Transcranial Ultrasound Therapy of Essential Tremor
Transcranial Ultrasound Therapy of Essential Tremor
Context. Essential tremor (ET) is a common disease, disabling in severe forms and resistant
 to drug treatment. In patients with severe ET, invasive neurosurgical technique such as deep
 brain stimulation of the Ventral Intermediate (VIM) nucleus of the thalamus is used. Focused
 ultrasound therapy, creating a small lesion of VIM represents an effective therapeutic
 alternative of low morbidity with the advantage of not requiring the opening of the skull and
 penetration into the brain. This therapy is performed under stereotactic guidance. Validation
 of the target before lesioning is done by testing the clinical effect by a gradual increase
 in temperature, resulting in tremor reduction. However, the gradual temperature increase in
 the targeting phase is suboptimal because it can decrease the efficiency of the lesioning
 procedure. The aim of this research project is to test an innovation of fundamental physics
 developed by the Langevin Institute, which would allow the reversible modulation of nerve
 tissue by ultrasonic waves without heating, to predict the effectiveness of treatment of the
 chosen target within the VIM before creating an irreversible lesion.

 Methodology: Fifteen patients with severe and resistant essential tremor will be included in
 the study. A multimodal MRI will be performed for target calculation using several targeting
 methods for VIM developed during step 1. For each target, the application of neuro-modulation
 by ultrasound will allow determine the effect obtained on the tremor (quantified with
 adequate clinical scales - as Tremor rating scale (CRST), and the recording of
 electromyographic activity of the upper limbs) and the absence of side effects. A definitive
 millimetric lesion will be performed at the level of the most relevant target in order to
 maintain the clinical effect obtained. The procedure will be controlled by thermal MRI
 sequences. Post-therapy clinical and MRI multimodal follow-up will take place on D1, D7, M1,
 M2, M3, M6, M12 and M24.

 Perspectives and Innovation: This project will test clinically the low intensity ultrasound
 neuromodulation jointly developed by the Langevin Institute and the Brain and Spine Institute
 ( ICM) in order to refine the targeting procedure of high intensity transcranial focused
 ultrasound therapy. In perspective, reversible neuromodulation performed in vivo in humans
 represents a considerable advance in the exploration and future treatment of neurological and
 psychiatric diseases such as depression. The translational collaboration between the
 physicists of the Langevin Institute, the ICM and the medical services of the
 Pitié-Salpêtrière guarantees the feasibility and quality of this first joint therapeutic
 trial.
Context:

 Essential tremor (ET) is the most common movement disorder, with a prevalence of 1-4% of the
 general population. ET is characterized by a rapid (6 and 12 Hz) attitude tremor with
 rhythmic oscillations of agonist and antagonist muscle groups. ET most often affects the
 upper limbs, the head and the voice but may involve the lower limbs in severe forms. The
 tremor worsens with age: it extends topographically towards the proximal end of the limbs. In
 severe forms, drug treatment is ineffective and tremor leads to impaired autonomy.

 ET is due to dysfunction of neural networks including the cerebellum, bulbar olive, red
 nucleus and thalamus nuclei . At the thalamic level, the ventral intermediate thalamic
 nucleus (VIM), a relay of the cerebellar pathways, is a key structure. This VIM core receives
 output channels from the cerebellum and projects massively onto the primary motor cortex, the
 final effector of movement. In humans, imaging studies have shown the involvement of these
 cerebellar-thalamo-cortical circuits in the pathophysiology of tremor. When drug treatment is
 ineffective and tremor is disabling, surgical treatments are considered. Deep brain
 stimulation is the most used reversible and modulable method consisting in implantation of
 the electrodes in the VIM. However, patients are often elderly with much comorbidity. Thus,
 in these patients, the act of invasive neurosurgery (neurostimulation) may be contraindicated
 (anticoagulation treatment) or risky. Also, the peroperative risks such as hematoma of
 infection exist, even if they are rare.

 As an alternative to Deep Brain Stimulation (DBS), radiosurgical thalamotomy was proposed.
 This method nevertheless has several major disadvantages, such as the use of radioactive
 sources, the fact that the dose actually delivered during irradiation of the patient cannot
 be controlled in terms of intensity. On the other hand, the biological effect on the tissues
 is not immediate and imposes a long waiting time (several months) to evaluate the
 effectiveness of the treatment. Finally, many cases of radionecrosis have been described with
 important clinical consequences, although transient in most cases.

 Given the limitations inherent to deep brain stimulation and gamma knife thalamotomy, a new
 method of neuromodulation followed by injury without penetration into the brain would
 represent a considerable therapeutic hope. In addition, in patients in whom treatment is
 planned, pre-therapeutic neuromodulation would better determine the target of treatment.

 In this context the ultrasonic therapy method was first successfully tested in 2013.These
 data suggested that the benefit obtained with unilateral ultrasound treatment allows an
 improvement in tremor comparable to that obtained with deep-brain stimulation of the VIM
 without significant side effects. More recent series of studies confirmed these initial
 results with nine studies involving 160 patients in total. These studies have shown a
 significant clinical improvement with a rate of complication considered as acceptable by the
 authors (mostly transient ataxia and hemi-chorea-hemiballism) . However, the number of
 adverse effects remains still rather high and the method of the lesion targeting remains
 challenging. Also, sometimes it is difficult to obtain the therapeutic effect.

 Main objective:

 The main objective is the evaluation of the efficacy of transcranial ultrasound treatment, ie
 the efficacy of the VIM lesion produced by HIFU on contralateral upper extremity tremor in
 the 3-month procedure.

 The secondary objectives are to evaluate:

 -  the interest of neuromodulation in the change of the initially defined target

 -  the relevance of the effect of neuromodulation for the prediction of the final clinical
 effect at 3 and 12 months on controlateral upper extremity tremor at the lesion

 -  Clinical and accelerometer-mediated symptomatic effects produced by ultrasound
 neuromodulation of VIM per-procedure

 -  the safety of ultrasound therapy (HIFU) until one year after the constitution of a
 unilateral lesion of the intermediate ventral nucleus (VIM) of the thalamus.

 -  the study of the relationships between precise size and location of the
 ultrasound-induced lesion and changes in anatomical and functional connectivity and
 treatment efficacy and side effects.

 -  the effectiveness of the VIM lesion produced by HIFU on tremor affecting the
 contralateral upper extremity

 -  the effectiveness of the VIM lesion produced by HIFU on the overall severity of the
 tremor

 -  the effectiveness of HIFU VIM injury on the quality of life of patients with essential
 tremor

 -  the overall clinical impression of the patient in terms of severity and evolution
 compared to the pre-operative state

 -  the effects of HIFU-induced VIM injury on neurological functions in a global manner

 -  the effects of HIFU-induced VIM injury on cognitive functions

 -  the effects of the VIM lesion produced by HIFU on gait and balance

 -  The study of the structural and functional modifications induced by VIM lesion using
 structural and functional MRI and its link with therapeutic efficacy.

 -  neuroanatomical changes and anatomical and functional connectivity The objective of
 ancillary study: - MRI analysis in diffusion spectroscopy: The investigators team will
 test the modification of GABAergic and glutamatergic systems of the cerebellum and
 striatum in TE patients before and after treatment using a newly developed spectroscopic
 MRI sequence at the neuroimaging center of research of the ICM (CENIR). This new
 sequence makes it possible to measure the higher-resolution signal in smaller voxels
 precisely located in the putamen and the cerebellar cortex containing the representation
 of the limbs. This sequence also makes it possible to obtain a better signal with
 respect to the noise than the conventional sequences. The investigators team will
 determine whether the detection of GABA / glutamate abnormalities specific to each
 region makes it possible to follow the evolution of the patients before and after the
 ultrasound treatment.

 Main steps of work Before the initiation of the ultrasound treatment, the Insightec system
 will be installed on the Siemens PRISMA MRI at the ICM, CENIR. Adaptation of the Insightec
 system to the Siemens environment will be performed by the Langevin Institute team, Insightec
 engineers, and ICM team. The MRI sequences, which are essential for the treatment, will be
 optimized and adapted to this new environment by concentrating in particular on (i) the
 correction of the distortions related to the introduction of the probe, and (ii) on the
 improvement of the spatial resolution. This preliminary work will be done on the phantom and
 healthy controls for anatomical and temperature sequence optimization.

 Fifteen patients with ET will be included in the study. The inclusion and evaluation of
 patients will take place between 2 months and 2 weeks before the inclusion visit. This visit
 will verify the inclusion and non-inclusion criteria and provide the information and consent
 form to the subject. An assessment of the severity of tremor will be made using the CRST
 scale and electromyographic recordings of the upper limb coupled to functional MRI.

 A multimodal MRI scan will be performed for the targeting of the area of interest. Several
 targeting methods will be performed to have an optimal definition of the target anatomical
 area. In anatomical sequences, in addition to traditional statistical methods , stereotaxic
 targeting will be carried out using the three-dimensional and deformable histological atlas
 of basal ganglia. This atlas allows adapting to the anatomical characteristics of each
 patient to specifically locate its VIM core. Several methods based on diffusion MRI
 tractography will also be tested: (i) targeting of the dentato-rubro-thalamic (DRT) pathway
 connecting the cerebellum to the motor cortex via VIM ; (ii) parcellation of the thalamus
 using cortical connectivity and (iii) use of the adjacent pathways of the VIM (ML and PT),
 the VIM being between these pathways. Functional MRI-based methods will also be tested using
 functional activation MRI to locate the network whose activity is synchronous with tremor
 electromyographic activity according to a previously developed method.

 Patients will be hospitalized in the neurosurgery department for a period of 24 hours. The
 stereotactic frame will be fixed on the subject's head in the neurosurgery department of the
 Pitié Salpêtrière under local anesthesia. The CT scan will be performed. Then, the patient
 will be transferred to CENIR at the ICM. The treatment will take place after placing the
 focused ultrasound helmet on the MRI bed and installing the subject in the MRI with the
 helmet.

 In the first step, the previously defined targets will be tested using neuro-modulation
 allowing a transient effect (a few minutes). For each target, the investigators team will
 determine (i) its level of efficiency through the CRST clinical scale and electromyographic
 activity of the upper limbs (with electrodes compatible with the MRI environment) and (ii)
 the absence of side effects (in particular, absence of ipsilateral dystonia, absence of
 dysarthria, cerebellar ataxia, oculomotor disturbances or sensitivity disorders). In a second
 step, a final lesion of very small size (1.5x1.5x5mm3) will be performed on the chosen target
 following the neuro-modulation. The ablation procedure will be controlled by thermal MR
 sequences.

 The visits of the clinical control, including the MRI will take place on D1, D7, M1, M2, M3,
 M6, M12 and M24. The visits will include general physical examination, collection of current
 treatments, collection of adverse effects / events, measurement of the severity of tremor:
 CRST scale, quality of life measurement: Short Form (36) Health Survey : SF-36, assessment of
 gait and balance: Gait and Balance Scale: GABS, evaluation of cognitive functions, multimodal
 MRI.
Inclusion Criteria:

 -  Men and women, aged 18 to 80

 -  Diagnosis of essential tremor according to the criteria of the Consensus Statement of
 the Movement Disorders Society (MDS)

 -  Patients with significant disability related to their essential Tremor, despite
 well-conducted medical treatment

 -  Stable drug therapy for at least 30 days prior to inclusion

 -  Contraindication or refusal of deep brain stimulation

 -  Patient receiving Social Security or Universal Medical Coverage or any equivalent plan

 -  Person who voluntarily and knowingly agreed to participate in the study (signing of a
 written consent)

 Exclusion criteria :

 -  Other neurological disorder, in particular previous history of multiple stroke or
 cerebral hemorrhage, intracranial aneurysm in the last 6 months

 -  Inability to stop anticoagulant or antiplatelet therapy or any other medication that
 may increase the risk of bleeding during the 2 weeks prior to the procedure

 -  Current state of health causing bleeding and / or abnormal coagulopathy

 -  Unstable cardiac pathology or severe hypertension that cannot be controlled by
 medication (diastolic blood pressure> 100 with drugs).

 -  Previous medical history of brain tumor

 -  Active epilepsy in the year preceding the inclusion

 -  Contraindications to magnetic resonance imaging such as non-compatible implanted metal
 devices (including pacemakers), size limits, etc.

 -  Known hypersensitivity to local anesthetics (Xylocaine 20mg / ml)

 -  Important claustrophobia that cannot be managed with mild medication

 -  Inability to maintain prolonged stationary supine position necessary for treatment
 (3-4 hours)

 -  Woman of childbearing age without means of contraception

 -  Pregnant or lactating woman

 -  Major persons subject to a measure of legal protection (guardianship, curators or
 under the protection of justice)

 -  Subject in exclusion period of another biomedical research or participating in any
 other biomedical stimulation or therapeutic trial

 -  Patients under AME (state medical aid) (except if exemption from affiliation)

 -  Presence of implants in the brain or skull

 -  Patient cannot communicate with the doctor during the treatment procedure

 -  Subjects with behavior compatible with the abuse of ethanol or psychoactive substances

 -  Cerebrovascular disease (multiple stroke or stroke within 6 months)

 -  Patients who have taken CNS (Central Nervous System) medications within the last 6
 months (eg, CNS stimulants, sympathomimetics)

 -  Significant healing in an area on the path of the planned energy path to the treatment
 area

 -  Recourse to neurosurgical treatments for essential tremor (deep brain stimulation or
 gamma knife