Subthalamic Stimulation in Tourette's Syndrome
Subthalamic Stimulation in Tourette's Syndrome
The main objective of this project is to evaluate the efficacy of subthalamic nucleus deep
 brain stimulation (STN DBS) in treating motor and phonic tics in medically refractory
 Tourette's syndrome (TS).

 Secondary objectives are to individuate and standardize the best electrical parameters for
 STN stimulation in TS, to evaluate the efficacy and safety on non-motor TS features, such as
 behavioral abnormalities and psychiatric disorders, during chronic STN stimulation, to
 correlate the improvement of TS motor and non-motor symptoms to the modification in brain
 activity recorded by PET study and to explore the pathophysiology of TS, and to evaluate the
 safety of STN DBS in TS patients.
Background Tourette's syndrome (TS) is characterized by the occurrence, before 18 years of
 age, of multiple motor and vocal tics, which do not necessarily occur concomitantly. Tics
 constitute the clinical hallmark of TS; they are sudden, brief, intermittent involuntary (or
 semi-involuntary) movements (motor tics) or noises (sound tics). Tic severity is variable:
 some patients have mild or bearable tics, whereas in others tics are so severe to cause bone
 fractures or cervical myelopathy. Diagnostic criteria set by the Tourette Syndrome
 Classification Study Group and the American Psychiatric Association are commonly used. It is
 currently recognized that TS is far more common than previously thought, with a prevalence of
 1 to 10 children of adolescents per 1000.

 Tics are usually treated in cases where disability at school, in the social environment or at
 home is severe enough to warrant medical intervention. TS commonly presents with co-morbid
 features, mainly consisting in obsessive-compulsive traits, attention deficit with
 hyperactivity disorder and depression. Psychopathologic features are partly an aftermath of
 tics, particularly in those patients who display severe tics affecting their social and work
 activities. Therefore, amelioration of tics may substantially improve daily life and
 adaptation to social and work environments.

 Medication is the first choice treatment, with the aim to reduce the intensity of tics and
 the associated clinical features. Different drugs, belonging to several pharmacologic
 classes, such as α-adrenergic drugs, typical and atypical neuroleptics, and tetrabenazine are
 used. In some cases drug treatment provides satisfactory symptomatic benefit. Overall, it is
 reckoned that a meaningful proportion of TS patients do not have adequate benefit with drug
 treatment and the majority of patients have side effects of variable severity.

 Ablative psychosurgery has been historically used to treat more severe cases of TS, but the
 results have been disappointing and burdened by irreversible side effects. The recently
 developed technique of deep brain stimulation (DBS) allows to selectively modulate the
 activity of brain structures that control movements and behaviors in patients with different
 neurological disorders. This approach is warranted in those patients who respond poorly to
 available medical therapy.

 Recently, therapeutic DBS trials have been performed in patients with severe TS, who were not
 satisfactorily controlled by medication. At first, the same thalamic nuclei targeted by
 ablative surgery, particularly the centromedian-parafascicular (CM-pf) nuclear complex, have
 been implanted with some success.

 Another anatomical target has been the anterior capsule in proximity of the nucleus accumbens
 or the nucleus accumbens itself, aiming at interfering with tics and obsessive-compulsive
 features at the same time. More recently, the globus pallidus internum (GPi) has been
 implanted. This constitutes the main output station of the basal ganglia towards the thalamus
 and the cerebral cortex.

 Hypothesis driven rationales

 1. There is preliminary evidence that the subthalamic nucleus can be another promising
 target in treating motor and non-motor feature of TS. A clinical observation has
 recently shown that STN DBS improved motor and vocal tics in a patient with consistence
 of Parkinson's disease and TS

 2. Literature evidences have showed that stereotyped behaviors in nonhuman primates,
 resembling tics and compulsive disorders, were related to dysfunction of the limbic
 parts of the globus pallidus externum, the STN, and the SN reticulata, rather than to
 dysfunction of the GPi

 3. From a physiologic perspective, STN occupies a privileged position influencing both
 output nuclei of the basal ganglia, GPi and substantia nigra (SN) reticulata. Several
 findings have highlighted the putative role of the STN in integrating emotional,
 cognitive and motor functions and this nucleus would thus be an effective target for the
 treatment of conditions that combine motor symptoms, behavioral disorders,
 obsessive-compulsive disorders

 4. Involvement of the SN in TS was also found in a functional MRI study. Furthermore,
 stimulation of the anterior STN was effective in reducing stereotypes in a primate model
 of behavioral disorder and STN DBS in PD can also result in behavioral changes. Indeed,
 the small size of this nucleus may allow modulation of abnormal neuronal activity of
 both limbic and sensorimotor territories, more easily than GPi or thalamic DBS

 5. The small and well-defined volume of the STN combined with well standardized implant
 techniques, would lead to a reduced inter-patient variability in targeting

 The novelty of the project The STN may be a potential target for DBS in TS. The choice of STN
 as a target for this project is the current model of basal ganglia functioning: this
 anatomical location aims at modulating the sensory-motor, associative and limbic subdivisions
 of cortico-subcortical-cortical loops that are thought to be dysfunctional in TS. STN DBS may
 provide a quicker relief of symptoms than medial thalamic nuclei or GPi stimulation.

 The main objective of this project is to evaluate the efficacy of subthalamic nucleus deep
 brain stimulation (STN DBS) in treating motor and phonic tics in medically refractory
 Tourette's syndrome (TS).

 Secondary objectives are to individuate and standardize the best electrical parameters for
 STN stimulation in TS, to evaluate the efficacy and safety on non-motor TS features, such as
 behavioral abnormalities and psychiatric disorders, during chronic STN stimulation, to
 correlate the improvement of TS motor and non-motor symptoms to the modification in brain
 activity recorded by PET study and to explore the pathophysiology of TS, and to evaluate the
 safety of STN DBS in TS patients.

 Clinical evaluation will include a complete neurological examination (videotaped tic scales
 throughout), a structured psychological interview and a psychiatric evaluation. Quantitative
 evaluations will be performed using appropriate validated neurological (including the Yale
 Tic Global Severity Scale (YTGSS) and neuropsychological rating scales, including the
 Yale-Brown Obsessive Compulsive scale (Y-BOCS), as detailed hereafter.

 Neurological evaluations

 -  Tourette's motor and phonic tics checklist

 -  YTGSS

 -  Global assessment scale (GAS)

 -  Global Clinical Impression Scale (GCI-S)

 -  Sickness Impact Profile (SIP)

 -  Gilles de la Tourette syndrome-quality of life scale (GTS-QOL)

 Behavioral evaluations

 -  Y-BOCS

 -  Depression (MADRS, HAM-D)

 -  ADHD and Anxiety (ADHD-RS, HAM-A)

 Neuropsychological evaluations

 -  Global deterioration

 -  Executive functions

 -  Working memory

 -  Fluency

 Power calculation. A retrospective analysis of published data on DBS-treated TS patients
 reports an average YGTSS at inclusion of 50 ±15 points. This is in keeping with our inclusion
 criteria of YGTSS >35. Considering a 50% improvement as meaningful, a 25-point variation is
 expected from baseline to post-implant in the active stimulation group and a 10% 5-point
 variation in the sham stimulation group. The investigators assume a comparable standard
 deviation at baseline and at end of the observational periods and a good correlation of YGTSS
 measures (correlation coefficient: 0.8). An actual number of at least 5 patients per group
 should allow to demonstrate a 25-point YGTSS difference between the two active stimulation
 and the sham stimulation groups, with a statistical potency of 85% (bilateral
 Mann-Whitney-Wilcoxon test, alpha = 5 %).
Inclusion Criteria:

 -  Age at least of 18 years (with potential exceptions)

 -  Diagnosis of TS based on the diagnostic criteria of the Tourette Syndrome
 Classification Study Group

 -  A Yale Tic Global Severity Scale (YTGSS) > 35/50 for at least 12 months, with tic
 severity documented by a standardized videotape assessment

 -  Inadequate response to standard drug treatment or botulinum toxin

 Exclusion Criteria:

 -  Diagnosis of secondary tic disorder, of heredodegenerative or neurometabolic diseases
 or history of toxic exposures or encephalitis

 -  Previous surgery for TS (with potential exceptions)