Functional connectivity of left Heschl's gyrus in vulnerability to auditory hallucinations in schizophrenia

Abstract

Background

Schizophrenia is a heterogeneous disorder that may consist of multiple etiologies and disease processes. Auditory hallucinations (AH), which are common and often disabling, represent a narrower and more basic dimension of psychosis than schizophrenia. Previous studies suggest that abnormal primary auditory cortex activity is associated with AH pathogenesis. We thus investigated functional connectivity, using a seed in primary auditory cortex, in schizophrenia patients with and without AH and healthy controls, to examine neural circuit abnormalities associated more specifically with AH than the myriad other symptoms that comprise schizophrenia.

Methods

Using resting-state fMRI (rsfMRI), we investigated functional connectivity of the primary auditory cortex, located on Heschl's gyrus, in schizophrenia spectrum patients with AH. Participants were patients with schizophrenia, schizoaffective disorder, or schizophreniform disorder with lifetime AH (n = 27); patients with the same diagnoses but no lifetime AH (n = 14); and healthy controls (n = 28).

Results

Patients with AH vulnerability showed increased left Heschl's gyrus functional connectivity with left frontoparietal regions and decreased functional connectivity with right hippocampal formation and mediodorsal thalamus compared to patients without lifetime AH. Furthermore, among AH patients, left Heschl's gyrus functional connectivity covaried positively with AH severity in left inferior frontal gyrus (Broca's area), left lateral STG, right pre- and postcentral gyri, cingulate cortex, and orbitofrontal cortex. There were no differences between patients with and without lifetime AH in right Heschl's gyrus seeded functional connectivity.

Conclusions

Abnormal interactions between left Heschl's gyrus and regions involved in speech/language, memory, and the monitoring of self-generated events may contribute to AH vulnerability.

Introduction

Schizophrenia (SZ) is a heterogeneous disorder, possibly consisting of several distinct though related disease processes. Here, we focused on the symptom dimension of auditory hallucinations (AH), a narrower and more basic phenotypic unit of analysis than SZ, with the goal to identify neural circuit abnormalities that are associated more specifically with AH than the myriad other symptoms seen in SZ. Though AH can also be phenomenologically heterogeneous, SZ patients with AH likely represent a more homogeneous group than all SZ patients. AH are common in SZ, can be disabling, and increase suicide risk (Falloon and Talbot, 1981). While antipsychotic medications can reduce their severity, AH often persist despite treatment.

Abnormalities of the primary auditory cortex (PAC), located on the superior temporal gyrus (STG), have been implicated in AH pathogenesis. SZ patients with AH have STG volume reductions (McCarley et al., 1999, Allen et al., 2008, Modinos et al., 2012), and the PAC in SZ contains morphologically abnormal pyramidal cells (Sweet et al., 2004, Sweet et al., 2009). Several, though not all, groups have reported increased activity in the dominant hemispheric PAC during AH (Matsuda et al., 1989, Suzuki et al., 1993, Dierks et al., 1999, Lennox et al., 2000, van de Ven et al., 2005). A perceptual basis for AH is supported by evidence that AH-related activity in the left STG competes with the processing of external sound (Woodruff et al., 1997, Ford et al., 2009, Kompus et al., 2011), and is consistent with patients' experience of AH as real.

Neuroimaging studies also implicate other brain regions [e.g., medial temporal lobe (Liddle et al., 1992), anterior cingulate cortex (Lahti et al., 2006), Broca's area (McGuire et al., 1993), thalamus, parahippocampal gyrus, ventral striatum, orbitofrontal cortex (Silbersweig et al., 1995)] during AH, suggesting that AH are associated with abnormal activity in a distributed network that includes multiple cortical and subcortical brain regions. The study of distributed brain abnormalities in AH may offer more broadly applicable insights into the neurobiology of SZ because subtle neurodevelopmental abnormalities (e.g., in neuronal migration, synaptogenesis, pruning) may lead to abnormal connectivity, and ultimately to symptom formation.

Low frequency (< 0.1 Hz) spontaneous fluctuations in activity occur continually in the human brain (Fox and Raichle, 2007). These fluctuations have been observed under anesthesia, suggesting that they reflect intrinsic properties of functional brain organization (Vincent et al., 2007). Several studies have used resting state fMRI (rsfMRI) to study these fluctuations in AH. One study suggested abnormal interhemispheric PAC connectivity (Gavrilescu et al., 2009); three highlighted altered connectivity in speech-related (Vercammen et al., 2010, Wolf et al., 2011) or default mode (Rotarska-Jagiela et al., 2010) networks and their association with limbic regions; and a fifth study reported abnormal connectivity between speech-related areas and the putamen (Hoffman et al., 2011). None explicitly focused on the PAC's connectivity with other brain circuits.

In this study, we investigated the functional connectivity (FC) of Heschl's gyrus (HG) in SZ patients with and without vulnerability to AH and healthy controls, using rsfMRI. This is the first study to examine the PAC's connectivity with distributed brain regions. We used HG as an anatomical proxy for PAC, as the PAC is consistently located in HG across the range of common morphological variants (Da Costa et al., 2011). We hypothesized that patients with lifetime AH, even if not currently hallucinating, will have abnormal FC in a network of HG and cortical and subcortical brain regions processing speech, language, affect, and source attribution.