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Objectives: Several components are known to underlie goal-directed pursuit, including executive, motivational and volitional functions. These were explored in schizophrenia spectrum disorders in order to identify subgroups with distinct profiles. Methods: Multiple executive, motivational and volitional tests were administered to a sample of outpatients with schizophrenia spectrum diagnoses ( n = 59) and controls ( n = 63). Research questions included whether distinct profiles exist and whether some functions are impacted disproportionately. These questions were addressed via cluster analysis and profile analysis, respectively. Results: Some such functions were significantly altered in schizophrenia while others were unaffected. Two distinct profiles emerged, one characterized by energizing deficits, reduced reward sensitivity and few subjective complaints; while another was characterized by markedly increased punishment sensitivity, intact reward sensitivity and substantial subjective reporting of avolitional symptoms and boredom susceptibility. Conclusion: These findings highlight the importance of considering distinct patterns of strengths and deficits in functions governing goal-directed pursuit in schizophrenia that demarcate identifiable subtypes. These distinctions have implications for treatment, assessment and research.

The N400 event-related brain potential (ERP) semantic priming effect is thought to reflect activation by meaningful stimuli of related concepts in semantic memory and has been found to be deficient in schizophrenia. We tested the hypothesis that, among individuals at clinical high risk (CHR) for psychosis, N400 semantic priming deficits predict worse symptomatic and functional outcomes after one year.We measured N400 semantic priming at baseline in CHR patients (n = 47) and healthy control participants (n = 25) who viewed prime words each followed by a related or unrelated target word, at stimulus-onset asynchronies (SOAs) of 300 or 750 ms. We measured patients' psychosis-like symptoms with the Scale of Prodromal Symptoms (SOPS) Positive subscale, and academic/occupational and social functioning with the Global Functioning (GF):Role and Social scales, respectively, at baseline and one-year follow-up (n = 29).CHR patients exhibited less N400 semantic priming than controls across SOAs; planned contrasts indicated this difference was significant at the 750-ms but not the 300-ms SOA. In patients, reduced N400 semantic priming at the 750-ms SOA was associated with lower GF:Social scores at follow-up, and greater GF:Social decrements from baseline to follow-up. Patients' N400 semantic priming was not associated with SOPS Positive or GF:Role scores at follow-up, or change in these from baseline to follow-up.In CHR patients, reduced N400 semantic priming at baseline predicted worse social functioning after one year, and greater decline in social functioning over this period. Thus, the N400 may be a useful prognostic biomarker of real-world functional outcome in CHR patients.

Aim Deficits in synchronous, gamma-frequency neural oscillations may contribute to schizophrenia patients’ real-world functional impairment and can be measured electroencephalographically using the auditory steady-state response (ASSR). Gamma ASSR deficits have been reported in schizophrenia patients and individuals at clinical high risk (CHR) for developing psychosis. We hypothesized that, in CHR patients, gamma ASSR would correlate with real-world functioning, consistent with a role for gamma synchrony deficits in functional impairment. Methods A total of 35 CHR patients rated on Global Functioning: Social and Role scales had EEG recorded while listening to 1-ms, 93-dB clicks presented at 40 Hz in 500-ms trains, in response to which 40-Hz evoked power and intertrial phase-locking factor (PLF) were measured. Results In CHR patients, lower 40-Hz PLF correlated with lower social functioning. Conclusions Gamma synchrony deficits may be a biomarker of real-world impairment at early stages of the schizophrenia disease trajectory.

Neurophysiological measures of cognitive functioning that are abnormal in patients with schizophrenia are promising candidate biomarkers for predicting development of psychosis in individuals at clinical high risk (CHR). We examined the relationships among event-related brain potential (ERP) measures of early sensory, pre-attentional, and attention-dependent cognition, in antipsychotic-naïve help-seeking CHR patients (n = 36) and healthy control participants (n = 22). These measures included the gamma auditory steady-state response (ASSR; early sensory); mismatch negativity (MMN) and P3a (pre-attentional); and N400 semantic priming effects - a measure of using meaningful context to predict related items - over a shorter and a longer time interval (attention-dependent). Compared to controls, CHR patients had significantly smaller P3a amplitudes (d = 0.62, p = 0.03) and N400 priming effects over the long interval (d = 0.64, p = 0.02). In CHR patients, gamma ASSR evoked power and phase-locking factor were correlated (r = 0.41, p = 0.03). Reductions in mismatch negativity (MMN) and P3a amplitudes were also correlated (r = -0.36, p = 0.04). Moreover, lower gamma ASSR evoked power correlated with smaller MMN amplitudes (r = -0.45, p = 0.02). MMN amplitude reduction was also associated with reduced N400 semantic priming over the shorter but not the longer interval (r = 0.52, p 0.002). This pattern of results suggests that, in a subset of CHR patients, impairment in pre-attentional measures of early information processing may contribute to deficits in attention-dependent cognition involving rapid, more automatic processing, but may be independent from pathological processes affecting more controlled or strategic processing. Thus, combining neurophysiological indices of cognitive deficits in different domains offers promise for improving their predictive power as prognostic biomarkers of clinical outcome.

Reductions in the auditory mismatch negativity (MMN) have been well-demonstrated in schizophrenia rendering it a promising biomarker for understanding the emergence of psychosis. According to the predictive coding theory of psychosis, MMN impairments may reflect disturbances in hierarchical information processing driven by maladaptive precision-weighted prediction errors (pwPEs) and enhanced belief updating. We applied a hierarchical Bayesian model of learning to single-trial EEG data from an auditory oddball paradigm in 31 help-seeking antipsychotic-naive high-risk individuals and 23 healthy controls to understand the computational mechanisms underlying the auditory MMN. We found that low-level sensory and high-level volatility pwPE expression correlated with EEG amplitudes, coinciding with the timing of the MMN. Furthermore, we found that prodromal positive symptom severity was associated with increased expression of sensory pwPEs and higher-level belief uncertainty. Our findings provide support for the role of pwPEs in auditory MMN generation, and suggest that increased sensory pwPEs driven by changes in belief uncertainty may render the environment seemingly unpredictable. This may predispose high-risk individuals to delusion-like ideation to explain this experience. These results highlight the value of computational models for understanding the pathophysiological mechanisms of psychosis.

Aim The N400 event-related potential is a neurophysiological index of cognitive processing of real-world knowledge. In healthy populations, N400 amplitude is smaller in response to stimuli that are more related to preceding context. This 'N400 semantic priming effect' is thought to reflect activation of contextually related information in semantic memory (SM). N400 semantic priming deficits have been found in schizophrenia, and in patients at clinical high risk (CHR) for this disorder. Because this abnormality in processing relationships between meaningful stimuli could affect ability to navigate everyday situations, we hypothesized it would be associated with real-world functional impairment in CHR patients. Second, we hypothesized it would correlate with global neurocognitive impairment in this group. Methods We measured N400 semantic priming in 35 CHR patients who viewed prime words each followed by a related or unrelated target word, at stimulus-onset asynchrony (SOA) of 300 or 750 ms. We measured academic/occupational and social function with the global function (GF): Role and Social scales, and cognitive function with the MATRICS Consensus Cognitive Battery (MCCB). Results Decreased N400 semantic priming at the 300-ms SOA correlated with lower GF:Role scores. Decreased N400 semantic priming at the 750-ms SOA correlated with lower MCCB composite scores. Conclusions Deficits in activating contextually related concepts in SM over short time intervals may contribute to functional impairment in CHR patients. Furthermore, N400 priming deficits over longer intervals may be a biomarker of global cognitive dysfunction in this population. Longitudinal studies are needed to determine whether these deficits are associated with schizophrenia risk within this population.

Cannabis use disorder (CUD) occurs at high rates in schizophrenia, which negatively impacts its clinical prognosis. These patients have greater difficulty quitting cannabis which may reflect putative deficits in the dorsolateral prefrontal cortex (DLPFC), a potential target for treatment development. We examined the effects of active versus sham high-frequency (20-Hz) repetitive transcranial magnetic stimulation (rTMS) on cannabis use in outpatients with schizophrenia and CUD. Secondary outcomes included cannabis craving/withdrawal, psychiatric symptoms, cognition and tobacco use. Twenty-four outpatients with schizophrenia and CUD were enrolled in a preliminary double-blind, sham-controlled randomized trial. Nineteen participants were randomized to receive active (n = 9) or sham (n = 10) rTMS (20-Hz) applied bilaterally to the DLPFC 5x/week for 4 weeks. Cannabis use was monitored twice weekly. A cognitive battery was administered pre- and post-treatment. rTMS was safe and well-tolerated with high treatment retention (~90%). Contrast estimates suggested greater reduction in self-reported cannabis use (measured in grams/day) in the active versus sham group (Estimate = 0.33, p = 0.21; Cohen’s d = 0.72), suggesting a clinically relevant effect of rTMS. A trend toward greater reduction in craving (Estimate = 3.92, p = 0.06), and significant reductions in PANSS positive (Estimate = 2.42, p = 0.02) and total (Estimate = 5.03, p = 0.02) symptom scores were found in the active versus sham group. Active rTMS also improved attention (Estimate = 6.58, p p = 0.01). Our preliminary findings suggest that rTMS to the DLPFC is safe and potentially efficacious for treating CUD in schizophrenia.

Introduction: The global COVID-19 pandemic has affected the economy, daily life, and mental/physical health. The latter includes the use of electroencephalography (EEG) in clinical practice and research. We report a survey of the impact of COVID-19 on the use of clinical EEG in practice and research in several countries, and the recommendations of an international panel of experts for the safe application of EEG during and after this pandemic. Methods: Fifteen clinicians from 8 different countries and 25 researchers from 13 different countries reported the impact of COVID-19 on their EEG activities, the procedures implemented in response to the COVID-19 pandemic, and precautions planned or already implemented during the reopening of EEG activities. Results: Of the 15 clinical centers responding, 11 reported a total stoppage of all EEG activities, while 4 reduced the number of tests per day. In research settings, all 25 laboratories reported a complete stoppage of activity, with 7 laboratories reopening to some extent since initial closure. In both settings, recommended precautions for restarting or continuing EEG recording included strict hygienic rules, social distance, and assessment for infection symptoms among staff and patients/participants. Conclusions: The COVID-19 pandemic interfered with the use of EEG recordings in clinical practice and even more in clinical research. We suggest updated best practices to allow safe EEG recordings in both research and clinical settings. The continued use of EEG is important in those with psychiatric diseases, particularly in times of social alarm such as the COVID-19 pandemic., SCOPUS: ed.j, info:eu-repo/semantics/published

Psychosis is associated with abnormal structural changes in the brain including decreased regional brain volumes and abnormal brain morphology. However, the underlying causes of these structural abnormalities are less understood. The immune system, including microglial activation, has been implicated in the pathophysiology of psychosis. Although previous studies have suggested a connection between peripheral proinflammatory cytokines and structural brain abnormalities in schizophrenia, no in-vivo studies have investigated whether microglial activation is also linked to brain structure alterations previously observed in schizophrenia and its putative prodrome. In this study, we investigated the link between mitochondrial 18kDa translocator protein (TSPO) and structural brain characteristics (i.e. regional brain volume, cortical thickness, and hippocampal shape) in key brain regions such as dorsolateral prefrontal cortex and hippocampus of a large group of participants (N = 90) including individuals at clinical high risk (CHR) for psychosis, first-episode psychosis (mostly antipsychotic naïve) patients, and healthy volunteers. The participants underwent structural brain MRI scan and [(18)F]FEPPA positron emission tomography (PET) targeting TSPO. A significant [(18)F]FEPPA binding-by-group interaction was observed in morphological measures across the left hippocampus. In first-episode psychosis, we observed associations between [(18)F]FEPPA V(T) (total volume of distribution) and outward and inward morphological alterations, respectively, in the dorsal and ventro-medial portions of the left hippocampus. These associations were not significant in CHR or healthy volunteers. There was no association between [(18)F]FEPPA V(T) and other structural brain characteristics. Our findings suggest a link between TSPO expression and alterations in hippocampal morphology in first-episode psychosis.

The ‘at-risk’ state for psychosis is a high-risk paradigm that examines factors that contribute to conversion to a first episode of psychosis. Although a multitude of contributing factors have been identified in one's susceptibility to conversion to psychosis, dimensional pathological personality traits have not been examined in ‘at-risk’ populations. In this study we examine lower- versus higher-risk for psychosis using traits from the DSM-5 Alternative Dimensional Model of Personality Disorders (AMPD) to investigate which AMPD personality traits distinguish those ‘at-risk’ patients at relatively lower-risk for conversion to psychosis versus those at higher-risk. Remitted schizophrenic patients served as the comparison group. MANOVA analyses revealed significant group differences on the PID-5, with the higher-risk patients scoring higher on two of the five AMPD trait domains – Negative Affectivity and Detachment – compared to lower-risk patients. Maladaptive personality traits from the AMPD may serve as potential risk factor for conversion to psychosis.

While alterations in striatal dopamine in psychosis and stress have been well studied, the role of dopamine in prefrontal cortex is poorly understood. To date, no study has investigated the prefrontocortical dopamine response to stress in the psychosis spectrum, even though the dorsolateral and medial prefrontal cortices are key regions in cognitive and emotional regulation, respectively. The present study uses the high-affinity dopamine D(2/3) receptor radiotracer (11)C-FLB457 and PET together with a validated psychosocial stress challenge to investigate the dorsolateral and medial prefrontocortical dopamine response to stress in schizophrenia and clinical high risk for psychosis. Forty participants completed two (11)C-FLB457 PET scans (14 antipsychotic-free schizophrenia, 14 clinical high risk for psychosis and 12 matched healthy volunteers), one while performing a Sensory Motor Control Task (control) and another while performing the Montreal Imaging Stress Task (stress). Binding potential (BP(ND)) was estimated using Simplified Reference Tissue Model with cerebellar cortex as reference region. Dopamine release was defined as per cent change in BP(ND) between control and stress scans (ΔBP(ND)) using a novel correction for injected mass. Salivary cortisol response (ΔAUC(I)) was assessed throughout the tasks and its relationship with dopamine release examined. (11)C-FLB457 binding at control conditions was significantly different between groups in medial [F(2,37) = 7.98, P = 0.0013] and dorsolateral [F(2,37) = 6.97, P = 0.0027] prefrontal cortex with schizophrenia patients having lower BP(ND) than participants at clinical high risk for psychosis and healthy volunteers, but there was no difference in ΔBP(ND) among groups [dorsolateral prefrontal cortex: F(2,37) = 1.07, P = 0.35; medial prefrontal cortex: F(2,37) = 0.54, P = 0.59]. We report a positive relationship between ΔAUC(I) and (11)C-FLB457 ΔBP(ND) in dorsolateral and medial prefrontal cortex in healthy volunteers (r = 0.72, P = 0.026; r = 0.76, P = 0.014, respectively) and in participants at clinical high risk for psychosis (r = 0.76, P = 0.0075; r = 0.72, P = 0.018, respectively), which was absent in schizophrenia (r = 0.46, P = 1.00; r = 0.19, P = 1.00, respectively). Furthermore, exploratory associations between ΔBP(ND) or ΔAUC(I) and stress or anxiety measures observed in clinical high risk for psychosis were absent in schizophrenia. These findings provide first direct evidence of a disrupted prefrontocortical dopamine-stress regulation in schizophrenia.

Altered neuroimmune response and oxidative stress have both been implicated in the pathophysiology of schizophrenia. While preclinical studies have proposed several pathways regarding potential interactions between oxidative stress and neuroimmune imbalance in the development of psychosis, the molecular mechanisms underlying this interaction are not yet understood. To date, no study has investigated this link in vivo in the human brain. We conducted the first in vivo study linking translocator protein 18 kDa (TSPO) expression and glutathione (a major brain antioxidant and a marker for redox status) in the medial prefrontal cortex (mPFC) of a relatively large sample of participants (N = 48) including 27 antipsychotic-naïve individuals at clinical high risk for psychosis and 21 matched healthy volunteers using high-resolution PET with TSPO radioligand, [(18)F]FEPPA, and 3T proton magnetic resonance spectroscopy ((1)H MRS). The omnibus model (including TSPO genotype as covariate) was significant (F((4, 43)) = 10.01, p

Substance use disorders (SUDs) have a devastating impact on society and place a heavy burden on health care systems. Given that alcohol, tobacco, and cannabis use have the highest prevalence, further understanding of the underlying pathophysiology of these SUDs is crucial. Electroencephalography is an inexpensive, temporally superior, and translatable technique which enables investigation of the pathobiology of SUDs through the evaluation of various event-related potential components, including mismatch negativity (MMN). The goals of this review were to investigate the effects of acute and chronic alcohol, tobacco, and cannabis use on MMN among nonpsychiatric populations and patients with comorbid psychosis. A literature search was performed using the database PubMed, and 36 articles met our inclusion and exclusion criteria. We found a pattern of attenuation of MMN amplitude among patients with alcoholism across acute and chronic alcohol use, and this dysregulation was not heritable. Reports were limited, and results were mixed on the effects of acute and chronic tobacco and cannabis use on MMN. Reports on comorbid SUDs and psychosis were even fewer, and also presented mixed findings. These preliminary results suggest that MMN deficits may be associated with SUDs, specifically alcohol use disorder, and serve as a possible biomarker for treating these common disorders.

There is emerging evidence that identification and treatment of individuals in the prodromal or clinical high-risk (CHR) state for psychosis can reduce the probability that they will develop a psychotic disorder. Event-related brain potentials (ERPs) are a noninvasive neurophysiological technique that holds promise for improving our understanding of neurocognitive processes underlying the CHR state. We aimed to systematically review the current literature on cognitive ERP studies of the CHR population, in order to summarize and synthesize the results, and their implications for our understanding of the CHR state. Across studies, amplitudes of the auditory P300 and duration mismatch negativity (MMN) ERPs appear reliably reduced in CHR individuals, suggesting that underlying impairments in detecting changes in auditory stimuli are a sensitive early marker of the psychotic disease process. There are more limited data indicating that an earlier-latency auditory ERP response, the N100, is also reduced in amplitude, and in the degree to which it is modulated by stimulus characteristics, in the CHR population. There is also evidence that a number of auditory ERP measures (including P300, MMN and N100 amplitudes, and N100 gating in response to repeated stimuli) can further refine our ability to detect which CHR individuals are most at risk for developing psychosis. Thus, further research is warranted to optimize the predictive power of algorithms incorporating these measures, which could help efforts to target psychosis prevention interventions toward those most in need.

Introduction Oxidative stress and glutathione dysregulation have been implicated in the etiology of schizophrenia. To date, most in vivo studies have investigated alterations in cerebral glutathione levels in patients in which the disorder is already established; however, whether oxidative stress actually predates the onset of psychosis remains unknown. In the current study, we investigated cerebral glutathione levels of antipsychotic-naïve individuals at clinical high risk for psychosis. As exploratory analyses, we also investigated the associations between cerebral glutathione levels and peripheral glutathione peroxidase activity and clinical and neuropsychological measures. Methods Glutathione levels were measured in the medial prefrontal cortex of 30 clinical high risk (n=26 antipsychotic naïve) and 26 healthy volunteers using 3T proton magnetic resonance spectroscopy. Each participant was assessed for glutathione peroxidase activity in plasma and genotyped for the glutamate cysteine ligase catalytic subunit polymorphism. Results No significant differences were observed in glutathione levels between clinical high risk and healthy volunteers in the medial prefrontal cortex (F(1,54)=0.001, P =0.98). There were no significant correlations between cerebral glutathione levels and clinical and neuropsychological measures. Similarly, no significant differences were found in peripheral glutathione peroxidase activity between clinical high risk and healthy volunteers (F(1,37)=0.15, P =0.70). However, in clinical high risk, we observed a significant effect of lifetime history of cannabis use on glutathione peroxidase activity (F(1,23)=7.41, P =0.01). Discussion The lack of significant differences between antipsychotic naïve clinical high risk and healthy volunteers suggests that alterations in glutathione levels in medial prefrontal cortex are not present in the clinical high risk state.

Different strategies may be spontaneously adopted to solve most navigation tasks. These strategies are associated with dissociable brain systems. Here, we use brain-imaging and cognitive tasks to test the hypothesis that individuals living with Schizophrenia Spectrum Disorders (SSD) have selective impairment using a hippocampal-dependent spatial navigation strategy. Brain activation and memory performance were examined using functional magnetic resonance imaging (fMRI) during the 4-on-8 virtual maze (4/8VM) task, a human analog of the rodent radial-arm maze that is amenable to both response-based (egocentric or landmark-based) and spatial (allocentric, cognitive mapping) strategies to remember and navigate to target objects. SSD (schizophrenia and schizoaffective disorder) participants who adopted a spatial strategy performed more poorly on the 4/8VM task and had less hippocampal activation than healthy comparison participants using either strategy as well as SSD participants using a response strategy. This study highlights the importance of strategy use in relation to spatial cognitive functioning in SSD. Consistent with a selective-hippocampal dependent deficit in SSD, these results support the further development of protocols to train impaired hippocampal-dependent abilities or harness non-hippocampal dependent intact abilities.

Several lines of evidence implicate microglial activation and abnormal immune response in the etiology of psychosis. Previous positron emission tomography (PET) neuroimaging studies of the translocator protein 18 kDa, TSPO, were limited by low affinity of the first-generation radioligand, low-resolution scanners, and small sample sizes. Moreover, there is a dearth of literature on microglial activation in individuals at clinical high risk (CHR) for psychosis. We used a novel second-generation TSPO radioligand, [18F]FEPPA, to examine whether microglial activation is elevated in the dorsolateral prefrontal cortex (DLPFC) and hippocampus of antipsychotic-naive CHR. Twenty-four CHR (antipsychotic-naive n=22) and 23 healthy volunteers (HV) completed a high resolution [18F]FEPPA PET scan and MRI. The PET data were analyzed using the validated two-tissue compartment model with arterial plasma input function with total volume of distribution (VT) as outcome measure. All analyses were controlled for the TSPO rs6971 polymorphism. We did not observe any significant differences in microglial activation, as indexed by [18F]FEPPA VT, between CHR and HV in either the DLPFC (F(1, 44)=0.41, p=0.52) or the hippocampus (F(1, 44)=2.78, p=0.10). Exploratory associations show that in CHR, [18F]FEPPA VT was positively correlated with apathy (DLPFC: r=0.55, p=0.008; hippocampus: r=0.52, p=0.013) and state anxiety (DLPFC: r=0.60, p=0.003; hippocampus: r=0.48, p=0.024). The lack of significant group differences in [18F]FEPPA VT suggests that microglial activation is not significantly elevated in the clinical high risk state that precedes psychosis.

Why are some people more religious than others? According to one hypothesis, people who strongly seek definitive explanations for situations with incomplete information are more likely to be religious. According to a different hypothesis, individuals with smaller "prediction error" responses to unexpected stimuli are more likely to discount evidence contradicting religious beliefs, predisposing them to maintain such beliefs. We sought neurophysiological evidence for these hypotheses using the N400 event-related potential (ERP), which is smaller to more contextually expected stimuli, reflecting prediction of probable completions for meaningful situations. We recorded ERPs from participants viewing category definitions followed by high-typicality category exemplar (HTE), low-typicality exemplar (LTE), or non-exemplar (NE) words. As expected, N400s were largest for NEs, intermediate for LTEs, and smallest for HTEs. Religiosity correlated with smaller N400 amplitude differences between HTEs and both LTEs and NEs. Less strong prediction of probable stimuli based on prior information may predispose to religiosity.

Background The brain’s endocannabinoid system, the primary target of cannabis, has been implicated in psychosis. The endocannabinoid anandamide is elevated in cerebrospinal fluid of patients with schizophrenia. Fatty acid amide hydrolase (FAAH) controls brain anandamide levels; however, it is unknown if FAAH is altered in vivo in psychosis or related to positive psychotic symptoms. Methods Twenty-seven patients with schizophrenia spectrum disorders and 36 healthy control subjects completed high-resolution positron emission tomography scans with the novel FAAH radioligand [11C]CURB and structural magnetic resonance imaging. Data were analyzed using the validated irreversible 2-tissue compartment model with a metabolite-corrected arterial input function. Results FAAH did not differ significantly between patients with psychotic disorders and healthy control subjects (F1,62.85 = 0.48, p = .49). In contrast, lower FAAH predicted greater positive psychotic symptom severity, with the strongest effect observed for the positive symptom dimension, which includes suspiciousness, delusions, unusual thought content, and hallucinations (F1,26.69 = 12.42, p = .002; Cohen’s f = 0.42, large effect). Shorter duration of illness (F1,26.95 = 13.78, p = .001; Cohen’s f = 0.39, medium to large effect) and duration of untreated psychosis predicted lower FAAH (F1,26.95 = 6.03, p = .021, Cohen’s f = 0.27, medium effect). These results were not explained by past cannabis exposure or current intake of antipsychotic medications. FAAH exhibited marked differences across brain regions (F7,112.62 = 175.85, p 1). Overall, FAAH was higher in female subjects than in male subjects (F1,62.84 = 10.05, p = .002; Cohen’s f = 0.37). Conclusions This first study of brain FAAH in psychosis indicates that FAAH may represent a biomarker of disease state of potential utility for clinical studies targeting psychotic symptoms or as a novel target for interventions to treat psychotic symptoms.

Altered mitochondrial electron transport chain function has been implicated in the pathophysiology and etiology of schizophrenia. To date, our previously published study (i.e. first cohort) is still the only study to demonstrate that mitochondrial electron transport chain is not altered in white blood cells from individuals at clinical high risk for psychosis. Here, we aimed to replicate our previous findings with an independent set of samples and validate the levels of mitochondrial complex I-V content in individuals at clinical high risk for psychosis. We demonstrated that the second cohort (i.e. validation cohort) expressed similar results as the first cohort. We combined the first cohort study with the second cohort and once more validated a lack of differential levels in mitochondrial complex I-V content between the two groups. In addition, we were able to validate a correlation between complex III content and prodromal negative symptom severity when the two cohorts studies were combined. Additionally, a correlation between complex V content and prodromal disorganization symptom severity was found when the two cohorts were combined. In conclusion, our results showed that dysfunction of the mitochondrial electron transport chain is not detected in peripheral blood mononuclear cells of individuals in the putative prodromal stage of schizophrenia.

BACKGROUND: Individuals at clinical high-risk (CHR) for schizophrenia experience subthreshold symptoms of this disorder and are at elevated risk for developing it. Among CHR patients as well as the general population, cannabis use has been associated with increased risk of developing psychosis. Psychosis and psychosis-like symptoms in schizophrenia patients, healthy individuals and regular cannabis users have been linked to deficits in processing relationships between meaningful (semantic) stimuli. To seek neurophysiological evidence that semantic processing deficits mediate the relationship between cannabis use and psychosis-like symptoms in the CHR state, we used the electroencephalographic N400 event-related potential (ERP) as a measure of semantic processing. The N400 is seen in response to meaningful stimuli and is smaller when the target stimulus is more related to a preceding prime. We hypothesized that there would be a smaller N400 amplitude difference between target stimuli that are related versus unrelated to a preceding prime stimulus (i.e., smaller semantic priming effects) in cannabis-using compared to non-cannabis-using CHR patients. METHODS: We recorded ERPs in 12 antipsychotic-naïve CHR patients with history of present or past cannabis dependence disorder, 11 CHR patients with no history of cannabis use and 13 healthy control participants (HCPs). Participants viewed prime words each followed by a target which was either a related or unrelated word, or a nonword, in a lexical-decision task. Equal numbers of each target type were presented at prime-target stimulus-onset asynchronies (SOAs) of 300 and 750 ms. RESULTS: Across SOAs, we saw a trend toward N400 semantic priming effects being smaller for both CHR/C+ and CHR/C- compared to controls (p = 0.078). DISCUSSION: The results suggest that cannabis use does not modulate semantic priming deficits in CHR patients. A limitation of the study was that some of the cannabis-dependent CHR group were in remission. Future studies of CHR patients comparing those who have current cannabis dependence with non-users might detect differences between these groups.

Spatial memory is core to wayfinding and everyday memory. Interestingly, individuals with schizophrenia using spatial navigation strategies (cognitive mapping) are impaired, whereas those using response-based (e.g., single-landmark) strategies show relatively intact memory performance. We observed abnormal brain communication in schizophrenia participants who used a spatial strategy during a virtual-reality navigation task, particularly between temporal and frontal brain regions. In contrast, schizophrenia participants using a response strategy recruited similar brain systems to healthy participants, but to a greater extent to support memory performance. These findings highlight that strategy use is an important consideration for understanding memory systems and navigation in schizophrenia.

Objective Schizophrenia is associated with poor spatial attention. However, although this deficit undermines the perception of target information, it may be helpful for ignoring irrelevant inputs. The present study examined whether event-related brain potential (ERP) indices of visual spatial attention predicted the magnitude of the brain response to interference in schizophrenia. Method ERPs were recorded in 16 schizophrenia patients and 20 healthy control participants who had to indicate whether the target E was global or local in compound letter stimuli. The nontarget could be either highly similar to the target (i.e., a global E composed of local Ss and vice versa) and thus produce more interference, or it could be dissimilar (i.e., a global E composed of local Hs and vice versa) and generate less interference. Results Both groups' responses were slowed by interference. Voltage amplitudes of the P1, and of ERP interference effects from 300-500 ms after stimulus onset, were significantly smaller in schizophrenia patients than in healthy participants when the target was global. In patients, larger P1 amplitudes were correlated with larger interference effects and with more severe symptoms of attentional deficits and conceptual disorganization. Schizophrenia participants thus exhibited abnormal ERPs to interference despite normal behavioral performance. Conclusions Schizophrenia patients likely pay less attention to stimuli in general; however, the impact of this impairment on target detection is compensated by relatively greater inattention to irrelevant components of the stimuli, and this explains why they are not more influenced by interference than healthy participants at the behavioral level. (PsycINFO Database Record

info:eu-repo/semantics/published, SCOPUS: ed.j, Introduction: The global COVID-19 pandemic has affected the economy, daily life, and mental/physical health. The latter includes the use of electroencephalography (EEG) in clinical practice and research. We report a survey of the impact of COVID-19 on the use of clinical EEG in practice and research in several countries, and the recommendations of an international panel of experts for the safe application of EEG during and after this pandemic. Methods: Fifteen clinicians from 8 different countries and 25 researchers from 13 different countries reported the impact of COVID-19 on their EEG activities, the procedures implemented in response to the COVID-19 pandemic, and precautions planned or already implemented during the reopening of EEG activities. Results: Of the 15 clinical centers responding, 11 reported a total stoppage of all EEG activities, while 4 reduced the number of tests per day. In research settings, all 25 laboratories reported a complete stoppage of activity, with 7 laboratories reopening to some extent since initial closure. In both settings, recommended precautions for restarting or continuing EEG recording included strict hygienic rules, social distance, and assessment for infection symptoms among staff and patients/participants. Conclusions: The COVID-19 pandemic interfered with the use of EEG recordings in clinical practice and even more in clinical research. We suggest updated best practices to allow safe EEG recordings in both research and clinical settings. The continued use of EEG is important in those with psychiatric diseases, particularly in times of social alarm such as the COVID-19 pandemic.

The experience sampling method (ESM) has revealed associations between fluctuations in stress and positive symptoms in psychosis. It is unknown, however, how negative symptoms including anhedonia respond to stress. Stress is divided according to its source: event-related stress stemming from negative events, and activity-related stress stemming from engaging in tasks beyond one's skill or control. Anhedonia is divided into consummatory and anticipatory anhedonia, reflecting a lack of pleasure in current and expected activities. This study uses ESM to determine whether each form of anhedonia increases in response to stress. Antipsychotic-naive individuals with first episode psychosis (n = 39), clinical high-risk states for psychosis (n = 44), and healthy controls (n = 34) responded to daily prompts on a palmtop computer for up to ten days by indicating levels of stress and anhedonia. Time-lagged multilevel modelling was employed to explore increases in anhedonia following increases in stress while controlling for prior levels of anhedonia. Mean levels of anhedonia were also compared across groups. Only activity-related stress produced increases in anhedonia. This effect did not vary between groups. Clinical groups showed greater overall levels of anhedonia than healthy controls, but did not differ from each other. Anhedonia responds only to activity-related stressors, suggesting that this form of stress has a specific causal role in anhedonia. The results also provide further evidence for global increases in anhedonia in antipsychotic-naive psychosis spectrum individuals.

Alterations in glutamate neurotransmission have been implicated in the pathophysiology of schizophrenia, as well as in symptom severity and cognitive deficits. The hippocampus, in particular, is a site of key functional and structural abnormalities in schizophrenia. Yet few studies have investigated hippocampal glutamate in antipsychotic-naïve first episode psychosis patients or in individuals at clinical high risk (CHR) of developing psychosis. Using proton magnetic resonance spectroscopy ((1)H-MRS), we investigated glutamate metabolite levels in the left hippocampus of 25 CHR (19 antipsychotic-naïve), 16 patients with first-episode psychosis (13 antipsychotic-naïve) and 31 healthy volunteers. We also explored associations between hippocampal glutamate metabolites and glial activation, as indexed by [(18)F]FEPPA positron emission tomography (PET); symptom severity; and cognitive function. Groups differed significantly in glutamate plus glutamine (Glx) levels (F((2, 69)) = 6.39, p = 0.003). Post-hoc analysis revealed that CHR had significantly lower Glx levels than both healthy volunteers (p = 0.003) and first-episode psychosis patients (p = 0.050). No associations were found between glutamate metabolites and glial activation. Our findings suggest that glutamate metabolites are altered in CHR.

Alterations in mitochondrial function have been implicated in the etiology of schizophrenia. Most studies have investigated alterations in mitochondrial function in patients in which the disorder is already established; however, whether mitochondrial dysfunction predates the onset of psychosis remains unknown. We measured peripheral mitochondrial complex (I–V) function and lactate/pyruvate levels in 27 antipsychotic-naïve individuals at clinical high risk for psychosis (CHR) and 16 healthy controls. We also explored the association between mitochondrial function and brain microglial activation and glutathione levels using a translocator protein 18 kDa [18F]FEPPA PET scan and 1H-MRS scan, respectively. There were no significant differences in mitochondrial complex function and lactate/pyruvate levels between CHR and healthy controls. In the CHR group, mitochondrial complex III function (r = −0.51, p = 0.008) and lactate levels (r = 0.61, p = 0.004) were associated with prodromal negative symptoms. As previously reported, there were no significant differences in microglial activation and glutathione levels between groups, however, mitochondrial complex IV function was inversely related to microglial activation in the hippocampus in CHR (r = −0.42, p = 0.04), but not in healthy controls. In conclusion, alterations in mitochondrial function are not yet evident in CHR, but may relate to the severity of prodromal symptoms, particularly negative symptoms.

Background Recent research has shown that patients with schizophrenia (SCZ) exhibit reduced directed forgetting (DF) for negative words, suggesting impaired ability to instantiate goal-directed inhibition in order to suppress a competing, emotion-driven responses (i.e., emotional memory enhancement). However, disrupted inhibition is not the only possible mechanism by which patients could manifest reduced emotional DF. Therefore, the primary objective of the current study was to use event-related brain potential (ERP) recordings to investigate alternative hypotheses. Methods ERPs were recorded while patients and controls completed an item-method DF paradigm using negative and neutral words. The N2 indexed goal-directed inhibition of to-be-forgotten items. The late positive potential (LPP) indexed emotional memory enhancement for negative study items. The P300 indexed selective rehearsal of to-be-remembered items. Results The SCZ group exhibited a reduced DF effect overall, but this was not modulated by emotion. N2 amplitude at anterior sites was larger for forget versus remember cues in the control group only, but this effect was not modulated by emotion. LPP amplitude was greater for negative versus neutral words in both groups, independent of region. P300 amplitude at posterior sites was greater for remember versus forget cues in the control group only. Discussion These data suggest that reduced DF in SCZ may be due, in part, to both diminished goal-directed inhibition of to-be-forgotten items and reduced selective rehearsal of to-be-remembered items. However, these data do not support the hypothesis that goal-directed, inhibitory processes are disrupted by competing, emotion-driven processes in SCZ. Patients' ERP data also suggested that they did not exhibit disproportionately heightened encoding of emotional stimuli, nor did they have deficient selective rehearsal of to-be-remembered emotional items.

Background: Dopamine (DA) synthesis capacity and release are elevated in schizophrenia (SCZ) and its putative prodrome, the clinical high risk state (CHR). Striatal DA results from the activity of midbrain DA neurons projecting mainly from the substantia nigra (SN). Elevated stress-induced DA release in SCZ and CHR was observed in the striatum, however whether it is also elevated in the SN is unclear. The current study aims to determine whether nigral DA release in response to a validated stress task is altered in CHR and in antipsychotic-naive SCZ. Further, we explore how DA release in the SN and striatum might be related. Methods: 24 CHR subjects, 9 antipsychotic-naive SCZ and 25 healthy volunteers (HV) underwent two positron emission tomography (PET) scans using the DA D2/3 agonist radiotracer, [11C]-(+)-PHNO, which allows simultaneous investigations of DA in the SN and striatum. Psychosocial stress-induced DA release was estimated as the percentage differences in BPND (%[11C]-(+)-PHNO displacement) between stress and sensory-motor control sessions. Results: We observed a significant group by sessions interaction on [11C]-(+)-PHNO BPND in the SN (F = 6.896, P = .002). The SCZ showed a 25.90% [11C]-(+)-PHNO binding change change in nigral [11C]-(+)-PHNO displacement, while HV showed -10.94% and CHR exhibited an intermediate response [11C]-(+)-PHNO binding change (−1.13%). Only among the CHR subjects, we found a positive trend of association between [11C]-(+)-PHNO binding changes displacement in the SN and the whole striatum (r = .382, P = .072). Conclusion: Our findings suggest a sensitized nigral DA response to stress in antipsychotic-naive SCZ. The unique trend association between nigral and striatal [11C]-(+)-PHNO binding changes, and a differential nigrostriatal DA pathway in CHR, which may suggest a stage specific biomarker warrants further investigation to confirm.

An overly negative self-schema is a proposed cognitive mechanism of major depressive disorder (MDD). Self-schema - one's core conception of self, including how strongly one believes one possesses various characteristics - is part of semantic memory (SM), our knowledge about concepts and their relationships. We used the N400 event-related potential (ERP) - elicited by meaningful stimuli, and reduced by greater association of the stimulus with preceding context - to measure association strength between self-concept and positive, negative, and neutral characteristics in SM. ERPs were recorded from MDD patients (n=16) and controls (n=16) who viewed trials comprising a self-referential phrase followed by a positive, negative, or neutral adjective. Participants' task was to indicate via button-press whether or not they felt each adjective described themselves. Controls endorsed more positive adjectives than did MDD patients, but the opposite was true for negative adjectives. Patients had smaller N400s than controls specifically for negative adjectives, suggesting that MDD is associated with stronger than normal functional neural links between self-concept and negative characteristics in SM.

Background: Dopamine (DA) synthesis capacity and release are elevated in schizophrenia (SCZ) and its putative prodrome, the clinical high risk state (CHR). Striatal DA results from the activity of midbrain DA neurons projecting mainly from the substantia nigra (SN). Elevated stress-induced DA release in SCZ and CHR was observed in the striatum, however whether it is also elevated in the SN is unclear. The current study aims to determine whether nigral DA release in response to a validated stress task is altered in CHR and in antipsychotic-naive SCZ. Further, we explore how DA release in the SN and striatum might be related.

The N400 event-related brain potential (ERP), a negative voltage deflection occurring approximately 400ms after onset of any meaningful stimulus, is reduced in amplitude when the stimulus is preceded by related context. Previous work has found this N400 semantic priming effect to be decreased in schizophrenia, suggesting impairment in using meaningful context to activate related concepts in semantic memory. Thus, N400 amplitude may be a useful biomarker of abnormal semantic processing and its response to treatment in schizophrenia. To help assess the validity of N400 amplitude as a longitudinal measure in schizophrenia, we evaluated its test-retest reliability. ERPs were recorded in sixteen schizophrenia patients who viewed prime words, each followed at 300- or 750-ms stimulus-onset asynchrony (SOA) by a target that was either a related or unrelated word, or nonword. Participants' task was to indicate whether or not the target was a real word. They were retested on the same procedure one week later. Test-retest reliability was assessed by calculating Pearson's r and intraclass correlation coefficients (ICCs) across timepoints for N400 amplitudes for related and unrelated targets, at each SOA. Consistent with previous results, there were no significant differences between patients' N400 amplitudes for related and unrelated targets, at any SOA/timepoint combination. Pearson's r and ICCs for N400 amplitudes at Fz across timepoints were significant for both target types at each SOA (ranges: r 0.52-0.64, ICC 0.52-0.63; all p

Background Abnormal brain structural alterations and microglial activation are implicated in the pathophysiology of psychosis. However, the connection between these two pathologies is not yet well understood. Although previous studies suggested a link between the level of proinflammatory cytokines and abnormalities in brain structure in patients with schizophrenia, there is no in-vivo study investigating whether microglial activation is also linked to morphological brain alterations previously reported in individuals with psychosis and psychosis risk. Methods In order to address the current gap in the literature, we investigated microglial activation and structural brain abnormalities in key brain regions affected in psychosis (i.e. hippocampus and dorsolateral prefrontal cortex) of a large group of participants (N = 90) including 35 individuals at clinical high risk (CHR) for psychosis, 27 first-episode psychosis (mostly antipsychotic naïve) patients, and 28 healthy volunteers. All the participants underwent a [18F]FEPPA positron emission tomography (PET) targeting mitochondrial 18 kDa translocator protein (TSPO) to determine microglial activation and a T1 MRI scan to study structural brain characteristics including brain volume, cortical thickness, and hippocampal shape. Results Using a vertex-wise analysis, we observed a significant microglial activation-by-diagnostic group interaction in morphological measures across the left hippocampus. We observed associations between microglial activation and outward and inward morphological alterations in the dorsal and ventro-medial portions of the left hippocampus, respectively. These associations were only observed in first-episode psychosis group. There was no association between [18F]FEPPA binding and other structural brain characteristics. Discussion Our results, for the first time, suggest a connection between microglial activation and morphological alterations in hippocampus of first-episode psychosis.

Several lines of evidence implicate microglial activation and abnormal immune response in the etiology of psychosis. Previous positron emission tomography (PET) neuroimaging studies of the translocator protein 18 kDa, TSPO, were limited by low affinity of the first-generation radioligand, low-resolution scanners, and small sample sizes. Moreover, there is a dearth of literature on microglial activation in individuals at clinical high risk (CHR) for psychosis. We used a novel second-generation TSPO radioligand, [18F]FEPPA, to examine whether microglial activation is elevated in the dorsolateral prefrontal cortex (DLPFC) and hippocampus of antipsychotic-naive CHR. Twenty-four CHR (antipsychotic-naive n=22) and 23 healthy volunteers (HV) completed a high resolution [18F]FEPPA PET scan and MRI. The PET data were analyzed using the validated two-tissue compartment model with arterial plasma input function with total volume of distribution (VT) as outcome measure. All analyses were controlled for the TSPO rs6971 polymorphism. We did not observe any significant differences in microglial activation, as indexed by [18F]FEPPA VT, between CHR and HV in either the DLPFC (F(1, 44)=0.41, p=0.52) or the hippocampus (F(1, 44)=2.78, p=0.10). Exploratory associations show that in CHR, [18F]FEPPA VT was positively correlated with apathy (DLPFC: r=0.55, p=0.008; hippocampus: r=0.52, p=0.013) and state anxiety (DLPFC: r=0.60, p=0.003; hippocampus: r=0.48, p=0.024). The lack of significant group differences in [18F]FEPPA VT suggests that microglial activation is not significantly elevated in the clinical high risk state that precedes psychosis.

Cross-sectional studies of the effects of cannabis on cognition in schizophrenia have produced mixed results. Heavy and persistent cannabis use in schizophrenia is a common clinical problem, and effects of controlled abstinence from cannabis in these patients have not been carefully evaluated. The present study sought to determine the effects of cannabis abstinence on cognition in patients with schizophrenia and co-occurring cannabis dependence. We utilized a 28-day cannabis abstinence paradigm to investigate the state-dependent effects of cannabis on select cognitive outcomes in cannabis-dependent patients with schizophrenia and non-psychiatric controls. Nineteen patients and 20 non-psychiatric male cannabis-dependent participants underwent 28 days of cannabis abstinence. Cognition was assessed on day 0, 14, and 28 using a comprehensive neuropsychological battery. Clinical symptoms were assessed weekly. Abstinence was facilitated by contingency reinforcement confirmed by twice weekly urinalysis. Forty-two percent of patients and 55% of controls achieved end-point abstinence (p=0.53), which was biochemically-verified (day 28 urinary THC-COOH

N400, an event-related brain potential (ERP) waveform elicited by meaningful stimuli, is normally reduced by stimulus repetition (N400 repetition priming), and relatedness between the eliciting stimulus and preceding ones (relatedness priming). Schizophrenia patients' N400 relatedness priming deficits suggest impairment in using meaningful prime stimuli to facilitate processing of related concepts in semantic memory. To examine whether this deficiency arises from difficulty activating the prime concept per se, as indexed by reduced N400 repetition priming; or from impaired functional connections among concepts in semantic memory, as reflected by reduced relatedness priming but normal repetition priming; we recorded ERPs from 16 schizophrenia patients and 16 controls who viewed prime words each followed at 300- or 750-ms stimulus-onset asynchrony (SOA) by an unrelated, related or repeated target word, or a nonword, in a lexical-decision task. In both groups, N400s were largest (most negative) for unrelated, intermediate for related, and smallest for repeated targets. Schizophrenia patients exhibited subnormal N400 relatedness priming at the 300-ms SOA, but normal repetition priming at both SOAs, suggesting that their impairment in using prime words to activate related concepts results from abnormal functional connections among concepts within semantic memory, rather than inability to activate the prime concept itself.

The schizotypal personality trait of odd speech shares features with disorganized speech in schizophrenia. Meehl's original model of schizotypy as manifestation of a genetic diathesis for schizophrenia included odd speech as a core feature, a view supported by results of subsequent family-genetic studies. Researchers have investigated the mechanisms of unusual language production in schizotypy using neuropsychological and neurophysiological methods. The results suggest that schizotypy is associated with differences in how meaningful stimuli activate related concepts in semantic memory, but the pattern of these results is mixed – with different studies reporting either increased or decreased activation of related concepts in schizotypy. However, these apparently discordant results may reflect increased activation of weakly related concepts at shorter intervals following meaningful stimuli, together with underactivation of both strongly and weakly related concepts at longer intervals. Further research is needed to clarify the neurophysiological basis of these anomalies, and the exact conditions under which each occurs; and to ascertain whether either or both mediate unusual speech. This knowledge could point to analogous mechanisms underlying schizophrenic disorganized speech.