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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.

Background Major depressive disorder (MDD) and borderline personality disorder (BPD) are highly prevalent and often comorbid psychiatric conditions, with abnormal processing of negative affect resulting from psychological stress. Characteristics of central processing of autonomic response to stress in each disorder are not clearly settled. Methods We obtained whole brain 3T fMRI with concurrent skin conductance, respiration rate, and heart rate variability measures in a cohort of MDD (N=19), BPD (N=19) patients, and healthy (N=20) individuals. Experiments were conducted in resting conditions, during a control mental arithmetic task, during highly stressful mental arithmetic, and in the period immediately following psychological stress. Results Widespread activation of central autonomic network (CAN) structures was observed during stress compared to a control task in the group of healthy participants, whereas CAN activation during stress was less intense in both BPD and MDD. Both patient groups displayed increased sympathetic and decreased parasympathetic activation compared to healthy subjects, as previously reported. The relationship between peripheral sympathetic or parasympathetic activity and simultaneous regional brain BOLD activity was similar in BPD patients and healthy subjects, and markedly different from that seen in MDD patients. Limitations The sample size, the fact it belonged to a single study site, and low grade affective symptomatology in both patient groups limit the generalizability of the present findings. Conclusions The diverging neurobiological signature in the homeostatic response to stress in MDD and BPD possibly represents a heuristically valuable candidate biomarker to help discern MDD and BPD patients.

Major depressive disorder (MDD) is associated with reductions in white matter microstructural integrity as measured by fractional anisotropy (FA), an index derived from diffusion tensor imaging (DTI). The neurotropic herpesvirus, human cytomegalovirus (HCMV), is a major cause of white matter pathology in immunosuppressed populations but its relationship with FA has never been tested in MDD despite the presence of inflammation and weakened antiviral immunity in a subset of depressed patients. We tested the relationship between FA and HCMV infection in two independent samples consisting of 176 individuals with MDD and 44 healthy controls (HC) (Discovery sample) and 88 participants with MDD and 48 HCs (Replication sample). Equal numbers of HCMV positive (HCMV+) and HCMV negative (HCMV−) groups within each sample were balanced on ten different clinical/demographic variables using propensity score matching. Anti-HCMV IgG antibodies were measured using a solid-phase ELISA. In the Discovery sample, significantly lower FA was observed in the right inferior fronto-occipital fasciculus (IFOF) in HCMV+ participants with MDD compared to HCMV− participants with MDD (cluster size 1316 mm3; pFWE d = −0.58). This association was confirmed in the replication sample by extracting the mean FA from this exact cluster and applying the identical statistical model (p d = −0.45). There was no significant effect of diagnosis or interaction between diagnosis and HCMV in either sample. The effect of chronic HCMV infection on white matter integrity may—in at-risk individuals—contribute to the psychopathology of depression. These findings may provide a novel target of intervention for a subgroup of patients with MDD.

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).

Human cytomegalovirus (HCMV) infection is associated with neuropathology in patients with impaired immunity and/or inflammatory diseases. However, the association between gray matter volume (GMV) and HCMV has never been examined in major depressive disorder (MDD) despite the presence of inflammation and impaired viral immunity in a subset of patients. We tested this relationship in two independent samples consisting of 179 individuals with MDD and 41 healthy controls (HC) (sample 1) and 124 MDD participants and 148 HCs (sample 2). HCMV positive (HCMV+) and HCMV negative (HCMV-) groups within each sample were balanced on up to 11 different clinical/demographic variables using inverse probability of treatment weighting. GMV of 87 regions was measured with FreeSurfer. There was a main effect of HCMV serostatus but not diagnosis that replicated across samples. Relative to HCMV- subjects, HCMV+ subjects in sample 1 showed a significant reduction of volume in six regions (puncorrected

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.

Background Electroencephalography (EEG) studies suggest that major depressive disorder (MDD) is associated with lower left than right frontal brain activity (asymmetry), a pattern appearing stronger in women than men, and when elicited during emotionally-relevant paradigms versus an uncontrolled resting state. However, it is unclear whether this asymmetry pattern generalizes to the common presentation of MDD with co-occurring anxiety. Moreover, asymmetry may differ for anxiety subtypes, wherein anxious apprehension (AnxApp: worry characteristic of generalized anxiety disorder) appears left-lateralized, but anxious arousal (AnxAro: panic characteristic of social anxiety, posttraumatic stress, and panic disorders) may be right-lateralized. Methods This analysis attempted to replicate frontal EEG asymmetry patterns using functional magnetic resonance imaging (fMRI). Participants completed clinical interviews and a monetary incentive delay (MID) task during fMRI recording. We compared five groups of right-handed women from the Tulsa 1000 study, MDD (n=40), MDD-AnxApp (n=26), MDD-AnxAro (n=34), MDD-Both (with AnxApp and AnxAro; n=26), and healthy controls (CTL; n=24), as a function of MID anticipation condition (no win/loss, win, loss) and hemisphere on frontal blood oxygen-level-dependent (BOLD) signal. Results CTL exhibited higher bilateral superior, middle, and inferior middle frontal gyrus BOLD signal than the four MDD groups for high arousal (win and loss) conditions. However, frontal attenuations were unrelated to current depression/anxiety symptoms, suggestive of a trait as opposed to a state marker. Limitations This was a cross-sectional analysis restricted to women. Conclusions Reduced prefrontal cortex recruitment during processing of both positively and negatively valenced stimuli is consistent with the emotion context insensitivity theory of MDD.

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.

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.

Recent studies suggest that transcranial electrical stimulation (tES) can be performed during functional magnetic resonance imaging (fMRI). The novel approach of using concurrent tES-fMRI to modulate and measure targeted brain activity/connectivity may provide unique insights into the causal interactions between the brain neural responses and psychiatric/neurologic signs and symptoms, and importantly, guide the development of new treatments. However, tES stimulation parameters to optimally influence the underlying brain activity in health and disorder may vary with respect to phase, frequency, intensity and electrode’s montage. Here, we delineate how a closed-loop tES-fMRI study of frontoparietal network modulation can be designed and performed. We also discuss the challenges of running a concurrent tES-fMRI, describing how we can distinguish clinically meaningful physiological changes caused by tES from tES-related artifacts. There is a large methodological parameter space including electrode types, electrolytes, electrode montages, concurrent tES-fMRI hardware, online fMRI processing pipelines and closed-loop optimization algorithms that should be carefully selected for closed-loop tES-fMRI brain modulation. We also provide technical details on how safety and quality of tES-fMRI settings can be tested, and how these settings can be monitored during the study to ensure they do not exceed safety standards. The initial results of feasibility and applicability of closed-loop tES-fMRI are reported and potential hypotheses for the outcomes are discussed.Highlight pointsMethodological details of a closed-loop tES-fMRI study protocol are provided.The protocol is performed successfully on a frontoparietal network without side-effects.The temperature of electrodes in concurrent tES-fMRI remains in the safe range.Properly setup concurrent tES does not introduce MRI artifacts and noise.Simplex optimizer could be used to find an optimal tES stimulation parameter.

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.

Understanding the neural processes that govern the human gut-brain connection has been challenging due to the inaccessibility of the body′s interior. In this study, we aimed to identify neural responses to gastrointestinal sensation (i.e., the neural basis of ′gut feelings′) in healthy humans using a minimally invasive mechanosensory probe. Combining electroencephalography and electrogastrography with signal detection theory measures, we quantified brain, stomach, and perceptual (button-press) responses following the ingestion of a vibrating capsule. The relationship between vibration strength and perceptual sensitivity was evaluated using two stimulation conditions (normal and enhanced). Most individuals successfully perceived capsule stimulation in both conditions, as evidenced by above chance accuracy scores. Perceptual accuracy improved significantly during the enhanced relative to normal stimulation, which was associated with faster reaction time and reduced reaction time variability. Stomach stimulation induced responses in a cluster of parieto-occipital leads near the midline via a late positive potential emerging 300-600 milliseconds after stimulation onset. Moreover, these ′gastric evoked potentials′ showed dose-dependent increases in amplitude and were significantly correlated with perceptual accuracy. Our findings are consistent with recent neurogastric and optogenetic studies demonstrating a role for posteromedial cortices in gastrointestinal interoception and body dissociation and highlight a unique form of enterically-focused sensory monitoring within the human brain. Overall, these results show that this minimally invasive approach could serve as a useful tool for understanding gut-brain interactions in healthy and clinical populations.

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.

Highlights • rtfMRI-nf LA emotional training reduces depressive symptoms. • rtfMRI-nf LA training increases KynA/3-HK, a neuroprotective index. • Baseline KynA/QA is associated with the ability to upregulate the LA. • In partial responder group LA upregulation positively correlates with KynA/QA. • In partial responder group LA upregulation inversely correlates with MADRS. • Modulation of the KP may drive rtfMRI-nf-induced changes in neuroplasticity. • Non-specific effects cannot be ruled out due to the lack of a sham control., Real-time fMRI neurofeedback (rtfMRI-nf) left amygdala (LA) training is a promising intervention for major depressive disorder (MDD). We have previously proposed that rtfMRI-nf LA training may reverse depression-associated regional impairments in neuroplasticity and restore information flow within emotion-regulating neural circuits. Inflammatory cytokines as well as the neuroactive metabolites of an immunoregulatory pathway, i.e. the kynurenine pathway (KP), have previously been implicated in neuroplasticity. Therefore, in this proof-of-principle study, we investigated the association between rtfMRI-nf LA training and circulating inflammatory mediators and KP metabolites. Based on our previous work, the primary variable of interest was the ratio of the NMDA-receptor antagonist, kynurenic acid to the NMDA receptor agonist, quinolinic acid (KynA/QA), a putative neuroprotective index. We tested two main hypotheses. i. Whether rtfMRI-nf acutely modulates KynA/QA, and ii. whether baseline KynA/QA predicts response to rtfMRI-nf. Twenty-nine unmedicated participants who met DSM-5 criteria for MDD based on the Mini-International Neuropsychiatric Interview and had current depressive symptoms (Montgomery-Åsberg Depression Rating Scale (MADRS) score > 6) completed two rtfMRI-nf sessions to upregulate LA activity (Visit1 and 2), as well as a follow-up (Visit3) without rtfMRI-nf. All visits occurred at two-week intervals. At all three visits, the MADRS was administered to participants and serum samples for the quantification of inflammatory cytokines and KP metabolites were obtained. First, the longitudinal changes in the MADRS score and immune markers were tested by linear mixed effect model analysis. Further, utilizing a linear regression model, we investigated the relationship between rtfMRI-nf performance and immune markers. After two sessions of rtfMRI-nf, MADRS scores were significantly reduced (t[58] = −4.07, p = 0.009, d = 0.56). Thirteen participants showed a ≥ 25% reduction in the MADRS score (the partial responder group). There was a significant effect of visit (F[2,58] = 3.17, p = 0.05) for the neuroprotective index, KynA to 3-hydroxykynurenine (3-HK), that was driven by a significant increase in KynA/3-HK between Visit1 and Visit3 (t[58] = 2.50, p = 0.03, d = 0.38). A higher baseline level of KynA/QA (β = 5.23, p = 0.06; rho = 0.49, p = 0.02) was associated with greater ability to upregulate the LA. Finally, for exploratory purposes correlation analyses were performed between the partial responder and the non-responder groups as well as in the whole sample including all KP metabolites and cytokines. In the partial responder group, greater ability to upregulate the LA was correlated with an increase in KynA/QA after rtfMRI-nf (rho = 0.75, p = 0.03). The results are consistent with the possibility that rtfMRI-nf decreases metabolism down the so-called neurotoxic branch of the KP. Nevertheless, non-specific effects cannot be ruled out due to the lack of a sham control. Future, controlled studies are needed to determine whether the increase in KynA/3HK and KynA/QA is specific to rtfMRI-nf or whether it is a non-specific correlate of the resolution of depressive symptoms. Similarly, replication studies are needed to determine whether KynA/QA has clinical utility as a treatment response biomarker.

ObjectiveComprehensive denoising is imperative in fMRI analysis to reliably evaluate neural activity from the blood oxygenation level dependent signal. In real-time fMRI, however, only a minimal denoising process has been applied and the impact of insufficient denoising on online brain activity estimation has not been assessed comprehensively. This study evaluated the noise reduction performance of online fMRI processes in a real-time estimation of regional brain activity and functional connectivity.ApproachWe performed a series of real-time processing simulations of online fMRI processing, including slice-timing correction, motion correction, spatial smoothing, signal scaling, and noise regression with high-pass filtering, motion parameters, motion derivatives, global signal, white matter/ventricle average signals, and physiological noise models with image-based retrospective correction of physiological motion effects (RETROICOR) and respiration volume per time (RVT).Main resultsAll the processing was completed in less than 400 ms for whole-brain voxels. Most processing had a benefit for noise reduction except for RVT that did not work due to the limitation of the online peak detection. The global signal regression, white matter/ventricle signal regression, and RETORICOR had a distinctive noise reduction effect, depending on the target signal, and could not substitute for each other. Global signal regression could eliminate the noise-associated bias in the mean dynamic functional connectivity across time.SignificanceThe results indicate that extensive real-time denoising is possible and highly recommended for real-time fMRI applications.

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.

Background Small hippocampal volume is a prevalent neurostructural abnormality in posttraumatic stress disorder (PTSD). However, whether the hippocampal atrophy is the cause of disease symptoms or a pre-existing risk factor and whether it is a reversible alteration or a permanent trait are unclear. The trait- or state-dependent alteration could also differ among the hippocampal subfields. Methods The study examined the longitudinal hippocampal volume changes due to positive emotional training with left amygdala (LA) real-time fMRI neurofeedback (rtfMRI-nf) in combat veterans with PTSD. The participants were trained to increase the neurofeedback signal from LA (experimental group, N = 20) or brain region not involved in emotion processing (control group, N = 9) by recalling a positive autobiographical memory. The pre- and post-training structural MRI brain images were processed with FreeSurfer to evaluate the hippocampal subfield volumes. Hippocampal volumes for healthy controls (N = 43) were also examined to evaluate the baseline abnormality in PTSD. Results A significant group difference in volume change was found in the left CA1 head region. This region had the most significant volume reduction at the baseline in PTSD. The experimental group showed a significant volume increase, while the control group showed a significant volume decrease in this region. The volume change in the control group negatively correlated with interval days between the scans. Limitations A cognitive improvement due to the hippocampal volume increase could not be found with symptom scales. Conclusions RtfMRI-nf positive emotional training increased the hippocampus volume among people with PTSD, suggesting that hippocampal atrophy in PTSD is modifiable.

Background/Introduction: Concurrent electroencephalography and resting-state functional magnetic resonance imaging (rsfMRI) have been widely used for studying the (presumably) awake and alert human brain with high temporal/spatial resolution. Although rsfMRI scans are typically collected while individuals are instructed to focus their eyes on a fixated cross, objective and verified experimental measures to quantify degree of vigilance are not readily available. Electroencephalography (EEG) is the modality extensively used for estimating vigilance, especially during eyes-closed resting state. However, pupil size measured using an eye-tracker device could provide an indirect index of vigilance. Methods: Three 12-min resting scans (eyes open, fixating on the cross) were collected from 10 healthy control participants. We simultaneously collected EEG, fMRI, physiological, and eye-tracker data and investigated the correlation between EEG features, pupil size, and heart rate. Furthermore, we used pupil size and EEG features as regressors to find their correlations with blood-oxygen-level-dependent fMRI measures. Results: EEG frontal and occipital beta power (FOBP) correlates with pupil size changes, an indirect index for locus coeruleus activity implicated in vigilance regulation (r = 0.306, p

Recently, we reported an emotion self-regulation study (Zotev et al., 2020), in which patients with major depressive disorder (MDD) used simultaneous real-time fMRI and EEG neurofeedback (rtfMRI-EEG-nf) to upregulate two fMRI and two EEG activity measures, relevant to MDD. The target measures included fMRI activities of the left amygdala and left rostral anterior cingulate cortex, and frontal EEG asymmetries in the alpha band (FAA) and high-beta band (FBA). Here we apply the exact low resolution brain electromagnetic tomography (eLORETA) to investigate EEG source activities during the rtfMRI-EEG-nf procedure. The exploratory analyses reveal significant changes in hemispheric lateralities of upper alpha and high-beta current source densities in the prefrontal regions, consistent with upregulation of the FAA and FBA during the rtfMRI-EEG-nf task. Similar laterality changes are observed for current source densities in the amygdala. Prefrontal upper alpha current density changes show significant negative correlations with anhedonia severity. Changes in prefrontal high-beta current density are consistent with reduction in comorbid anxiety. Comparisons with results of previous LORETA studies suggest that the rtfMRI-EEG-nf training is beneficial to MDD patients, and may have the ability to correct functional deficiencies associated with anhedonia and comorbid anxiety in MDD., 15 pages, 9 figures, to appear in NeuroImage: Clinical

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.

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

There exists little human neuroscience research to explain why some individuals lose their appetite when they become depressed, while others eat more. Answering this question may reveal much about the various pathophysiologies underlying depression. The present study combined neuroimaging, salivary cortisol, and blood markers of inflammation and metabolism collected prior to scanning. We compared the relationships between peripheral endocrine, metabolic, and immune signaling and brain activity to food cues between depressed participants experiencing increased (N = 23) or decreased (N = 31) appetite and weight in their current depressive episode and healthy control participants (N = 42). The two depression subgroups were unmedicated and did not differ in depression severity, anxiety, anhedonia, or body mass index. Depressed participants experiencing decreased appetite had higher cortisol levels than subjects in the other two groups, and their cortisol values correlated inversely with the ventral striatal response to food cues. In contrast, depressed participants experiencing increased appetite exhibited marked immunometabolic dysregulation, with higher insulin, insulin resistance, leptin, CRP, IL-1RA, and IL-6, and lower ghrelin than subjects in other groups, and the magnitude of their insulin resistance correlated positively with the insula response to food cues. These findings provide novel evidence linking aberrations in homeostatic signaling pathways within depression subtypes to the activity of neural systems that respond to food cues and select when, what, and how much to eat. In conjunction with prior work, the present findings strongly support the existence of pathophysiologically distinct depression subtypes for which the direction of appetite change may be an easily measured behavioral marker.

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.

Posttraumatic stress disorder (PTSD) is a chronic and disabling neuropsychiatric disorder characterized by insufficient top-down modulation of the amygdala activity by the prefrontal cortex. Real-time fMRI neurofeedback (rtfMRI-nf) is an emerging method with potential for modifying the amygdala-prefrontal interactions. We report the first controlled emotion self-regulation study in veterans with combat-related PTSD utilizing rtfMRI-nf of the amygdala activity. PTSD patients in the experimental group (EG, n = 20) learned to upregulate blood‑oxygenation-level-dependent (BOLD) activity of the left amygdala (LA) using the rtfMRI-nf during a happy emotion induction task. PTSD patients in the control group (CG, n = 11) were provided with a sham rtfMRI-nf. The study included three rtfMRI-nf training sessions, and EEG recordings were performed simultaneously with fMRI. PTSD severity was assessed before and after the training using the Clinician-Administered PTSD Scale (CAPS). The EG participants who completed the study showed a significant reduction in total CAPS ratings, including significant reductions in avoidance and hyperarousal symptoms. They also exhibited a significant reduction in comorbid depression severity. Overall, 80% of the EG participants demonstrated clinically meaningful reductions in CAPS ratings, compared to 38% in the CG. No significant difference in the CAPS rating changes was observed between the groups. During the first rtfMRI-nf session, functional connectivity of the LA with the orbitofrontal cortex (OFC) and the dorsolateral prefrontal cortex (DLPFC) was progressively enhanced, and this enhancement significantly and positively correlated with the initial CAPS ratings. Left-lateralized enhancement in upper alpha EEG coherence also exhibited a significant positive correlation with the initial CAPS. Reduction in PTSD severity between the first and last rtfMRI-nf sessions significantly correlated with enhancement in functional connectivity between the LA and the left DLPFC. Our results demonstrate that the rtfMRI-nf of the amygdala activity has the potential to correct the amygdala-prefrontal functional connectivity deficiencies specific to PTSD., Highlights • Regulation of amygdala fMRI activity was studied using neurofeedback (nf) in PTSD. • In combat veterans, fMRI-nf modulation of amygdala activity reduces PTSD severity. • PTSD symptom reduction with nf was not statistically better than for control group. • Amygdala fMRI connectivity with DLPFC and OFC brain regions is enhanced with nf. • fMRI connectivity and EEG coherence changes due to nf correlate with PTSD severity.

Cardiorespiratory fluctuations such as changes in heart rate or respiration volume influence the temporal dynamics of cerebral blood flow (CBF) measurements during arterial spin labeling (ASL) fMRI. This ‘physiological noise’ can confound estimates of resting state network activity, and it may lower the signal-to-noise ratio of ASL during task-related experiments. In this study we examined several methods for minimizing the contributions of both synchronized and non-synchronized physiological noise in ASL measures of CBF, by combining the RETROICOR approach with different linear deconvolution models. We evaluated the amount of variance in CBF that could be explained by each method during physiological rest, in both resting state and task performance conditions. To further demonstrate the feasibility of this approach, we induced low-frequency cardiorespiratory deviations via peripheral adrenergic stimulation with isoproterenol, and determined how these fluctuations influenced CBF, before and after applying noise correction. By suppressing physiological noise, we observed substantial improvements in the signal-to-noise ratio at the individual and group activation levels. Our results suggest that variations in cardiac and respiratory parameters can account for a large proportion of the variance in resting and task-based CBF, and indicate that regressing out these non-neuronal signal variations improves the intrinsically low signal-to-noise ratio of ASL. This approach may help to better identify and control physiologically driven activations in ASL resting state and task-based analyses.

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

Background In patients with degenerative cervical myelopathy (DCM) that have spinal cord compression and sensorimotor deficits, surgical decompression is often performed. However, there is heterogeneity in clinical presentation and post-surgical functional recovery. Objectives Primary: a) to assess differences in muscle fat infiltration (MFI) in patients with DCM versus controls, b) to assess association between MFI and clinical disability. Secondary: to assess association between MFI pre-surgery and post-surgical functional recovery. Study design Cross-sectional case control study. Methods Eighteen patients with DCM (58.6 ± 14.2 years, 10 M/8F) and 25 controls (52.6 ± 11.8 years, 13M/12 F) underwent 3D Dixon fat-water imaging. A convolutional neural network (CNN) was used to segment cervical muscles (MFSS- multifidus and semispinalis cervicis, LC- longus capitis/colli) and quantify MFI. Modified Japanese Orthopedic Association (mJOA) and Nurick were collected. Results Patients with DCM had significantly higher MFI in MFSS (20.63 ± 5.43 vs 17.04 ± 5.24, p = 0.043) and LC (18.74 ± 6.7 vs 13.66 ± 4.91, p = 0.021) than controls. Patients with increased MFI in LC and MFSS had higher disability (LC: Nurick (Spearman’s ρ = 0.436, p = 0.003) and mJOA (ρ = -0.399, p = 0.008)). Increased MFI in LC pre-surgery was associated with post-surgical improvement in Nurick (ρ = -0.664, p = 0.026) and mJOA (ρ = -0.603, p = 0.049). Conclusion In DCM, increased muscle adiposity is significantly associated with sensorimotor deficits, clinical disability, and functional recovery after surgery. Accurate and time efficient evaluation of fat infiltration in cervical muscles may be conducted through implementation of CNN models.