-sample, and not across both test datasets. Predictions from both models were also negatively correlated with predictions from a well-established mind-wandering connectome model. Conclusions: We present preliminary neural evidence for a generalizable connectivity models of trait mindfulness based on specific affective and cognitive facets. However, the incomplete generalization of the models across all sites and scanners, limited stability of the models, as well as the substantial overlap between the models, underscores the difficulty of finding robust brain markers of mindfulness facets.

Resting-State Functional Connectivity Change in Frontoparietal and Default Mode Networks After Acute Exercise in Youth.

BACKGROUND: A single bout of aerobic exercise can provide acute benefits to cognition and emotion in children. Yet, little is known about how acute exercise may impact children's underlying brain networks' resting-state functional connectivity (rsFC). OBJECTIVE: Using a data-driven multivariate pattern analysis, we investigated the effects of a single dose of exercise on acute rsFC changes in 9-to-13-year-olds. METHODS: On separate days in a crossover design, participants (N = 21) completed 20-mins of acute treadmill walking at 65-75% heart rate maximum (exercise condition) and seated reading (control condition), with pre- and post-fMRI scans. Multivariate pattern analysis was used to investigate rsFC change between conditions. RESULTS: Three clusters in the left lateral prefrontal cortex (lPFC) of the frontoparietal network (FPN) had significantly different rsFC after the exercise condition compared to the control condition. Post-hoc analyses revealed that from before to after acute exercise, activity of these FPN clusters became more correlated with bilateral lPFC and the left basal ganglia. Additionally, the left lPFC became more anti-correlated with the precuneus of the default mode network (DMN). An opposite pattern was observed from before to after seated reading. CONCLUSIONS: The findings suggest that a single dose of exercise increases connectivity within the FPN, FPN integration with subcortical regions involved in movement and cognition, and segregation of FPN and DMN. Such patterns, often associated with healthier cognitive and emotional control, may underlie the transient mental benefits observed following acute exercise in youth.

Cross-sectional analysis reveals COVID-19 pandemic community lockdown was linked to dysregulated cortisol and salivary alpha amylase in children.

The COVID-19 pandemic altered everyday life starting in March 2020. These alterations extended to the lives of children as their normal routines were disrupted by community lockdowns, online learning, limited in-person social contact, increased screen time, and reduced physical activity. Considerable research has investigated the physical health impact of COVID-19 infection, but far fewer studies have investigated the physiological impact of stressful pandemic-related changes to daily life, especially in children. The purpose of this study was to leverage an ongoing clinical trial to investigate physiological consequences associated with chronic stress of pandemic community lockdown on children. As a part of the clinical trial, children provided saliva samples. Saliva samples were analyzed for cortisol and salivary alpha amylase (sAA) content. This secondary cross-sectional analysis included 94 preadolescent children located within the Greater Boston, Massachusetts community. Children participated in the study either before, during, or following the pandemic community lockdown to form three groups for comparison. In response to chronic stress caused by the pandemic community lockdown, participants demonstrated dysregulation of fast-acting catecholamine response of the locus-coeruleus-norepinephrine system and slower-acting glucocorticoid response, resulting in an asymmetrical relationship of hypocortisolism (M = 0.78 ± 0.19 µg/mL, p < 0.001) paired with higher sAA (M = 12.73 ± 4.06 U/mL, p = 0.01). Results suggest that the abrupt COVID-19 disruption to daily life, including the stressful experience of community lockdown, had physiological effects on typically developing children. Further research is required to investigate mental health outcomes of children following the chronic stress of the pandemic community lockdown.

Functional network antagonism and consciousness.

Spontaneous brain activity changes across states of consciousness. A particular consciousness-mediated configuration is the anticorrelations between the default mode network and other brain regions. What this antagonistic organization implies about consciousness to date remains inconclusive. In this Perspective Article, we propose that anticorrelations are the physiological expression of the concept of segregation, namely the brain's capacity to show selectivity in the way areas will be functionally connected. We postulate that this effect is mediated by the process of neural inhibition, by regulating global and local inhibitory activity. While recognizing that this effect can also result from other mechanisms, neural inhibition helps the understanding of how network metastability is affected after disrupting local and global neural balance. In combination with relevant theories of consciousness, we suggest that anticorrelations are a physiological prior that can work as a marker of preserved consciousness. We predict that if the brain is not in a state to host anticorrelations, then most likely the individual does not entertain subjective experience. We believe that this link between anticorrelations and the underlying physiology will help not only to comprehend how consciousness happens, but also conceptualize effective interventions for treating consciousness disorders in which anticorrelations seem particularly affected.

The fMRI resting paradigm can quantify brain function by surpassing communication and sophisticated setups, hence helping to infer consciousness in individuals who are unable to communicate with their environment. A particular consciousness-mediated rsfMRI configuration is that of functional anticorrelations, that is, the antagonistic relationship between a specific set of brain regions. We suggest that anticorrelations are a key physiological prior, without which consciousness cannot be supported, because the brain cannot segregate how regions get connected. We postulate that segregation is possible thanks to neural inhibition, by regulating global and local inhibitory activity. We believe that the link between anticorrelations and the underlying physiology can help not only to comprehend how consciousness happens, but also conceptualize effective interventions for treating its disorders.