Search

Human cytomegalovirus (HCMV) is a neurotropic herpes virus known to cause neuropathology in patients with impaired immunity. Previously, we reported a reduction in the gray matter volume (GMV) of several brain regions in two independent samples of participants who were seropositive for HCMV (HCMV+) compared to matched participants who were seronegative for HCMV (HCMV−). In addition to an independent replication of the GMV findings, this study aimed to examine whether HCMV+ was associated with differences in resting-state functional connectivity (rsfMRI-FC). After balancing on 11 clinical/demographic variables using inverse probability of treatment weighting (IPTW), GMV and rsfMRI-FC were obtained from 99 participants with major depressive disorder (MDD) who were classified into 42 HCMV+ and 57 HCMV− individuals. Relative to the HCMV− group, the HCMV+ group showed a significant reduction of GMV in nine cortical regions. Volume reduction in the right lateral orbitofrontal cortex (standardized beta coefficient (SBC) = −0.32, [95%CI, −0.62 to −0.02]) and the left pars orbitalis (SBC = −0.34, [95%CI, −0.63 to −0.05]) in the HCMV+ group was also observed in the previous study. Regardless of the parcellation method or analytical approach, relative to the HCMV− group, the HCMV+ group showed hypoconnectivity between the hubs of the sensorimotor network (bilateral postcentral gyrus) and the hubs of the salience network (bilateral insula) with effect sizes ranging from SBC = −0.57 to −0.99. These findings support the hypothesis that a positive HCMV serostatus is associated with altered connectivity of regions that are important for stress and affective processing and further supports a possible etiological role of HCMV in depression.

Rumination, repetitively thinking about the causes, consequences, and one's negative affect, has been considered as an important factor of depression. The intrusion of ruminative thoughts is not easily controlled, and it may be useful to visualize one's neural activity related to rumination and to use that information to facilitate one's self‐control. Real‐time fMRI neurofeedback (rtfMRI‐nf) enables one to see and regulate the fMRI signal from their own brain. This proof‐of concept study utilized connectivity‐based rtfMRI‐nf (cnf) to normalize brain functional connectivity (FC) associated with rumination. Healthy participants were instructed to brake or decrease FC between the precuneus and the right temporoparietal junction (rTPJ), associated with high levels of rumination, while engaging in a self‐referential task. The cnf group (n = 14) showed a linear decrease in the precuneus‐rTPJ FC across neurofeedback training (trend [112] = −0.180, 95% confidence interval [CI] −0.330 to −0.031, while the sham group (n = 14) showed a linear increase in the target FC (trend [112] = 0.151, 95% CI 0.017 to 0.299). Although the cnf group showed a greater reduction in state‐rumination compared to the sham group after neurofeedback training (p, Regions of interest (ROI) for the connectivity‐based rtfMRI‐nf and the neurofeedback algorithm. (a) ROIs for the connectivity‐based rtfMRI‐nf. (b) Neurofeedback algorithm and display. Red circles and arrows indicate the precuneus ROI and BOLD activities, and blue circles and arrows indicate the right temporoparietal junction (rTPJ) ROI and BOLD activities. The sidebars on the screen were updated every 2‐s with positive feedback (+1: light blue color) or no feedback (0: blank color).

Hyperscanning—simultaneous brain scanning of two or more individuals—holds great promise in elucidating the neurobiological underpinnings of social cognitive functions. This article focuses on functional magnetic resonance imaging (fMRI) hyperscanning and identifies promising targets for studying the neuroscience of social interaction with fMRI hyperscanning. Specifically, we present applications of fMRI hyperscanning in the study of social interaction along with promising analysis approaches for fMRI hyperscanning, with its high spatial and low temporal resolution. We first review fMRI hyperscanning studies in social neuroscience and evaluate the premise of using this costly neuroimaging paradigm. Many second-person social neuroscience studies are possible without fMRI hyperscanning. However, certain fundamental aspects of social cognition in real-life social interactions, including different roles of interactors, shared intention emerging through interaction and history of interaction, can be addressed only with hyperscanning. We argue that these fundamental aspects have not often been investigated in fMRI hyperscanning studies. We then discuss the implication of the signal coupling found in fMRI hyperscanning and consider analysis approaches that make fair use of it. With fMRI hyperscanning, we can explore not only synchronous brain activations but whole-brain asymmetric activation patterns with a lagged association between interacting individuals.

Introduction Treatment effectiveness for major depressive disorder (MDD) is often affected by client non-adherence, dropout, and non-response. Identification of client characteristics predicting successful treatment completion and/or response (i.e., symptom reduction) may be an important tool to increase intervention effectiveness. It is unclear whether neural attenuations in reward processing associated with MDD predict behavioral treatment outcome. Methods This study aimed to determine whether blunted neural responses to reward at baseline differentiate MDD (n = 60; 41 with comorbid anxiety) and healthy control (HC; n = 40) groups; and predict MDD completion of and response to 7–10 sessions of behavior therapy. Participants completed a monetary incentive delay (MID) task. The N200, P300, contingent negative variation (CNV) event related potentials (ERPs) and behavioral responses (reaction time [RT], correct hits) were quantified and extracted for cross-sectional group analyses. ERPs and behavioral responses demonstrating group differences were then used to predict therapy completion and response within MDD. Results MDD exhibited faster RT and smaller P300 amplitudes than HC across conditions. Within the MDD group, treatment completers (n = 37) exhibited larger P300 amplitudes than non-completers (n = 21). Limitations : This study comprises secondary analyses of EEG data; thus task parameters are not optimized to examine feedback ERPs from the paradigm. We did not examine heterogenous presentations of MDD; however, severity and comorbidity did not influence findings. Conclusions Previous studies suggest that P300 is an index of motivational salience and stimulus resource allocation. In sum, individuals who deploy greater neural resources to task demands are more likely to persevere in behavioral therapy.

Real-time fMRI neurofeedback is an increasingly popular neuroimaging technique that allows an individual to gain control over his/her own brain signals, which can lead to improvements in behavior in healthy participants as well as to improvements of clinical symptoms in patient populations. However, a considerably large ratio of participants undergoing neurofeedback training do not learn to control their own brain signals and, consequently, do not benefit from neurofeedback interventions, which limits clinical efficacy of neurofeedback interventions. As neurofeedback success varies between studies and participants, it is important to identify factors that might influence neurofeedback success. Here, for the first time, we employed a big data machine learning approach to investigate the influence of 20 different design-specific (e.g. activity vs. connectivity feedback), region of interest-specific (e.g. cortical vs. subcortical) and subject-specific factors (e.g. age) on neurofeedback performance and improvement in 608 participants from 28 independent experiments. With a classification accuracy of 60% (considerably different from chance level), we identified two factors that significantly influenced neurofeedback performance: Both the inclusion of a pre-training no-feedback run before neurofeedback training and neurofeedback training of patients as compared to healthy participants were associated with better neurofeedback performance. The positive effect of pre-training no-feedback runs on neurofeedback performance might be due to the familiarization of participants with the neurofeedback setup and the mental imagery task before neurofeedback training runs. Better performance of patients as compared to healthy participants might be driven by higher motivation of patients, higher ranges for the regulation of dysfunctional brain signals, or a more extensive piloting of clinical experimental paradigms. Due to the large heterogeneity of our dataset, these findings likely generalize across neurofeedback studies, thus providing guidance for designing more efficient neurofeedback studies specifically for improving clinical neurofeedback-based interventions. To facilitate the development of data-driven recommendations for specific design details and subpopulations the field would benefit from stronger engagement in open science research practices and data sharing. publishedVersion

The parent-adolescent relationship is important for adolescents' emotion regulation (ER), yet little is known regarding the neural patterns of dyadic ER that occur during parent-adolescent interactions. A novel measure that can be used to examine such patterns is cross-brain connectivity (CBC)-concurrent and time-lagged connectivity between two individuals' brain regions. This study sought to provide evidence of CBC and explore associations between CBC, parenting, and adolescent internalizing symptoms. Thirty-five adolescents (mean age = 15 years, 69% female, 72% Non-Hispanic White, 17% Black, 11% Hispanic or Latino) and one biological parent (94% female) completed an fMRI hyperscanning conflict discussion task. Results revealed CBC between emotion-related brain regions. Exploratory analyses indicated CBC is associated with parenting and adolescent depressive symptoms.

The ventromedial prefrontal cortex (vmPFC) is involved in regulation of negative emotion and decision‐making, emotional and behavioral control, and active resilient coping. This pilot study examined the feasibility of training healthy subjects (n = 27) to self‐regulate the vmPFC activity using a real‐time functional magnetic resonance imaging neurofeedback (rtfMRI‐nf). Participants in the experimental group (EG, n = 18) were provided with an ongoing vmPFC hemodynamic activity (rtfMRI‐nf signal represented as variable‐height bar). Individuals were instructed to raise the bar by self‐relevant value‐based thinking. Participants in the control group (CG, n = 9) performed the same task; however, they were provided with computer‐generated sham neurofeedback signal. Results demonstrate that (a) both the CG and the EG show a higher vmPFC fMRI signal at the baseline than during neurofeedback training; (b) no significant positive training effect was seen in the vmPFC across neurofeedback runs; however, the medial prefrontal cortex, middle temporal gyri, inferior frontal gyri, and precuneus showed significant decreasing trends across the training runs only for the EG; (c) the vmPFC rtfMRI‐nf signal associated with the fMRI signal across the default mode network (DMN). These findings suggest that it may be difficult to modulate a single DMN region without affecting other DMN regions. Observed decreased vmPFC activity during the neurofeedback task could be due to interference from the fMRI signal within other DMN network regions, as well as interaction with task‐positive networks. Even though participants in the EG did not show significant positive increase in the vmPFC activity among neurofeedback runs, they were able to learn to accommodate the demand of self‐regulation task to maintain the vmPFC activity with the help of a neurofeedback signal.

Floatation‐Reduced Environmental Stimulation Therapy (REST) is a procedure that reduces stimulation of the human nervous system by minimizing sensory signals from visual, auditory, olfactory, gustatory, thermal, tactile, vestibular, gravitational, and proprioceptive channels, in addition to minimizing musculoskeletal movement and speech. Initial research has found that Floatation‐REST can elicit short‐term reductions in anxiety, depression, and pain, yet little is known about the brain networks impacted by the intervention. This study represents the first functional neuroimaging investigation of Floatation‐REST, and we utilized a data‐driven exploratory analysis to determine whether the intervention leads to altered patterns of resting‐state functional connectivity (rsFC). Healthy participants underwent functional magnetic resonance imaging (fMRI) before and after 90 min of Floatation‐REST or a control condition that entailed resting supine in a zero‐gravity chair for an equivalent amount of time. Multivariate Distance Matrix Regression (MDMR), a statistically‐stringent whole‐brain searchlight approach, guided subsequent seed‐based connectivity analyses of the resting‐state fMRI data. MDMR identified peak clusters of rsFC change between the pre‐ and post‐float fMRI, revealing significant decreases in rsFC both within and between posterior hubs of the default‐mode network (DMN) and a large swath of cortical tissue encompassing the primary and secondary somatomotor cortices extending into the posterior insula. The control condition, an active form of REST, showed a similar pattern of reduced rsFC. Thus, reduced stimulation of the nervous system appears to be reflected by reduced rsFC within the brain networks most responsible for creating and mapping our sense of self., This study represents the first functional neuroimaging investigation of Floatation‐Reduced Environmental Stimulation Therapy (REST), an intervention that minimizes stimulation of the human nervous system. Utilizing a data‐driven exploratory analysis and an active control condition, this study found that Floatation‐REST elicited a consistent pattern of decreased resting‐state functional connectivity within and between posterior hubs of the default‐mode network and a large swath of cortical tissue centered around the somatosensory cortices.

Interactions between the prefrontal cortex and the amygdala during emotion regulation make it possible to link blood oxygenation-level-dependent (BOLD) activity of the amygdala and EEG activity measured over the cortex. Real-time fMRI neurofeedback (rtfMRI-nf) with simultaneous EEG is a promising neuromodulation approach that allows volitional regulation of the amygdala BOLD activity and investigation of related electrophysiological processes. In this chapter, we review relevant concepts and neuroimaging findings regarding emotion regulation and motivation in depression. We summarize results of our recent study that investigated connections between BOLD activity of the amygdala and frontal EEG during rtfMRI-nf training of emotion self-regulation in patients with major depressive disorder. The study revealed both temporal and mean-value correlations between the amygdala BOLD activity and variations in frontal alpha EEG asymmetry (FAA). It also demonstrated significant associations between mean FAA changes and depression severity. We discuss implications of these results for understanding emotion regulation mechanisms in depression.

Parents’ emotion socialization (ES) practices impact socioemotional development throughout adolescence. Little is known, however, regarding the neurobiology underlying these effects. This study used functional magnetic resonance imaging (fMRI) to examine how parent ES practices relate to adolescent brain function during emotion processing. Thirty-three adolescents (ages 14–16) reported on ES practices of a focal parent (primarily mothers) using the Emotions as a Child (EAC) Scale. Adolescents also completed a conflict discussion task with this parent, and parents’ statements were coded for emotional valence. Adolescents performed two fMRI tasks: a standard emotion processing (EP) task (n = 32) and the Testing Emotional Attunement and Mutuality (TEAM) task (n = 27). The EP task consisted of viewing emotional pictures and either reacting naturally or using cognitive reappraisal to regulate emotional responses. The TEAM task was performed with the parent and included trials during which adolescents were shown that their parent made an error, costing the dyad $5. Parent negative verbalizations during the conflict discussion were associated with greater activity in the thalamus during the emotion reactivity condition of the EP task and in the thalamus, superior medial and superior frontal gyri, anterior insula, and dorsolateral prefrontal cortex during the costly error condition of the TEAM task. Unsupportive ES was associated with greater activity in the supplementary motor area and less activity in the paracentral gyrus and amygdala during the costly error condition of the TEAM task. This study supports the premise that ES influences adolescents’ emotion-related neural processing, particularly when using ecologically valid tasks in social contexts.

Real-time fMRI neurofeedback is an increasingly popular neuroimaging technique that allows an individual to gain control over his/her own brain signals, which can lead to improvements in behavior in healthy participants as well as to improvements of clinical symptoms in patient populations. However, a considerably large ratio of participants undergoing neurofeedback training do not learn to control their own brain signals and, consequently, do not benefit from neurofeedback interventions, which limits clinical efficacy of neurofeedback interventions. As neurofeedback success varies between studies and participants, it is important to identify factors that might influence neurofeedback success. Here, for the first time, we employed a big data machine learning approach to investigate the influence of 20 different design-specific (e.g. activity vs. connectivity feedback), region of interest-specific (e.g. cortical vs. subcortical) and subject-specific factors (e.g. age) on neurofeedback performance and improvement in 608 participants from 28 independent experiments.With a classification accuracy of 60% (considerably different from chance level), we identified two factors that significantly influenced neurofeedback performance: Both the inclusion of a pre-training no-feedback run before neurofeedback training and neurofeedback training of patients as compared to healthy participants were associated with better neurofeedback performance. The positive effect of pre-training no-feedback runs on neurofeedback performance might be due to the familiarization of participants with the neurofeedback setup and the mental imagery task before neurofeedback training runs. Better performance of patients as compared to healthy participants might be driven by higher motivation of patients, higher ranges for the regulation of dysfunctional brain signals, or a more extensive piloting of clinical experimental paradigms. Due to the large heterogeneity of our dataset, these findings likely generalize across neurofeedback studies, thus providing guidance for designing more efficient neurofeedback studies specifically for improving clinical neurofeedback-based interventions. To facilitate the development of data-driven recommendations for specific design details and subpopulations the field would benefit from stronger engagement in Open Science and data sharing.

Electroencephalography microstates (EEG-ms) capture and reflect the spatio-temporal neural dynamics of the brain. A growing literature is employing EEG-ms-based analyses to study various mental illnesses and to evaluate brain mechanisms implicated in cognitive and emotional processing. The spatial and functional interpretation of the EEG-ms is still being investigated. Previous works studied the association of EEG-ms time courses with blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) signal and suggested an association between EEG-ms and resting-state networks (RSNs). However, the distinctive association between EEG-ms temporal dynamics and brain neuronal activities is still not clear, despite the assumption that EEG-ms are an electrophysiological representation of RSNs activity. Recent works suggest a role for brain spontaneous EEG rhythms in contributing to and modulating canonical EEG-ms topographies and determining their classes (coined A through D) and metrics. This work simultaneously utilized EEG and fMRI to understand the EEG-ms and their properties further. We adopted the canonical EEG-ms analysis to extract three types of regressors for EEG-informed fMRI analyses: EEG-ms direct time courses, temporal activity per microstate, and pairwise temporal transitions among microstates (the latter two coined activity regressors). After convolving EEG-ms regressors with a hemodynamic response function, a generalized linear model whole-brain voxel-wise analysis was conducted to associate EEG-ms regressors with fMRI signals. The direct time course regressors replicated prior findings of the association between the fMRI signal and EEG-ms time courses but to a smaller extent. Notably, EEG-ms activity regressors were mostly anticorrelated with fMRI, including brain regions in the somatomotor, visual, dorsal attention, and ventral attention fMRI networks with no significant overlap for default mode, limbic or frontoparietal networks. A similar pattern emerged in using the transition regressors among microstates but not in self-transitions. The relatively short duration of each EEG-ms and the significant association of EEG-ms activity regressors with fMRI signals suggest that EEG-ms manifests successive transition from one brain functional state to another rather than being associated with specific brain functional state or RSN networks.

Psychological theories of suicide suggest that certain traits may reduce aversion to physical threat and increase the probability of transitioning from suicidal ideation to action. Here, we investigated whether blunted sensitivity to bodily signals is associated with suicidal action by comparing individuals with a history of attempted suicide to a matched psychiatric reference sample without suicide attempts. We examined interoceptive processing across a panel of tasks: breath-hold challenge, cold-pressor challenge, and heartbeat perception during and outside of functional magnetic resonance imaging. Suicide attempters tolerated the breath-hold and cold-pressor challenges for significantly longer and displayed lower heartbeat perception accuracy than non-attempters. These differences were mirrored by reduced activation of the mid/posterior insula during attention to heartbeat sensations. Our findings suggest that suicide attempters exhibit an ‘interoceptive numbing’ characterized by increased tolerance for aversive sensations and decreased awareness of non-aversive sensations. We conclude that blunted interoception may be implicated in suicidal behavior., eLife digest The human brain closely monitors body signals essential for our survival, including our heartbeat, our breathing and even the temperature of our skin. This mostly unconscious process is called interoception. It helps people perceive potential or actual threats and helps them to respond appropriately. For example, a person charged by a wild animal will act instinctively to run, fight or freeze. Unlike most creatures, humans show an ability to counteract these survival instincts, and are capable of intentionally engaging in behaviors that result in physical harm. Recent increases in the rate of suicide have made it more urgent to try to understand what leads to this behavior in humans. Now, DeVille et al. show that people with psychiatric disorders who have survived a suicide attempt have blunted interoception. In four experiments, people with a history of suicide attempts were compared to another group of individuals without a history of suicide attempts. The groups were carefully matched such that there were no significant differences in the demographic and clinical characteristics of the two groups, including in terms of their age, sex, body mass index and psychiatric symptoms. Both groups completed uncomfortable tasks like holding their breath or keeping their hand in icy cold water. The participants also completed two tasks that required them to focus on their own heartbeat, one of which was paired with functional magnetic resonance imaging. Those with a history of suicide attempts held their breath and kept their hand in cold water for longer, and also were less in tune with their heart rate. This “interoceptive numbing” was associated with less activity in part of the brain called the insular cortex. These differences could not be explained by the individuals having a psychiatric disorder or a history of considering suicide, or by them taking psychiatric medications. Instead, the interoceptive numbing was most often seen in individuals who made an attempt on their own life. The experiments identify physical characteristics that may differentiate people who attempt suicide from those who do not. This lays the groundwork for future research aimed at identifying biological indicators of suicide risk. More studies are needed to verify the results. If the results are verified, the next step would be prospective studies to determine whether measuring interoception can help clinicians predict who is at risk of a suicide attempt. If it does, it might give clinicians a new tool to try to prevent suicide by ensuring those at greatest risk receive appropriate care.

Major depressive disorder (MDD) is associated with physiological changes commonly observed with increasing age, such as inflammation and impaired immune function. Age-related impaired adaptive immunity is characterized by the loss of naive T-cells and the reciprocal accumulation of memory T-cells together with the loss of T-cell co-stimulatory molecules. Additionally, the presence and activity of cytomegalovirus (CMV) alters the architecture of the T-cell compartment in a manner consistent with premature aging. Because CMV is also thought to reactivate with psychological stress, this study tested whether MDD influences age-related phenotypes of T-cell populations in the context of CMV infection in young and middle-aged adults. Morning blood samples from volunteers with a DSM-IV diagnosis of MDD (n=98, mean age(SD)=36(10) years, 74.5% female, 57.1% CMV+) and comparison controls (n=98, mean age(SD)=34(10) years, 68.4% female, 51.0% CMV+) were evaluated for CMV IgG antibody status and the distribution of late differentiated (CD27-CD28-) cells within CD4+ and CD8+ T-cell subsets, i.e. naive (CCR7+CD45RA+), effector memory (EM, CCR7-CD45RA-), central memory (CM, CCR7+CD45RA-) and effector memory cells re-expressing CD45RA (EMRA, CCR7-CD45RA+). Mixed linear regression models controlling for age, sex, ethnicity and flow cytometry batch showed that CMV seropositivity was associated with a reduction in naive T-cells, expansion of EMRA T-cells, and a greater percent distribution of CD27-CD28- cells within CD4+ and CD8+ memory T-cell subsets (p's&nbsp

Neurofeedback is going through a renaissance. Advances in brain imaging and computing have renewed efforts to modify brain activity and behaviour using this technique. Here, over 80 neurofeedback researchers present a consensus-derived checklist – CRED-nf – for reporting and experimental design standards in the field., Neurofeedback has begun to attract the attention and scrutiny of the scientific and medical mainstream. Here, neurofeedback researchers present a consensus-derived checklist that aims to improve the reporting and experimental design standards in the field.

The parent-child relationship and family context influence the development of emotion regulation (ER) brain circuitry and related skills in children and adolescents. Although both parents' and children's ER neurocircuitry simultaneously affect how they interact with one another, neuroimaging studies of parent-child relationships typically include only one member of the dyad in brain imaging procedures. The current study examined brain activation related to parenting and ER in parent-adolescent dyads during concurrent fMRI scanning with a novel task - the Testing Emotional Attunement and Mutuality (TEAM) task. The TEAM task includes feedback trials indicating the other dyad member made an error, resulting in a monetary loss for both participants. Results indicate that positive parenting practices as reported by the adolescent were positively correlated with parents' hemodynamic activation of the ventromedial prefrontal cortex, a region related to empathy, during these error trials. Additionally, during feedback conditions both parents and adolescents exhibited fMRI activation in ER-related regions, including the dorsolateral prefrontal cortex, anterior insula, fusiform gyrus, thalamus, caudate, precuneus, and superior parietal lobule. Adolescents had higher left amygdala activation than parents during the feedback condition. These findings demonstrate the utility of dyadic fMRI scanning for investigating relational processes, particularly in the parent-child relationship.

Author(s): Cosgrove, Kelly T; Kerr, Kara L; Aupperle, Robin L; Ratliff, Erin L; DeVille, Danielle C; Silk, Jennifer S; Burrows, Kaiping; Moore, Andrew J; Antonacci, Chase; Misaki, Masaya; Tapert, Susan F; Bodurka, Jerzy; Simmons, W Kyle; Morris, Amanda Sheffield | Abstract: The authors regret that the article was published with the incorrect grant number listed for the funding source. The correct Centers of Biomedical Research Excellence grant number is P20GM109097 (PD: Jennifer Hays-Grudo; funded by the National Institutes of Health). The authors apologize for any inconvenience caused.

Highlights • Introduced connectome-wide approach of neurofeedback target identification. • Identified connectivity related to rumination severity with resting-state data. • Positively correlated precuneus-RTPJ connectivity with rumination severity. • Performed simulation analysis to design the optimal neurofeedback signal. • The two-point method was optimal online connectivity measure robust to motion., Real-time fMRI neurofeedback (rtfMRI-nf) enables noninvasive targeted intervention in brain activation with high spatial specificity. To achieve this promise of rtfMRI-nf, we introduced and demonstrated a data-driven framework to design a rtfMRI-nf intervention through the discovery of precise target location associated with clinical symptoms and neurofeedback signal optimization. Specifically, we identified the functional connectivity locus associated with rumination symptoms, utilizing a connectome-wide search in resting-state fMRI data from a large cohort of mood and anxiety disorder individuals (N = 223) and healthy controls (N = 45). Then, we performed a rtfMRI simulation analysis to optimize the online functional connectivity neurofeedback signal for the identified functional connectivity. The connectome-wide search was performed in the medial prefrontal cortex and the posterior cingulate cortex/precuneus brain regions to identify the precise location of the functional connectivity associated with rumination severity as measured by the ruminative response style (RRS) scale. The analysis found that the functional connectivity between the loci in the precuneus (-6, −54, 48 mm in MNI) and the right temporo-parietal junction (RTPJ; 49, −49, 23 mm) was positively correlated with RRS scores (depressive, p

Neurofeedback training has been shown to influence behavior in healthy participants as well as to alleviate clinical symptoms in neurological, psychosomatic, and psychiatric patient populations. However, many real-time fMRI neurofeedback studies report large interindividual differences in learning success. The factors that cause this vast variability between participants remain unknown and their identification could enhance treatment success. Thus, here we employed a meta-analytic approach including data from 24 different neurofeedback studies with a total of 401 participants, including 140 patients, to determine whether levels of activity in target brain regions during pre-training functional localizer or no-feedback runs (i.e., self-regulation in the absence of neurofeedback) could predict neurofeedback learning success. We observed a slightly positive correlation between pre-training activity levels during a functional localizer run and neurofeedback learning success, but we were not able to identify common brain-based success predictors across our diverse cohort of studies. Therefore, advances need to be made in finding robust models and measures of general neurofeedback learning, and in increasing the current study database to allow for investigating further factors that might influence neurofeedback learning.

Neurofeedback training has been shown to influence behavior in healthy participants as well as to alleviate clinical symptoms in neurological, psychosomatic, and psychiatric patient populations. However, many real‐time fMRI neurofeedback studies report large inter‐individual differences in learning success. The factors that cause this vast variability between participants remain unknown and their identification could enhance treatment success. Thus, here we employed a meta‐analytic approach including data from 24 different neurofeedback studies with a total of 401 participants, including 140 patients, to determine whether levels of activity in target brain regions during pretraining functional localizer or no‐feedback runs (i.e., self‐regulation in the absence of neurofeedback) could predict neurofeedback learning success. We observed a slightly positive correlation between pretraining activity levels during a functional localizer run and neurofeedback learning success, but we were not able to identify common brain‐based success predictors across our diverse cohort of studies. Therefore, advances need to be made in finding robust models and measures of general neurofeedback learning, and in increasing the current study database to allow for investigating further factors that might influence neurofeedback learning., Many real‐time fMRI neurofeedback studies report large inter‐individual differences in learning success, but the factors that cause this vast variability between participants remain unknown. Here, we used a meta‐analytic approach including data from 24 different neurofeedback studies with a total of 401 participants to determine whether levels of activity in target brain regions during pretraining functional localizer or no‐feedback runs could predict neurofeedback learning success. We were not able to identify common brain‐based success predictors across our diverse cohort of studies.

Highlights • Simultaneous real-time fMRI and EEG neurofeedback (rtfMRI-EEG-nf) was used in MDD. • Amygdala fMRI activity and its connectivity with rACC were significantly enhanced. • Frontal alpha and high-beta EEG asymmetries were significantly increased during nf. • MDD patients showed significant mood improvements after the rtfMRI-EEG-nf training. • The rtfMRI-EEG-nf may have potential for treatment of MDD., Simultaneous real-time fMRI and EEG neurofeedback (rtfMRI-EEG-nf) is an emerging neuromodulation approach, that enables simultaneous volitional regulation of both hemodynamic (BOLD fMRI) and electrophysiological (EEG) brain activities. Here we report the first application of rtfMRI-EEG-nf for emotion self-regulation training in patients with major depressive disorder (MDD). In this proof-of-concept study, MDD patients in the experimental group (n = 16) used rtfMRI-EEG-nf during a happy emotion induction task to simultaneously upregulate two fMRI and two EEG activity measures relevant to MDD. The target measures included BOLD activities of the left amygdala (LA) and left rostral anterior cingulate cortex (rACC), and frontal EEG asymmetries in the alpha band (FAA, [7.5–12.5] Hz) and high-beta band (FBA, [21–30] Hz). MDD patients in the control group (n = 8) were provided with sham feedback signals. An advanced procedure for improved real-time EEG-fMRI artifact correction was implemented. The experimental group participants demonstrated significant upregulation of the LA BOLD activity, FAA, and FBA during the rtfMRI-EEG-nf task, as well as significant enhancement in fMRI connectivity between the LA and left rACC. Average individual FAA changes during the rtfMRI-EEG-nf task positively correlated with depression and anhedonia severities, and negatively correlated with after-vs-before changes in depressed mood ratings. Temporal correlations between the FAA and FBA time courses and the LA BOLD activity were significantly enhanced during the rtfMRI-EEG-nf task. The experimental group participants reported significant mood improvements after the training. Our results suggest that the rtfMRI-EEG-nf may have potential for treatment of MDD.

How parents manifest symptoms of anxiety or depression may affect how children learn to modulate their own distress, thereby influencing the children's risk for developing an anxiety or mood disorder. Conversely, children’s mental health symptoms may impact parents' experiences of negative emotions. Therefore, mental health symptoms can have bidirectional effects in parent-child relationships, particularly during moments of distress or frustration (e.g., when a parent or child makes a costly mistake). The present study used simultaneous functional magnetic resonance imaging (fMRI) of parent-adolescent dyads to examine how brain activity when responding to each other's costly errors (i.e., dyadic error processing) may be associated with symptoms of anxiety and depression. While undergoing simultaneous fMRI scans, healthy dyads completed a task involving feigned errors that indicated their family member made a costly mistake. Inter-brain, random-effects multivariate modeling revealed that parents who exhibited decreased medial prefrontal cortex and posterior cingulate cortex activation when viewing their child's costly error response had children with more symptoms of depression and anxiety. Adolescents with increased anterior insula activation when viewing a costly error made by their parent had more anxious parents. These results reveal cross-brain associations between mental health symptomatology and brain activity during parent-child dyadic error processing. Keywords: fMRI, Parent-child interactions, Error processing, Adolescence, Anxiety, Depression

Background Theoretical models assert that the brain's interoceptive network links external stimuli with their interoceptive consequences, thereby supporting later recall of these associations to guide the selection of healthy behaviors. If these accounts are correct, previously reported interoceptive abnormalities in major depressive disorder (MDD) should lead to altered recall of associations between external stimuli and their interoceptive (somatic) consequences. To date, the processes underlying interoceptive recall have never been experimentally investigated. Methods We designed and implemented the Interoceptive Encoding and Recall (IER) task to compare interoceptive and exteroceptive recall among MDD (n=24) and healthy comparison subjects (n=21). During the encoding phase, subjects learned to pair neutral visual cues (geometric shapes) with aversive interoceptive and exteroceptive stimuli. Later, while undergoing fMRI, subjects were prompted to recall the stimulus associated with each shape. Results Interoceptive recall, relative to exteroceptive recall, was associated with bilateral mid-to-posterior insula activation. Relative to the healthy controls, depressed participants exhibited marked hypo-activation of the right dorsal mid-insula during interoceptive recall. Conclusions In non-depressed subjects, simply recalling a stimulus associated with a previous interoceptive challenge activated a key region in the brain's interoceptive network. Although previous research has linked MDD with aberrant processing of interoceptive stimuli, the current study is the first to demonstrate that individuals with MDD exhibit decreased insula activity while recalling interoceptive memories . It is possible that insula hypo-activation during interoceptive recall may affect the representation of prior interoceptive experiences in ways that contribute to depressive symptomology and the relationship between depression and systemic health.

Advances in imaging technologies have allowed for the analysis of functional magnetic resonance imaging data in real-time (rtfMRI), leading to the development of neurofeedback (nf) training. This rtfMRI-nf training utilizes functional magnetic resonance imaging (fMRI) tomographic localization capacity to allow a person to see and regulate the localized hemodynamic signal from his or her own brain. In this review, we summarize the results of several studies that have developed and applied neurofeedback training to healthy and depressed individuals with the amygdala as the neurofeedback target and the goal to increase the hemodynamic response during positive autobiographical memory recall. We review these studies and highlight some of the challenges and advances in developing an rtfMRI-nf paradigm for broader use in psychiatric populations. The work described focuses on our line of research aiming to develop the rtfMRI-nf into an intervention, and includes a discussion of the selection of a region of interest for feedback, selecting a control condition, behavioral and cognitive effects of training, and predicting which participants are most likely to respond well to training. While the results of these studies are encouraging and suggest the clinical potential of amygdala rtfMRI-nf in alleviating symptoms of major depressive disorder, larger studies are warranted to confirm its efficacy.

Self-regulation of brain activation using real-time functional magnetic resonance imaging neurofeedback (rtfMRI-nf) is an emerging approach for treating mood and anxiety disorders. The effect of neurofeedback training on resting-state functional connectivity warrants investigation as changes in spontaneous brain activation could reflect the association between sustained symptom relief and brain alteration. We investigated the effect of amygdala-focused rtfMRI-nf training on resting-state functional connectivity in combat veterans with and without posttraumatic stress disorder (PTSD) who were trained to increase a feedback signal reflecting left amygdala activity while recalling positive autobiographical memories (Zotev et al., 2018). The analysis was performed in three stages: i) first, we investigated the connectivity in the left amygdala region; ii) next, we focused on the abnormal resting-state functional connectivity identified in our previous analysis of this data (Misaki et al., 2018); and iii) finally, we performed a novel data-driven longitudinal connectome-wide analysis. We introduced a longitudinal multivariate distance matrix regression (MDMR) analysis to comprehensively examine neurofeedback training effects beyond those associated with abnormal baseline connectivity. These comprehensive exploratory analyses suggested that abnormal resting-state connectivity for combat veterans with PTSD was partly normalized after the training. This included hypoconnectivities between the left amygdala and the left ventrolateral prefrontal cortex (vlPFC) and between the supplementary motor area (SMA) and the dorsal anterior cingulate cortex (dACC). The increase of SMA-dACC connectivity was associated with PTSD symptom reduction. Longitudinal MDMR analysis found a connectivity change between the precuneus and the left superior frontal cortex. The connectivity increase was associated with a decrease in hyperarousal symptoms. The abnormal connectivity for combat veterans without PTSD - such as hypoconnectivity in the precuneus with a superior frontal region and hyperconnectivity in the posterior insula with several regions - could also be normalized after the training. These results suggested that the rtfMRI-nf training effect was not limited to a feedback target region and symptom relief could be mediated by brain modulation in several regions other than in a feedback target area. While further confirmatory research is needed, the results may provide valuable insight into treatment effects on the whole brain resting-state connectivity., Highlights • fMRI neurofeedback training effect on resting-state connectivity was examined • Left amygdala activity was trained to increase with positive memory • Neurofeedback normalized altered connectivity in veterans with and without PTSD • PTSD symptom reductions were significant but not specific to group (exp/ctrl) • Connectivity-symptom association was seen in mPFC and precuneus

Posttraumatic stress disorder (PTSD) is a trauma- and stressor-related disorder that may emerge following a traumatic event. Neuroimaging studies have shown evidence of functional abnormality in many brain regions and systems affected by PTSD. Exaggerated threat detection associated with abnormalities in the salience network, as well as abnormalities in executive functions involved in emotions regulations, self-referencing and context evaluation processing are broadly reported in PTSD. Here we aimed to investigate the behavior and dynamic properties of fMRI resting state networks in combat-related PTSD, using a novel, multimodal imaging approach. Simultaneous electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) was employed to measure neurobiological brain activity among 36 veterans with combat-related PTSD and 20 combat-exposed veterans without PTSD. Based on the recently established method of measuring temporal-independent EEG microstates, we developed a novel strategy to integrate EEG and fMRI by quantifying the fast temporal dynamics associated with the resting state networks. We found distinctive occurrence rates of microstates associated with the dorsal default mode network and salience networks in the PTSD group as compared with control. Furthermore, the occurrence rate of the microstate for the dorsal default mode network was positively correlated with PTSD severity, whereas the occurrence rate of the microstate for the anterior salience network was negatively correlated with hedonic tone reported by participants with PTSD. Our findings reveal a novel aspect of abnormal network dynamics in combat-related PTSD and contribute to a better understanding of the pathophysiology of the disorder. Simultaneous EEG and fMRI will be a valuable tool in continuing to study the neurobiology underlying PTSD., Highlights • Concurrent EEG-fMRI study of resting brain activity in combat related PTSD. • EEG-microstates were associated with fMRI resting state networks in PTSD. • PTSD associated with alterations in dorsal default mode and salience networks. • Occurrence rates of EEG-microstates were related to PTSD symptoms.

Background We have previously shown that in participants with major depressive disorder (MDD) trained to upregulate their amygdala hemodynamic response during positive autobiographical memory (AM) recall with real-time fMRI neurofeedback (rtfMRI-nf) training, depressive symptoms diminish. Here, we assessed the effect of rtfMRI-nf on amygdala functional connectivity during both positive AM recall and rest. Method The current manuscript consists of a secondary analysis on data from our published clinical trial of neurofeedback. Patients with MDD completed two rtfMRI-nf sessions (18 received amygdala rtfMRI-nf, 16 received control parietal rtfMRI-nf). One-week prior-to and following training participants also completed a resting-state fMRI scan. A GLM-based functional connectivity analysis was applied using a seed ROI in the left amygdala. We compared amygdala functional connectivity changes while recalling positive AMs from the baseline run to the final transfer run during rtfMRI-nf training, as well during rest from the baseline to the one-week follow-up visit. Finally, we assessed the correlation between change in depression scores and change in amygdala connectivity, as well as correlations between amygdala regulation success and connectivity changes. Results Following training, amygdala connectivity during positive AM recall increased with widespread regions in the frontal and limbic network. During rest, amygdala connectivity increased following training within the fronto-temporal-limbic network. During both task and resting-state analyses, amygdala-temporal pole connectivity decreased. We identified increased amygdala-precuneus and amygdala-inferior frontal gyrus connectivity during positive memory recall and increased amygdala-precuneus and amygdala-thalamus connectivity during rest as functional connectivity changes that explained significant variance in symptom improvement. Amygdala-precuneus connectivity changes also explain a significant amount of variance in neurofeedback regulation success. Conclusions Neurofeedback training to increase amygdala hemodynamic activity during positive AM recall increased amygdala connectivity with regions involved in self-referential, salience, and reward processing. Results suggest future targets for neurofeedback interventions, particularly interventions involving the precuneus., Highlights • Changes in amygdala functional connectivity following neurofeedback were examined. • Amygdala rtfMRI-nf training alters functional connectivity with prefrontal regions. • Increased amygdala-precuneus connectivity may underlie clinical improvements.

Altered resting-state functional connectivity in posttraumatic stress disorder (PTSD) suggests neuropathology of the disorder. While seed-based fMRI connectivity analysis is often used for the studies, such analysis requires defining a seed location a priori, which restricts search scope and could bias findings toward presupposed areas. Recently, a comprehensive exploratory voxel-wise connectivity analysis, the connectome-wide association approach, has been introduced using multivariate distance matrix regression (MDMR) for resting-state functional connectivity analysis. The current study performed a connectome-wide investigation of resting-state functional connectivity for war veterans with and without PTSD compared to non-trauma-exposed healthy controls using MDMR. Thirty-five male combat veterans with PTSD (unmedicated), 18 male combat veterans without PTSD (veterans control, VC), and 28 age-matched non-trauma-exposed healthy males (NC) participated in a resting-state fMRI scan. MDMR analysis was used to identify between-groups differences in regions with altered connectivity. The identified regions were used as a seed for post-hoc functional connectivity analysis. The analysis revealed that PTSD patients had hypoconnectivity between the left lateral prefrontal regions and the salience network regions as well as hypoconnectivity between the parahippocampal gyrus and the visual cortex areas. Connectivity between the ventromedial prefrontal cortex and the middle frontal gyrus and between the parahippocampal gyrus and the anterior insula were negatively correlated with PTSD symptom severity. VC subjects also had altered functional connectivity compared to NC, including increased connectivity between the posterior insula and several brain regions and decreased connectivity between the precuneus region and several other brain areas. The decreased connectivity between the lateral prefrontal regions and the salience network regions in PTSD was consistent with previous reports that indicated lowered emotion-regulation function in these regions. The decreased connectivity between the parahippocampal gyrus and visual cortex supported the dual representation theory of PTSD, which suggests dissociation between sensory and contextual memory representations in PTSD. The theory also supposes that the precuneus is a region that triggers retrieval of sensory memory of traumatic events. The decreased connectivity at the precuneus for VC might be associated with suppressing such a process., Highlights • PTSD resting-state connectivity was examined with connectome-wide analysis. • War veterans with PTSD had hypoconnectivity among emotion-regulation areas. • PTSD had hypoconnectivity between parahippocampal and visual cortex regions. • War veterans without PTSD had hypoconnectivity at the precuneus region. • War veterans without PTSD had hyperconnectivity at the posterior insula.

Biological Psychiatry, 3 (6), ISSN:0006-3223, ISSN:1873-2402

Palpitations and dyspnea are fundamental to the human experience of panic anxiety, but it remains unclear how the brain dynamically represents changes in these interoceptive sensations. We used isoproterenol, a rapidly acting peripheral beta-adrenergic agonist similar to adrenaline, to induce sensations of palpitation and dyspnea in healthy individuals (n=23) during arterial spin labeling functional magnetic resonance imaging (fMRI). We hypothesized that the right mid-insular cortex, a central recipient of viscerosensory input, would preferentially respond during the peak period of cardiorespiratory stimulation. Bolus infusions of saline and isoproterenol (1 or 2 μg) were administered in a blinded manner while participants continuously rated the intensity of their cardiorespiratory sensation using a dial. Isoproterenol elicited dose-dependent increases in cardiorespiratory sensation, with all participants reporting palpitations and dyspnea at the 2 μg dose. Consistent with our hypothesis, the right mid-insula was maximally responsive during the peak period of sympathetic arousal, heart rate increase, and cardiorespiratory sensation. Furthermore, a shift in insula activity occurred during the recovery period, after the heart rate had largely returned to baseline levels, with an expansion of activation into anterior and posterior sectors of the right insula, as well as bilateral regions of the mid-insula. These results confirm the right mid-insula is a key node in the interoceptive network, and inform computational models proposing specific processing roles for insula subregions during homeostatic inference. The combination of isoproterenol and fMRI offers a powerful approach for evaluating insula function, and could be a useful probe for examining interoceptive dysfunction in psychiatric disorders.

BackgroundFemales are more likely than males to develop major depressive disorder (MDD). The current study used fMRI to compare the neural correlates of autobiographical memory (AM) recall between males and females diagnosed with MDD. AM overgenerality is a persistent cognitive deficit in MDD, the magnitude of which is correlated with depressive severity only in females. Delineating the neurobiological correlates of this deficit may elucidate the nature of sex-differences in the diathesis for developing MDD.MethodsParticipants included unmedicated males and females diagnosed with MDD (n = 20/group), and an age and sex matched healthy control group. AM recall in response to positive, negative, and neutral cue words was compared with a semantic memory task.ResultsThe behavioral properties of AMs did not differ between MDD males and females. In contrast, main effects of sex on cerebral hemodynamic activity were observed in left dorsolateral prefrontal cortex and parahippocampal gyrus during recall of positive specific memories, and middle prefrontal cortex (mPFC), and precuneus during recall of negative specific memories. Moreover, main effects of diagnosis on regional hemodynamic activity were observed in left ventrolateral prefrontal cortex and mPFC during positive specific memory recall, and dorsal anterior cingulate cortex during negative specific memory recall. Sex × diagnosis interactions were evident in the dorsomedial prefrontal cortex, caudate, and precuneus during positive memory recall, and in the posterior cingulate cortex, insula, precuneus and thalamus during negative specific memory recall.ConclusionsThe differential hemodynamic changes conceivably may reflect sex-specific cognitive strategies during recall of AMs irrespective of the phenomenological properties of those memories.

The homeostatic regulation of feeding behavior requires an organism to be able to integrate information from its internal environment, including peripheral visceral signals about the body's current energy needs, with information from its external environment, such as the palatability of energy-rich food stimuli. The insula, which serves as the brain's primary sensory cortex for representing both visceral signals from the body and taste signals from the mouth and tongue, is a likely candidate region in which this integration might occur. However, to date it has been unclear whether information from these two homeostatically critical faculties is merely co-represented in the human insula, or actually integrated there. Recent functional neuroimaging evidence of a common substrate for visceral interoception and taste perception within the human dorsal mid-insula suggests a model whereby a single population of neurons may integrate viscerosensory and gustatory signals. To test this model, we used fMRI-Adaptation to identify whether insula regions that exhibit repetition suppression following repeated interoception trials would then also exhibit adapted responses to subsequent gustatory stimuli. Multiple mid and anterior regions of the insula exhibited adaptation to interoceptive trials specifically, but only the dorsal mid-insula regions exhibited an adapted gustatory response following interoception. The discovery of this gustatory-interoceptive convergence within the neurons of the human insula supports the existence of a heretofore-undocumented neural pathway by which visceral signals from the periphery modulate the activity of brain regions involved in feeding behavior. Hum Brain Mapp 38:2150-2164, 2017. © 2017 Wiley Periodicals, Inc.

Twice as many women as men suffer from mood and anxiety disorders, yet the biological underpinnings of this phenomenon have been understudied and remain unclear. We and others have shown that the hemodynamic response to subliminally presented sad or happy faces during functional MRI (fMRI) is a robust biomarker for the attentional bias toward negative information classically observed in major depression. Here we used fMRI to compare the performance of healthy females (n = 28) and healthy males (n = 28) on a backward masking task using a fast event-related design with gradient-recalled, echoplanar imaging with sensitivity encoding. The image data were compared across groups using a region-of-interest analysis with small-volume correction to control for multiple testing (Pcorrected

The United States is in the midst of an opioid epidemic and lacks a range of successful interventions to reduce this public health burden. Many individuals with opioid use disorder (OUD) consume drugs to relieve physical and/or emotional pain, a pattern that may increasingly result in death. The field of addiction research lacks a comprehensive understanding of physiological and neural mechanisms instantiating this cycle of Negative Reinforcement in OUD, resulting in limited interventions that successfully promote abstinence and recovery. Given the urgency of the opioid crisis, the present review highlights faulty brain circuitry and processes associated with OUD within the context of the Three-Stage Model of Addiction (1). This model underscores Negative Reinforcement processes as crucial to the maintenance and exacerbation of chronic substance use together with Binge/Intoxication and Preoccupation/Anticipation processes. This review focuses on cross-sectional as well as longitudinal studies of relapse and treatment outcome that employ magnetic resonance imaging (MRI), functional near-infrared spectroscopy (fNIRs), brain stimulation methods, and/or electroencephalography (EEG) explored in frequency and time domains (the latter measured by event-related potentials, or ERPs). We discuss strengths and limitations of this neuroimaging work with respect to study design and individual differences that may influence interpretation of findings (e.g., opioid use chronicity/recency, comorbid symptoms, and biological sex). Lastly, we translate gaps in the OUD literature, particularly with respect to Negative Reinforcement processes, into future research directions involving operant and classical conditioning involving aversion/stress. Overall, opioid-related stimuli may lessen their hold on frontocingulate mechanisms implicated in Preoccupation/Anticipation as a function of prolonged abstinence and that degree of frontocingulate impairment may predict treatment outcome. In addition, longitudinal studies suggest that brain stimulation/drug treatments and prolonged abstinence can change brain responses during Negative Reinforcement and Preoccupation/Anticipation to reduce salience of drug cues, which may attenuate further craving and relapse. Incorporating this neuroscience-derived knowledge with the Three-Stage Model of Addiction may offer a useful plan for delineating specific neurobiological targets for OUD treatment.

Electroencephalography (EEG) measures the brain’s electrophysiological spatio-temporal activities with high temporal resolution. Multichannel and broadband analysis of EEG signals is referred to as EEG microstates (EEG-ms) and can characterize such dynamic neuronal activity. EEG-ms have gained much attention due to the increasing evidence of their association with mental activities and large-scale brain networks identified by functional magnetic resonance imaging (fMRI). Spatially independent EEG-ms are quasi-stationary topographies (e.g., stable, lasting a few dozen milliseconds) typically classified into four canonical classes (microstates A through D). They can be identified by clustering EEG signals around EEG global field power (GFP) maxima points. We examined the EEG-ms properties and the dynamics of cohorts of mood and anxiety (MA) disorders subjects (n = 61) and healthy controls (HCs; n = 52). In both groups, we found four distinct classes of EEG-ms (A through D), which did not differ among cohorts. This suggests a lack of significant structural cortical abnormalities among cohorts, which would otherwise affect the EEG-ms topographies. However, both cohorts’ brain network dynamics significantly varied, as reflected in EEG-ms properties. Compared to HC, the MA cohort features a lower transition probability between EEG-ms B and D and higher transition probability from A to D and from B to C, with a trend towards significance in the average duration of microstate C. Furthermore, we harnessed a recently introduced theoretical approach to analyze the temporal dependencies in EEG-ms. The results revealed that the transition matrices of MA group exhibit higher symmetrical and stationarity properties as compared to HC ones. In addition, we found an elevation in the temporal dependencies among microstates, especially in microstate B for the MA group. The determined alteration in EEG-ms temporal dependencies among the cohorts suggests that brain abnormalities in mood and anxiety disorders reflect aberrant neural dynamics and a temporal dwelling among ceratin brain states (i.e., mood and anxiety disorders subjects have a less dynamicity in switching between different brain states).

The adolescent brain undergoes profound structural changes which is influenced by many factors. Screen media activity (SMA; e.g., watching television or videos, playing video games, or using social media) is a common recreational activity in children and adolescents; however, its effect on brain structure is not well understood. A multivariate approach with the first cross-sectional data release from the Adolescent Brain Cognitive Development (ABCD) study was used to test the maturational coupling hypothesis, i.e. the notion that coordinated patterns of structural change related to specific behaviors. Moreover, the utility of this approach was tested by determining the association between these structural correlation networks and psychopathology or cognition. ABCD participants with usable structural imaging and SMA data (N = 4277 of 4524) were subjected to a Group Factor Analysis (GFA) to identify latent variables that relate SMA to cortical thickness, sulcal depth, and gray matter volume. Subject scores from these latent variables were used in generalized linear mixed-effect models to investigate associations between SMA and internalizing and externalizing psychopathology, as well as fluid and crystalized intelligence. Four SMA-related GFAs explained 37% of the variance between SMA and structural brain indices. SMA-related GFAs correlated with brain areas that support homologous functions. Some but not all SMA-related factors corresponded with higher externalizing (Cohen's d effect size (ES) 0.06-0.1) but not internalizing psychopathology and lower crystalized (ES: 0.08-0.1) and fluid intelligence (ES: 0.04-0.09). Taken together, these findings support the notion of SMA related maturational coupling or structural correlation networks in the brain and provides evidence that individual differences of these networks have mixed consequences for psychopathology and cognitive performance.

The Adolescent Brain Cognitive Development (ABCD) Study is an ongoing, nationwide study of the effects of environmental influences on behavioral and brain development in adolescents. The ABCD Study is a collaborative effort, including a Coordinating Center, 21 data acquisition sites across the United States, and a Data Analysis and Informatics Center (DAIC). The main objective of the study is to recruit and assess over eleven thousand 9-10-year-olds and follow them over the course of 10 years to characterize normative brain and cognitive development, the many factors that influence brain development, and the effects of those factors on mental health and other outcomes. The study employs state-of-the-art multimodal brain imaging, cognitive and clinical assessments, bioassays, and careful assessment of substance use, environment, psychopathological symptoms, and social functioning. The data will provide a resource of unprecedented scale and depth for studying typical and atypical development. Here, we describe the baseline neuroimaging processing and subject-level analysis methods used by the ABCD DAIC in the centralized processing and extraction of neuroanatomical and functional imaging phenotypes. Neuroimaging processing and analyses include modality-specific corrections for distortions and motion, brain segmentation and cortical surface reconstruction derived from structural magnetic resonance imaging (sMRI), analysis of brain microstructure using diffusion MRI (dMRI), task-related analysis of functional MRI (fMRI), and functional connectivity analysis of resting-state fMRI.HighlightsAn overview of the MRI processing pipeline for the ABCD StudyA discussion on the challenges of large, multisite population studiesA methodological reference for users of publicly shared data from the ABCD Study

Inflammation-related changes in the concentrations of inflammatory mediators such as c-reactive protein (CRP), interleukin 1β (IL-1), and IL-6 as well as kynurenine metabolites are associated with major depressive disorder (MDD) and affect depressive behavior, cognition, and hippocampal plasticity in animal models. We previously reported that the ratios of kynurenic acid (KynA) to the neurotoxic metabolites, 3-hydroxykynurenine (3HK) and quinolinic acid (QA), were positively correlated with hippocampal volume in depression. The hippocampus is critical for autobiographical memory (AM) recall which is impaired in MDD. Here we tested whether the ratios, KynA/3HK and KynA/QA were associated with AM recall performance as well as hippocampal activity during AM recall. Thirty-five unmedicated depressed participants and 25 healthy controls (HCs) underwent fMRI scanning while recalling emotionally-valenced AMs and provided serum samples for the quantification of kynurenine metabolites, CRP, and cytokines (IL-1 receptor antagonist - IL-1RA; IL-6, tumor necrosis factor alpha - TNF, interferon gamma -IFN-γ, IL-10). KynA/3HK and KynA/QA were lower in the MDD group relative to the HCs. The concentrations of the CRP and the cytokines did not differ significantly between the HCs and the MDD group. Depressed individuals recalled fewer specific AMs and displayed increased left hippocampal activity during the recall of positive and negative memories. KynA/3HK was inversely associated with left hippocampal activity during specific AM recall in the MDD group. Further, KynA/QA was positively correlated with percent negative specific memories recalled in the MDD group and showed a non-significant trend toward a positive correlation with percent positive specific memories recalled in HCs. In contrast, neither CRP nor the cytokines were significantly associated with AM recall or activity of the hippocampus during AM recall. Conceivably, an imbalance in levels of KynA versus QA-pathway metabolites may adversely impact the function of the hippocampus and AM recall, raising the possibility that kynurenine pathway may affect emotion-dependent memory within the context of depression.

Discontinuing unhealthy behaviors, such as overeating or drug use, depends upon an individual's ability to overcome the influence of environmental reward cues. The strength of that influence, however, varies greatly depending upon the internal state of the body. Characterizing the relationship between interoceptive signaling and shifting drug cue valuation provides an opportunity for understanding the neural bases of how changing internal states alter reward processing more generally. A total of 17 cigarette smokers rated the pleasantness of cigarette pictures when they were nicotine sated or nicotine abstinent. On both occasions, smokers also underwent functional magnetic resonance imaging (fMRI) scanning while performing a visceral interoceptive attention task and a resting-state functional connectivity scan. Hemodynamic, physiological, and behavioral parameters were compared between sated and abstinent scans. The relationships between changes in these parameters across scan sessions were also examined. Smokers rated cigarette pictures as significantly more pleasant while nicotine abstinent than while nicotine sated. Comparing abstinent with sated scans, smokers also exhibited significantly decreased mid-insula, amygdala, and orbitofrontal activity while attending to interoceptive signals from the body. Change in interoceptive activity within the left mid-insula predicted the increase in smoker's pleasantness ratings of cigarette cues. This increase in pleasantness ratings was also correlated with an increase in resting-state functional connectivity between the mid-insula and the ventral striatum and ventral pallidum. These findings support a model wherein interoceptive processing in the mid-insula of withdrawal signals from the body potentiates the motivational salience of reward cues through the recruitment of hedonic 'hot spots' within the brain's reward circuitry.

Reductions in gray matter volume of the medial prefrontal cortex (mPFC), especially the rostral and subgenual anterior cingulate cortex (rACC, sgACC) are a widely reported finding in major depressive disorder (MDD). Inflammatory mediators, which are elevated in a subgroup of patients with MDD, activate the kynurenine metabolic pathway and increase production of neuroactive metabolites such as kynurenic acid (KynA), 3-hydroxykynurenine (3HK) and quinolinic acid (QA) which influence neuroplasticity. It is not known whether the alterations in brain structure and function observed in major depressive disorders are due to the direct effect of inflammatory mediators or the effects of neurotoxic kynurenine metabolites. Here, using partial posterior predictive distribution mediation analysis, we tested whether the serum concentrations of kynurenine pathway metabolites mediated reductions in cortical thickness in mPFC regions in MDD. Further, we tested whether any association between C-reactive protein (CRP) and cortical thickness would be mediated by kynurenine pathway metabolites. Seventy-three unmedicated subjects who met DSM-IV-TR criteria for MDD and 91 healthy controls (HC) completed MRI scanning using a pulse sequence optimized for tissue contrast resolution. Automated cortical parcellation was performed using the PALS-B12 Brodmann area atlas as implemented in FreeSurfer in order to compare the cortical thickness and cortical area of six PFC regions: Brodmann areas (BA) 9, 10, 11, 24, 25, and 32. Serum concentrations of kynurenine pathway metabolites were determined by high performance liquid chromatography (HPLC) with tandem mass spectrometry (MS/MS) detection, while high-sensitivity CRP concentration was measured immunoturbidimetrically. Compared with HCs, the MDD group showed a reduction in cortical thickness of the right BA24 (p

Inflammation, which may be present in a subgroup of individuals with major depressive disorder (MDD), activates the kynurenine metabolic pathway to produce kynurenine metabolites kynurenic acid (KynA) and quinolinic acid (QA). We have previously reported an association between the ratio of KynA to QA and hippocampal volume in MDD. In animals, inflammation leads to deficits in incentive motivation. Given the central role of the nucleus accumbens (NAcc) and other regions of the striatum in motivated behavior, reward processing, and anhedonia, we hypothesized that abnormalities in the concentrations of kynurenine pathway metabolites would be associated with striatal volumes. As previously reported, after controlling for relevant confounds, the KynA/QA ratio was reduced in the serum of unmedicated patients with MDD (n=53) versus healthy controls (HC, n=47) and there was a non-significant trend in the correlation between KynA/QA and severity of anhedonia (r=−0.27, p

Several imaging modalities, including T1-weighted structural imaging, diffusion tensor imaging, and functional MRI can show chronological age related changes. Employing machine learning algorithms, an individual’s imaging data can predict their age with reasonable accuracy. While details vary according to modality, the general strategy is to: 1) extract image-related features, 2) build a model on a training set that uses those features to predict an individual’s age, 3) validate the model on a test dataset, producing a predicted age for each individual, 4) define the “Brain Age Gap Estimate” (BrainAGE) as the difference between an individual’s predicted age and his/her chronological age, and 5) estimate the relationship between BrainAGE and other variables of interest, and 6) make inferences about those variables and accelerated or delayed brain aging. For example, a group of individuals with overall positive BrainAGE may show signs of accelerated aging in other variables as well. There is inevitably an overestimation of the age of younger individuals and an underestimation of the age of older individuals due to ‘regression to the mean’. The correlation between chronological age and BrainAGE may significantly impact the relationship between BrainAGE and other variables of interest when they are also related to age. In this study, we examine the detectability of variable effects under different assumptions. We use empirical results from two separate datasets [training=475 healthy volunteers, aged 18 – 60 years (259 female); testing=489 participants including people with mood/anxiety, substance use, eating disorders and healthy controls, aged 18 – 56 years (312 female)] to inform simulation parameter selection. Outcomes in simulated and empirical data strongly support the proposal that models incorporating BrainAGE should include chronological age as a covariate. We propose either including age as a covariate in step 5 of the above framework, or employing a multistep procedure where age is regressed on BrainAGE prior to step 5, producing BrainAGE Residualized (BrainAGER) scores.

The Adolescent Brain Cognitive Development (ABCD) Study is an ongoing, nationwide study of the effects of environmental influences on behavioral and brain development in adolescents. The main objective of the study is to recruit and assess over eleven thousand 9–10-year-olds and follow them over the course of 10 years to characterize normative brain and cognitive development, the many factors that influence brain development, and the effects of those factors on mental health and other outcomes. The study employs state-of-the-art multimodal brain imaging, cognitive and clinical assessments, bioassays, and careful assessment of substance use, environment, psychopathological symptoms, and social functioning. The data is a resource of unprecedented scale and depth for studying typical and atypical development. The aim of this manuscript is to describe the baseline neuroimaging processing and subject-level analysis methods used by ABCD. Processing and analyses include modality-specific corrections for distortions and motion, brain segmentation and cortical surface reconstruction derived from structural magnetic resonance imaging (sMRI), analysis of brain microstructure using diffusion MRI (dMRI), task-related analysis of functional MRI (fMRI), and functional connectivity analysis of resting-state fMRI. This manuscript serves as a methodological reference for users of publicly shared neuroimaging data from the ABCD Study.

We employ a time-dependent Hurst analysis to identify EEG signals that differentiate between healthy controls and combat-related PTSD subjects. The Hurst exponents, calculated using a rescaled range analysis, demonstrate a significant differential response between healthy and PTSD samples which may lead to diagnostic applications. To overcome the non-stationarity of EEG data, we apply an appropriate window length wherein the EEG data displays stationary behavior. We then use the Hurst exponents for each channel as hypothesis test statistics to identify differences between PTSD cases and controls. Our study included a cohort of 12 subjects with half healthy controls. The Hurst exponent of the PTSD subjects is found to be significantly smaller than the healthy controls in channel F3. Our results indicate that F3 may be a useful channel for diagnostic applications of Hurst exponents in distinguishing PTSD and healthy subjects.

Anorexia nervosa (AN) is a devastating psychiatric illness that is associated with significant morbidity and mortality. Aberrant visceral interoceptive processing within the insula has been hypothesized to be an important mechanism in AN's pathophysiology due to the theoretical link between interoception and emotional experience. We therefore utilized functional magnetic resonance imaging (fMRI) to examine whether altered insula functioning underlies visceral interoception in AN. Fifteen females with restricting-type AN and 15 healthy control females underwent fMRI while performing an interoceptive attention task during which they focused on sensations in their heart, stomach, and bladder. Participants also performed an anxious rumination task while in the scanner. AN participants were weight-restored and free of psychotropic medications. Two distinct regions of the insula—anterior insula and dorsal mid-insula—exhibited a significant (p

The insula serves as the primary gustatory and viscerosensory region in the mammalian cortex. It receives visceral and gustatory afferent projections through dedicated brainstem and thalamic nuclei, which suggests a potential role as a site for homeostatic integration. For example, while human neuroimaging studies of gustation have implicated the dorsal mid-insular cortex as one of the primary gustatory regions in the insula, other recent studies have implicated this same region of the insula in interoception. This apparent convergence of gustatory and interoceptive information could reflect a common neural representation in the insula shared by both interoception and gustation. This idea finds support in translational studies in rodents, and may constitute a medium for integrating homeostatic information with feeding behavior. To assess this possibility, healthy volunteers were asked to undergo fMRI while performing tasks involving interoceptive attention to visceral sensations as well as a gustatory mapping task. Analysis of the unsmoothed, high-resolution fMRI data confirmed shared representations of gustatory and visceral interoception within the dorsal mid-insula. Group conjunction analysis revealed overlapping patterns of activation for both tasks in the dorsal mid-insula, and region-of-interest analyses confirmed that the dorsal mid-insula regions responsive for visceral interoception also exhibit strong responses to tastants.