Essential Tremor

To be classified as idiopathic PD, patients must meet the inclusion criteria proposed by the United Kingdom Parkinson’s Disease Society Brain Bank Clinical Diagnostic Criteria (Hughes et al., 1992 (link)).
Patients who do not fulfill the proposed criteria will be classified as unspecified PD or as atypical PD based on the respective criteria. In the atypical PD subgroup, further classification will include subtypes, including PSP (Litvan et al., 1996 (link); Höglinger et al., 2017 (link)), MSA (Gilman et al., 2008 (link)), CBS (Boeve et al., 2003 (link)) or vascular parkinsonism (VP) (Zijlmans et al., 2004 (link)), based on internationally established criteria. All diagnostic classifications will be regularly updated. Patients with essential tremor are excluded from the patients group, and included into the control group. They may convert into typical PD and would then qualify for the inclusion into the patient group (Unal Gulsuner et al., 2014 (link); Laroia and Louis, 2011 (link)).
Patients with a secondary cause of parkinsonism (e.g., normal pressure hydrocephalus, toxic parkinsonism, medication-induced parkinsonism, symptomatic parkinsonism due to structural lesions) are excluded. Here, separation was based on established diagnostic criteria that include clinical symptoms as well as available clinical imaging results. Whereas normal pressure hydrocephalus may still be clinically over suspected (Espay et al., 2017 (link)), and presents with parkinsonism, gait disturbance, urinary symptoms, as observed for VP, the cardiovascular risk profile and the typical imaging findings with vascular lesions vs. symmetric enlargement of ventricles and diapedesis of CSF defines the difference of both secondary causes of parkinsonism (Rektor et al., 2018 (link)).

The research has been approved by the Chinese Clinical Trial Registry (Registration No.: ChiCTR2100054804) and the local Ethics Committee of Shanghai Jiao Tong University, China (Approved No. of Ethic Committee: 2019 Clinical Trial No. 136). All subjects provided written consent after being informed of the purpose and the procedures of the experiment. The overall experiment was strictly performed in accordance with all relevant guidelines and regulations of the institutional review board and the Declaration of Helsinki. Patients were recruited by the department of neurology of Rui Jin Hospital (Shanghai, China). All of them were out-patients with upper limb tremor resulted from Parkinson's disease (Excluded N = 11; Not meeting the inclusion criteria N = 7; Declined to participate N = 4) (Figure 1).
The inclusion criteria for subjects were: (1) age between 50 and 80 years old, (2) confirmed diagnosis of idiopathic Parkinson's disease according to the MDS clinical diagnostic criteria for PD (Postuma et al., 2015 (link)), (3) symptom of upper limb tremor (rest tremor or postural tremor) resulted from PD, and (4) modified Hoen & Yahr (H&Y) Stage 1 to 3 (Hoehn and Yahr, 1967 (link)). The exclusion criteria included: (1) history of other diseases that may lead to pathological tremor, such as essential tremor (Deuschl et al., 1998 (link)), (2) under the treatment of other neuromodulation therapy, such as DBS, within recent 1 month, (3) history of mental problems, including anxiety, dementia, hallucination or delusion etc., (4) strong reliance on anti-Parkinson medications, or (5) history of cognitive disorder [Mini-mental State Examination (MMSE) score ≤ 16] (Tombaugh and McIntyre, 1992 (link)).
The average disease duration of PD among all subjects [7M/6F, all right-handed, aged 67.5 ± 4.9 (mean ± SD)] were 4.38 ± 1.86 (mean ± SD) years. The Unified Parkinson's Disease Rating Scale (UPDRS) score ranged from 20 to 78 [31.7 ± 15.4 (mean ± SD)] while the modified H&Y stage ranged from 1.0 to 3.0 [1.8 ± 0.8 (mean ± SD)]. The tremor was found to be lateralized in all subjects. Throughout the manuscript, we refer to the more-affected side (MAS) as the side of body exhibiting more severe tremor, which was determined visually by an experienced physician, while the less-affected side (LAS)was defined as the other. Of all subjects, about half (n = 7) were found to be more-affected by tremor on the left side with the other half (n = 6) on the right side. The average levodopa-equivalent daily dose (LEDD) among all subjects was 278.8 ± 203.3 (mean ± SD) mg according to the calculation protocol provided by Tomlinson et al. (2010 (link)). In order to exclude drug effects, all subjects were told to discontinue anti-Parkinson medications on the day of the experiment, which ensured a withdrawal period of more than 12 h. Anti-Parkinson medications were resumed immediately after the experiment session of the day.

We consecutively enrolled patients who visited our study group for PD between November 2021 and September 2022. Eligible patients were those who were diagnosed with PD according to the International Parkinson and Movement Disorder Society (MDS) criteria (Postuma et al., 2015 (link)). Exclusion criteria were any neurological disorder other than PD including parkinsonism secondary to trauma or drugs, metabolic diseases, encephalitis, progressive supranuclear palsy, essential tremor, and hepatolenticular degeneration. All eligible patients underwent assessment via APP tests including DST, VOT, FRT, and VMT in the APP with raw scores recorded, at the same time, CDT, CCT, and MMSE were also evaluated as classic evaluation tools for comparison. Patients with the CDT score of 5 (Spenciere et al., 2017 (link)) and the CCT score ≥ 18 (Bu et al., 2013 (link)) were classified to no visuospatial disorder group, while patients with the CDT score $<$ 5 or CCT score $<$ 18 were classified to visuospatial disorder group. Information on patients’ demographic characteristics and clinical profile were collected from medical records. This study was performed in accordance with the Declaration of Helsinki and approved by the ethics committee of China-Japan friendship Hospital (2020-129-K82). All participants gave their informed consent to participate in the study in written form.

Patients undergoing awake GPi DBS implantation surgery for the treatment of Parkinson’s disease at the University of Florida Norman Fixel Institute for Neurological Diseases were included in the study. Patients undergoing DBS implantation surgery targeted to the STN for Parkinson’s disease or the ventralis intermedius (VIM) nucleus for the treatment of essential tremor were included for comparison as controls. Informed consent was obtained for all patients for inclusion in our institutional database (Institutional Review Board #201901807). Both hemispheres were tested in a subset of patients who underwent staged bilateral DBS.