Thalamic-Auditory Cortical-Hippocampal Dysconnectivity in First-Episode Schizophrenia Patients with Auditory Verbal Hallucinations

Long-Biao Cui¹, Baojuan Li², Yi-Bin Xi¹, and Hong Yin¹

¹Xijing Hospital, Fourth Mililtary Medical University, Xi'an, China, People's Republic of, ²School of Biomedical Engineering, Fourth Mililtary Medical University, Xi'an, China, People's Republic of

Synopsis

We found hyperconnectivity from the thalamus to auditory cortex and hypoconnectivity from the auditory cortex to the hippocampus in AVHs. The thalamic-auditory cortical-hippocampal circuit seems to be crucial for AVHs in SZ. In SZ patients with AVHs, there is a failure to attenuate the sensitivity of auditory cortex to thalamic inputs with a complementary down-regulation of hippocampal responses to ascending auditory input. These findings are consistent with current thinking about dysconnection syndromes in SZ; particularly the aberrant modulation of neuromodulatory gain control and its role assigning aberrant precision or salience to sensory evidence in conditions like SZ. Our findings might provide support for dysconnectivity hypothesis of AVHs associated with auditory/language-processing regions, default mode regions, and other networks (insula and striatum), as reviewed most recently. Dysconnectivity of this circuit may also serve as a potential diagnostic biomarker and therapeutic target of AVHs in SZ based on the direct evidence in vivo we found.

Background: Evidence suggests the interactions among auditory and language processing-related brain regions may be crucially implicated in the pathophysiology of auditory verbal hallucinations (AVHs) in schizophrenia (SZ). However, information flow within these brain networks remains unclear. Methods: Seventeen first-episode drug naïve SZ patients – according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision – with AVHs, 15 without AVHs, and 19 HCs underwent resting-state functional magnetic resonance imaging. We used stochastic dynamic causal modeling (sDCM) to quantify directed connections among distinct brain regions, including the left dorsolateral prefrontal cortex, auditory cortex, hippocampus, thalamus, and Broca’s area. Results: sDCM revealed symptom-specific abnormal effective connectivity involving the thalamic-auditory cortical-hippocampal circuit in SZ patients with AVHs, with an increased sensitivity of auditory cortex to its thalamic afferents and a decrease in hippocampal sensitivity to auditory inputs. Furthermore, a positive correlation between the strength of the connectivity from Broca’s area to the auditory cortex and the severity of AVHs was observed in SZ patients with AVHs. Disccusion: Notably, Dauvermann et al found decreased thalamocortical connectivity in first- or second-degree relatives of SZ patients using nonlinear deterministic DCM during verbal fluency processing (1). Using sDCM, we observed that drug-naïve SZ patients with AVHs showed dysconnectivity within three brain regions (thalamus, auditory cortex, and hippocampus), involving increased thalamic-auditory cortical and reduced auditory cortical-hippocampal effective connectivity, compared to SZ patients without AVHs. Additionally, in our recent volumetric study, we found decreased bilateral thalamic gray matter volume in first-episode SZ patients with AVHs (2). In other words, SZ patients with AVHs have a compensated augmented excitatory response to afferents from the thalamus in the auditory cortex due to reduced thalamic volume, which may be the mechanism responsible for AVHs in SZ. Our current study characterizes effective connectivity in a system that has direct relevance to AVHs. The fact that we found these abnormalities may reflect the homogeneity of SZ subgroups that we compared. This approach may be useful when studying SZ on the basis of symptom-based subtyping. Our findings might provide support for dysconnectivity hypothesis of AVHs associated with auditory/language-processing regions, default mode regions, and other networks (insula and striatum), as reviewed most recently (3). Conclusions: These findings indicated augmented excitatory afferents from the thalamus to the auditory cortex in SZ patients with AVHs, resulting in auditory perception without external auditory stimuli. Our results may provide insights into the neural mechanisms underlying AVHs in SZ. Thalamic-auditory cortical-hippocampal dysconnectivity may also serve as a potential diagnostic biomarker and therapeutic target of AVHs in SZ based on the direct evidence in vivo we found.

Acknowledgements

This work was supported by the National Key Basic Research and Development Program (973) (Grant No. 2011CB707805).

References

1. Dauvermann MR, Whalley HC, Romaniuk L, et al. The application of nonlinear Dynamic Causal Modelling for fMRI in subjects at high genetic risk of schizophrenia. Neuroimage. 2013;73:16-29.

2. Huang P, Xi Y, Lu ZL, et al. Decreased bilateral thalamic gray matter volume in first-episode schizophrenia with prominent hallucinatory symptoms: A volumetric MRI study. Sci Rep. 2015;5:14505.

3. Alderson-Day B, McCarthy-Jones S, Fernyhough C. Hearing voices in the resting brain: A review of intrinsic functional connectivity research on auditory verbal hallucinations. Neurosci Biobehav Rev. 2015;55:78-87.

Figures

Fig. 1. Locations of the masks and extracted ROIs time series DLPFC, dorsolateral prefrontal cortex.

Fig. 2. Significant effective connectivity (at the group level) among ROIs in the SZ patients and HCs. Significant connectivities in the AVHs group (A), Non-AVHs group (B), and HCs (C).

Fig. 3. Significant effective connectivity (at the between group level) among ROIs between the SZ patients with and without AVHs, ROC analysis and correlation analysis.

Fig. 4. Proposed mechanism responsible for AVHs in SZ. Thalamic-auditory cortical-hippocampal dysconnectivity may lead to increased activation of the auditory cortex and false perceptual inference in the absence of auditory stimuli.

Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)

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