Posterior cingulate cortex targeted real-time fMRI neurofeedback recalibrates functional connectivity with the amygdala, posterior insula, and default-mode network in PTSD.

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.

Differential mechanisms of posterior cingulate cortex downregulation and symptom decreases in posttraumatic stress disorder and healthy individuals using real-time fMRI neurofeedback.

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.

Introduction to the special issue: Complementary medicine and integrative health approaches to trauma therapy and recovery.

The popularity of complementary and integrative health (also complementary integrated health; CIH) approaches has significantly increased in recent years. According to the National Center for Complementary and Integrative Health (NCCIH), part of the National Institutes of Health, about 1 in 3 adults and 1 in 9 children used CIH approaches to healing. Some reports estimate that the use of CIH approaches will continue to increase (Clarke et al., 2015) as these therapies are cost effective and also due to the difficulties in finding trained mental health professionals (Simon et al., 2020). For the purpose of this special issue, we use the NCCIH's definition of CIH as "a group of diverse medical and health care systems, practices, and products that are not presently considered to be part of conventional medicine" (Barnes et al., 2004, p. v). However, the integration of these therapies into the health system has not followed the same pattern despite the fact that patients report the need to discuss CIH therapies with their doctors or are actually using them (de Jonge et al., 2018; Jou & Johnson, 2016; Stapleton et al., 2015). This inability to keep up with the demand or patients' preference is possibly due to providers' lack of understanding and/or knowledge of these therapies, as well as scientific skepticism (Ali & Katz, 2015; Fletcher et al., 2017). Using data from the 2012 National Health Interview Survey, Jou & Johnson (2016) identified patterns of CIH use in the United States and reasons for patients' nondisclosure of the use of these therapies. Patients' fear of disclosure due to perceived skepticism or disapproval from their provider was frequently attributed as a cause of patients' nondisclosures to providers about the use of these therapies (Eisenberg et al., 2001; Jou & Johnson, 2016; Thomson et al., 2012). The arrival of patient-centered care models is beginning to shift the ways we understand the patient's role in treatment engagement. Patient-centered approaches often emphasize the use of preventative and holistic wellness models that go beyond the use of evidence-based treatments. This approach also seeks to be culturally responsive, which is a key factor in addressing health disparities in the United States (American Psychological Association [APA], 2019). The Institute of Medicine, in its report on CIH therapies, highlighted the importance of engaging patients in their own care, including having a decision about therapeutic options (Bondurant et al., 2005). Likewise, the Race and Ethnicity Guidelines in Psychology (APA, 2019) recommend psychologists engage the patient's cultural beliefs, or what Kleinman called the "explanatory belief model" (Kleinman, 1978)- for example, by "aim[ing] to understand and encourage indigenous/ ethnocultural sources of healing within professional practice" (APA, 2019, p. 24). (PsycInfo Database Record (c) 2020 APA, all rights reserved).

A randomized, controlled trial of alpha-rhythm EEG neurofeedback in posttraumatic stress disorder: A preliminary investigation showing evidence of decreased PTSD symptoms and restored default mode and salience network connectivity using fMRI.

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.

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.

Restoring large-scale brain networks in PTSD and related disorders: a proposal for neuroscientifically-informed treatment interventions.

BACKGROUND: Three intrinsic connectivity networks in the brain, namely the central executive, salience, and default mode networks, have been identified as crucial to the understanding of higher cognitive functioning, and the functioning of these networks has been suggested to be impaired in psychopathology, including posttraumatic stress disorder (PTSD). OBJECTIVE: 1) To describe three main large-scale networks of the human brain; 2) to discuss the functioning of these neural networks in PTSD and related symptoms; and 3) to offer hypotheses for neuroscientifically-informed interventions based on treating the abnormalities observed in these neural networks in PTSD and related disorders. METHODS: Literature relevant to this commentary was reviewed. RESULTS: Increasing evidence for altered functioning of the central executive, salience, and default mode networks in PTSD has been demonstrated. We suggest that each network is associated with specific clinical symptoms observed in PTSD, including cognitive dysfunction (central executive network), increased and decreased arousal/interoception (salience network), and an altered sense of self (default mode network). Specific testable neuroscientifically-informed treatments aimed to restore each of these neural networks and related clinical dysfunction are proposed. CONCLUSIONS: Neuroscientifically-informed treatment interventions will be essential to future research agendas aimed at targeting specific PTSD and related symptoms.

Effect of direct eye contact in women with PTSD related to interpersonal trauma: Psychophysiological interaction analysis of connectivity of an innate alarm system.

In healthy individuals, direct eye contact is thought to modulate a cortical route eliciting social cognitive processes via activation of a fast subcortical pathway. This study aimed to examine functional brain connectivity during direct eye contact in women with posttraumatic stress disorder (PTSD) related to childhood abuse as compared with healthy controls. We conducted psychophysiological interaction (PPI) analyses in Statistical Parametric Mapping-8 (SPM8) using the superior colliculus (SC) and locus coeruleus (LC) as seed regions while 16 healthy subjects and 16 patients with a primary diagnosis of PTSD related to childhood maltreatment viewed a functional magnetic resonance imaging (fMRI) paradigm involving direct (D) versus averted (A) gaze (happy, sad, neutral). The PTSD group showed a significantly enhanced connectivity between the SC and the anterior cingulate, and between the LC and the thalamus, caudate, putamen, insula, cingulate gyrus, and amygdala, as compared with healthy individuals. Symptom severity scores on the Clinician-Administered PTSD Scale (CAPS) showed significant positive correlations with superior colliculus connectivity with the perigenual and posterior cingulate, insula, and sublenticular extended amygdala. Functional connectivity data suggest increased recruitment of brain regions involved in emotion processing during direct gaze in PTSD in association with the fast subcortical pathway. The interpretation of eye contact as a signal of threat may require more emotion regulatory capacities in patients with PTSD.

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.

Evaluation of the evidence for the trauma and fantasy models of dissociation.

The relationship between a reported history of trauma and dissociative symptoms has been explained in 2 conflicting ways. Pathological dissociation has been conceptualized as a response to antecedent traumatic stress and/or severe psychological adversity. Others have proposed that dissociation makes individuals prone to fantasy, thereby engendering confabulated memories of trauma. We examine data related to a series of 8 contrasting predictions based on the trauma model and the fantasy model of dissociation. In keeping with the trauma model, the relationship between trauma and dissociation was consistent and moderate in strength, and remained significant when objective measures of trauma were used. Dissociation was temporally related to trauma and trauma treatment, and was predictive of trauma history when fantasy proneness was controlled. Dissociation was not reliably associated with suggestibility, nor was there evidence for the fantasy model prediction of greater inaccuracy of recovered memory. Instead, dissociation was positively related to a history of trauma memory recovery and negatively related to the more general measures of narrative cohesion. Research also supports the trauma theory of dissociation as a regulatory response to fear or other extreme emotion with measurable biological correlates. We conclude, on the basis of evidence related to these 8 predictions, that there is strong empirical support for the hypothesis that trauma causes dissociation, and that dissociation remains related to trauma history when fantasy proneness is controlled. We find little support for the hypothesis that the dissociation-trauma relationship is due to fantasy proneness or confabulated memories of trauma.

Emotional numbing in posttraumatic stress disorder: a functional magnetic resonance imaging study.

OBJECTIVE: To explore the functional neural correlates of emotional numbing symptoms in individuals with posttraumatic stress disorder (PTSD). METHOD: The study was conducted between September 2006 and June 2008 at the University of Western Ontario. Women with (n = 14) and without (n = 16) PTSD (based on DSM-IV criteria) completed a standardized emotional imagery task while undergoing functional magnetic resonance imaging, in addition to an assessment for emotional numbing symptoms. The study design was correlational, with primary outcome measures being blood oxygenation level-dependent (BOLD) response to emotional imagery task and self-reported severity of emotional numbing symptoms. Women without PTSD were not trauma exposed. RESULTS: In women with PTSD, emotional numbing symptoms predicted less positive affect in response to positive-valence scripts (P < .05) and less BOLD response within the dorsomedial prefrontal cortex during imagery of positive and negative scripts that were explicitly socially relevant (P < .001). In contrast, in women without PTSD, emotional numbing symptoms, while unrelated to subjective emotional responses, predicted greater response within the ventromedial prefrontal cortex during positive and negative scripts, in addition to scripts that elicited fear anxiety by nonsocial means (all P values < .001). The findings could not be attributed to dysphoria. CONCLUSIONS: These findings are consistent with previous research regarding emotional numbing and emotional awareness. Less response within the medial prefrontal cortex during emotional imagery in individuals with high emotional numbing may indicate deficient conscious and reflective emotional processing. Further study is required to elucidate associations between state and trait emotional numbing and the neural correlates of psychological treatments specific to emotional numbing.

Neural correlates of reexperiencing, avoidance, and dissociation in PTSD: symptom dimensions and emotion dysregulation in responses to script-driven trauma imagery.

Research suggests that responses to script-driven trauma imagery in posttraumatic stress disorder (PTSD) include reexperiencing and dissociative symptom subtypes. This functional magnetic resonance imaging (fMRI) study employed a dimensional approach to characterizing script-driven imagery responses, using the Responses to Script-Driven Imagery Scale and correlational analyses of relationships between severity of state posttraumatic symptoms and neural activation. As predicted, state reexperiencing severity was associated positively with right anterior insula activity and negatively with right rostral anterior cingulate cortex (rACC). Avoidance correlated negatively with rACC and subcallosal anterior cingulate activity. In addition, as predicted, dissociation correlated positively with activity in the left medial prefrontal and right superior temporal cortices, and negatively with the left superior temporal cortex. Theoretical and clinical implications are discussed, particularly with respect to an emotion-dysregulation account of PTSD.

Neural correlates of trauma script-imagery in posttraumatic stress disorder with and without comorbid major depression: a functional MRI investigation.

The goal of this study was to compare neural activation patterns in patients with PTSD with and without current comorbid major depression. Traumatized subjects with PTSD (n=11), PTSD+major depression (MDD, n=15), and subjects (n=16) who met criterion A for PTSD but never developed the disorder were studied using the script-driven symptom-provocation paradigm adapted to functional magnetic resonance imaging (fMRI) at a 4-Tesla field strength. Both the PTSD+MDD and PTSD-MDD groups revealed decreased brain activation in the anterior cingulate gyrus (BA 24) and the right ventrolateral prefrontal cortex (BA 47). After covariation for differences in PTSD severity between these groups, the left insula (BA 13) remained more significantly activated in the PTSD-MDD group than in the PTSD+MDD group. In contrast, the PTSD+MDD group showed greater activation than the PTSD-MDD group in the bilateral anterior cingulate gyrus (BA 24) and posterior cingulate cortices (BA 23, 31). These results suggest different patterns of brain activation related to comorbid major depression occurring in the context of PTSD.

Alexithymia in PTSD: psychometric and FMRI studies.

Two studies examined correlates of alexithymia in posttraumatic stress disorder (PTSD). In study 1 (n = 77 individuals with PTSD and 45 controls) Toronto alexithymia scale (TAS-20) scores were positively correlated with PTSD symptoms, dissociation, and childhood abuse and neglect. In study 2, TAS-20 scores were examined as correlates of functional magnetic resonance imaging (fMRI) blood oxygen level dependent (BOLD) response to trauma script imagery. In 16 controls, TAS-20 scores correlated positively with response in medial prefrontal cortex (mPFC), and negatively with response in anterior cingulate cortex (ACC) and thalamus. In 26 individuals with PTSD, TAS-20 scores correlated positively with response in insula, posterior cingulate cortex (PCC), and thalamus, and negatively with response in ACC.