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Background: Recent advances in data-driven computational approaches have been helpful in devising tools to objectively diagnose psychiatric disorders. However, current machine learning studies limited to small homogeneous samples, different methodologies, and different imaging collection protocols, limit the ability to directly compare and generalize their results. Here we aimed to classify individuals with PTSD versus controls and assess the generalizability using a large heterogeneous brain datasets from the ENIGMA-PGC PTSD Working group. Methods: We analyzed brain MRI data from 3,477 structural-MRI; 2,495 resting state-fMRI; and 1,952 diffusion-MRI. First, we identified the brain features that best distinguish individuals with PTSD from controls using traditional machine learning methods. Second, we assessed the utility of the denoising variational autoencoder (DVAE) and evaluated its classification performance. Third, we assessed the generalizability and reproducibility of both models using leave-one-site-out cross-validation procedure for each modality. Results: We found lower performance in classifying PTSD vs. controls with data from over 20 sites (60 % test AUC for s-MRI, 59 % for rs-fMRI and 56 % for d-MRI), as compared to other studies run on single-site data. The performance increased when classifying PTSD from HC without trauma history in each modality (75 % AUC). The classification performance remained intact when applying the DVAE framework, which reduced the number of features. Finally, we found that the DVAE framework achieved better generalization to unseen datasets compared with the traditional machine learning frameworks, albeit performance was slightly above chance. Conclusion: These results have the potential to provide a baseline classification performance for PTSD when using large scale neuroimaging datasets. Our findings show that the control group used can heavily affect classification performance. The DVAE framework provided better generalizability for the multi-site data. This may be more significant in clinical practice since the neuroimaging-based diagnostic DVAE classification models are much less site-specific, rendering them more generalizable.

IntroductionReal-time fMRI-based neurofeedback (rt-fMRI-NFB) is a non-invasive technology that enables individuals to self-regulate brain activity linked to neuropsychiatric symptoms, including those associated with post-traumatic stress disorder (PTSD). Selecting the target brain region for neurofeedback-mediated regulation is primarily informed by the neurobiological characteristics of the participant population. There is a strong link between PTSD symptoms and multiple functional disruptions in the brain, including hyperactivity within both the amygdala and posterior cingulate cortex (PCC) during trauma-related processing. As such, previous rt-fMRI-NFB studies have focused on these two target regions when training individuals with PTSD to regulate neural activity. However, the differential effects of neurofeedback target selection on PTSD-related neural activity and clinical outcomes have not previously been investigated.MethodsHere, we compared whole-brain activation and changes in PTSD symptoms between PTSD participants (n = 28) that trained to downregulate activity within either the amygdala (n = 14) or the PCC (n = 14) while viewing personalized trauma words.ResultsFor the PCC as compared to the amygdala group, we observed decreased neural activity in several regions implicated in PTSD psychopathology – namely, the bilateral cuneus/precuneus/primary visual cortex, the left superior parietal lobule, the left occipital pole, and the right superior temporal gyrus/temporoparietal junction (TPJ) – during target region downregulation using rt-fMRI-NFB. Conversely, for the amygdala as compared to the PCC group, there were no unique (i.e., over and above that of the PCC group) decreases in neural activity. Importantly, amygdala downregulation was not associated with significantly improved PTSD symptoms, whereas PCC downregulation was associated with reduced reliving and distress symptoms over the course of this single training session. In this pilot analysis, we did not detect significant between-group differences in state PTSD symptoms during neurofeedback. As a critical control, the PCC and amygdala groups did not differ in their ability to downregulate activity within their respective target brain regions. This indicates that subsequent whole-brain neural activation results can be attributed to the effects of the neurofeedback target region selection in terms of neurophysiological function, rather than as a result of group differences in regulatory success.ConclusionIn this study, neurofeedback-mediated downregulation of the PCC was differentially associated with reduced state PTSD symptoms and simultaneous decreases in PTSD-associated brain activity during a single training session. This novel analysis may guide researchers in choosing a neurofeedback target region in future rt-fMRI-NFB studies and help to establish the clinical efficacy of specific neurofeedback targets for PTSD. A future multi-session clinical trial of rt-fMRI-NFB that directly compares between PCC and amygdala target regions is warranted.

Abstract Cholinergic dysfunction has been implicated in the pathophysiology of psychosis and psychiatric disorders such as schizophrenia, depression, and bipolar disorder. The basal forebrain (BF) cholinergic nuclei, defined as cholinergic cell groups Ch1-3 and Ch4 (Nucleus Basalis of Meynert; NBM), provide extensive cholinergic projections to the rest of the brain. Here, we examined microstructural neuroimaging measures of the cholinergic nuclei in patients with untreated psychosis (~31 weeks of psychosis, 0.05). Case-control differences in qT1 and AxD were observed in the Ch1-3, with increased qT1 (reflecting reduced myelin content) and AxD (reflecting reduced axonal integrity). We found clinical correlates between left NBM qT1 with manic symptom severity, and AxD with negative symptom burden in FEP. Intracortical and subcortical myelin maps were derived and correlated with BF myelin. BF-cortical and BF-subcortical myelin correlations demonstrate known projection patterns from the BF. Using data from the Allen Human Brain Atlas, cholinergic nuclei showed significant enrichment for schizophrenia and depression-related genes. Cell-type specific enrichment indicated enrichment for cholinergic neuron markers as expected. Further relating the neuroimaging correlations to transcriptomics demonstrated links with cholinergic receptor genes and cell type markers of oligodendrocytes and cholinergic neurons, providing biological validity to the measures. These results provide genetic, neuroimaging, and clinical evidence for cholinergic dysfunction in schizophrenia.

Abstract Background Alterations within large‐scale brain networks—namely, the default mode (DMN) and salience networks (SN)—are present among individuals with posttraumatic stress disorder (PTSD). Previous real‐time functional magnetic resonance imaging (fMRI) and electroencephalography neurofeedback studies suggest that regulating posterior cingulate cortex (PCC; the primary hub of the posterior DMN) activity may reduce PTSD symptoms and recalibrate altered network dynamics. However, PCC connectivity to the DMN and SN during PCC‐targeted fMRI neurofeedback remains unexamined and may help to elucidate neurophysiological mechanisms through which these symptom improvements may occur. Methods Using a trauma/emotion provocation paradigm, we investigated psychophysiological interactions over a single session of neurofeedback among PTSD (n = 14) and healthy control (n = 15) participants. We compared PCC functional connectivity between regulate (in which participants downregulated PCC activity) and view (in which participants did not exert regulatory control) conditions across the whole‐brain as well as in a priori specified regions‐of‐interest. Results During regulate as compared to view conditions, only the PTSD group showed significant PCC connectivity with anterior DMN (dmPFC, vmPFC) and SN (posterior insula) regions, whereas both groups displayed PCC connectivity with other posterior DMN areas (precuneus/cuneus). Additionally, as compared with controls, the PTSD group showed significantly greater PCC connectivity with the SN (amygdala) during regulate as compared to view conditions. Moreover, linear regression analyses revealed that during regulate as compared to view conditions, PCC connectivity to DMN and SN regions was positively correlated to psychiatric symptoms across all participants. Conclusion In summary, observations of PCC connectivity to the DMN and SN provide emerging evidence of neural mechanisms underlying PCC‐targeted fMRI neurofeedback among individuals with PTSD. This supports the use of PCC‐targeted neurofeedback as a means by which to recalibrate PTSD‐associated alterations in neural connectivity within the DMN and SN, which together, may help to facilitate improved emotion regulation abilities in PTSD.

Abstract Myo-inositol is mainly found in astroglia and its levels has been shown to be reduced in the anterior cingulate cortex (ACC) of patients with schizophrenia. We investigate the status of astroglial integrity indexed by ACC myo-inositol at the onset and over the first 6 months of treatment of first episode schizophrenia. We employed 7 T magnetic resonance spectroscopy (1H-MRS) and quantified myo-inositol spectra at the dorsal ACC in 31 participants; 21 patients with schizophrenia with median lifetime antipsychotic exposure of less than 3 days, followed up after 6 months of treatment, and 10 healthy subjects scanned twice over the same period. We studied the time by group interaction for myo-inositol after adjusting for gender and age. We report significant reduction in myo-inositol concentration in the ACC in schizophrenia at an early, untreated state of acute illness that becomes insignificant over time, after instituting early intervention. This trajectory indicates that dynamic astroglial changes are likely to operate in the early stages of schizophrenia. MRS myo-inositol may be a critical marker of amelioration of active psychosis in early stages of schizophrenia.

Neural representations of sensory percepts and motor responses constitute key elements of autobiographical memory. However, these representations may remain as unintegrated sensory and motor fragments in traumatic memory, thus contributing toward re-experiencing and reliving symptoms in trauma-related conditions such as post-traumatic stress disorder (PTSD). Here, we investigated the sensorimotor network (SMN) and posterior default mode network (pDMN) using a group independent component analysis (ICA) by examining their functional connectivity during a script-driven memory retrieval paradigm of (potentially) morally injurious events in individuals with PTSD and healthy controls. Moral injury (MI), where an individual acts or fails to act in a morally aligned manner, is examined given its inherent ties to disrupted motor planning and thus sensorimotor mechanisms. Our findings revealed significant differences in functional network connectivity across the SMN and pDMN during MI retrieval in participants with PTSD (n = 65) as compared to healthy controls (n = 25). No such significant group-wise differences emerged during retrieval of a neutral memory. PTSD-related alterations included hyperconnectivity between the SMN and pDMN, enhanced within-network connectivity of the SMN with premotor areas, and increased recruitment of the supramarginal gyrus into both the SMN and the pDMN during MI retrieval. In parallel with these neuroimaging findings, a positive correlation was found between PTSD severity and subjective re-experiencing intensity ratings after MI retrieval. These results suggest a neural basis for traumatic re-experiencing, where reliving and/or re-enacting a past morally injurious event in the form of sensory and motor fragments occurs in place of retrieving a complete, past-contextualized narrative as put forth by Brewin and colleagues (1996) and Conway and Pleydell-Pearce (2000). These findings have implications for bottom-up treatments targeting directly the sensory and motoric elements of traumatic experiences.

IntroductionSymptoms of schizophrenia are closely related to aberrant language comprehension and production. Macroscopic brain changes seen in some patients with schizophrenia are suspected to relate to impaired language production, but this is yet to be reliably characterized. Since heterogeneity in language dysfunctions, as well as brain structure, is suspected in schizophrenia, we aimed to first seek patient subgroups with different neurobiological signatures and then quantify linguistic indices that capture the symptoms of “negative formal thought disorder” (i.e., fluency, cohesion, and complexity of language production).MethodsAtlas-based cortical thickness values (obtained with a 7T MRI scanner) of 66 patients with first-episode psychosis and 36 healthy controls were analyzed with hierarchical clustering algorithms to produce neuroanatomical subtypes. We then examined the generated subtypes and investigated the quantitative differences in MRS-based glutamate levels [in the dorsal anterior cingulate cortex (dACC)] as well as in three aspects of language production features: fluency, syntactic complexity, and lexical cohesion.ResultsTwo neuroanatomical subtypes among patients were observed, one with near-normal cortical thickness patterns while the other with widespread cortical thinning. Compared to the subgroup of patients with relatively normal cortical thickness patterns, the subgroup with widespread cortical thinning was older, with higher glutamate concentration in dACC and produced speech with reduced mean length of T-units (complexity) and lower repeats of content words (lexical cohesion), despite being equally fluent (number of words).ConclusionWe characterized a patient subgroup with thinner cortex in first-episode psychosis. This subgroup, identifiable through macroscopic changes, is also distinguishable in terms of neurochemistry (frontal glutamate) and language behavior (complexity and cohesion of speech). This study supports the hypothesis that glutamate-mediated cortical thinning may contribute to a phenotype that is detectable using the tools of computational linguistics in schizophrenia.

Abstract Background Accurate quantification of radioactivity, measured by an integrated positron emission tomography (PET) and magnetic resonance imaging (MRI) system, is still a challenge. One aspect of such a challenge is to correct for the hardware attenuation, such as the patient table and radio frequency (RF) resonators. For PET/MRI systems, computed tomography (CT) is commonly used to produce hardware attenuation correction (AC) maps, by converting Hounsfield units (HU) to a linear attenuation coefficients (LAC) map at the PET energy level 511 keV, using a bilinear model. The model does not address beam hardening, nor higher density materials, which can lead to inaccurate corrections. Purpose In this study, we introduce a transmission-based (TX-based) AC technique with a static Germanium-68 (Ge-68) transmission source to generate hardware AC maps using the PET/MRI system itself, without the need for PET or medical CT scanners. The AC TX-based maps were generated for a homogeneous cylinder, made of acrylic as a validator. The technique thereafter was applied to the patient table and posterior part of an RF-phased array used in cardiovascular PET/MRI imaging. The proposed TX-based, and the CT-based, hardware maps were used in reconstructing PET images of one cardiac patient, and the results were analysed and compared. Results The LAC derived by the TX-based method for the acrylic cylinder is estimated to be 0.10851 ± 0.00380 cm−1 compared to the 0.10698 ± 0.00321 cm−1 theoretical value reported in the literature. The PET photon counts were reduced by 8.7 ± 1.1% with the patient table, at the region used in cardiac scans, while the CT-based map, used for correction, over-estimated counts by 4.3 ± 1.3%. Reconstructed in vivo images using TX-based AC hardware maps have shown 4.1 ± 0.9% mean difference compared to those reconstructed images using CT-based AC. Conclusions The LAC of the acrylic cylinder measurements using the TX-based technique was in agreement with those in the literature confirming the validity of the technique. The over-estimation of photon counts caused by the CT-based model used for the patient table was improved by the TX-based technique. Therefore, TX-based AC of hardware using the PET/MRI system itself is possible and can produce more accurate images when compared to the CT-based hardware AC in cardiac PET images.

BackgroundIncreasing evidence points toward the need to extend the neurobiological conceptualization of posttraumatic stress disorder (PTSD) to include evolutionarily conserved neurocircuitries centered on the brainstem and the midbrain. The reticular activating system (RAS) helps to shape the arousal state of the brain, acting as a bridge between brain and body. To modulate arousal, the RAS is closely tied to the autonomic nervous system (ANS). Individuals with PTSD often reveal altered arousal patterns, ranging from hyper- to blunted arousal states, as well as altered functional connectivity profiles of key arousal-related brain structures that receive direct projections from the RAS. Accordingly, the present study aims to explore resting state functional connectivity of the RAS and its interaction with the ANS in participants with PTSD and its dissociative subtype.MethodsIndividuals with PTSD (n = 57), its dissociative subtype (PTSD + DS, n = 32) and healthy controls (n = 40) underwent a 6-min resting functional magnetic resonance imaging and pulse data recording. Resting state functional connectivity (rsFC) of a central node of the RAS – the pedunculopontine nuclei (PPN) – was investigated along with its relation to ANS functioning as indexed by heart rate variability (HRV). HRV is a prominent marker indexing the flexibility of an organism to react adaptively to environmental needs, with higher HRV representing greater effective adaptation.ResultsBoth PTSD and PTSD + DS demonstrated reduced HRV as compared to controls. HRV measures were then correlated with rsFC of the PPN. Critically, participants with PTSD and participants with PTSD + DS displayed inverse correlations between HRV and rsFC between the PPN and key limbic structures, including the amygdala. Whereas participants with PTSD displayed a positive relationship between HRV and PPN rsFC with the amygdala, participants with PTSD + DS demonstrated a negative relationship between HRV and PPN rsFC with the amygdala.ConclusionThe present exploratory investigation reveals contrasting patterns of arousal-related circuitry among participants with PTSD and PTSD + DS, providing a neurobiological lens to interpret hyper- and more blunted arousal states in PTSD and PTSD + DS, respectively.

Abstract Background Simultaneous cardiovascular imaging with positron emission tomography (PET) and magnetic resonance imaging (MRI) requires tools such as radio frequency (RF) phased arrays to achieve high temporal and spatial resolution in the MRI, as well as accurate quantification of PET. Today, high-density phased arrays (> 16 channels) used for cardiovascular PET/MRI are not designed to achieve low PET attenuation, and correcting the PET attenuation they cause requires off-line reconstruction, extra time and resources. Purpose Motivated by previous work assessing the MRI performance of a novel prospectively designed 32-channel phased array, this study assessed the PET image quality with this array in place. Guided by NEMA standards, PET performance was measured using global PET counts, regional background variation (BV), contrast recovery (CR) and contrast-to-noise ratio (CNR) for both the novel array and standard arrays (mMR 12-channel and MRI 32-channel). Nonattenuation-corrected (NAC) data from all arrays (and each part of the array) were processed and compared to no-array, and relative percentage difference (RPD) of the global means was estimated and reported for each part of the arrays. Attenuation correction (AC) of PET images (water in the phantom) using two approaches, MR-based AC map (MRAC) and dual-energy CT-based map (DCTAC), was performed, and RPD compared for each part of the arrays. Percent mean attenuation within regions of interests of the phantom images from each array were compared using a two-way analysis of variance (ANOVA). Results The NAC data of the anterior part of the novel array recorded the least PET attenuation (≤ 2%); while the full novel array (anterior and posterior together) AC data, produced by MRAC and DCTAC approaches, recorded attenuation of 1.5 ± 2.9% and 0.0 ± 2.5%, respectively. The novel array PET count loss was significantly lower (p = 0.001) than those caused by the standard arrays. Conclusions Results of this novel 32-channel cardiac array PET performance evaluation, together with its previously reported MRI performance assessment, suggest the novel array to be a strong alternative to the standard arrays currently used for cardiovascular hybrid PET/MRI imaging. It enables accurate PET quantification and high-temporal and spatial resolution for MR imaging.

Microstates offer a promising framework to study fast-scale brain dynamics in the resting-state electroencephalogram (EEG). However, microstate dynamics have yet to be investigated in post-traumatic stress disorder (PTSD), despite research demonstrating resting-state alterations in PTSD. We performed microstate-based segmentation of resting-state EEG in a clinical population of participants with PTSD (N = 61) and a non-traumatized, healthy control group (N = 61). Microstate-based measures (i.e., occurrence, mean duration, time coverage) were compared group-wise using broadband (1–30 Hz) and frequency-specific (i.e., delta, theta, alpha, beta bands) decompositions. In the broadband comparisons, the centro-posterior maximum microstate (map E) occurred significantly less frequently (d = -0.64, pFWE = 0.03) and had a significantly shorter mean duration in participants with PTSD as compared to controls (d = -0.71, pFWE

Abstract Background Intrinsic connectivity networks, including the default mode network (DMN), are frequently disrupted in individuals with posttraumatic stress disorder (PTSD). The posterior cingulate cortex (PCC) is the main hub of the posterior DMN, where the therapeutic regulation of this region with real‐time fMRI neurofeedback (NFB) has yet to be explored. Methods We investigated PCC downregulation while processing trauma/stressful words over 3 NFB training runs and a transfer run without NFB (total n = 29, PTSD n = 14, healthy controls n = 15). We also examined the predictive accuracy of machine learning models in classifying PTSD versus healthy controls during NFB training. Results Both the PTSD and healthy control groups demonstrated reduced reliving symptoms in response to trauma/stressful stimuli, where the PTSD group additionally showed reduced symptoms of distress. We found that both groups were able to downregulate the PCC with similar success over NFB training and in the transfer run, although downregulation was associated with unique within‐group decreases in activation within the bilateral dmPFC, bilateral postcentral gyrus, right amygdala/hippocampus, cingulate cortex, and bilateral temporal pole/gyri. By contrast, downregulation was associated with increased activation in the right dlPFC among healthy controls as compared to PTSD. During PCC downregulation, right dlPFC activation was negatively correlated to PTSD symptom severity scores and difficulties in emotion regulation. Finally, machine learning algorithms were able to classify PTSD versus healthy participants based on brain activation during NFB training with 80% accuracy. Conclusions This is the first study to investigate PCC downregulation with real‐time fMRI NFB in both PTSD and healthy controls. Our results reveal acute decreases in symptoms over training and provide converging evidence for EEG‐NFB targeting brain networks linked to the PCC.

Abstract Background Posttraumatic stress disorder (PTSD) is associated with markers of accelerated aging. Estimates of brain age, compared to chronological age, may clarify the effects of PTSD on the brain and may inform treatment approaches targeting the neurobiology of aging in the context of PTSD. Method Adult subjects (N = 2229; 56.2% male) aged 18–69 years (mean = 35.6, SD = 11.0) from 21 ENIGMA‐PGC PTSD sites underwent T1‐weighted brain structural magnetic resonance imaging, and PTSD assessment (PTSD+, n = 884). Previously trained voxel‐wise (brainageR) and region‐of‐interest (BARACUS and PHOTON) machine learning pipelines were compared in a subset of control subjects (n = 386). Linear mixed effects models were conducted in the full sample (those with and without PTSD) to examine the effect of PTSD on brain predicted age difference (brain PAD; brain age − chronological age) controlling for chronological age, sex, and scan site. Results BrainageR most accurately predicted brain age in a subset (n = 386) of controls (brainageR: ICC = 0.71, R = 0.72, MAE = 5.68; PHOTON: ICC = 0.61, R = 0.62, MAE = 6.37; BARACUS: ICC = 0.47, R = 0.64, MAE = 8.80). Using brainageR, a three‐way interaction revealed that young males with PTSD exhibited higher brain PAD relative to male controls in young and old age groups; old males with PTSD exhibited lower brain PAD compared to male controls of all ages. Discussion Differential impact of PTSD on brain PAD in younger versus older males may indicate a critical window when PTSD impacts brain aging, followed by age‐related brain changes that are consonant with individuals without PTSD. Future longitudinal research is warranted to understand how PTSD impacts brain aging across the lifespan.

Abstract Background Cardiovascular imaging using hybrid positron emission tomography (PET) and magnetic resonance imaging (MRI) requires a radio frequency phased array resonator capable of high acceleration factors in order to achieve the shortest breath-holds while maintaining optimal MRI signal-to-noise ratio (SNR) and minimum PET photon attenuation. To our knowledge, the only two arrays used today for hybrid PET/MRI cardiovascular imaging are either incapable of achieving high acceleration or affect the PET photon count greatly. Purpose This study is focused on the evaluation of the MRI performance of a novel third-party prototype 32-channel phased array designed for simultaneous PET/MRI cardiovascular imaging. The study compares the quality parameters of MRI parallel imaging, such as g-factor, noise correlation coefficients, and SNR, to the conventional arrays (mMR 12-channel and MRI-only 32-channel) currently used with hybrid PET/MRI systems. The quality parameters of parallel imaging were estimated for multiple acceleration factors on a phantom and three healthy volunteers. Using a Germanium-68 (Ge-68) phantom, preliminary measurements of PET photon attenuation caused by the novel array were briefly compared to the photon counts produced from no-array measurements. Results The global mean of the g-factor and SNRg produced by the novel 32-channel PET/MRI array were better than those produced by the MRI-only 32-channel array by 5% or more. The novel array has resulted in MRI SNR improvements of > 30% at all acceleration factors, in comparison to the mMR12-channel array. Preliminary evaluation of PET transparency showed less than 5% photon attenuation caused by both anterior and posterior parts of the novel array. Conclusions The MRI performance of the novel PET/MRI 32-channel array qualifies it to be a viable alternative to the conventional arrays for cardiovascular hybrid PET/MRI. A detailed evaluation of the novel array’s PET performance remains to be conducted, but cursory assessment promises significantly reduced attenuation.

In people with mental health issues, approximately 20% have co-occurring substance use, often involving cannabis. Although emotion regulation can be affected both by major depressive disorder (MDD) and by cannabis use, the relationship among all three factors is unknown. In this study, we used fMRI to evaluate the effect that cannabis use and MDD have on brain activation during an emotion regulation task. Differences were assessed in 74 emerging adults aged 16–23 with and without MDD who either used or did not use cannabis. Severity of depressive symptoms, emotion regulation style, and age of cannabis use onset were also measured. Both MDD and cannabis use interacted with the emotion regulation task in the left temporal lobe, however the location of the interaction differed for each factor. Specifically, MDD showed an interaction with emotion regulation in the middle temporal gyrus, whereas cannabis use showed an interaction in the superior temporal gyrus. Emotion regulation style predicted activity in the right superior frontal gyrus, however, this did not interact with MDD or cannabis use. Severity of depressive symptoms interacted with the emotion regulation task in the left middle temporal gyrus. The results highlight the influence of cannabis use and MDD on emotion regulation processing, suggesting that both may have a broader impact on the brain than previously thought.

Schizophrenia continues to be an illness with poor outcome. Most mechanistic changes occur many years before the first episode of schizophrenia; these are not reversible after the illness onset. A developmental mechanism that is still modifiable in adult life may center on intracortical glutathione (GSH). A large body of pre-clinical data has suggested the possibility of notable GSH-deficit in a subgroup of patients with schizophrenia. Nevertheless, studies of intracortical GSH are not conclusive in this regard. In this review, we highlight the recent ultra-high field magnetic resonance spectroscopic studies linking GSH to critical outcome measures across various stages of schizophrenia. We discuss the methodological steps required to conclusively establish or refute the persistence of GSH-deficit subtype and clarify the role of the central antioxidant system in disrupting the brain structure and connectivity in the early stages of schizophrenia. We propose in-vivo GSH quantification for patient selection in forthcoming antioxidant trials in psychosis. This review offers directions for a promising non-dopaminergic early intervention approach in schizophrenia.

Objective: The default-mode network (DMN) and salience network (SN) have been shown to display altered connectivity in posttraumatic stress disorder (PTSD). Restoring aberrant connectivity within these networks with electroencephalogram neurofeedback (EEG-NFB) has been shown previously to be associated with acute decreases in symptoms. Here, we conducted a double-blind, sham-controlled randomized trial of alpha-rhythm EEG-NFB in participants with PTSD (n = 36) over 20-weeks. Our aim was to provide mechanistic evidence underlying clinical improvements by examining changes in network connectivity via fMRI. Methods: We randomly assigned participants with a primary diagnosis of PTSD to either the experimental group (n = 18) or sham-control group (n = 18). We collected resting-state fMRI scans pre- and post-NFB intervention, for both the experimental and sham-control PTSD groups. We further compared baseline brain connectivity measures pre-NFB to age-matched healthy controls (n = 36). Results: With regard to the primary outcome measure of PTSD severity, we found a significant main effect of time in the absence of a group × time interaction. Nevertheless, we found significantly decreased PTSD severity scores in the experimental NFB group only, when comparing post-NFB (dz = 0.71) and 3-month follow-up scores (dz = 0.77) to baseline measures. Interestingly, we found evidence to suggest a shift towards normalization of DMN and SN connectivity post-NFB in the experimental group only. Both decreases in PTSD severity and NFB performance were correlated to DMN and SN connectivity post-NFB in the experimental group. Critically, remission rates of PTSD were significant higher in the experimental group (61.1%) as compared to the sham-control group (33.3%). Conclusion: The current study shows mechanistic evidence for therapeutic changes in DMN and SN connectivity that are known to be associated with PTSD psychopathology with no patient dropouts. This preliminary investigation merits further research to demonstrate fully the clinical efficacy of EEG-NFB as an adjunctive therapy for PTSD.

Self-related processes define assorted self-relevant or social-cognitive functions that allow us to gather insight and to draw inferences related to our own mental conditions. Self-related processes are mediated by the default mode network (DMN), which, critically, shows altered functionality in individuals with posttraumatic stress disorder (PTSD). In PTSD, the midbrain periaqueductal gray (PAG) demonstrates stronger functional connectivity with the DMN [i.e., precuneus (PCN), medial prefrontal cortex (mPFC)] as compared to healthy individuals during subliminal, trauma-related stimulus processing. Here, we analyzed the directed functional connectivity between the PAG and the PCN, as well as between the PAG and the mPFC to more explicitly characterize the functional connectivity we have observed previously on the corresponding sample and paradigm. We evaluated three models varying with regard to context-dependent modulatory directions (i.e., bi-directional, bottom-up, top-down) among individuals with PTSD (n = 26) and healthy participants (n = 20), where Bayesian model selection was used to identify the most optimal model for each group. We then compared the effective connectivity strength for each parameter across the models and between our groups using Bayesian model averaging. Bi-directional models were found to be favoured across both groups. In PTSD, we revealed the PAG to show stronger excitatory effective connectivity to the PCN, as well as to the mPFC as compared to controls. In PTSD, we further demonstrated that PAG-mediated effective connectivity to the PCN, as well as to the mPFC were modulated more strongly during subliminal, trauma-related stimulus conditions as compared to controls. Clinical disturbances towards self-related processes are reported widely by participants with PTSD during trauma-related stimulus processing, where altered functional connectivity directed by the PAG to the DMN may elucidate experiential links between self- and trauma-related processing in traumatized individuals.

Intrinsic connectivity networks (ICNs), including the default mode network (DMN), the central executive network (CEN), and the salience network (SN) have been shown to be aberrant in patients with posttraumatic stress disorder (PTSD). The purpose of the current study was to a) compare ICN functional connectivity between PTSD, dissociative subtype PTSD (PTSD+DS) and healthy individuals; and b) to examine the use of multivariate machine learning algorithms in classifying PTSD, PTSD+DS, and healthy individuals based on ICN functional activation. Our neuroimaging dataset consisted of resting-state fMRI scans from 186 participants [PTSD (n = 81); PTSD + DS (n = 49); and healthy controls (n = 56)]. We performed group-level independent component analyses to evaluate functional connectivity differences within each ICN. Multiclass Gaussian Process Classification algorithms within PRoNTo software were then used to predict the diagnosis of PTSD, PTSD+DS, and healthy individuals based on ICN functional activation. When comparing the functional connectivity of ICNs between PTSD, PTSD+DS and healthy controls, we found differential patterns of connectivity to brain regions involved in emotion regulation, in addition to limbic structures and areas involved in self-referential processing, interoception, bodily self-consciousness, and depersonalization/derealization. Machine learning algorithms were able to predict with high accuracy the classification of PTSD, PTSD+DS, and healthy individuals based on ICN functional activation. Our results suggest that alterations within intrinsic connectivity networks may underlie unique psychopathology and symptom presentation among PTSD subtypes. Furthermore, the current findings substantiate the use of machine learning algorithms for classifying subtypes of PTSD illness based on ICNs.

Background: Oculomotor movements have been shown to aid in the retrieval of episodic memories, serving as sensory cues that engage frontoparietal brain regions to reconstruct visuospatial details of a memory. Frontoparietal brain regions not only are involved in oculomotion, but also mediate, in part, the retrieval of autobiographical episodic memories and assist in emotion regulation. Objective: We sought to investigate how oculomotion influences retrieval of traumatic memories by examining patterns of frontoparietal brain activation during autobiographical memory retrieval in post-traumatic stress disorder (PTSD) and in healthy controls. Method: Thirty-nine participants (controls, n = 19; PTSD, n = 20) recollected both neutral and traumatic/stressful autobiographical memories while cued simultaneously by horizontal and vertical oculomotor stimuli. The frontal (FEF) and supplementary (SEF) eye fields were used as seed regions for psychophysiological interaction analyses in SPM12. Results: As compared to controls, upon retrieval of a traumatic/stressful memory while also performing simultaneous horizontal eye movements, PTSD showed: i) increased SEF and FEF connectivity with the right dorsolateral prefrontal cortex, ii) increased SEF connectivity with the right dorsomedial prefrontal cortex, and iii) increased SEF connectivity with the right anterior insula. By contrast, as compared to PTSD, upon retrieval of a traumatic/stressful memory while also performing simultaneous horizontal eye movements, controls showed: i) increased FEF connectivity with the right posterior insula and ii) increased SEF connectivity with the precuneus. Conclusions: These findings provide a neurobiological account for how oculomotion may influence the frontoparietal cortical representation of traumatic memories. Implications for eye movement desensitization and reprocessing are discussed.

Background Brainstem and midbrain neuronal circuits that control innate, reflexive responses and arousal are increasingly recognized as central to the neurobiological framework of post-traumatic stress disorder (PTSD). The reticular activation system represents a fundamental neuronal circuit that plays a critical role not only in generating arousal but also in coordinating innate, reflexive responding. Accordingly, the present investigation aims to characterize the resting state functional connectivity of the reticular activation system in PTSD and its dissociative subtype. Methods We investigated patterns of resting state functional connectivity of a central node of the reticular activation system, namely, the pedunculopontine nuclei, among individuals with PTSD (n = 77), its dissociative subtype (PTSD+DS; n = 48), and healthy controls (n = 51). Results Participants with PTSD and PTSD+DS were characterized by within-group pedunculopontine nuclei resting state functional connectivity to brain regions involved in innate threat processing and arousal modulation (i.e., midbrain, amygdala, ventromedial prefrontal cortex). Critically, this pattern was most pronounced in individuals with PTSD+DS, as compared to both control and PTSD groups. As compared to participants with PTSD and controls, individuals with PTSD+DS showed enhanced pedunculopontine nuclei resting state functional connectivity to the amygdala and the parahippocampal gyrus as well as to the anterior cingulate and the ventromedial prefrontal cortex. No group differences emerged between PTSD and control groups. In individuals with PTSD+DS, state derealization/depersonalization was associated with reduced resting state functional connectivity between the left pedunculopontine nuclei and the anterior nucleus of the thalamus. Altered connectivity in these regions may restrict the thalamo-cortical transmission necessary to integrate internal and external signals at a cortical level and underlie, in part, experiences of depersonalization and derealization. Conclusions The present findings extend the current neurobiological model of PTSD and provide emerging evidence for the need to incorporate brainstem structures, including the reticular activation system, into current conceptualizations of PTSD and its dissociative subtype.

Background The innate alarm system consists of a subcortical network of interconnected midbrain, lower brainstem, and thalamic nuclei, which together mediate the detection of evolutionarily-relevant stimuli. The periaqueductal gray is a midbrain structure innervated by the innate alarm system that coordinates the expression of defensive states following threat detection. In participants with post-traumatic stress disorder, the periaqueductal gray displays overactivation during the subliminal presentation of trauma-related stimuli as well as altered resting-state functional connectivity. Aberrant functional connectivity is also reported in post-traumatic stress disorder for the default-mode network, a large-scale brain network recruited during self-referential processing and autobiographical memory. Here, research lacks investigation on the extent to which functional interactions are displayed between the midbrain and the large-scale cortical networks in post-traumatic stress disorder. Methods Using a subliminal threat presentation paradigm, we investigated psycho-physiological interactions during functional neuroimaging in participants with post-traumatic stress disorder (n = 26) and healthy control subjects (n = 20). Functional connectivity of the periaqueductal gray was investigated across the whole-brain of each participant during subliminal exposure to trauma-related and neutral word stimuli. Results As compared to controls during subliminal threat presentation, the post-traumatic stress disorder group showed significantly greater periaqueductal gray functional connectivity with regions of the default-mode network (i.e., angular gyrus, precuneus, superior frontal gyrus). Moreover, multiple regression analyses revealed that the functional connectivity between the periaqueductal gray and the regions of the default-mode network correlated positively to symptoms of avoidance and state dissociation in post-traumatic stress disorder. Conclusion Given that the periaqueductal gray engages the expression of defensive states, stronger midbrain functional coupling with the default-mode network may have clinical implications to self-referential and trauma-related processing in participants with post-traumatic stress disorder.

A substantial number of individuals with clinical high-risk (CHR) mental state do not transition to psychosis. However, regardless of future diagnostic trajectories, many of these individuals develop poor social and occupational functional outcomes. The levels of glutathione, a crucial cortical antioxidant, may track variations in functional outcomes in early psychosis and prodromal states. Thirteen clinical high-risk and 30 healthy control volunteers were recruited for a 7-Tesla magnetic resonance spectroscopy scan with a voxel positioned within the dorsal anterior cingulate cortex (ACC). Clinical assessment scores were collected to determine if any association was observable with glutathione levels. The Bayesian Spearman’s test revealed a positive association between the Social and Occupational Functioning Assessment Scale (SOFAS) and the glutathione concentration in the clinical high-risk group but not in the healthy control group. After accounting for variations in the SOFAS scores, the CHR group had higher GSH levels than the healthy subjects. This study is the first to use 7-Tesla magnetic resonance spectroscopy to test whether ACC glutathione levels relate to social and occupational functioning in a clinically high-risk group and offers preliminary support for glutathione levels as a clinically actionable marker of prognosis in emerging adults presenting with risk features for various severe mental illnesses.

Background Examining neurometabolic abnormalities in critical brain areas in schizophrenia and major depressive disorder (MDD) may help guide future pharmacological interventions including glutamate-modulating treatments. Aims To measure metabolite concentrations within the anterior cingulate cortex (ACC) and thalamus of people with schizophrenia and people with MDD. Methods Spectra were acquired from 16 volunteers with schizophrenia, 17 with MDD and 18 healthy controls using magnetic resonance spectroscopy on a 7 Tesla scanner. Results In the thalamus, there were lower glycine concentrations in the schizophrenia group relative to control (P=0.017) and MDD groups (P=0.012), and higher glutamine concentrations relative to healthy controls (P=0.009). In the thalamus and the ACC, the MDD group had lower myo-inositol concentrations than the control (P=0.014, P=0.009, respectively) and schizophrenia (P=0.004, P=0.002, respectively) groups. Conclusion These results support the glutamatergic theory of schizophrenia and indicate a potential glycine deficiency in the thalamus. In addition, reduced myo-inositol concentrations in MDD suggest its involvement in the disorder.

Oxidative stress plays a key role in the pathophysiology of schizophrenia. While free radicals produced by glutamatergic excess and oxidative metabolism have damaging effects on brain tissue, antioxidants such as glutathione (GSH) counteract these effects. The interaction between glutamate (GLU) and GSH is centered on N-Methyl-D-aspartate (NMDA) receptors. GSH levels increase during glutamate-mediated excitatory neuronal activity, which serves as a checkpoint to protect neurons from oxidative damage and reduce excitatory overdrive. We studied the possible influence of GSH on the glutamate-mediated dysconnectivity in 19 first-episode schizophrenia (FES) patients and 20 healthy control (HC) subjects. Using ultra-high field (7 Tesla) magnetic resonance spectroscopy (MRS) and resting state functional magnetic resonance imaging (fMRI), we measured GSH and GLU levels in the dorsal anterior cingulate cortex (dACC) and blood-oxygenation level-dependent activity in both the dACC and the anterior insula (AI). Using spectral dynamic causal modeling, we found that when compared to HCs, in FES patients inhibitory activity within the dACC decreased with GLU levels whereas inhibitory activity in both the dACC and AI increased with GSH levels. Our model explains how higher levels of GSH can reverse the downstream pathophysiological effects of a hyperglutamatergic state in FES. This provides an initial insight into the possible mechanistic effect of antioxidant system on the excitatory overdrive in the salience network (dACC-AI).

Background The temporoparietal junction (TPJ) has been linked to lower-level attentional and higher-level social processing, both of which are affected in schizophrenia (SZ) and major depressive disorder (MDD). We examined resting functional connectivity of bilateral anterior and posterior TPJ in SZ and MDD to evaluate potential anomalies in each disorder and differences between disorders. Methods Resting-state functional magnetic resonance imaging data were acquired from 24 patients with SZ, 24 patients with MDD, and 24 age-matched healthy controls. We performed seed-based functional connectivity analyses with seed regions in bilateral anterior and posterior TPJ, covarying for gender and smoking. Results SZ had reduced connectivity versus controls between left anterior TPJ and dorsolateral prefrontal cortex (dlPFC) and posterior cingulate cortex (PCC); between left posterior TPJ and middle cingulate cortex, left dorsal PFC, and right lateral PFC; between right anterior TPJ and bilateral PCC; and between right posterior TPJ and middle cingulate cortex, left posterior insula, and right insula. MDD had reduced connectivity versus controls between left posterior TPJ and right dlPFC and between right posterior TPJ and PCC and dlPFC. SZ had reduced connectivity versus MDD between right posterior TPJ and left fusiform gyrus and right superior-posterior temporal cortex. Conclusion Functional connectivity to the TPJ was demonstrated to be disrupted in both SZ and MDD. However, TPJ connectivity may differ in these disorders with reduced connectivity in SZ versus MDD between TPJ and posterior brain regions.

Background: Several lines of evidence support a role for astroglial pathology in schizophrenia. Myo-inositol is particularly abundant in astroglia. Many small sized studies have reported on myo-inositol concentration in schizophrenia, but to date these have not been pooled to estimate a collective effect size.Methods: We reviewed all proton magnetic resonance spectroscopy (1H-MRS) studies reporting myo-inositol values for patients satisfying DSM or ICD based criteria for schizophrenia in comparison to a healthy controls group in the medial prefrontal cortex published until February 2018. A random-effects model was used to calculate the pooled effect size using metafor package. A meta-regression analysis of moderator variables was also undertaken.Results: The literature search identified 19 studies published with a total sample size of 585 controls, 561 patients with schizophrenia. Patients with schizophrenia had significantly reduced medial prefrontal myo-inositol compared to controls (RFX standardized mean difference = 0.19, 95% CI [0.05–0.32], z = 2.72, p = 0.0067; heterogeneity p = 0.09). Studies with more female patients reported more notable schizophrenia-related reduction in myo-inositol (z = 2.53, p = 0.011).Discussion: We report a small, but significant reduction in myo-inositol concentration in the medial prefrontal cortex in schizophrenia. The size of the reported effect indicates that the biological pathways affecting the astroglia are likely to operate only in a subset of patients with schizophrenia. MRS myo-inositol could be a useful tool to stratify and investigate such patients.

Objective: Electroencephalogram (EEG) neurofeedback aimed at reducing the amplitude of the alpha-rhythm has been shown to alter neural networks associated with posttraumatic stress disorder (PTSD), leading to symptom alleviation. Critically, the amygdala is thought to be one of the central brain regions mediating PTSD symptoms. In the current study, we compare directly patterns of amygdala complex connectivity using fMRI, before and after EEG neurofeedback, in order to observe subcortical mechanisms associated with behavioural and alpha oscillatory changes among patients. Method: We examined basolateral (BLA), centromedial (CMA), and superficial (SFA) amygdala complex resting-state functional connectivity using a seed-based approach via SPM Anatomy Toolbox. Amygdala complex connectivity was measured in twenty-one individuals with PTSD, before and after a 30-minute session of EEG neurofeedback targeting alpha desynchronization. Results: EEG neurofeedback was associated with a shift in amygdala complex connectivity from areas implicated in defensive, emotional, and fear processing/memory retrieval (left BLA and left SFA to the periaqueductal gray, and left SFA to the left hippocampus) to prefrontal areas implicated in emotion regulation/modulation (right CMA to the medial prefrontal cortex). This shift in amygdala complex connectivity was associated with reduced arousal, greater resting alpha synchronization, and was negatively correlated to PTSD symptom severity. Conclusion: These findings have significant implications for developing targeted non-invasive treatment interventions for PTSD patients that utilize alpha oscillatory neurofeedback, showing evidence of neuronal reconfiguration between areas highly implicated in the disorder, in addition to acute symptom alleviation.

Functional magnetic resonance imaging at 7.0 Tesla was undertaken among Schizophrenia participants (Sz), and clinical (major mood disorder; MDD) and healthy controls (HC), during performance of the Stoop task. Stroop conditions included congruent and incongruent word color items, color-only items, and word-only items. Previous modeling results extended to this most widely used selective-attention task. All groups executed item-encoding operations (subprocesses of the item encoding process) at the same rate (performance accuracy being similarly high throughout), thus displaying like processing capacity; Sz participants, however, employed more subprocesses for item completions than did the MDD participants, who in turn used more subprocesses than the HC group. The reduced efficiency in deploying cognitive-workload capacity among the Sz participants was paralleled by more diffuse neuroconnectivity (Blood-Oxygen-Level-Dependent co-activation) with the anterior cingulate cortex (Broadman Area 32), spreading away from this encoding-intensive region; and by less evidence of network dissociation across Stroop conditions. Estimates of cognitive work done to accomplish item completion were greater for the Sz participants, as were estimates of entropy in both the modeled trial-latency distribution, and its associated neuro-circuitry. Findings are held to be symptom and assessment significant, and to have potential implications for clinical intervention

Post-traumatic stress disorder (PTSD) is characterized by altered functional connectivity of the amygdala complexes at rest. However, amygdala complex connectivity during conscious and subconscious threat processing remains to be elucidated. Here, we investigate specific connectivity of the centromedial amygdala (CMA) and basolateral amygdala (BLA) during conscious and subconscious processing of trauma-related words among individuals with PTSD (n = 26) as compared to non-trauma-exposed controls (n = 20). Psycho-physiological interaction analyses were performed using the right and left amygdala complexes as regions of interest during conscious and subconscious trauma word processing. These analyses revealed a differential, context-dependent responses by each amygdala seed during trauma processing in PTSD. Specifically, relative to controls, during subconscious processing, individuals with PTSD demonstrated increased connectivity of the CMA with the superior frontal gyrus, accompanied by a pattern of decreased connectivity between the BLA and the superior colliculus. During conscious processing, relative to controls, individuals with PTSD showed increased connectivity between the CMA and the pulvinar. These findings demonstrate alterations in amygdala subregion functional connectivity in PTSD and highlight the disruption of the innate alarm network during both conscious and subconscious trauma processing in this disorder.