Automatic auditory processing features in distinct subtypes of patients at clinical high risk for psychosis: Forecasting remission with mismatch negativity.

Individuals at clinical high risk (CHR) for psychosis exhibit a compromised mismatch negativity (MMN) response, which indicates dysfunction of pre-attentive deviance processing. Event-related potential and time-frequency (TF) information, in combination with clinical and cognitive profiles, may provide insight into the pathophysiology and psychopathology of the CHR stage and predict the prognosis of CHR individuals. A total of 92 individuals with CHR were recruited and followed up regularly for up to 3 years. Individuals with CHR were classified into three clinical subtypes demonstrated previously, specifically 28 from Cluster 1 (characterized by extensive negative symptoms and cognitive deficits), 31 from Cluster 2 (characterized by thought and behavioral disorganization, with moderate cognitive impairment), and 33 from Cluster 3 (characterized by the mildest symptoms and cognitive deficits). Auditory MMN to frequency and duration deviants was assessed. The event-related spectral perturbation (ERSP) and inter-trial coherence (ITC) were acquired using TF analysis. Predictive indices for remission were identified using logistic regression analyses. As expected, reduced frequency MMN (fMMN) and duration MMN (dMMN) responses were noted in Cluster 1 relative to the other two clusters. In the TF analysis, Cluster 1 showed decreased theta and alpha ITC in response to deviant stimuli. The regression analyses revealed that dMMN latency and alpha ERSP to duration deviants, theta ITC to frequency deviants and alpha ERSP to frequency deviants, and fMMN latency were significant MMN predictors of remission for the three clusters. MMN variables outperformed behavioral variables in predicting remission of Clusters 1 and 2. Our findings indicate relatively disrupted automatic auditory processing in a certain CHR subtype and a close affinity between these electrophysiological indexes and clinical profiles within different clusters. Furthermore, MMN indexes may serve as predictors of subsequent remission from the CHR state. These findings suggest that the auditory MMN response is a potential neurophysiological marker for distinct clinical subtypes of CHR.

Common abnormal connectivity in first-episode and chronic schizophrenia in pre- and post-central regions: Implications for neuromodulation targeting.

Schizophrenia is a neurodevelopmental disorder manifesting differing impairments at early onset and chronic disease stages. Brain imaging research suggests a core pathological region in patients with first-episode schizophrenia is Broca's area. With disease progression, alterations in thalamic connectivity becomes more prevalent. Understanding the common circuitry underlying pathology in these two groups might highlight a critical common network and novel targets for treatment. In this study, 937 subject samples were collected including patients with first-episode schizophrenia and those with chronic schizophrenia. We used hypothesis-based voxel-level functional connectivity analyses to calculate functional connectivity using the left Broca's area and thalamus as regions of interest in those with first-episode and chronic schizophrenia, respectively. We show for the first time that in both patients with first-episode and chronic schizophrenia the greatest functional connectivity disruption ended in the pre- and postcentral regions. At the early-onset stage, the core brain region is abnormally connected to pre- and postcentral areas responsible for mouth movement, while in the chronic stage, it expanded to a wider range of sensorimotor areas. Our findings suggest that expanding the focus on the low-order sensory-motor systems beyond high-order cognitive impairments in schizophrenia may show potential for neuromodulation treatment, given the relative accessibility of these cortical regions and their functional and structural connections to the core region at different stages of illness.

Test-retest reliability of mismatch negativity and gamma-band auditory steady-state response in patients with schizophrenia.

Patients with schizophrenia show widespread impairments in clinical, cognitive and psychosocial functioning. Mismatch negativity (MMN) and gamma-band auditory steady-state response (ASSR) are two neurophysiological biomarkers widely used to inform diagnosis, guide treatments and track response to interventions in schizophrenia. However, evidence for the test-retest reliability of these indices across multiple sessions in schizophrenia patients remains scarce. In the present study, we included 34 schizophrenia patients (17 females) and obtained duration MMN (dMMN), frequency MMN (fMMN) and 40-Hz ASSR data across three sessions with intervals of 2 days. Event-related spectrum perturbation (ERSP) and inter-trial coherence (ITC) were calculated following Morlet wavelet time-frequency decomposition of ASSR data. The intra-class correlation coefficient (ICC) was used to quantify the reliability of MMN and ASSR measures among the three sessions. We found fair to good reliability for dMMN amplitudes but poor reliability for fMMN amplitudes. For the ASSR measures, ERSP showed good to excellent test-retest reliability while ITC had poor to fair test-retest reliability. In addition, the average of dMMN amplitudes was significantly correlated with that of ERSP across the three sessions. In summary, we established for the first time the short-term test-retest reliability of MMN and ASSR measures in schizophrenia patients. These findings demonstrate that dMMN amplitudes and ERSP of ASSR are reliable indices which may be used in longitudinal observational studies.

Temporal and time-frequency features of auditory oddball response in distinct subtypes of patients at clinical high risk for psychosis.

Individuals at clinical high risk (CHR) for psychosis exhibit a reduced P300 oddball response, which indicates deficits in attention and working memory processes. Previous studies have mainly researched these responses in the temporal domain; hence, non-phase-locked or induced neural activities may have been ignored. Event-related potential (ERP) and time-frequency (TF) information, combined with clinical and cognitive profiles, may provide an insight into the pathophysiology and psychopathology of the CHR stage. The 104 CHR individuals who completed cognitive assessments and ERP tests were recruited and followed up between 2016 and 2018. Individuals with CHR were classified by three clinical subtypes demonstrated before, specifically 32 from Cluster-1 (characterized by extensive negative symptoms and cognitive deficits, at the highest risk for conversion to psychosis), 34 from Cluster-2 (characterized by thought and behavioral disorganization, with moderate cognitive impairment), and 38 from Cluster-3 (characterized by the mildest symptoms and cognitive deficits). Electroencephalograms were recorded during the auditory oddball paradigm. The P300 ERPs were analyzed in the temporal domain. The event-related spectral perturbation (ERSP) and inter-trial coherence (ITC) were acquired by TF analysis. A reduced P300 response to target tones was noted in Cluster-1 relative to the other two clusters. Moreover, the P300 amplitude of Cluster-1 was associated with speed of processing (SoP) scores. Furthermore, the P300 amplitude of Cluster-3 was significantly correlated with verbal and visual learning scores. In the TF analysis, decreased delta ERSP and ITC were observed in Cluster-1; delta ITC was associated with SoP scores in Cluster-3. The results indicate relatively disrupted oddball responses in a certain CHR subtype and a close affinity between these electrophysiological indexes and attention, working memory, and declarative memory within different CHR clusters. These findings suggest that the auditory oddball response is a potential neurophysiological marker for distinct clinical subtypes of CHR.

From Receptive to Perceptive Fields: Size-Dependent Asymmetries in Both Negative Afterimages and Subcortical On and Off Post-Stimulus Responses.

Negative afterimages are perceptual phenomena that occur after physical stimuli disappear from sight. Their origin is linked to transient post-stimulus responses of visual neurons. The receptive fields (RFs) of these subcortical ON- and OFF-center neurons exhibit antagonistic interactions between central and surrounding visual space, resulting in selectivity for stimulus polarity and size. These two features are closely intertwined, yet their relationship to negative afterimage perception remains unknown. Here we tested whether size differentially affects the perception of bright and dark negative afterimages in humans of both sexes, and how this correlates with neural mechanisms in subcortical ON and OFF cells. Psychophysically, we found a size-dependent asymmetry whereby dark disks produce stronger and longer-lasting negative afterimages than bright disks of equal contrast at sizes >0.8°. Neurophysiological recordings from retinal and relay cells in female cat dorsal lateral geniculate nucleus showed that subcortical ON cells exhibited stronger sustained post-stimulus responses to dark disks, than OFF cells to bright disks, at sizes >1°. These sizes agree with the emergence of center-surround antagonism, revealing stronger suppression to opposite-polarity stimuli for OFF versus ON cells, particularly in dorsal lateral geniculate nucleus. Using a network-based retino-geniculate model, we confirmed stronger antagonism and temporal transience for OFF-cell post-stimulus rebound responses. A V1 population model demonstrated that both strength and duration asymmetries can be propagated to downstream cortical areas. Our results demonstrate how size-dependent antagonism impacts both the neuronal post-stimulus response and the resulting afterimage percepts, thereby supporting the idea of perceptual RFs reflecting the underlying neuronal RF organization of single cells.SIGNIFICANCE STATEMENT Visual illusions occur when sensory inputs and perceptual outcomes do not match, and provide a valuable tool to understand transformations from neural to perceptual responses. A classic example are negative afterimages that remain visible after a stimulus is removed from view. Such perceptions are linked to responses in early visual neurons, yet the details remain poorly understood. Combining human psychophysics, neurophysiological recordings in cats and retino-thalamo-cortical computational modeling, our study reveals how stimulus size and the receptive-field structure of subcortical ON and OFF cells contributes to the parallel asymmetries between neural and perceptual responses to bright versus dark afterimages. Thus, this work provides a deeper link from the underlying neural mechanisms to the resultant perceptual outcomes.

Magnetic seizure therapy for treatment-resistant depression.

BACKGROUND: Magnetic seizure therapy (MST) is a potential alternative to electroconvulsive therapy (ECT). Reports to date on use of MST for patients with treatment-resistant depression (TRD) are limited. OBJECTIVES: To evaluate the effects of MST in comparison with sham-MST, antidepressant, and other forms of electric or magnetic treatment for adults with TRD. SEARCH METHODS: In March 2020, we searched a wide range of international electronic sources for published, unpublished, and ongoing studies. We handsearched the reference lists of all included studies and relevant systematic reviews and conference proceedings of the Annual Meeting of the American College of Neuropsychopharmacology (ACNP), the Annual Scientific Convention and Meeting, and the Annual Meeting of the European College of Neuropsychopharmacology (ECNP) to identify additional studies. SELECTION CRITERIA: All randomised clinical trials (RCTs) focused on MST for adults with TRD. DATA COLLECTION AND ANALYSIS: Two review authors extracted data independently. For binary outcomes, we calculated risk ratios (RRs) and 95% confidence intervals (CIs). For continuous data, we estimated mean differences (MDs) between groups and 95% CIs. We employed a random-effects model for analyses. We assessed risk of bias for included studies and created a 'Summary of findings' table using the GRADE approach. Our main outcomes of interest were symptom severity, cognitive function, suicide, quality of life, social functioning, dropout for any reason, serious adverse events, and adverse events that led to discontinuation of treatment. MAIN RESULTS: We included three studies (65 participants) comparing MST with ECT. Two studies reported depressive symptoms with the Hamilton Rating Scale for Depression (HAMD). However, in one study, the data were skewed and there was an imbalance in baseline characteristics. Analysis of these two studies showed no clear differences in depressive symptoms between treatment groups (MD 0.71, 95% CI -2.23 to 3.65; 2 studies, 40 participants; very low-certainty evidence). Two studies investigated multiple domains of cognitive function. However most of the outcomes were not measured by validated neuropsychological tests, and many of the data suffered from unbalanced baseline and skewed distribution. Analysis of immediate memory performance measured by the Wechsler Memory Scale showed no clear differences between treatment groups (MD 0.40, 95% CI -4.16 to 4.96; 1 study, 20 participants; very low-certainty evidence). Analysis of delayed memory performance measured by the Wechsler Memory Scale also showed no clear differences between treatment groups (MD 2.57, 95% CI -2.39 to 7.53; 1 study, 20 participants; very low-certainty evidence). Only one study reported quality of life, but the data were skewed and baseline data were unbalanced across groups. Analysis of quality of life showed no clear differences between treatment groups (MD 14.86, 95% CI -42.26 to 71.98; 1 study, 20 participants; very low-certainty evidence). Only one study reported dropout and adverse events that led to discontinuation of treatment. Analysis of reported data showed no clear differences between treatment groups for this outcome (RR 1.38, 95% CI 0.28 to 6.91; 1 study, 25 participants; very low-certainty evidence). Adverse events occurred in only two participants who received ECT (worsening of preexisting coronary heart disease and a cognitive adverse effect). None of the included studies reported outcomes on suicide and social functioning. No RCTs comparing MST with other treatments were identified. AUTHORS' CONCLUSIONS: Evidence regarding effects of MST on patients with TRD is currently insufficient. Our analyses of available data did not reveal clearly different effects between MST and ECT. We are uncertain about these findings because of risk of bias and imprecision of estimates. Large, long, well-designed, and well-reported trials are needed to further examine the effects of MST.

The lateralization and reliability of spatial mismatch negativity elicited by auditory deviants with virtual spatial location.

Mismatch negativity (MMN) is an intensively studied event-related potential component that reflects pre-attentive auditory processing. Existing spatial MMN (sMMN) studies usually use loud-speakers in different locations or deliver sound with binaural localization cues through earphones to elicit MMN, which either was practically complicated or sounded unnatural to the subjects. In the present study, we generated head related transfer function (HRTF)-based spatial sounds and verified that the HRTF-based sounds retained the left and the right spatial localization cues. We further used them as deviants to elicit sMMN with conventional oddball paradigm. Results showed that sMMN was successfully elicited by the HRTF-based deviants in 18 of 21 healthy subjects in two separate sessions. Furthermore, the left deviants elicited higher sMMN amplitudes in the right hemisphere compared to the left hemisphere, while the right deviants elicited sMMN with similar amplitudes in both hemispheres, which supports a combination of contralateral and right-hemispheric dominance in spatial auditory information processing. In addition, the sMMN in response to the right deviants showed good test-retest reliability, while the sMMN in response to the left deviants had weak test-retest reliability. These findings implicate that HRTF-based sMMN could be a robust paradigm to investigate spatial localization and discrimination abilities.

Altered functional connectivity of the thalamus induced by modified electroconvulsive therapy for schizophrenia.

BACKGROUND: Electroconvulsive therapy (ECT) has been shown to be effective in schizophrenia (SZ), particularly in drug-refractory cases or when rapid symptom relief is needed. However, its precise mechanisms of action remain largely unclear. To clarify the mechanisms underlying modified electroconvulsive therapy (mECT) for SZ, we conducted a longitudinal cohort study evaluating functional connectivity of the thalamus before and after mECT treatment using sub-regions of thalamus as regions of interest (ROIs). METHODS: Twenty-one SZ individuals taking only antipsychotics (DSZ group) for 4 weeks and 21 SZ patients receiving a regular course of mECT combining with antipsychotics (MSZ group) were observed in parallel. All patients underwent magnetic resonance imaging scans at baseline (t1) and follow-up (t2, ~4 weeks) time points. Data were compared to a matched healthy control group (HC group) consisting of 23 persons who were only scanned at baseline. Group differences in changes of thalamic functional connectivity between two SZ groups over time, as well as in functional connectivity among two SZ groups and HC group were assessed. RESULTS: Significant interaction of group by time was found in functional connectivity of the right thalamus to right putamen during the course of about 4-week treatment. Post-hoc analysis showed a significantly enhanced functional connectivity of the right thalamus to right putamen in the MSZ group contrasting to the DSZ group. In addition, a decreased and an increased functional connectivity of the thalamus to sensory cortex were observed within the MSZ and DSZ group after 4-week treatment trial, respectively. CONCLUSION: Our findings suggest that changes in functional connectivity of the thalamus may be associated with the brain mechanisms of mECT for schizophrenia.

Aberrant resting-state functional connectivity of salience network in first-episode schizophrenia.

The disruption of salience network (SN) has been consistently found in patients with schizophrenia and thought to give rise to specific symptoms. However, the functional dysconnectivity pattern of SN remains unclear in first-episode schizophrenia (FES). Sixty-five patients with FES and sixty-six health controls (HC) were enrolled in this study and underwent resting-state functional magnetic resonance imaging (rs-fMRI). The eleven regions of interest (ROIs) within SN were derived from the peaks of the group independent component analysis (gICA). Seed-based whole-brain functional connectivity (FC) analyses were performed with all SN ROIs as the seeds. Both hyper- and hypo-connectivity of SN were found in the FES. Specifically, the increased FC mainly existed between the SN and cortico-cerebellar sub-circuit and prefrontal cortex, while the reduced FC mainly existed within cortico-striatal-thalamic-cortical (CSTC) sub-circuit. Our findings suggest that FES is associated with pronounced dysregulation of SN, characterized prominently by hyperconnectivity of SN-prefrontal cortex and cerebellum, as well as hypoconnectivity of CSTC sub-circuit of the SN.

Aberrant Prefrontal-Thalamic-Cerebellar Circuit in Schizophrenia and Depression: Evidence From a Possible Causal Connectivity.

Neuroimaging studies have suggested the presence of abnormalities in the prefrontal-thalamic-cerebellar circuit in schizophrenia (SCH) and depression (DEP). However, the common and distinct structural and causal connectivity abnormalities in this circuit between the two disorders are still unclear. In the current study, structural and resting-state functional magnetic resonance imaging (fMRI) data were acquired from 20 patients with SCH, 20 depressive patients and 20 healthy controls (HC). Voxel-based morphometry analysis was first used to assess gray matter volume (GMV). Granger causality analysis, seeded at regions with altered GMVs, was subsequently conducted. To discover the differences between the groups, ANCOVA and post hoc tests were performed. Then, the relationships between the structural changes, causal connectivity and clinical variables were investigated. Finally, a leave-one-out resampling method was implemented to test the consistency. Statistical analyses showed the GMV and causal connectivity changes in the prefrontal-thalamic-cerebellar circuit. Compared with HC, both SCH and DEP exhibited decreased GMV in middle frontal gyrus (MFG), and a lower GMV in MFG and medial prefrontal cortex (MPFC) in SCH than DEP. Compared with HC, both patient groups showed increased causal flow from the right cerebellum to the MPFC (common causal connectivity abnormalities). And distinct causal connectivity abnormalities (increased causal connectivity from the left thalamus to the MPFC in SCH than HC and DEP, and increased causal connectivity from the right cerebellum to the left thalamus in DEP than HC and SCH). In addition, the structural deficits in the MPFC and its causal connectivity from the cerebellum were associated with the negative symptom severity in SCH. This study found common/distinct structural deficits and aberrant causal connectivity patterns in the prefrontal-thalamic-cerebellar circuit in SCH and DEP, which may provide a potential direction for understanding the convergent and divergent psychiatric pathological mechanisms between SCH and DEP. Furthermore, concomitant structural and causal connectivity deficits in the MPFC may jointly contribute to the negative symptoms of SCH.

"Brain Connectivity Deviates by Sex and Hemisphere in the First Episode of Schizophrenia"-A Route to the Genetic Basis of Language and Psychosis?

Schizophrenia is genetic in origin and associated with a fecundity disadvantage. The deficits in schizophrenia have been attributed to variation related to the human capacity for language or brain laterality. How sex influences the relative connectivity of the 2 hemispheres is a route to understanding these 2 functions. Using resting-state functional magnetic resonance imaging (fMRI) we searched for sex- and hemisphere-specific changes in whole-brain functional-connectivity in multi-site datasets (altogether 672 subjects including 286 patients, all right-handed) in the first-episode schizophrenia (illness duration ≤ 1 year, mostly drug naive) and in chronic stages of schizophrenia (illness duration > 1 year), respectively. We used meta-analyses to integrate data from different sources concerning individuals at the same illness stage. We found first-episode male patients are predominantly left-lateralized in aberrant connectivity with a focus on Broca's area. Female patients show a lesser degree of lateralization than males, but to the right particularly in orbital frontal cortex. In the chronic stage, the focus of aberrant connectivity shifted from anterior to posterior structures with prominent involvement of the thalamus and pre- and post-central gyri bilaterally and in both sexes. While the "deviant connectivity" is right-sided in both the first-episode and the chronic stages in females, in males there is a shift between stages from the left to the right hemisphere. We hypothesized that the pathophysiology of schizophrenia may lie in the interaction between sex and lateralization, ie, in genetic mechanisms located on the X and Y chromosomes, intrinsic to the evolution of language.

Abnormal auditory-evoked gamma band oscillations in first-episode schizophrenia during both eye open and eye close states.

Abnormal auditory steady state response (ASSR) is a typical finding among schizophrenia patients, which is thought to directly reflect deficient gamma band oscillations in the brain. However, whether these ASSR alterations are state dependent, e.g. during eye-open or eye-closed conditions, has not yet been carefully elucidated in schizophrenia. Our study aimed to explore whether the abnormality of ASSR in patients with first-episode schizophrenia (FEP) is altered under eye-open (EO) and eye-closed (EC) states. ASSR was elicited using 40 Hz click trains under EO and EC states. Twenty-eight healthy control subjects (HC) and thirty-three FEP individuals, 17 of whom were medication-naïve, were recruited. The event-related spectrum perturbation (ERSP) and intertrial coherence (ITC) in response to 40 Hz click sounds were quantified. Compared to HC group, FEP group showed a lower ITC and ERSP during EO state, as well as a decreased ITC during EC state. Our results suggest that abnormalities in gamma band oscillations among first-episode schizophrenia patients are present under both eye open and eye close states. Although differences in gamma band oscillations between EO and EC states within the FEP group were not observed, exploratory results suggest that state-sensitivity may be contingent on medication use.

Effectiveness of Traditional Chinese Medicineas as an Adjunct Therapy for Refractory Schizophrenia: A Systematic Review and Meta Analysis.

Although recent studies focused on traditional Chinese medicine (TCM) for the treatment of refractory schizophrenia have reported that it may be beneficial, there is still lack of convincing evidence and critical meta-analytic work regarding its effectiveness as an adjunctive therapy. Therefore, we performed a meta-analysis to investigate the effectiveness of TCM in combination with antipsychotics for refractory schizophrenia. Fourteen articles involving 1725 patients published as of December 2016 were included which compared antipsychotic therapies to either TCM alone, or TCM as an adjunctive therapy. TCM was observed to have beneficial effects on aspects of the Positive and Negative Syndrome Scale (PANSS) including total score changes and negative score changes, as well as clinical effects estimated with PANSS or the Brief Psychiatric Rating Scale (BPRS). The changes in extrapyramidal side effects (RSESE) scores from baseline to the end of the treatment period were similar in two groups of related trials. TCM was also reported to mitigate some anti-psychotic related side-effects and overall, TCM adjuvant therapy was generally safe and well tolerated. While, the results indicated the potential utility of TCM as an alternative adjunctive therapeutic for refractory schizophrenia treatment, there remains a need for further high-quality studies.

Huaier Extract Inhibits Breast Cancer Progression Through a LncRNA-H19/MiR-675-5p Pathway.

BACKGROUND/AIMS: Increasing evidence indicates that Huaier extract has promising therapeutic effects against cancer. However, the mechanisms that underlie its anti-tumor effects remain unclear. In recent years, various studies have shown that long noncoding RNAs (lncRNAs) play a critical role in the regulation of cancer development and progression. Here, we explored the role of lncRNAs in Huaier-induced tumor suppression. METHODS: Microarray profiling was performed to identify the candidate lncRNAs affected by Huaier extract. Quantitative realtime PCR (qPCR) was used to evaluate the transfection efficiency and the influence of Huaier extract on H19 expression. The effect of Huaier extract on the cell viability was examined by MTT. Moreover, the rates of apoptotic cells were detected using flow-cytometric analysis. Western blot analysis was applied to show the protein levels of CBL. RESULTS: Microarray data derived from Huaier-treated breast cancer cells identified H19 as a potential target. Huaier extract reduced the expression of H19. The over-expression of H19 inhibited the cytotoxic effects of Huaier extract; in contrast, reduced H19 expression enhanced the function of Huaier extract. MiR-675-5p was identified as a mature product of H19. Moreover, Huaier extract reduced the miR-675-5p expression. Upregulating miR-675-5p reversed the inhibitory effects of Huaier extract, whereas downregulating miR-675-5p sensitized breast cancer cells to the effect of Huaier extract. In addition, Huaier extract increased the expression of CBL protein, a direct target of miR-675-5p. CONCLUSION: Collectively, the data demonstrate that Huaier extract reduces viability and induces apoptosis in breast cancer cells via H19-miR-675-5p-CBL axis regulation.

Brain-Wide Analysis of Functional Connectivity in First-Episode and Chronic Stages of Schizophrenia.

Published reports of functional abnormalities in schizophrenia remain divergent due to lack of staging point-of-view and whole-brain analysis. To identify key functional-connectivity differences of first-episode (FE) and chronic patients from controls using resting-state functional MRI, and determine changes that are specifically associated with disease onset, a clinical staging model is adopted. We analyze functional-connectivity differences in prodromal, FE (mostly drug naïve), and chronic patients from their matched controls from 6 independent datasets involving a total of 789 participants (343 patients). Brain-wide functional-connectivity analysis was performed in different datasets and the results from the datasets of the same stage were then integrated by meta-analysis, with Bonferroni correction for multiple comparisons. Prodromal patients differed from controls in their pattern of functional-connectivity involving the inferior frontal gyri (Broca's area). In FE patients, 90% of the functional-connectivity changes involved the frontal lobes, mostly the inferior frontal gyrus including Broca's area, and these changes were correlated with delusions/blunted affect. For chronic patients, functional-connectivity differences extended to wider areas of the brain, including reduced thalamo-frontal connectivity, and increased thalamo-temporal and thalamo-sensorimoter connectivity that were correlated with the positive, negative, and general symptoms, respectively. Thalamic changes became prominent at the chronic stage. These results provide evidence for distinct patterns of functional-dysconnectivity across FE and chronic stages of schizophrenia. Importantly, abnormalities in the frontal language networks appear early, at the time of disease onset. The identification of stage-specific pathological processes may help to understand the disease course of schizophrenia and identify neurobiological markers crucial for early diagnosis.

Correlation Between Brain Activation Changes and Cognitive Improvement Following Cognitive Remediation Therapy in Schizophrenia: An Activation Likelihood Estimation Meta-analysis.

BACKGROUND: Several studies using functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) have indicated that cognitive remediation therapy (CRT) might improve cognitive function by changing brain activations in patients with schizophrenia. However, the results were not consistent in these changed brain areas in different studies. The present activation likelihood estimation (ALE) meta-analysis was conducted to investigate whether cognitive function change was accompanied by the brain activation changes, and where the main areas most related to these changes were in schizophrenia patients after CRT. Analyses of whole-brain studies and whole-brain + region of interest (ROI) studies were compared to explore the effect of the different methodologies on the results. METHODS: A computerized systematic search was conducted to collect fMRI and PET studies on brain activation changes in schizophrenia patients from pre- to post-CRT. Nine studies using fMRI techniques were included in the meta-analysis. Ginger ALE 2.3.1 was used to perform meta-analysis across these imaging studies. RESULTS: The main areas with increased brain activation were in frontal and parietal lobe, including left medial frontal gyrus, left inferior frontal gyrus, right middle frontal gyrus, right postcentral gyrus, and inferior parietal lobule in patients after CRT, yet no decreased brain activation was found. Although similar increased activation brain areas were identified in ALE with or without ROI studies, analysis including ROI studies had a higher ALE value. CONCLUSIONS: The current findings suggest that CRT might improve the cognition of schizophrenia patients by increasing activations of the frontal and parietal lobe. In addition, it might provide more evidence to confirm results by including ROI studies in ALE meta-analysis.

Decreased P300 current source density in drug-naive first episode schizophrenics revealed by high density recording.

Decreased P300 amplitude has been reported in schizophrenics during their first episode. The brain sources that contribute to this abnormality have not yet been well documented, and were investigated in the present study using high density EEG recordings. Nineteen drug-naive first episode schizophrenics were compared to 25 normal controls. Auditory P300 was elicited using an oddball paradigm. The brain sources of P300 ERP were reconstructed by performing low resolution of electromagnetic tomography (LORETA) analysis. No group difference in P300 latency was found. P300 amplitude was smaller for schizophrenics than for controls. Topographical analysis revealed that P300 amplitude reduction in schizophrenics was significant over left and medial regions of interest (ROIs). LORETA analysis of the P300 peak revealed that, the brain sources of P300 were symmetrically distributed over left and right hemispheres among the normal controls, but were asymmetrically distributed among the patients, with a reduction predominantly over the left temporal area. Statistical non-Parametric Mapping analysis identified 29 voxels of a significant group difference, which focused on left insula, left superior temporal gyrus (STG) and left postcentral gyrus (PCG). In addition, the mean P300 current source density over left insula, left STG and left PCG correlated inversely with the patients' Positive and Negative Syndrome Scale scores. The neural substrates that contributed to the decreased P300 amplitude in drug-naive first episode schizophrenia relatively focused on left STG and its nearby areas. These areas are probably involved in the pathogenesis of schizophrenia, and possible mechanisms for pathology need to be further clarified.

Abnormalities of auditory P300 cortical current density in patients with schizophrenia using high density recording.

While P300 current density analysis has been performed in schizophrenic patients, the event-related potential data have never been obtained using a high density recording, nor have their cortical images been well demonstrated. In this study, the auditory P300 elicited by an oddball paradigm was recorded using a high density recording system of 128 channels. Thirteen male patients who met DSM-IV criteria for schizophrenia were compared with 20 healthy male controls. The cortical current density analysis of low resolution electromagnetic tomography (LORETA) was applied to the P300 component, and this resulted in the values of 6222 current density points over the surface of a cortex model. The inter-group difference of P300 current density was assessed using a point-by-point comparison by t-test. While the normal controls demonstrated the cortical activation of bilateral frontal, temporal and parietal cortex during the oddball paradigm, visual inspection suggested that in the schizophrenic patients these areas were less activated. The inter-group significance of P300 current density was dominant over the left hemisphere, and particularly over the left prefrontal area. It is concluded that the LORETA current density analysis localizes the neural activity from the cortical fronto-temporo-parietal network as the neural substrates of the scalp recorded P300. The dysfunction of such a network, especially over the left hemisphere, possibly subserves the scalp recorded P300 abnormality in schizophrenia.