Neural markers of negative symptom outcomes in distributed working memory brain activity of antipsychotic-naive schizophrenia patients.

Since working memory deficits in schizophrenia have been linked to negative symptoms, we tested whether features of the one could predict the treatment outcome in the other. Specifically, we hypothesized that working memory-related functional connectivity at pre-treatment can predict improvement of negative symptoms in antipsychotic-treated patients. Fourteen antipsychotic-naive patients with first-episode schizophrenia were clinically assessed before and after 7 months of quetiapine monotherapy. At baseline, patients underwent functional magnetic resonance imaging while performing a verbal n-back task. Spatial independent component analysis identified task-modulated brain networks. A linear support vector machine was trained with these components to discriminate six patients who showed improvement in negative symptoms from eight non-improvers. Classification accuracy and significance was estimated by leave-one-out cross-validation and permutation tests, respectively. Two frontoparietal and one default mode network components predicted negative symptom improvement with a classification accuracy of 79% (p = 0.003). Discriminating features were found in the frontoparietal networks but not the default mode network. These preliminary data suggest that functional patterns at baseline can predict negative symptom treatment-response in schizophrenia. This information may be used to stratify patients into subgroups thereby facilitating personalized treatment.

Brain connectivity studies in schizophrenia: unravelling the effects of antipsychotics.

Impaired brain connectivity is a hallmark of schizophrenia brain dysfunction. However, the effect of drug treatment and challenges on the dysconnectivity of functional networks in schizophrenia is an understudied area. In this review, we provide an overview of functional magnetic resonance imaging studies examining dysconnectivity in schizophrenia and discuss the few studies which have also attempted to probe connectivity changes with antipsychotic drug treatment. We conclude with a discussion of possible avenues for further investigation.

Processing of Positive Visual Stimuli Before and After Symptoms Provocation in Posttraumatic Stress Disorder - A Functional Magnetic Resonance Imaging Study of Trauma-Affected Male Refugees.

BACKGROUND: Symptoms of anhedonia are often central to posttraumatic stress disorder (PTSD), but it is unclear how anhedonia is affected by processes induced by reliving past traumatic memories. METHODS: Sixty-nine male refugees (PTSD = 38) were interviewed and scanned with functional magnetic resonance imaging while viewing positive, neutral and Scrambled Pictures after being read personalized scripts evoking an emotionally neutral memory and a traumatic memory. We further measured postprovocation state symptoms, physiological measures and PTSD symptoms. We tested whether neural activity associated with positive picture viewing in participants with PTSD was differentially affected by symptom provocation compared to controls. RESULTS: For the pictures > scrambled contrast (Positive contrast), PTSD participants had significantly less activity than controls in fusiform gyrus, right inferior temporal gyrus and left middle occipital gyrus. The Positive contrast activity in fusiform gyrus scaled negatively with anhedonia symptoms in PTSD participants after controlling for total PTSD severity. Relative to the emotionally Neutral Script, the Trauma Script decreased positive picture viewing activity in posterior cingulate cortex, precuneus and left calcarine gyrus, but there was no difference between PTSD participants and controls. CONCLUSIONS: We found reduced responsiveness of higher visual processing of emotionally positive pictures in PTSD. The significant correlation found between positive picture viewing activity and anhedonia suggests the reduced responsiveness to be due to the severity of anhedonia.

Medial prefrontal disengagement during self-focus in formerly depressed patients prone to rumination.

BACKGROUND: Medial prefrontal cortex (MPFC) activity during self-referential processing has been associated with rumination and found aberrant in depression. We investigated whether this aberrant activity reflects a trait marker that persists in remitted patients. METHODS: Twenty-five patients fully remitted from major depression for at least 6 months, and 29 matched healthy controls were scanned with fMRI while presented with personality trait words in two conditions: Self condition asked whether the trait described themselves; General condition asked whether the trait was generally desirable. Contrasts-of-interest were examined in a factorial model and rumination correlates were examined in 2-sample t-tests with Ruminative Response Style score as covariate. All findings were reported at a conservative p < 0.05, with whole-brain peak-level family-wise error correction. RESULTS: Self-referential processing increased anterior cortical midline activity to a similar extent in both groups. Dorsal anterior cingulate cortex (MNI(x,y,z) = -12,20,26) and dorsal MPFC (MNI(x,y,z) = -6,46,40) activity during self-referential processing was positively associated with rumination in healthy control subjects and negatively associated with rumination in remitted patients. LIMITATIONS: A longitudinal design tracking the relationship between rumination and MPFC activity would have aided the interpretation of our findings as to whether high ruminators are exhibiting an adaptive process to maintain remission or whether it represents a maladaptive process considering that high ruminators have an increased vulnerability for relapse. CONCLUSIONS: The association between increased anterior cortical midline activity during self-referential processing and rumination differentiated healthy controls from formerly depressed patients. Self-referential neural processing during remission from depression may depend on the cognitive tendencies to ruminate.

The Danish High Risk and Resilience Study-VIA 11: Study Protocol for the First Follow-Up of the VIA 7 Cohort -522 Children Born to Parents With Schizophrenia Spectrum Disorders or Bipolar Disorder and Controls Being Re-examined for the First Time at Age 11.

Introduction: Offspring of parents with severe mental illness have an increased risk of developing mental illnesses themselves. Familial high risk cohorts give a unique opportunity for studying the development over time, both the illness that the individual is predisposed for and any other diagnoses. These studies can also increase our knowledge of etiology of severe mental illness and provide knowledge about the underlying mechanisms before illness develops. Interventions targeting this group are often proposed due to the potential possibility of prevention, but evidence about timing and content is lacking. Method: A large, representative cohort of 522 7-year old children born to parents with schizophrenia, bipolar disorder or controls was established based on Danish registers. A comprehensive baseline assessment including neurocognition, motor functioning, psychopathology, home environment, sociodemographic data, and genetic information was conducted from January 1, 2013 to January 31, 2016. This study is the first follow-up of the cohort, carried out when the children turn 11 years of age. By assessing the cohort at this age, we will evaluate the children twice before puberty. All instruments have been selected with a longitudinal perspective and most of them are identical to those used at inclusion into the study at age 7. A diagnostic interview, motor tests, and a large cognitive battery are conducted along with home visits and information from teachers. This time we examine the children's brains by magnetic resonance scans and electroencephalograms. Measures of physical activity and sleep are captured by a chip placed on the body, while we obtain biological assays by collecting blood samples from the children. Discussion: Findings from the VIA 7 study revealed large variations across domains between children born to parents with schizophrenia, bipolar and controls, respectively. This study will further determine whether the children at familial risk reveal delayed developmental courses, but catch up at age 11, or whether the discrepancies between the groups have grown even larger. We will compare subgroups within each of the familial high risk groups in order to investigate aspects of resilience. Data on brain structure and physical parameters will add a neurobiological dimension to the study.

Impaired temporoparietal deactivation with working memory load in antipsychotic-naïve patients with first-episode schizophrenia.

OBJECTIVES: Neuroimaging studies have shown abnormal task-related deactivations during working memory (WM) in schizophrenia patients with recent emphasis on brain regions within the default mode network. Using fMRI, we tested whether antipsychotic-naïve schizophrenia patients were impaired at deactivating brain regions that do not subserve WM. METHODS: Twenty-three antipsychotic-naïve patients with first-episode schizophrenia and 35 healthy individuals underwent whole-brain 3T fMRI scans while performing a verbal N-back task including 0-back (no WM load), 1-back (low WM load), and 2-back (high WM load) conditions. RESULTS: Contrasting the 2-back and 0-back conditions revealed that patients deactivated default mode network regions to a similar degree as controls. However, patients were impaired in deactivating large bilateral clusters centred on the superior temporal gyrus with increasing WM load. These regions activated with the no WM load condition (0-back) in both groups. CONCLUSIONS: Because 0-back activation reflects verbal attention processes, patients' persistent activation in the 1-back and 2-back conditions may reflect an inability to shift cognitive strategy with onset of WM demands. Since patients were antipsychotic-naïve and task performance was equal to controls, we infer that this impaired temporoparietal deactivation may represent a primary dysfunction in schizophrenia.