FreeSurfer 7 quality control: Key problem areas and importance of manual corrections.

We have studied the effects of manual quality control of brain Magnetic Resonance Imaging (MRI) images processed with Freesurfer. T1 images of first episode psychosis patients (N = 60) and healthy controls (N = 41) were inspected for gray matter boundary errors. The errors were fixed, and the effects of error correction on brain volume, thickness, and surface area were measured. It is commonplace to apply quality control to Freesurfer MRI recordings to ensure that the edges of gray and white matter are detected properly, as incorrect edge detection leads to changes in variables such as volume, cortical thickness, and cortical surface area. We find that while Freesurfer v7.1.1. does regularly make mistakes in identifying the edges of cortical gray matter, correcting these errors yields limited changes in the commonly measured variables listed above. We further find that the software makes fewer gray matter boundary errors when processing female brains. The results suggest that manually correcting gray matter boundary errors may not be worthwhile due to its small effect on the measurements, with potential exceptions for studies that focus on the areas that are more commonly affected by errors: the areas around the cerebellar tentorium, paracentral lobule, and the optic nerves, specifically the horizontal segment of the middle cerebral artery.

Hippocampus-Centered Network Is Associated With Positive Symptom Alleviation in Patients With First-Episode Psychosis.

BACKGROUND: Previous functional magnetic resonance imaging studies have reported widespread brain functional connectivity alterations in patients with psychosis. These studies have mostly used either resting-state or simple-task paradigms, thereby compromising experimental control or ecological validity, respectively. Additionally, in a conventional functional magnetic resonance imaging intrasubject functional connectivity analysis, it is difficult to identify which connections relate to extrinsic (stimulus-induced) and which connections relate to intrinsic (non-stimulus-related) neural processes. METHODS: To mitigate these limitations, we used intersubject functional connectivity (ISFC) to analyze longitudinal functional magnetic resonance imaging data collected while 36 individuals with first-episode psychosis (FEP) and 29 age- and sex-matched population control participants watched scenes from the fantasy movie Alice in Wonderland at baseline and again at 1-year follow-up. Furthermore, to allow unconfounded comparison and to overcome possible circularity of ISFC, we introduced a novel approach wherein ISFC in both the FEP and population control groups was calculated with respect to an independent group of participants (not included in the analyses). RESULTS: Using this independent-reference ISFC approach, we found an interaction effect wherein the independent-reference ISFC in individuals with FEP, but not in the control group participants, was significantly stronger at baseline than at follow-up in a network centered in the hippocampus and involving thalamic, striatal, and cortical regions, such as the orbitofrontal cortex. Alleviation of positive symptoms, particularly delusions, from baseline to follow-up was correlated with decreased network connectivity in patients with FEP. CONCLUSIONS: These findings link deviation of naturalistic information processing in the hippocampus-centered network to positive symptoms.

Depression core network-based individualized targeting for transcranial magnetic stimulation.

BACKGROUND: Transcranial magnetic stimulation (TMS) of the dorsolateral prefrontal cortex (DLPFC) is an established treatment for major depressive disorder (MDD). Recent attempts to improve TMS efficacy by individually targeting DLPFC subregions that are functionally connected to the subgenual anterior cingulate cortex (sgACC) appear promising. However, sgACC covers only a small subset of core MDD-related areas. Further, fMRI connectivity of sgACC is poorly repeatable within subjects. METHODS: Based on an fMRI database analysis, we first constructed a novel core network model (CNM), capturing voxelwise emotion regulation- and MDD-related DLPFC connectivity. Then, in a sample of 15 healthy subjects and 29 MDD patients, we assessed (i) within-subject repeatability of the DLPFC connectivity patterns computed from time segments of varying lengths of individual-level fMRI data and (ii) association of MDD severity with the individual DLPFC connectivity strengths. We extracted group-level connectivity strengths in CNM from individual DLPFC coordinates stimulated with neuronavigated TMS in a separate sample of 25 MDD patients. These connectivity strengths were then correlated with individual TMS efficacy. RESULTS: Compared with sgACC connectivity, CNM increased intraindividual repeatability 5-fold. DLPFC connectivity strength from CNM was associated with MDD severity and TMS efficacy. While the locations of CNM-based individual TMS targets remained constant within individuals, they varied considerably between individuals. CONCLUSIONS: CNM increased repeatability of functional targeting to a clinically feasible level. The observed association of MDD severity and TMS efficacy with DLPFC connectivity supports the validity of the CNM. The interindividual differences in target locations motivate future individualized clinical trials leveraging the CNM.

Connectivity alterations of mesostriatal pathways in first episode psychosis.

BACKGROUND AND HYPOTHESIS: Pathogenic understanding of the psychotic disorders converges on regulation of dopaminergic signaling in mesostriatocortical pathways. Functional connectivity of the mesostriatal pathways may inform us of the neuronal networks involved. STUDY DESIGN: This longitudinal study of first episode psychosis (FEP) (49 patients, 43 controls) employed seed-based functional connectivity analyses of fMRI data collected during a naturalistic movie stimulus. STUDY RESULTS: We identified hypoconnectivity of the dorsal striatum with the midbrain, associated with antipsychotic medication dose in FEP, in comparison with the healthy control group. The midbrain regions that showed hypoconnectivity with the dorsal striatum also showed hypoconnectivity with cerebellar regions suggested to be involved in regulation of the mesostriatocortical dopaminergic pathways. None of the baseline hypoconnectivity detected was seen at follow-up. CONCLUSIONS: These findings extend earlier resting state findings on mesostriatal connectivity in psychotic disorders and highlight the potential for cerebellar regulation of the mesostriatocortical pathways as a target of treatment trials.

Associations between acceptance of the implausible bias, theory of mind and delusions in first-episode psychosis patients; A longitudinal study.

Multiple different cognitive biases, among them the liberal acceptance (LA) bias, have been suggested to contribute to reality distortion in psychotic disorders. Earlier studies have been cross-sectional and considered a limited set of cognitive correlates of psychosis, thus the relationship between LA bias and psychosis remains poorly known. We studied a similar bias (acceptance of the implausible (AOI)) in 62 first-episode psychosis (FEP) patients and 62 control subjects, who watched movie scenes with varying degrees of realism and were asked to evaluate the probability of these events occurring in real life. We assessed theory of mind (ToM) performance using the Hinting task and delusion severity using Brief Psychiatric Rating Scale item 11. We correlated the magnitude of AOI with the severity of delusions and performance in the ToM task. Furthermore, we used 1-year follow-up data from 40 FEP patients and 40 control subjects to disentangle state vs trait-like characteristics of AOI. At baseline FEP patients expressed more AOI than control subjects, and the magnitude of AOI correlated positively with the severity of delusions and negatively with ToM performance. At the one-year follow-up, when most patients were in remission, patients still displayed increased AOI, which no longer correlated with delusions. These findings support the notion that the AOI bias could represent a trait rather than a state feature and support further studies to test the hypothesis that it could be one of the causal factors of psychotic disorders, possibly associated with ToM.

State-like changes in the salience network correlate with delusion severity in first-episode psychosis patients.

BACKGROUND AND HYPOTHESIS: Delusions are characteristic of psychotic disorders; however, the brain correlates of delusions remain poorly known. Imaging studies on delusions typically compare images across individuals. Related confounding of inter-individual differences beyond delusions may be avoided by comparing delusional and non-delusional states within individuals. STUDY DESIGN: We studied correlations of delusions using intra-subject correlation (intra-SC) and inter-subject correlation of functional magnetic resonance imaging (fMRI) signal time series, obtained during a movie stimulus at baseline and follow-up. We included 27 control subjects and 24 first-episode psychosis patients, who were free of delusions at follow-up, to calculate intra-SC between fMRI signals obtained during the two time points. In addition, we studied changes in functional connectivity at baseline and during the one-year follow-up using regions where delusion severity correlated with intra-SC as seeds. RESULTS: The intra-SC correlated negatively with the baseline delusion severity in the bilateral anterior insula. In addition, we observed a subthreshold cluster in the anterior cingulate. These three regions constitute the cortical salience network (SN). Functional connectivity between the bilateral insula and the precuneus was weaker in the patients at baseline than in patients at follow-up or in control subjects at any time point. CONCLUSIONS: The results suggest that intra-SC is a powerful tool to study brain correlates of symptoms and highlight the role of the SN and internetwork dysconnectivity between the SN and the default mode network in delusions.

Functional network connectivity and topology during naturalistic stimulus is altered in first-episode psychosis.

BACKGROUND: Psychotic disorders have been suggested to derive from dysfunctional integration of signaling between brain regions. Earlier studies have found several changes in functional network synchronization as well as altered network topology in patients with psychotic disorders. However, studies have used mainly resting-state that makes it more difficult to link functional alterations to any specific stimulus or experience. We set out to examine functional connectivity as well as graph (topological) measures and their association to symptoms in first-episode psychosis patients during movie viewing. Our goal was to understand whole-brain functional dynamics of complex naturalistic information processing in psychosis and changes in brain functional organization related to symptoms. METHODS: 71 first-episode psychosis patients and 57 control subjects watched scenes from the movie Alice in Wonderland during 3 T fMRI. We compared functional connectivity and graph measures indicating integration, segregation and centrality between groups, and examined the association between topology and symptom scores in the patient group. RESULTS: We identified a subnetwork with predominantly decreased links of functional connectivity in first-episode psychosis patients. The subnetwork was mainly comprised of nodes of and links between the cingulo-opercular, sensorimotor and default-mode networks. In topological measures, we observed between-group differences in properties of centrality. CONCLUSIONS: Functional brain networks are affected during naturalistic information processing already in the early stages of psychosis, concentrated in salience- and cognitive control-related hubs and subnetworks. Understanding these aberrant dynamics could add to better targeted cognitive and behavioral interventions in the early stages of psychotic disorders.

Delineating insight-processing-related functional activations in the precuneus in first-episode psychosis patients.

Poor insight is a central characteristic of psychotic disorders, and it has been suggested to result from a general dysfunction in self-reflection. However, brain processing of clinical insight and more general self-reflection has not been directly compared. We compared tasks on (1) self-reflection on psychosis-related mental functioning (clinical insight, in patients only), (2) self-reflection on mental functioning unrelated to psychosis (general metacognition), and (3) semantic control during blood-oxygenation-level-dependent (BOLD) functional magnetic resonance imaging with 19 first-episode psychosis patients and 24 control participants. Arterial-spin-labeling (ASL) images were collected at rest. Clinical insight was evaluated with the Schedule for the Assessment of Insight. In patients, posterosuperior precuneus showed stronger activation during the insight task than during the semantic control task, while anteroinferior precuneus and posterior cingulate cortex (PCC) showed stronger activation during the insight task than during the general metacognition task. No significant group differences in brain activation emerged during the general metacognition task. Although the BOLD measures did not correlate with clinical insight measures, ASL-measured cerebral blood flow (CBF) values did correlate when extracted from the task-selective precuneus/PCC areas: higher CBF correlated with higher clinical insight scores. These results suggest that regions in the posteromedial cortex are selective for clinical insight.

Escitalopram enhances synchrony of brain responses during emotional narratives in patients with major depressive disorder.

One-week treatment with escitalopram decreases amygdala responses to fearful facial expressions in depressed patients, but it remains unknown whether it also modulates processing of complex and freely processed emotional stimuli resembling daily life emotional situations. Inter-subject correlation (ISC) offers a means to track brain activity during complex, dynamic stimuli in a model-free manner. Twenty-nine treatment-seeking patients with major depressive disorder were randomized in a double-blind study design to receive either escitalopram or placebo for one week, after which functional magnetic resonance imaging (fMRI) was performed. During fMRI the participants listened to spoken emotional narratives. Level of ISC between the escitalopram and the placebo group was compared across all the narratives and separately for the episodes with positive and negative valence. Across all the narratives, the escitalopram group had higher ISC in the default mode network of the brain as well as in the fronto-temporal narrative processing regions, whereas lower ISC was seen in the middle temporal cortex, hippocampus and occipital cortex. Escitalopram increased ISC during positive parts of the narratives in the precuneus, medial prefrontal cortex, anterior cingulate and fronto-insular cortex, whereas there was no significant synchronization in brain responses to positive vs negative events in the placebo group. Increased ISC may imply improved emotional synchronization with others, particularly during observation of positive events. Further studies are needed to test whether this contributes to the later therapeutic effect of escitalopram.

Immunomodulatory effects of antipsychotic treatment on gene expression in first-episode psychosis.

Previous studies suggest immunological alterations in patients with first-episode psychosis (FEP). Some studies show that antipsychotic compounds may cause immunomodulatory effects. To evaluate the immunological changes and the possible immunomodulatory effects in FEP, we recruited patients with FEP (n = 67) and matched controls (n = 38), aged 18-40 years, from the catchment area of the Helsinki University Hospital and the City of Helsinki, Finland. Fasting peripheral blood samples were collected between 8 and 10 a.m. in 10 ml PAXgene tubes. We applied the NanoString nCounter in-solution hybridization technology to determine gene expression levels of 147 candidate genes reflecting activation of the immune system. Cases had higher gene expression levels of BDKRB1 and SPP1/osteopontin compared with controls. Of the individual medications used as monotherapy, risperidone was associated with a statistically significant upregulation of 11 immune system genes, including cytokines and cytokine receptors (SPP1, IL1R1, IL1R2), pattern recognition molecules (TLR1, TLR2 and TLR6, dectin-1/CLEC7A), molecules involved in apoptosis (FAS), and some other molecules with functions in immune activation (BDKRB1, IGF1R, CR1). In conclusion, risperidone possessed strong immunomodulatory properties affecting mainly innate immune response in FEP patients, whereas the observed effects of quetiapine and olanzapine were only marginal. Our results further emphasize the importance of understanding the immunomodulatory mechanisms of antipsychotic treatment, especially in terms of specific compounds, doses and duration of medication in patients with severe mental illness. Future studies should evaluate the response pre- and post-treatment, and the possible role of this inflammatory activation for the progression of psychiatric and metabolic symptoms.

Activation of the motivation-related ventral striatum during delusional experience.

Delusion is the most characteristic symptom of psychosis, occurring in almost all first-episode psychosis patients. The motivational salience hypothesis suggests delusion to originate from the experience of abnormal motivational salience. Whether the motivation-related brain circuitries are activated during the actual delusional experience remains, however, unknown. We used a forced-choice answering tree at random intervals during functional magnetic resonance imaging to capture delusional and non-delusional spontaneous experiences in patients with first-episode psychosis (n = 31) or clinical high-risk state (n = 7). The motivation-related brain regions were identified by an automated meta-analysis of 149 studies. Thirteen first-episode patients reported both delusional and non-delusional spontaneous experiences. In these patients, delusional experiences were related to stronger activation of the ventral striatum in both hemispheres. This activation overlapped with the most strongly motivation-related brain regions. These findings provide an empirical link between the actual delusional experience and the motivational salience hypothesis. Further use and development of the present methods in localizing the neurobiological basis of the most characteristic symptoms may be useful in the search for etiopathogenic pathways that result in psychotic disorders.

Is It Possible to Predict the Future in First-Episode Psychosis?

The outcome of first-episode psychosis (FEP) is highly variable, ranging from early sustained recovery to antipsychotic treatment resistance from the onset of illness. For clinicians, a possibility to predict patient outcomes would be highly valuable for the selection of antipsychotic treatment and in tailoring psychosocial treatments and psychoeducation. This selective review summarizes current knowledge of prognostic markers in FEP. We sought potential outcome predictors from clinical and sociodemographic factors, cognition, brain imaging, genetics, and blood-based biomarkers, and we considered different outcomes, like remission, recovery, physical comorbidities, and suicide risk. Based on the review, it is currently possible to predict the future for FEP patients to some extent. Some clinical features-like the longer duration of untreated psychosis (DUP), poor premorbid adjustment, the insidious mode of onset, the greater severity of negative symptoms, comorbid substance use disorders (SUDs), a history of suicide attempts and suicidal ideation and having non-affective psychosis-are associated with a worse outcome. Of the social and demographic factors, male gender, social disadvantage, neighborhood deprivation, dysfunctional family environment, and ethnicity may be relevant. Treatment non-adherence is a substantial risk factor for relapse, but a small minority of patients with acute onset of FEP and early remission may benefit from antipsychotic discontinuation. Cognitive functioning is associated with functional outcomes. Brain imaging currently has limited utility as an outcome predictor, but this may change with methodological advancements. Polygenic risk scores (PRSs) might be useful as one component of a predictive tool, and pharmacogenetic testing is already available and valuable for patients who have problems in treatment response or with side effects. Most blood-based biomarkers need further validation. None of the currently available predictive markers has adequate sensitivity or specificity used alone. However, personalized treatment of FEP will need predictive tools. We discuss some methodologies, such as machine learning (ML), and tools that could lead to the improved prediction and clinical utility of different prognostic markers in FEP. Combination of different markers in ML models with a user friendly interface, or novel findings from e.g., molecular genetics or neuroimaging, may result in computer-assisted clinical applications in the near future.

Aberrant Cortical Integration in First-Episode Psychosis During Natural Audiovisual Processing.

BACKGROUND: Functional magnetic resonance imaging studies of psychotic disorders have reported both hypoactivity and hyperactivity in numerous brain regions. In line with the dysconnection hypothesis, these regions include cortical integrative hub regions. However, most earlier studies focused on a single cognitive function at a time, assessed by delivering artificial stimuli to patients with chronic psychosis. Thus, it remains unresolved whether these findings are present already in early psychosis and whether they translate to real-life-like conditions that require multisensory processing and integration. METHODS: Scenes from the movie Alice in Wonderland (2010) were shown to 51 patients with first-episode psychosis (16 women) and 32 community-based control subjects (17 women) during 3T functional magnetic resonance imaging. We compared intersubject correlation, a measure of similarity of brain signal time courses in each voxel, between the groups. We also quantified the hubness as the number of connections each region has. RESULTS: Intersubject correlation was significantly lower in patients with first-episode psychosis than in control subjects in the medial and lateral prefrontal, cingulate, precuneal, and parietotemporal regions, including the default mode network. Regional magnitude of between-group difference in intersubject correlation was associated with the hubness. CONCLUSIONS: Our findings provide novel evidence for the dysconnection hypothesis by showing that during complex real-life-like stimulation, the most prominent functional alterations in psychotic disorders relate to integrative brain functions. Presence of such abnormalities in first-episode psychosis rules out long-term effects of illness or medication. These methods can be used in further studies to map widespread hub alterations in a single functional magnetic resonance imaging session and link them to potential downstream and upstream pathways.

Short-term escitalopram treatment normalizes aberrant self-referential processing in major depressive disorder.

BACKGROUND: Increased self-focus and negative self-concept play an important role in depression. Antidepressants influence self-referential processing in healthy volunteers, but their function in self-processing of depressed patients remains unknown. METHODS: Thirty-two depressed patients were randomly allocated to receive either escitalopram 10 mg or placebo for one week. After one week, neural responses to positive and negative self-referential adjectives and neutral control stimuli were assessed with functional magnetic resonance imaging. A group of matched healthy volunteers served as a control group. RESULTS: Escitalopram decreased responses of medial fronto-parietal regions to self-referential words relative to non-emotional control stimuli, driven by increased responses to the control condition. Escitalopram also increased responses in the pre-defined region of the medial prefrontal cortex (MPFC) and the anterior cingulate cortex (ACC) to positive relative to negative words. Importantly, the changes in neural responses occurred before any effect on depressive symptoms, implying a direct effect of escitalopram. Furthermore, the placebo group had decreased responses of the MPFC and the ACC to positive self-referential processing relative to the matched healthy controls. However, neural responses of the escitalopram group and the healthy unmedicated controls were similar. LIMITATIONS: Differences between the groups in self-reported depression symptoms and personality traits may have influenced the results. CONCLUSION: One-week treatment with escitalopram normalized aberrant self-referential processing in depressed patients, shifting the focus from the self to the external environment and potentiating positive self-referential processing. This may be an important factor in mechanism of action of antidepressants.

Connectivity of the precuneus-posterior cingulate cortex with the anterior cingulate cortex-medial prefrontal cortex differs consistently between control subjects and first-episode psychosis patients during a movie stimulus.

BACKGROUND: Functional connectivity is altered in psychotic disorders. Multiple findings concentrate on the default mode network, anchored on the precuneus-posterior cingulate cortex (PC-PCC). However, the nature of the alterations varies between studies and connectivity alterations have not been studied during an ecologically valid natural stimulus. In the present study, we investigated the functional and structural connectivity of a PC-PCC region, where functioning differentiated first-episode psychosis patients from control subjects during free viewing of a movie in our earlier study. METHODS: 14 first-episode psychosis patients and 12 control subjects were imaged with GE 3T, and 29 patients and 19 control subjects were imaged with a Siemens Skyra 3T scanner while watching scenes from the movie Alice in Wonderland. Group differences in functional connectivity were analysed for both scanners separately and results were compared to identify any overlap. Diffusion tensor measures of 26 patients and 19 control subjects were compared for the related white matter tracts, identified by deterministic tractography. RESULTS: Functional connectivity was increased in patients across scanners between the midline regions of the PC-PCC and the anterior cingulate cortex-medial prefrontal cortex (ACC-mPFC). We found no group differences in any of the diffusion tensor imaging measures. CONCLUSIONS: Already in the early stages of psychosis functional connectivity between the midline structures of the PC-PCC and the ACC-mPFC is consistently increased during naturalistic stimulus.

Single dose of mirtazapine modulates whole-brain functional connectivity during emotional narrative processing.

The link between neurotransmitter-level effects of antidepressants and their clinical effect remain poorly understood. A single dose of mirtazapine decreases limbic responses to fearful faces in healthy subjects, but it is unknown whether this effect applies to complex emotional situations and dynamic connectivity between brain regions. Thirty healthy volunteers listened to spoken emotional narratives during functional magnetic resonance imaging (fMRI). In an open-label design, 15 subjects received 15mg of mirtazapine two hours prior to fMRI while 15 subjects served as a control group. We assessed the effects of mirtazapine on regional neural responses and dynamic functional connectivity associated with valence and arousal. Mirtazapine attenuated responses to unpleasant events in the right fronto-insular cortex, while modulating responses to arousing events in the core limbic regions and the cortical midline structures (CMS). Mirtazapine decreased responses to unpleasant and arousing events in sensorimotor areas and the anterior CMS implicated in self-referential processing and formation of subjective feelings. Mirtazapine increased functional connectivity associated with positive valence in the CMS and limbic regions. Mirtazapine triggers large-scale changes in regional responses and functional connectivity during naturalistic, emotional stimuli. These span limbic, sensorimotor, and midline brain structures, and may be relevant to the clinical effectiveness of mirtazapine.

The interaction of emotion and pain in the insula and secondary somatosensory cortex.

Pain is processed in a large neural network that partially overlaps structures involved in emotion processing. Despite the fact that pain and emotion are known to share neural regions and interact in numerous clinical conditions, relatively little is known about the interaction of pain and emotion at the neural level. This study on healthy adults aimed to investigate the interaction between negative and positive emotional stimuli and experimental pain in an essential pain processing network. Sixteen healthy young adult subjects were exposed to pictures from the International Affective Picture System (IAPS) with negative, neutral or positive valence, along with laser pain stimuli. The stimuli were pseudo-randomly arranged in three 15-min experiment series comprising 49 stimuli each (picture, laser or simultaneous picture and laser stimuli). The whole-brain blood-oxygen-level-dependent (BOLD) signal was acquired using 3T functional magnetic resonance imaging (fMRI). As expected, the pain stimulus elicited activation in the secondary somatosensory cortex (SII), insula and anterior cingulate cortex (ACC) when compared to the baseline. The interaction of negative emotion and laser stimuli related to the activation of the left SII. The interaction of positive emotion and pain stimuli led to bilateral activation of the SII and left insula. These findings reveal interaction in parts of the pain processing network during simultaneous emotion and physical pain. We demonstrated a valence-independent interaction of emotion and pain in SII.

A single dose of mirtazapine attenuates neural responses to self-referential processing.

Increased self-focus is a core factor in the psychopathology of depression. Cortical midline structures (CMS) are implicated in the neurobiology of self, depression and antidepressant treatment response. Mirtazapine, an antidepressant that increases serotonin and norepinephrine release, enhances processing of positive and attenuates processing of negative emotional information in healthy volunteers after a single dose. These early changes, which are opposite to the negative information bias in depression, may be important for the therapeutic effect of mirtazapine. It nevertheless remains unresolved whether/how mirtazapine specifically influences processing of self-referential emotional information.Half of the healthy volunteers (n=15/30) received a single dose of mirtazapine, in an open-label design, two hours before functional magnetic resonance imaging (fMRI), and the other half was scanned as a control group without medication. During fMRI the participants categorized positive and negative self-referential adjectives.Mirtazapine attenuated responses to self-referential processing in the medial prefrontal cortex and the anterior cingulate cortex. Mirtazapine further decreased responses to positive self-referential processing in the posterior cingulate cortex and parietal cortex.These decreased responses of the CMS suggest that mirtazapine may rapidly improve the ability of the CMS to down-regulate self-referential processing. In depressed patients, this could lead to decreased self-focus and rumination, contributing to the antidepressant effect.

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.

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.