Functional Impairment In Schizophrenia Research Articles

Social cognition and psychosocial functioning in schizophrenia and bipolar disorder: Theory of mind as a key to understand schizophrenia dysfunction

Functional impairment is a common symptom in schizophrenia (SZ) and bipolar disorder (BD). Pharmacological treatments have limited functional recovery in both disorders. Social cognition, a cognitive process, has been associated with functioning in mental disorders. Theory of mind (ToM) is considered a key factor in understanding the social cognitive deficits in SZ and BD. Our study aimed to investigate the relationship between ToM and functioning in SZ, BD, and healthy controls (HC) and compare ToM and functioning impairments between groups. A total of 208 participants (HC n = 69; BD n = 89; SZ n = 50) were evaluated with the Functioning Assessment Short Test (FAST), Reading the Mind in the Eyes Test (RMET), the Vocabulary subtest of the Wechsler Abbreviated Scale for Intelligence (WASI) and the Hopkins Verbal Learning Test - Revised (HVLT-R). Comparisons of RMET between low- and high-functioning individuals and multiple linear regression analyses were conducted for each group. Multiple regression analysis revealed that the association between ToM and psychosocial functioning was observed only in SZ (β = –1.352, p = 0.008). Low-functioning SZ participants showed a lower ToM performance compared to participants with high-functioning SZ (t = 1.80, p = 0.039, Cohen's d = 0.938). No significant associations were found in the other groups. ToM is essential to understand the functional impairment in SZ, more than in BD. Furthermore, ToM may be a primary target for intervention strategies in improving functioning in SZ.

Multivariate associations between cognition and neighborhood geospatial characteristics in schizophrenia.

Cognitive impairment contributes to functional impairment in schizophrenia. Yet, little is known about how environmental characteristics are related to cognition in schizophrenia. By examining how cognition and the environment are intertwined, it may be possible to identify modifiable risk and protective factors that can improve cognitive outcomes in schizophrenia. We aimed to identify multivariate associations between cognition and three geospatial characteristics (built-space density, habitable green spaces, and public spaces for social interaction) within one's immediate neighborhood among individuals with schizophrenia. We recruited participants with schizophrenia from three sites - an urban metropolitan and two towns in southern India. We administered standard cognitive assessments and performed a principal axis factoring to identify episodic memory, cognitive control, and social inference-making factors for use in further analyses. We estimated geospatial characteristics of an individual's neighborhood, i.e., up to 1km2 around the residence, by sourcing data from Google Earth. We performed unconditional and conditional (to examine the effect of clinical covariates) canonical correlation analyses to understand the multivariate relationship between cognition and geospatial characteristics. We analyzed data from 208 participants; the first canonical cognitive variate (higher social inference-making and poorer cognitive control) shared 24% of the variance (r=0.49; P<0.001) with the first geospatial variate (lower built density and poorer access to public spaces). Years of education, age at onset, and place of residence significantly modulated this relationship. We observe differential associations of the built environment with social and non-social cognition in schizophrenia, and highlight the clinical and demographic characteristics that shape these associations.

Implicit cognitive effort monitoring impairments are associated with expressive negative symptoms in schizophrenia

Negative symptoms are a strong predictor of functional impairment in schizophrenia (SZ). Unfortunately, mechanisms underlying negative symptoms are poorly understood and available treatments are minimally effective. The current study evaluated the novel hypothesis that negative symptoms are associated with an implicit cognitive effort monitoring impairment that manifests during tasks requiring sustained allocation of cognitive control. Outpatients with SZ (n = 33) and healthy controls (CN; n = 29) completed an adapted Demand Selection Task (DST) in which subjects made choices between pairs of cognitive tasks that were implicitly and then explicitly made discrepant in effort demands. The SZ group demonstrated a reduced probability of avoiding the high effort cognitive task in the implicit choice condition but were able to become effort avoidant when the demands of the task were made explicit. Implicit cognitive effort monitoring deficits were associated with greater severity of the expressivity dimension of negative symptoms, but not the motivation and pleasure dimension. The association between diminished expressivity and implicit cognitive effort monitoring deficits is interpreted in light of a novel cognitive resource depletion theory, whereby individuals with SZ may become less expressive due to difficulty implicitly monitoring ongoing cognitive effort exertion and dynamically adjusting effort expenditure as task demands fluctuate.

Dysfunctional Overnight Memory Consolidation in Patients with Schizophrenia in Comparison to Healthy Controls: Disturbed Slow-Wave Sleep as Contributing Factor?

Introduction: Memory deficiency has been shown in schizophrenia patients, but results on the role of sleep parameters in overnight consolidation of associative verbal memory are still missing. Therefore, the aim of our study was to elucidate underlying processes of impaired sleep-related consolidation of associative word pairs in schizophrenia including standard sleep parameters as well as sleep spindle counts and spectral analysis. Methods: Eighteen stably medicated schizophrenia patients and 24 healthy age-matched controls performed an associative declarative memory task before and after polysomnographic recordings. Part of the participants expected verbal associative memory testing in the morning, while the others did not. Furthermore, participants filled in self-rating questionnaires of schizophrenia-typical experiences (Eppendorf Schizophrenia Inventory [ESI] and Psychotic Symptom Rating Scale). Results: Schizophrenia patients performed worse in verbal declarative memory in the evening as well as in overnight consolidation (morning compared to evening performance). While duration of slow-wave sleep was nearly comparable between groups, schizophrenia patients showed lower sleep spindle count, reduced delta power during slow-wave sleep, and reduced spindle power during the slow oscillation (SO) up-state. In healthy but not in schizophrenia patients, a linear relationship between overnight memory consolidation and slow-wave sleep duration as well as delta power was evident. No significant effect with respect to the expectation of memory retrieval was evident in our data. Additionally, we observed a negative linear relationship between total number of sleep spindles and ESI score in healthy participants. Discussion/Conclusion: As expected, schizophrenia patients showed deficient overnight verbal declarative memory consolidation as compared to healthy controls. Reduced sleep spindles, delta power, and spindle power during the SO up-state may link sleep and memory deficiency in schizophrenia. Additionally, the absence of a linear relationship between sleep-related memory consolidation and slow-wave sleep as well as delta power suggests further functional impairments in schizophrenia. Note that this conclusion is based on observational data. Future studies should investigate if stimulation of delta waves during sleep could improve memory performance and thereby quality of life in schizophrenia.

Unique contributions of sensory discrimination and gamma synchronization deficits to cognitive, clinical, and psychosocial functional impairments in schizophrenia

BackgroundSchizophrenia patients show widespread deficits in neurocognitive, clinical, and psychosocial functioning. Mismatch negativity (MMN) and gamma-band auditory steady-state response (ASSR) are robust translational biomarkers associated with schizophrenia and associated with cognitive dysfunction, negative symptom severity, and psychosocial disability. Although these biomarkers are conceptually linked as measures of early auditory information processing, it is unclear whether MMN and gamma-band ASSR account for shared vs. non-shared variance in cognitive, clinical, and psychosocial functioning. MethodsMultiple regression analyses with MMN, gamma-band ASSR, and clinical measures were performed in large cohorts of schizophrenia outpatients (N = 428) and healthy comparison subjects (N = 283). ResultsReduced MMN (d = 0.67), gamma-band ASSR (d = −0.40), and lower cognitive function were confirmed in schizophrenia patients. Regression analyses revealed that reduced MMN amplitude showed unique associations with lower verbal learning and negative symptoms, reduced gamma-band ASSR showed a unique association with working memory deficits, and both reduced MMN amplitude and reduced gamma-band ASSR showed an association with daily functioning impairment in schizophrenia patients. ConclusionMMN and ASSR measures are non-redundant and complementary measures of early auditory information processing that are associated with important domains of functioning. Studies are needed to clarify the neural substrates of MMN and gamma-band ASSR to improve our understanding of the pathophysiology of schizophrenia and accelerate their use in the development of novel therapeutic interventions.

Hierarchical Pathways from Sensory Processing to Cognitive, Clinical, and Functional Impairments in Schizophrenia.

Cognitive impairment is a hallmark of schizophrenia and a robust predictor of functional outcomes. Impairments are found in all phases of the illness and are only moderately attenuated by currently approved therapeutics. Neurophysiological indices of sensory discrimination (ie, mismatch negativity (MMN) and P3a amplitudes) and gamma-band auditory steady-state response (ASSR; power and phase locking) are translational biomarkers widely used in the development of novel therapeutics for neuropsychiatric disorders. It is unclear whether laboratory-based EEG measures add explanatory power to well-established models that use only cognitive, clinical, and functional outcome measures. Moreover, it is unclear if measures of sensory discrimination and gamma-band ASSR uniquely contribute to putative causal pathways linking sensory discrimination, neurocognition, negative symptoms, and functional outcomes in schizophrenia. To answer these questions, hierarchical associations among sensory processing, neurocognition, clinical symptoms, and functional outcomes were assessed via structural equation modeling in a large sample of schizophrenia patients (n = 695) and healthy comparison subjects (n = 503). The results showed that the neurophysiologic indices of sensory discrimination and gamma-band ASSR both significantly contribute to and yield unique hierarchical, "bottom-up" effects on neurocognition, symptoms, and functioning. Measures of sensory discrimination showed direct effects on neurocognition and negative symptoms, while gamma-band ASSR had a direct effect on neurocognition in patients. Continued investigation of the neural mechanisms underlying abnormal networks of MMN/P3a and gamma-band ASSR is needed to clarify the pathophysiology of schizophrenia and the development of novel therapeutic interventions.

S221. THE EFFICACY OF LUMATEPERONE 42 MG IN THE TREATMENT OF SCHIZOPHRENIA SYMPTOMS ASSOCIATED WITH SOCIAL FUNCTIONING: POST HOC ANALYSIS OF AN ACUTE PLACEBO- AND ACTIVE-CONTROLLED TRIAL

BackgroundDeficits in social functioning are a core feature of schizophrenia and may be due to the interaction of multiple factors including negative symptoms, depression symptoms, and deficits in social cognition. Social and functional impairment in schizophrenia can be difficult to treat, may not correlate with improvements in psychotic symptoms, and has been associated with poor long-term patient outcomes.Lumateperone (lumateperone tosylate, ITI-007) is a mechanistically novel agent for the treatment of schizophrenia that simultaneously modulates serotonin, dopamine, and glutamate neurotransmission. Lumateperone was shown to be efficacious and well tolerated in 2 acute placebo-controlled studies and its safety and effectiveness was further supported in a long-term open-label study.The effects of lumateperone 42 mg (ITI-007 60 mg) on schizophrenia symptoms associated with social function were investigated in a post hoc analysis of a study that included risperidone 4 mg as an active control (Study 005, NCT01499563). Symptoms associated with social functioning were assessed with the Positive and Negative Syndrome Scale (PANSS)-derived Prosocial factor (PANSS items P3, P6, N2, N4, N7, G16), which has been utilized previously to evaluate the efficacy of various antipsychotics on this functional domain.MethodsThis is a post hoc analysis of data from a positive placebo- and active-controlled study in patients with an acute exacerbation of schizophrenia. Change from baseline in the PANSS Prosocial factor was assessed in the intent-to-treat (ITT) population and in patients with prominent negative symptoms (PNS, score ≥4 on at least 3 negative symptom items) or moderate-to-severe depression symptoms (Calgary Depression Scale for Schizophrenia [CDSS] ≥6) at baseline. Inferential analysis was conducted using a mixed-effects model for repeated measures (MMRM).ResultsThe ITT population comprised 231 patients (placebo, n=80; lumateperone 42 mg, n=76; risperidone 4 mg, n=75); the PNS and CDSS ≥6 populations comprised 110 and 54 patients, respectively. Lumateperone 42-mg treatment was associated with significantly greater improvement compared with placebo on the PANSS Prosocial factor (least-squares mean difference [LSMD] vs placebo = −2.7; P<.001). Risperidone also was superior to placebo on the PANSS Prosocial factor (LSMD= −1.8; P=.011). Similar treatment effects for lumateperone 42 mg were seen on the PANSS Prosocial factor in patients with PNS at baseline (LSMD −2.6, P=.006). Conversely, in patients with PNS, risperidone treatment showed small and non-significant treatment effects on the PANSS Prosocial factor (LSMD= −0.4; P=.707). In patients with moderate-to-severe depression symptoms at baseline, marked and significant improvements on the PANSS Prosocial factor were seen in lumateperone-treated patients (LSMD= −4.9; P<.001) but not in risperidone-treated patients (LSMD=−1.3; P=.397).DiscussionLumateperone 42 mg significantly improved schizophrenia symptoms related to social functioning. In contrast to risperidone, lumateperone was associated with similar or greater treatment effects on the PANSS Prosocial factor in patients with prominent negative symptoms or moderate-to-severe depression symptoms at baseline. These results suggest that lumateperone may have benefits on schizophrenia symptoms associated with social function.

Subjective Scale to Investigate Cognition in Schizophrenia (SSTICS): a validation study in Italian population.

Although cognitive deficit in persons with schizophrenia is well documented, the assessment of the patient's perception of its own cognitive functioning is a relevant issue not adequately studied. Several evaluation tools have been elaborated, however none has been validated in Italian. The aim of the study is the validation of the Subjective Scale to Investigate Cognition in Schizophrenia (SSTICS), a rating scale designed to measure subjective cognitive deficits complaints in persons with schizophrenia. < span class="text116">Method. 146 persons meeting the DSM-5 diagnostic criteria for schizophrenia have been recruited. The SSTICS was translated in Italian in accordance with international standard methods. Subjects were also evaluated using the Positive and Negative Syndrome Scale (PANSS) and the Subjective Well-being under Neuroleptic scale (SWN). Cronbach's alpha coefficient was used to assess internal consistency. Constructs were examined using exploratory factor analysis (principal component with varimax rotation). The factorial model was then tested via confirmatory factor analysis. The factorial analysis revealed a 4-factor structure, which is more parsimonious than those obtained in previous studies. Correlations between STICSS and the other rating scales were significant for several domains. The Italian version of the SSTICS showed good psychometric properties and is suitable to measure the patients' subjective perception of cognitive impairment. Subjective evaluation can integrate objective measures of cognitive performances, supporting a multidimensional model of functional impairment in schizophrenia.

Polygenic Risk Scores Shed Light on the Relationship between Schizophrenia and Cognitive Functioning: Review and Meta-Analysis.

Schizophrenia is a multifactorial disease associated with widespread cognitive impairment. Although cognitive deficits are one of the factors most strongly associated with functional impairment in schizophrenia (SZ), current treatment strategies hardly tackle these impairments. To develop more efficient treatment strategies in patients, a better understanding of their pathogenesis is needed. Recent progress in genetics, driven by large genome-wide association studies (GWAS) and the use of polygenic risk scores (PRS), has provided new insights about the genetic architecture of complex human traits, including cognition and SZ. Here, we review the recent findings examining the genetic links between SZ and cognitive functions in population-based samples as well as in participants with SZ. The performed meta-analysis showed a negative correlation between the polygenetic risk score of schizophrenia and global cognition (p < 0.001) when the samples rely on general and healthy participants, while no significant correlation was detected when the three studies devoted to schizophrenia patients were meta-analysed (p > 0.05). Our review and meta-analysis therefore argues against universal pleiotropy for schizophrenia alleles and cognition, since cognition in SZ patients would be underpinned by the same genetic factors than in the general population, and substantially independent of common variant liability to the disorder.

Development and Evaluation of a Visual Remediation Intervention for People with Schizophrenia.

It is now well documented that schizophrenia is associated with impairments in visual processing at all levels of vision, and that these disturbances are related to deficits in multiple higher-level cognitive and social cognitive functions. Visual remediation methods have been slow to appear in the literature as a potential treatment strategy to target these impairments, however, in contrast to interventions that aim to improve auditory and higher cognitive functions in schizophrenia. In this report, we describe a National Institute of Mental Health (NIMH)-funded R61/R33 grant that uses a phased approach to optimize and evaluate a novel visual remediation intervention for people with schizophrenia. The goals of this project are: (1) in the R61 phase, to establish the optimal components and dose (number of sessions) of a visual remediation intervention from among two specific visual training strategies (and their combination) for improving low and mid-level visual functions in schizophrenia; and (2) in the R33 phase, to determine the extent to which the optimal intervention improves not only visual processing but also higher-level cognitive and role functions. Here we present the scientific background for and innovation of the study, along with our methods, hypotheses, and preliminary data. The results of this study will help determine the utility of this novel intervention approach for targeting visual perceptual, cognitive, and functional impairments in schizophrenia.

Independent support for corticopallidal contributions to schizophrenia-related functional impairment

BackgroundAbnormalities between the prefrontal cortex and basal ganglia have been described by numerous studies of schizophrenia (SZ). We recently reported that individuals with first episode SZ who develop greater vocational and social impairments show lower baseline functional connectivity between the globus pallidus (GP) and regions of the intrinsic salience network. Here we extend these findings to probe the integrity of this system in individuals with chronic illness. MethodsAll data were obtained from a publicly available Center of Biomedical Research Excellence dataset (http://fcon_1000.projects.nitric.org/indi/retro/cobre.html) that included resting-state fMRI and structural scans, and an array of clinical and neuropsychological measures. Participants with SZ were divided into high- or low-functioning groups based on scores across measures of psychopathology and cognitive functioning. Corticopallidal functional connectivity was examined between low- and high-functioning individuals with SZ and matched healthy control participants. We focused on connectivity between GP structures and a priori regions of the salience network that were significant in our previous study. Exploratory voxel-wise analyses were also conducted. ResultsLower functioning individuals with SZ demonstrated less connectivity between bilateral GP externa and nodes within the salience network, relative to healthy controls. No connectivity differences were observed between low- and high-functioning individuals with SZ. Exploratory voxel-wise analyses highlighted additional large-scale corticopallidal abnormalities in lower-functioning participants with SZ. ConclusionsThese results confirm our previous work in a more chronic cohort of individuals with SZ. Our findings further advance corticopallidal connectivity as a biomarker of functional impairments in SZ and lay the groundwork for treatment-based studies.

Reduced mu opioid receptor availability in schizophrenia revealed with [11C]-carfentanil positron emission tomographic Imaging

Negative symptoms, such as amotivation and anhedonia, are a major cause of functional impairment in schizophrenia. There are currently no licensed treatments for negative symptoms, highlighting the need to understand the molecular mechanisms underlying them. Mu-opioid receptors (MOR) in the striatum play a key role in hedonic processing and reward function and are reduced post-mortem in schizophrenia. However, it is unknown if mu-opioid receptor availability is altered in-vivo or related to negative symptoms in schizophrenia. Using [11 C]-carfentanil positron emission tomography (PET) scans in 19 schizophrenia patients and 20 age-matched healthy controls, here we show a significantly lower MOR availability in patients with schizophrenia in the striatum (Cohen’s d = 0.7), and the hedonic network. In addition, we report a marked global increase in inter-regional covariance of MOR availability in schizophrenia, largely due to increased cortical-subcortical covariance.

Latent ERP components of cognitive dysfunctions in ADHD and schizophrenia

ObjectiveThe main goal was to assess common and specific deficits of cognitive control in (Attention Deficit Hyperactivity Disorder) ADHD and schizophrenia (SZ) using event-related potentials (ERPs). MethodBehavioral and EEG data in cued GO/NOGO task were recorded in 132 healthy controls (HC) and age, gender and education matched 63 ADHD adults, and 68 SZ patients. ResultsN2d wave in NOGO-GO contrast of ERPs did not differ between the groups while the P3d wave discriminated SZ group from two other groups. Latent components of ERPs were extracted by blind source separation method based on second-order statistics Kropotov et al. (2017) and compared between the groups. A counterpart of N2d wave of a frontally distributed latent component was smaller in SZ indicating a specific frontal dysfunction of conflict detection in SZ. Two centrally distributed P3 sub-components were reduced in both groups indicating a non-specific dysfunction of action inhibition operations in ADHD and SZ. ConclusionA pattern of specific and common dysfunctions in terms of latent ERP components shows a more complex picture of functional impairment in schizophrenia and ADHD in comparison to conventional N2/P3 ERP description. SignificanceThe latent component approach shows a functionally different pattern of cognitive control impairment in comparison to the conventional ERP analysis.

Reverse translated and gold standard continuous performance tests predict global cognitive performance in schizophrenia

Attentional dysfunction contributes to functional impairments in schizophrenia (SZ). Sustained attention is typically assessed via continuous performance tasks (CPTs), though many CPTs have limited cross-species translational validity and place demands on additional cognitive domains. A reverse-translated 5-Choice Continuous Performance Task (5C-CPT) for human testing—originally developed for use in rodents—was designed to minimize demands on perceptual, visual learning, processing speed, or working memory functions. To-date, no studies have validated the 5C-CPT against gold standard attentional measures nor evaluated how 5C-CPT scores relate to cognition in SZ. Here we examined the relationship between the 5C-CPT and the CPT-Identical Pairs (CPT-IP), an established and psychometrically robust measure of vigilance from the MATRICS Consensus Cognitive Battery (MCCB) in a sample of SZ patients (n = 35). Relationships to global and individual subdomains of cognition were also assessed. 5C-CPT and CPT-IP measures of performance (d-prime) were strongly correlated (r = 0.60). In a regression model, the 5C-CPT and CPT-IP collectively accounted for 54% of the total variance in MCCB total scores, and 27.6% of overall cognitive variance was shared between the 5C-CPT and CPT-IP. These results indicate that the reverse translated 5C-CPT and the gold standard CPT-IP index a common attentional construct that also significantly overlaps with variance in general cognitive performance. The use of simple, cross-species validated behavioral indices of attentional/cognitive functioning such as the 5C-CPT could accelerate the development of novel generalized pro-cognitive therapeutics for SZ and related neuropsychiatric disorders.

12.4 BRAIN LACTATE IS RELATED TO COGNITION IN SCHIZOPHRENIA

Laura Rowland, University of Maryland School of Med: Bioenergetic function may be altered in schizophrenia as supported by post-mortem, preclinical, cerebrospinal fluid, and 31P-magnetic resonance spectroscopy (MRS) research. Impairments in bioenergetic function may lead to cognitive and functional dysfunction, characteristics of the illness. First, a 7T MRS study that tested the hypothesis that frontal lactate concentrations are elevated in schizophrenia and related to cognitive impairments will be presented. Second, recent advances in brain lactate measurements with 3T MRS will be presented.MethodsTwenty-nine controls and 27 participants with schizophrenia completed the study. MRS scanning was conducted on a Philips ‘Achieva’ 7T scanner, and spectra were acquired from a frontal voxel using STEAM (TE/TM/TR=14/33/3000 ms, 128 NEX, 16 NEX water). Participants completed the MATRICS Consensus Cognitive Battery (MCCB) for cognitive function and UCSD Performance-Based Skills Assessment (UPSA) for functional capacity. The relationships between lactate, MCCB, and UPSA were examined. 3T MRS test-retest measures of lactate were conducted on a Siemens Prisma scanner using spectra editing (TE/TR=140/3, editing pulse at 4.1ppm with 30Hz bandwidth, 360 NEX, 16 NEX water).ResultsPatients had significantly higher lactate compared to controls (p = 0.045). Higher lactate was associated with poorer general cognitive function (r=-0.36, p=0.01) Visual learning, processing speed, and reasoning/problem solving cognitive domains showed the strongest relationships with lactate. Poorer functional capacity (r=-0.43, p=0.001) was also related to higher lactate. 3T spectral editing studies showed excellent reproducibility with a mean coefficient of variation of 4%.DiscussionHigher frontal lactate levels in schizophrenia support the hypothesis that brain bioenergetics are altered and related to cognitive and functional impairments in schizophrenia. Higher lactate could be due to inefficient aerobic metabolism causing a shift towards anaerobic metabolism or poor utilization of lactate. Lactate measurements are doable at 3T field strength and may be a useful biomarker of cognition in schizophrenia. Interventions to promote efficient mitochondrial energy metabolism may prove useful for enhancing cognition and alleviating functional impairments in schizophrenia.

Spared motivational modulation of cognitive effort in a maternal immune activation model of schizophrenia risk.

Maternal immune activation (MIA) during gestation is a significant risk factor for development of schizophrenia and other neurodevelopmental diseases. In animal models of this risk factor, MIA during pregnancy can produce offspring that recapitulate certain aspects of the behavioral and neurophysiological impairments seen in schizophrenia. Here, the authors tested the effect of polyinosinic-polycytidylic acid (poly I:C)-induced MIA in a task that explicitly assays the interaction between motivation and cognition. In our paradigm, discrimination accuracy during a sustained-attention task is differentially impacted by environmental cues that signal the probability of reward for accurate performance. Cognition-motivation interactions are implicated in producing functional impairments in patients. Therefore, to the extent that this MIA model recapitulates such impairments, the authors predicted impaired ability of reward-associated signals to modulate cognitive performance in MIA rat offpsring. Adult offspring of dams in which MIA was induced displayed impaired prepulse inhibition relative to controls, verifying a functional effect of poly I:C induction. Despite this deficit, there were no differences between MIA and control rats in any aspects of task learning or performance, including under extinction and reacquisition conditions. These results indicate that MIA spares functioning of some of the cognitive, motivational, and decision-making processes that are impacted in schizophrenia and suggest that MIA as an isolated manipulation does not model the full range and nuance of the cognitive and motivational impairments in the disease. The authors suggest that some aspects of the functional impairment in schizophrenia and other neurodevelopmental diseases may be better modeled using multiple "hit" models of disease risk. (PsycINFO Database Record

Translating advances in the molecular basis of schizophrenia into novel cognitive treatment strategies

The presence and severity of cognitive symptoms, including working memory, executive dysfunction and attentional impairment, contributes materially to functional impairment in schizophrenia. Cognitive symptoms have proved to be resistant to both first- and second-generation antipsychotic drugs. Efforts to develop a consensus set of cognitive domains that are both disrupted in schizophrenia and are amenable to cross-species validation (e.g. the National Institute of Mental Health Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia and Research Domain Criteria initiatives) are an important step towards standardization of outcome measures that can be used in preclinical testing of new drugs. While causative genetic mutations have not been identified, new technologies have identified novel genes as well as hitherto candidate genes previously implicated in the pathophysiology of schizophrenia and/or mechanisms of antipsychotic efficacy. This review comprises a selective summary of these developments, particularly phenotypic data arising from preclinical genetic models for cognitive dysfunction in schizophrenia, with the aim of indicating potential new directions for pro-cognitive therapeutics. Linked Articles This article is part of a themed section on Pharmacology of Cognition: a Panacea for Neuropsychiatric Disease? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.19/issuetoc.

176.3 Elevated Brain Lactate and Glutamine/glutamate in Schizophrenia: A 7T MRS Study

Background: Mitochondrial and bioenergetic alterations may play a role in the pathophysiology of schizophrenia, either directly or via alterations in underlying neurotransmitter systems. Postmortem, preclinical, cerebrospinal fluid, and 31P-magnetic resonance spectroscopy (MRS) studies provide some support. A recent 31P magnetization transfer MRS study found reduced creatine kinase reaction rate and pH in schizophrenia, consistent with dysfunctional glucose metabolism and the accumulation of lactate. This study tested the hypothesis that abnormal glycolysis leads to elevated lactate concentrations in subjects with schizophrenia. The high sensitivity of 7T MRS was used to measure brain lactate levels in vivo. The glutamatergic metabolites were also examined with the prediction that glutamine to glutamate (Gln/Glu) ratio would be higher in schizophrenia. Methods: Thirty-one controls and 29 participants with schizophrenia completed the study. MRS scanning was conducted on a Philips “Achieva” 7T scanner, and spectra were acquired from a voxel in the anterior cingulate cortex using STEAM (TE/TM/TR=14/33/3000 ms, 128 NEX, and 16 NEX water). Patients were assessed for psychiatric symptom severity, and all participants completed the MATRICS Consensus Cognitive Battery (MCCB) for general cognitive function and UCSD Performance-Based Skills Assessment (UPSA) for functional capacity. The relationship between lactate, psychiatric symptom severity, MCCB, and UPSA were examined. Results: Lactate was significantly higher in patients compared to controls (P = .045). Higher lactate was associated with lower general cognitive function (r = −.36, P = .01) and functional capacity (r = −.43, P = .001). The glutamine to glutamate ratio (Gln/Glu) was higher in patients compared to controls (P = .021). Similar to lactate, higher Gln/Glu was significantly related to lower general cognitive function (r = −.4, P = .004) and functional capacity (r = −.45, P = .001). Conclusion: This is the first study to report elevated in vivo anterior cingulate lactate levels in schizophrenia. Anterior cingulate Gln–Glu ratio was also higher in schizophrenia, which is consistent with previous reports. The results support the hypothesis that brain bioenergetics are altered in schizophrenia reflecting inefficient or diminished aerobic metabolism and a shift towards anaerobic metabolism. Elevated lactate may prove to be a useful biomarker of cognitive and functional capacity in schizophrenia. Interventions to promote more efficient mitochondrial energy metabolism may prove useful for enhancing cognition and alleviating functional impairments in schizophrenia.

Elevated brain lactate in schizophrenia: a 7 T magnetic resonance spectroscopy study.

Various lines of evidence suggest that brain bioenergetics and mitochondrial function may be altered in schizophrenia. On the basis of prior phosphorus-31 (31P)-magnetic resonance spectroscopy (MRS), post-mortem and preclinical studies, this study was designed to test the hypothesis that abnormal glycolysis leads to elevated lactate concentrations in subjects with schizophrenia. The high sensitivity of 7 Tesla proton (1H)-MRS was used to measure brain lactate levels in vivo. Twenty-nine controls and 27 participants with schizophrenia completed the study. MRS scanning was conducted on a Philips ‘Achieva' 7T scanner, and spectra were acquired from a voxel in the anterior cingulate cortex. Patients were assessed for psychiatric symptom severity, and all participants completed the MATRICS Consensus Cognitive Battery (MCCB) and University of California, San Diego Performance-Based Skills Assessment (UPSA). The relationship between lactate, psychiatric symptom severity, MCCB and UPSA was examined. Lactate was significantly higher in patients compared with controls (P=0.013). Higher lactate was associated with lower MCCB (r=−0.36, P=0.01) and UPSA total scores (r=−0.43, P=0.001). We believe this is the first study to report elevated in vivo cerebral lactate levels in schizophrenia. Elevated lactate levels in schizophrenia may reflect increased anaerobic glycolysis possibly because of mitochondrial dysfunction. This study also suggests that altered cerebral bioenergetics contribute to cognitive and functional impairments in schizophrenia.

Social cognition and prefrontal hemodynamic responses during a working memory task in schizophrenia.

Social cognition is an important determinant of functional impairment in schizophrenia, but its relationship with the prefrontal functional abnormalities associated with the condition is still unclear. The present study aimed to explore the relationship between social cognition and prefrontal function in patients with schizophrenia using 52-channel near-infrared spectroscopy (NIRS). Twenty-six patients with schizophrenia and 26 age-, gender-, and intelligence quotient-matched healthy controls (HCs) participated in the study. Hemodynamic responses in the prefrontal and superior temporal cortical regions were assessed during a working memory task using NIRS. Social cognition was assessed using the Social Cognition Screening Questionnaire (SCSQ). The observed hemodynamic responses were significantly reduced in the lateral prefrontal cortex (PFC), the frontopolar cortex, and temporal regions in subjects with schizophrenia compared to HCs. Additionally, lateral PFC hemodynamic responses assessed during the working memory task demonstrated a strong positive correlation with the SCSQ theory of mind (ToM) subscale score even after controlling for working memory performance. These results suggest that ToM integrity is closely related to lateral PFC functional abnormalities found in patients with schizophrenia. In addition, this study provides evidence to suggest that NIRS could be used to identify biomarkers of social cognition function in subjects with schizophrenia.