Imaging Violence in Schizophrenia: A Systematic Review and Critical Discussion of the MRI Literature

Background: Persons with schizophrenia have a small but significant increase in risk of violence, which remains after controlling for known environmental risk factors. In vivo MRI-studies may point toward the biological underpinnings of psychotic violence, and neuroimaging has increasingly been used in forensic and legal settings despite unclear relevance.Objectives: (1) To present the first systematic review, following standardized guidelines, of MRI studies of violence with schizophrenia. (2) To critically discuss the promises and pitfalls of using this literature to understand violence in schizophrenia in clinical, forensic, and legal settings.Methods: Following the PRISMA guidelines and literature searches until January 2018, we found 21 original studies that fulfilled the inclusion criteria: (1) Studies of persons with schizophrenia, (2) a history of violence or aggressive behavior, (3) the use of one or more MRI-modalities (sMRI, DTI, fMRI).Results: The most consistent findings from the structural studies were reduced volumes of the hippocampus and the frontal lobe (in particular the orbitofrontal and anterior cingulate cortex) in schizophrenia patients with a history of violence or higher aggression scores. The functional studies mainly showed differences and aggression correlates in the frontal lobe and amygdala. However, the studies were methodologically heterogeneous, with four particular areas of concern: different definitions of violence, region of interest vs. whole-brain studies, small subject samples, and group comparisons in a heterogeneous diagnostic category (schizophrenia).Conclusion: The literature reports subtle, but inconsistent group level differences in brain structure and function associated with violence and aggression with schizophrenia, in particular in areas involved in the formation of psychosis symptoms and affective regulation. Due to methodological challenges the results should be interpreted with caution. In order to come closer to the neurobiological underpinnings of violence in schizophrenia future studies could: (1) address the neurobiological differences of premeditated and reactive violence, (2) use RDoC criteria, for example, or other symptom-based systems to categorize psychosis patients, (3) increase subject cohorts and apply new data driven methods. In this perspective, MRI-studies of violence in schizophrenia have the potential to inform clinical violence prediction and legal evaluations in the future

Effects of obstetric complications on brain morphology in schizophrenia : four MRI studies

Magnetic resonance imaging (MRI) studies have shown the brains of schizophrenia patients to have smaller hippocampi, larger ventricles, and reduced cortical thickness and regional brain volumes, as compared to the brains of mentally healthy subjects. The abnormal brain morphology may reflect subtle deviances from normal brain development. Early adverse somatic events, in the current thesis studied in the form of obstetric complications (OCs), in the pre-, peri-, or postnatal periods can cause or influence a deviant neurodevelopment. In scientific studies, it has been demonstrated that occurrence of OCs increase the risk of schizophrenia. Moreover, results from experimental animal studies demonstrate that different OCs cause both abnormal changes in brain morphology and behaviour that parallel what is observed in schizophrenia. In humans, OCs have been related to smaller hippocampi, larger lateral ventricles, and reduced cortical volume in schizophrenia patients with as compared to patients without a history of OCs. Taken together, these findings suggest that early somatic trauma such as OCs may exert an influence on neurodevelopment, detectable in the brain decades later. The main aim of this PhD thesis was to investigate the relationship between a history of (OCs) and brain morphology in patients with schizophrenia. The subaims were to study 1) if such a putative effect could explain some of the differences in brain morphology observed between schizophrenia patients and healthy controls, and 2) if the effect of OCs on hippocampal volume, if demonstrated, is modified by genetic variation (allele variation in single nucleotide polymorphisms). The subject sample included in the current four studies comprises 54 schizophrenia patients and 54 healthy control subjects. They all underwent clinical examination, genotyping, and MRI scanning at the Karolinska Institutet and Karolinska University Hospital in Stockholm, Sweden. Automated software tools were used to obtain measures of basal ganglia nuclei and hippocampal volumes, cortical thickness, and cortical folding patterns. Information on OCs was independently collected from original birth records. The main findings were that OCs are not associated with basal ganglia volumes (study I) or cortical thickness (study II), but significantly associated with reduced cortical folding in the left pars triangularis (Broca’s area) (study III) and with altered hippocampal volumes (study IV). The effect of OCs on hippocampal volume appeared to be modulated by allele variation in the hypoxia-regulated GRM3 gene (study IV). Furthermore, schizophrenia patients did not differ from healthy control subjects with respect to the rate or severity of OCs per se; the effects of OCs on basal ganglia volumes, cortical thickness, and cortical gyrification; or the gene*OCs interaction effect on hippocampal volume. In conclusion, while some brain structures (cortical thickness, basal ganglia volumes) were unaffected by a history OCs, OCs influenced other aspects of brain morphology (hippocampal volume, cortical folding) in the same way in both patients with schizophrenia and healthy controls. The differences in brain morphology found between schizophrenia patients and healthy controls were not effects of OCs. Genetic variation may modulate the effect of OCs on hippocampal volume

Remodelling criminal insanity: Exploring philosophical, legal, and medical premises of the medical model used in Norwegian law

This paper clarifies the conceptual space of discussion of legal insanity by considering the virtues of the ‘medical model’ model that has been used in Norway for almost a century. The medical model identifies insanity exclusively with mental disorder, and especially with psychosis, without any requirement that the disorder causally influenced the commission of the crime. We explore the medical model from a transdisciplinary perspective and show how it can be utilised to systematise and reconsider the central philosophical, legal and medical premises involved in the insanity debate. A key concern is how recent transdiagnostic and dimensional approaches to psychosis can illuminate the law's understanding of insanity and its relation to mental disorder. The authors eventually raise the question whether the medical model can be reconstructed into a unified insanity model that is valid across the related disciplinary perspectives, and that moves beyond current insanity models.publishedVersio

Remodelling criminal insanity: Exploring philosophical, legal, and medical premises of the medical model used in Norwegian law

This paper clarifies the conceptual space of discussion of legal insanity by considering the virtues of the ‘medical model’ model that has been used in Norway for almost a century. The medical model identifies insanity exclusively with mental disorder, and especially with psychosis, without any requirement that the disorder causally influenced the commission of the crime. We explore the medical model from a transdisciplinary perspective and show how it can be utilised to systematise and reconsider the central philosophical, legal and medical premises involved in the insanity debate. A key concern is how recent transdiagnostic and dimensional approaches to psychosis can illuminate the law\u27s understanding of insanity and its relation to mental disorder. The authors eventually raise the question whether the medical model can be reconstructed into a unified insanity model that is valid across the related disciplinary perspectives, and that moves beyond current insanity models

Criminal Insanity, Psychosis and Impaired Reality Testing in Norwegian Law

How mental disorder relates to criminal insanity is a contested matter. Norway has a tradition of using a ‘medical model’ for the definition of criminal insanity that is unique in an international perspective. According to this model, insanity is determined only in relation to a medical criterion, so that all that is required is the presence of a qualifying mental disorder. Criminal insanity is, under the current rule, equated with psychosis, although this rule has recently been subject to a law reform. This article explains and discusses this medical model by gathering together legal, forensic, and clinical empirical perspectives on the legal meaning and relevance of psychosis. The article will provide an explanation of the background of the medical model in Norwegian law, and the justifications for tying criminal insanity to psychosis. It will also explain how criminal insanity is operationalised in forensic practice, and discuss the legal conceptualisation of psychosis from a medical perspective. A main conclusion is that the legal meaning of psychosis is unclear, and the authors describe several challenges in legal and forensic practice. The authors emphasise the need for further knowledge development in the intersection between law and medicine

Association of Birth Asphyxia With Regional White Matter Abnormalities Among Patients With Schizophrenia and Bipolar Disorders

Importance: White matter (WM) abnormalities are commonly reported in psychiatric disorders. Whether peripartum insufficiencies in brain oxygenation, known as birth asphyxia, are associated with WM of patients with severe mental disorders is unclear. Objective: To examine the association between birth asphyxia and WM in adult patients with schizophrenia and bipolar disorders (BDs) compared with healthy adults. Design, setting, and participants: In this case-control study, all individuals participating in the ongoing Thematically Organized Psychosis project were linked to the Medical Birth Registry of Norway (MBRN), where a subset of 271 patients (case group) and 529 healthy individuals (control group) had undergone diffusion-weighted imaging (DWI). Statistical analyses were performed from June 16, 2020, to March 9, 2021. Exposures: Birth asphyxia was defined based on measures from standardized reporting at birth in the MBRN. Main outcomes and measures: Associations between birth asphyxia and WM regions of interest diffusion metrics, ie, fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD), were compared between groups using analysis of covariance, adjusted for age, age squared, and sex. Results: Of the 850 adults included in the study, 271 were in the case group (140 [52%] female individuals; mean [SD] age, 28.64 [7.43] years) and 579 were in the control group (245 [42%] female individuals; mean [SD] age, 33.54 [8.31] years). Birth asphyxia measures were identified in 15% to 16% of participants, independent of group. The posterior limb of the internal capsule (PLIC) showed a significant diagnostic group × birth asphyxia interaction (F(1, 843) = 11.46; P = .001), reflecting a stronger association between birth asphyxia and FA in the case group than the control group. RD, but not AD, also displayed a significant diagnostic group × birth asphyxia interaction (F(1, 843) = 9.28; P = .002) in the PLIC, with higher values in patients with birth asphyxia and similar effect sizes as observed for FA. Conclusions and relevance: In this case-control study, abnormalities in the PLIC of adult patients with birth asphyxia may suggest a greater susceptibility to hypoxia in patients with severe mental illness, which could lead to myelin damage or impeded brain development. Echoing recent early-stage schizophrenia studies, abnormalities of the PLIC are relevant to psychiatric disorders, as the PLIC contains important WM brain pathways associated with language, cognitive function, and sensory function, which are impaired in schizophrenia and BDs

What we learn about bipolar disorder from large-scale neuroimaging:Findings and future directions from the ENIGMA Bipolar Disorder Working Group

MRI-derived brain measures offer a link between genes, the environment and behavior and have been widely studied in bipolar disorder (BD). However, many neuroimaging studies of BD have been underpowered, leading to varied results and uncertainty regarding effects. The Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Bipolar Disorder Working Group was formed in 2012 to empower discoveries, generate consensus findings and inform future hypothesis-driven studies of BD. Through this effort, over 150 researchers from 20 countries and 55 institutions pool data and resources to produce the largest neuroimaging studies of BD ever conducted. The ENIGMA Bipolar Disorder Working Group applies standardized processing and analysis techniques to empower large-scale meta- and mega-analyses of multimodal brain MRI and improve the replicability of studies relating brain variation to clinical and genetic data. Initial BD Working Group studies reveal widespread patterns of lower cortical thickness, subcortical volume and disrupted white matter integrity associated with BD. Findings also include mapping brain alterations of common medications like lithium, symptom patterns and clinical risk profiles and have provided further insights into the pathophysiological mechanisms of BD. Here we discuss key findings from the BD working group, its ongoing projects and future directions for large-scale, collaborative studies of mental illness

Widespread white matter microstructural abnormalities in bipolar disorder: Evidence from mega- and meta-analyses across 3,033 individuals

Fronto-limbic white matter (WM) abnormalities are assumed to lie at the heart of the pathophysiology of bipolar disorder (BD); however, diffusion tensor imaging (DTI) studies have reported heterogeneous results and it is not clear how the clinical heterogeneity is related to the observed differences. This study aimed to identify WM abnormalities that differentiate patients with BD from healthy controls (HC) in the largest DTI dataset of patients with BD to date, collected via the ENIGMA network. We gathered individual tensor-derived regional metrics from 26 cohorts leading to a sample size of N = 3033 (1482 BD and 1551 HC). Mean fractional anisotropy (FA) from 43 regions of interest (ROI) and average whole-brain FA were entered into univariate mega- and meta-analyses to differentiate patients with BD from HC. Mega-analysis revealed significantly lower FA in patients with BD compared with HC in 29 regions, with the highest effect sizes observed within the corpus callosum (R2 = 0.041, Pcorr < 0.001) and cingulum (right: R2 = 0.041, left: R2 = 0.040, Pcorr < 0.001). Lithium medication, later onset and short disease duration were related to higher FA along multiple ROIs. Results of the meta-analysis showed similar effects. We demonstrated widespread WM abnormalities in BD and highlighted that altered WM connectivity within the corpus callosum and the cingulum are strongly associated with BD. These brain abnormalities could represent a biomarker for use in the diagnosis of BD. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org

In vivo hippocampal subfield volumes in bipolar disorder—A mega-analysis from The Enhancing Neuro Imaging Genetics through Meta-Analysis Bipolar Disorder Working Group

The hippocampus consists of anatomically and functionally distinct subfields that may be differentially involved in the pathophysiology of bipolar disorder (BD). Here we, the Enhancing NeuroImaging Genetics through Meta‐Analysis Bipolar Disorder workinggroup, study hippocampal subfield volumetry in BD. T1‐weighted magnetic resonance imaging scans from 4,698 individuals (BD = 1,472, healthy controls [HC] = 3,226) from 23 sites worldwide were processed with FreeSurfer. We used linear mixed‐effects models and mega‐analysis to investigate differences in hippocampal subfield volumes between BD and HC, followed by analyses of clinical characteristics and medication use. BD showed significantly smaller volumes of the whole hippocampus (Cohen's d = −0.20), cornu ammonis (CA)1 (d = −0.18), CA2/3 (d = −0.11), CA4 (d = −0.19), molecular layer (d = −0.21), granule cell layer of dentate gyrus (d = −0.21), hippocampal tail (d = −0.10), subiculum (d = −0.15), presubiculum (d = −0.18), and hippocampal amygdala transition area (d = −0.17) compared to HC. Lithium users did not show volume differences compared to HC, while non‐users did. Antipsychotics or antiepileptic use was associated with smaller volumes. In this largest study of hippocampal subfields in BD to date, we show widespread reductions in nine of 12 subfields studied. The associations were modulated by medication use and specifically the lack of differences between lithium users and HC supports a possible protective role of lithium in BD