On the Emergence of Tremor in Prodromal Parkinson’s Disease

Abstract

Clinical, neuropathological and neuroimaging research suggests that pathological changes in Parkinson’s disease (PD) start many years before the emergence of motor signs. Since disease-modifying treatments are likely to be most effective when initiated early in the disease process, there has been significant interest in characterizing prodromal PD. Some people with PD describe autonomic symptoms at the time of diagnosis suggesting that autonomic dysfunction is a common feature of prodromal PD. Furthermore, subtle motor signs may be present and emerge prior to the time of diagnosis. We present a series of patients who, in the prodromal phase of PD, experienced the emergence of tremor initially only while yawning or straining at stool and discuss how early involvement of autonomic brainstem nuclei could lead to these previously unreported phenomena. The hypothalamic paraventricular nucleus (PVN) plays a central role in autonomic control including bowel/bladder function, cardiovascular homeostasis and yawning and innervates multiple brainstem nuclei involved in autonomic functions (including brainstem reticular formation, locus ceruleus, dorsal raphe nucleus and motor nucleus of the vagus). The PVN is affected in PD and evidence from related phenomena suggest that the PVN could increase tremor either by increasing downstream cholinergic activity on brainstem nuclei such as the reticular formation or by stimulating the locus ceruleus to activate the cerebellothalamocortical network via the ventrolateral nucleus of the thalamus. Aberrant cholinergic/noradrenergic transmission between these brainstem nuclei early in PD couldlead to tremor before the emergence of other parkinsonian signs, representing an early clinical clue to prodromal PD.

Parkinson disease following COVID‐19: Report of six cases

“…An alternative explanation is related to the potential, direct viral invasion of brainstem nuclei. Recently, aberrant cholinergic/noradrenergic transmission between the hypothalamic paraventricular nucleus and different brainstem nuclei (including reticular formation, locus coeruleus, dorsal raphe nucleus, and motor nucleus of the vagus) has been postulated, and indicated as a possible source of tremor, in early, prodromal PD [28]. Finally, the contribution of the isolation resulting from lockdown during the pandemic, and the ensuing neurochemical changes caused by a depressive state remain to be determined [29].…”

Monopolar transcranial direct current stimulation (tDCS) might selectively affect brainstem reflex pathways: a computational and neurophysiological study.

“…As for SP2 response, stimulus is conducted to the lateral reticular formation, where an inhibitory interneuron conducts it to ipsilateral and contralateral trigeminal motoneurons (De Visser et al, 1990). In order to integrate computational data with the neurophysiological outcome, we can hypothesize that tDCS may interfere with diencephalic nuclei strictly connected to pontine and medullary areas from which BR and MIR originate; in particular, a cholinergic downstream has been recently identified between the hypothalamic paraventricular nucleus and different brainstem nuclei (comprising reticular formation, locus ceruleus, dorsal raphe nucleus and motor nucleus of the vagus) (Fearon et al, 2021). However, BR parameters might be influenced by structures above the brainstem, e.g., motor cortex and basal ganglia (Esteban, 1999).…”

Pharmacological Treatment of Tremor in Parkinson’s Disease Revisited

“…Resting tremor is a presenting feature in approximately 70% of patients [8,9] and was recorded in about 77% of patients at some stage during the course of PD in a clinicopathological study [9]. Ephemeral episodes of tremor may be observed in some people years before the onset of classical motor signs and a diagnosis of PD [10].…”