CnF-DBS for Levodopa-Resistant FOG

This is a multi-site, prospective, randomized, sham-controlled, crossover, double-blinded feasibility clinical trial assessing the extent to which cuneiform nucleus deep brain stimulation (CnF DBS) can ameliorate freezing of gait (FOG) in Parkinson's Disease (PD) patients with severe, Levodopa-resistant gait freezing. The study intends to determine the optimal stimulation parameters (frequency, pulse, amplitude) that maximize gait performance while minimizing any potential side effects and to evaluate the effect of CnF DBS on other PD symptoms (including pain) and quality of life.

Participation in the study is expected to last approximately eight months from enrollment through completion of study activities. Study procedures include medical and neurological evaluations, walking and mobility assessments, questionnaires, brain imaging, device programming visits, and collection of information about your symptoms, safety, and quality of life.

The most significant risks of participation are those associated with DBS surgery and chronic brain stimulation, including bleeding, infection, stroke, seizure, device-related complications, worsening of neurological symptoms, falls, and stimulation-related side effects.

Inclusion criteria

• Age between 35 and 80 years
• Confirmed diagnosis of PD, according to a movement disorder neurologist, with documented exclusion of other disorders such as Frontotemporal Dementia (FTD), frontal gait disorder, Normal Pressure Hydrocephalus (NPH), or Progressive Supranuclear Palsy (PSP)
• Postural Instability and Gait Difficulty (PIGD)-predominant PD, defined by a Tremor-Dominant (TD)/PIGD ratio of ≤ 0.90, as calculated from MDS-UPDRS items, according to previously validated methods46
• FOGQ score of > 12, consistent with severe gait disorder47-49
• Clinical observation of FOG in ON and/or OFF medication states by a movement disorder neurologist
• FOG refractory to optimized dopaminergic therapy by a movement disorder neurologist
• Minimal tremor, bradykinesia, and rigidity, or well controlled motor symptoms with optimized dopaminergic therapy and/or previously implanted STN or GPi DBS, such that FOG and axial dysfunction represent the predominant disabling motor features
• Adequate cognitive function (e.g., Mattis Dementia Rating Scale-2 (DRS-2) > 130) and absence of major uncontrolled psychiatric illness (e.g., Beck's Depression Inventory-II (BDI-II) ≤ 25)
• Willingness and ability to comply with protocol requirements (e.g., procedure visits, treatment schedule, follow-up visit schedule, evaluations, etc.), at the principal investigator's discretion
• Willingness and ability to provide written agreement to allow any and all forms of communication between the research team and treating clinician(s)
• Willingness and ability to provide informed consent, at the principal investigator's discretion

Exclusion criteria

• Major executive dysfunction or dementia (DRS-2 ≤ 130) or other neurocognitive impairments that would interfere with informed consent or study participation, at the principal investigator's discretion
• Depression, defined, for example, by BDI-II > 25 or diagnosis of one or more other high-risk psychiatric conditions (e.g., substance use disorder, severe anxiety, uncontrolled bipolar disorder), at the principal investigator's discretion
• Presence of high suicide risk on the Columbia-Suicide Severity Rating Scale (C-SSRS) as defined below Participants will be excluded if they endorse active suicidal ideation with intent to act (C-SSRS Severity Level 4 or 5) during screening, report a suicide attempt, interrupted attempt, or aborted attempt within the previous 6 months, or are determined by the study psychiatrist and/or principal investigator to present clinically significant suicide risk.
• Major medical co-morbidities and other surgical contraindications such as uncontrolled hypertension, severe cardiopulmonary disease, coagulopathy, epilepsy, prior intracranial hemorrhage, or significant cerebrovascular disease, at the principal investigator's discretion
• Need for diathermy, TMS, or ECT during the study
• History of prior intracranial surgery (other than prior STN or GPi DBS for PD) that substantially alters anatomy or risk at the CnF target, at the principal investigator's discretion
• Any metallic implant in the head that is not MRI-compatible (e.g., certain aneurysm clips, cochlear implants)
• Active implantable devices anywhere in the body (e.g. pacemaker, defibrillator, spinal cord stimulator, implanted medication pump) that may affect imaging quality or interact with DBS, unless specifically permitted by device labeling and investigator judgment
• Pregnancy, intent to become pregnant during the study, breastfeeding, or unwillingness to use an acceptable method of contraception throughout the course of the trial
• Current participation in other interventional trials or use of investigational drugs or devices that may influence gait or DBS outcomes, at the principal investigator's discretion