Helena Fatouros-Bergman

Meta-analysis of cognitive performance in drug-naïve patients with schizophrenia

Cognitive deficits represent a significant characteristic of schizophrenia. However, a majority of the clinical studies have been conducted in antipsychotic drug treated patients. Thus, it remains unclear if significant cognitive impairments exist in the absence of medication. This is the first meta-analysis of cognitive findings in drug-naïve patients with schizophrenia. Cognitive data from 23 studies encompassing 1106 patients and 1385 controls published from 1992 to 2013 were included. Tests were to a large extent ordered in cognitive domains according to the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) battery. Analysis was performed with STATA using the random-effects model and heterogeneity as well as Eggers publication bias was assessed. Overall the results show that patients performed worse than healthy controls in all cognitive domains with medium to large effect sizes. Verbal memory, speed of processing and working memory were three of the domains with the greatest impairments. The pattern of results is in line with previous meta-analytic findings in antipsychotic treated patients. The present meta-analysis confirms the existence of significant cognitive impairments at the early stage of the illness in the absence of antipsychotic medication.

Lower levels of the glial cell marker TSPO in drug-naive first-episode psychosis patients as measured using PET and |[lsqb]|11C|[rsqb]|PBR28

Several lines of evidence are indicative of a role for immune activation in the pathophysiology of schizophrenia. Nevertheless, studies using positron emission tomography (PET) and radioligands for the translocator protein (TSPO), a marker for glial activation, have yielded inconsistent results. Whereas early studies using a radioligand with low signal-to-noise in small samples showed increases in patients, more recent studies with improved methodology have shown no differences or trend-level decreases. Importantly, all patients investigated thus far have been on antipsychotic medication, and as these compounds may dampen immune cell activity, this factor limits the conclusions that can be drawn. Here, we examined 16 drug-naive, first-episode psychosis patients and 16 healthy controls using PET and the TSPO radioligand [11C]PBR28. Gray matter (GM) volume of distribution (VT) derived from a two-tissue compartmental analysis with arterial input function was the main outcome measure. Statistical analyses were performed controlling for both TSPO genotype, which is known to affect [11C]PBR28 binding, and gender. There was a significant reduction of [11C]PBR28 VT in patients compared with healthy controls in GM as well as in secondary regions of interest. No correlation was observed between GM VT and clinical or cognitive measures after correction for multiple comparisons. The observed decrease in TSPO binding suggests reduced numbers or altered function of immune cells in brain in early-stage schizophrenia.

Consistent Functional Connectivity Alterations in Schizophrenia Spectrum Disorder: A Multisite Study

Schizophrenia (SZ) is a severe mental illness with high heritability and complex etiology. Mounting evidence from neuroimaging has implicated disrupted brain network connectivity in the pathophysiology. However, previous findings are inconsistent, likely due to a combination of methodological and clinical variability and relatively small sample sizes. Few studies have used a data-driven approach for characterizing pathological interactions between regions in the whole brain and evaluated the generalizability across independent samples. To overcome this issue, we collected resting-state functional magnetic resonance imaging data from 3 independent samples (1 from Norway and 2 from Sweden) consisting of 182 persons with a SZ spectrum diagnosis and 348 healthy controls. We used a whole-brain data-driven definition of network nodes and regularized partial correlations to evaluate and compare putatively direct brain network node interactions between groups. The clinical utility of the functional connectivity features and the generalizability of effects across samples were evaluated by training and testing multivariate classifiers in the independent samples using machine learning. Univariate analyses revealed 14 network edges with consistent reductions in functional connectivity encompassing frontal, somatomotor, visual, auditory, and subcortical brain nodes in patients with SZ. We found a high overall accuracy in classifying patients and controls (up to 80%) using independent training and test samples, strongly supporting the generalizability of connectivity alterations across different scanners and heterogeneous samples. Overall, our findings demonstrate robust reductions in functional connectivity in SZ spectrum disorders, indicating disrupted information flow in sensory, subcortical, and frontal brain regions.

Determinants of subjective and objective burden of informal caregiving of patients with psychotic disorders

Background: In a previous study, the objective burden of informal caregiving to patients with psychotic disorders amounted to 22 hours/week, and the subjective burden was huge with predominately anxiety and depression as main symptoms. In this study, determinants of the informal caregiving burden are analyzed to find foci for interventions to ease the size of burden. Methods: Patients with psychotic disorders (n = 107) and their informal caregivers (n = 118) were included. They were assessed with a comprehensive battery of rating scales including patient and caregiver characteristics as well as the amount and quality of health-care provision. Results: A multiple linear regression analysis showed that the subjective burden was significantly lower when patients had higher levels of functioning and when the health status of the informal caregivers was good. No significant determinants were found for the objective burden, but an association was found between a higher socioeconomic status of the caregivers and the amount of money provided for the patient. An association was also found between a positive perception of caregiving and more hours spent on caregiving. Conclusion: The functioning level of the patients was the main determinant of the subjective burden of informal care. For the objective burden, no main determinant was found.

CSF GABA is reduced in first-episode psychosis and associates to symptom severity

Schizophrenia is characterized by a multiplicity of symptoms arising from almost all domains of mental function. γ-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the brain and is increasingly recognized to have a significant role in the pathophysiology of the disorder. In the present study, cerebrospinal fluid (CSF) concentrations of GABA were analyzed in 41 first-episode psychosis (FEP) patients and 21 age- and sex-matched healthy volunteers by high-performance liquid chromatography. We found lower CSF GABA concentration in FEP patients compared with that in the healthy volunteers, a condition that was unrelated to antipsychotic and/or anxiolytic medication. Moreover, lower CSF GABA levels were associated with total and general score of Positive and Negative Syndrome Scale, illness severity and probably with a poor performance in a test of attention. This study offers clinical in vivo evidence for a potential role of GABA in early-stage schizophrenia.

Cerebellar volume and cerebellocerebral structural covariance in schizophrenia: a multisite mega-analysis of 983 patients and 1349 healthy controls

Although cerebellar involvement across a wide range of cognitive and neuropsychiatric phenotypes is increasingly being recognized, previous large-scale studies in schizophrenia (SZ) have primarily focused on supratentorial structures. Hence, the across-sample reproducibility, regional distribution, associations with cerebrocortical morphology and effect sizes of cerebellar relative to cerebral morphological differences in SZ are unknown. We addressed these questions in 983 patients with SZ spectrum disorders and 1349 healthy controls (HCs) from 14 international samples, using state-of-the-art image analysis pipelines optimized for both the cerebellum and the cerebrum. Results showed that total cerebellar grey matter volume was robustly reduced in SZ relative to HCs (Cohens’s d=−0.35), with the strongest effects in cerebellar regions showing functional connectivity with frontoparietal cortices (d=−0.40). Effect sizes for cerebellar volumes were similar to the most consistently reported cerebral structural changes in SZ (e.g., hippocampus volume and frontotemporal cortical thickness), and were highly consistent across samples. Within groups, we further observed positive correlations between cerebellar volume and cerebral cortical thickness in frontotemporal regions (i.e., overlapping with areas that also showed reductions in SZ). This cerebellocerebral structural covariance was strongest in SZ, suggesting common underlying disease processes jointly affecting the cerebellum and the cerebrum. Finally, cerebellar volume reduction in SZ was highly consistent across the included age span (16–66 years) and present already in the youngest patients, a finding that is more consistent with neurodevelopmental than neurodegenerative etiology. Taken together, these novel findings establish the cerebellum as a key node in the distributed brain networks underlying SZ.

5‐HT1B receptor imaging and cognition: A positron emission tomography study in control subjects and parkinson's disease patients

The serotonin 5‐HT1B receptor subtype is involved in the modulation of serotonin release and is a target of interest for neuroreceptor imaging. Previous studies have shown that the serotonin system is affected in Parkinsons disease (PD). Cognitive function, frequently impaired in PD, has been linked to the serotonin system. The aim of this study was to examine whether 5‐HT1B receptor availability in the brain of healthy subjects and PD patients is associated with measures of cognitive function.

Prefrontal cortical thinning links to negative symptoms in schizophrenia via the ENIGMA consortium

BACKGROUND Our understanding of the complex relationship between schizophrenia symptomatology and etiological factors can be improved by studying brain-based correlates of schizophrenia. Research showed that impairments in value processing and executive functioning, which have been associated with prefrontal brain areas [particularly the medial orbitofrontal cortex (MOFC)], are linked to negative symptoms. Here we tested the hypothesis that MOFC thickness is associated with negative symptom severity. METHODS This study included 1985 individuals with schizophrenia from 17 research groups around the world contributing to the ENIGMA Schizophrenia Working Group. Cortical thickness values were obtained from T1-weighted structural brain scans using FreeSurfer. A meta-analysis across sites was conducted over effect sizes from a model predicting cortical thickness by negative symptom score (harmonized Scale for the Assessment of Negative Symptoms or Positive and Negative Syndrome Scale scores). RESULTS Meta-analytical results showed that left, but not right, MOFC thickness was significantly associated with negative symptom severity (β std = -0.075; p = 0.019) after accounting for age, gender, and site. This effect remained significant (p = 0.036) in a model including overall illness severity. Covarying for duration of illness, age of onset, antipsychotic medication or handedness weakened the association of negative symptoms with left MOFC thickness. As part of a secondary analysis including 10 other prefrontal regions further associations in the left lateral orbitofrontal gyrus and pars opercularis emerged. CONCLUSIONS Using an unusually large cohort and a meta-analytical approach, our findings point towards a link between prefrontal thinning and negative symptom severity in schizophrenia. This finding provides further insight into the relationship between structural brain abnormalities and negative symptoms in schizophrenia.

Positive symptoms associate with cortical thinning in the superior temporal gyrus via the ENIGMA Schizophrenia consortium

Based on the role of the superior temporal gyrus (STG) in auditory processing, language comprehension and self‐monitoring, this study aimed to investigate the relationship between STG cortical thickness and positive symptom severity in schizophrenia.

Stability of Facial Affective Expressions in Schizophrenia

Thirty-two videorecorded interviews were conducted by two interviewers with eight patients diagnosed with schizophrenia. Each patient was interviewed four times: three weekly interviews by the first interviewer and one additional interview by the second interviewer. 64 selected sequences where the patients were speaking about psychotic experiences were scored for facial affective behaviour with Emotion Facial Action Coding System (EMFACS). In accordance with previous research, the results show that patients diagnosed with schizophrenia express negative facial affectivity. Facial affective behaviour seems not to be dependent on temporality, since within-subjects ANOVA revealed no substantial changes in the amount of affects displayed across the weekly interview occasions. Whereas previous findings found contempt to be the most frequent affect in patients, in the present material disgust was as common, but depended on the interviewer. The results suggest that facial affectivity in these patients is primarily dominated by the negative emotions of disgust and, to a lesser extent, contempt and implies that this seems to be a fairly stable feature.