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Two established staging models outline the longitudinal progression in bipolar disorder (BD) based on episode recurrence or inter-episodic functioning. However, underlying neurobiological mechanisms and corresponding biomarkers remain unexplored. This study aimed to investigate if global and (sub)cortical brain structures, along with brain-predicted age difference (brain-PAD) reflect illness progression as conceptualized in these staging models, potentially identifying brain-PAD as a biomarker for BD staging.
In total, 199 subjects with bipolar-I-disorder and 226 control subjects from the Dutch Bipolar Cohort with a high-quality T1-weighted magnetic resonance imaging scan were analyzed. Global and (sub)cortical brain measures and brain-PAD (the difference between biological and chronological age) were estimated. Associations between individual brain measures and the stages of both staging models were explored.
A higher brain-PAD (higher biological age than chronological age) correlated with an increased likelihood of being in a higher stage of the inter-episodic functioning model, but not in the model based on number of mood episodes. However, after correcting for the confounding factors lithium-use and comorbid anxiety, the association lost significance. Global and (sub)cortical brain measures showed no significant association with the stages.
These results suggest that brain-PAD may be associated with illness progression as defined by impaired inter-episodic functioning. Nevertheless, the significance of this association changed after considering lithium-use and comorbid anxiety disorders. Further research is required to disentangle the intricate relationship between brain-PAD, illness stages, and lithium intake or anxiety disorders. This study provides a foundation for potentially using brain-PAD as a biomarker for illness progression.
Obesity is highly prevalent and disabling, especially in individuals with severe mental illness including bipolar disorders (BD). The brain is a target organ for both obesity and BD. Yet, we do not understand how cortical brain alterations in BD and obesity interact.
We obtained body mass index (BMI) and MRI-derived regional cortical thickness, surface area from 1231 BD and 1601 control individuals from 13 countries within the ENIGMA-BD Working Group. We jointly modeled the statistical effects of BD and BMI on brain structure using mixed effects and tested for interaction and mediation. We also investigated the impact of medications on the BMI-related associations.
BMI and BD additively impacted the structure of many of the same brain regions. Both BMI and BD were negatively associated with cortical thickness, but not surface area. In most regions the number of jointly used psychiatric medication classes remained associated with lower cortical thickness when controlling for BMI. In a single region, fusiform gyrus, about a third of the negative association between number of jointly used psychiatric medications and cortical thickness was mediated by association between the number of medications and higher BMI.
We confirmed consistent associations between higher BMI and lower cortical thickness, but not surface area, across the cerebral mantle, in regions which were also associated with BD. Higher BMI in people with BD indicated more pronounced brain alterations. BMI is important for understanding the neuroanatomical changes in BD and the effects of psychiatric medications on the brain.
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.
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.
In the total sample, trauma-related gray matter reductions were found in the frontal lobe (β = −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.
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.
The prevalence of psychotic experiences (PEs) is higher in low-and-middle-income-countries (LAMIC) than in high-income countries (HIC). Here, we examine whether this effect is explicable by measurement bias.
A community sample from 13 countries (N = 7141) was used to examine the measurement invariance (MI) of a frequently used self-report measure of PEs, the Community Assessment of Psychic Experiences (CAPE), in LAMIC (n = 2472) and HIC (n = 4669). The CAPE measures positive (e.g. hallucinations), negative (e.g. avolition) and depressive symptoms. MI analyses were conducted with multiple-group confirmatory factor analyses.
MI analyses showed similarities in the structure and understanding of the CAPE factors between LAMIC and HIC. Partial scalar invariance was found, allowing for latent score comparisons. Residual invariance was not found, indicating that sum score comparisons are biased. A comparison of latent scores before and after MI adjustment showed both overestimation (e.g. avolition, d = 0.03 into d = −0.42) and underestimation (e.g. magical thinking, d = −0.03 into d = 0.33) of PE in LAMIC relative to HIC. After adjusting the CAPE for MI, participants from LAMIC reported significantly higher levels on most CAPE factors but a significantly lower level of avolition.
Previous studies using sum scores to compare differences across countries are likely to be biased. The direction of the bias involves both over- and underestimation of PEs in LAMIC compared to HIC. Nevertheless, the study confirms the basic finding that PEs are more frequent in LAMIC than in HIC.
Studying offspring of schizophrenia (SZo) and bipolar disorder patients (BDo) provides important information on the putative neurodevelopmental trajectories underlying development toward severe mental illnesses. We compared intracranial volume (ICV), as a marker for neurodevelopment, and global and local brain measures between SZo or BDo and control offspring (Co) in relation to IQ and psychopathology.
T1-weighted magnetic resonance imaging (MRI) brain scans were obtained from 146 participants (8–19 years; 40 SZo, 66 BDo, 40 Co). Linear mixed models were applied to compare ICV, global, and local brain measures between groups. To investigate the effect of ICV, IQ (four subtests Wechsler Intelligence Scale for Children/Wechsler Adult Intelligence Scale-III) or presence of psychopathology these variables were each added to the model.
SZo and BDo had significantly lower IQ and more often met criteria for a lifetime psychiatric disorder than Co. ICV was significantly smaller in SZo than in BDo (d = −0.56) and Co (d = −0.59), which was largely independent of IQ (respectively, d = −0.54 and d = −0.35). After ICV correction, the cortex was significantly thinner in SZo than in BDo (d = −0.42) and Co (d = −0.75) and lateral ventricles were larger in BDo than in Co (d = 0.55). Correction for IQ or lifetime psychiatric diagnosis did not change these findings.
Despite sharing a lower IQ and a higher prevalence of psychiatric disorders, brain abnormalities in BDo appear less pronounced (but are not absent) than in SZo. Lower ICV in SZo implies that familial risk for schizophrenia has a stronger association with stunted early brain development than familial risk for bipolar disorder.
Neuroanatomical abnormalities in first-episode psychosis (FEP) tend to be subtle and widespread. The vast majority of previous studies have used small samples, and therefore may have been underpowered. In addition, most studies have examined participants at a single research site, and therefore the results may be specific to the local sample investigated. Consequently, the findings reported in the existing literature are highly heterogeneous. This study aimed to overcome these issues by testing for neuroanatomical abnormalities in individuals with FEP that are expressed consistently across several independent samples.
Structural Magnetic Resonance Imaging data were acquired from a total of 572 FEP and 502 age and gender comparable healthy controls at five sites. Voxel-based morphometry was used to investigate differences in grey matter volume (GMV) between the two groups. Statistical inferences were made at p < 0.05 after family-wise error correction for multiple comparisons.
FEP showed a widespread pattern of decreased GMV in fronto-temporal, insular and occipital regions bilaterally; these decreases were not dependent on anti-psychotic medication. The region with the most pronounced decrease – gyrus rectus – was negatively correlated with the severity of positive and negative symptoms.
This study identified a consistent pattern of fronto-temporal, insular and occipital abnormalities in five independent FEP samples; furthermore, the extent of these alterations is dependent on the severity of symptoms and duration of illness. This provides evidence for reliable neuroanatomical alternations in FEP, expressed above and beyond site-related differences in anti-psychotic medication, scanning parameters and recruitment criteria.
Positive symptoms are a useful predictor of aggression in schizophrenia. Although a similar pattern of abnormal brain structures related to both positive symptoms and aggression has been reported, this observation has not yet been confirmed in a single sample.
To study the association between positive symptoms and aggression in schizophrenia on a neurobiological level, a prospective meta-analytic approach was employed to analyze harmonized structural neuroimaging data from 10 research centers worldwide. We analyzed brain MRI scans from 902 individuals with a primary diagnosis of schizophrenia and 952 healthy controls.
The result identified a widespread cortical thickness reduction in schizophrenia compared to their controls. Two separate meta-regression analyses revealed that a common pattern of reduced cortical gray matter thickness within the left lateral temporal lobe and right midcingulate cortex was significantly associated with both positive symptoms and aggression.
These findings suggested that positive symptoms such as formal thought disorder and auditory misperception, combined with cognitive impairments reflecting difficulties in deploying an adaptive control toward perceived threats, could escalate the likelihood of aggression in schizophrenia.
To investigate whether genetic and/or disease-related factors are involved in progressive structural brain changes in schizophrenia, magnetic resonance imaging scans with a 5-year scan interval were acquired in patients, their same-gender siblings and matched healthy controls. Structural equation modelling was applied to assess disease and familial effects. Whole brain and cerebral grey matter volumes decreased excessively in patients compared with their siblings and the controls, suggesting that the progressive brain loss in schizophrenia may be related to the disease process.
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