Schizophrenia Research

Past research has demonstrated that patients with schizophrenia (SP) have visual processing and multisensory integration deficits. Additional studies report that sensory abnormalities are related to positive symptoms. To further understand how multisensory abnormalities relate to positive symptoms, we administered a multisensory integration task requiring the evaluation of perceived distance from auditory, visual, and multisensory stimuli with varying synchrony as well as clinical and neurocognitive assessments. Overall, patients had greater facilitation than healthy controls and the near synchronous condition had the most facilitation in comparison to other conditions. To further examine how multisensory facilitation relates to symptom severity, we performed a Ward cluster analysis that grouped participants by their multisensory facilitation profile. In contrast to what was expected, none of the Ward clusters were populated by a single group. Patients in cluster 3 had a significantly greater disorganization factor score than those in cluster 1. Our in-depth comparison between Ward clusters and neuropsychological tests reveal patients with greater multisensory facilitation experience the most cognitive deficits. Overall, our results demonstrate that multisensory integration is related to behavioral and cognitive deficits in complex ways. Further research is needed to understand the relationship between multisensory integration and schizophrenia symptomology. HighlightsO_LIPatients with schizophrenia have greater multisensory facilitation in perceived synchronous conditions C_LIO_LIMultisensory facilitation patterns are heterogenous across patients with Schizophrenia. C_LIO_LIDifferent multisensory patterns relate to cognitive decline and disorganized thinking in Schizophrenia. C_LI

Background and HypothesisAbnormalities in the encoding of the space close to the body, named peripersonal space (PPS), is thought to play a crucial role in the disruption of the bodily self observed in schizophrenia (SCZ). Empirical evidence indicates a narrower extension of the PPS in SCZ compared to controls but preserved plasticity of the PPS. Computational studies suggest that increased excitation of sensory neurons could explain the smaller PPS observed in SCZ. However, it is unclear why SCZ patients preserve PPS plasticity and how such an excitation imbalance influences learning during the extension of the PPS boundaries. Study DesignWe hypothesise that Hebbian plasticity can account for PPS expansion after active tool use training, which occurs in spite of E/I imbalance and reduced synaptic density. Using simulations in a SCZ network model, we explored the effects of such impairments on PPS plasticity and fitted the model to behavioural data before and after a training routine. Study ResultsWe found that increased excitation of sensory neurons does not impede the expansion of PPS and could explain a sharper demarcation of PPS boundaries after training. In addition, we found that a reduction in the learning rate is required to reproduce the post-training PPS representation of SCZ patients. ConclusionsWe discuss how the neural mechanisms behind the plasticity of PPS in the SCZ spectrum are related to the core pathophysiology of the disease.

BackgroundSchizophrenia is a disorder of higher mental attributes, and is characterized by psychotic symptoms that are believed to involve a basic inability to make valid predictions about expected sensations and experiences. These have been reported separately while monitoring either externally generated environmental patterns (e.g. gestalt-perception) or self-generated sensory experiences (e.g. corollary-discharge). As the pathophysiology behind predictive dysfunction is better viewed as an aberration in brains functional synchrony, a whole brain assessment using electroencephalographic (EEG) event related potential (ERP) and functional magnetic resonance imaging (fMRI) techniques, would offer a wider perspective to brain network abnormalities in schizophrenia.\n\nMethodWe used our lab-developed game-based task which presents degraded two-tone images to assess gestalt-perception, and simultaneously alters the congruency between participants button-press response and its auditory feedback to assess corollary-discharge. In both patients with schizophrenia and age-matched healthy controls, we explored event-related changes in an EEG-ERP study (n=21 each) and whole brain functional connectivity changes in a fMRI study (patients,n=12; controls,n=16), using the same task.\n\nResultsPatients showed reduced event-related EEG dynamics during both the error-prediction conditions (gestalt-perception and corollary-discharge), which include reduction in average waveforms (around N170 and N1-P2 complex, respectively) and altered theta dynamics (power and phase). Source-level EEG measures were clustered around the cingulo-insular network. fMRI functional connectivity analysis also found the abnormality in these brain regions, forming significantly weak connections with right insular/opercular cortex.\n\nConclusionsThis is the first study to explore thalamo-cortical dysfunction hypothesis in schizophrenia by integrating prediction-error-coding during perception ( gestalt-perception) and action ( corollary-discharge) using two neuroimaging modalities (EEG-ERP and fMRI). Besides adding to the knowledgebase of schizophrenia research, our novel task design and findings on theta-oscillation could benefit in the development of effective neuromodulatory therapeutic tools for patients with schizophrenia such as neurofeedback and transcranial brain stimulation.

ObjectiveGut microbiota dysbiosis and aberrant gut-brain functional modules including short-chain fatty acid (SCFA) production and long-lasting immune activation (IA) are presented in schizophrenia. Given the key roles of gut microbiota and SCFA in shaping immunity, we propose that dysbiosis-induced SCFA upregulation could contribute to IA and behavioral symptoms in schizophrenia. DesignGut microbiota, SCFA, and IA biomarkers were compared between schizophrenic patients and healthy controls. The roles of SCFA in schizophrenia-related IA were analyzed in cultured peripheral blood mononuclear cells (PBMCs) and a mouse model of schizophrenia. The effects of SCFAs on schizophrenia-related phenotypes were analyzed in both human and mouse. ResultsBoth microbial-derived SCFA and SCFA-producing bacteria were elevated in the guts of schizophrenic patients, and this increased SCFA production in gut was associated with IA in schizophrenia. The microbiome signature underpinning schizophrenia-related IA includes increased diversity and increased SCFA-producing bacteria and inflammation-associated bacteria. The impact of SCFAs on immune responses of cultured PBMC depend on the diagnosis and IA status of donors. Small-molecule serum filtrates from immune-activated schizophrenic patients increased the inflammatory response of PBMCs from healthy volunteers, which can be enhanced and attenuated by SCFAs supplementation and inhibition of SCFA signaling, respectively. Chronically elevated SCFAs in adolescence induced neuroinflammation and schizophrenia-like behaviors in adult mice. Moreover, chronically elevated SCFAs in adult mice prenatally exposed to IA potentiated their expression of schizophrenia-like behaviors. Conclusionmicrobiota-derived SCFAs are important mediators of dysregulated gut-brain axis and participant in pathogenesis via enhance IA in schizophrenia. SummaryO_ST_ABSSignificance of this studyC_ST_ABSO_LIWhat is already known about this subject? [tpltrtarr]Schizophrenia pathogenesis goes beyond the brain since increasing peripheral abnormalities are revealed including gut microbiota dysbiosis, GI dysfunction, and systemic immune activation (IA). [tpltrtarr]Systemic IA/inflammation contributes to the neuroinflammation and brain impairment underlying schizophrenia, and adjunctive immunotherapy can improve psychotic symptoms. [tpltrtarr]Short-chain fatty acids (SCFA) mediate the microbiota-gut-brain communication and modulate several pathways involved in schizophrenia, including pathways of immunity and neurotransmitters. C_LIO_LIWhat are the new findings? [tpltrtarr]Patients with schizophrenia displayed increased rates of IA and increased SCFA production compared with healthy controls, and increased SCFA is associated with IA in patients. [tpltrtarr]A unique microbiota signature including enriched SCFA-producing bacterial species can distinguish patients with IA from other patients and controls. [tpltrtarr]Small molecules in the serum of immune-activated patients with schizophrenia enhance LPS-induced immune response of cultured peripheral blood mononuclear cell (PBMCs), which is partially mediated by SCFA signaling. [tpltrtarr]SCFA intake upregulates both peripheral and brain inflammation and potentiates the expression of schizophrenia-like behaviors in mice prenatally exposed to IA. C_LIO_LIHow might it impact on clinical practice in the foreseeable future? [tpltrtarr]Interference of SCFA signaling or targeted destruction of SCFA-producing bacteria may provide a new approach for the prevention and treatment of schizophrenia. [tpltrtarr]Immune activation status of patients should be an important condition considered when selecting immunotherapy for future precision psychiatric therapy. C_LI

NMDAR hypofunction is a pathophysiological mechanism relevant for schizophrenia. Acute administration of the NMDAR antagonist phencyclidine (PCP) induces psychosis in patients and animals while subchronic PCP (sPCP) produces cognitive dysfunction for weeks. We investigated the neural correlates of memory and perceptual impairments in mice treated with sPCP and the rescuing abilities of the atypical antipsychotic drug risperidone administered daily for two weeks. We recorded neural activities in the medial prefrontal cortex (mPFC) and the dorsal hippocampus (dHPC) during memory acquisition, short-term, and long-term memory in the novel object recognition test and during auditory perception and mismatch negativity (MMN) and examined the effects of sPCP and sPCP followed by risperidone. We found that the information about the new object and its short-term storage were associated with mPFC[->]dHPC high gamma connectivity whereas long-term memory retrieval depended on dHPC[->]mPFC theta connectivity. sPCP impaired short-term and long-term memory, which was associated with increased mPFC and decreased dHPC neural network activities, and disrupted mPFC-dHPC connectivity. Risperidone rescued the memory deficits and attenuated hippocampal desynchronization. sPCP also impaired auditory perception and its neural correlates (evoked potentials and MMN) in the mPFC, which were also ameliorated by risperidone. Our study suggests that during NMDAR hypofunction the mPFC and the dHPC disconnect possibly underlying cognitive impairment in schizophrenia, and that risperidone targets this circuit to ameliorate cognitive abilities in patients.

IntroductionExercise is a promising intervention for clinical high-risk for psychosis (CHR) populations, who have attenuated positive symptoms, but evidence suggests that these youth may require tailored exercise interventions. Presently, the scope of the problem is unknown, as these youth may not be reliable reporters on fitness. This issue is compounded by the fact that there have been no investigations that utilized a formal fitness assessment in this critical population. The present study aims to determine the level of fitness in CHR youth with lab-based measures, test how effectively self-report measures characterize objective fitness indices, and explore clinical factors that may be interrupting reliable self-report-an important tool if these interventions are to be taken to scale. MethodsForty CHR individuals completed an exercise survey and lab-based indices of fitness (i.e., VO2max and BMI). Forty healthy volunteers completed lab indices of fitness and a structured clinical interview ruling out the presence of psychiatric illness. ResultsCHR youth showed greater BMI and lower VO2max compared to healthy volunteers. In the CHR group, abstract self-report items (perceived fitness) did not reflect lab indices of fitness, whereas specific exercise behaviors (intensity of exercise) showed stronger correlations with laboratory-based fitness measurements. Exploratory analyses suggested that positive symptoms involving grandiosity, and negative symptoms such as avolition, correlated with discrepancy between self-perception and laboratory findings of fitness. DiscussionResults suggest that CHR individuals are less objectively fit than matched controls, and that it will be important to consider unique population characteristics when weighing self-report data.

IntroductionTo tackle the phenotypic heterogeneity of schizophrenia, data-driven methods are often applied to identify subtypes of its (sub)clinical symptoms though there is no systematic review. AimsTo summarize the evidence from cluster- and trajectory-based studies of positive, negative and cognitive symptoms in patients with schizophrenia spectrum disorders, their siblings and healthy people. Additionally, we aimed to highlight knowledge gaps and point out future directions to optimize the translatability of cluster- and trajectory-based studies. MethodsA systematic review was performed through searching PsycINFO, PubMed, PsycTESTS, PsycARTICLES, SCOPUS, EMBASE, and Web of Science electronic databases. Both cross-sectional and longitudinal studies published from 2008 to 2019, which reported at least two statistically derived clusters or trajectories were included. Two reviewers independently screened and extracted the data. ResultsOf 2,285 studies retrieved, 50 studies (17 longitudinal and 33 cross-sectional) conducted in 30 countries were selected for review. Longitudinal studies discovered two to five trajectories of positive and negative symptoms in patient, and four to five trajectories of cognitive deficits in patient and sibling. In cross-sectional studies, three clusters of positive and negative symptoms in patient, four clusters of positive and negative schizotypy in sibling, and three to five clusters of cognitive deficits in patient and sibling were identified. These studies also reported multidimensional predictors of clusters and trajectories. ConclusionsOur findings indicate that (sub)clinical symptoms of schizophrenia are more heterogeneous than currently recognized. Identified clusters and trajectories can be used as a basis for personalized psychiatry.

BackgroundDeficits in the way the brain processes rewards may contribute to negative symptoms in schizophrenia. Synchronization of alpha band neural oscillations is a dominant EEG signal when people are awake, but at rest. In contrast, alpha desynchronization to salient events is thought to direct allocation of information processing resources away from the internal state, to process salient stimuli in the external environment. Here, we hypothesize that alpha event-related desynchronization (ERD) during reward processing is altered in schizophrenia, leading to less difference in alpha ERD magnitude between winning and losing outcomes. MethodsEEG was recorded while participants (patients with schizophrenia (SZ)=54; healthy controls (HC) = 54) completed a casino-style slot machine gambling task. Total power, a measure of neural oscillation magnitude was measured in the alpha frequency range (8-14 Hz), time-locked to reward delivery, extracted via principal components analysis, and then compared between groups and equiprobable win and near miss loss reward outcomes. Associations between alpha power and negative symptoms and trait rumination were examined. ResultsA significant Group X Reward Outcome interaction (p=.018) was explained by differences within the HC group, driven by significant posterior-occipital alpha desynchronization to wins, relative to near miss losses (p<.001). In contrast, SZ did not modulate alpha power to wins vs. near miss losses (p>.1), nor did alpha power relate to negative symptoms (p>.1). However, across all participants, less alpha ERD to reward outcomes was related to more trait rumination, for both wins (p=.005) and near-miss losses (p=.002), with no group differences observed in the slopes of these relationships. ConclusionThese findings suggest that event-related modulation of alpha power is altered in schizophrenia during reward outcome processing, even when reward attainment places minimal demands on higher-order cognitive processes during slot machine play. In addition, high trait rumination is associated with less event-related desynchronization to reward feedback, suggesting that rumination covaries with less external attentional allocation to reward processing, regardless of reward outcome valence and group membership.

BackgroundDevelopment of synaptic activity is a neuronal key characteristic that relies largely on interactions between neurons and astrocytes. Although astrocytes have known roles in regulating synaptic function and malfunction, the use of human or donor-specific astrocytes in disease models is still rare. Rodent astrocytes are routinely used to enhance neuronal activity in cell cultures, but less is known how human astrocytes influence neuronal activity. MethodsWe established human induced pluripotent stem cell (hiPSC)-derived neuron-astrocyte co-cultures and studied their functional development on microelectrode array (MEA). We used cell lines from 5 neurotypical control individuals and 3 pairs of monozygotic twins discordant for schizophrenia. A method combining Ngn2 overexpression and dual SMAD inhibition was used for neuronal differentiation. The neurons were co-cultured with hiPSC-derived astrocytes differentiated from 6-month-old astrospheres or rat astrocytes. ResultsWe found that the hiPSC-derived co-cultures develop complex network bursting activity similarly to neuronal co-cultures with rat astrocytes. However, the effect of NMDA receptors on neuronal network burst frequency (NBF) differed between co-cultures containing human or rat astrocytes. By using co-cultures derived from patients with schizophrenia and unaffected individuals, we found lowered NBF in the affected cells. We continued to demonstrate how astrocytes from an unaffected individual rescue the lowered NBF in the affected neurons by increasing NMDA receptor activity. ConclusionsOur results indicate that astrocytes participate in the regulation of neuronal NBF through a mechanism involving NMDA receptors. These findings shed light on the importance of using human and donor-specific astrocytes in disease modeling.

BackgroundSchizophrenia is characterised by widespread neural dysconnectivity and impaired temporal coordination. Despite these pervasive disruptions, patients can maintain coherent perception and functional behaviour, particularly during remission. This paradox is underexplored in the literature, which has primarily focused on symptom emergence. We propose a dual-role hypothesis of sensorimotor temporal recalibration, a process known for adapting to temporal discrepancies in sensorimotor integration. We hypothesise that temporal recalibration may serve both as a compensatory mechanism mitigating neural incoherence and as a trigger for positive symptoms. MethodTo investigate its compensatory role, we compared 20 clinically stable schizophrenia patients to 20 matched healthy controls using a visuomotor temporal order judgement task following adaptation to varying sensorimotor asynchronies (0, 150 and 300 ms). ResultsOur findings revealed that patients with schizophrenia exhibited significantly greater temporal recalibration compared to controls. Across participants, recalibration was stronger for longer delays. No group differences were observed in just noticeable differences (JNDs) suggesting comparable task difficulty and temporal precision. ConclusionsThese findings suggest that patients not only have an intact temporal recalibration mechanism but also may engage it more to counteract neural delays and preserve temporal coherence. We further propose that overreliance on this adaptive mechanism may paradoxically contribute to symptom emergence under conditions of temporal instability by distorting the perceived order of actions and their sensory consequences. This dual-role hypothesis offers a novel perspective for understanding how the same temporal mechanism can sustain perceptual coherence, yet under certain conditions, contribute to the breakdown of causality and agency, which underlie control delusions and hallucinations.

To comprehensively investigate the white matter (WM) features of cerebellum in patients with schizophrenia, and further assess the correlation between altered WM features and clinical and cognitive assessments. Forty-two patients and fifty-two matched healthy controls (HCs) of the Collaborative Informatics and Neuroimaging Suite Data Exchange tool were involved in this study. The cerebellar WM volume was calculated by voxel-based morphometry. And tract-based spatial statistics was used to analysis the diffusion changes in patients when compared to HCs. Furthermore, we investigated the correlation between altered imaging feature and clinical, cognitive assessments. Compared to HCs, the schizophrenia patients did not reveal difference in cerebellar WM volume and schizophrenia patients showed decreased fractional anisotropy and increased radial diffusivity in left middle cerebellar peduncles and inferior cerebellar peduncles in voxel-wise but not in tract-wise. Critically, these cerebellar changes were associated with disease duration in schizophrenia patients. And significant correlation between the altered cerebellar WM features and cognitive assessments only revealed in HCs but disrupted in schizophrenia patients. The present findings suggested that the voxel-wise WM integrity analysis might was the more sensitive way to investigate the structural abnormalities in schizophrenia patients. Middle cerebellar peduncles and inferior cerebellar peduncles may be a crucial neurobiological substrate of cognition and thus might be regarded as a biomarker for treatment.

Psychotic disorders are conceptualized as brain-network diseases and both the cerebellum (CB) and basal ganglia (BG) are implicated in widely used conceptual models. Previous research has focused on these structures and their respective circuits as distinct, however, both are functionally and anatomically connected to each other and to cortical networks via domain-specific, topographically organized thalamo-cortical loops. Currently, it is unclear how CB-BG network dysfunction may play a mechanistic role in the course of psychosis; however, network global efficiency (GE), a measure of functional integration, is a novel approach that aims to represent cognitive and motor CB-BG network (CCBN, MCBN, respectively) connectivity in cross- sectional groups of healthy control (HC), clinical high-risk (CHR), early course psychosis (ECP), and chronic psychosis (CP) participants. We compared network GE between groups and inspected individual differences in CCBN- and MCBN-GE as it relates to group membership and to psychosis symptoms. We also associated CB-BG network GE with cortical network GE. Results indicated that CCBN-GE was associated with cognitive dysfunction and lower in CHR individuals, compared to HC and CP; while MCBN was associated with negative psychosis symptoms. Last, we detailed CB-BG associations with sensory, motor, default mode, and salience networks across groups, with group effects demonstrating complex differences within the ECP group. Findings indicating that CB-BG network dysfunction may play an important role in early pathogenesis and authors argue for CB-BG dysfunction to be analyzed from a network perspective. Future work is needed however to incorporate this approach into our understanding of psychosis.

BackgroundMismatch negativity (MMN) is elicited upon detecting background irregularities in the sensory environment and subsequent updating of the sensory context. Auditory MMN amplitude is reliably attenuated in schizophrenia patients. However, due to diversity in MMN deviant types (duration, frequency, intensity, gap, etc.), considerable variability exists in MMN findings reported from the early course and chronic samples. MMN is sometimes reported to be impaired or associated with schizotypy, but MMN and schizotypy are yet to be well examined in unaffected first-degree relatives of schizophrenia patients. MethodsFifty-two schizophrenia patients (SZ) were compared with thirty-six unaffected first-degree relatives (FDR) of schizophrenia patients and thirty-two age and sex-matched healthy controls (HC) on MMN indices using a two-tone passive auditory oddball paradigm with two conditions - duration deviant (MMNd) and frequency deviant (MMNf) event-related potential experiment. SZ sample was further split into two sub-groups 1) early-course/drug-naive or drug-free (dSZ), and 2) chronic/medicated (cSZ) to examine the effect of illness chronicity and medication on MMN indices. We also checked whether schizotypy scores associated with MMNd and MMNf amplitudes in the FDR group. ResultsAt baseline, SZ group had significantly diminished MMNd amplitude compared to both HC and FDR groups (p<0.001). The SZ group also had significantly lower MMNd latency than the FDR group (p<0.014). The cSZ and dSZ groups did not differ from each other on MMN amplitude or latency, though cSZ group had lower MMN amplitude. Only cSZ patients showed negative correlation of MMNd amplitude with hallucinations scores and total duration of illness. In FDRs, MMNd and MMNf amplitudes showed negative correlation with the cognitive-perceptual factor of schizotypy. DiscussionDeficient MMNd in SZ patients adds further support to the prediction error estimation abnormalities in schizophrenia. MMNd is a more robust measure than MMNf in differentiating SZ from FDR and HC. MMNd amplitude could be more impaired in hallucinating SZ patients and associate with illness chronicity. Though unaffected FDRs have MMN comparable to healthy controls, higher schizotypy in FDR is associated with lower MMN amplitude. MMN and schizotypy are potentially linked and deserve a nuanced examination.

Background and HypothesisAuditory verbal hallucinations (AHs) are a cardinal symptom of schizophrenia that can cause distress but are not always responsive to antipsychotic medications. There is a critical need to develop novel interventions that target neural mechanisms underlying AHs. We developed a real-time fMRI neurofeedback (NFB) paradigm for AHs that aims at modulating default mode network (DMN) functional connectivity. Study DesignPatients with schizophrenia or schizoaffective disorders who were experiencing AHs (N = 25) attempted to decrease brain activation while listening to sentences recorded in another persons voice and increase brain activation while listening to sentences recorded in their own voice. Participants randomly assigned to the real group (n = 12) received neurofeedback based on signals from their auditory cortex in the superior temporal gyrus (STG) and those assigned to the sham group (n = 13) received neurofeedback based on motor cortex signals. Study ResultsAnalyzing resting state fMRI data collected pre- and post-NFB, we found that: (1) at baseline, stronger within-DMN connectivity between the medial prefrontal cortex (MPFC) and posterior cingulate cortex was associated with higher AHs severity; (2) after NFB, participants in the real group, compared to those in the sham group, showed greater reduction in functional connectivity between the MPFC and auditory cortices in the STG and middle temporal gyrus (MTG). Notably, the reduction in MPFC-STG/MTG connectivity was found in all participants in the real group. ConclusionsThese findings suggest that NFB can effectively and non-invasively modulate functional connectivity in regions associated with AHs in psychosis.

PurposeP50 suppression (sensory gating or inhibition), MMN (mismatch negativity; bottom-up detection of change), ERN (error related negativity; conflict monitoring) and P300 (attention allocation and memory updating for salient events) are event related potentials (ERPs) widely reported to show abnormal cognitive functioning among patients with schizophrenia. In real-life scenarios the brain processing underlying these ERPs occur simultaneously, and yet prior ERP studies have evaluated them in isolation. The current study uses a novel paradigm that can examine these multiple ERPs simultaneously, and explore if the reported ERP deficits would hold true during a more realistic setting.\n\nMethodData from 21 patients with schizophrenia and 25 age- and gender-matched healthy controls were used, who underwent ERP recordings during the Assessing Neurocognition via Gamified Experimental Logic (ANGEL) paradigm. This is a gamified visual odd-ball paradigm that generates P300, the error responses generate ERN, and paired-tone audio distractors generate P50 and MMN. Peak-peak amplitude, mean amplitude and area-under-curve measures of ERP were measured at electrodes reflecting best morphology.\n\nResultsThough patients showed apparent ERP morphology differences relative to the controls, the standard ERP measures were comparable between groups, except for reduced ERN among patients. Interestingly, significant group differences were seen in N1-P2 complex suppression, despite comparable P50 suppression.\n\nContribution of the researchThe current study is the first to report multiple ERP component measures simultaneously evoked among patients with schizophrenia, and shows greater signs for impaired prediction mechanism. The findings of the study would provide a more ecologically valid evaluation of ERP-based cognitive functioning, and need to be replicated in a larger sample as well as other mental disorders.

Schizophrenia is a serious psychotic disorder caused by both individuals genetic background and their living environment. However, how the cognitive and negative symptoms can be treated is still a challenge since most anti-psychotic drugs are only effective for positive symptoms. Previous epidemic studies have demonstrated that plant exposure could decrease the risk of schizophrenia and shorten the length of psychiatric hospital admissions for patients. However, it is still unknown whether plant exposure could improve cognition-related defects in schizophrenia, with no related animal studies. In the present study, we first induced a schizophrenia mice model by giving mice long-term (2 weeks) injections of the antagonist of the NMDA receptor: MK801. We then raised the animals in environments containing plants (4 weeks) including Epipremnum aureum and rosemary, and tested their locomotive, anxious and social behaviors. We found that plant exposure did not change the locomotion behaviors of wild-type animals, but significantly reduced the schizophrenia-related social and anxious behaviors in the schizophrenic animals. In addition, we tested the expression of c-Fos in animals exposed to plants after social behavioral testing and found that the deficits in c-Fos expression in both the hippocampus and prefrontal cortex were partially rescued after plant exposure. These results indicate plant exposure will be a new tool to improve the clinical deficits of schizophrenia.

Schizophrenia (SZ) is a debilitating disorder in which patients exhibit psychotic behavior due to aberrant connectivity between different regions of the brain. Advances in neuroimaging have now enabled the diagnosis and analysis of SZ in order to elucidate the whole brain functional connectivity networks. In the present study, we have used resting-state functional magnetic resonance imaging (rs-fMRI) to elucidate the causal relationships amongst the differentially activated brain regions between SZ patients (n=10) and healthy controls (n=10). Vector auto-regression (VAR) model and Granger causality (GC) were then applied to construct a functional connectivity network and analyze the causal effects in SZ patients. Our results revealed that the average voxel activation in the frontal lobe (FL), basal ganglia (BG), and ventricular system (VS) was significantly higher in patients indicating hyper-activity as compared to controls. Conversely, cerebellum white matter (CBWM) showed higher activation in the controls as compared to patients. A higher Pearson correlation was observed between the controls as compared to patients while VAR and GC showed higher functional connectivity among all the regions of interest (ROIs) along with more causal relations in the controls. Finally, mediation analysis showed that right middle superior frontal gyrus acts as a strong partial mediator between left accumbens area and left middle superior frontal gyrus. Taken together, this study decodes the dysregulated brain activity in schizophrenia showing hyperactivation in patients when compared with the healthy controls which leads to alterations in neural connections resulting in hypoconnectivity.

Repetitive transcranial magnetic stimulation (rTMS), when applied to left dorsolateral prefrontal cortex (LDLPFC), reduces negative symptoms of schizophrenia, but has no effect on positive symptoms. In a small number of cases, it appears to worsen the severity of positive symptoms. It has been hypothesized that high frequency rTMS of the LDLPFC might increase the dopaminergic neurotransmission by driving the activity of the left striatum in the basal ganglia (LSTR)--increasing striatal dopaminergic activity. This hypothesis relies on the assumption that either the frontal-striatal connection or the intrinsic frontal and/or striatal connections covary with the severity of positive symptoms. The current work aimed to evaluate this assumption by studying the association between positive and negative symptoms severity and the effective connectivity within the frontal and striatal network using dynamic causal modeling (DCM) of ultra-high field (7 Tesla) resting state fMRI in a sample of 19 first episode psychosis (FEP) subjects. We found that of all core symptoms of schizophrenia, only delusions are strongly associated with the fronto striatal circuitry. Stronger intrinsic inhibitory tone of LDLPFC and LSTR, as well as a pronounced backward inhibition of the LDLPFC on the LSTR related to the severity of delusions. We interpret that an increase in striatal dopaminergic tone that underlies delusional symptoms, is likely associated with increased prefrontal inhibitory tone, strengthening the frontostriatal brake. Furthermore, based on our model, we propose that lessening of positive symptoms could be achieved by means of continuous theta-burst or low frequency (1Hz) rTMS of the prefrontal area.

The 22q11 deletion syndrome (22q11DS) is an interstitial microdeletion associated to an increased risk of developing schizophrenia. In this disorder, there is a dysfunction in the overall connectivity of the brain. Parvalbumin-expressing (PV+) interneurons have been associated with multiple pre- and post-synaptic impairments that affect various brain regions. Specifically, previous results have suggested that alterations in hippocampal networks may be related to PV+ interneurons dysfunction. In this study, we used the Df1 mouse model that carries the 22q11 deletion to examine the excitability of PV+ cells in the dorsal CA1 region of the hippocampus, due to its importance in memory and cognition. We found that PV+ interneurons were hyperexcitable in this region. To understand the source of the altered excitability, we measured potassium currents, highly involved in the intrinsic firing properties of neurons. We observed that voltage-gated potassium channel subfamily A member 1 (Kv1.1) was impaired in PV+ cells. Specific activation of this channel recovered some of the excitability disturbances observed in Df1 mice. Furthermore, blockade of synaptic inputs also restored PV+ interneurons excitability. Taken together, these results suggest that PV excitability is increased in the CA1 region of the hippocampus and it is partially mediated by Kv1.1 in a mouse model of 22q11DS.

IntroductionBrain connectivity is disturbed in schizophrenia, both during resting state and during active tasks. Schizophrenia is characterised by a corpus callosum pathology and an inability to suppress overstimulation, both of which relate to this disturbed connectivity. We wanted to verify whether network analysis on EEG sensor level can reveal the corpus callosum pathology in schizophrenia.\n\nMethodsWe measured 62-channel EEG on 46 schizophrenia patients and 43 healthy controls during eyes-closed and eyes-open resting-state, mismatch negativity and visual and auditory oddball. We assessed connectivity through correlation, coherence and directed transfer function (DTF) in the delta, theta, alpha, low- and high beta bands.\n\nResultsThe coherence and the DTF picked up a consistent pattern of reduced interhemispheric and enhanced intrahemispheric connectivity strength in schizophrenia in the alpha and beta band. This disturbance pattern appeared across all paradigms in the parietal and the occipital region and was generally more pronounced in the right hemisphere.\n\nConclusionsThis is the first study to use multiple similarity measures and different tasks to confirm disturbed brain connectivity on EEG sensor level. We hypothesise that the interhemispheric reductions reflect transcallosal disconnection, while the intrahemispheric increases indicate the inability to suppress the response to stimuli.