Grey matter microstructural alterations in schizophrenia patients with treatment-resistant auditory verbal hallucinations.

Treatment-resistant auditory verbal hallucinations (TRAVH) are a relatively prevalent and devastating symptom in patients with schizophrenia (SCZ). Even though their pathological mechanisms are poorly understood, they seem to differ from those underlying non-hallucinating SCZ. In this study, we characterise structural brain changes in SCZ patients with TRAVH. With respect to non-hallucinating patients and healthy controls, we studied macrostructural grey matter changes through cortical thickness and subcortical volumetric data. Additionally, we analysed microstructural differences across groups using intracortical and subcortical mean diffusivity data. This latter imaging metric has been claimed to detect incipient neuronal damage, as water can diffuse more freely in regions with reduced neural density. We found brain macrostructrural and microstructural alterations in SCZ patients with TRAVH (n = 29), both with respect to non-hallucinating (n = 20) patients and healthy controls (n = 27). Importantly, a microstructural -rather than a macrostructural- compromise was found in key brain regions such as the ventral ACC, the NAcc and the hippocampus. These microstructural alterations correlated, in turn, with clinical severity. TRAVH patients also showed accentuated age-related cortical deterioration and an abnormal longitudinal loss of cortical integrity over a one-year period. These findings highlight the potential role of microstructural imaging biomarkers in SCZ. Notably, they could be used both to detect and to monitor subtle grey matter alterations in critical brain regions such as deep brain stimulation targets. Moreover, our results support the existence of a more aggressive and active pathological mechanism in patients with TRAVH, providing new insight into the aetiology of this debilitating illness.

Altered amplitude of low frequency fluctuations in schizophrenia patients with persistent auditory verbal hallucinations.

The aim of this study is to analyze the differences in low frequency fluctuation (LFF) values between schizophrenia patients with and without auditory verbal hallucinations (AVH). Nineteen schizophrenia patients with persistent AVH (HP), fourteen non-hallucinating schizophrenia patients (nHP) and twenty healthy controls (HC) underwent R-fMRI. LFF values were calculated in the slow frequency band (0.01-0.08Hz). By means of group level contrasts, we performed direct voxel-wise group comparisons. Both groups of patients showed decreased amplitude LFF (ALFF) values in the occipital pole and lingual gyrus compared to HC, whereas increased ALFF values were found in the temporal pole and fusifom gyrus. Schizophrenia patients exhibited decreased fractional ALFF (fALFF) values in the precuneus, occipital pole and bilateral occipital cortex, and increased fALFF in the insula compared to HC. There were also differences between patients with and without AVH. (Ok to start with lower case?) fALFF values were higher in the putamen and insular cortex and lower in the frontal pole in HP compared to nHP and HC. ALFF increased in HP patients in the bilateral thalamus and bilateral parahippocampal gyrus, compared to nHP patients and HC. Our results suggest that altered dynamics in low-frequency fluctuations may play a key role in the neurophysiology of auditory hallucinations.

Cerebrospinal Fluid Anti-Amyloid-ß Autoantibodies and Amyloid PET in Cerebral Amyloid Angiopathy-Related Inflammation.

We report a biomarker and genetic evaluation of four patients with cerebral amyloid angiopathy-related inflammation (CAA-ri) treated with corticosteroids. Patients presented with focal symptomatology and cognitive impairment. MRI revealed cortical microbleeds and asymmetrical hyperintense white matter lesions (WML). Cerebrospinal fluid (CSF) biomarker analyses showed increased anti-Aß autoantibodies, t-Tau, and p-Tau and decreased Aß40 and Aß42. After treatment, focal symptomatology disappeared, and WML and anti-Aß autoantibodies decreased. The APOEɛ4 allele was overrepresented. Florbetapir-PET showed cortical deposition with lower retention in swollen areas. In the case of suspected CAA-ri, both CSF anti-Aß autoantibodies levels and Florbetapir-PET could provide highly useful data to guide the correct diagnosis.

Resting-state functional connectivity alterations in the default network of schizophrenia patients with persistent auditory verbal hallucinations.

To understand the neural mechanism that underlies treatment resistant auditory verbal hallucinations (AVH), is still an important issue in psychiatric research. Alterations in functional connectivity during rest have been frequently reported in patients with schizophrenia. Though the default mode network (DN) appears to be abnormal in schizophrenia patients, little is known about its role in resistant AVH. We collected resting-state functional magnetic resonance imaging (R-fMRI) data with a 3T scanner from 19 schizophrenia patients with chronic AVH resistant to pharmacological treatment, 14 schizophrenia patients without AVH and 20 healthy controls. Using seed-based correlation analysis, we created spherical seed regions of interest (ROI) to examine functional connectivity of the two DN hub regions (posterior cingulate cortex and anteromedial prefrontal cortex) and the two DN subsystems: dorsomedial prefrontal cortex subsystem and medial temporal lobe subsystem (p<0.0045 corrected). Patients with hallucinations exhibited higher FC between dMPFC ROI and bilateral central opercular cortex, bilateral insular cortex and bilateral precentral gyrus compared to non hallucinating patients and healthy controls. Additionally, patients with hallucinations also exhibited lower FC between vMPFC ROI and bilateral paracingulate and dorsal anterior cingulate cortex. As the anterior cingulate cortex and the insula are two hubs of the salience network, our results suggest cross-network abnormalities between DN and salience system in patients with persistent hallucinations.

Altered default network resting state functional connectivity in patients with a first episode of psychosis.

BACKGROUND: Default network (DN) abnormalities have been identified in patients with chronic schizophrenia using "resting state" functional magnetic resonance imaging (R-fMRI). Here, we examined the integrity of the DN in patients experiencing their first episode of psychosis (FEP) compared with sex- and age-matched healthy controls. METHODS: We collected R-fMRI data from 19 FEP patients (mean age 24.9 ± 4.8 yrs, 14 males) and 19 healthy controls (26.1 ± 4.8 yrs, 14 males) at 3T. Following standard preprocessing, we examined the functional connectivity (FC) of two DN subsystems and the two DN hubs (P<0.0045, corrected). RESULTS: Patients with FEP exhibited abnormal FC that appeared largely restricted to the dorsomedial prefrontal cortex (dMPFC) DN subsystem. Relative to controls, FEP patients exhibited weaker positive FC between dMPFC and posterior cingulate cortex (PCC) and precuneus, extending laterally through the parietal lobe to the posterior angular gyrus. Patients with FEP exhibited weaker negative FC between the lateral temporal cortex and the intracalcarine cortex, bilaterally. The PCC and temporo-parietal junction also exhibited weaker negative FC with the right fusiform gyrus extending to the lingual gyrus and lateral occipital cortex, in FEP patients, compared to controls. By contrast, patients with FEP showed stronger negative FC between the temporal pole and medial motor cortex, anterior precuneus and posterior mid-cingulate cortex. CONCLUSIONS: Abnormalities in the dMPFC DN subsystem in patients with a FEP suggest that FC patterns are altered even in the early stages of psychosis.