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Background Altered cerebral blood flow (CBF) has been found in people at risk for psychosis, with first-episode psychosis (FEP) and with chronic schizophrenia (SCZ). Studies using arterial spin labelling (ASL) have shown reduction of cortical CBF and increased subcortical CBF in SCZ. Previous studies have investigated CBF using ASL in FEP, reporting increased CBF in striatum and reduced CBF in frontal cortex. However, as these people were taking antipsychotics, it is unclear whether these changes are related to the disorder or antipsychotic treatment and how they relate to treatment response. Methods We examined CBF in FEP free from antipsychotic medication (N = 21), compared to healthy controls (N = 22). Both absolute and relative-to-global CBF were assessed. We also investigated the association between baseline CBF and treatment response in a partially nested follow-up study (N = 14). Results There was significantly lower absolute CBF in frontal cortex (Cohen's d = 0.84, p = 0.009) and no differences in striatum or hippocampus. Whole brain voxel-wise analysis revealed widespread cortical reductions in absolute CBF in large cortical clusters that encompassed occipital, parietal and frontal cortices (Threshold-Free Cluster Enhancement (TFCE)-corrected r = 0.67, p = 0.008). Conclusions These results show lower cortical absolute perfusion in FEP prior to starting antipsychotic treatment and suggest relative-to-global frontal CBF as assessed with magnetic resonance imaging could potentially serve as a biomarker for antipsychotic response.

According to influential theories about mood, exposure to environments characterized by specific patterns of punishments and rewards could shape mood response to future stimuli. This raises the intriguing possibility that mood could be trained by exposure to controlled environments. The aim of the present study is to investigate experimental settings that increase resilience of mood to negative stimuli. We developed a new task where participants register their mood when rewards are added or subtracted from their score. We examined sixteen experimental environments with different mood-reward relationships. In an exploratory experiment, we identified environments that produce the greatest improvements in mood resilience, as measured by decreased sensitivity to loss. In a next step, we replicated our results around mood training and tested mood’s resilience over time in a novel sample. We found that training effects are detectable and remain significant after multiple task rounds (approximately two minutes). These findings are a first step in our effort to better understand the mechanisms behind mood training and its potential clinical utility.

Background Ketamine as an antidepressant improves anhedonia as early as 2 hours after infusion. These drug effects are thought to be exerted via actions on reward-related brain areas—yet these actions remain largely unknown. Our study investigates ketamine’s effects during the anticipation and receipt of an expected reward, after the psychotomimetic effects of ketamine have passed, when early antidepressant effects are reported. Methods We examined ketamine’s effects during the anticipation and receipt of expected rewards on predefined brain areas, namely, the dorsal and ventral striatum, ventral tegmental area, amygdala, and insula. We recruited 37 male and female participants with remitted depression who were free from symptoms and antidepressant treatments at the time of the scan. Participants were scanned 2 hours after drug administration in a double-blind crossover design (ketamine: 0.5 mg/kg and placebo) while performing a monetary reward task. Results A significant main effect of ketamine was observed across all regions of interest during the anticipation and feedback phases of win and no-win trials. The drug effects were particularly prominent in the nucleus accumbens and putamen, which showed increased activation on the receipt of smaller rewards compared with neutral. The levels of (2R,6R)-hydroxynorketamine 2 hours after infusion significantly correlated with the activation observed in the ventral tegmental area for that contrast. Conclusions These findings demonstrate that ketamine can produce detectable changes in reward-related brain areas 2 hours after infusion, which occur without symptom changes and support the idea that ketamine might improve reward-related symptoms via modulation of response to feedback.

Introduction: The fast, intuitive and autonomous system 1 along with the slow, analytical and more logical system 2 constitute the dual system processing model of decision making. Whether acting independently or influencing each other both systems would, to an extent, rely on randomness in order to reach a decision. The role of randomness however, would be more pronounced when arbitrary choices need to be made, typically engaging system 1. The present exploratory study aims to capture the expression of a possible innate randomness mechanism by trying to isolate system 1 and examine arbitrary decision making in high functioning ASD individuals. Methods: High functioning ASD participants and age and gender matched neurotypicals performed the random number generation task. The task was modified to limit the contribution of working memory and allow any innate randomness mechanisms expressed through system 1, to emerge.Results: Utilizing a standard analyses approach, the random number sequences produced by ASD individuals and neurotypicals did not differ in their randomness characteristics. No significant differences were identified when the sequences were examined using a moving window approach. When machine learning was used, random sequences’ features could discriminate the groups with relatively high accuracy.Conclusions: Our findings indicate the possibility that individual patterns during random sequence production could be consistent enough between groups to allow for an accurate discrimination between the ASD group and neurotypicals. In order however, to draw firm conclusions around innate randomness and further validate our experiment, our findings need to be replicated in a bigger sample.

A leading hypothesis for schizophrenia and related psychotic disorders proposes that cortical brain disruption leads to subcortical dopaminergic dysfunction, which underlies psychosis in the majority of patients who respond to treatment. Although supported by preclinical findings that prefrontal cortical lesions lead to striatal dopamine dysregulation, the relationship between prefrontal structural volume and striatal dopamine function has not been tested in people with psychosis. We therefore investigated the in vivo relationship between striatal dopamine synthesis capacity and prefrontal grey matter volume in treatment-responsive patients with psychosis, and compared them to treatment non-responsive patients, where dopaminergic mechanisms are not thought to be central. Forty patients with psychosis across two independent cohorts underwent 18F-DOPA PET scans to measure dopamine synthesis capacity (indexed as the influx rate constant Kicer) and structural 3T MRI. The PET, but not MR, data have been reported previously. Structural images were processed using DARTEL-VBM. GLM analyses were performed in SPM12 to test the relationship between prefrontal grey matter volume and striatal Kicer. Treatment responders showed a negative correlation between prefrontal grey matter and striatal dopamine synthesis capacity, but this was not evident in treatment non-responders. Specifically, we found an interaction between treatment response, whole striatal dopamine synthesis capacity and grey matter volume in left (pFWE corr. = 0.017) and right (pFWE corr. = 0.042) prefrontal cortex. We replicated the finding in right prefrontal cortex in the independent sample (pFWE corr. = 0.031). The summary effect size was 0.82. Our findings are consistent with the long-standing hypothesis of dysregulation of the striatal dopaminergic system being related to prefrontal cortex pathology in schizophrenia, but critically also extend the hypothesis to indicate it can be applied to treatment-responsive schizophrenia only. This suggests that different mechanisms underlie the pathophysiology of treatment-responsive and treatment-resistant schizophrenia.

Anesthesia-resistant memory (ARM) was described decades ago, but the mechanisms that underlie this protein synthesis-independent form of consolidated memory in Drosophila remain poorly understood. Whether the several signaling molecules, receptors, and synaptic proteins currently implicated in ARM operate in one or more pathways and how they function in the process remain unclear. We present evidence that Drk, the Drosophila ortholog of the adaptor protein Grb2, is essential for ARM within adult mushroom body neurons. Significantly, Drk signals engage the Rho kinase Drok, implicating dynamic cytoskeletal changes in ARM, and this is supported by reduced F-actin in the mutants and after pharmacological inhibition of Drok. Interestingly, Drk-Drok signaling appears independent of the function of Radish (Rsh), a protein long implicated in ARM, suggesting that the process involves at least two distinct molecular pathways. Based on these results, we propose that signaling pathways involved in structural plasticity likely underlie this form of translation-independent memory.

Background Abnormal Cerebral Blood Flow (CBF) has been found in patients with chronic schizophrenia (SCZ), first-episode psychosis patients (FEP) and individuals at clinical high-risk (CHR). In particular, previous studies using Arterial Spin Labelling (ASL) found that SCZ have a global reduction of CBF in the cortex and increased CBF in the basal ganglia, the hippocampus, and the amygdala as compared with controls. To date, only one study investigated CBF using ASL in a small cohort of medicated FEP reporting increased CBF in the striatum and reduced frontal CBF as compared with controls. However, it is still not clear whether these abnormalities are related to antipsychotic treatment or rather they reflect a disease state independent from medication. Critically, clinical and pre-clinical evidence suggests that antipsychotics increase CBF, especially in the basal ganglia through dopamine D2 receptors blockade. Here, we assessed CBF differences between FEP and controls in a larger cohort of unmedicated or minimally treated patients. In addition, we tested the association between CBF abnormalities and clinical features. Methods 26 FEP (13 medication-free, 9 antipsychotics naïve, 4 minimally treated) and 22 healthy controls (HC) were recruited. FEP and HC were matched for age and gender. Among FEP, 11 had a diagnosis of affective psychosis and 15 of non-affective psychosis. MRI scans were acquired using a GE MR750 3T scanner and a 12-channel head coil. ASL data was acquired using a pseudo-continuous ASL sequence (pCASL). Four control-label pairs were used. Quantification of the CBF data was made using a coil sensitivity map and a proton density image. CBF maps were normalized using non-linear registration and smoothed using a 6 mm full width at half maximum (FWHM) kernel. Grey matter CBF and regional CBF values in each Region of Interest (ROI) were extracted using individual grey matter images and WFU-Pickatlas ROIs with the MarsBar toolbox. Based on previous studies the following ROIs were selected: right and left hippocampus, right and left striatum, right and left frontal cortex. Whole-brain voxel-wise analysis was performed using a non-parametric independent t-test as implemented in FSL randomize (Threshold Free Cluster Enhancement, TFCE, and 5000 permutations). Bonferroni method was used to correct ROI analysis for multiple comparisons (alpha = 0.05, n = 7). Results Significantly reduced CBF was found in FEP as compared with controls in total grey matter CBF (p = 0.004). Whole-brain voxel-wise analysis FEP-HC comparison revealed a widespread cortical reduction in large cortical clusters that encompass the occipital, parietal and frontal cortices (pFWE TFCE corrected < 0.05). ROI analysis revealed a significant reduction in CBF in the right frontal cortex (p = 0.002). A nominal significant reduction was also detected in the left frontal cortex (p = 0.014). No statistically significant differences were found in the other ROI considered (all p > 0.1). Sub-analysis after removing minimally treated patients did not change the results. Both global grey matter CBF and right frontal CBF were reduced in both affective and non-affective psychosis as compared with controls (p < 0.05), whereas no differences were detected between the two clinical groups. Discussion Our results confirm earlier evidence on reduction of cortical perfusion in FEP. However, in contrast with previous studies, we did not detect any difference in striatal perfusion in our cohort of unmedicated/minimally treated patients. Hence, our results support the hypothesis that alteration in striatal perfusion are likely due to medication. Finally, our results suggest that CBF alterations might have a trans-diagnostic role in the pathophysiology of psychosis.

Aberrant glutamate neurotransmission, and in particular dysfunction of the N-methyl-D-aspartate receptor (NMDAR), has been implicated in psychiatric disorders and represents a novel therapeutic target. Low-dose administration of the NMDA antagonist ketamine in healthy volunteers elicits a strong blood oxygenation level dependent (BOLD) imaging signal that can be attenuated by pretreatment with single, therapeutically effective doses of marketed medicines interacting with the glutamate system.To test the attenuation of the ketamine-induced BOLD signal by pretreatment with either a metabotropic glutamate receptor (mGluR) 2/3 or a mGluR2 agonist in healthy volunteers METHODS: We used a ketamine challenge pharmacological magnetic resonance imaging (phMRI) paradigm to assess the modulatory effects of single acute doses of LY2140023 (pomaglumetad methionil), the methionine prodrug of the mGluR2/3 agonist LY404039 (10, 40, and 160 mg; N = 16 subjects) and of LY2979165, and the alanine prodrug of the selective orthosteric mGluR2 agonist 2812223 (20 and 60 mg; N = 16 subjects).A reduction in the ketamine-evoked BOLD phMRI signal relative to placebo was observed at the highest doses tested of both LY2140023 and LY2979165. A relationship was observed between reduction of the BOLD signal and increasing plasma levels of 2812223 in the LY2979165 cohort.These results identify pharmacologically active doses of the group II mGluR agonist prodrugs LY2140023 and LY2979165 in humans. They also extend the classes of compounds that have been experimentally shown to reverse the ketamine-evoked phMRI signal in humans, further supporting the use of this method as a neuroimaging biomarker for assessing functional effects.

Ketamine produces effects in healthy humans that resemble the positive, negative and cognitive symptoms of schizophrenia. We investigated the effect of ketamine administration on brain activity as indexed by blood-oxygen-level-dependent (BOLD) signal change response, and its relationship to ketamine-induced subjective changes, including perceptual distortion. Thirteen healthy participants volunteered for the study. All underwent a 15-min functional MRI acquisition with a ketamine infusion commencing after 5 min (approx 0.26 mg/kg over 20s followed by an infusion of approx. 0.42 mg/kg/h). Following the scan, participants self-rated ketamine-induced effects using the Psychotomimetic States Inventory. Ketamine led to widespread cortical and subcortical increases in BOLD response (FWE-corrected p < 0.01). Self-rated perceptual distortions and delusional thoughts correlated with increased BOLD response in the paracentral lobule (FWE-corrected p < 0.01). The findings suggest that BOLD increases in parietal cortices reflect ketamine effects on circuits that contribute to its capacity to produce perceptual alterations and delusional interpretations.