Evidence for excessive frontal evoked gamma oscillatory activity in schizophrenia during working memory

Abstract

Gamma (γ) oscillations (30–50 Hz) elicited during working memory (WM) are altered in schizophrenia (SCZ). However, the nature of the relationship between evoked frontal oscillatory activity, WM performance and symptom severity has yet to be ascertained. This study had two objectives. First, to extend previous studies by examining delta, theta, alpha, beta, and gamma (δ, θ, α, β, and γ) oscillatory activities during the N-back task in SCZ patients compared to healthy subjects; second, to evaluate the relationship between oscillatory activities elicited during the N-back, performance, and clinical symptoms in SCZ patients. Patients with SCZ elicited excessive frontal γ oscillatory activity that was most pronounced in the 3-back condition compared to healthy subjects. Reduced frontal β activity at all WM loads was also observed in patients with SCZ compared to healthy subjects. Task performance was inversely correlated with negative symptoms but not with positive symptoms. Our findings suggest that evoked frontal oscillatory activities during WM are selectively altered in the γ and β frequency bands that may contribute to WM impairment in SCZ patients. These findings may provide important insights into the pathophysiology underlying WM deficits, its relationship to negative symptoms and may represent a potential neurobiological marker for cognitive enhancing strategies in SCZ.

Introduction

Gamma (γ) oscillations (30–50 Hz) have been shown to be a key neurophysiological mechanism underlying working memory (WM), a cognitive process involving the maintenance and manipulation of information on-line (Baddeley, 1986). Increased γ oscillatory activity with increased WM load has been demonstrated in epileptic patients (Howard et al., 2003) and healthy subjects (Basar-Eroglu et al., 2007) with electroencephalography (EEG) especially in the dorsolateral prefrontal cortex (DLPFC). Although γ modulation in the DLPFC is most consistently associated with WM, delta (δ; 1–3.5 Hz), theta (θ; 4–8 Hz), alpha (α; 9–12 Hz), and beta (β; 14–28 Hz) activities also vary with WM load (Barr et al., 2009).

Altered oscillatory activity during WM has been demonstrated in SCZ. Abnormal δ (Ince et al., 2009), θ (Haenschel et al., 2009, Schmiedt et al., 2005), α (Bachman et al., 2008, Ince et al., 2009, Stephane et al., 2008) and β (Stephane et al., 2008) activation during WM has been shown in SCZ patients. However, inconsistent reports reveal both similar (Haenschel et al., 2009) and abnormally increased (Basar-Eroglu et al., 2007) γ oscillatory activity during WM in SCZ compared to healthy subjects. Furthermore, Basar-Eroglu et al. (2007) demonstrated that SCZ patients failed to modulate γ oscillatory activity with WM load as found in healthy subjects (Basar-Eroglu et al., 2007). The lack of γ modulation with WM load in SCZ patients may be attributed to alterations in γ-aminobutyric acid (GABA) interneurons in the DLPFC (Akbarian et al., 1995, Benes and Berretta, 2001, Hashimoto et al., 2008, Lewis et al., 2005) critical to γ oscillatory activity. Considering the importance of GABA in the generation (Bartos et al., 2007, Wang and Buzsaki, 1996, Whittington et al., 1995) and modulation (Brown et al., 2007, Whittington et al., 1995) of γ oscillations, GABAergic impairments in patients with SCZ may underlie altered modulation of γ oscillatory during WM.

The relationship between γ oscillatory activity, WM performance, and clinical symptoms has yet to be determined. In a behavioural study, Park et al. (1999) reported on a relationship between WM performance and negative symptoms in SCZ patients, such that increased negative symptoms related to poor WM (Park et al., 1999). Additionally, an fMRI study in SCZ patients demonstrated a correlation between strength of prefrontal-parietal connectivity and WM performance, while positive symptoms related to decreased connectivity (Henseler et al., 2009). Relationships have also been uncovered between γ oscillatory activity with both positive and negative symptoms although through an auditory odd-ball task and not WM (Lee et al., 2003). In this study, patients were divided by symptom predominance and found that positive symptoms correlated with increased γ, while negative symptoms were related to a reduction of γ (Lee et al., 2003). As such, γ oscillations during WM may be related to both performance and symptom severity in SCZ patients. In the current study, therefore, we aimed to extend previous findings by examining evoked oscillatory activity during WM across δ, θ, α, β, and γ frequency components measured from the frontal region in SCZ patients compared to healthy subjects. We also sought to examine if neuronal oscillations during WM were related to task performance and symptom severity.