Multimodal morphometry and functional magnetic resonance imaging in schizophrenia and auditory hallucinations

AIM: To validate a multimodal [structural and functional magnetic resonance (MR)] approach as coincidence brain clusters are hypothesized to correlate with clinical severity of auditory hallucinations. METHODS: Twenty-two patients meeting Diagnostic and Statistical Manual of Mental Disorders (fourth edition, DSM-IV) criteria for schizophrenia and experiencing persistent hallucinations together with 28 healthy controls were evaluated with structural and functional MR imaging with an auditory paradigm designed to replicate those emotions related to the patients’ hallucinatory experiences. Coincidence maps were obtained by combining structural maps of gray matter reduction with emotional functional increased activation. Abnormal areas were correlated with the brief psychiatric rating scale (BPRS) and the psychotic symptom rating scale (PSYRATS) scales. RESULTS: The coincidence analysis showed areas with coexistence gray matter reductions and emotional activation in bilateral middle temporal and superior temporal gyri. Significant negative correlations between BPRS and PSYRATS scales were observed. BPRS scores were negatively correlated in the middle temporal gyrus (right) (t = 6.86, P = 0.001), while negative PSYRATS correlation affected regions in both the superior temporal gyrus (left) (t = 7.85, P = 0.001) and middle temporal gyrus (left) (t = 4.97, P = 0.002). CONCLUSION: Our data identify left superior and middle temporal gyri as relevant areas for the understanding of auditory hallucinations in schizophrenia. The use of multimodal approaches, sharing structural and functional information, may demonstrate areas specifically linked to the severity of auditory hallucinations.

40 Hz Auditory Steady State Response to Linguistic Features of Stimuli during Auditory Hallucinations

The auditory steady state response （ASSR） may reflect activity from different regions of the brain, depending on the modulation frequency used. In general, responses induced by low rates （_〈40 Hz） emanate mostly from central structures of the brain, and responses from high rates （〉80 Hz） emanate mostly from the peripheral auditory nerve or brainstem structures. Besides, it was reported that the gamma band ASSR （30-90 Hz） played an important role in working memory, speech understanding and recognition. This paper investigated the 40 Hz ASSR evoked by modulated speech and reversed speech. The speech was Chinese phrase voice, and the noise-like reversed speech was obtained by temporally reversing the speech. Both auditory stimuli were modulated with a frequency of 40 Hz. Ten healthy subjects and 5 patients with hallucination symptom participated in the experiment. Results showed re- duction in left auditory cortex response when healthy subjects listened to the reversed speech compared with the speech. In contrast, when the patients who experienced auditory hallucinations listened to the reversed speech, the auditory cortex of left hemispheric responded more actively. The ASSR results were consistent with the behavior results of patients. Therefore, the gamma band ASSR is expected to be helpful for rapid and objective diagnosis of hallucination in clinic.

Enhanced Beta2-band Oscillations Denote Auditory Hallucination in Schizophrenia Patients and a Monkey Model of Psychosis

An electroencephalographic(EEG)signature of auditory hallucinations(AHs)is important for facilitating the diagnosis and treatment of AHs in schizophrenia.We recorded EEG from 25 schizophrenia patients with recurrent AHs.During the period of AHs,EEG recordings exhibited significantly elevated beta2-band power in the temporal region,as compared to those recorded in the absence of AHs or during stimulation with verbal sounds.We further generated methamphetamine-treated rhesus monkeys exhibiting psychosis-like behaviors,including repetitive sudden searching actions in the absence of external intrusion,suggesting the occurrence of AHs.Epidural EEG beta2-band power in the temporal region of these monkeys was enhanced immediately after methamphetamine treatment and positively correlated with the frequency of sudden searching actions.Thus,the enhancement of temporal beta2-band oscillations represents a signature for AHs in both patients and a monkey model of psychosis,and this monkey model can be used for developing closed-loop neuromodulation approaches for the treatment of refractory AHs in schizophrenia.

Transcranial direct current stimulation for auditory verbal hallucinations:a systematic review of clinical trials

Transcranial direct current stimulation(tDCS)has been reportedly beneficial for different neurodegenerative disorders.tDCS has been reported as a potential adjunctive or alternative treatment for auditory verbal hallucination(AVH).This study aims to review the effects of tDCS on AVH in patients with schizophrenia through combining the evidence from randomized clinical trials(RCTs).The databases of PsycINFO(2000–2019),PubMed(2000–2019),EMBASE(2000–2019),CINAHL(2000–2019),Web of Science(2000–2019),and Scopus(2000–2019)were systematically searched.The clinical trials with RCT design were selected for final analysis.A total of nine RCTs were eligible and included in the review.Nine RCTs were included in the final analysis.Among them,six RCTs reported a significant reduction of AVH after repeated sessions of tDCS,whereas three RCTs did not show any advantage of active tDCS over sham tDCS.The current studies showed an overall decrease of approximately 28%of AVH after active tDCS and 10%after sham tDCS.The tDCS protocols targeting the sensorimotor frontal-parietal network showed greater treatment effects compared with the protocols targeting other regions.In this regard,cathodal tDCS over the left temporoparietal area showed inhibitory effects on AVHs.The most effective tDCS protocol on AVHs was twice-daily sessions(2 mA,20-minute duration)over 5 consecutive days(10 sessions)with the anode over the left dorsolateral prefrontal cortex and the cathode over the left temporal area.Some patient-specific and diseasespecific factors such as young age,nonsmoking status,and higher frequencies of AVHs seemed to be the predictors of treatment response.Taken together,the results of tDCS as an alternative treatment option for AVH show controversy among current literatures,since not all studies were positive.However,the studies targeting the same site of the brain showed that the tDCS could be a promising treatment option to reduce AVH.Further RCTs,with larger sample sizes,should be conducted to reach a conclusion on the efficacy of tDCS for AVH and to develop an effective therapeutic protocol for clinical setting.

Abnormal Local Activity and Functional Dysconnectivity in Patients with Schizophrenia Having Auditory Verbal Hallucinations

Auditory verbal hallucination(AVH)is emphasized as a pathological hallmark of schizophrenia.Neuroimaging studies provide evidence linking AVH to overlapping functional abnormalities in distributed networks.However,no clear conclusion has still been reached.This study aimed to further explore the brain activity of patients with schizophrenia having AVH from both local activity(LA)and functional connectivity(FC)insights,while excluding confounding factors from other positive symptoms.A total of 42 patients with AVH(AVH patients group,APG),26 without AVH(non-AVH patients group,NPG),and 82 normal controls(NC)underwent resting-state functional magnetic resonance imaging(fMRI).LA measures,including regional homogeneity(ReHo)and fractional amplitude of low-frequency fluctuations(fALFF),and FC measures were evaluated to understand the neuroimaging mechanism of AVH.APG showed increased ReHo and fALFF in the bilateral putamen(Put)compared with NPG and NC.FC analysis(using bilateral putamen as seeds)revealed that all patients showed abnormal FC of multiple resting state network regions,including the anterior and post cingulate cortex,middle frontal gyrus,inferior parietal gyrus,and left angular gyrus.Interestingly,APG showed significantly decreased FC of insula extending to the superior temporal gyrus and inferior frontal gyrus compared with NPG and NC.The present findings suggested a significant correlation of abnormal LA and dysfunctional putamen-auditory cortical connectivity with the neuropathological mechanism of AVH,providing evidence for the functional disconnection hypothesis of schizophrenia.

Repetitive transcranial magnetic stimulation for hallucination in schizophrenia spectrum disorders A meta-analysis

OBJECTIVE： This study assessed the efficacy and tolerability of repetitive transcranial magnetic stimulation for treatment of auditory hallucination of patients with schizophrenia spectrum disorders. DATA SOURCES： Online literature retrieval was conducted using PubMed, ISI Web of Science, EMBASE, Medline and Cochrane Central Register of Controlled Trials databases from January 1985 to May 2012. Key words were ＂transcranial magnetic stimulation＂, ＂TMS＂, ＂repetitive tran- scranial magnetic stimulation＂, and ＂hallucination＂. STUDY SELECTION： Selected studies were randomized controlled trials assessing therapeutic ef- ficacy of repetitive transcranial magnetic stimulation for hallucination in patients with schizophrenia spectrum disorders. Experimental intervention was low-frequency repetitive transcranial magnetic stimulation in left temporoparietal cortex for treatment of auditory hallucination in schizophrenia spectrum disorders. Control groups received sham stimulation. MAIN OUTCOME MEASURES： The primary outcome was total scores of Auditory Hallucinations Rating Scale, Auditory Hallucination Subscale of Psychotic Symptom Rating Scale, Positive and Negative Symptom Scale-Auditory Hallucination item, and Hallucination Change Scale. Secondary outcomes included response rate, global mental state, adverse effects and cognitive function. RESULTS： Seventeen studies addressing repetitive transcranial magnetic stimulation for treatment of schizophrenia spectrum disorders were screened, with controls receiving sham stimulation. All data were completely effective, involving 398 patients. Overall mean weighted effect size for repeti- tive transcranial magnetic stimulation versus sham stimulation was statistically significant （MD = -0.42, 95%C/： -0.64 to -0.20, P = 0.000 2）. Patients receiving repetitive transcranial magnetic stimulation responded more frequently than sham stimulation （OR = 2.94, 95%C/： 1.39 to 6.24, P =0.005）. No significant differences were found between active repetitive transcranial magnetic stimulation and sham stimulation for positive or negative symptoms. Compared with sham stimulation, active repeti- tive transcranial magnetic stimulation had equivocal outcome in cognitive function and commonly caused headache and facial muscle twitching. CONCLUSION： Repetitive transcranial magnetic stimulation is a safe and effective treatment for auditory hallucination in schizophrenia spectrum disorders,

Abnormal Degree Centrality of Bilateral Putamen and Left Superior Frontal Gyrus in Schizophrenia with Auditory Hallucinations： A Resting-state Functional Magnetic Resonance Imaging Study

Background： Dysconnectivity hypothesis of schizophrenia has been increasingly emphasized. Recent researches showed that this dysconnectivity might be related to occurrence of auditory hallucination （AH）. However, there is still no consistent conclusion. This study aimed to explore intrinsic dysconnectivity pattern of whole-brain functional networks at voxel level in schizophrenic with AH. Methods： Auditory hallucinated patients group （n = 42 APG）, no hallucinated patients group （n = 42 NPG） and normal controls （n = 84 NCs） were analyzed by resting-state functional magnetic resonance imaging. The functional connectivity metrics index （degree centrality [DC]） across the entire brain networks was calculated and evaluated among three groups. Results： DC decreased in the bilateral putamen and increased in the left superior frontal gyrus in all the patients. However, in APG. the changes of DC were more obvious compared with NPG. Symptomology scores were negatively correlated with the DC of bilateral putamen in all patients. AH score of APG positively correlated with the DC in left superior frontal gyrus but negatively correlated with the DC in bilateral putamen. Conclusion： Our findings corroborated that schizophrenia was characterized by functional dysconnectivity, and the abnormal DC in bilateral putamen and left superior frontal gyrus might be crucial in the occurrence of AH.

An Integrative Account of Neural Network Interaction: Neuro-Messenger Theory

Neural interaction is realized by information exchange. It seemed that the information amount does not keep constant and may be reduced during the travel between neural nodes. In addition, recent research of neural coding has suggested that neural information could be represented by parsimonious spiking pattern, named sparse coding. Based on the above observation, neuro-messenger theory (NMT) is proposed to explicate the communicative process between the source and the target neural nodes. Neuro-messenger is a sparse code which does not have to carry every detail of the dynamics in source node. Other formats of neural coding (e.g., temporal and rate coding) could be the precursors of neuro-messengers, and the repeated spatiotemporal patterns buried in the ongoing brain activities may be the circulated neuro-messengers from diverse origins. Referred to chaos/complexity theory, information can be recovered at target node where neuro-messenger serves as a facilitator to locate the trajectory at proper attractor, and hence the associated psychological entity. In contrast to conventional concepts of encoding and decoding, the processes of encoding in source node, issuing neuro-messengers, and recovering information at target node are summarized as “three-facet coding scheme”. The design of neuro-messenger enables the brain to utilize energy in an efficient and economical way. NMT may have substantial implication in several major psychiatric disorders. Some psychiatric conditions could be mediated by abnormal neuro-messengers that coerce the regional neuro-dynamics to delve into maladaptive attractors and hence the characteristic symptoms.

Increased Local Spontaneous Neural Activity in the Left Precuneus Specific to Auditory Verbal Hallucinations of Schizophrenia

Background： Auditory verbal hallucinations （AVHs） of schizophrenia have been associated with structural and functional alterations of some brain regions. However, the brain regional homogeneity （ReHo） alterations specific to AVHs of schizophrenia remain unclear. In the current study, we aimed to investigate ReHo alterations specific to schizophrenic AVHs. Methods： Thirty-five schizophrenic patients with AVH, 41 schizophrenic patients without AVHs, and fifty healthy subjects underwent resting-state functional magnetic resonance imaging. ReHo differences across the three groups were tested using a voxel-wise analysis. Results： Compared with the healthy control group, the two schizophrenia groups showed significantly increased ReHo in the right caudate and inferior temporal gyrus and decreased ReHo in the bilateral postcentral gyrus and thalamus and the right inferior occipital gyrus （false discovery rate corrected, P 〈 0.05）. More importantly, the AVH group exhibited significantly increased ReHo in the left precuneus compared with the non-AVH group. However, using correlation analysis, we did not find any correlation between the auditory hallucination rating scale score and the ReHo of brain regions. Conclusions： Our results suggest that increased ReHo in the left precuneus may be a pathological feature exclusive to schizophrenic AVHs.

Abnormal Effective Connectivity in the Brain is Involved in Auditory Verbal Hallucinations in Schizophrenia

Information flow among auditory and language processing-related regions implicated in the pathophysiology of auditory verbal hallucinations（AVHs） in schizophrenia（SZ） remains unclear. In this study, we used stochastic dynamic causal modeling（s DCM） to quantify connections among the left dorsolateral prefrontal cortex（inner speech monitoring）, auditory cortex（auditory processing）, hippocampus（memory retrieval）, thalamus（information filtering）, and Broca＇s area（language production） in 17 first-episode drug-na？¨ve SZ patients with AVHs, 15 without AVHs, and 19 healthy controls using resting-state functional magnetic resonance imaging.Finally, we performed receiver operating characteristic（ROC） analysis and correlation analysis between image measures and symptoms. s DCM revealed an increasedsensitivity of auditory cortex to its thalamic afferents and a decrease in hippocampal sensitivity to auditory inputs in SZ patients with AVHs. The area under the ROC curve showed the diagnostic value of these two connections to distinguish SZ patients with AVHs from those without AVHs. Furthermore, we found a positive correlation between the strength of the connectivity from Broca＇s area to the auditory cortex and the severity of AVHs. These findings demonstrate, for the first time, augmented AVHspecific excitatory afferents from the thalamus to the auditory cortex in SZ patients, resulting in auditory perception without external auditory stimuli. Our results provide insights into the neural mechanisms underlying AVHs in SZ. This thalamic-auditory cortical-hippocampal dysconnectivity may also serve as a diagnostic biomarker of AVHs in SZ and a therapeutic target based on direct in vivo evidence.