Childhood trauma is associated with reduced frontal gray matter volume: a large transdiagnostic structural MRI study.

BACKGROUND: Childhood trauma increases risk for psychopathology and cognitive impairment. Prior research mainly focused on the hippocampus and amygdala in single diagnostic categories. However, other brain regions may be impacted by trauma as well, and effects may be independent of diagnosis. This cross-sectional study investigated cortical and subcortical gray matter volume in relation to childhood trauma severity. METHODS: We included 554 participants: 250 bipolar-I patients, 84 schizophrenia-spectrum patients and 220 healthy individuals without a psychiatric history. Participants filled in the Childhood Trauma Questionnaire. Anatomical T1 MRI scans were acquired at 3T, regional brain morphology was assessed using Freesurfer. RESULTS: In the total sample, trauma-related gray matter reductions were found in the frontal lobe (ß = -0.049, p = 0.008; q = 0.048), this effect was driven by the right medial orbitofrontal, paracentral, superior frontal regions and the left precentral region. No trauma-related volume reductions were observed in any other (sub)cortical lobes nor the hippocampus or amygdala, trauma-by-group (i.e. both patient groups and healthy subjects) interaction effects were absent. A categorical approach confirmed a pattern of more pronounced frontal gray matter reductions in individuals reporting multiple forms of trauma and across quartiles of cumulative trauma scores. Similar dose-response patterns were revealed within the bipolar and healthy subgroups, but did not reach significance in schizophrenia-spectrum patients. CONCLUSIONS: Findings show that childhood trauma is linked to frontal gray matter reductions, independent of psychiatric morbidity. Our results indicate that childhood trauma importantly contributes to the neurobiological changes commonly observed across psychiatric disorders. Frontal volume alterations may underpin affective and cognitive disturbances observed in trauma-exposed individuals.

Lower fractional anisotropy without evidence for neuro-inflammation in patients with early-phase schizophrenia spectrum disorders.

Various lines of research suggest immune dysregulation as a potential therapeutic target for negative and cognitive symptoms in schizophrenia spectrum disorders (SSD). Immune dysregulation would lead to higher extracellular free-water (EFW) in cerebral white matter (WM), which may partially underlie the frequently reported lower fractional anisotropy (FA) in SSD. We aim to investigate differences in EFW concentrations - a presumed proxy for neuro-inflammation - between early-phase SSD patients (n = 55) and healthy controls (HC; n = 37), and to explore immunological and cognitive correlates. To increase specificity for EFW, we study several complementary magnetic resonance imaging contrasts that are sensitive to EFW. FA, mean diffusivity (MD), magnetization transfer ratio (MTR), myelin water fraction (MWF) and quantitative T1 and T2 were calculated from diffusion-weighted imaging (DWI), magnetization transfer imaging (MTI) and multicomponent driven equilibrium single-pulse observation of T1/T2 (mcDESPOT). For each measure, WM skeletons were constructed with tract-based spatial statistics. Multivariate SSD-HC comparisons with WM skeletons and their average values (i.e. global WM) were not statistically significant. In voxel-wise analyses, FA was significantly lower in SSD in the genu of the corpus callosum and in the left superior longitudinal fasciculus (p < 0.04). Global WM measures did not correlate with immunological markers (i.e. IL1-RA, IL-6, IL-8, IL-10 and CRP) or cognition in HC and SSD after corrections for multiple comparisons. We confirmed lower FA in early-phase SSD patients. However, nonFA measures did not provide additional evidence for immune dysregulation or for higher EFW as the primary mechanism underlying the reported lower FA values in SSD.

Occurrence and phenomenology of hallucinations in the general population: A large online survey.

Although epidemiological studies report that hallucinations occur in 6-15% of the general population, little is known about their phenomenology. To overcome this paucity, this study investigates the phenomenological characteristics of hallucinations in the general population, by using a nationally promoted online survey to assess hallucination phenomenology in four sensory modalities, through a self-report version of the Questionnaire for Psychotic Experiences (QPE), in 10,448 participants (aged 14-88 years). The phenomenology of hallucinations was assessed if hallucinations reportedly occurred in the past month. In the past month, auditory hallucinations were reported most frequently (29.5%), followed by visual (21.5%), tactile (19.9%), and olfactory hallucinations (17.3%); hallucinations in two or more modalities were reported by 47.6%. Substantial numbers of participants rated their hallucinations as severe, due to negative content (16.0-31.6%), previous bothersome experiences (14.8-20.2%), ensuing distress (10.5-16.8%), and/or ensuing disfunctioning (12.7-17.3%). Decreased insight was found in 10.2-11.4%. Hypnagogia was reported by 9.0-10.6%, and bereavement hallucinations by 2.8%. Despite a low prevalence of delusions (7.0%), these phenomena were significantly associated with recent hallucinations, observed in up to 13.4% of the participants with hallucinations during the past week (p < 0.001). Our results indicate a wide variety of the phenomenology of hallucinations in the general population and support the existence of a phenomenological continuum.

Modular-Level Functional Connectome Alterations in Individuals With Hallucinations Across the Psychosis Continuum.

Functional connectome alterations, including modular network organization, have been related to the experience of hallucinations. It remains to be determined whether individuals with hallucinations across the psychosis continuum exhibit similar alterations in modular brain network organization. This study assessed functional connectivity matrices of 465 individuals with and without hallucinations, including patients with schizophrenia and bipolar disorder, nonclinical individuals with hallucinations, and healthy controls. Modular brain network organization was examined at different scales of network resolution, including (1) global modularity measured as Qmax and Normalised Mutual Information (NMI) scores, and (2) within- and between-module connectivity. Global modular organization was not significantly altered across groups. However, alterations in within- and between-module connectivity were observed for higher-order cognitive (e.g., central-executive salience, memory, default mode), and sensory modules in patients with schizophrenia and nonclinical individuals with hallucinations relative to controls. Dissimilar patterns of altered within- and between-module connectivity were found bipolar disorder patients with hallucinations relative to controls, including the visual, default mode, and memory network, while connectivity patterns between visual, salience, and cognitive control modules were unaltered. Bipolar disorder patients without hallucinations did not show significant alterations relative to controls. This study provides evidence for alterations in the modular organization of the functional connectome in individuals prone to hallucinations, with schizophrenia patients and nonclinical individuals showing similar alterations in sensory and higher-order cognitive modules. Other higher-order cognitive modules were found to relate to hallucinations in bipolar disorder patients, suggesting differential neural mechanisms may underlie hallucinations across the psychosis continuum.

Functional connectome differences in individuals with hallucinations across the psychosis continuum.

Hallucinations may arise from an imbalance between sensory and higher cognitive brain regions, reflected by alterations in functional connectivity. It is unknown whether hallucinations across the psychosis continuum exhibit similar alterations in functional connectivity, suggesting a common neural mechanism, or whether different mechanisms link to hallucinations across phenotypes. We acquired resting-state functional MRI scans of 483 participants, including 40 non-clinical individuals with hallucinations, 99 schizophrenia patients with hallucinations, 74 bipolar-I disorder patients with hallucinations, 42 bipolar-I disorder patients without hallucinations, and 228 healthy controls. The weighted connectivity matrices were compared using network-based statistics. Non-clinical individuals with hallucinations and schizophrenia patients with hallucinations exhibited increased connectivity, mainly among fronto-temporal and fronto-insula/cingulate areas compared to controls (P < 0.001 adjusted). Differential effects were observed for bipolar-I disorder patients with hallucinations versus controls, mainly characterized by decreased connectivity between fronto-temporal and fronto-striatal areas (P = 0.012 adjusted). No connectivity alterations were found between bipolar-I disorder patients without hallucinations and controls. Our results support the notion that hallucinations in non-clinical individuals and schizophrenia patients are related to altered interactions between sensory and higher-order cognitive brain regions. However, a different dysconnectivity pattern was observed for bipolar-I disorder patients with hallucinations, which implies a different neural mechanism across the psychosis continuum.

Hallucinations and other psychotic experiences across diagnoses: A comparison of phenomenological features.

Although psychotic experiences are prevalent across many psychiatric, neurological, and medical disorders, investigation of these symptoms has largely been restricted to diagnostic categories. This study aims to examine phenomenological similarities and differences across a range of diagnoses. We assessed frequency, severity and phenomenology of psychotic experiences in 350 outpatients including; participants with schizophrenia spectrum disorders, hearing impairment, Parkinson's disease, Lewy Body Dementia, Alzheimer's disease, visual impairment, posttraumatic stress disorder, borderline personality disorder, and participants with recent major surgery. Psychotic phenomena were explored between these groups using the Questionnaire for Psychotic Experiences (QPE). Participants with major psychiatric disorders reported a combination of several psychotic experiences, and more severe experiences compared to all other disorders. Participants with recent major surgery or visual impairment experienced isolated visual hallucinations. Participants with hearing impairment reported isolated auditory hallucinations, whereas the neurodegenerative disorders reported visual hallucinations, occasionally in combination with hallucinations in another modality or delusions. The phenomenology between neurodegenerative disorders, and within major psychiatric disorders showed many similarities. Our findings indicate that the phenomenology of psychotic experiences is not diagnosis specific, but may rather point to the existence of various subtypes across diagnoses. These subtypes could have a different underlying etiology requiring specific treatment.

Atopy Increases Risk of Psychotic Experiences: A Large Population-Based Study.

Introduction: Building upon the comorbidity between atopy and schizophrenia, we conducted a large cross-sectional, observational population-based study to examine if such associations also exist between atopic disorders (eczema, allergic rhinitis, and asthma) and nonclinical psychotic experiences. Methods: We examined psychotic experiences in a Dutch population sample through an online survey (≥14 years of age). Participants filled out the Questionnaire for Psychotic Experiences, together with questions screening for atopic disorders (eczema, allergic rhinitis, and asthma). Prevalence rates were calculated; binary logistic regression was used to determine odds ratios (ORs) (age, gender, and years of education as covariates). Results: We included 6,479 participants. Individuals diagnosed with one or more atopic disorders had an increased risk of psychotic experiences as compared with controls (OR = 1.26). Analysis of individual symptoms revealed an OR of 1.27 for hallucinations, whereas delusions only showed a trend. With each additional atopic disorder, the risk of psychotic experiences increased. This was also observed for hallucinations alone but not for delusions alone. Atopy was associated with hallucinations across all modalities (OR ranging from 1.19 to 1.40). These results did not appear to be driven specifically by any one of the atopic disorders. Conclusion: In the largest population sample of adolescents and adults to date, we found that atopic disorders (asthma, eczema, and allergic rhinitis) increase the risk of psychotic experiences, in a dose-response fashion. These results provide further support for the role of immunological components in the predisposition for psychosis and can serve as a base for further research.

The Questionnaire for Psychotic Experiences: An Examination of the Validity and Reliability.

Psychotic experiences are prevalent across a wide variety of psychiatric, neurological, and medical conditions. Yet current assessments are often designed for one disorder, or are limited in their examination of phenomenological features; this has hindered transdiagnostic research. This article describes an examination of the validity and reliability of the English version of a new assessment, the Questionnaire for Psychotic Experiences (QPE). This study aimed to use the QPE to examine hallucinations and delusions across a number of different conditions, and to ensure that the QPE had acceptable psychometric properties. An International Consortium on Hallucination Research working group, along with consumer groups, developed the 50-item QPE to assess the presence, severity, and phenomenology of hallucinations and delusions. Participants in the study who reported psychotic experiences included those with schizophrenia, schizoaffective disorder, bipolar affective disorder, and major depressive disorder, and those without a need for care (ie, nonclinical participants). There were 173 participants in total. Convergent and discriminant validity were assessed. Reliability was examined in terms of stability, equivalence, and internal consistency. The data confirmed that the QPE had good psychometric properties and could be put forward as an accepted measure of the transdiagnostic evaluation of psychotic experiences. Further validation is recommended with neurological and medical populations. Given its validity and reliability, comprehensive evaluation of psychotic phenomena, and relatively quick administration time, we propose that the QPE is a valuable instrument for both clinical and research settings.

Resting-state fMRI reveals network disintegration during delirium.

Delirium is characterized by inattention and other cognitive deficits, symptoms that have been associated with disturbed interactions between remote brain regions. Recent EEG studies confirm that disturbed global network topology may underlie the syndrome, but lack an anatomical basis. The aim of this study was to increase our understanding of the global organization of functional connectivity during delirium and to localize possible alterations. Resting-state fMRI data from 44 subjects were analyzed, and motion-free data were available in nine delirious patients, seven post delirium patients and thirteen non-delirious clinical controls. We focused on the functional network backbones using the minimum spanning tree, which allows unbiased network comparisons. During delirium a longer diameter (mean (M) = 0.30, standard deviation (SD) = 0.05, P = .024) and a lower leaf fraction (M = 0.32, SD = 0.03, P = .027) was found compared to the control group (M = 0.28, SD = 0.04 respectively M = 0.35, SD = 0.03), suggesting reduced functional network integration and efficiency. Delirium duration was strongly related to loss of network hierarchy (rho = -0.92, P = .001). Connectivity strength was decreased in the post delirium group (M = 0.16, SD = 0.01) compared to the delirium group (M = 0.17, SD = 0.03, P = .024) and the control group (M = 0.19, SD = 0.02, P = .001). Permutation tests revealed a decreased degree of the right posterior cingulate cortex during delirium and complex regional alterations after delirium. These findings indicate that delirium reflects disintegration of functional interactions between remote brain areas and suggest long-term impact after the syndrome resolves.

Theta Burst Transcranial Magnetic Stimulation for Auditory Verbal Hallucinations: Negative Findings From a Double-Blind-Randomized Trial.

BACKGROUND: Auditory verbal hallucinations (AVH) in schizophrenia are resistant to antipsychotic medication in approximately 25% of patients. Treatment with repetitive transcranial magnetic stimulation (rTMS) for refractory AVH has shown varying results. A stimulation protocol using continuous theta burst rTMS (TB-rTMS) showed high efficacy in open label studies. We tested TB-rTMS as a treatment strategy for refractory AVH in a double-blind, placebo-controlled trial. METHODS: Seventy-one patients with AVH were randomly allocated to TB-rTMS or placebo treatment. They received 10 TB-rTMS or sham treatments over the left temporoparietal cortex in consecutive days. AVH severity was assessed at baseline, end of treatment and follow-up using the Psychotic Symptom Rating Scale (PSYRATS) and the Auditory Hallucinations Rating Scale (AHRS). Other schizophrenia-related symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS). RESULTS: Seven patients dropped out before completing the study. In the remaining 64, AVH improved significantly after treatment in both groups as measured with both PSYRATS and AHRS. PANSS positive and general subscores also decreased, but the negative subscores did not. However, improvement did not differ significantly between the TB-rTMS and the placebo group on any outcome measure. CONCLUSIONS: Symptom reduction could be achieved in patients with medication-resistant hallucinations, even within 1 week time. However, as both groups showed similar improvement, effects were general (ie, placebo-effects) rather than specific to treatment with continuous TB-rTMS. Our findings highlight the importance of double-blind trials including a sham-control condition to assess efficacy of new treatments such as TMS.