The goal of this clinical trial is to find out if a non-invasive procedure called focused ultrasound can safely and effectively treat limb dystonia in adults who have not improved with medications or botulinum toxin injections. The main questions it aims to answer are: * Does focused ultrasound reduce the severity of limb dystonia symptoms? * Is the procedure safe and well tolerated? Researchers will compare people who receive focused ultrasound treatment to those who receive a sham procedure (a look-alike procedure without active treatment) to see if the treatment works. Focused ultrasound works by producing a very small (millimeter-size) lesion in a deep brain region. In this study, the lesion is located in a region called globus pallidus, which helps control movement. Participants will: * Be randomly assigned to one of two groups: focused ultrasound or sham * Undergo a procedure using MRI and focused ultrasound to target a part of the brain called the globus pallidus * Be followed for 6 months after treatment to assess changes in symptoms, quality of life, and brain function * Participants in the sham group will be offered the real treatment after 3 months This study may offer a new non-surgical treatment option for people with dystonia affecting the arm or leg, whose pharmacological control is unsatisfactory.
The FUTURE study is a prospective, randomized, double-blind, sham-controlled, multicenter national clinical trial aimed at assessing the efficacy and safety of unilateral MR-guided focused ultrasound (MRgFUS) pallidotomy in patients with limb dystonia that is refractory to standard pharmacological treatments. Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions, causing abnormal movements or postures. In many cases, focal or segmental dystonias affecting the limbs can be managed with oral medications and botulinum toxin (BoNT) injections. However, a subset of patients does not respond adequately to these treatments. For such individuals, surgical intervention may offer relief, yet it remains underutilized due to concerns about invasiveness and complications. Recent advancements in non-invasive neurosurgical techniques have introduced MRgFUS pallidotomy, a procedure that uses focused ultrasound beams under real-time MRI guidance to precisely ablate small brain targets-in this case, the globus pallidus internus (GPi). The FUTURE study specifically explores this technique as a less invasive alternative to deep brain stimulation, especially for patients with focal or segmental limb dystonia who are ineligible or reluctant to undergo conventional surgery. The trial will enroll 34 adult patients with idiopathic or genetic limb dystonia that has proven resistant to pharmacologic and BoNT treatment. These patients will be randomly assigned in a 1:1 ratio to either: * an active treatment group, undergoing unilateral GPi lesioning via MRgFUS, * or a sham control group, receiving the same procedural setup but without therapeutic sonications. At three months post-randomization, all patients in the sham group will cross over to receive the active MRgFUS treatment, allowing within-subject comparisons while ensuring ethical access to the therapeutic intervention. The follow-up period for each patient will last six months after active treatment, totaling a maximum of nine months of participation. The primary endpoint is the change in motor severity as measured by the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) at three months post-treatment. Secondary endpoints include adverse event frequency, patient and clinician global impressions of change, disability assessments (e.g., QuickDASH), quality of life (SF-36), and neurocognitive testing. Additionally, the study will incorporate neurophysiological (TMS) and neuroimaging (resting-state fMRI) techniques to investigate treatment-induced changes in cortical excitability, plasticity, and functional connectivity, providing insight into the neural mechanisms underlying clinical improvement. The FUTURE study is coordinated by the Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy with participation from other three major Italian neurological institutes. It represents a pioneering effort to evaluate focused ultrasound as a non-invasive therapeutic option for patients with disabling and treatment-resistant forms of limb dystonia.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
34
Active Pallidotomy
Sham procedure. Identical setup without thermal lesioning. Participants cross over to Active Pallidotomy after 3 months.
Azienda ULSS3 Serenissima
Mestre, (Venice), Italy
RECRUITINGIRCCS Centro Neurolesi "Bonino-Pulejo"
Messina, Italy
RECRUITINGFondazione IRCCS Istituto Neurologico Carlo Besta
Milan, Italy
RECRUITINGAzienda Ospedaliera Ospedali Riuniti Villa Sofia
Palermo, Italy
RECRUITINGChenge in the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS)
The BFMDRS has a maximum score of 120 for the movement subscale and 30 for the disability subscale. Higher scores indicating more severe dystonia.
Time frame: Baseline to Week 12
Incidence of treatment-related adverse events
Assessment of any treatment-related adverse events throughout the whole study period
Time frame: Baseline to Week 24
Changes in the Quick Disabilities of Arm, Shoulder & Hand (Quick-DASH) score
The QuickDASH is a shortened, 11-item version of the DASH Outcome Measure, designed to assess physical function and symptom severity related to the arm, shoulder, and hand. Maximum score 100; the greater the score the grear the disability.
Time frame: Baseline, Week 12 and Week 24
Changes in the Clinical Global Impression of Change (CGIC) score
The CGIC is a 7-point scale used to assess the degree of change in a patient's condition since the start of treatment or another defined baseline. Lower scores indicates improvement and higher scores indicating worsening of the patient's condition.
Time frame: Baseline, week 12 and week 24
Patient Global Impression of Change (PGIC)
The maximum score of the PGIC is 7: the higher the score the higher the improvement reported by a patient.
Time frame: Baseline, Week 12 and week 24
Change in the 36-Item Short Form Survey (SF-36) score
The SF-36 questionnaire has a maximum score of 100 for each of its eight scaled scores (physical functioning, role limitations due to physical health, bodily pain, general health, vitality, social functioning, role limitations due to emotional problems, and mental health). The higher the scores the more favorable is health state within that specific dimension.
Time frame: Baseline, week 12 and week 24
Changes in the Short-Interval Cortical Inhibition (SICI)
This is a neurophysiological measure of inhibitory processes within the motor cortex, assessed using Transcranial Magnetic Stimulation, which is measured as the relative amplitude reduction of motor evoked potentials from the test stimulus when it is preceded by the conditioning stimulus. The greater the change in SICI, the greater the pallidotomy-induced changes in motor cortex intracortical inhibitory circuits
Time frame: Baseline and Week 24
Changes in intracortical facilitation (ICF)
This is a neurophysiological measures of cortical excitability, assessed using paired-pulse Transcranial Magnetic Stimulation, which describes an increase in the magnitude of a motor evoked potential in a target muscle when a suprathreshold test pulse is preceded by a subthreshold conditioning pulse at specific interstimulus intervals. The greater the change in ICF, the greater the pallidotomy-induced changes in intracortical excitatory circuits
Time frame: Baseline and Week 24
Changes in Paired Associative Stimulation (PAS)
This is a neurophysiological measure of cortical plasticity assessed using transcranial magnetic stimulation. The greater the change in PAS, the greater the pallidotomy-induced changes in motor cortex synaptic plasticity
Time frame: Baseline and week 24
Changes in brain activity (using functional connectivity) using resting-state functional magnetic resonance imaging (rs-fMRI)
The investigators will conduct a region-of-interest analysis to calculate changes of fMRI functional connectivity between baseline and post-pallidotomy.
Time frame: Baseline and Week 24
Changes in pallidotomy lesion morphology via contrast MRI
To evaluate the morphological changes of the lesion after 24 hours, 3 months and 6 months from pallidotomy using contrast-enhanced brain MRI and their relationship with clinical changes including adverse events.
Time frame: 24-hour after the procedure, week 12 and week 24
Changes in the Montreal Cognitive Assessment (MoCA) score
Changes in the Montreal Cognitive Assessment (MoCA) score, a 30-point test of global cognitive functions. Score range: 0-30, with lower scores indicating worse cognitive function and higher scores indicating better cognitive function.
Time frame: Baseline, week 12 and week 24
Change in Digit Span test score
Change in Digit Span test score, a cognitive test assessing memory functions. Score range: 0-\[insert maximum score for the test\], with lower scores indicating greater memory impairment and higher scores indicating better memory function.
Time frame: Baseline, week 12 and week 24]
Change in the Stroop Test score
Change in Stroop Test scores, a neuropsychological test assessing frontal-lobe executive cognitive function. Score range: \[insert minimum\]-\[insert maximum\], with higher scores or slower reaction times indicating worse executive cognitive function.
Time frame: Baseline, week 12 and week 24
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.