Effects of acute nicotine on brain function in healthy smokers and non-smokers: Estimation of inter-individual response heterogeneity

Abstract

The present study used functional magnetic resonance imaging (fMRI) to investigate the neural mechanisms of nicotine effects on antisaccades (an oculomotor measure of the conflict between a reflexive response and a spatially complex volitional response) and prosaccades (involving reflexive overt attentional shifts). Given the known inter-individual variability in drug response we aimed to identify oculomotor variables and brain areas in which significant inter-individual heterogeneity in response to nicotine is observed. To do so we calculated within-session intraclass correlation (ICC) coefficients over measurements obtained before and after nicotine/placebo administration and reasoned that a significant reduction in ICC with nicotine compared to placebo would reflect the operation of significant inter-individual response heterogeneity. Thirteen light-to-moderate smokers and 11 non-smokers completed fMRI during antisaccades before and after subcutaneous injection of 12 μg/kg nicotine or saline placebo in a double-blind, randomised, cross-over design. All participants were healthy, right-handed males. Nicotine and placebo were given on separate occasions approximately 1 week apart with time of injection kept constant. Nicotine significantly reduced antisaccade latencies in both groups. At the level of brain function, during antisaccades the blood oxygen level dependent (BOLD) response in the left frontal eye field was non-significantly reduced by nicotine while it significantly increased following placebo in non-smokers, but there was no discernible effect in smokers. During prosaccades, it was found that deactivation areas (posterior cingulate gyrus and precuneus; right superior temporal gyrus) showed enhanced deactivations following nicotine administration in both groups. ICC analysis identified significant inter-individual response heterogeneity in antisaccade reflexive errors in smokers, and in a number of brain regions, particularly in non-smokers. These findings suggest that nicotine has beneficial effects at the cognitive level and leads to reductions in task-related activations and further decreases of BOLD in deactivation areas. The comparison of within-session ICCs across drug conditions suggests that the effects of nicotine are subject to inter-individual variability at behavioural and neural levels.

Introduction

Nicotine is a cholinergic agonist compound with stimulant properties. Administration of nicotine is known to enhance cognitive function in humans and experimental animals (Levin et al., 2006). Effects in humans are shown particularly in the domains of psychomotor functions, visual attention and memory (Heishman, 1998, Newhouse et al., 2004). Cholinergic agonists are being investigated intensively as potential cognitive enhancers for a range of neuropsychiatric conditions, including schizophrenia, Alzheimer's disease, Parkinson's disease, and attention deficit hyperactivity disorder (Newhouse et al., 1997, Martin et al., 2004, Kumari and Postma, 2005, Levin et al., 2006).

Saccadic eye movements are widely studied psychopharmacological biomarkers (Ettinger and Kumari, 2003). One of the most commonly studied tasks is the antisaccade task. An antisaccade is a saccadic eye movement away from a peripheral visual stimulus (Hallett, 1978). The task involves cognitive processes such as the suppression of an unwanted reflexive, or prepotent response, and the sensorimotor transformation along the dorsal visual stream of a peripheral visual signal into a volitional response (Reuter and Kathmann, 2004, Moon et al., 2007). The task is a sensitive measure of neural pathology associated with a range of psychiatric and neurological conditions (Hutton and Ettinger, 2006). Functional imaging studies show that antisaccade performance recruits the dorsal fronto-parietal demand network seen in high-level cognitive tasks consisting of dorsolateral prefrontal cortex (DLPFC), frontal eye fields (FEF), and intraparietal sulcus (IPS), as well as thalamus and striatum (O'Driscoll et al., 1995, Sweeney et al., 1996, McDowell et al., 2002).

Antisaccade performance is sensitive to the effects of nicotine. In healthy smokers, nicotine reduces the rate of reflexive errors (Powell et al., 2002, Dépatie et al., 2002, Larrison-Faucher et al., 2004, Rycroft et al., 2006) and the latency of antisaccades (Larrison et al., 2004, Rycroft et al., 2006, Rycroft et al., 2007), although one study found no effects (Thaker et al., 1991). Healthy non-smokers also show reduced antisaccade latency with nicotine (Rycroft et al., 2007). Additionally, there is evidence of the beneficial effects of nicotine on antisaccade performance in schizophrenia (Dépatie et al., 2002, Larrison-Faucher et al., 2004), a psychiatric condition associated with increased frequency and intensity of nicotine consumption through cigarette smoking (Kumari and Postma, 2005).

However, the neural mechanisms underlying these enhancements have not been studied. Given that the antisaccade task is a well-validated indicator of psychopathology and brain damage (Hutton and Ettinger, 2006) and a promising biomarker for pharmacological studies (Ettinger and Kumari, 2003), it is crucial to understand the neural mechanisms by which nicotine improves performance. Previous studies have shown that nicotine improves cognitive function by selectively increasing (Lawrence et al., 2002, Kumari et al., 2003, Jacobsen et al., 2004) or decreasing (Thiel et al., 2005) task-related neural activity or by enhancing task-induced deactivations (Hahn et al., 2007). The first aim of this study is to investigate the effects of nicotine on blood oxygen level dependent (BOLD) response during antisaccade performance using functional magnetic resonance imaging (fMRI). Additionally we evaluated prosaccade performance (overt attentional shifts achieved by reflexive saccades towards a peripheral target) and underlying BOLD response, in order to probe for nicotine effects on basic saccadic control.

An intriguing finding from previous research is that the behavioural response to nicotine is subject to considerable inter-individual variability. The precise reasons for this variability are unclear but are likely to be manifold, including genetic factors, receptor availability, gender, absorption, level of withdrawal in smokers, and performance as well as neural activation levels at baseline or under placebo (Heishman, 1998, Perkins, 1999, Smith et al., 2003, Larrison-Faucher et al., 2004, Berrettini and Lerman, 2005, Giessing et al., 2007, de Jongh et al., 2008). However, the extent of heterogeneity in neural response to nicotine in humans is not known.

Therefore, a second aim of the study is to investigate the extent of inter-individual heterogeneity in nicotine response in a sample of psychiatrically, neurologically and medically healthy, right-handed males. In order to do so we calculated intraclass (ICC) correlations over BOLD and saccadic measures taken before and after nicotine administration and compared these to ICCs derived from the placebo scans. Heterogeneity in drug response is reflected by inter-individual differences in the magnitude of change following drug administration. Therefore, we reasoned that heterogeneity in response to nicotine would perturb the rank order of inter-individual differences within the sample and would result in lower ICCs when compared to placebo. In order to explore whether effects of nicotine are mediated by smoking status, we studied smokers and non-smokers, and to avoid significant impairments following withdrawal, we studied light-to-moderate smokers who were only minimally withdrawn (Heishman, 1998).