Effects of pharmacologic catecholamine manipulation on smooth pursuit eye movements in normals

doi:10.1016/0920-9964(94)90096-5

Schizophrenia Research

Volume 13, Issue 2, September 1994, Pages 151-159

https://doi.org/10.1016/0920-9964(94)90096-5 Get rights and content

Abstract

The pathophysiology of schizophrenia may be related directly or indirectly to abnormal dopaminergic activity. Both subcortical excess and frontal cortical deficiency of dopamine have been suggested, and primary or downstream failures of dopamine activation to the prefrontal cortex has been posited to explain some of the cognitive deficiencies in schizophrenia patients. Although the prefrontal cortex may also be a site for the disruption of smooth pursuit eye movements (SPEM), the most substantially described psychophysiological marker for schizophrenia vulnerability, no relationship of SPEM to dopaminergic activity has been demonstrated. In this study we explored the effect of altered dopamine function on SPEM quality through pharmacological manipulation of catecholamine tone in 11 healthy subjects. The subjects had SPEM measured at baseline, and under challenge conditions including amphetamine (0.3 mg/kg), haloperidol (2mg), placebo, and combined amphetamine with haloperidol. Changes in the profile of mood scale (POMS) confirmed the expected subjective central nervous system effects of the agents. Placebo and amphetamine had no effect on qualitative ratings of SPEM, but haloperidol, alone and in combination with amphetamine, disrupted eye tracking, producing a pattern of small saccadic intrusions characteristic of patients with schizophrenia. These findings link dopaminergic blockade with SPEM disruption in normal subjects.

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Amphetamine-induced alteration to gaze parameters: A novel conceptual pathway and implications for naturalistic behavior
2021, Progress in Neurobiology
Citation Excerpt :
Initial reports of an effect of single oral dose of amphetamine (20 mg) on select measures of SPEM (positive saccades, negative saccades and overshoots) employed a qualitative analytic methodology, and quantitative reanalysis confirmed an effect on small saccades only (Filip et al., 1978). More recent studies employing quantitative analytical methods indicate no effect of small acute oral doses of amphetamine [at 15 mg (Tedeschi et al., 1983) or 0.3 mg/kg (Malaspina et al., 1994)] on SPEM capabilities in healthy adults. It is important to note that the dose administration schedules in these available studies are considerably lower than those typically consumed in recreational settings and that acute methodology protocols do not accurately reflect typical modes of consumption among user groups.
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.
Cerebellar hyperactivity during smooth pursuit eye movements in bipolar disorder
2011, Journal of Psychiatric Research
Citation Excerpt :
Feil et al found no effect of alcohol abuse history on smooth pursuit performance (RMS, Feil et al., 1994). The acute administration of amphetamine may or may not have an effect on qualitative ratings of SPEM (Malaspina et al., 1994; Siever et al., 1987). Abstinent cocaine users have impaired gain (Rosse et al., 1992).
Smooth pursuit eye movements (SPEM) are abnormal in individuals with schizophrenia and individuals with bipolar disorder. Functional imaging methods have revealed greater hippocampal activity and less frontotemporal, visual, and posterior cerebellar activity in individuals with schizophrenia when performing a SPEM task. The underlying neurobiology of SPEM deficits in bipolar disorder is unknown.
Functional magnetic resonance imaging at 3T was performed on fourteen subjects with bipolar disorder and 14 subjects without psychiatric illness during a block design SPEM task. Clinical measures were assessed on the day of testing and related to imaging measures.
Subjects with bipolar disorder had greater hemodynamic response than control subjects in cerebellar vermis. Responses were associated with levels of depressive symptoms on the day of study.
Increased cerebellar vermis activity during the smooth pursuit eye movement task in individuals with bipolar disorder further implicates cerebellar involvement in bipolar disorder. Increased hemodynamic response within the hippocampus was not seen in these individuals and may be a finding specific to schizophrenia.
Pharmacological treatment effects on eye movement control
2008, Brain and Cognition
The increasing use of eye movement paradigms to assess the functional integrity of brain systems involved in sensorimotor and cognitive processing in clinical disorders requires greater attention to effects of pharmacological treatments on these systems. This is needed to better differentiate disease and medication effects in clinical samples, to learn about neurochemical systems relevant for identified disturbances, and to facilitate identification of oculomotor biomarkers of pharmacological effects. In this review, studies of pharmacologic treatment effects on eye movements in healthy individuals are summarized and the sensitivity of eye movements to a variety of pharmacological manipulations is established. Primary findings from these studies of healthy individuals involving mainly acute effects indicate that: (i) the most consistent finding across several classes of drugs, including benzodiazepines, first- and second- generation antipsychotics, anticholinergic agents, and anticonvulsant/mood stabilizing medications is a decrease in saccade and smooth pursuit velocity (or increase in saccades during pursuit); (ii) these oculomotor effects largely reflect the general sedating effects of these medications on central nervous system functioning and are often dose-dependent; (iii) in many cases changes in oculomotor functioning are more sensitive indicators of pharmacological effects than other measures; and (iv) other agents, including the antidepressant class of serotonergic reuptake inhibitors, direct serotonergic agonists, and stimulants including amphetamine and nicotine, do not appear to adversely impact oculomotor functions in healthy individuals and may well enhance aspects of saccade and pursuit performance. Pharmacological treatment effects on eye movements across several clinical disorders including schizophrenia, affective disorders, attention deficit hyperactivity disorder, Parkinson’s disease, and Huntington’s disease are also reviewed. While greater recognition and investigation into pharmacological treatment effects in these disorders is needed, both beneficial and adverse drug effects are identified. This raises the important caveat for oculomotor studies of neuropsychiatric disorders that performance differences from healthy individuals cannot be attributed to illness effects alone. In final sections of this review, studies are presented that illustrate the utility of eye movements for use as potential biomarkers in pharmacodynamic and pharmacogenetic studies. While more systematic studies are needed, we conclude that eye movement measurements hold significant promise as tools to investigate treatment effects on cognitive and sensorimotor processes in clinical populations and that their use may be helpful in speeding the drug development pathway for drugs targeting specific neural systems and in individualizing pharmacological treatments.
Amphetamine disrupts P50 suppression in normal subjects
1999, Biological Psychiatry
Background: P50 suppression is viewed as an operational measure of sensory “gating” that is reduced in patients with schizophrenia and their family members. Previous reports have demonstrated that neural gating is regulated by monoaminergic tone in rodent models of P50 suppression.
Methods: In this study, 11 healthy subjects participated in P50 event-related potential recordings at baseline and after either oral administration of dextroamphetamine (.3 mg/kg) or placebo, to determine if the administration of a monoaminergic agonist produces P50 suppression deficits similar to those observed in patients with schizophrenia.
Results: As hypothesized, amphetamine disrupted the suppression of the P50 event-related potential. There was a statistically significant decrement in P50 suppression during the amphetamine challenge condition (t₁₀ = 3.15, p < .01, mean difference = −44.1%, d = −2.5) relative to the baseline P50 condition. A comparison of P50 suppression in the placebo and amphetamine conditions (both after a baseline recording session) revealed a significant amphetamine-induced disruption of P50 suppression (t₆ = 3.71, p < .01, mean difference = −54.4%, d = −3.14).
Conclusions: The biochemical alterations associated with an amphetamine-induced disruption of P50 suppression in this study may be related to the pathophysiology of P50 suppression deficits in schizophrenia. The findings are consistent with several careful examinations of suppression deficits in rodent models that have identified the monoaminergic regulation of P50 suppression. These data indicate that amphetamine induces a disruption of P50 suppression in normal subjects.
The role of dopamine in anticipatory pursuit eye movements: Insights from genetic polymorphisms in healthy adults
2016, eNeuro
Effects of methylphenidate on basic and higher-order oculomotor functions
2012, Journal of Psychopharmacology

View all citing articles on Scopus

View full text

Effects of pharmacologic catecholamine manipulation on smooth pursuit eye movements in normals

Abstract

Schizophr. Res.

Trends Neurosci.

Neurosci. Behav. Rev.

Int. Rev. Neurobiology

J. Psychiatric Res.

J. Psychiatric Res.

Schizophr. Res. (Abs.)

J. Psychiatric Res.

Biol. Psychiatry

Smooth pursuit eye movements of schizophrenics and normal people under stress

Br. J. Psychiatry

Dopamine receptors and average clinical doses

Science

Single dose amphetamine on smooth pursuit eye movements in man

Activ Nerv

Working memory and mind

Scientific American

Smooth pursuit ocular motor dysfunction in schizophrenia: evidence for a major gene

Am. J. Psychiatry

Eye tracking patterns in schizophrenia

Science

Eye tracking dysfunctions in schizophrenic patients and their relatives

Arch. Gen. Psychiatry

Smooth pursuit eye movements and diazepam, CPZ and secobarbital

Psychopharmacologia

Deviant eye tracking in twins discordant for psychosis: A replication

Arch. Gen. Psychiatry

A single dominant gene can account for eye tracking dysfunctions and schizophrenia in offspring of discordant twins

Arch. Gen. Psychiatry

Eye tracking in patients with unipolar and bipolar affective disorders in remission

J. Abnormal Psychol.

Eye tracking in Normal Twins

Behav. Genet.