Auditory hallucinations (AH), typically hearing voices, are a core symptom in schizophrenia. They may result from deficits in dynamic functional connectivity (FC) between cortical regions supporting speech production and language perception that interfere with the ability to recognize self-generated speech as not coming from external sources. We tested this hypothesis by investigating dynamic connectivity between the frontal cortex region related to language production and the temporal cortex region related to auditory processing. Resting-state fMRI scans were acquired from 18 schizophrenia patients with AH (AH+), 17 schizophrenia patients without AH (AH-) and 22 healthy controls. A multiband sequence with TR = 427 ms was adopted to provide relatively high temporal resolution data for characterizing dynamic FC. Analysis focused on connectivity between speech production and language comprehension areas, eloquent language cortex in the left hemisphere. Two frequency bands of brain oscillatory activity were evaluated (0.01-0.027 Hz, 0.027-0.08 Hz) in which differential alterations that have been previously linked to schizophrenia. Conventional static FC maps of these seeds were also calculated. Dynamic connectivity analysis indicated that AH+ patients showed not only less temporal variability but transient lower strength in connectivity between speech and auditory areas than healthy controls, while AH- patients not. These findings were restricted to 0.027-0.08 Hz activity. In static connectivity analysis, no significant differences were observed in connectivity between speech production and language comprehension areas in either frequency band. Reduced temporal variability and connectivity strength between key regions of eloquent language cortex may represent a mechanism for AH in schizophrenia.

It has previously been shown that cerebello-thalamo-cortical (CTC) hyperconnectivity is likely a state-independent neural signature for psychosis. However, the potential clinical utility of this change has not yet been evaluated. Here, using fMRI and clinical data acquired from 214 untreated first-episode patients with schizophrenia (62 of whom were clinically followed-up at least once at the 12th and 24th months after treatment initiation) and 179 healthy controls, we investigated whether CTC hyperconnectivity would serve as an individualized biomarker for diagnostic classification and prediction of long-term treatment outcome. Cross-validated LASSO regression was conducted to estimate the accuracy of baseline CTC connectivity for patient-control classification, with the generalizability of classification performance tested in an independent sample including 42 untreated first-episode patients and 65 controls. Associations between baseline CTC connectivity and clinical outcomes were evaluated using linear mixed model and leave-one-out cross validation. We found significantly increased baseline CTC connectivity in patients (P = .01), which remained stable after treatment. Measures of CTC connectivity discriminated patients from controls with moderate classification accuracy (AUC = 0.68, P < .001), and the classification model had good generalizability in the independent sample (AUC = 0.70, P < .001). Higher CTC connectivity at baseline significantly predicted poorer long-term symptom reduction in negative symptoms (R = 0.31, P = .01) but not positive or general symptoms. These findings provide initial evidence for the putative “CTC hyperconnectivity” anomaly as an individualized diagnostic and prognostic biomarker for schizophrenia, and highlight the potential of this measure in precision psychiatry.

A large number of neuroimaging studies have detected brain abnormalities in first-episode schizophrenia both before and after treatment, but it remains unclear how these abnormalities reflect the effects of antipsychotic treatment on the brain. To summarize the findings in this regard and provide potential directions for future work, we reviewed longitudinal structural and functional imaging studies in patients with first-episode schizophrenia before and after antipsychotic treatment. A total of 36 neuroimaging studies was included, involving 21 structural imaging studies and 15 functional imaging studies. Both anatomical and functional brain changes in patients after treatment were consistently observed in the frontal and temporal lobes, basal ganglia, limbic system and several key components within the default mode network (DMN). Alterations in these regions were affected by factors such as antipsychotic type, course of treatment, and duration of untreated psychosis (DUP). Over all we showed that: (a) The striatum and DMN were core target regions of treatment in schizophrenia, and their changes were related to different antipsychotics; (b) The gray matter of frontal and temporal lobes tended to reduce after long-term treatment; and (c) Longer DUP was accompanied with faster hippocampal atrophy after initial treatment, which was also associated with poorer outcome. These findings are in accordance with previous notions but should be interpreted with caution. Future studies are needed to clarify the effects of different antipsychotics in multiple conditions and to identify imaging or other biomarkers that may predict antipsychotic treatment response. With such progress, it may help choose effective pharmacological interventional strategies for individuals experiencing recent-onset schizophrenia.

Background: Cerebellar functional dysconnectivity has long been implicated in schizophrenia. However, the detailed dysconnectivity pattern and its underlying biological mechanisms have not been well-charted. This study aimed to conduct an in-depth characterization of cerebellar dysconnectivity maps in early schizophrenia.Study design: Resting-state fMRI data were processed from 196 drug-naïve patients with first-episode schizophrenia and 167 demographically matched healthy controls. The cerebellum was parcellated into nine functional systems based on a state-of-the-art atlas, and seed-based connectivity for each cerebellar system was examined. The observed connectivity alterations were further associated with schizophrenia risk gene expressions using data from the Allen Human Brain Atlas.Study results: Overall, we observed significantly increased cerebellar connectivity with the sensorimotor cortex, default-mode regions, ventral part of visual cortex, insula, and striatum. In contrast, decreased connectivity was shown chiefly within the cerebellum, and between the cerebellum and the lateral prefrontal cortex, temporal lobe, and dorsal visual areas. Such dysconnectivity pattern was statistically similar across seeds, with no significant group by seed interactions identified. Moreover, connectivity strengths of hypoconnected but not hyperconnected regions were significantly correlated with schizophrenia risk gene expressions, suggesting potential genetic underpinnings for the observed hypoconnectivity.Conclusions: These findings suggest a common bidirectional dysconnectivity pattern across different cerebellar subsystems, and imply that such bidirectional alterations may relate to different biological mechanisms.