Disrupted GABAergic facilitation of working memory performance in people with schizophrenia.

ObjectivesGamma-Amiobutyric acid (GABA) is a primary inhibitory neurotransmitter that facilitates neural oscillations that coordinate neural activity between brain networks to facilitate cognition. The present magnetic resonance spectroscopy (MRS) study tests the hypothesis that GABAergic facilitation of working memory is disrupted in people with schizophrenia (PSZ).Methods51 healthy participants and 40 PSZ from the UC Davis Early Psychosis Program performed an item and temporal order working memory (WM) task and underwent resting MRS to measure GABA and glutamate concentrations in dorsolateral prefrontal (DLPFC) and anterior cingulate (ACC) regions of interest. MRS was acquired on a 3 Tesla Siemens scanner and GABA and glutamate concentrations were referenced to creatine. Percent correct on the WM task indexed performance and correlation coefficients examined GABAergic or Glutamatergic facilitation of WM, with Fisher's Z transformation testing for group differences.ResultsThere were no group differences in GABA or glutamate concentrations, but WM correlations were reversed between groups. In patients, higher DLPFC GABA was associated with worse rather than better WM performance. This pattern was not observed for glutamate or in the ACC. Although under-powered, there was no indication of medication effects.Conclusions and relevanceResults cannot be explained by group differences in DLPFC GABA or glutamate concentrations but, instead, indicate that schizophrenia disrupts the GABAergic facilitation of WM seen in healthy individuals. Results appear to parallel post mortem findings in suggesting that schizophrenia alters the distribution of different classes of GABAergic interneurons rather than producing a general deficit across the total population of neurons

Impact of schizophrenia on anterior and posterior hippocampus during memory for complex scenes.

ObjectivesHippocampal dysfunction has been proposed as a mechanism for memory deficits in schizophrenia. Available evidence suggests that the anterior and posterior hippocampus could be differentially affected. Accordingly, we used fMRI to test the hypothesis that activity in posterior hippocampus is disproportionately reduced in schizophrenia, particularly during spatial memory retrieval.Methods26 healthy participants and 24 patients with schizophrenia from the UC Davis Early Psychosis Program were studied while fMRI was acquired on a 3 Tesla Siemens scanner. During encoding, participants were oriented to critical items through questions about item features (e.g., "Does the lamp have a square shade?") or spatial location (e.g., "Is the lamp on the table next to the couch?"). At test, participants determined whether scenes were changed or unchanged. fMRI analyses contrasted activation in a priori regions of interest (ROI) in anterior and posterior hippocampus during correct recognition of item changes and spatial changes.ResultsAs predicted, patients with schizophrenia exhibited reduced activation in the posterior hippocampus during detection of spatial changes but not during detection of item changes. Unexpectedly, patients exhibited increased activation of anterior hippocampus during detection of item changes. Whole brain analyses revealed reduced fronto-parietal and striatal activation in patients for spatial but not for item change trials.ConclusionsResults suggest a gradient of hippocampal dysfunction in which posterior hippocampus - which is necessary for processing fine-grained spatial relationships - is underactive, and anterior hippocampus - which may process context more globally - is overactive

Model selection and prediction of outcomes in recent onset schizophrenia patients who undergo cognitive training.

Predicting treatment outcomes in psychiatric populations remains a challenge, but is increasingly important in the pursuit of personalized medicine. Patients with schizophrenia have deficits in cognition, and targeted cognitive training (TCT) of auditory processing and working memory has been shown to improve some of these impairments; but little is known about the baseline patient characteristics predictive of cognitive improvement. Here we use a model selection and regression approach called least absolute shrinkage and selection operator (LASSO) to examine predictors of cognitive improvement in response to TCT for patients with recent onset schizophrenia. Forty-three individuals with recent onset schizophrenia randomized to undergo TCT were assessed at baseline on measures of cognition, symptoms, functioning, illness duration, and demographic variables. We carried out 10-fold cross-validation of LASSO for model selection and regression. We followed up on these results using linear models for statistical inference. No individual variable was found to correlate with improvement in global cognition using a Pearson correlation approach, and a linear model including all variables was also found not to be significant. However, the LASSO model identified baseline global cognition, education, and gender in a model predictive of improvement on global cognition following TCT. These findings offer guidelines for personalized approaches to cognitive training for patients with schizophrenia

A History of Trauma is Associated with Aggression, Depression, Non-Suicidal Self-Injury Behavior, and Suicide Ideation in First-Episode Psychosis.

The association between trauma and psychosis outcomes is well-established, and yet the impact of trauma on comorbid clinical symptoms-such as aggression, non-suicidal self-injury behavior (NSSIB), suicide ideation, and suicide behavior-for those with psychosis is unclear. To effectively treat those with first-episode psychosis (FEP) and a history of trauma, we need to understand the impact of trauma on their whole presentation. FEP participants were recruited from an Early Psychosis Program (N = 187, ages 12-35, 72.2% male). Clinicians gathered history of trauma, aggression, and suicide data, and rated current symptom severity and functioning. Data was coded using clinician rated measures, self-report measures, and retrospective clinical chart review. Regression analyses examined whether trauma was associated with a history of aggression, suicidal ideation, suicide behavior, NSSIB, symptoms, and functioning. Trauma was associated with aggression, aggression severity and type of aggression (aggression towards others). Trauma was also associated with depression severity, suicide ideation, most severe suicide ideation, and NSSIB. Trauma was not associated with suicide behavior, severity of suicide behavior or psychosocial functioning. Integrating trauma treatment into FEP care could reduce rates of depression, aggression, suicide ideation, and NSSIB for those with a history of trauma. To reduce suicide attempt occurrence and improve functioning, more research is needed

Uncharted Waters: Treating Trauma Symptoms in the Context of Early Psychosis.

Psychosis is conceptualized in a neurodevelopmental vulnerability-stress framework, and childhood trauma is one environmental factor that can lead to psychotic symptoms and the development of psychotic disorders. Higher rates of trauma are associated with higher psychosis risk and greater symptom frequency and severity, resulting in increased hospitalization rates and demand on outpatient primary care and mental health services. Despite an estimated 70% of individuals in the early stages of psychosis reporting a history of experiencing traumatic events, trauma effects (post-traumatic anxiety or depressive symptoms) are often overlooked in psychosis treatment and current interventions typically do not target commonly comorbid post-traumatic stress symptoms. We presented a protocol for Trauma-Integrated Cognitive Behavioral Therapy for Psychosis (TI-CBTp), an approach to treating post-traumatic stress symptoms in the context of early psychosis care. We provided a brief summary of TI-CBTp as implemented in the context of Coordinated Specialty Care and presented preliminary data supporting the use of TI-CBTp in early psychosis care. The preliminary results suggest that individuals with comorbid psychosis and post-traumatic stress symptoms can be appropriately and safely treated using TI-CBTp within Coordinated Specialty Care

Extracellular free water and glutathione in first-episode psychosis-a multimodal investigation of an inflammatory model for psychosis.

Evidence has been accumulating for an immune-based component to the etiology of psychotic disorders. Advancements in diffusion magnetic resonance imaging (MRI) have enabled estimation of extracellular free water (FW), a putative biomarker of neuroinflammation. Furthermore, inflammatory processes may be associated with altered brain levels of metabolites, such as glutathione (GSH). Consequently, we sought to test the hypotheses that FW is increased and associated with decreased GSH in patients with first-episode schizophrenia (SZ) compared with healthy controls (HC). SZ (n = 36) and HC (n = 40) subjects underwent a multi-shell diffusion MRI scan on a Siemens 3T scanner. 1H-MR spectroscopy data were acquired using a GSH-optimized MEGA-PRESS editing sequence and GSH/creatine ratios were calculated for DLPFC (SZ: n = 33, HC: n = 37) and visual cortex (SZ: n = 29, HC: n = 35) voxels. Symptoms and functioning were measured using the SANS, SAPS, BPRS, and GSF/GRF. SZ demonstrated significantly elevated FW in whole-brain gray (p = .001) but not white matter (p = .060). There was no significant difference between groups in GSH in either voxel. However, there was a significant negative correlation between DLPFC GSH and both whole-brain and DLPFC-specific gray matter FW in SZ (r = -.48 and -.47, respectively; both p < .05), while this relationship was nonsignificant in HC and in both groups in the visual cortex. These data illustrate an important relationship between a metabolite known to be important for immune function-GSH-and the diffusion extracellular FW measure, which provides additional support for these measures as neuroinflammatory biomarkers that could potentially provide tractable treatment targets to guide pharmacological intervention

Proactive and reactive cognitive control and dorsolateral prefrontal cortex dysfunction in first episode schizophrenia.

Cognitive control deficits have been consistently documented in patients with schizophrenia. Recent work in cognitive neuroscience has hypothesized a distinction between two theoretically separable modes of cognitive control-reactive and proactive. However, it remains unclear the extent to which these processes are uniquely associated with dysfunctional neural recruitment in individuals with schizophrenia. This functional magnetic resonance imaging (fMRI) study utilized the color word Stroop task and AX Continuous Performance Task (AX-CPT) to tap reactive and proactive control processes, respectively, in a sample of 54 healthy controls and 43 patients with first episode schizophrenia. Healthy controls demonstrated robust dorsolateral prefrontal, anterior cingulate, and parietal cortex activity on both tasks. In contrast, patients with schizophrenia did not show any significant activation during proactive control, while showing activation similar to control subjects during reactive control. Critically, an interaction analysis showed that the degree to which prefrontal activity was reduced in patients versus controls depended on the type of control process engaged. Controls showed increased dorsolateral prefrontal cortex (DLPFC) and parietal activity in the proactive compared to the reactive control task, whereas patients with schizophrenia did not demonstrate this increase. Additionally, patients' DLPFC activity and performance during proactive control was associated with disorganization symptoms, while no reactive control measures showed this association. Proactive control processes and concomitant dysfunctional recruitment of DLPFC represent robust features of schizophrenia that are also directly associated with symptoms of disorganization

Can obsessions drive you mad? Longitudinal evidence that obsessive-compulsive symptoms worsen the outcome of early psychotic experiences

Although there is substantial comorbidity between psychotic disorder and obsessive-compulsive disorder (OCD), little is known about how these clinical phenotypes, and their subclinical extended phenotypes, covary and impact on each other over time. This study examined cross-sectional and longitudinal associations between both (extended) phenotypes in the general population.status: publishe

Connectivity-based parcellation of the thalamus explains specific cognitive and behavioural symptoms in patients with bilateral thalamic infarct

A novel approach based on diffusion tractography was used here to characterise the cortico-thalamic connectivity in two patients, both presenting with an isolated bilateral infarct in the thalamus, but exhibiting partially different cognitive and behavioural profiles. Both patients (G.P. and R.F.) had a pervasive deficit in episodic memory, but only one of them (R.F.) suffered also from a dysexecutive syndrome. Both patients had an MRI scan at 3T, including a T1-weighted volume. Their lesions were manually segmented. T1-volumes were normalised to standard space, and the same transformations were applied to the lesion masks. Nineteen healthy controls underwent a diffusion-tensor imaging (DTI) scan. Their DTI data were normalised to standard space and averaged. An atlas of Brodmann areas was used to parcellate the prefrontal cortex. Probabilistic tractography was used to assess the probability of connection between each voxel of the thalamus and a set of prefrontal areas. The resulting map of corticothalamic connections was superimposed onto the patients' lesion masks, to assess whether the location of the thalamic lesions in R.F. (but not in G. P.) implied connections with prefrontal areas involved in dysexecutive syndromes. In G.P., the lesion fell within areas of the thalamus poorly connected with prefrontal areas, showing only a modest probability of connection with the anterior cingulate cortex (ACC). Conversely, R.F.'s lesion fell within thalamic areas extensively connected with the ACC bilaterally, with the right dorsolateral prefrontal cortex, and with the left supplementary motor area. Despite a similar, bilateral involvement of the thalamus, the use of connectivity-based segmentation clarified that R.F.'s lesions only were located within nuclei highly connected with the prefrontal cortical areas, thus explaining the patient's frontal syndrome. This study confirms that DTI tractography is a useful tool to examine in vivo the effect of focal lesions on interconnectivity brain patterns