Deficits In Schizophrenia Patients Research Articles

Correlation Between Cortical Thickness Abnormalities of the Olfactory Sulcus and Olfactory Identification Disorder and Persistent Auditory Verbal Hallucinations in Chinese Patients With Chronic Schizophrenia.

Persistent auditory verbal hallucinations (pAVHs) and olfactory identification impairment are common in schizophrenia (SCZ), but the neuroimaging mechanisms underlying both pAVHs and olfactory identification impairment are unclear. This study aimed to investigate whether pAVHs and olfactory identification impairment in SCZ patients are associated with changes in cortical thickness. In this study, cortical thickness was investigated in 78 SCZ patients with pAVHs (pAVH group), 58 SCZ patients without AVHs (non-AVH group), and 83 healthy controls (HC group) using 3T magnetic resonance imaging. The severity of pAVHs was assessed by the Auditory Hallucination Rating Scale. Olfactory identification deficits were assessed using the Odor Stick Identification Test for Japanese (OSIT-J). In addition, the relationship between the severity of pAVHs and olfactory identification disorder and cortical thickness abnormalities was determined. Significant reductions in cortical thickness were observed in the right medial orbital sulcus (olfactory sulcus) and right orbital sulcus (H-shaped sulcus) in the pAVH group compared to both the non-AVH and HC groups (P < .003, Bonferroni correction). Furthermore, the severity of pAVHs was found to be negatively correlated with the reduction in cortical thickness in the olfactory sulcus and H-shaped sulcus. Additionally, a decrease in cortical thickness in the olfactory sulcus showed a positive correlation with the OSIT-J scores (P < .05, false discovery rate correction). Cortical thickness abnormalities in the olfactory sulcus may be a common neuroimaging mechanism for pAVHs and olfactory identification deficits in SCZ patients.

Relation between task-related activity modulation and cortical inhibitory function in schizophrenia and healthy controls: a TMS–EEG study

Schizophrenia has been associated with a reduced task-related modulation of cortical activity assessed through electroencephalography (EEG). However, to the best of our knowledge, no study so far has assessed the underpinnings of this decreased EEG modulation in schizophrenia. A possible substrate of these findings could be a decreased inhibitory function, a replicated finding in the field. In this pilot study, our aim was to explore the association between EEG modulation during a cognitive task and the inhibitory system function in vivo in a sample including healthy controls and patients with schizophrenia. We hypothesized that the replicated decreased task-related activity modulation during a cognitive task in schizophrenia would be related to a hypofunction of the inhibitory system. For this purpose, 27 healthy controls and 22 patients with schizophrenia (including 13 first episodes) performed a 3-condition auditory oddball task from which the spectral entropy modulation was calculated. In addition, cortical reactivity—as an index of the inhibitory function—was assessed by the administration of 75 monophasic transcranial magnetic stimulation single pulses over the left dorsolateral prefrontal cortex. Our results replicated the task-related cortical activity modulation deficit in schizophrenia patients. Moreover, schizophrenia patients showed higher cortical reactivity following transcranial magnetic stimulation single pulses over the left dorsolateral prefrontal cortex compared to healthy controls. Cortical reactivity was inversely associated with EEG modulation, supporting the idea that a hypofunction of the inhibitory system could hamper the task-related modulation of EEG activity.

Using virtual reality to assess gesture performance deficits in schizophrenia patients.

Gesture performance deficits are prevalent in schizophrenia patients and are strongly associated with poor social communication skills and community functioning, affecting their overall quality of life. Currently, video-recording technology is widely used in clinical settings to assess gesture production deficits in schizophrenia patients. Nevertheless, the subjective evaluation of video-recordings can encumber task assessment. The present study will aim to use virtual reality to examine its potential use as an alternative tool to objectively measure gesture performance accuracy in schizophrenia patients and healthy controls. Gesture performance in the virtual reality setting will be based on the well-established Test of Upper Limb Apraxia. Participants will be immersed in a virtual environment where they will experience themselves being embodied in a collocated virtual body seen from a first-person perspective. Motion trackers will be placed on participants' hands and elbows to track upper body movements in real-time, and to record gesture movement for later analysis. Participants will see a virtual agent sitting across from them, with a virtual table in between. The agent will perform various types of gestures and the participants' task will be to imitate those gestures as accurately as possible. Measurements from the tracking devices will be stored and analyzed to address gesture performance accuracy across groups. This study aims to provide objective measurements of gesture performance accuracy in schizophrenia patients. If successful, the results will provide new knowledge to the gesture literature and offer the potential for novel therapeutic interventions using virtual reality technologies. Such interventions can improve gesturing and thus advance social communication skills in schizophrenia patients.

Antipsychotic drugs and their effects on cognitive function: protocol for a systematic review, pairwise, and network meta-analysis

BackgroundThere is evidence that antipsychotic drugs differ in their effect on the cognitive symptoms of schizophrenia. So far, there is no comprehensive systematic review available that would enable providers and patients to make informed choices regarding this important aspect of treatment. With a large number of substances available, conventional pairwise meta-analyses will not be sufficient to inform this choice. To fill this gap, we will conduct a network meta-analysis (NMA), integrating direct and indirect comparisons from randomized controlled trials (RCTs) to rank antipsychotics according to their effect on cognitive functioning.MethodsIn our NMA, we will include RCTs in patients with schizophrenia or schizophrenia-like psychoses comparing one antipsychotic agent with another antipsychotic agent or placebo that measures cognitive function. We will include studies on patients of every age group, in any phase of illness (e.g., acute or stable, first episode or chronic schizophrenia, in- or outpatients) with an intervention time of at least 3 weeks. The primary outcome will be the composite score of cognitive functioning, preferentially measured with the test battery developed by the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative. The secondary outcomes include the seven cognitive domains that the composite score is composed of, as well as functioning and quality of life. Study selection and data extraction will be conducted by at least two independent reviewers. We will use the Cochrane Risk of Bias tool 2 to determine the risk of bias in studies, and we will evaluate the confidence in the results using Confidence in Network Meta-Analysis (CINeMA). We will perform NMA using R (package netmeta). We will conduct subgroup and sensitivity analyses to explore the heterogeneity and assess the robustness of our findings.DiscussionThis systematic review and network meta-analysis aims to inform evidence-based antipsychotic treatment choice for cognitive deficits in schizophrenia patients by analyzing existing RCTs on this subject. The results have the potential to support patients’ and physicians’ decision-making processes based on the latest available evidence.Systematic review registrationPROSPERO CRD42022312483

Working memory deficit in schizophrenia: a systematic review and meta-analysis of fMRI studies examining frontal and parietal brain activity.

The role of functional magnetic resonance imaging (fMRI) findings in investigation of working memory (WM) deficit in schizophrenia patients is still debatable. The aim of the study was to investigate the role of fMRI findings of the frontal and parietal brain activity in investigation of WM deficit in schizophrenia patients. We used Medline, Embase, and the Cochrane Database to conduct a comprehensive search up to January 2023. Functional MRI findings of schizophrenia patients were compared with healthy patients in comparative studies for assessing their WM capacity in terms of dorsolateral prefrontal cortex and parietal region activation. The Cochrane Risk of Bias Assessment Tool was used to evaluate the research quality. Ten trials and 676 schizophrenia patients were included in our analysis. For the comparative assessment of primary outcome - alteration in dorsolateral prefrontal cortex and parietal region activity in schizophrenic patients versus healthy controls - we found the pooled odds ratio (OR) of 1.58 [95% CI: 1.09-2.29], I 2 = 61% and p = 0.01 and risk ratio (RR) was 1.27 [95% CI: 1.06-1.53], I 2 = 55% and p = 0.01. The AUC value of 0.944 indicates a favourable overall diagnostic performance of fMRI for the diagnosis of schizophrenia. fMRI findings showing abnormalities in the parietal and frontal regions can be used to study schizophrenia patients' WM deficits.

Smoking affects the association between cognitive impairment and P50 inhibition defects in patients with chronic schizophrenia: A case-control study.

Smoking affects sensory gating, as assessed by the event related potential P50, which is evoked by auditory stimuli and is considered to be involved in the pathophysiology of schizophrenia (SCZ). However, few studies have compared sensory gating and cognitive performance between smoking and non-smoking SCZ patients in the Chinese Han population. We recruited two groups of Chinese subjects: 128 male chronic SCZ patients and 76 male healthy controls, measuring cognition with the MATRICS Consensus Cognitive Battery (MCCB) and sensory gating with the P50 EEG components. Based on their smoking status, they were further divided into 4 subgroups: smoking SCZ patients, non-smoking SCZ patients, smoking healthy controls, and non-smoking healthy controls. We assessed psychopathological symptoms of the patients using the Positive and Negative Syndrome Scale (PANSS). Compared with healthy controls, SCZ patients had lower MCCB total score and scores of all 10 tests (all p<0.05), while SCZ patients had higher S2 amplitudes and P50 ratios (both p<0.05). When comparing smoking versus non-smoking SCZ patients, non-smokers had significantly better spatial span (p<0.05). Furthermore, the S1 amplitude was negatively correlated with the Brief Visuospatial Memory Test (BVMT-R) in smoking patients (p<0.05), while the S1 latency was negatively correlated with spatial span in non-smoking patients (p<0.01). Our finding shows a difference in the relationship between sensory gated P50 and cognition in smoking and non-smoking SCZ patients, suggesting that nicotine may improve cognitive and P50 deficits in SCZ patients.

Captured by associations: Semantic distractibility during analogical reasoning in schizophrenia

Impaired cognitive control, for instance increased distractibility in simple conflict tasks such as Stroop, is considered one of fundamental cognitive deficits in schizophrenia patients. Relatively less is known about patients proneness to distraction in more complex, longer-lasting cognitive tasks. We applied the four-term analogies with and without distraction to 51 schizophrenia patients in order to examine whether they display increased distractibility during analogical reasoning, and to test which kind of distractors (semantic, categorical, or perceptual) elicits their strongest distraction, as compared to 51 matched controls. We found that (a) both groups reasoned by analogy comparably well when distraction was absent; (b) in both groups distraction significantly decreased performance; (c) schizophrenia patients were significantly more distracted than the controls; (d) in both groups the semantic distractors were selected more frequently than the categorical distractors, while the perceptual distractors were virtually ignored; as well as (e) in both groups distractibility in the four-term analogies was unrelated with distractibility in the simple perceptual conflict task, suggesting that these two distraction types tap into different cognitive mechanisms. Importantly, a significantly stronger distractibility in the schizophrenia group could not be explained by their lower intelligence, because the two groups were matched on the fluid reasoning test. We conclude that during complex cognitive processing schizophrenia patients become captured by irrelevant semantic associations. The patients are also less willing to critically evaluate their responses.

Decreased integration of default-mode network during a working memory task in schizophrenia with severe attention deficits.

Working memory (WM) and attention deficits are both important features of schizophrenia. WM is closely related to attention, for it acted as an important characteristic in activating and manipulating WM. However, the knowledge of neural mechanisms underlying the relationship between WM and attention deficits in schizophrenia is poorly investigated. Graph theory was used to examine the network topology at the whole-brain and large-scale network levels among 125 schizophrenia patients with different severity of attention deficits (65 mild attention deficits; 46 moderate attention deficits; and 14 severe attention deficits) and 53 healthy controls (HCs) during an N-back WM task. These analyses were repeated in the same participants during the resting state. In the WM task, there were omnibus differences in small-worldness and normalized clustering coefficient at a whole-brain level and normalized characterized path length of the default-mode network (DMN) among all groups. Post hoc analysis further indicated that all patient groups showed increased small-worldness and normalized clustering coefficient of the whole brain compared with HCs, and schizophrenia with severe attention deficits showed increased normalized characterized path length of the DMN compared with schizophrenia with mild attention deficits and HCs. However, these observations were not persisted under the resting state. Further correlation analyses indicated that the increased normalized characterized path length of the DMN was correlated with more severe attentional deficits and poorer accuracy of the WM task. Our research demonstrated that, compared with the schizophrenia patients with less attention deficits, disrupted integration of the DMN may more particularly underlie the WM deficits in schizophrenia patients with severe attention deficits.

Delayed improvements in visual memory task performance among chronic schizophrenia patients after high-frequency repetitive transcranial magnetic stimulation.

BACKGROUNDCognitive impairments are core characteristics of schizophrenia, but are largely resistant to current treatments. Several recent studies have shown that high-frequency repetitive transcranial magnetic stimulation (rTMS) of the left dor-solateral prefrontal cortex (DLPFC) can reduce negative symptoms and improve certain cognitive deficits in schizophrenia patients. However, results are inconsistent across studies.AIMTo examine if high-frequency rTMS of the DLPFC can improve visual memory deficits in patients with schizophrenia.METHODSForty-seven chronic schizophrenia patients with severe negative symptoms on stable treatment regimens were randomly assigned to receive active rTMS to the DLPFC (n = 25) or sham stimulation (n = 22) on weekdays for four consecutive weeks. Patients performed the pattern recognition memory (PRM) task from the Cambridge Neuropsychological Test Automated Battery at baseline, at the end of rTMS treatment (week 4), and 4 wk after rTMS treatment (week 8). Clinical symptoms were also measured at these same time points using the Scale for the Assessment of Negative Symptoms (SANS) and the Positive and Negative Syndrome Scale (PANSS).RESULTSThere were no significant differences in PRM performance metrics, SANS total score, SANS subscores, PANSS total score, and PANSS subscores between active and sham rTMS groups at the end of the 4-wk treatment period, but PRM performance metrics (percent correct and number correct) and changes in these metrics from baseline were significantly greater in the active rTMS group at week 8 compared to the sham group (all P < 0.05). Active rTMS treatment also significantly reduced SANS score at week 8 compared to sham treatment. Moreover, the improvement in visual memory was correlated with the reduction in negative symptoms at week 8. In contrast, there were no between-group differences in PANSS total score and subscale scores at either week 4 or week 8 (all P > 0.05).CONCLUSIONHigh-frequency transcranial magnetic stimulation improves visual memory and reduces negative symptoms in schizophrenia, but these effects are delayed, potentially due to the requirement for extensive neuroplastic changes within DLPFC networks.

Nicotine-conditioned place preference, reversal learning and social interaction in MK-801-induced schizophrenia model: Effects of post-weaning enriched environment.

Based on the clinical observations of severe cognitive deficits in schizophrenia patients and the relationship between environmental parameters and the severity of schizophrenia symptoms, the present study investigated these parameters in an dizocilpine (MK-801)-induced schizophrenia model in rats. In addition to, it evaluated whether a post-weaning enriched environment (EE) would affect the nicotine-induced conditioned place preference (CPP) and the motor and cognitive deficits caused by MK-801 treatment. Male Wistar rat pups were injected peritoneally with MK-801 (1 mg/kg) on a daily basis between the 6th and the 10th postnatal days (P) and were exposed to either an enriched or a standard cage from P21 until the end of the experiments. The rats were evaluated in open-field and three-chamber social interaction tests. Moreover, spatial and reversal learning was assessed by the Morris water maze (MWM). The animals were conditioned with 0.6 mg/kg nicotine and tested for CPP. Increased self-grooming, exploratory behaviour, potentiated nicotine-CPP and decreased social behaviours, delayed spatial learning and memory and impaired reversal learning in the water maze were observed in the MK-801 treatment group. Housing in an EE improved cognitive and behavioural deficits associated with postnatal MK-801 treatment. The results suggested that neonatal N-methyl-d-aspartate (NMDA) receptor hypofunction may cause susceptibility to these behaviours and indicated the importance of environmental conditions in the development of schizophrenia and probably other neuropsychiatric disorders.

Brain Stimulation and Group Therapy to Improve Gesture and Social Skills in Schizophrenia-The Study Protocol of a Randomized, Sham-Controlled, Three-Arm, Double-Blind Trial.

An important component of nonverbal communication is gesture performance, which is strongly impaired in 2/3 of patients with schizophrenia. Gesture deficits in schizophrenia are linked to poor social functioning and reduced quality of life. Therefore, interventions that can help alleviate these deficits in schizophrenia are crucial. Here, we describe an ongoing randomized, double-blind 3-arm, sham-controlled trial that combines two interventions to reduce gesture deficits in schizophrenia patients. The combined interventions are continuous theta burst stimulation (cTBS) and social cognitive remediation therapy (SCRT). We will randomize 72 patients with schizophrenia spectrum disorders in three different groups of 24 patients. The first group will receive real cTBS and real SCRT, the second group will receive sham cTBS and real SCRT, and finally the third group will receive sham SCRT. Here, the sham treatments are, as per definition, inactive interventions that mimic as closely as possible the real treatments (similar to placebo). In addition, 24 age- and gender-matched controls with no interventions will be added for comparison. Measures of nonverbal communication, social cognition, and multimodal brain imaging will be applied at baseline and after intervention. The main research aim of this project will be to test whether the combination of cTBS and SCRT improves gesture performance and social functioning in schizophrenia patients more than standalone cTBS, SCRT or sham psychotherapy. We hypothesize that the patient group receiving the combined interventions will be superior in improving gesture performance.Clinical Trial Registration[www.ClinicalTrials.gov], identifier [NCT04106427].

Selective mGlu1 Potentiation Reverses Cortical Disinhibition and Schizophrenia‐like Social and Cognitive Deficits

There is a critical need to develop novel therapeutic strategies for addressing the negative and cognitive symptom domains in schizophrenia (SCZ). Multiple clinical and preclinical studies support the hypothesis that loss of GABAergic inhibitory transmission in the prefrontal cortex (PFC) and other forebrain regions may play a critical role in the pathophysiological changes underlying cognitive and social behavioral deficits in SCZ patients. Recently, we demonstrated that activation of the mGlu1 subtype of metabotropic glutamate receptor increases inhibitory transmission in the PFC by selective excitation of somatostatin‐expressing GABA interneurons. Genetic studies in humans reveal an association between deleterious non‐synonymous single nucleotide polymorphisms (nsSNPS) in of the human gene encoding mGlu1 (GRM1) and SCZ, raising the possibility that mGlu1 signaling is critical to the function of brain circuits underlying symptoms associated with this disorder.Here, we examine whether novel positive allosteric modulators (PAMs) selective for mGlu1 reverse electrophysiological effects and behavioral deficits in an MK‐801‐induced animal model of SCZ. We used ex vivo whole‐cell patch‐clamp electrophysiology to show that MK‐801 decreased the frequency of spontaneous inhibitory postsynaptic currents onto layer V pyramidal cells of the PFC, and this cortical disinhibition was reversed by mGlu1 activation. Furthermore, acute MK‐801 treatment induces inhibitory deficits onto PFC‐basolateral amygdala (BLA), but not PFC‐nucleus accumbens, projecting layer V pyramidal cells that can be reversed by selective mGlu1 activation. PFC‐BLA projections are known to contribute functionally to social‐approach behavior, while the BLA plays a critical role in object recognition and cognition broadly. We found that the mGlu1 PAM VU6004909 effectively reversed MK801‐induced deficits in social interaction and social novelty preference in a three‐chamber assay. Additionally, VU6004909 restored novel object recognition following MK‐801 treatment. In combination with our previous reports that mGlu1 PAMs reverse deficits in inhibitory transmission in the PFC, the current study provides strong evidence for mGlu1 PAMs as a promising novel approach for the treatment of social and cognitive deficits in SCZ patients.

Dysfunctional monocytic toll-like receptor 4 signaling pathway and cognitive deficits in chronic schizophrenia patients with tardive dyskinesia

BackgroundMounting evidence suggests that the innate immune system is disrupted in schizophrenia patients with tardive dyskinesia (TD); however, the role of the toll-like receptor 4 (TLR4) signaling pathway remains unclear. MethodsIn this study, we quantified the expression of the monocytic TLR4 signaling pathway using flow cytometry, before and after lipopolysaccharide (LPS) stimulation, in chronic schizophrenia patients with (n = 61) and without TD (NTD, n = 61) and healthy controls (HCs, n = 74). Psychopathological symptoms, the severity of TD, and cognitive function were assessed using the Positive and Negative Syndrome Scale (PANSS), Abnormal Involuntary Movement Scale (AIMS), and MATRICS Consensus Cognitive Battery (MCCB), respectively. Results1) Both TD and NTD patients showed higher TLR4 signaling pathway activity at baseline than that in HCs, but their responses to LPS were weaker than those in HCs; 2) the alteration of the TLR4 signaling pathway was less severe in TD patients than in NTD patients; 3) TLR4 levels and MCCB scores were negatively correlated at baseline but positively correlated after LPS stimulation in TD patients; 4) there was no correlation between the TLR4 signals and PANSS or AIMS scores. ConclusionsOur findings suggested the TLR4 signaling pathway disturbance might be related to cognitive deficits in schizophrenia patients with TD.

Intrinsic cerebellar functional connectivity of social cognition and theory of mind in first-episode psychosis patients

Neuroimaging studies have revealed how intrinsic dysconnectivity among cortical regions of the mentalizing network (MENT) and the mirror neuron system (MNS) could explain the theory of mind (ToM) deficit in schizophrenia patients. However, despite the concurrent involvement of the cerebellum with the cortex in social cognition, the dysfunction in intrinsic interplay between the cerebellar nodes of MENT/MNS and the cortex in schizophrenia patients remains unknown. Thus, we aimed to investigate whether resting-state cerebello–cortical dysconnectivity exists in first-episode psychosis (FEP) patients in relationship with their ToM deficit. A total of 37 FEP patients and 80 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging. Using a priori-defined cerebellar seeds that functionally connect to the MENT (right crus II) and MNS (right crus I), we compared cerebello–cortical functional connectivities (FCs) in FEP patients and HCs. Correlations between cerebello–parietal connectivities and ToM performance were investigated in FEP patients. FEP patients showed hyperconnectivity between the right crus II and anterior cingulate gyrus and between the right crus I and supplementary motor area, bilateral postcentral gyrus, and right central/parietal operculum (CO/PO). Hypoconnectivity was found between the right crus II and left supramarginal gyrus (SMG) in FEP patients. FCs between the right crus II and left SMG and between the right crus I and right CO/PO were significantly correlated with ToM scores in FEP patients. In accordance with the “cognitive dysmetria” hypothesis, our results highlight the importance of cerbello-cortical dysconnectivities in understanding social cognitive deficits in schizophrenia patients.

Implications for Early Diagnosis and Treatment in Schizophrenia Due to Correlation between Auditory Perceptual Deficits and Cognitive Impairment.

It is indicated that auditory perception deficits are present in schizophrenia and related to formal thought disorder. The purpose of the present study was to investigate the association of auditory deficits with cognitive impairment in schizophrenia. An experimental group of 50 schizophrenia patients completed a battery of auditory processing evaluation and a neuropsychological battery of tests. Correlations between neuropsychological battery scores and auditory processing scores were examined. Cognitive impairment was correlated with auditory processing deficits in schizophrenia patients. All neuropsychological test scores were significantly correlated with at least one auditory processing test score. Our findings support the coexistence of auditory processing disorder, severe cognitive impairment, and formal thought disorder in a subgroup of schizophrenia patients. This may have important implications in schizophrenia research, as well as in early diagnosis and nonpharmacological treatment of the disorder.

Sex differences between serum total bilirubin levels and cognition in patients with schizophrenia

BackgroundCognitive deficits are common in patients with schizophrenia (SCZ). Abnormal serum total bilirubin (TBIL) levels have been involved in cognitive deficits associated with neuropsychiatric diseases such as mild cognitive impairment and subcortical ischemic vascular disease. However, this relationship has not yet been fully investigated in patients with SCZ. Therefore, the aim of this study was to investigate the association between the serum TBIL concentration and cognitive deficits in SCZ patients and to determine whether a sex difference exists in the association.MethodsA total of 455 participants were eligible and included in this cross-sectional study. Cognition was evaluated using the Montreal Cognitive Assessment. Serum TBIL concentration was measured with an automatic biochemistry analyzer according to the routine protocol in the hospital medical laboratory.ResultsSerum TBIL levels were lower in the cognition impairment group than in the cognition normal group in male patients. In contrast, serum TBIL levels tended to be increased in the cognition impairment group in female patients, although the difference was not significant. Further stepwise multiple regression analysis stratified by sex showed that serum TBIL was independently and positively associated with cognitive function in male patients but not in female patients. Moreover, the association between serum TBIL level and cognitive function was also identified by the propensity score matching (PSM) method in male patients, but not in female patients.ConclusionThese findings suggest that lower serum TBIL levels may be associated with cognitive impairment in male SCZ patients.

Early and middle latency auditory event-related potentials do not explain differences in neuropsychological performance between schizophrenia spectrum patients and matched healthy controls

Abnormalities of early and middle latency auditory event-related potentials (ERPs) are widespread in schizophrenia and have been suggested to be associated with cognitive deficits in schizophrenia patients. In this cross-sectional study with schizophrenia patients (n=30) and psychiatrically healthy counterparts (n=31) (matched for age, sex, education), we investigated whether auditory information processing (measured via amplitudes and gating of the auditory ERPs P50, N100 and P200) correlates with neuropsychological performance across cognitive domains. The groups differed significantly in amplitudes and gating of N100 and P200 potentials as well as in neuropsychological performance, but not in P50 amplitude and gating. Neither amplitudes nor gating of auditory ERPs correlated with neuropsychological performance. Neuropsychological intergroup differences could not be explained by abnormalities in auditory information processing. Although pronounced impairments exist on the levels of both auditory information processing and cognitive performance in schizophrenia, these abnormalities are not directly associated with each other.

Selective mGlu 1 potentiation enhances cortical inhibition to rescue schizophrenia‐like cognitive and social deficits

Accumulating evidence suggests that selective activators of the mGlu1 subtype of metabotropic glutamate (mGlu) receptor may provide a promising novel therapeutic approach for the treatment of schizophrenia. Genetic studies in humans reveal an association of the human gene encoding mGlu1 (GRM1) and, specifically, loss of function single nucleotide polymorphisms in GRM1 with schizophrenia, raising the possibility that mGlu1 signaling is critical to the function of brain circuits underlying symptoms associated with this disorder. Multiple clinical and preclinical studies support the hypothesis that loss of GABAergic inhibitory transmission in the prefrontal cortex (PFC) and other forebrain regions may play a critical role in the pathophysiological changes underlying behavioral deficits in schizophrenia patients, including cognitive and social impairment. This is especially interesting in light of our recent studies demonstrating that activation of mGlu1 increases inhibitory transmission in the PFC by selective excitation of somatostatin-expressing GABA interneurons. Here, we leverage recently developed positive allosteric modulators (PAMs) selective for mGlu1 to examine whether mGlu1 activation might reverse electrophysiological effects and behavioral deficits induced by MK-801, an NMDA receptor antagonist commonly used to model cortical pathophysiology relevant to behavioral and cognitive deficits observed in schizophrenia patients. Using ex vivo whole-cell patch-clamp electrophysiology, we found that MK-801 decreased the frequency of spontaneous inhibitory postsynaptic currents onto layer V pyramidal cells of the PFC and this cortical disinhibition was reversed by mGlu1 activation, suggesting that mGlu1 activation is a pertinent mechanism to restore inhibitory signaling in the PFC. Importantly, the mGlu1 PAM VU6004909 effectively reversed MK-801-induced deficits in working memory as measured by spontaneous alternation in a Y-maze task and restored social interaction in a three-chamber assay. In combination with our previous reports that mGlu1 PAMs possess potential antipsychotic-like efficacy and reverse deficits in inhibitory transmission in the PFC, the current study provides strong evidence that mGlu1 PAMs could serve as a novel approach that could reduce positive symptoms and also treat cognitive and social deficits in schizophrenia patients, providing an exciting improvement over current antipsychotics.

Eye-movements deficits in schizophrenia: A metanalysis of evidence

IntroductionAlthough eye-movement disorders are one of the most replicated deficits in the psychiatric literature, the strong heterogeneity of results is still an unexplained issue that could be effectively addressed with a quantitative review of evidence.ObjectivesFor this reason, a large-scale metanalytic study comprising more than 200 studies was conducted to analyse the presence of eye-movement deficits in schizophrenia patients, as compared to healthy controls.MethodsTo this aim, saccadic eye movements were grouped based on the type of task required (e.g., standard, predictive) and the quantification method used (e.g., number, duration, amplitude). For each sub-group separate meta-analysis were computed. Cohen’s d was used as measure of effect size. Risk of bias within and between studies and heterogeneity were also analysed.Resultsindicated low Cohen’s d with the exception of the number of correct antisaccades – where schizophrenia patients reportedless correct anti-saccadesthan healthy controls - and antisaccades error rate – where schizophrenia patients reported a higher number of errors than healthy controls.ConclusionsAntisaccades emerged as better suited to differentiate between patients and healthy controls, thus making them the most promising candidate as a possible biomarker for schizophrenia.

The microRNA-195 - BDNF pathway and cognitive deficits in schizophrenia patients with minimal antipsychotic medication exposure

Cognitive impairment is a core characteristic of schizophrenia, but its underlying neural mechanisms remain poorly understood. Reduced brain-derived neurotrophic factor (BDNF), a protein critical for neural plasticity and synaptic signaling, is one of the few molecules consistently associated with cognitive deficits in schizophrenia although the etiological pathway leading to BDNF reduction in schizophrenia is unclear. We examined microRNA-195 (miR-195), a known modulator of BDNF protein expression, as a potential mechanistic component. One-hundred and eighteen first-episode patients with schizophrenia either antipsychotic medication-naïve or within two weeks of antipsychotic medication exposure and forty-seven age- and sex-matched healthy controls were enrolled. MiR-195 and BDNF mRNA and BDNF protein levels in peripheral blood were tested. Cognitive function was assessed using the MATRICS Consensus Cognitive Battery (MCCB). MiR-195 was significantly higher (p = 0.01) whereas BDNF mRNA (p < 0.001) and protein (p = 0.016) levels were significantly lower in patients compared with controls. Higher miR-195 expression was significantly correlated to lower BDNF protein levels in patients (partial r = −0.28, p = 0.003) and lower BDNF protein levels were significantly associated with poorer overall cognitive performance by MCCB and also in speed of processing, working memory, and attention/vigilance domains composite score (p = 0.002–0.004). The subgroup of patients with high miR-195 and low BDNF protein showed the lowest level of cognitive functions, and miR-195 showed significant mediation effects on cognitive functions through BDNF protein. Elevated miR-195 may play a role in regulating BDNF protein expression thereby influencing cognitive impairments in schizophrenia, suggesting that development of cognition enhancing treatment for schizophrenia may consider a micro-RNA based strategy.