Quantitative MRI at 7-Tesla reveals novel frontocortical myeloarchitecture anomalies in major depressive disorder.

Whereas meta-analytical data highlight abnormal frontocortical macrostructure (thickness/surface area/volume) in Major Depressive Disorder (MDD), the underlying microstructural processes remain uncharted, due to the use of conventional MRI scanners and acquisition techniques. We uniquely combined Ultra-High Field MRI at 7.0 Tesla with Quantitative Imaging to map intracortical myelin (proxied by longitudinal relaxation time T1) and iron concentration (proxied by transverse relaxation time T2*), microstructural processes deemed particularly germane to cortical macrostructure. Informed by meta-analytical evidence, we focused specifically on orbitofrontal and rostral anterior cingulate cortices among adult MDD patients (N = 48) and matched healthy controls (HC; N = 10). Analyses probed the association of MDD diagnosis and clinical profile (severity, medication use, comorbid anxiety disorders, childhood trauma) with aforementioned microstructural properties. MDD diagnosis (p's < 0.05, Cohen's D = 0.55-0.66) and symptom severity (p's < 0.01, r = 0.271-0.267) both related to decreased intracortical myelination (higher T1 values) within the lateral orbitofrontal cortex, a region tightly coupled to processing negative affect and feelings of sadness in MDD. No relations were found with local iron concentrations. These findings allow uniquely fine-grained insights on frontocortical microstructure in MDD, and cautiously point to intracortical demyelination as a possible driver of macroscale cortical disintegrity in MDD.

Inter-identity amnesia in dissociative identity disorder resolved: A behavioural and neurobiological study.

INTRODUCTION: Dissociative identity disorder (DID) is characterised by, among others, subjectively reported inter-identity amnesia, reflecting compromised information transfer between dissociative identity states. Studies have found conflicting results regarding memory transfer between dissociative identity states. Here, we investigated inter-identity amnesia in individuals with DID using self-relevant, subject specific stimuli, and behavioural and neural measures. METHODS: Data of 46 matched participants were included; 14 individuals with DID in a trauma-avoidant state, 16 trauma-avoiding DID simulators, and 16 healthy controls. Reaction times and neural activation patterns related to three types of subject specific words were acquired and statistically analysed, namely non-self-relevant trauma-related words (NSt), self-relevant trauma-related words from a trauma-avoidant identity state (St), and trauma-related words from a trauma-related identity state (XSt). RESULTS: We found no differences in reaction times between XSt and St words and faster reaction times for XSt over NSt. Reaction times of the diagnosed DID group were the longest. Increased brain activation to XSt words was found in the frontal and parietal regions, while decreased brain activity was found in the anterior cingulate cortex in the diagnosed DID group. DISCUSSION: The current study reproduces and amalgamates previous behavioural reports as well as brain activation patterns. Our finding of increased cognitive control over self-relevant trauma-related knowledge processing has important clinical implications and calls for the redefinition of "inter-identity amnesia" to "inter-identity avoidance".

When a test is more than just a test: Findings from patient interviews and survey in the trial of a technology to measure antidepressant medication response (the PReDicT Trial).

BACKGROUND: A RCT of a novel intervention to detect antidepressant medication response (the PReDicT Test) took place in five European countries, accompanied by a nested study of its acceptability and implementation presented here. The RCT results indicated no effect of the intervention on depression at 8 weeks (primary outcome), although effects on anxiety at 8 weeks and functioning at 24 weeks were found. METHODS: The nested study used mixed methods. The aim was to explore patient experiences of the Test including acceptability and implementation, to inform its use within care. A bespoke survey was completed by trial participants in five countries (n = 778) at week 8. Semi-structured interviews were carried out in two countries soon after week 8 (UK n = 22, Germany n = 20). Quantitative data was analysed descriptively; for qualitative data, thematic analysis was carried out using a framework approach. Results of the two datasets were interrogated together. OUTCOMES: Survey results showed the intervention was well received, with a majority of participants indicating they would use it again, and it gave them helpful extra information; a small minority indicated the Test made them feel worse. Qualitative data showed the Test had unexpected properties, including: instigating a process of reflection, giving participants feedback on progress and new understanding about their illness, and making participants feel supported and more engaged in treatment. INTERPRETATION: The qualitative and quantitative results are generally consistent. The Test's unexpected properties may explain why the RCT showed little effect, as properties were experienced across both trial arms. Beyond the RCT, the qualitative data sheds light on measurement reactivity, i.e., how measurements of depression can impact patients.

Intrusive Traumatic Re-Experiencing Domain: Functional Connectivity Feature Classification by the ENIGMA PTSD Consortium.

Background: Intrusive traumatic re-experiencing domain (ITRED) was recently introduced as a novel perspective on posttraumatic psychopathology, proposing to focus research of posttraumatic stress disorder (PTSD) on the unique symptoms of intrusive and involuntary re-experiencing of the trauma, namely, intrusive memories, nightmares, and flashbacks. The aim of the present study was to explore ITRED from a neural network connectivity perspective. Methods: Data were collected from 9 sites taking part in the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) PTSD Consortium (n= 584) and included itemized PTSD symptom scores and resting-state functional connectivity (rsFC) data. We assessed the utility of rsFC in classifying PTSD, ITRED-only (no PTSD diagnosis), and trauma-exposed (TE)-only (no PTSD or ITRED) groups using a machine learning approach, examining well-known networks implicated in PTSD. A random forest classification model was built on a training set using cross-validation, and the averaged cross-validation model performance for classification was evaluated using the area under the curve. The model was tested using a fully independent portion of the data (test dataset), and the test area under the curve was evaluated. Results: rsFC signatures differentiated TE-only participants from PTSD and ITRED-only participants at about 60% accuracy. Conversely, rsFC signatures did not differentiate PTSD from ITRED-only individuals (45% accuracy). Common features differentiating TE-only participants from PTSD and ITRED-only participants mainly involved default mode network-related pathways. Some unique features, such as connectivity within the frontoparietal network, differentiated TE-only participants from one group (PTSD or ITRED-only) but to a lesser extent from the other group. Conclusions: Neural network connectivity supports ITRED as a novel neurobiologically based approach to classifying posttrauma psychopathology.

Smaller total and subregional cerebellar volumes in posttraumatic stress disorder: a mega-analysis by the ENIGMA-PGC PTSD workgroup.

Although the cerebellum contributes to higher-order cognitive and emotional functions relevant to posttraumatic stress disorder (PTSD), prior research on cerebellar volume in PTSD is scant, particularly when considering subregions that differentially map on to motor, cognitive, and affective functions. In a sample of 4215 adults (PTSD n = 1642; Control n = 2573) across 40 sites from the ENIGMA-PGC PTSD working group, we employed a new state-of-the-art deep-learning based approach for automatic cerebellar parcellation to obtain volumetric estimates for the total cerebellum and 28 subregions. Linear mixed effects models controlling for age, gender, intracranial volume, and site were used to compare cerebellum volumes in PTSD compared to healthy controls (88% trauma-exposed). PTSD was associated with significant grey and white matter reductions of the cerebellum. Compared to controls, people with PTSD demonstrated smaller total cerebellum volume, as well as reduced volume in subregions primarily within the posterior lobe (lobule VIIB, crus II), vermis (VI, VIII), flocculonodular lobe (lobule X), and corpus medullare (all p-FDR < 0.05). Effects of PTSD on volume were consistent, and generally more robust, when examining symptom severity rather than diagnostic status. These findings implicate regionally specific cerebellar volumetric differences in the pathophysiology of PTSD. The cerebellum appears to play an important role in higher-order cognitive and emotional processes, far beyond its historical association with vestibulomotor function. Further examination of the cerebellum in trauma-related psychopathology will help to clarify how cerebellar structure and function may disrupt cognitive and affective processes at the center of translational models for PTSD.

How does it feel? An exploration of neurobiological and clinical correlates of alexithymia in trauma-exposed police-officers with and without PTSD.

Background: Alexithymia, an inability to recognise one's emotions, has been associated with trauma-exposure and posttraumatic stress disorder (PTSD). Previous research suggests involvement of the oxytocin system, and socio-emotional neural processes. However, the paucity of neurobiological research on alexithymia, particularly in trauma-exposed populations, warrants further investigation.Objective: Explore associations between alexithymia, endogenous oxytocin levels, and socio-emotional brain function and morphometry in a trauma-exposed sample.Method: Dutch trauma-exposed police officers with (n = 38; 18 females) and without PTSD (n = 40; 20 females) were included. Alexithymia was assessed with the Toronto Alexithymia Scale (TAS-20). Endogenous salivary oxytocin was assessed during rest, using radioimmunoassay. Amygdala and insula reactivity to socio-emotional stimuli were assessed with functional MRI, amygdala and insula grey matter volume were derived using Freesurfer.Results: Alexithymia was higher in PTSD patients compared to trauma-exposed controls (F(1,70) = 54.031, p < .001). Within PTSD patients, alexithymia was positively associated with PTSD severity (ρ(36) = 0.497, p = .002). Alexithymia was not associated with childhood trauma exposure (ß = 0.076, p = .509), police work-related trauma exposure (ß = -0.107, p = .355), oxytocin levels (ß = -0.164, p = .161), insula (ß = -0.170, p = .158) or amygdala (ß = -0.175, p = .135) reactivity, or amygdala volume (ß = 0.146, p = .209). Insula volume was positively associated with alexithymia (ß = 0.222, p = .016), though not significant after multiple testing corrections. Bayesian analyses supported a lack of associations.Conclusions: No convincing neurobiological correlates of alexithymia were observed with any of the markers included in the current study. Yet, the current study confirmed high levels of alexithymia in PTSD patients, independent of trauma-exposure, substantiating alexithymia's relevance in the clinical phenotype of PTSD.

Little is known about neurobiological correlates of alexithymia in trauma-exposed and posttraumatic stress disorder (PTSD) populations.In this highly trauma-exposed sample, alexithymia was associated with PTSD symptoms, but not with childhood or adult trauma exposure, suggesting alexithymia is not a direct consequence of trauma.Alexithymia was not convincingly associated with salivary oxytocin, amygdala and insula reactivity to socio-emotional stimuli, amygdala or insula grey matter volume.

Recalibrating single-study effect sizes using hierarchical Bayesian models.

Introduction: There are growing concerns about commonly inflated effect sizes in small neuroimaging studies, yet no study has addressed recalibrating effect size estimates for small samples. To tackle this issue, we propose a hierarchical Bayesian model to adjust the magnitude of single-study effect sizes while incorporating a tailored estimation of sampling variance. Methods: We estimated the effect sizes of case-control differences on brain structural features between individuals who were dependent on alcohol, nicotine, cocaine, methamphetamine, or cannabis and non-dependent participants for 21 individual studies (Total cases: 903; Total controls: 996). Then, the study-specific effect sizes were modeled using a hierarchical Bayesian approach in which the parameters of the study-specific effect size distributions were sampled from a higher-order overarching distribution. The posterior distribution of the overarching and study-specific parameters was approximated using the Gibbs sampling method. Results: The results showed shrinkage of the posterior distribution of the study-specific estimates toward the overarching estimates given the original effect sizes observed in individual studies. Differences between the original effect sizes (i.e., Cohen's d) and the point estimate of the posterior distribution ranged from 0 to 0.97. The magnitude of adjustment was negatively correlated with the sample size (r = -0.27, p < 0.001) and positively correlated with empirically estimated sampling variance (r = 0.40, p < 0.001), suggesting studies with smaller samples and larger sampling variance tended to have greater adjustments. Discussion: Our findings demonstrate the utility of the hierarchical Bayesian model in recalibrating single-study effect sizes using information from similar studies. This suggests that Bayesian utilization of existing knowledge can be an effective alternative approach to improve the effect size estimation in individual studies, particularly for those with smaller samples.