Danai Dima

White Matter Alterations in Early Stages of Schizophrenia: A Systematic Review of Diffusion Tensor Imaging Studies

Several lines of evidence suggest that the normal integration of cerebral communication may be compromised in schizophrenia, with white matter (WM) abnormalities being integral to these functional deficits. Diffusion tensor imaging (DTI) is a neuroimaging technique which has increasingly been used to study WM through quantitative indices of its structural and orientational characteristics. Identifying the WM differences early in the course of schizophrenia may assist in prevention, early diagnosis and identification of treatment targets. In that respect, the aims of the present study were to (a) systematically review WM integrity in the early stages of schizophrenia as inferred by DTI and (b) specifically examine parameters that may affect WM: age, duration of illness and treatment. In summary, DTI studies in early schizophrenia suggest that structural dysconnectivity may be already present in recent‐onset and drug‐naïve patients, as well as in individuals clinically at high risk for developing schizophrenia. Although the pattern of WM differences is not totally consistent frontal, fronto‐temporal and fronto‐limbic connections, with tracts including the superior longitudinal fasciculus, cingulum bundle, uncinate fasciculus and corpus callosum seem to be affected. These differences may depend on the developmental stage of the subjects, the duration of illness and exposure to antipsychotic medication.

Subcortical volumetric abnormalities in bipolar disorder.

Considerable uncertainty exists about the defining brain changes associated with bipolar disorder (BD). Understanding and quantifying the sources of uncertainty can help generate novel clinical hypotheses about etiology and assist in the development of biomarkers for indexing disease progression and prognosis. Here we were interested in quantifying case–control differences in intracranial volume (ICV) and each of eight subcortical brain measures: nucleus accumbens, amygdala, caudate, hippocampus, globus pallidus, putamen, thalamus, lateral ventricles. In a large study of 1710 BD patients and 2594 healthy controls, we found consistent volumetric reductions in BD patients for mean hippocampus (Cohen’s d=−0.232; P=3.50 × 10−7) and thalamus (d=−0.148; P=4.27 × 10−3) and enlarged lateral ventricles (d=−0.260; P=3.93 × 10−5) in patients. No significant effect of age at illness onset was detected. Stratifying patients based on clinical subtype (BD type I or type II) revealed that BDI patients had significantly larger lateral ventricles and smaller hippocampus and amygdala than controls. However, when comparing BDI and BDII patients directly, we did not detect any significant differences in brain volume. This likely represents similar etiology between BD subtype classifications. Exploratory analyses revealed significantly larger thalamic volumes in patients taking lithium compared with patients not taking lithium. We detected no significant differences between BDII patients and controls in the largest such comparison to date. Findings in this study should be interpreted with caution and with careful consideration of the limitations inherent to meta-analyzed neuroimaging comparisons.

Impaired top-down processes in schizophrenia: A DCM study of ERPs

Perception is not simply based on a hierarchical organization of the brain; it arises from an interplay between inputs from the environment and internal predictions of these inputs. It is an active process which involves an interaction between bottom-up information coming from the senses and feedback connections coming from higher-order cortical areas. In our experiment, we use the hollow-mask illusion to investigate the strength of top-down processes in schizophrenic patients and healthy controls. By using dynamic causal modelling (DCM) on functional magnetic resonance tomography (fMRI) data, we have presented evidence to suggest that patients with schizophrenia are less constrained by top-down processes during perception (Dima, D., Roiser, J.P., Dietrich, D.E., Bonnemann, C., Lanfermann, H., Emrich, H.M., Dillo, W., 2009. Understanding why patients with schizophrenia do not perceive the hollow-mask illusion using dynamic causal modeling. Neuroimage 46, 1180-1186). In this study, we re-address this issue by using DCM on event-related potentials (ERPs) data. Our aim was to validate our previous findings by conducting the same connectivity analysis--DCM--on data obtained from a different neuroimaging method. Our results confirm our initial hypothesis that top-down influences are constrained in schizophrenia, especially in perceptual tasks that require top-down control, like the hollow-mask illusion.

Effective Connectivity during Processing of Facial Affect: Evidence for Multiple Parallel Pathways

The perception of facial affect engages a distributed cortical network. We used functional magnetic resonance imaging and dynamic causal modeling to characterize effective connectivity during explicit (conscious) categorization of affective stimuli in the human brain. Specifically, we examined the modulation of connectivity from posterior regions of the face-processing network to the lateral ventral prefrontal cortex (VPFC) during affective categorization and we tested for a potential role of the amygdala (AMG) in mediating this modulation. We found that explicit processing of facial affect led to prominent modulation (increase) in the effective connectivity from the inferior occipital gyrus (IOG) to the VPFC, while there was less evidence for modulation of the afferent connections from fusiform gyrus and AMG to VPFC. More specifically, the forward connection from IOG to the VPFC exhibited a selective increase under anger (as opposed to fear or sadness). Furthermore, Bayesian model comparison suggested that the modulation of afferent connections to the VPFC was mediated directly by facial affect, as opposed to an indirect modulation mediated by the AMG. Our results thus suggest that affective information is conveyed to the VPFC along multiple parallel pathways and that AMG activity is not sufficient to account for the gating of information transfer to the VPFC during explicit emotional processing.

Is avolition in schizophrenia associated with a deficit of dorsal caudate activity? A functional magnetic resonance imaging study during reward anticipation and feedback

Background The neurobiological underpinnings of avolition in schizophrenia remain unclear. Most brain imaging research has focused on reward prediction deficit and on ventral striatum dysfunction, but findings are not consistent. In the light of accumulating evidence that both ventral striatum and dorsal caudate play a key role in motivation, we investigated ventral striatum and dorsal caudate activation during processing of reward or loss in patients with schizophrenia. Method We used functional magnetic resonance imaging to study brain activation during a Monetary Incentive Delay task in patients with schizophrenia, treated with second-generation antipsychotics only, and in healthy controls (HC). We also assessed the relationships of ventral striatum and dorsal caudate activation with measures of hedonic experience and motivation. Results The whole patient group had lower motivation but comparable hedonic experience and striatal activation than HC. Patients with high avolition scores showed lower dorsal caudate activation than both HC and patients with low avolition scores. A lower dorsal caudate activation was also observed in patients with deficit schizophrenia compared to HC and patients with non-deficit schizophrenia. Dorsal caudate activity during reward anticipation was significantly associated with avolition, but not with anhedonia in the patient group. Conclusions These findings suggest that avolition in schizophrenia is linked to dorsal caudate hypoactivation.

Dissociable functional connectivity changes during the Stroop task relating to risk, resilience and disease expression in bipolar disorder

Reduced cognitive control is considered a core feature of bipolar disorder (BD). Abnormalities in ventrolateral prefrontal cortex (VLPFC) and other functionally linked regions that underpin cognitive control during the Stroop Colour Word Task (SCWT) have been reported in patients with BD and their relatives. In this functional magnetic resonance study we used psychophysiological interaction analysis to examine functional connectivity during the SCWT in 39 euthymic BD patients, 39 of their first-degree relatives (25 with no Axis I disorders and 14 with major depressive disorder) and 48 healthy controls. The aim of this study was to identify potential diagnosis-specific functional connectivity changes differentiating patients with BD from their relatives with MDD, as well as functional connectivity correlates of resilience in relatives of BD patients who remain well. Psychophysiological interactions in healthy controls revealed a negative functional connectivity between the VLPFC and the ventral anterior cingulate cortex and insula and a positive connectivity between the VLPFC and the caudate and parietal cortices. Abnormalities in fronto-insular connectivity emerged as a key correlate of predisposition and disease expression for BD. Reduced fronto-cingulate connectivity was also observed in association with predisposition to BD irrespective of clinical outcome. BD patients and their MDD relatives showed additional abnormalities in frontal-basal ganglia connectivity while increased coupling between the ventral and dorsal lateral PFC was observed in relatives without any Axis I disorder. These findings suggest that during the SCWT the VLPFC and subcortical regions are involved in a dynamic interplay. Breakdown in these interactions is associated with risk and disease expression for mood disorders while increased functional coupling between dorsal and ventral prefrontal regions may reflect adaptive functional changes associated with resilience.

ENIGMA and the Individual: Predicting Factors that Affect the Brain in 35 Countries Worldwide

In this review, we discuss recent work by the ENIGMA Consortium (http://enigma.ini.usc.edu) – a global alliance of over 500 scientists spread across 200 institutions in 35 countries collectively analyzing brain imaging, clinical, and genetic data. Initially formed to detect genetic influences on brain measures, ENIGMA has grown to over 30 working groups studying 12 major brain diseases by pooling and comparing brain data. In some of the largest neuroimaging studies to date – of schizophrenia and major depression – ENIGMA has found replicable disease effects on the brain that are consistent worldwide, as well as factors that modulate disease effects. In partnership with other consortia including ADNI, CHARGE, IMAGEN and others1, ENIGMAs genomic screens – now numbering over 30,000 MRI scans – have revealed at least 8 genetic loci that affect brain volumes. Downstream of gene findings, ENIGMA has revealed how these individual variants – and genetic variants in general – may affect both the brain and risk for a range of diseases. The ENIGMA consortium is discovering factors that consistently affect brain structure and function that will serve as future predictors linking individual brain scans and genomic data. It is generating vast pools of normative data on brain measures – from tens of thousands of people – that may help detect deviations from normal development or aging in specific groups of subjects. We discuss challenges and opportunities in applying these predictors to individual subjects and new cohorts, as well as lessons we have learned in ENIGMAs efforts so far.

Independent Modulation of Engagement and Connectivity of the Facial Network During Affect Processing by CACNA1C and ANK3 Risk Genes for Bipolar Disorder

IMPORTANCE Genome-wide association studies (GWASs) indicate that single-nucleotide polymorphisms in the CACNA1C and ANK3 genes increase the risk for bipolar disorder (BD). The genes influence neuronal firing by modulating calcium and sodium channel functions, respectively. Both genes modulate γ-aminobutyric acid-transmitting interneuron function and can thus affect brain regional activation and interregional connectivity. OBJECTIVE To determine whether the genetic risk for BD associated with 2 GWAS-supported risk single-nucleotide polymorphisms at CACNA1C rs1006737 and ANK3 rs10994336 is mediated through changes in regional activation and interregional connectivity of the facial affect-processing network. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional functional magnetic resonance imaging study at a research institute of 41 euthymic patients with BD and 46 healthy participants, all of British white descent. MAIN OUTCOMES AND MEASURES Blood oxygen level-dependent signal and effective connectivity measures during the facial affect-processing task. RESULTS In healthy carriers, both genetic risk variants were independently associated with increased regional engagement throughout the facial affect-processing network and increased effective connectivity between the visual and ventral prefrontal cortical regions. In contrast, BD carriers of either genetic risk variant exhibited pronounced reduction in ventral prefrontal cortical activation and visual-prefrontal effective connectivity. CONCLUSIONS AND RELEVANCE Our data demonstrate that the effect of CACNA1C rs1006737 and ANK3 rs10994336 (or genetic variants in linkage disequilibrium) on the brain converges on the neural circuitry involved in affect processing and provides a mechanism linking BD to genome-wide genetic risk variants.

Frontopolar cortical inefficiency may underpin reward and working memory dysfunction in bipolar disorder.

Abstract Objectives. Emotional dysregulation in bipolar disorder is thought to arise from dysfunction within prefrontal cortical regions involved in cognitive control coupled with increased or aberrant activation within regions engaged in emotional processing. The aim of this study was to determine the common and distinct patterns of functional brain abnormalities during reward and working memory processing in patients with bipolar disorder. Methods. Participants were 36 euthymic bipolar disorder patients and 37 healthy comparison subjects matched for age, sex and IQ. Functional magnetic resonance imaging (fMRI) was conducted during the Iowa Gambling Task (IGT) and the n-back working memory task. Results. During both tasks, patients with bipolar disorder demonstrated a pattern of inefficient engagement within the ventral frontopolar prefrontal cortex with evidence of segregation along the medial-lateral dimension for reward and working memory processing, respectively. Moreover, patients also showed greater activation in the anterior cingulate cortex during the Iowa Gambling Task and in the insula during the n-back task. Conclusions. Our data implicate ventral frontopolar dysfunction as a core abnormality underpinning bipolar disorder and confirm that overactivation in regions involved in emotional arousal is present even in tasks that do not typically engage emotional systems.

Abnormal Functional Activation and Connectivity in the Working Memory Network in Early-Onset Schizophrenia

OBJECTIVE Disruption within the working memory (WM) neural network is considered an integral feature of schizophrenia. The WM network, and the dorsolateral prefrontal cortex (DLPFC) in particular, undergo significant remodeling in late adolescence. Potential interactions between developmental changes in the WM network and disease-related processes for schizophrenia remain unclear. The aim of this study was to determine whether DLPFC activation and functional connectivity are impaired during WM in patients with early-onset schizophrenia (EOS; age of onset <18 years). METHOD We used functional magnetic resonance imaging and psychophysiological interaction analysis to respectively measure blood oxygenation level-dependent signal and to derive functional connectivity estimates in response to the two-back WM task from 25 youths with EOS and 20 matched healthy adolescents. RESULTS Compared with healthy adolescents, patients with EOS showed reduced engagement of the DLPFC, the anterior cingulate cortex (ACC), and frontal operculum, and had reduced DLPFC connectivity within the WM network. Patients with EOS showed abnormal reduction in the coupling of the DLPFC with the ACC, the inferior parietal lobule, and the middle occipital gyrus. In contrast to healthy adolescents, patients with EOS expressed age-related decrease in the activity of the DLPFC and an increase in its connectivity with the ACC. CONCLUSIONS Patients with EOS show dysfunctional engagement and reduced integration within the WM neural network. The pattern of abnormal age-related correlations in DLPFC activity and connectivity suggests that schizophrenia-related processes have an impact on brain regions that show significant late developmental changes.