Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium.

Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.

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.

Obesity and brain structure in schizophrenia - ENIGMA study in 3021 individuals.

Schizophrenia is frequently associated with obesity, which is linked with neurostructural alterations. Yet, we do not understand how the brain correlates of obesity map onto the brain changes in schizophrenia. We obtained MRI-derived brain cortical and subcortical measures and body mass index (BMI) from 1260 individuals with schizophrenia and 1761 controls from 12 independent research sites within the ENIGMA-Schizophrenia Working Group. We jointly modeled the statistical effects of schizophrenia and BMI using mixed effects. BMI was additively associated with structure of many of the same brain regions as schizophrenia, but the cortical and subcortical alterations in schizophrenia were more widespread and pronounced. Both BMI and schizophrenia were primarily associated with changes in cortical thickness, with fewer correlates in surface area. While, BMI was negatively associated with cortical thickness, the significant associations between BMI and surface area or subcortical volumes were positive. Lastly, the brain correlates of obesity were replicated among large studies and closely resembled neurostructural changes in major depressive disorders. We confirmed widespread associations between BMI and brain structure in individuals with schizophrenia. People with both obesity and schizophrenia showed more pronounced brain alterations than people with only one of these conditions. Obesity appears to be a relevant factor which could account for heterogeneity of brain imaging findings and for differences in brain imaging outcomes among people with schizophrenia.

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.

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.

Using structural MRI to identify bipolar disorders - 13 site machine learning study in 3020 individuals from the ENIGMA Bipolar Disorders Working Group.

Bipolar disorders (BDs) are among the leading causes of morbidity and disability. Objective biological markers, such as those based on brain imaging, could aid in clinical management of BD. Machine learning (ML) brings neuroimaging analyses to individual subject level and may potentially allow for their diagnostic use. However, fair and optimal application of ML requires large, multi-site datasets. We applied ML (support vector machines) to MRI data (regional cortical thickness, surface area, subcortical volumes) from 853 BD and 2167 control participants from 13 cohorts in the ENIGMA consortium. We attempted to differentiate BD from control participants, investigated different data handling strategies and studied the neuroimaging/clinical features most important for classification. Individual site accuracies ranged from 45.23% to 81.07%. Aggregate subject-level analyses yielded the highest accuracy (65.23%, 95% CI = 63.47-67.00, ROC-AUC = 71.49%, 95% CI = 69.39-73.59), followed by leave-one-site-out cross-validation (accuracy = 58.67%, 95% CI = 56.70-60.63). Meta-analysis of individual site accuracies did not provide above chance results. There was substantial agreement between the regions that contributed to identification of BD participants in the best performing site and in the aggregate dataset (Cohen's Kappa = 0.83, 95% CI = 0.829-0.831). Treatment with anticonvulsants and age were associated with greater odds of correct classification. Although short of the 80% clinically relevant accuracy threshold, the results are promising and provide a fair and realistic estimate of classification performance, which can be achieved in a large, ecologically valid, multi-site sample of BD participants based on regional neurostructural measures. Furthermore, the significant classification in different samples was based on plausible and similar neuroanatomical features. Future multi-site studies should move towards sharing of raw/voxelwise neuroimaging data.

Evidence from comprehensive independent validation studies for smooth pursuit dysfunction as a sensorimotor biomarker for psychosis.

Smooth pursuit eye movements are considered a well-established and quantifiable biomarker of sensorimotor function in psychosis research. Identifying psychotic syndromes on an individual level based on neurobiological markers is limited by heterogeneity and requires comprehensive external validation to avoid overestimation of prediction models. Here, we studied quantifiable sensorimotor measures derived from smooth pursuit eye movements in a large sample of psychosis probands (N = 674) and healthy controls (N = 305) using multivariate pattern analysis. Balanced accuracies of 64% for the prediction of psychosis status are in line with recent results from other large heterogenous psychiatric samples. They are confirmed by external validation in independent large samples including probands with (1) psychosis (N = 727) versus healthy controls (N = 292), (2) psychotic (N = 49) and non-psychotic bipolar disorder (N = 36), and (3) non-psychotic affective disorders (N = 119) and psychosis (N = 51) yielding accuracies of 65%, 66% and 58%, respectively, albeit slightly different psychosis syndromes. Our findings make a significant contribution to the identification of biologically defined profiles of heterogeneous psychosis syndromes on an individual level underlining the impact of sensorimotor dysfunction in psychosis.

Supramodal representation of emotions.

Supramodal representation of emotion and its neural substrates have recently attracted attention as a marker of social cognition. However, the question whether perceptual integration of facial and vocal emotions takes place in primary sensory areas, multimodal cortices, or in affective structures remains unanswered yet. Using novel computer-generated stimuli, we combined emotional faces and voices in congruent and incongruent ways and assessed functional brain data (fMRI) during an emotional classification task. Both congruent and incongruent audiovisual stimuli evoked larger responses in thalamus and superior temporal regions compared with unimodal conditions. Congruent emotions were characterized by activation in amygdala, insula, ventral posterior cingulate (vPCC), temporo-occipital, and auditory cortices; incongruent emotions activated a frontoparietal network and bilateral caudate nucleus, indicating a greater processing load in working memory and emotion-encoding areas. The vPCC alone exhibited differential reactions to congruency and incongruency for all emotion categories and can thus be considered a central structure for supramodal representation of complex emotional information. Moreover, the left amygdala reflected supramodal representation of happy stimuli. These findings document that emotional information does not merge at the perceptual audiovisual integration level in unimodal or multimodal areas, but in vPCC and amygdala.

Cholinergic blockade under working memory demands encountered by increased rehearsal strategies: evidence from fMRI in healthy subjects.

The connection between cholinergic transmission and cognitive performance has been established in behavioural studies. The specific contribution of the muscarinic receptor system on cognitive performance and brain activation, however, has not been evaluated satisfyingly. To investigate the specific contribution of the muscarinic transmission on neural correlates of working memory, we examined the effects of scopolamine, an antagonist of the muscarinic receptors, using functional magnetic resonance imaging (fMRI). Fifteen healthy male, non-smoking subjects performed a fMRI scanning session following the application of scopolamine (0.4 mg, i.v.) or saline in a placebo-controlled, repeated measure, pseudo-randomized, single-blind design. Working memory was probed using an n-back task. Compared to placebo, challenging the cholinergic transmission with scopolamine resulted in hypoactivations in parietal, occipital and cerebellar areas and hyperactivations in frontal and prefrontal areas. These alterations are interpreted as compensatory strategies used to account for downregulation due to muscarinic acetylcholine blockade in parietal and cerebral storage systems by increased activation in frontal and prefrontal areas related to working memory rehearsal. Our results further underline the importance of cholinergic transmission to working memory performance and determine the specific contribution of muscarinic transmission on cerebral activation associated with executive functioning.

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

Neuromagnetic oscillations and hemodynamic correlates of P50 suppression in schizophrenia.

Behavioral and electrophysiological data indicate compromised stimulus suppression in schizophrenia. The physiological basis of this effect and its contributions to the etiology of the disease are poorly understood. We examined neural and metabolic measures of P50 suppression in 12 patients with schizophrenia and controls. First, whole-head magnetoencephalography (MEG) assessed amplitudes of left- and right-hemispheric evoked responses and induced oscillations. Secondly, functional magnetic resonance imaging (fMRI) measured the hemodynamic responses to pairs of beeps with a short interval (500ms) as compared with those with a long interval (1500ms). The suppression of alpha power (8-13Hz) time-locked to the stimuli was negatively correlated with the suppression of evoked components and the hemodynamic measures. Remarkably, the suppression of alpha power was reduced in the patients already prior to stimulus onset. Conceivably, alpha oscillations play a central role in stimulus adaptation of neuronal networks and reflect an active mechanism for sensory suppression. The reduced stimulus suppression in schizophrenia seems to be in part due to impaired generation of alpha oscillations in the auditory cortex, resulting in higher metabolic demand as detected by fMRI. Delayed recovery of alpha rhythm may reflect an impaired gating function and contribute to sensory and cognitive deficits in schizophrenia.

The influence of multiple primes on bottom-up and top-down regulation during meaning retrieval: evidence for 2 distinct neural networks.

Meaning retrieval of a word can proceed fast and effortlessly or can be characterized by a controlled search for candidate lexical items and a subsequent selection process. In the current study, we facilitated meaning retrieval by increasing the number of words that were related to the final target word in a triplet (e.g., lion-stripes-tiger). To induce higher search and selection demands, we presented ambiguous words as targets (i.e., homonyms like ball) in half of the trials. Hereby, the dominant (game), low-frequent (dance), or both meanings of the homonym were primed. Participants performed a relatedness judgment during functional magnetic resonance imaging. Activation in a bilateral network (angular gyrus, rostromedial prefrontal cortex) increased linearly with multiple related primes, whereas the posterior left inferior prefrontal cortex (pLIPC) showed the reverse activation pattern for unambiguous trials. When homonyms served as targets, pLIPC responded strongest when both meanings or low-frequent concepts were addressed. Additional anterior left inferior prefrontal cortex activation was observed for the latter trials only. The data support an interaction between 2 distinct cerebral networks that can be linked to automatic bottom-up support and top-down control during meaning retrieval. They further imply a functional specialization of the LIPC along an anterior-posterior dimension.

Disorders of agency in schizophrenia correlate with an inability to compensate for the sensory consequences of actions.

Psychopathological symptoms in schizophrenia patients suggest that the concept of self might be disturbed in these individuals [1]. Delusions of influence make them feel that someone else is guiding their actions, and certain kinds of their hallucinations seem to be misinterpretations of their own inner voice as an external voice, the common denominator being that self-produced information is perceived as if coming from outside. If this interpretation were correct, we might expect that schizophrenia patients might also attribute the sensory consequences of their own eye movements to the environment rather than to themselves, challenging the percept of a stable world. Indeed, this seems to be the case because we found a clear correlation between the strength of delusions of influence and the ability of schizophrenia patients to cancel out such self-induced retinal information in motion perception. This correlation reflects direct experimental evidence supporting the view that delusions of influence in schizophrenia might be due to a specific deficit in the perceptual compensation of the sensory consequences of one's own actions [1, 2, 3, 4, 5 and 6].

Laterality in metaphor processing: lack of evidence from functional magnetic resonance imaging for the right hemisphere theory.

We investigated processing of metaphoric sentences using event-related functional magnetic resonance imaging (fMRI). Seventeen healthy subjects (6 female, 11 male) read 60 novel short German sentence pairs with either metaphoric or literal meaning and performed two different tasks: judging the metaphoric content and judging whether the sentence has a positive or negative connotation. Laterality indices for 8 regions of interest were calculated: Inferior frontal gyrus (opercular part and triangular part), superior, middle, and inferior temporal gyrus, precuneus, temporal pole, and hippocampus. A left lateralised network was activated with no significant differences in laterality between the two tasks. The lowest degree of laterality was found in the temporal pole. Other factors than metaphoricity per se might trigger right hemisphere recruitment. Results are discussed in the context of lesion and hemifield studies.

White matter integrity and symptom dimensions of schizophrenia: A diffusion tensor imaging study.

Impaired fiber bundle connectivity between brain regions is a key neuropathological finding in schizophrenia. Symptom dimensions in schizophrenia can be clustered into factor models. Single syndromes have been related to grey and white matter brain structure alterations. We associated all core syndromes of schizophrenia in a single patient group with changes in white matter integrity. Diffusion weighted images (3T MRI) and SAPS/SANS scores were measured in 26 male patients and 26 healthy controls. First, group differences in fractional anisotropy (FA) were calculated with TBSS. Second, core symptom dimensions of schizophrenia were correlated with FA within these altered tracts. We found differences between groups in nine white matter tracts. Hallucinations were positively correlated with FA in the left uncinate fasciculus and left corticospinal tract. Ego-disturbances (passivity phenomena) showed a positive correlation with FA in the right anterior thalamic radiation. Positive formal thought disorders (FTD) corresponded negatively with FA in the right cingulum bundle. Negative symptoms were positively associated with the right anterior thalamic radiation and negatively with the right ventral cingulum bundle. For the first time, we analyzed the whole range of psychopathological factors in one schizophrenia patient group. We could validate our novel results for positive FTD and passivity phenomena by replicating findings for hallucinations and negative symptoms. Only those brain circuits which are most vulnerable at a given time during neurodevelopment are affected by a particular pathological impact (genetic, environmental). This scenario could explain the predominance of particular psychopathological syndromes related to specific white matter anomalies.

Functional brain imaging of symptoms and cognition in schizophrenia.

The advent of functional magnetic resonance imaging and positron emission tomography has provided novel insights into the neural correlates of cognitive function and psychopathological symptoms. In patients with mental disorders, cognitive and emotional processes are disrupted. In this chapter, we review the basic methodological and conceptual principles for neuroimaging studies in these patients. By taking schizophrenia as an example, we outline the cerebral processes involved in the symptoms of this disorder, such as auditory hallucinations and formal thought disorder. We also characterize the neural networks involved in their emotional and cognitive dysfunction.

Mismatch negativity responses in schizophrenia: a combined fMRI and whole-head MEG study.

OBJECTIVE: Mismatch negativity is an event-related brain response sensitive to deviations within a sequence of repetitive auditory stimuli. It is thought to reflect short-term sensory memory and is independent of higher-level cognitive processes. Mismatch negativity response is diminished in patients with schizophrenia. Little is known about the mechanisms of this decreased response, the contribution of the different hemispheres, and its locus of generation. METHOD: Patients with schizophrenia (N=12) and matched comparison subjects (N=12) were studied. A novel design to measure mismatch negativity responses to deviant auditory stimuli was generated by using the switching noises from the functional magnetic resonance imaging (fMRI) scanner, thus avoiding any interfering background sound. Stimuli included deviants of amplitude (9 dB lower) and duration (76 msec shorter) presented in a random sequence. The scanner noise was recorded and applied to the same subjects in a whole-head magnetoencephalography (MEG) device. Neuromagnetic and hemodynamic responses to the identical stimuli were compared between the patients and comparison subjects. RESULTS: As expected, neuromagnetic mismatch fields were smaller in the patient group. More specifically, a lateralization to the right for duration deviance was only found in comparison subjects. For the relative amplitude of the blood-oxygen-level-dependent signal (measured with fMRI), differences emerged in the secondary (planum temporale), but not primary (Heschl's gyrus), auditory cortex. Duration deviants achieved a right hemispheric advantage only in the comparison group. A significantly stronger lateralization to the left was found for the deviant amplitude stimuli in the patients. CONCLUSIONS: The data support the view of altered hemispheric interactions in the formation of the short-term memory traces necessary for the integration of auditory stimuli. This process is predominantly mediated by the planum temporale (secondary auditory cortex). Altered interaction of regions within the superior temporal plane and across hemispheres could be in part responsible for language-mediated cognitive (e.g., verbal memory) and psychopathological (hallucinations, formal thought disorder) symptoms in schizophrenia.

The neural correlates of intentional and incidental self processing.

The neuroscientific study of the 'Self' is just beginning to emerge. We used functional Magnetic Resonance Imaging (fMRI) to investigate cerebral activation while subjects processed words describing personality traits and physical features, in two experiments with contrasting designs: incidental and intentional. In the first experiment (intentional self processing), subjects were presented with personality trait adjectives and made judgements as to their self descriptiveness (versus non self descriptiveness). In the second experiment (incidental self processing), subjects categorised words according to whether they described physical versus psychological attributes, while unaware that the words had been arranged in blocks according to self descriptiveness. The subjects had previously rated all words for self descriptiveness 6 weeks prior to the scanning session. A reaction time advantage was present in both experiments for self descriptive trait words, suggesting a facilitation effect. Common areas of activation for the two experiments included the left superior parietal lobe, with adjacent regions of the lateral prefrontal cortex also active in both experiments. Differential signal changes were present in the left precuneus for the intentional and the right middle temporal gyrus for the incidental experiment. The results suggest that self processing involves distinct processes and can occur on more than one cognitive level with corresponding functional neuroanatomic correlates in areas previously implicated in the awareness of one's own state.