Amphetamine-induced alteration to gaze parameters: A novel conceptual pathway and implications for naturalistic behavior

Highlights

• We propose a novel model for amphetamine-induced alterations to gaze behavior.

• Gaze parameters are dependent on visual input via component oculomotor processes.

• Amphetamine reduces continuity and accuracy of visuomotor movement and control.

• Mismatch between these systems produces perceptual narrowing or ‘tunnel vision’.

• Quantifying gaze behaviour may index amphetamine-related visual scanning efficiency.

Abstract

Amphetamine produces a multiplicity of well-documented end-order biochemical, pharmacological and biobehavioural effects. Mechanistically, amphetamine downregulates presynaptic and postsynaptic striatal monoamine (primarily dopaminergic) systems, producing alterations to key brain regions which manifest as stereotyped ridged behaviour which occurs under both acute and chronic dosing schedules and persists beyond detoxification. Despite evidence of amphetamine-induced visual attentional dysfunction, no conceptual synthesis has yet captured how characteristic pharmaco-behavioural processes are critically implicated via these pathways, nor described the potential implications for safety-sensitive behaviours. Drawing on known pathomechanisms, we propose a cross-disciplinary, novel conceptual functional system framework for delineating the biobehavioural consequences of amphetamine use on visual attentional capacity and discuss the implications for functional and behavioural outcomes. Specifically, we highlight the manifest implications for behaviours that are conceptually driven and highly dependent on visual information processing for timely execution of visually-guided movements. Following this, we highlight the potential impact on safety-sensitive, but common behaviours, such as driving a motor vehicle. The close pathophysiological relationship between oculomotor control and higher-order cognitive processes further suggests that dynamic measurement of movement related to the motion of the eye (gaze behaviour) may be a simple, effective and direct measure of behavioural performance capabilities in naturalistic settings. Consequently, we discuss the potential efficacy of ocular monitoring for the detection and monitoring of driver states for this drug user group, and potential wider application.

Significance statement: We propose a novel biochemical-physiological-behavioural pathway which delineates how amphetamine use critically alters oculomotor function, visual-attentional performance and information processing capabilities. Given the manifest implications for behaviours that are conceptually driven and highly dependent on these processes, we recommend oculography as a novel means of detecting and monitoring gaze behaviours during naturalistic tasks such as driving. Real-word examination of gaze behaviour therefore present as an effective means to detect driver impairment and prevent performance degradation due to these drugs.

Introduction

Amphetamine and its congeners belong to a class of direct and indirect-acting sympathomimetic amines which produce potent biochemical, pharmacological and biobehavioural effects. As one of the oldest pharmacological compounds, amphetamine has a long and varied history, both as an early therapeutic and effective pharmacological agent, and more recently, as a contentious and (mostly) illicit drug with abuse potential. Amphetamine-type substances are experiencing a resurgence in popularity due to increased scientific interest in their potential therapeutic applications [such as 3,4- Methylenedioxymethamphetamine (MDMA) for treatment of psychiatric illness]. Importantly, their increased recreational popularity has several important implications for health and safety, not least in their overrepresentation among drivers injured or killed due to road traffic crashes. The biochemical effects of amphetamine and its derivatives (as well as emerging designer drugs) are described in considerable detail across several excellent scoping review articles [See; (de la Torre et al., 2004; Heal et al., 2013)]. The aim of this current review is therefore not intended to provide in-depth comparison of each component derivative in relation to its complex biochemical or pharmacological characteristics, nor attempt to closely re-examine their individual mechanisms of action. Rather, we aim to synthesise current knowledge regarding the pharmacological effects of salient amphetamine derivatives (judged here as those of illicit and/or therapeutic significance) on key brain regions of interest (Chapters 1–3). In doing so, we propose a novel pharmacological-biobehavioural pathway to delineate their effects on specific aspects of oculomotor function and subsequent changes to visual attention and information processing (Chapter 4). Using extant clinicopathological frameworks, we develop a surrogate model to support a neuromodulatory origin for altered oculomotor control and visual attention (Chapter 5). Introducing our novel pathomechanistic model (Chapter 6), we propose that amphetamine-induced alterations are examinable through quantifying dynamic gaze behaviour. Here, gaze behaviour refers to the process of utilising oculomotor events to scan the environment and selectively prioritise the intake and processing of visual information. Considering this framework, we propose gaze metrics as a novel means for providing a quantifiable estimation of the spatial and temporal distribution of gaze in real-time (Chapter 6). Discussing the potential application for co-developing systems designed to detect and monitor amphetamine-specific impairment in naturalistic settings, we contextualise this in terms of safety-critical behaviours for which amphetamine use is increasingly common and negatively implicated, such as driving a car (Chapter 7).

Amphetamine (contracted from 1-methyl-2-phenylthylamine) was first synthesised in 1887 in Berlin, Germany, by Romanian chemist Lazar Edeleanu (1862–1941) (Pancu, 2013). It was subsequently adapted and patented for commercial use in 1927 by American biochemist Gordon Alles as a cheap synthetic decongestant and bronchodilator ephedrine substitute (Prinzmetal and Alles, 1939). In 1935 Smith, Kline and French (SKF) produced Benzedrine Sulphate®, a commercially available racemic α-amphetamine. First available as an inhalant (containing 250 mg of amphetamine base), and, later as a tablet (mainly 10 mg), Benzedrine® was widely marketed as a cognitive enhancer and wakefulness aid (McNamara and Miller, 1937; Molitch and Sullivan, 1937), appetite suppressant (Tainter, 1944), antidepressant, anti-narcoleptic aid (Prinzmetal and Bloomberg, 1935), and even as a novel treatment Parkinson’s disease (Fahn, 2015). SKF later synthesised the two amphetamine isomers (D- and L-), further producing d-amphetamine (marketed as Dexedrine®). Due to many of the drugs desirable effects, amphetamine was widely consumed by the general public, students, health practitioners, and allied military personal throughout the 40’s and 50’s (Guttmann and Sargant, 1937). An overview of the clinical and pharmacological parameters for amphetamine and its key congeners is provided in Table 1.

The widespread public and therapeutic use of amphetamine was increasingly linked to reports of adverse effects (Young and Scoville, 1938) and abuse potential (Monroe and Drell, 1947). From the 1960’s and into the 1970’s, the Federal Drug Administration (FDA) in the USA incited motions to restrict the storage, sale and availability of over-the-couther amphetamine to limited prescription purposes only. Perhaps counterintuitively, a subsequent surge in prescribing occurred during this transition period (Rasmussen, 2008). In 1971, the Controlled Substances Act formally declared amphetamine a Schedule-II controlled substance of abuse and addiction potential as part of the United Nations Convention on Psychotropic Substances treaty, thus placing it in the same category as heroin, morphine and cocaine. Despite these constraints, amphetamine derivatives and mixed enantiomer products have continued to have clinical utility in recent years (albeit more highly controlled) as short-term pharmaceutical aid for reducing the symptoms of attention deficit hyperactivity disorder (ADHD) in adults (Castells et al., 2018) and children (Punja et al., 2016), and for weight loss/control (Haslam, 2016).