Mania-related effects on structural brain changes in bipolar disorder - a narrative review of the evidence.

Cross-sectional neuroimaging studies show that bipolar disorder is associated with structural brain abnormalities, predominantly observed in prefrontal and temporal cortex, cingulate gyrus, and subcortical regions. However, longitudinal studies are needed to elucidate whether these abnormalities presage disease onset or are consequences of disease processes, and to identify potential contributing factors. Here, we narratively review and summarize longitudinal structural magnetic resonance imaging studies that relate imaging outcomes to manic episodes. First, we conclude that longitudinal brain imaging studies suggest an association of bipolar disorder with aberrant brain changes, including both deviant decreases and increases in morphometric measures. Second, we conclude that manic episodes have been related to accelerated cortical volume and thickness decreases, with the most consistent findings occurring in prefrontal brain areas. Importantly, evidence also suggests that in contrast to healthy controls, who in general show age-related cortical decline, brain metrics remain stable or increase during euthymic periods in bipolar disorder patients, potentially reflecting structural recovering mechanisms. The findings stress the importance of preventing manic episodes. We further propose a model of prefrontal cortical trajectories in relation to the occurrence of manic episodes. Finally, we discuss potential mechanisms at play, remaining limitations, and future directions.

Altered Neural and Behavioral Response to Sexually Implicit Stimuli During a Pictorial-Modified Stroop Task in Pedophilic Disorder.

Background: Pedophilic disorder (PD) entails sexual attraction to prepubertal children. A risk factor for committing child sexual abuse in PD is impaired cognitive control. However, the underlying neurocognitive mechanisms remain unclear. Methods: We performed a case-control study including 51 self-identified and help-seeking males with PD and 55 matched healthy control subjects. Functional magnetic resonance imaging and a pictorial-modified Stroop task involving computer-generated sexually implicit images were used to measure response time and brain activation. Increases in response time during the pictorial-modified Stroop task are presumably due to image-induced interference in executive functions required for task performance. Results: In PD, during the presentation of images of children compared with adults, we found increased response time (p = .005; 848 ± 92 ms vs. 826 ± 88 ms), and compared with healthy control subjects, we found increased activation in the occipital, temporal (bilateral hippocampus), parietal, frontal, cingulate, and left insular cortices; caudate (bilaterally); thalamus (mediodorsal); and cerebellum. Conclusions: Presentation of child images was associated with response interference in PD and increased engagement of brain regions involved in the processing of sexual stimuli, visual perception, self-referential thought, and executive function. We conclude that processing of child images is associated with functional and behavioral alterations in PD.

Mega-analysis of association between obesity and cortical morphology in bipolar disorders: ENIGMA study in 2832 participants.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

In Vivo 7-Tesla MRI Investigation of Brain Iron and Its Metabolic Correlates in Chronic Schizophrenia.

Brain iron is central to dopaminergic neurotransmission, a key component in schizophrenia pathology. Iron can also generate oxidative stress, which is one proposed mechanism for gray matter volume reduction in schizophrenia. The role of brain iron in schizophrenia and its potential link to oxidative stress has not been previously examined. In this study, we used 7-Tesla MRI quantitative susceptibility mapping (QSM), magnetic resonance spectroscopy (MRS), and structural T1 imaging in 12 individuals with chronic schizophrenia and 14 healthy age-matched controls. In schizophrenia, there were higher QSM values in bilateral putamen and higher concentrations of phosphocreatine and lactate in caudal anterior cingulate cortex (caCC). Network-based correlation analysis of QSM across corticostriatal pathways as well as the correlation between QSM, MRS, and volume, showed distinct patterns between groups. This study introduces increased iron in the putamen in schizophrenia in addition to network-wide disturbances of iron and metabolic status.

Neural and behavioral correlates of sexual stimuli anticipation point to addiction-like mechanisms in compulsive sexual behavior disorder.

Background and aims: Compulsive sexual behavior disorder (CSBD) is characterized by persistent patterns of failure to control sexual impulses resulting in repetitive sexual behavior, pursued despite adverse consequences. Despite previous indications of addiction-like mechanisms and the recent impulse-control disorder classification in the International Classification of Diseases (ICD-11), the neurobiological processes underlying CSBD are unknown. Methods: We designed and applied a behavioral paradigm aimed at disentangling processes related to anticipation and viewing of erotic stimuli. In 22 male CSBD patients (age: M = 38.7, SD = 11.7) and 20 healthy male controls (HC, age: M = 37.6, SD = 8.5), we measured behavioral responses and neural activity during functional magnetic resonance imaging (fMRI). The main outcomes were response time differences between erotic and non-erotic trials and ventral striatum (VS) activity during anticipation of visual stimuli. We related these outcomes with each other, to CSBD diagnosis, and symptom severity. Results: We found robust case-control differences on behavioral level, where CSBD patients showed larger response time differences between erotic and non-erotic trials than HC. The task induced reliable main activations within each group. While we did not observe significant group differences in VS activity, VS activity during anticipation correlated with response time differences and self-ratings for anticipation of erotic stimuli. Discussion and Conclusions: Our results support the validity and applicability of the developed task and suggest that CSBD is associated with altered behavioral correlates of anticipation, which were associated with ventral striatum activity during anticipation of erotic stimuli. This supports the idea that addiction-like mechanisms play a role in CSBD.

Longitudinal Structural Brain Changes in Bipolar Disorder: A Multicenter Neuroimaging Study of 1232 Individuals by the ENIGMA Bipolar Disorder Working Group.

BACKGROUND: Bipolar disorder (BD) is associated with cortical and subcortical structural brain abnormalities. It is unclear whether such alterations progressively change over time, and how this is related to the number of mood episodes. To address this question, we analyzed a large and diverse international sample with longitudinal magnetic resonance imaging (MRI) and clinical data to examine structural brain changes over time in BD. METHODS: Longitudinal structural MRI and clinical data from the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) BD Working Group, including 307 patients with BD and 925 healthy control subjects, were collected from 14 sites worldwide. Male and female participants, aged 40 ± 17 years, underwent MRI at 2 time points. Cortical thickness, surface area, and subcortical volumes were estimated using FreeSurfer. Annualized change rates for each imaging phenotype were compared between patients with BD and healthy control subjects. Within patients, we related brain change rates to the number of mood episodes between time points and tested for effects of demographic and clinical variables. RESULTS: Compared with healthy control subjects, patients with BD showed faster enlargement of ventricular volumes and slower thinning of the fusiform and parahippocampal cortex (0.18

Diagnosis of bipolar disorders and body mass index predict clustering based on similarities in cortical thickness-ENIGMA study in 2436 individuals.

AIMS: Rates of obesity have reached epidemic proportions, especially among people with psychiatric disorders. While the effects of obesity on the brain are of major interest in medicine, they remain markedly under-researched in psychiatry. METHODS: We obtained body mass index (BMI) and magnetic resonance imaging-derived regional cortical thickness, surface area from 836 bipolar disorders (BD) and 1600 control individuals from 14 sites within the ENIGMA-BD Working Group. We identified regionally specific profiles of cortical thickness using K-means clustering and studied clinical characteristics associated with individual cortical profiles. RESULTS: We detected two clusters based on similarities among participants in cortical thickness. The lower thickness cluster (46.8% of the sample) showed thinner cortex, especially in the frontal and temporal lobes and was associated with diagnosis of BD, higher BMI, and older age. BD individuals in the low thickness cluster were more likely to have the diagnosis of bipolar disorder I and less likely to be treated with lithium. In contrast, clustering based on similarities in the cortical surface area was unrelated to BD or BMI and only tracked age and sex. CONCLUSIONS: We provide evidence that both BD and obesity are associated with similar alterations in cortical thickness, but not surface area. The fact that obesity increased the chance of having low cortical thickness could explain differences in cortical measures among people with BD. The thinner cortex in individuals with higher BMI, which was additive and similar to the BD-associated alterations, may suggest that treating obesity could lower the extent of cortical thinning in BD.

Genetic risk for bipolar disorder and schizophrenia predicts structure and function of the ventromedial prefrontal cortex.

BACKGROUND: Bipolar disorder is highly heritable and polygenic. The polygenic risk for bipolar disorder overlaps with that of schizophrenia, and polygenic scores are normally distributed in the population. Bipolar disorder has been associated with structural brain abnormalities, but it is unknown how these are linked to genetic risk factors for psychotic disorders. METHODS: We tested whether polygenic risk scores for bipolar disorder and schizophrenia predict structural brain alterations in 98 patients with bipolar disorder and 81 healthy controls. We derived brain cortical thickness, surface area and volume from structural MRI scans. In post-hoc analyses, we correlated polygenic risk with functional hub strength, derived from resting-state functional MRI and brain connectomics. RESULTS: Higher polygenic risk scores for both bipolar disorder and schizophrenia were associated with a thinner ventromedial prefrontal cortex (vmPFC). We found these associations in the combined group, and separately in patients and drug-naive controls. Polygenic risk for bipolar disorder was correlated with the functional hub strength of the vmPFC within the default mode network. LIMITATIONS: Polygenic risk is a cumulative measure of genomic burden. Detailed genetic mechanisms underlying brain alterations and their cognitive consequences still need to be determined. CONCLUSION: Our multimodal neuroimaging study linked genomic burden and brain endophenotype by demonstrating an association between polygenic risk scores for bipolar disorder and schizophrenia and the structure and function of the vmPFC. Our findings suggest that genetic factors might confer risk for psychotic disorders by influencing the integrity of the vmPFC, a brain region involved in self-referential processes and emotional regulation. Our study may also provide an imaging-genetics vulnerability marker that can be used to help identify individuals at risk for developing bipolar disorder.

Association between body mass index and subcortical brain volumes in bipolar disorders-ENIGMA study in 2735 individuals.

Individuals with bipolar disorders (BD) frequently suffer from obesity, which is often associated with neurostructural alterations. Yet, the effects of obesity on brain structure in BD are under-researched. We obtained MRI-derived brain subcortical volumes and body mass index (BMI) from 1134 BD and 1601 control individuals from 17 independent research sites within the ENIGMA-BD Working Group. We jointly modeled the effects of BD and BMI on subcortical volumes using mixed-effects modeling and tested for mediation of group differences by obesity using nonparametric bootstrapping. All models controlled for age, sex, hemisphere, total intracranial volume, and data collection site. Relative to controls, individuals with BD had significantly higher BMI, larger lateral ventricular volume, and smaller volumes of amygdala, hippocampus, pallidum, caudate, and thalamus. BMI was positively associated with ventricular and amygdala and negatively with pallidal volumes. When analyzed jointly, both BD and BMI remained associated with volumes of lateral ventricles  and amygdala. Adjusting for BMI decreased the BD vs control differences in ventricular volume. Specifically, 18.41% of the association between BD and ventricular volume was mediated by BMI (Z = 2.73, p = 0.006). BMI was associated with similar regional brain volumes as BD, including lateral ventricles, amygdala, and pallidum. Higher BMI may in part account for larger ventricles, one of the most replicated findings in BD. Comorbidity with obesity could explain why neurostructural alterations are more pronounced in some individuals with BD. Future prospective brain imaging studies should investigate whether obesity could be a modifiable risk factor for neuroprogression.

Brain structure and clinical profile point to neurodevelopmental factors involved in pedophilic disorder.

OBJECTIVE: Pedophilic disorder (PD) is characterized bypersistent, intense sexual attraction to prepubertal children that the individual has acted on, or causes marked distress or interpersonal difficulty. Although prior research suggests that PD has neurodevelopmental underpinnings, the evidence remains sparse. To aid the understanding of etiology and treatment development, we quantified neurobiological and clinical correlates of PD. METHOD: We compared 55 self-referred, help-seeking, non-forensic male patients with DSM-5 PD with 57 age-matched, healthy male controls (HC) on clinical, neuropsychological, and structural brain imaging measures (cortical thickness and surface area, subcortical and white matter volumes). Structural brain measures were related to markers for aberrant neurodevelopment including IQ, and the 2nd to 4th digit ratio (2D:4D). RESULTS: PD was associated with psychiatric disorder comorbidity and ADHD and autism spectrum disorder symptoms. PD patients had lower total IQ than HC. PD individuals exhibited cortical surface area abnormalities in regions belonging to the brain's default mode network and showed abnormal volume of white matter underlying those regions. PD subjects had smaller hippocampi and nuclei accumbens than HC. Findings were not related to history of child-related sexual offending. IQ correlated negatively with global expression of PD-related brain features and 2D:4D correlated with surface area in PD. CONCLUSIONS: In the largest single-center study to date, we delineate psychiatric comorbidity, neurobiological and cognitive correlates of PD. Our morphometric findings, their associations with markers of aberrant neurodevelopment, and psychiatric comorbidities suggest that neurodevelopmental mechanisms are involved in PD. The findings may need consideration in future development of clinical management of PD patients.

Influence of genetic variations in IL1B on brain region volumes in bipolar patients and controls.

Involvement of the immune system has been implicated in the etiology and pathophysiology of mood disorders, including bipolar disorder. Neuroimaging studies have reported structural brain pathology in bipolar disorder patients, and both levels of and genetic variants in cytokines have been associated with altered volumes of brain regions. The aim of this study was to investigate associations between single nucleotide polymorphisms in the gene coding for the pro-inflammatory cytokine interleukin-1 beta (IL1B) and whole brain grey matter volume, as well as volumes of several brain regions shown to be of importance in mood disorders. Structural magnetic resonance imaging and vertex-based morphometry were used to obtain volume of different brain regions in subjects with bipolar disorder (n=188) and healthy controls (n=54). Four IL1B polymorphisms were genotyped: rs1143623, rs1143627, and rs16944 in the promoter region together with the synonymous variant rs1143634 in the IL1B gene. The genotype distribution did not differ between bipolar subjects and controls. The T allele at rs16944 and the C allele at rs1143627 were associated with increased volumes of the putamen of the left hemisphere in patients and controls, which lends support to the role of this immune system mediator for brain structure.

[11 C]raclopride positron emission tomography study of dopamine-D2/3 receptor binding in patients with severe major depressive episodes before and after electroconvulsive therapy and compared to control subjects.

AIM: The aim of the study was to test: (i) if D2 /D3 binding in three functional subsections of striatum is different in patients with severe major depressive episodes than in controls; and (ii) if this difference is normalized after electroconvulsive therapy (ECT). METHODS: Nine inpatients were examined with positron emission tomography (PET) and the radioligand [11 C]raclopride before and after an average of 8.4 ECT sessions. Treatment response was assessed using the Montgomery-Åsberg Depression Rating Scale. Nine age- and sex-matched controls were examined twice with PET and [11 C]raclopride. RESULTS: [11 C]raclopride binding was significantly lower in all three subsections of striatum in patients compared to controls (Cohen's dz , 1.14-1.68; P = 0.003-0.027). Montgomery-Åsberg Depression Ratings decreased significantly after ECT (P < 0.001; Cohen's dz , 2.9). ECT had no statistically significant effect on [11 C]raclopride binding, although post-ECT binding estimates were more similar to those obtained in controls in all subsections of striatum. CONCLUSION: Using PET and [11 C]raclopride, we found support for the notion that severe major depressive episodes are associated with significantly lower dopamine D2 /D3 binding in all three subsections of striatum compared to controls. We noted no significant effect on D2 /D3 binding in the patient group after response to ECT.

Longitudinal Cortical Thickness Changes in Bipolar Disorder and the Relationship to Genetic Risk, Mania, and Lithium Use.

BACKGROUND: Bipolar disorder (BD) is a highly heritable psychiatric disorder characterized by episodes of manic and depressed mood states and associated with cortical brain abnormalities. Although the course of BD is often progressive, longitudinal brain imaging studies are scarce. It remains unknown whether brain abnormalities are static traits of BD or result from pathological changes over time. Moreover, the genetic effect on implicated brain regions remains unknown. METHODS: Patients with BD and healthy control (HC) subjects underwent structural magnetic resonance imaging at baseline (123 patients, 83 HC subjects) and after 6 years (90 patients, 61 HC subjects). Cortical thickness maps were generated using FreeSurfer. Using linear mixed effects models, we compared longitudinal changes in cortical thickness between patients with BD and HC subjects across the whole brain. We related our findings to genetic risk for BD and tested for effects of demographic and clinical variables. RESULTS: Patients showed abnormal cortical thinning of temporal cortices and thickness increases in visual/somatosensory brain areas. Thickness increases were related to genetic risk and lithium use. Patients who experienced hypomanic or manic episodes between time points showed abnormal thinning in inferior frontal cortices. Cortical changes did not differ between diagnostic BD subtypes I and II. CONCLUSIONS: In the largest longitudinal BD study to date, we detected abnormal cortical changes with high anatomical resolution. We delineated regional effects of clinical symptoms, genetic factors, and medication that may explain progressive brain changes in BD. Our study yields important insights into disease mechanisms and suggests that neuroprogression plays a role in BD.

Glucose metabolism in completed suicide: a forensic-pathological pilot study.

AIM: To determine whether antemortem blood levels of glycated hemoglobin (HbA1c) and glucose predict completed suicide and, by extension, whether markers of glucose metabolism might be associated with a prosuicidal trait or state. METHOD: From consecutively performed autopsies, samples of blood and vitreous humor from 17 suicide victims and 27 non-suicide controls were compared with regard to levels of glucose, lactate, and HbA1c. RESULTS: Mean HbA1c was higher, and mean estimated blood glucose lower, among suicide victims, although tests revealed no significant differences (P=0.171 and P=0.395, respectively). HbA1c levels exceeding 48.0 mmol/mol, which were indicative of persistent hyperglycemia, were twice as common in suicide victims (59% vs 30%; P=0.068). CONCLUSION: The finding of this pilot study suggest that deranged glucose metabolism may reflect biological events antecedent to, or concomitant with, completed suicide, with the following clinical implications: recurring hyperglycemia due to defective glucose transport, which may give rise to depression and suicidal ideation, and elevated HbA1c levels, which may represent an assayable correlate to neurobiological conditions predisposing to suicide.

Neuregulin-1 and schizophrenia in the genome-wide association study era.

Clinical and pre-clinical evidence has implicated neuregulin 1 (NRG1) as a critical component in the pathophysiology of schizophrenia. However, the arrival of the genome-wide association study (GWAS) era has yielded results that challenge the relevance of NRG1 in schizophrenia due to the absence of a genome-wide significant NRG1 variant associated with schizophrenia. To assess NRG1's relevance to schizophrenia in the GWAS era, we provide a targeted review of recent preclinical evidence on NRG1's role in regulating several aspects of excitatory/inhibitory neurotransmission and in turn schizophrenia risk. We also present a systematic review of the last decade of clinical research examining NRG1 in the context of schizophrenia. We include concise summaries of genotypic variation, gene-expression, protein expression, structural and functional neuroimaging as well as cognitive studies conducted during this time period. We conclude with recommendations for future clinical and preclinical work that we hope will help prioritize a strategy forward to further advance our understanding of the relationship between NRG1 and schizophrenia.

Brain change trajectories that differentiate the major psychoses.

BACKGROUND: Bipolar disorder and schizophrenia are highly heritable, often chronic and debilitating psychotic disorders that can be difficult to differentiate clinically. Their brain phenotypes appear to overlap in both cross-sectional and longitudinal structural neuroimaging studies, with some evidence to suggest areas of differentiation with differing trajectories. The aim of this review was to investigate the notion that longitudinal trajectories of alterations in brain structure could differentiate the two disorders. DESIGN: Narrative review. We searched MEDLINE and Web of Science databases in May 2016 for studies that used structural magnetic resonance imaging to investigate longitudinal between-group differences in bipolar disorder and schizophrenia. Ten studies met inclusion criteria, namely longitudinal structural magnetic resonance studies comparing bipolar disorder (or affective psychosis) and schizophrenia within the same study. RESULTS: Our review of these studies implicates illness-specific trajectories of morphological change in total grey matter volume, and in regions of the frontal, temporal and cingulate cortices. The findings in schizophrenia suggest a trajectory involving progressive grey matter loss confined to fronto-temporal cortical regions. Preliminary findings identify a similar but less severely impacted trajectory in a number of regions in bipolar disorder, however, bipolar disorder is also characterized by differential involvement across cingulate subregions. CONCLUSION: The small number of available studies must be interpreted with caution but provide initial evidence supporting the notion that bipolar disorder and schizophrenia have differential longitudinal trajectories that are influenced by brain maturation.

The functional anatomy of psychomotor disturbances in major depressive disorder.

Psychomotor disturbances (PMD) are a classic feature of depressive disorder that provides rich clinical information. The aim our narrative review was to characterize the functional anatomy of PMD by summarizing findings from neuroimaging studies. We found evidence across several neuroimaging modalities that suggest involvement of fronto-striatal neurocircuitry, and monoaminergic pathways and metabolism. We suggest that PMD in major depressive disorder emerge from an alteration of limbic signals, which influence emotion, volition, higher-order cognitive functions, and movement.

Negative symptoms in schizophrenia show association with amygdala volumes and neural activation during affective processing.

OBJECTIVES: Negative symptoms in schizophrenia have been associated with structural and functional alterations of the amygdala. We hypothesised that there would be between-group differences in amygdala volume and neural activation patterns during processing of affective stimuli among patients with schizophrenia and healthy controls. We further hypothesised correlations between neuroimaging metrics and clinical ratings of negative symptoms in patients with schizophrenia. METHODS: We used structural and functional magnetic resonance imaging to assess volume and neural activation of the amygdala in 28 patients with schizophrenia and 28 healthy controls. RESULTS: We found no between-group differences in amygdala volume or neural activation. However, we found a significant negative correlation between emotional blunting and neural activation in the left amygdala during processing of positive affect. We also found a significant negative correlation between stereotyped thinking and the volume of right amygdala. CONCLUSION: Our findings implicate the amygdala in a subgroup of negative symptoms in schizophrenia that are characterised by reduced expression with blunted affect and stereotyped thinking.