Abstract Background: Individuals with schizophrenia (Sz) show abnormal functional connectivity between resting state networks (RSNs), yet the relation between disrupted connectivity and symptoms remains unclear. Using a combination of resting-state fMRI analyses – independent component analysis (ICA) and analysis of the mean amplitudes of low-frequency fluctuations (ALFF)—we probed the relation between cross-network communication, low frequency fluctuations and reported experience(s) of auditory hallucinations (AH) and visual hallucinations (VH) in Sz. Methods: Resting-state fMRI data were analyzed (143 Sz, 155 controls) from the Function Biomedical Informatics Research Network (FBIRN) dataset. Sz were divided into subgroups: patients reporting AH, patients reporting VH and patients reporting neither AH nor VH (NH). Most patients reporting VH also reported AH. Group spatial ICA and ALFF analyses were performed on preprocessed images using GIFT and REST software respectively. Eight RSNs were selected (two insular components, two precuneus components, along with anterior cingulate cortex (ACC), superior temporal gyrus (STG), hippocampus and putamen components). ALFF was calculated across two frequency ranges ([0.01–0.027 Hz]; [0.027–0.08 Hz]). General linear models examined the impact of group on functional network connectivity (FNC) (P < .05 FDR-corrected) and ALFF (P < .05, corrected for multiple comparisons at cluster level). Results: AH and VH were not different in FNC, but VH had significantly elevated left hippocampal ALFF. The 2 hallucination subgroups (VH, AH) were combined to form a larger (HALL) subgroup. Both NH and HALL showed elevated FNC between STG and hippocampus relative to healthy controls (HC). In comparison to HC, HALL in particular, showed significantly increased FNC between two precuneus RSNs, precuneus-ACC, STG-ACC, and STG-putamen. They also showed decreased FNC between insula-precuneus and the two insular RSNs. In post-hoc analyses, we examined the relationship between left hippocampal ALFF variation, FNC values, and symptom severity. AH (b = −.28, t = −2.857, P < .001) and VH (b = 0.40, t = 4.054, P < .001) severity, but not overall positive symptoms, were significantly linked to hippocampal ALFF. Hippocampal ALFF was negatively correlated with FNC between insular RSNs, but positively correlated with FNC between two precuneus RSNs, precuneus-ACC, STG-putamen, and STG-hippocampus. Conclusion: Our results suggest that hippocampal low-frequency fluctuations are linked to cross-network functional communication. More severe VH are associated with elevated hippocampal low-frequency fluctuations, while more severe AH is associated with decreased hippocampal low-frequency fluctuations. We propose a novel hypothesis of hallucinations in Sz in which altered hippocampal oscillation dynamics disrupt functional communication between dispersed networks.

Hallucinations characterize schizophrenia, with approximately 59% of patients reporting auditory hallucinations and 27% reporting visual hallucinations. Prior neuroimaging studies suggest that hallucinations are linked to disrupted communication across distributed (sensory, salience-monitoring and subcortical) networks. Yet, our understanding of the neurophysiological mechanisms that underlie auditory and visual hallucinations in schizophrenia remains limited. This study integrates two resting-state functional magnetic resonance imaging (fMRI) analysis methods - amplitudes of low-frequency fluctuations (ALFF) and functional network connectivity (FNC) - to explore the hypotheses that (1) abnormal FNC between salience and sensory (visual/auditory) networks underlies hallucinations in schizophrenia, and (2) disrupted hippocampal oscillations (as measured by hippocampal ALFF) beget changes in FNC linked to hallucinations. Our first hypothesis was supported by the finding that schizophrenia patients reporting hallucinations have higher FNC between the salience network and an associative auditory network relative to healthy controls. Hippocampal ALFF was negatively associated with FNC between primary auditory cortex and the salience network in healthy subjects, but was positively associated with FNC between these networks in patients reporting hallucinations. These findings provide indirect support favoring our second hypothesis. We suggest future studies integrate fMRI with electroencephalogram (EEG) and/or magnetoencephalogram (MEG) methods to directly probe the temporal relation between altered hippocampal oscillations and changes in cross-network functional communication.