Precision of metabolite-selective MRS measurements of glutamate, GABA and glutathione: A review of human brain studies.

Single-voxel proton magnetic resonance spectroscopy (SV 1 H-MRS) is an in vivo noninvasive imaging technique used to detect neurotransmitters and metabolites. It enables repeated measurements in living participants to build explanatory neurochemical models of psychiatric symptoms and testing of therapeutic approaches. Given the tight link among glutamate, gamma-amino butyric acid (GABA), glutathione and glutamine within the cellular machinery, MRS investigations of neurocognitive and psychiatric disorders must quantify a network of metabolites simultaneously to capture the pathophysiological states of interest. Metabolite-selective sequences typically provide improved metabolite isolation and spectral modelling simplification for a single metabolite at a time. Non-metabolite-selective sequences provide information on all detectable human brain metabolites, but feature many signal overlaps and require complicated spectral modelling. Although there are short-echo time (TE) MRS sequences that do not use spectral editing and are optimised to target either glutamate, GABA or glutathione, these approaches usually imply a precision tradeoff for the remaining two metabolites. Given the interest in assessing psychiatric and neurocognitive diseases that involve excitation-inhibition imbalances along with oxidative stress, there is a need to survey the literature on the quantification precision of current metabolite-selective MRS techniques. In this review, we locate and describe 17 studies that report on the quality of simultaneously acquired MRS metabolite data in the human brain. We note several factors that influence the data quality for single-shot acquisition of multiple metabolites of interest using metabolite-selective MRS: (1) internal in vivo references; (2) brain regions of interests; (3) field strength of scanner; and/or (4) optimised acquisition parameters. We also highlight the strengths and weaknesses of various SV spectroscopy techniques that were able to quantify in vivo glutamate, GABA and glutathione simultaneously. The insights from this review will assist in the development of new MRS pulse sequences for simultaneous, selective measurements of these metabolites and simplified spectral modelling.

Hemodialysis-Related Acute Brain Injury Demonstrated by Application of Intradialytic Magnetic Resonance Imaging and Spectroscopy.

SIGNIFICANCE STATEMENT: Hemodialysis (HD) results in reduced brain blood flow, and HD-related circulatory stress and regional ischemia are associated with brain injury over time. However, studies to date have not provided definitive direct evidence of acute brain injury during a HD treatment session. Using intradialytic magnetic resonance imaging (MRI) and spectroscopy to examine HD-associated changes in brain structure and neurochemistry, the authors found that multiple white (WM) tracts had diffusion imaging changes characteristic of cytotoxic edema, a consequence of ischemic insult and a precursor to fixed structural WM injury. Spectroscopy showed decreases in prefrontal N -acetyl aspartate (NAA) and choline concentrations consistent with energy deficit and perfusion anomaly. This suggests that one HD session can cause brain injury and that studies of interventions that mitigate this treatment's effects on the brain are warranted. BACKGROUND: Hemodialysis (HD) treatment-related hemodynamic stress results in recurrent ischemic injury to organs such as the heart and brain. Short-term reduction in brain blood flow and long-term white matter changes have been reported, but the basis of HD-induced brain injury is neither well-recognized nor understood, although progressive cognitive impairment is common. METHODS: We used neurocognitive assessments, intradialytic anatomical magnetic resonance imaging, diffusion tensor imaging, and proton magnetic resonance spectroscopy to examine the nature of acute HD-associated brain injury and associated changes in brain structure and neurochemistry relevant to ischemia. Data acquired before HD and during the last 60 minutes of HD (during maximal circulatory stress) were analyzed to assess the acute effects of HD on the brain. RESULTS: We studied 17 patients (mean age 63±13 years; 58.8% were male, 76.5% were White, 17.6% were Black, and 5.9% were of Indigenous ethnicity). We found intradialytic changes, including the development of multiple regions of white matter exhibiting increased fractional anisotropy with associated decreases in mean diffusivity and radial diffusivity-characteristic features of cytotoxic edema (with increase in global brain volumes). We also observed decreases in proton magnetic resonance spectroscopy-measured N -acetyl aspartate and choline concentrations during HD, indicative of regional ischemia. CONCLUSIONS: This study demonstrates for the first time that significant intradialytic changes in brain tissue volume, diffusion metrics, and brain metabolite concentrations consistent with ischemic injury occur in a single dialysis session. These findings raise the possibility that HD might have long-term neurological consequences. Further study is needed to establish an association between intradialytic magnetic resonance imaging findings of brain injury and cognitive impairment and to understand the chronic effects of HD-induced brain injury. CLINICAL TRIALS INFORMATION: NCT03342183 .

The Vestibulocerebellum and the Shattered Self: a Resting-State Functional Connectivity Study in Posttraumatic Stress Disorder and Its Dissociative Subtype.

The flocculus is a region of the vestibulocerebellum dedicated to the coordination of neck, head, and eye movements for optimal posture, balance, and orienting responses. Despite growing evidence of vestibular and oculomotor impairments in the aftermath of traumatic stress, little is known about the effects of chronic psychological trauma on vestibulocerebellar functioning. Here, we investigated alterations in functional connectivity of the flocculus at rest among individuals with post-traumatic stress disorder (PTSD) and its dissociative subtype (PTSD + DS) as compared to healthy controls. Forty-four healthy controls, 57 PTSD, and 32 PTSD + DS underwent 6-min resting-state MRI scans. Seed-based functional connectivity analyses using the right and left flocculi as seeds were performed. These analyses revealed that, as compared to controls, PTSD and PTSD + DS showed decreased resting-state functional connectivity of the left flocculus with cortical regions involved in bodily self-consciousness, including the temporo-parietal junction, the supramarginal and angular gyri, and the superior parietal lobule. Moreover, as compared to controls, the PTSD + DS group showed decreased functional connectivity of the left flocculus with the medial prefrontal cortex, the precuneus, and the mid/posterior cingulum, key regions of the default mode network. Critically, when comparing PTSD + DS to PTSD, we observed increased functional connectivity of the right flocculus with the right anterior hippocampus, a region affected frequently by early life trauma. Taken together, our findings point toward the crucial role of the flocculus in the neurocircuitry underlying a coherent and embodied self, which can be compromised in PTSD and PTSD + DS.

Moral wounds run deep: exaggerated midbrain functional network connectivity across the default mode network in posttraumatic stress disorder.

BACKGROUND: A moral injury occurs when a deeply held moral code has been violated, and it can lead to the development of symptoms of posttraumatic stress disorder (PTSD). However, the neural correlates that differentiate moral injury and PTSD remain largely unknown. Intrinsic connectivity networks such as the default mode network (DMN) appear to be altered in people with PTSD who have experienced moral injury. However, brainstem, midbrain and cerebellar systems are rarely integrated into the intrinsic connectivity networks; this is a critical oversight, because these systems display marked differences in people with PTSD and are thought to underlie strong moral emotions such as shame, guilt and betrayal. METHODS: We conducted an independent component analysis on data generated during script-driven memory recall of moral injury in participants with military- or law enforcement-related PTSD (n = 28), participants with civilian-related PTSD (n = 28) and healthy controls exposed to a potentially morally injurious event (n = 18). We conducted group-wise comparisons of functional network connectivity differences across a DMN-correlated independent component, with a particular focus on brainstem, midbrain and cerebellar systems. RESULTS: We found stronger functional network connectivity in the midbrain periaqueductal grey (t 71 = 4.95, p FDR = 0.028, k = 39) and cerebellar lobule IX (t 71 = 4.44, p FDR = 0.046, k = 49) in participants with civilian-related PTSD as compared to healthy controls. We also found a trend toward stronger functional network connectivity in the midbrain periaqueductal grey (t 71 = 4.22, p FDR = 0.076, k = 60) in participants with military- or law enforcement-related PTSD as compared to healthy controls. LIMITATIONS: The significant clusters were large, but resolution is generally lower for subcortical structures. CONCLUSION: In PTSD, the DMN appears to be biased toward lower-level, midbrain systems, which may drive toxic shame and related moral emotions that are common in PTSD, highlighting the depth at which moral injuries are represented neurobiologically.

The functional and structural associations of aberrant microglial activity in major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is a debilitating mental illness that has been linked to increases in markers of inflammation, as well as to changes in brain functional and structural connectivity, particularly between the insula and the subgenual anterior cingulate cortex (sgACC). In this study, we directly related inflammation and dysconnectivity in treatment-resistant MDD by concurrently measuring the following: microglial activity with [18F]N-2-(fluoroethoxyl)benzyl-N-(4phenoxypyridin-3-yl)acetamide ([18F]FEPPA) positron emission tomography (PET); the severity of MDD; and functional or structural connectivity among insula or sgACC nodes. METHODS: Twelve patients with treatment-resistant MDD (8 female, 4 male; mean age ± standard deviation 54.9 ± 4.5 years and 23 healthy controls (11 female, 12 male; 60.3 ± 8.5 years) completed a hybrid [18F]FEPPA PET and MRI acquisition. From these, we extracted relative standardized uptake values for [18F]FEPPA activity and Pearson r-to-z scores representing functional connectivity from our regions of interest. We extracted diffusion tensor imaging metrics from the cingulum bundle, a key white matter bundle in MDD. We performed regressions to relate microglial activity with functional connectivity, structural connectivity and scores on the 17-item Hamilton Depression Rating Scale. RESULTS: We found significantly increased [18F]FEPPA uptake in the left sgACC in patients with treatment-resistant MDD compared to healthy controls. Patients with MDD also had a reduction in connectivity between the sgACC and the insula. The [18F]FEPPA uptake in the left sgACC was significantly related to functional connectivity with the insula, and to the structural connectivity of the cingulum bundle. [18F]FEPPA uptake also predicted scores on the Hamilton Depression Rating Scale.Limitations: A relatively small sample size, lack of functional task data and concomitant medication use may have affected our findings. CONCLUSION: We present preliminary evidence linking a network-level dysfunction relevant to the pathophysiology of depression and related to increased microglial activity in MDD.

Early treatment response in first episode psychosis: a 7-T magnetic resonance spectroscopic study of glutathione and glutamate.

Early response to antipsychotic medications is one of the most important determinants of later symptomatic and functional outcomes in psychosis. Glutathione and glutamate have emerged as promising therapeutic targets for patients demonstrating inadequate response to dopamine-blocking antipsychotics. Nevertheless, the role of these neurochemicals in the mechanism of early antipsychotic response remains poorly understood. Using a longitudinal design and ultrahigh field 7-T magnetic resonance spectroscopy (MRS) protocol in 53 subjects, we report the association between dorsal anterior cingulate cortex glutamate and glutathione, with time to treatment response in drug naive (34.6% of the sample) or minimally medicated first episode patients with schizophreniform disorder, schizophrenia, and schizoaffective disorder. Time to response was defined as the number of weeks required to reach a 50% reduction in the PANSS-8 scores. Higher glutathione was associated with shorter time to response (F = 4.86, P = 0.017), while higher glutamate was associated with more severe functional impairment (F = 5.33, P = 0.008). There were no significant differences between patients and controls on measures of glutamate or glutathione. For the first time, we have demonstrated an association between higher glutathione and favorable prognosis in FEP. We propose that interventions that increase brain glutathione levels may improve outcomes of early intervention in psychosis.

Acute conceptual disorganization in untreated first-episode psychosis: a combined magnetic resonance spectroscopy and diffusion imaging study of the cingulum.

Background: Disorganized thinking is a core feature of acute psychotic episodes that is linked to social and vocational functioning. Several lines of evidence implicate disrupted cognitive control, excitatory overdrive and oxidative stress relating to the anterior cingulate cortex as mechanisms of conceptual disorganization (CD). We examined 3 candidate mechanistic markers related to CD in firstepisode psychosis: glutamate excess, cortical antioxidant (glutathione) status and the integrity of the cingulum bundle that connects regions implicated in cognitive control. Methods: We used fractional anisotropy maps from 7 T diffusion-weighted imaging to investigate the bilateral cingulum based on a probabilistic white matter atlas. We compared high CD, low CD and healthy control groups and performed probabilistic fibre tracking from the identified clusters (regions of interest within the cingulum) to the rest of the brain. We quantified glutamate and glutathione using magnetic resonance spectroscopy (MRS) in the dorsal anterior cingulate cortex. Results: We found a significant fractional anisotropy reduction in a cluster in the left cingulum in the high CD group compared to the low CD group (Cohen's d = 1.39; p < 0.001) and controls (Cohen's d = 0.86; p = 0.009). Glutamate levels did not vary among groups, but glutathione levels were higher in the high CD group than in the low CD group. We also found higher glutathione related to lower fractional anisotropy in the cingulum cluster in the high CD group. Limitations: The MRS measures of glutamine were highly uncertain, and MRS was acquired from a single voxel only. Conclusion: Acute CD relates to indicators of oxidative stress, as well as reduced white matter integrity of the cingulum, but not to MRI-based glutamatergic excess. We propose that both oxidative imbalance and structural dysconnectivity underlie acute disorganization.

Shame on the brain: Neural correlates of moral injury event recall in posttraumatic stress disorder.

BACKGROUND: Moral injury (MI) is consistently associated with adverse mental health outcomes, including the development of posttraumatic stress disorder (PTSD) and suicidality. METHODS: We investigated neural activation patterns associated with MI event recall using functional magnetic resonance imaging in participants with military and public safety-related PTSD, relative to civilian MI-exposed controls. RESULTS: MI recall in the PTSD as compared to control group was associated with increased neural activation among salience network nodes involved in viscerosensory processing and hyperarousal (right posterior insula, dorsal anterior cingulate cortex; dACC), regions involved in defensive responding (left postcentral gyrus), and areas responsible for top-down cognitive control of emotions (left dorsolateral prefrontal cortex; dlPFC). Within the PTSD group, measures of state and trait shame correlated negatively with activity among default mode network regions associated with self-related processing and moral cognition (dorsomedial prefrontal cortex; dmPFC) and salience network regions associated with viscerosensory processing (left posterior insula), respectively. CONCLUSIONS: These findings suggest that MI event processing is altered in military and public safety-related PTSD, relative to MI-exposed controls. Here, it appears probable that as individuals with PTSD recall their MI event, they experience a surge of blame-related processing of bodily sensations within salience network regions, including the right posterior insula and the dACC, which in turn, prompt regulatory strategies at the level of the left dlPFC aimed at increasing cognitive control and inhibiting emotional affect. These results are consistent with previous findings showing enhanced sensory processing and altered top-down control in PTSD samples during autobiographical memory recall.

Machine learning multivariate pattern analysis predicts classification of posttraumatic stress disorder and its dissociative subtype: a multimodal neuroimaging approach.

BACKGROUND: The field of psychiatry would benefit significantly from developing objective biomarkers that could facilitate the early identification of heterogeneous subtypes of illness. Critically, although machine learning pattern recognition methods have been applied recently to predict many psychiatric disorders, these techniques have not been utilized to predict subtypes of posttraumatic stress disorder (PTSD), including the dissociative subtype of PTSD (PTSD + DS). METHODS: Using Multiclass Gaussian Process Classification within PRoNTo, we examined the classification accuracy of: (i) the mean amplitude of low-frequency fluctuations (mALFF; reflecting spontaneous neural activity during rest); and (ii) seed-based amygdala complex functional connectivity within 181 participants [PTSD (n = 81); PTSD + DS (n = 49); and age-matched healthy trauma-unexposed controls (n = 51)]. We also computed mass-univariate analyses in order to observe regional group differences [false-discovery-rate (FDR)-cluster corrected p < 0.05, k = 20]. RESULTS: We found that extracted features could predict accurately the classification of PTSD, PTSD + DS, and healthy controls, using both resting-state mALFF (91.63% balanced accuracy, p < 0.001) and amygdala complex connectivity maps (85.00% balanced accuracy, p < 0.001). These results were replicated using independent machine learning algorithms/cross-validation procedures. Moreover, areas weighted as being most important for group classification also displayed significant group differences at the univariate level. Here, whereas the PTSD + DS group displayed increased activation within emotion regulation regions, the PTSD group showed increased activation within the amygdala, globus pallidus, and motor/somatosensory regions. CONCLUSION: The current study has significant implications for advancing machine learning applications within the field of psychiatry, as well as for developing objective biomarkers indicative of diagnostic heterogeneity.

The cerebellum after trauma: Resting-state functional connectivity of the cerebellum in posttraumatic stress disorder and its dissociative subtype.

The cerebellum plays a key role not only in motor function but also in affect and cognition. Although several psychopathological disorders have been associated with overall cerebellar dysfunction, it remains unclear whether different regions of the cerebellum contribute uniquely to psychopathology. Accordingly, we compared seed-based resting-state functional connectivity of the anterior cerebellum (lobule IV-V), of the posterior cerebellum (Crus I), and of the anterior vermis across posttraumatic stress disorder (PTSD; n = 65), its dissociative subtype (PTSD + DS; n = 37), and non-trauma-exposed healthy controls (HC; n = 47). Here, we observed decreased functional connectivity of the anterior cerebellum and anterior vermis with brain regions involved in somatosensory processing, multisensory integration, and bodily self-consciousness (temporo-parietal junction, postcentral gyrus, and superior parietal lobule) in PTSD + DS as compared to PTSD and HC. Moreover, the PTSD + DS group showed increased functional connectivity of the posterior cerebellum with cortical areas related to emotion regulation (ventromedial prefrontal and orbito-frontal cortex, subgenual anterior cingulum) as compared to PTSD. By contrast, PTSD showed increased functional connectivity of the anterior cerebellum with cortical areas associated with visual processing (fusiform gyrus), interoceptive awareness (posterior insula), memory retrieval, and contextual processing (hippocampus) as compared to HC. Finally, we observed decreased functional connectivity between the posterior cerebellum and prefrontal regions involved in emotion regulation, in PTSD as compared to HC. These findings not only highlight the crucial role of each cerebellar region examined in the psychopathology of PTSD but also reveal unique alterations in functional connectivity distinguishing the dissociative subtype of PTSD versus PTSD.

Superior colliculus resting state networks in post-traumatic stress disorder and its dissociative subtype.

OBJECTIVES: The innate alarm system (IAS) models the neurocircuitry involved in threat processing in posttraumatic stress disorder (PTSD). Here, we investigate a primary subcortical structure of the IAS model, the superior colliculus (SC), where the SC is thought to contribute to the mechanisms underlying threat-detection in PTSD. Critically, the functional connectivity between the SC and other nodes of the IAS remains unexplored. EXPERIMENTAL DESIGN: We conducted a resting-state fMRI study to investigate the functional architecture of the IAS, focusing on connectivity of the SC in PTSD (n = 67), its dissociative subtype (n = 41), and healthy controls (n = 50) using region-of-interest seed-based analysis. PRINCIPAL OBSERVATIONS: We observed group-specific resting state functional connectivity between the SC for both PTSD and its dissociative subtype, indicative of dedicated IAS collicular pathways in each group of patients. When comparing PTSD to its dissociative subtype, we observed increased resting state functional connectivity between the left SC and the right dorsolateral prefrontal cortex (DLPFC) in PTSD. The DLPFC is involved in modulation of emotional processes associated with active defensive responses characterising PTSD. Moreover, when comparing PTSD to its dissociative subtype, increased resting state functional connectivity was observed between the right SC and the right temporoparietal junction in the dissociative subtype. The temporoparietal junction is involved in depersonalization responses associated with passive defensive responses typical of the dissociative subtype. CONCLUSIONS: Our findings suggest that unique resting state functional connectivity of the SC parallels the unique symptom profile and defensive responses observed in PTSD and its dissociative subtype. Hum Brain Mapp 39:563-574, 2018. © 2017 Wiley Periodicals, Inc.

Resting-state pulvinar-posterior parietal decoupling in PTSD and its dissociative subtype.

Key evidence points toward alterations in the neurocircuitry of large-scale networks among patients with posttraumatic stress disorder (PTSD). The pulvinar is a thalamic region displaying reciprocal connectivity with the cortex and has been shown to modulate alpha synchrony to facilitate network communication. During rest, the pulvinar displays functional connectivity with the posterior parietal cortex (PPC), a heteromodal network of brain areas underlying multisensory integration and socioaffective functions that are shown at deficit in PTSD. Accordingly, this study seeks to reveal the resting-state functional connectivity (rsFC) patterns of individuals with PTSD, its dissociative subtype (PTSD + DS) and healthy controls. A whole-brain rsFC analysis was conducted using SPM12 and PickAtlas. Connectivity was analyzed for the left and right pulvinar across groups of individuals with PTSD (n = 81), PTSD + DS (n = 49), and controls (n = 51). As compared to PTSD, controls displayed significantly greater pulvinar rsFC with the superior parietal lobule and precuneus. Moreover, as compared to PTSD + DS, controls showed increased pulvinar connectivity with the superior parietal lobule, inferior parietal lobule and the precuneus. PTSD groups did not display stronger connectivity with any region as compared to controls. Last, PTSD had greater rsFC in the supramarginal gyrus relative to PTSD + DS. Reduced connectivity between the pulvinar and PPC may explain impairments to autobiographical memory, self-referential processing, and socioaffective domains in PTSD and PTSD + DS even at "rest." Critically, these alterations appear to be exacerbated in individuals with PTSD + DS, which may have important implications for treatment.

Intrinsic connectivity network dynamics in PTSD during amygdala downregulation using real-time fMRI neurofeedback: A preliminary analysis.

Posttraumatic stress disorder (PTSD) has been associated with a disturbance in neural intrinsic connectivity networks (ICN), including the central executive network (CEN), default mode network (DMN), and salience network (SN). Here, we conducted a preliminary investigation examining potential changes in ICN recruitment as a function of real-time fMRI neurofeedback (rt-fMRI-NFB) during symptom provocation where we targeted the downregulation of neural response within the amygdala-a key region-of-interest in PTSD neuropathophysiology. Patients with PTSD (n = 14) completed three sessions of rt-fMRI-NFB with the following conditions: (a) regulate: decrease activation in the amygdala while processing personalized trauma words; (b) view: process trauma words while not attempting to regulate the amygdala; and (c) neutral: process neutral words. We found that recruitment of the left CEN increased over neurofeedback runs during the regulate condition, a finding supported by increased dlPFC activation during the regulate as compared to the view condition. In contrast, DMN task-negative recruitment was stable during neurofeedback runs, albeit was the highest during view conditions and increased (normalized) during rest periods. Critically, SN recruitment was high for both the regulate and the view conditions, a finding potentially indicative of CEN modality switching, adaptive learning, and increasing threat/defense processing in PTSD. In conclusion, this study provides provocative, preliminary evidence that downregulation of the amygdala using rt-fMRI-NFB in PTSD is associated with dynamic changes in ICN, an effect similar to those observed using EEG modalities of neurofeedback.

Desynchronization of autonomic response and central autonomic network connectivity in posttraumatic stress disorder.

OBJECTIVES: Although dysfunctional emotion regulatory capacities are increasingly recognized as contributing to posttraumatic stress disorder (PTSD), little work has sought to identify biological markers of this vulnerability. Heart rate variability (HRV) is a promising biomarker that, together with neuroimaging, may assist in gaining a deeper understanding of emotion dysregulation in PTSD. The objective of the present study was, therefore, to characterize autonomic response patterns, and their related neuronal patterns in individuals with PTSD at rest. METHODS: PTSD patients (N = 57) and healthy controls (N = 41) underwent resting-state fMRI. Connectivity patterns of key regions within the central autonomic network (CAN)-including the ventromedial prefrontal cortex (vmPFC), amygdala, and periaqueductal gray (PAG)-were examined using a seed-based approach. Observed connectivity patterns were then correlated to resting HRV. RESULTS: In contrast to controls, individuals with PTSD exhibited lower HRV. In addition, whereas controls engaged a localized connectivity pattern of CAN-related brain regions, in PTSD, key CAN regions were associated with widespread connectivity patterns in regions related to emotional reactivity (vmPFC and amygdala to insular cortex and lentiform nucleus; PAG to insula) and motor readiness (vmPFC and amygdala to precentral gyrus; PAG to precentral gyrus and cerebellum). Critically, whereas CAN connectivity in controls was strongly related to higher HRV (insula, mPFC, superior frontal cortex, thalamus), HRV covariation was absent in PTSD subjects. CONCLUSIONS: This study provides the first evidence for a specific psychophysiological-neuronal profile in PTSD individuals characterized by lower resting HRV and a lack of HRV covariation with CAN-related brain connectivity. Hum Brain Mapp 38:27-40, 2017. © 2016 Wiley Periodicals, Inc.

Neural correlates of heart rate variability in PTSD during sub- and supraliminal processing of trauma-related cues.

BACKGROUND: Posttraumatic stress disorder (PTSD) is characterized by dysregulated arousal and altered cardiac autonomic response as evidenced by decreased high-frequency heart rate variability (HF-HRV), an indirect measure of parasympathetic modulation of the heart. Indeed, subtle threatening cues can cause autonomic dysregulation, even without explicit awareness of the triggering stimulus. Accordingly, examining the neural underpinnings associated with HF-HRV during both sub- and supraliminal exposure to trauma-related cues is critical to an enhanced understanding of autonomic nervous system dysfunction in PTSD. METHODS: We compared neural activity in brain regions associated with HF-HRV in PTSD (n = 18) and healthy controls (n = 18) during exposure to sub- and supraliminal processing of personalized trauma-related words. RESULTS: As compared to controls, PTSD exhibited decreased HF-HRV reactivity in response to sub- and supraliminal cues. Notably, during subliminal processing of trauma-related versus neutral words, as compared to controls, PTSD showed decreased neural response associated with HF-HRV within the left dorsal anterior insula. By contrast, during supraliminal processing of trauma-related versus neutral words, decreased neural activity associated with HF-HRV within the posterior insula/superior temporal cortex, and increased neural activity associated with HF-HRV within the left centromedial amygdala was observed in PTSD as compared to controls. CONCLUSIONS: Impaired parasympathetic modulation of autonomic arousal in PTSD appears related to altered activation of cortical and subcortical regions involved in the central autonomic network. Interestingly, both sub- and supraliminal trauma-related cues appear to elicit dysregulated arousal and may contribute to the maintenance of hyperarousal in PTSD. Hum Brain Mapp 38:4898-4907, 2017. © 2017 Wiley Periodicals, Inc.

The neurobiology of emotion regulation in posttraumatic stress disorder: Amygdala downregulation via real-time fMRI neurofeedback.

Amygdala dysregulation has been shown to be central to the pathophysiology of posttraumatic stress disorder (PTSD) representing a critical treatment target. Here, amygdala downregulation was targeted using real-time fMRI neurofeedback (rt-fMRI-nf) in patients with PTSD, allowing us to examine further the regulation of emotional states during symptom provocation. Patients (n = 10) completed three sessions of rt-fMRI-nf with the instruction to downregulate activation in the amygdala, while viewing personalized trauma words. Amygdala downregulation was assessed by contrasting (a) regulate trials, with (b) viewing trauma words and not attempting to regulate. Training was followed by one transfer run not involving neurofeedback. Generalized psychophysiological interaction (gPPI) and dynamic causal modeling (DCM) analyses were also computed to explore task-based functional connectivity and causal structure, respectively. It was found that PTSD patients were able to successfully downregulate both right and left amygdala activation, showing sustained effects within the transfer run. Increased activation in the dorsolateral and ventrolateral prefrontal cortex (PFC), regions related to emotion regulation, was observed during regulate as compared with view conditions. Importantly, activation in the PFC, rostral anterior cingulate cortex, and the insula, were negatively correlated to PTSD dissociative symptoms in the transfer run. Increased functional connectivity between the amygdala- and both the dorsolateral and dorsomedial PFC was found during regulate, as compared with view conditions during neurofeedback training. Finally, our DCM analysis exploring directional structure suggested that amygdala downregulation involves both top-down and bottom-up information flow with regard to observed PFC-amygdala connectivity. This is the first demonstration of successful downregulation of the amygdala using rt-fMRI-nf in PTSD, which was critically sustained in a subsequent transfer run without neurofeedback, and corresponded to increased connectivity with prefrontal regions involved in emotion regulation during the intervention. Hum Brain Mapp 38:541-560, 2017. © 2016 Wiley Periodicals, Inc.

Dynamic causal modeling in PTSD and its dissociative subtype: Bottom-up versus top-down processing within fear and emotion regulation circuitry.

OBJECTIVE: Posttraumatic stress disorder (PTSD) is associated with decreased top-down emotion modulation from medial prefrontal cortex (mPFC) regions, a pathophysiology accompanied by hyperarousal and hyperactivation of the amygdala. By contrast, PTSD patients with the dissociative subtype (PTSD + DS) often exhibit increased mPFC top-down modulation and decreased amygdala activation associated with emotional detachment and hypoarousal. Crucially, PTSD and PTSD + DS display distinct functional connectivity within the PFC, amygdala complexes, and the periaqueductal gray (PAG), a region related to defensive responses/emotional coping. However, differences in directed connectivity between these regions have not been established in PTSD, PTSD + DS, or controls. METHODS: To examine directed (effective) connectivity among these nodes, as well as group differences, we conducted resting-state stochastic dynamic causal modeling (sDCM) pairwise analyses of coupling between the ventromedial (vm)PFC, the bilateral basolateral and centromedial (CMA) amygdala complexes, and the PAG, in 155 participants (PTSD [n = 62]; PTSD + DS [n = 41]; age-matched healthy trauma-unexposed controls [n = 52]). RESULTS: PTSD was characterized by a pattern of predominant bottom-up connectivity from the amygdala to the vmPFC and from the PAG to the vmPFC and amygdala. Conversely, PTSD + DS exhibited predominant top-down connectivity between all node pairs (from the vmPFC to the amygdala and PAG, and from the amygdala to the PAG). Interestingly, the PTSD + DS group displayed the strongest intrinsic inhibitory connections within the vmPFC. CONCLUSIONS: These results suggest the contrasting symptom profiles of PTSD and its dissociative subtype (hyper- vs. hypo-emotionality, respectively) may be driven by complementary changes in directed connectivity corresponding to bottom-up defensive fear processing versus enhanced top-down regulation. Hum Brain Mapp 38:5551-5561, 2017. © 2017 Wiley Periodicals, Inc.

Mind over chatter: plastic up-regulation of the fMRI salience network directly after EEG neurofeedback.

Neurofeedback (NFB) involves a brain-computer interface that allows users to learn to voluntarily control their cortical oscillations, reflected in the electroencephalogram (EEG). Although NFB is being pioneered as a noninvasive tool for treating brain disorders, there is insufficient evidence on the mechanism of its impact on brain function. Furthermore, the dominant rhythm of the human brain is the alpha oscillation (8-12 Hz), yet its behavioral significance remains multifaceted and largely correlative. In this study with 34 healthy participants, we examined whether during the performance of an attentional task, the functional connectivity of distinct fMRI networks would be plastically altered after a 30-min session of voluntary reduction of alpha rhythm (n=17) versus a sham-feedback condition (n=17). We reveal that compared to sham-feedback, NFB induced an increase of connectivity within regions of the salience network involved in intrinsic alertness (dorsal anterior cingulate), which was detectable 30 min after termination of training. The increase in salience network (default-mode network) connectivity was negatively (positively) correlated with changes in 'on task' mind-wandering as well as resting state alpha rhythm. Crucially, we observed a causal dependence between alpha rhythm synchronization during NFB and its subsequent change at resting state, not exhibited by the SHAM group. Our findings provide neurobehavioral evidence for the brain's exquisite functional plasticity, and for a temporally direct impact of NFB on a key cognitive control network, suggesting a promising basis for its use to treat cognitive disorders under physiological conditions.

Non-linear variations in glutamate dynamics during a cognitive task engagement in schizophrenia.

To investigate the role of glutamate in psychosis, we employ functional magnetic resonance spectroscopy at an ultra-high magnetic field (7T) and employ fuzzy-approximate entropy (F-ApEn) and Hurst Exponent (HE) to capture time-varying nature of glutamate signaling during a cognitive task. We recruited thirty first-episode psychosis patients (FEP) with age- and gender-matched healthy controls (HC) and administered the Color-Word Stroop paradigm, providing 128 raw MRS time-points per subject over a period of 16 min. We then performed metabolite quantification of glutamate in the dorsal anterior cingulate cortex, a region reliably activated during the Stroop task. Symptoms/cognitive functioning was measured using Positive and Negative Syndrome Scale-8 score, Social and Occupational Functioning (SOFAS) score, digit symbol) coding score, and Stroop accuracy. These scores were related to the Entropy/HE data from the overall glutamate time-series. Patients with FEP had significantly higher HE compared to HC, with individuals displaying significantly higher HE having lower functional performance (SOFAS) in both HC and FEP groups. Among healthy individuals, higher HE also indicated significantly lower cognitive function through Stroop accuracy and DSST scores. F-ApEn had an inverse Pearson correlation with HE, and tracked diagnosis, cognition and function as expected, but with lower effect sizes not reaching statistical significance. We demonstrate notable diagnostic differences in the temporal course of glutamate signaling during a cognitive task in psychosis.

'I am afraid you will see the stain on my soul': Direct gaze neural processing in individuals with PTSD after moral injury recall.

Direct eye contact is essential to understanding others' thoughts and feelings in social interactions. However, those with post-traumatic stress disorder (PTSD) and exposure to moral injury (MI) may exhibit altered theory-of-mind (ToM)/mentalizing processes and experience shame which precludes one's capacity for direct eye contact. We investigated blood oxygenation level-dependent (BOLD) responses associated with direct vs averted gaze using a virtual reality paradigm in individuals with PTSD (n = 28) relative to healthy controls (n = 18) following recall of a MI vs a neutral memory. Associations between BOLD responses and clinical symptomatology were also assessed. After MI recall, individuals with PTSD showed greater activation in the right temporoparietal junction as compared to controls (T = 4.83; pFDR < 0.001; k = 237) during direct gaze. No significant activation occurred during direct gaze after neutral memory recall. Further, a significant positive correlation was found between feelings of distress and right medial superior frontal gyrus activation in individuals with PTSD (T = 5.03; pFDR = 0.049; k = 123). These findings suggest that direct gaze after MI recall prompts compensatory ToM/mentalizing processing. Implications for future interventions aimed at mitigating the effects of PTSD on social functioning are discussed.