Teemu Mäntylä

Altered Activation of Innate Immunity Associates with White Matter Volume and Diffusion in First-Episode Psychosis

First-episode psychosis (FEP) is associated with inflammatory and brain structural changes, but few studies have investigated whether systemic inflammation associates with brain structural changes in FEP. Thirty-seven FEP patients (median 27 days on antipsychotic medication), and 19 matched controls were recruited. Serum levels of 38 chemokines and cytokines, and cardiovascular risk markers were measured at baseline and 2 months later. We collected T1- and diffusion-weighted MRIs with a 3 T scanner from the patients at baseline. We analyzed the association of psychosis-related inflammatory markers with gray and white matter (WM) volume using voxel-based morphometry and WM diffusion using tract-based spatial statistics with whole-brain and region-of-interest (ROI) analyses. FEP patients had higher CCL22 and lower TGFα, CXCL1, CCL7, IFN-α2 and ApoA-I than controls. CCL22 decreased significantly between baseline and 2 months in patients but was still higher than in controls. The association between inflammatory markers and FEP remained significant after adjusting for age, sex, smoking and BMI. We did not observe a correlation of inflammatory markers with any symptoms or duration of antipsychotic treatment. Baseline CCL22 levels correlated negatively with WM volume and positively with mean diffusivity and radial diffusivity bilaterally in the frontal lobes in ROI analyses. Decreased serum level of ApoA-I was associated with smaller volume of the medial temporal WM. In whole-brain analyses, CCL22 correlated positively with mean diffusivity and radial diffusivity, and CXCL1 associated negatively with fractional anisotropy and positively with mean diffusivity and radial diffusivity in several brain regions. This is the first report to demonstrate an association between circulating chemokine levels and WM in FEP patients. Interestingly, CCL22 has been previously implicated in autoimmune diseases associated with WM pathology. The results suggest that an altered activation of innate immunity may contribute to WM damage in psychotic disorders.

Early insulin resistance predicts weight gain and waist circumference increase in first-episode psychosis--A one year follow-up study.

First-episode psychosis (FEP) is associated with weight gain during the first year of treatment, and risk of abdominal obesity is particularly increased. To identify early risk markers of weight gain and abdominal obesity, we investigated baseline metabolic differences in 60 FEP patients and 27 controls, and longitudinal changes during the first year of treatment in patients. Compared to controls at baseline, patients had higher low-density lipoprotein, triglyceride and apolipoprotein B levels, and lower levels of high-density lipoprotein and apolipoprotein A-I but no difference in body mass index or waist circumference. At 12-month follow-up, 60.6% of patients were overweight or obese and 58.8% had abdominal obesity. No significant increase during follow-up was seen in markers of glucose and lipid metabolism or blood pressure, but increase in C-reactive protein between baseline and 12-month follow-up was statistically significant. Weight increase was predicted by baseline insulin resistance and olanzapine use, while increase in waist circumference was predicted by baseline insulin resistance only. In conclusion, insulin resistance may be an early marker of increased vulnerability to weight gain and abdominal obesity in young adults with FEP. Olanzapine should be avoided as a first-line treatment in FEP due to the substantial weight increase it causes. In addition, the increase in the prevalence of overweight and abdominal obesity was accompanied by the emergence of low-grade systemic inflammation.

Aberrant functioning of the putamen links delusions, antipsychotic drug dose, and compromised connectivity in first episode psychosis—Preliminary fMRI findings

The dopamine theory proposes the relationship of delusions to aberrant signaling in striatal circuitries that can be normalized with dopamine D2 receptor-blocking drugs. Localization of such circuitries, as well as their upstream and downstream signaling, remains poorly known. We collected functional magnetic resonance images from first-episode psychosis patients and controls during an audiovisual movie. Final analyses included 20 patients and 20 controls; another sample of 10 patients and 10 controls was used to calculate a comparison signal-time course. We identified putamen circuitry in which the signal aberrance (poor correlation with the comparison signal time course) was predicted by the dopamine theory, being greater in patients than controls; correlating positively with delusion scores; and correlating negatively with antipsychotic-equivalent dosage. In Granger causality analysis, patients showed a compromised contribution of the cortical salience network to the putamen and compromised contribution of the putamen to the default mode network. Results were corrected for multiple comparisons at the cluster level with primary voxel-wise threshold p < 0.005 for the salience network contribution, but liberal primary threshold p < 0.05 was used in other group comparisons. If replicated in larger studies, these findings may help unify and extend current hypotheses on dopaminergic dysfunction, salience processing and pathogenesis of delusions.

F166. LOW-GRADE INFLAMMATION IN FIRST-EPISODE PSYCHOSIS IS DETERMINED BY WAIST CIRCUMFERENCE INCREASE

Abstract Background There is evidence of low-grade inflammation in psychosis, as measured by the high-sensitivity C-reactive protein (hs-CRP). Significant weight gain is common during the first months of antipsychotic treatment. In the general population, overweight and obesity often lead to systemic low-grade inflammation. Lifestyle factors, such as smoking, can contribute to the pro-inflammatory changes. The metabolic changes in people with first-episode psychosis (FEP) taking place after the onset of psychosis can be especially harmful as these individuals are typically young and without major somatic illnesses. We aimed to study how the low-grade inflammation, measured by hs-CRP, develops in FEP and to clarify the effect of waist circumference increase in the inflammation. Methods The Helsinki Early Psychosis Study recruited FEP patients (age 18 to 40 years) attaining their first treatment for psychosis from the catchment area of the Helsinki University Hospital. We recruited 95 FEP patients and 62 controls. The inclusion criterion for the study was receiving a score of at least 4 in Unusual thought content or Hallucinations in the Brief Psychiatric Rating Scale - Extended (BPRS-E). Diagnoses of psychotic disorders according to the DSM-IV criteria were later verified using the Structured Diagnostic Interview for DSM-IV and reviewing all medical records. Substance-induced psychotic disorders and psychotic disorders due to a general medical condition were excluded. We measured the changes in hs-CRP, weight, waist circumference, glucose metabolism and lipids at baseline and at follow-ups of 2 and 12 months. We used linear mixed effects models to analyze the relationship between hs-CRP and waist circumference. In the model, we included a random intercept for each patient and, as fixed effects, we entered sex, time (days from baseline measurement), waist circumference and antipsychotic use at each assessment point, and baseline cigarette smoking. Results At baseline, FEP patients (mean age 26.1 years) had higher insulin resistance, total and LDL cholesterol, apolipoprotein B and triglyceride levels than controls. However, baseline weight and waist circumference, hs-CRP, fasting glucose and HDL cholesterol were similar between patients and controls. A robust change in anthropometric measures and inflammation was evident among patients by 12 months. Hs-CRP was significantly higher in patients at 12-month follow up than at baseline (baseline hs-CRP 0.67 mg/l, IQR 0.33–2.54; 12-month 1.73 mg/l, IQR 0.49–4.21; Wilcoxon signed-rank p = 0.007). When at the baseline the prevalence of overweight or obesity was 30% (28/94) in patients with FEP, by 12 months the prevalence was 59% (35/59) (McNemar′s test p < 0.001). The proportion of patients gaining ≥ 7 % of baseline weight was 68 % (40/59). The median weight gain among patients was 9.6 kg (IQR 1.5–13.6 kg), and the waist circumference increase 6.0 cm (IQR 2.0–13.0 cm). In the mixed effects model waist circumference (p < 0.0001) and sex (p = 0.014) were significantly associated with hs-CRP level. Discussion We detected a significant elevation in hs-CRP in people with FEP during the first treatment year. The rise in hs-CRP was determined by waist circumference increase. Patients with FEP are in a marked risk of developing abdominal obesity and subsequent low-grade inflammation during the first year of treatment. Prevention of the early metabolic changes in first-episode psychosis is important, as abdominal obesity and inflammation are associated with increased risk of cardiovascular events and mortality.

O3.4. INCREASED ENGAGEMENT OF THE FRONTO-PARIETAL NETWORK AND DECREASED ENGAGEMENT OF THE DEFAULT-MODE – CINGULO-OPERCULAR – SENSORIMOTOR BETWEEN-NETWORK CONNECTIVITY IN FIRST-EPISODE PSYCHOSIS PATIENTS

Abstract Background The brain basis of psychotic disorders is still inadequately understood; however, evidence strongly suggests a central role of the dysfunctional integration of signaling between brain systems, i.e. “dysconnectivity”. Resting-state functional connectivity (FC) studies of chronic schizophrenia have revealed several illness-related, network-level changes. Patients have shown reduced modular structure, changes in the subcortical-cortical interactions, increased FC within the default-mode network (DMN) and reduced FC between fronto-parietal (FP) network components. Network-level changes in earlier stages of psychotic illnesses are less studied but DMN hyperconnectivity, loss of anticorrelation between task-positive and task-negative networks and both hypo- and hyper- corticostriatal connectivity have been reported in early and at-risk stages of psychosis. While studies using tasks and resting-state have yielded plenty of valuable information, regular fmri tasks capture only a narrow field of brain functioning and during rest, behavior may vary greatly between subjects. In this study we assessed subnetworks of first-episode psychosis (FEP) patients during processing of a movie stimulus that includes every-day-like rich variety of stimuli. Methods We recorded 3T fMRI of 71 FEP patients and 57 control subjects, recruited from the Helsinki Early Psychosis Study, while they watched scenes from the movie Alice in Wonderland (Tim Burton, 2010). We then constructed a network of 160 nodes based upon a meta-analysis of regions related to a wide range of cognitive and emotional processing, we extracted signal time courses from each node and created a 160x160 correlation matrix for each subject. Using GraphVar software, we first identified all pairs of nodes where FC was statistically significantly different between groups (p < 0.05, FDR-corrected for multiple comparisons) and then extracted Graph-Components, or subnetworks, in which all pairs of nodes are connected by significant links. Results We identified a statistically significant subnetwork of 49 nodes with mainly decreased but also some increased links of FC in patients. Nodes that had a high number of decreased FC links in patients were mostly situated bilaterally in the medial prefrontal (mPFC) regions of the DMN and subcortical regions of the cingulo-opercular (CO) network, concentrated in the basal ganglia. The decreased FC links of the DMN were relatively wide-spread, connecting to some nodes within the DMN and several nodes of the CO and sensorimotor (SM) networks as well as the cerebellum. The decreased FC links of the basal ganglia were mainly connected to nodes of the SM network and the cerebellum. Patients had nodes with several links of increased FC mainly in the FP network, connecting to nodes within the FP as well as nodes of the CO network and the cerebellum. Discussion Our results indicate that during naturalistic stimulus, network-level changes in FC are already present at the early stages of psychoses implicating similar networks and links as seen in earlier studies using resting state and simple stimuli in mainly chronic patients. However, we found the within FP as well as FP-CO connectivity to be increased in patients, seemingly contradicting earlier evidence of reduced FC between FP components. It would seem that during movie viewing patients engage more regions involved in attentional control (perhaps for compensatory purposes) whereas control subjects have stronger involvement of regions related to spontaneous cognition and high-order integration.

T146. AROUSAL AFFECTS DIFFERENTIALLY FIRST-EPISODE PSYCHOSIS PATIENTS AND CONTROL SUBJECTS’ DEFAULT MODE NETWORK FUNCTIONING DURING MOVIE VIEWING

Abstract Background Functional alterations of the default mode network (DMN) are frequently reported in psychotic disorders, but the functional role of these alterations remains poorly known. In addition to previous studies that have applied different types of tasks or recorded resting-state neuroimaging data, there has recently been more interest in the use of movie stimuli in studying brain functioning in patient populations, because this could provide a more naturalistic account of brain functioning in real life-like situations. Methods Seventy-one first-episode psychosis (FEP) patients (mean age = 26.0 yrs, 47 (66%) males) and 57 controls (mean age = 26.86 yrs, 24 (42%) males) from the Helsinki Early Psychosis Study watched scenes from the movie Alice in Wonderland (Tim Burton, 2010) during 3 T fMRI-BOLD imaging. We used intersubject correlation (ISC) analysis, in which the correlation between voxel-wise BOLD time series in every within-group pair of subjects is calculated. In this study, time-windowed ISC was calculated with a 10-TR (time of repetition, 1.8 s) window with 1-TR steps over the fMRI time series. In each ISC window, a two-sample t test was performed to obtain a t-statistic time series of differences between the groups. An independent group of control subjects (n = 17, 10 males, mean age 26.5 yrs) rated how emotionally arousing the currently seen events of the stimulus are, producing a time-varying rating used as a regressor. General linear model was used to identify brain regions where the t-statistic time series covaries with the arousal rating. To make the interpretation of results less ambiguous, the arousal rating was divided into high and low arousal regressor by z scoring the rating and taking only the positive and negative values, respectively. Nonparametric clusterwise permutation test was used for statistical inference (cluster-defining threshold of p = 0.05, familywise error corrected threshold of p = 0.05, number of permutations = 5000). Furthermore, by using an experience-sampling setup during the same brain-scanning session, a partially overlapping sample of participants reported how emotionally aroused they were feeling during scanning. Results The results show significant correlation between the t-statistic time series and low arousal regressor, especially in the DMN including the anterior and posterior cingulate cortex, medial prefrontal cortex, precuneus, and bilateral lateral temporoparietal regions. Closer inspection reveals that during moments of low arousal in the movie stimulus, the ISC of healthy controls goes up but the ISC of patients does not. In the experience-sampling portion of the study, the patients reported more arousal than the control subjects. Discussion Intersubject correlation in the DMN depended differentially on arousal in FEP patients and control subjects. More specifically, during moments when the stimulus was rated less emotionally arousing, control subjects’ DMN functioning synchronized more while the patients’ did not. In connection with the difference in reported arousal during the same imaging session, our findings provide preliminary evidence for a contribution of arousal on the functional alterations of the DMN and suggest that this may be related to higher baseline arousal in the patients. Higher arousal and the related distortion of high order integrative functioning that characterizes DMN could contribute to the pathogenesis of psychosis.

Low-grade inflammation in first-episode psychosis is determined by increased waist circumference

Psychosis is associated with low-grade inflammation as measured by high-sensitivity C-reactive protein (hs-CRP), a risk factor for cardiovascular events and mortality in the general population. We investigated the relationship between hs-CRP and anthropometric and metabolic changes in first-episode psychosis (FEP) during the first treatment year. We recruited 95 FEP patients and 62 controls, and measured longitudinal changes in hs-CRP, weight, waist circumference, insulin resistance, and lipids. We used linear mixed models to analyze the longitudinal relationship between hs-CRP and clinical, anthropometric and metabolic measures. At baseline, patients with FEP had higher levels of insulin resistance, total and low-density lipoprotein cholesterol, apolipoprotein B, and triglycerides. Baseline weight, waist circumference, hs-CRP, fasting glucose, and high-density lipoprotein cholesterol were similar between patients and controls. Marked increases in anthropometric measures and hs-CRP were observed in FEP during the 12-month follow-up. However, glucose and lipid parameters did not change significantly. In the mixed models, waist circumference and female sex were significant predictors of hs-CRP levels in FEP. Prevention of the early development of abdominal obesity in FEP is crucial, as abdominal obesity is accompanied by chronic low-grade inflammation, which increases further the cardiovascular risk in this vulnerable population.