Noradrenergic modulation of saccades in Parkinson's disease

Noradrenaline is a powerful modulator of cognitive processes, including action-decisions underlying saccadic control. Changes in saccadic eye movements are common across neurodegenerative diseases of ageing, including Parkinson's disease. With growing interest in noradrenergic treatment potential for non-motor symptoms in Parkinson's disease, the temporal precision of oculomotor function is advantageous to assess the effects of this modulation. Here we studied the effect of 40 mg atomoxetine, a noradrenaline reuptake inhibitor, in nineteen people with idiopathic Parkinson's disease using a single dose, randomised double-blind crossover placebo-controlled design. Twenty-five healthy adult participants completed the assessments to provide normative data. Participants performed prosaccade and antisaccade tasks. The latency, velocity and accuracy of saccades, and resting pupil diameter, were measured. Increased pupil diameter on the drug confirmed its expected effect on the locus coeruleus ascending arousal system. Atomoxetine improved key aspects of saccade performance: prosaccade latencies were faster and the saccadic main sequence was normalised. These improvements were accompanied by increased antisaccade error rates on the drug. Together these findings suggest a shift in the speed-accuracy trade-off for visuo-motor decisions in response to noradrenergic treatment. Our results provide new evidence to substantiate a role for noradrenergic modulation of saccades, and based on known circuitry we advance the hypothesis that this reflects modulation at the level of the locus coeruleus-superior colliculus pathway. Given the potential for noradrenergic treatment of non-motor symptoms of Parkinson's disease and related conditions, the oculomotor system can support the assessment of cognitive effects without limb-motor confounds on task performance. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial ISRCTN46299660 ### Funding Statement This study was supported by Parkinson's UK (K-1702) and the Cambridge Centre for Parkinson-Plus. F.H.H. was supported by a Cambridge Trust Vice-Chancellor's Award and Fitzwilliam College Scholarship. N.H. was supported by the Association of British Neurologists-Patrick Berthoud Charitable Trust (RG99368). A.G.M. was supported by the Holt Fellowship (RG86564). C.H.W-G. was supported by a RCUK/UKRI Research Innovation Fellowship awarded by the Medical Research Council (MR/R007446/1). J.B.R. is funded from the Welcome Trust (103838; 220258), the Medical Research Council (MC\_UU\_00030/14; MR/T033371/1), the National Institute for Health Research Cambridge Biomedical Research Centre (NIHR203312: BRC-1215-20014); and a James S. McDonnell Foundation 21st Century Science Initiative Scholar Award in Understanding Human Cognition. C.O. was supported by a University of Sydney Robinson Fellowship and an Australian National Health and Medical Research Council EL2 Fellowship (2016866). This study was carried out at/supported by the NIHR Cambridge Clinical Research Facility and supported by the NIHR Cambridge Biomedical Research Centre (NIHR203312). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. For the purpose of open access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the Health Research Authority East of England-Cambridge Central Research Ethics Committee (REC 10/H0308/34). The trial was registered on ISRCTN registry with study ID [ISRCTN46299660][1] (https://doi.org/10.1186/[ISRCTN46299660][1]). The study was retrospectively registered because it was exempt from Clinical Trials status by the UK Medicines and Healthcare Products Regulatory Authority (MHRA). However, we have endeavoured to retrospectively register it in order to meet compliance requirements for preprint and journal submissions. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Code and data to reproduce figures and statistical analyses are available through the Open Science Framework. [1]: /external-ref?link_type=ISRCTN&access_num=ISRCTN46299660