PSP - Progressive Supranuclear Palsy
Conditions
Keywords
PSP, Progressive Supranuclear Palsy, Transcranial direct current stimulation (tDCS), GFI
Brief summary
Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease with a prevalence estimated at 6 per 100,000 in France and a rapidly progressive course. In its classic form (known as the Richardson type), it presents with a predominantly axial Parkinsonian syndrome, postural instability with early falls, oculomotor disorders, and cognitive and behavioral disturbances. Apart from levodopa, which may provide a modest improvement in Parkinsonian syndrome in some patients, the current therapeutic approach relies primarily on rehabilitation techniques, with no proven efficacy. Cognitive-behavioral symptoms are common in this disease and are primarily characterized by impaired executive functions, linked to dysfunction of the frontal cortex. They often have a devastating effect on quality of life, are associated with an increased risk of falls, and represent a considerable burden for caregivers. Among these symptoms, apathy is the most commonly described symptom. Impulsivity, associated with impaired inhibitory control, is present in 32-74% of cases and may coexist with apathy. Cognitive and behavioral inhibition depends on a complex brain network that includes, among others, the right inferior frontal gyrus (IFG), the dorsolateral prefrontal cortex, the supplementary motor area, the motor cortex, and the basal ganglia. It has recently been shown that patients with PSP have impaired functional connectivity between the right LFC and other brain structures in the network, and that neurotransmitter deficits in the right LFC correlate with their impulsivity Alongside pharmacological approaches, non-invasive brain stimulation techniques are rapidly expanding as a potential therapeutic tool. Transcranial direct current stimulation (tDCS), by modulating cortical excitability, is a promising technique. It is simple to administer and has demonstrated efficacy in several clinical settings. Furthermore, a recent meta-analysis of 45 clinical studies shows that single or repeated tDCS sessions could modestly but significantly improve the inhibitory response-measured by reaction time in the stop-signal paradigm-especially when active (anodal) stimulation was applied to the right GFI. These studies primarily involved healthy subjects. A few studies have examined the effects of tDCS in neurodegenerative diseases and in PSP. These studies are still preliminary, involving small sample sizes, but are encouraging. Among these, a randomized study comparing tDCS to sham tDCS demonstrated a beneficial effect of a single-session tDCS session targeting the dorsolateral prefrontal cortex on verbal fluency in patients with PSP. The hypothesis of our study is that applying tDCS stimulation over the right GFI will improve certain cognitive functions and reduce behavioral impulsivity in patients. Very little data on tDCS in PSP is available to date. Only three studies have been published. With very different designs-including only one randomized trial comparing tDCS to sham tDCS-these studies evaluated the effects of tDCS applied to the dorsolateral prefrontal cortex or to motor and premotor areas on language and motor symptoms, respectively. In this randomized, double-blind, controlled study, the investigators propose to explore the effects of tDCS on the right GFI on executive functions and, more specifically, on inhibitory control. Another strength of our study is that only patients with proven frontal cerebral hypometabolism on FDG-PET-MRI will be included, which will allow us to test the effect of tDCS on a clearly dysfunctional neural network. Furthermore, as a secondary objective, the investigators will be able to assess whether the effects of tDCS depend on the intensity and/or topography of cerebral hypometabolism. The neurophysiological effects of a single tDCS session appear to last up to 60 to 90 minutes. In this proof-of-concept study, the assessment tests were deliberately chosen for their short administration time and low test-retest effect. Finally, the Stop Signal Test, already used in this population, is widely used and well-standardized. This pilot study will provide initial data on the cognitive and motor effects of a tDCS session on the GFI, with a focus on inhibition. Given the limited effectiveness of symptomatic treatments-particularly pharmacological ones-having a new option capable of improving cognitive and/or behavioral performance would have a significant impact on the quality of life of patients and their families. tDCS has the advantage of being easily accessible and generally well-tolerated by patients and could eventually be administered in patients' homes. If our study demonstrates an improvement in certain cognitive/motor functions, it would lead to a larger-scale study with repeated sessions to assess its benefits over a longer period. Finally, if an improvement in executive functions is demonstrated in PSP, this could apply to other neurodegenerative diseases.
Interventions
DEVICEtDCS, or transcranial direct current stimulation
Each participant will receive both active tDCS and sham tDCS during two 20-minute sessions spaced one month apart, with the order of the sessions determined at random.
Sponsors
Nantes University Hospital
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to 89 Years
Healthy volunteers
No
Inclusion criteria
* Aged 40 to 89 years * Patients with probable PSP according to the MDS-9 diagnostic criteria * BREF score \>10; * 18-FDG PET-MRI performed no more than 6 months prior to enrollment and showing: * Glucose hypometabolism defined as \> 2.5 SD compared to an atlas of healthy subjects and * No severe right frontal cortical atrophy according to F Pasquier's global cortical atrophy scale 53 * Concomitant treatments must have been stable for at least 4 weeks prior to enrollment and must remain stable throughout participation * Patient must have provided written informed consent * Patient must be enrolled in a social security program * Patient must be able to understand French and comply with the protocol * Women must use adequate contraceptive measures for the duration of the clinical trial (in accordance with CTFG recommendations)
Exclusion criteria
* Left-handed Patients; * Patients with severe apraxia that interferes with performance of the SST (at the investigator's discretion) * Known visual or hearing impairment that prevents performance of cognitive tests or the stop-signal test; * History of severe psychiatric or neurological disorders other than PSP; * Known significant brain injury(ies) (stroke, tumor, inflammation, post-traumatic, etc.), at the investigator's discretion * Atrophy of the right frontal lobe ≥3 on the F Pasquier Global Cortical Atrophy Scale 53 * History of epilepsy and seizures (or cerebral impairment with unexplained loss of consciousness), severe cardiac disorders, neurosurgical procedures, or severe or frequent headaches; * Presence of a cardiac, neural, drug-delivery, or cerebral stimulator * Presence of cerebral medical devices (such as vascular clips or electronically sensitive devices), intracerebral or intracochlear metal implants, * Patients with any electrically, magnetically, or mechanically activated implant * Patients suffering from a serious, life-threatening condition such as congestive heart failure, chronic obstructive pulmonary disease (COPD), or active neoplasia * Patients with skin conditions (dermatitis, psoriasis, or eczema) or lesions on the scalp or skull that preclude tDCS * Patients under legal guardianship or protective supervision * Pregnant or breastfeeding women * For patients in the ancillary study, contraindication to MRI: Presence of metallic foreign bodies
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To evaluate the effect of anodal tDCS targeting the right inferior frontal gyrus (IFG) on a motor-modality cognitive inhibition task, the Stop Signal Task (SST), in patients with PSP. | during the hour before each tDCS session and within 1 hour after each tDCS session | Stop Signal Reaction Time (SSRT) during the SST (seconds) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To evaluate, in PSP, the effect of anodal tDCS targeting the right GFI on the components of cognitive inhibition assessed by the SST | during the hour before each tDCS session and within 1 hour after each tDCS session | Results for each of the two conditions (active / sham) regarding the components of cognitive inhibition in the stop-signal test: reaction time (seconds), number of failed inhibitions, and number of unresponded-to Go stimuli will be combined to obtain a grade (low/high) |
| To evaluate, within the PSP, the effect of anodal tDCS targeting the right GFI on scores on the following neuropsychological assessments of verbal cognitive inhibition | during the hour before each tDCS session and within 1 hour after each tDCS session | Results for each of the two conditions (active / sham) on the Color Word Interference test from the Delis Kaplan Executive System (or Stroop D-KEFS)(scale: Preserved executive functions-Difficulty adapting to novelty) |
| To evaluate, within the PSP, the effect of anodal tDCS targeting the right GFI on scores on the following neuropsychological assessments of perseverative motor behavior | during the hour before each tDCS session and within 1 hour after each tDCS session | Results for each of the two conditions (active / sham) regarding the presence or absence of an applause sign and the presence or absence of palilalia |
| To evaluate, within the PSP, the effect of anodal tDCS targeting the right GFI on scores on the following neuropsychological assessments of other executive functions | during the hour before each tDCS session and within 1 hour after each tDCS session | Results for each of the two conditions (active / sham) on the Phonological and Categorical Verbal Fluency Test-which measures perseverations and clusters-and the Symbol-Digit Modality Test. |
| To evaluate, within the PSP, the effect of anodal tDCS targeting the right GFI on scores on the following neuropsychological assessments of social cognition | during the hour before each tDCS session and within 1 hour after each tDCS session | Results for each of the two conditions (active / sham) on the modified Ekman Emotion Recognition Test (6 emotions). |
| To evaluate, within the PSP, the effect of anodal tDCS targeting the right GFI on scores on the following neuropsychological assessments of overall cognitive efficiency | during the hour before each tDCS session and within 1 hour after each tDCS session | Results for each of the two conditions (active / sham) on the MoCA |
| To evaluate, in the PSP, the effect of anodal tDCS targeting the right GFI on motor and bulbar symptoms | during the hour before each tDCS session and within 1 hour after each tDCS session | Results for each of the two conditions (active / sham) on the PSP-RS scale subscores (ocular motility, bulbar examination, limb examination, gait examination) |
| To evaluate the effect of anodal tDCS targeting the right GFI on motor function in PSP | during the hour before each tDCS session and within 1 hour after each tDCS session | Results for each of the two conditions (active / sham) on the Timed Up and Go Test |
| To analyze the effects of tDCS on brain metabolism patterns as assessed by 18-FDG PET-MRI | before and after each tDCS session | Effect of tDCS as described in Sections 3 and 4 and the brain binding pattern of the FDG tracer in PET-MRI |
| To evaluate the clinical effects of tDCS on patients' clinical characteristics | Baseline, before and after each tDCS session | Effect of tDCS as described in Sections 3 and 4, and baseline scores on the PSP-RS scales |
| Assess participants' perception and acceptance of tDCS stimulation | within 1 hour after each tDCS session | Number and severity of targeted symptoms (itching, burning, pain, etc.) based on the structured questionnaire developed by Antal et al.40 |
| Safety Assessment | within 1 hour after each tDCS session | Number of EI and Defects |
Countries
France
Contacts
CONTACTAnne-Gaëlle Dr CORBILLE
Outcome results
None listed