Long-range synchrony of gamma oscillations and auditory hallucination symptoms in schizophrenia

https://doi.org/10.1016/j.ijpsycho.2010.08.004Get rights and content

Abstract

Phase locking in the gamma-band range has been shown to be diminished in patients with schizophrenia. Moreover, there have been reports of positive correlations between phase locking in the gamma-band range and positive symptoms, especially hallucinations. The aim of the present study was to use a new methodological approach in order to investigate gamma-band phase synchronization between the left and right auditory cortex in patients with schizophrenia and its relationship to auditory hallucinations.

Subjects were 18 patients with chronic schizophrenia (SZ) and 16 healthy control (HC) subjects. Auditory hallucination symptom scores were obtained using the Scale for the Assessment of Positive Symptoms. Stimuli were 40-Hz binaural click trains. The generators of the 40 Hz-ASSR were localized using eLORETA and based on the computed intracranial signals lagged interhemispheric phase locking between primary and secondary auditory cortices was analyzed.

Current source density of the 40 ASSR response was significantly diminished in SZ in comparison to HC in the right superior and middle temporal gyrus (p < 0.05). Interhemispheric phase locking was reduced in SZ in comparison to HC for the primary auditory cortices (p < 0.05) but not in the secondary auditory cortices. A significant positive correlation was found between auditory hallucination symptom scores and phase synchronization between the primary auditory cortices (p < 0.05, corrected for multiple testing) but not for the secondary auditory cortices.

These results suggest that long-range synchrony of gamma oscillations is disturbed in schizophrenia and that this deficit is related to clinical symptoms such as auditory hallucinations.

Research highlights

► Reduced ASSR response in the right superior and middlete temporal gyrus in schizophrenia. ► Reduced phase locking between primary auditory areas in schizophrenia. ► Positive correlation between auditory hallucination symptom scores and interhemispheric gamma phase synchronization.

Introduction

Synchronous neural oscillations in the gamma band (> 30 Hz) of the electroencephalogram (EEG) have been hypothesized to play an important role in the linking of neurons into cell assemblies both locally and in the inter-regional communications of the brain (Singer, 1999). While much of this evidence was provided in animal studies, investigations of gamma oscillations have now also been extensively done in healthy controls and patients with neuropsychiatric diseases. Experimental data obtained in both animals and in humans suggest that gamma-band oscillations are involved in perception and cognition (Herrmann et al., 2004, Ribary, 2005). For example, gamma-band phase synchronization between the inferior temporal lobe and the medial temporal lobe was recently demonstrated to play an important role in working memory using intracranial recordings (Axmacher et al., 2008). Interestingly, it was shown that anatomical connectivity rather than physical distance, determines the coupling strength of the oscillating neurons in the gamma-band range (Csicsvari et al., 2003).

The long-range synchrony of gamma oscillations has been demonstrated to be dependent on excitatory postsynaptic potentials (EPSPs) of γ-aminobutyric acid (GABA)ergic interneurons (Fuchs et al., 2001). Since gamma-band oscillations depend on intact function of the fast-spiking GABAergic (parvalbumin containing) interneurons (Fuchs et al., 2001, Hajos et al., 2004, Vreugdenhil et al., 2003), gamma-band oscillations may provide a means to investigate the function of GABAergic interneurons at a macroscopic level (Lisman et al., 2008). This might be especially interesting for the investigation of schizophrenia, since there is much evidence now suggesting disturbances of the GABAergic interneurons in schizophrenia, such as changes in the concentration of particular proteins, notably glutamate decarboxylase (GAD), the enzyme that synthesizes GABA, and the Ca2+-binding protein parvalbumin (Lewis et al., 2005, Woo et al., 1997). Reductions in the overall number of GABAergic interneurons have also been described by post-mortem analyses (Benes et al., 1991). Alterations in other neurotransmitter systems in schizophrenia (e.g. the dopaminergic and the glutamatergic system) can well be integrated in current models about the pathophysiology of schizophrenia suggesting a key-role for the disturbance of the GABAergic interneurons (Lisman et al., 2008). Dysfunction of GABAergic interneurons is likely to be a major factor of disturbed gamma-band oscillations and related changes in perception and cognition. In schizophrenia, there is now an increasing number of studies describing altered gamma-band oscillation patterns (Hall et al., 2009, Leicht et al., 2010, Spencer et al., 2004, Symond et al., 2005, Uhlhaas & Singer, 2010, Woo et al., 2010).

Although different kinds of paradigms have been used during the last few years, some of the most reliable findings so far come from studies of auditory steady state response (ASSR) (Brenner et al., 2009, Kwon et al., 1999, Spencer et al., 2008, Teale et al., 2008). The ASSR is an EEG response to periodic auditory stimulation (such as click trains or amplitude-modulated tones) in which the sensory cortex acts as a tuned oscillator, synchronizing to the phase and frequency of the presented stimulus. The ASSR appears to have a “resonant” frequency at ~ 40 Hz at which the power and phase locking of the ASSR are enhanced in comparison with other stimulation frequencies (Pastor et al., 2002). In addition to assessing the frequency response characteristics of sensory neural circuits, the ASSR may be a tool to investigate oscillatory mechanisms which might have a more general significance in the pathophysiology of schizophrenia. The typical finding in patients with schizophrenia is reduced power (related to the amplitude of the response) and phase-synchrony in the gamma-band across trials, measured at scalp electrodes or after source localization in the two auditory areas separately (Spencer et al., 2009, Teale et al., 2008).

Even more pronounced than in the visual or somatosensory system, there are extensive commissural links between the primary auditory cortices of both hemispheres linking tonotopically and binaurally matched subregions across the representational axis of characteristic frequency (Lee and Winer, 2008). Although there is a substantial degree of interhemispheric transfer at subcortical levels of the auditory system, the callosal pathway in hearing is generally assumed to play an important role e.g. due to the left hemisphere supremacy in language perception and the contralateral pathway dominance in auditory signal transmission (Bamiou et al., 2007). According to the “callosal relay” model, speech stimuli entering the right hemisphere will require callosal transfer to the left hemisphere in order to be processed (Hugdahl et al., 1997, Zaidel, 1986). The temporal–callosal pathway has been demonstrated to be related to phonological skills in children (Dougherty et al., 2007) and it was shown that an intact posterior third of the corpus callosum (where the fibers of the auditory cortex are crossing) is important for the integration of prosodic information (right hemisphere function) and syntactic information (left hemisphere function) which is necessary for language comprehension (Friederici et al., 2007).

During the last few years, structural connectivity in the brain has been investigated by means of Diffusion Tensor Imaging (DTI) (Kubicki et al., 2007). Comparing schizophrenic patients with auditory hallucinations versus patients without hallucinations, increased directionality (suggested as representing stronger connectivity) was found in that part of the corpus callosum (CC, see Hubl et al., 2004), Fig. 1, where the inter-hemispheric auditory fibers are assumed to cross (posterior part of the middle third and probably adjacent parts of the posterior third) (Bamiou et al., 2007). While structural connectivity can be assessed using DTI, EEG can be used to investigate functional connectivity (Teipel et al., 2009).

Accordingly, the aim of the present study was to investigate the gamma-band phase synchronization between the left and right auditory areas in patients with schizophrenia during auditory steady-state stimulation. We re-analyzed data from a previously-published study (Spencer et al., 2009) which utilized dipole source analysis to examine the ASSR deficit in schizophrenia. Since a positive correlation was found in that study between auditory hallucination symptoms and a left auditory cortex source, and since functional imaging studies have suggested that both unilateral and bilateral activation of the primary auditory cortex is relevant for auditory hallucinations, we also looked for a possible relationship between phase-synchrony coupling of the left and right primary auditory cortex in the gamma-band range and auditory hallucination symptoms. Here we utilized low-resolution tomography (LORETA) (Pascual-Marqui, 2002, Pascual-Marqui et al., 1994), a linear source localization method that has been widely used during the last few years by us (Mulert et al., 2004, Mulert et al., 2006, Mulert et al., 2007) and others (Babiloni et al., 2010, van der Loo et al., 2009) in order to estimate oscillatory activity in the left and right auditory cortex as well as interhemispheric phase synchrony. Previous studies have demonstrated substantial congruence between LORETA and fMRI localization (Mulert et al., 2005, Mulert et al., 2010).

Section snippets

Subjects

This study was approved by the Institutional Review Boards of the VA Boston Healthcare System and Harvard Medical School. After complete description of the study to the subjects, written informed consent was obtained. All subjects were paid for their participation in the study.

Subjects were 18 patients with chronic schizophrenia (SZ) and 16 healthy control subjects (HC), all right-handed males (see Table 1). The HC were recruited from the local community. They were free of Axis I or II

Results

For the description of the scalp data please refer to Fig. 3.

Discussion

This study was intended to use a new methodological approach in order to investigate whether long-range synchrony of gamma oscillations is disturbed in schizophrenia and whether a relationship between inter-hemispheric phase synchronization and auditory hallucination symptoms can be found. The major finding was reduced phase synchronization in schizophrenia only between the left and right primary auditory cortex (Heschl´s gyrus), but not between the bilateral secondary auditory cortices.

Acknowledgments

This work was supported by a US Department of Veterans Affairs Research Enhancement Award Program and Schizophrenia Center (RWM); US National Institute of Mental Health Grants R01 40799 (RWM), R03 076760 (KMS), and R01 MH080187 (KMS); and a NARSAD Young Investigator Award (KMS). CM was supported by a grant of the German Society for Psychiatry, Psychotherapy and Neurology (DGPPN).

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