摘要
In stressful or anxiety-provoking situations,most people with Parkinson’s disease(PD)experience a general worsening of motor symptoms,including their gait impairments.However,a proportion of patients actually report benefits from experiencing-or even purposely inducing-stressful or high-arousal situations.Using data from a large-scale international survey study among 4324 people with PD and gait impairments within the online Fox Insight(USA)and ParkinsonNEXT(NL)cohorts,we demonstrate that individuals with PD deploy an array of mental state alteration strategies to cope with their gait impairment.Crucially,these strategies differ along an axis of arousal-some act to heighten,whereas others diminish,overall sympathetic tone.Together,our observations suggest that arousal may act as a double-edged sword for gait control in PD.We propose a theoretical,neurobiological framework to explain why heightened arousal can have detrimental effects on the occurrence and severity of gait impairments in some individuals,while alleviating them in others.Specifically,we postulate that this seemingly contradictory phenomenon is explained by the inherent features of the ascending arousal system:namely,that arousal is related to task performance by an inverted u-shaped curve(the so-called Yerkes and Dodson relationship).We propose that the noradrenergic locus coeruleus plays an important role in modulating PD symptom severity and expression,by regulating arousal and by mediating network-level functional integration across the brain.The ability of the locus coeruleus to facilitate dynamic‘cross-talk’between distinct,otherwise largely segregated brain regions may facilitate the necessary cerebral compensation for gait impairments in PD.In the presence of suboptimal arousal,compensatory networks may be too segregated to allow for adequate compensation.Conversely,with supraoptimal arousal,increased cross-talk between competing inputs of these complementary networks may emerge and become dysfunctional.Because the locus coeruleus degenerates with disease progression,finetuning of this delicate balance becomes increasingly difficult,heightening the need for mental strategies to self-modulate arousal and facilitate shifting from a sub-or supraoptimal state of arousal to improve gait performance.Recognition of this underlying mechanism emphasises the importance of PD-specific rehabilitation strategies to alleviate gait disability.
基金
supported by an Academy Van Leersum grant of the Academy Medical Sciences Fund,Royal Netherlands Academy of Arts&Sciences
supported by a Parkinson Canada New Investigator grant,as well as a Natural Sciences and Engineering Research Council of Canada Discovery grant.RCH was supported by a research grant(VIDI,#09150172010044)from the Netherlands Organization for Scientific Research
He has acted as consultant for UCB(unrelated to this work)
supported by a grant from the European Regional Development Fund(ERDF/EFRO,grant number PROJ-00928)outside the submitted work
supported by the National Health and Medical Research Council(1193857)
supported by the Australian Government Research Training Program(RTP)Scholarship.GW reports no disclosures.SJGL was supported by a National Health and Medical Research Council Leadership Fellowship(1195830)
supported by a ZonMW Veni grant(16.196.022).
