Veerle Visser-Vandewalle

Surgery in Tourette syndrome

Tourette syndrome (TS) is a neuropsychiatric disorder with onset in early childhood. It is characterized by tics and often accompanied by disturbances in behavior, such as obsessive–compulsive disorder (OCD). In most cases, the disorder is self‐limited or can be treated by medication or behavioral therapy. In a small percentage, however, symptoms are intractable to any conservative treatment. Since 1955, various attempts have been made to treat these patients through neurosurgical procedures. The target sites have been diverse and include the frontal lobe (prefrontal lobotomy and bimedial frontal leucotomy), the limbic system (limbic leucotomy and anterior cingulotomy), the thalamus, and the cerebellum. Combined approaches have also been tried such as anterior cingulotomies plus infrathalamic lesions. The results have often been unsatisfactory or major side effects have occurred, such as hemiplegia or dystonia. Our review of the literature from 1960 until 2003 revealed 21 reports and 3 descriptions in textbooks covering about 65 patients in total who had undergone ablative procedures for intractable TS, the first being reported in 1962. In 1999, deep brain stimulation (DBS) was introduced as a new approach for intractable TS. To date, 3 patients have been reported who underwent bilateral thalamic stimulation, with promising results on tics and obsessive‐compulsive symptoms.

Patient selection and assessment recommendations for deep brain stimulation in Tourette syndrome

In response to recent publicity regarding the potential use of deep brain stimulation (DBS) for reducing tic severity in Tourettes syndrome (TS), the Tourette Syndrome Association convened a group of TS and DBS experts to develop recommendations to guide the early use and potential clinical trials of DBS for TS and other tic disorders. The goals of these recommendations are to ensure that all surgical candidates are (1) fully informed about the risks, benefits, and alternative treatments available; (2) receive a comprehensive evaluation before surgery to ensure that DBS is clearly the appropriate clinical treatment choice; and (3) that early clinical experience will be documented publicly to facilitate rational decision‐making for both clinical care and future clinical trials.

Inhibition of 5-HT neuron activity and induction of depressive-like behavior by high-frequency stimulation of the subthalamic nucleus.

Bilateral, high-frequency stimulation (HFS) of the subthalamic nucleus (STN) is the surgical therapy of choice for movement disability in advanced Parkinsons disease (PD), but this procedure evokes debilitating psychiatric effects, including depressed mood, of unknown neural origin. Here, we report the unexpected finding that HFS of the STN inhibits midbrain 5-hydroxytryptamine (5-HT) neurons to evoke depression-related behavioral changes. We found that bilateral HFS of the STN consistently inhibited (40–50%) the firing rate of 5-HT neurons in the dorsal raphe nucleus of the rat, but not neighboring non-5-HT neurons. This effect was apparent at clinically relevant stimulation parameters (≥100 Hz, ≥30 μA), was not elicited by HFS of either neighboring or remote structures to the STN, and was still present in rat models of PD. We also found that bilateral HFS of the STN evoked clear-cut, depressive-like behavior in a widely used experimental paradigm of depression (forced swim test), and this effect was also observed in a PD model. Importantly, the depressive-like behavior elicited by HFS of the STN was reversed by a selective 5-HT-enhancing antidepressant, thereby linking the behavioral change to decreased 5-HT neuronal activity. Overall, these findings link reduced 5-HT function to the psychiatric effects of HFS of the STN observed in PD patients and provide a rational basis for their clinical management. More generally, the powerful interaction between the STN and 5-HT system uncovered here offers insights into the high level of comorbidity of basal ganglia disease and mood disorder.

Deep Brain Stimulation in Tourette's Syndrome: Two Targets?

In this report, we describe the effects of bilateral thalamic stimulation in one patient and of bilateral pallidal stimulation in another patient. Both patients suffered from intractable Tourette’s syndrome (TS). Any conservative treatment had failed or had been stopped because of unbearable side effects in the 2 patients. In both cases, there was no comorbidity except for associated behavioral symptoms (compulsions). Electrodes were implanted at the level of the medial part of the thalamus (centromedian nucleus, the substantia periventricularis, and the nucleus ventro‐oralis internus) in one patient and in the posteroventral part of the globus pallidus internus (GPi) in the other patient. In both cases, deep brain stimulation (DBS) resulted in a substantial reduction of tics and compulsions. These data show that bilateral DBS of the thalamus as well as of the GPi can have a good effect on tics and behavioral symptoms in patients suffering from intractable TS.

Nucleus accumbens and impulsivity

The multifaceted concept of impulsivity implies that different impulsivity aspects, mediated by different neural processes, influence behavior at different levels. The nucleus accumbens (NAc) is a key component of the neural processes regulating impulsivity. In this review, we discuss the findings of lesion studies in animals and functional imaging studies in humans focusing on the role of the NAc in impulsivity. Evidence supports that the extent and pattern of involvement of the NAc, and its subregions, the core and the shell, vary among different facets of impulsivity. Data from imaging studies reviewed in this article suggest the involvement of the ventral striatum/NAc in impulsive choice. Findings of animal studies indicate that lesions of the NAc core subregion facilitated impulsivity in tasks involving intertemporal choice, and promoted a risk-averse, less impulsive, tendency in tasks involving options with probability differences. Modification of neurotransmitter activity, especially of dopamine, which is proposed to underlie the changes observed in functional imaging studies, has been shown to influence afferent input pattern in the NAc and the generation of the behavioral output. Parameters of behavioral tasks reflecting response inhibition function are altered by neurochemical interventions and local electrical stimulation in both the core and the shell subregions. In toto, NAcs pattern of neuronal activity, either genetically determined or acquired, has a critical impact on the interindividual variation in the expression of impulsivity. Nevertheless, the NAc is not the only substrate responsible for impulsivity and it is not involved in each facet of impulsivity to the same extent.

Protection of nigral cell death by bilateral subthalamic nucleus stimulation

In Parkinson disease (PD), the subthalamic nucleus (STN) becomes hyperactive (disinhibited), which is reported to cause excitotoxic damage to midbrain dopaminergic neurons. Here, we examined whether silencing of the hyperactive STN by chronic bilateral deep brain stimulation (DBS) increased the survival of midbrain dopaminergic neurons in a rat model of PD. High-precision design-based stereologic examination of the total number of neurons and tyrosine tydroxylase (TH) immunoreactive neurons in the substantia nigra pars compacta revealed that STN DBS resulted in a significant survival of these neurons. These data provide the first evidence in vivo that bilateral STN DBS is useful for protecting midbrain dopaminergic neurons from cell death in PD.

Tourette syndrome deep brain stimulation: A review and updated recommendations

Deep brain stimulation (DBS) may improve disabling tics in severely affected medication and behaviorally resistant Tourette syndrome (TS). Here we review all reported cases of TS DBS and provide updated recommendations for selection, assessment, and management of potential TS DBS cases based on the literature and implantation experience. Candidates should have a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM V) diagnosis of TS with severe motor and vocal tics, which despite exhaustive medical and behavioral treatment trials result in significant impairment. Deep brain stimulation should be offered to patients only by experienced DBS centers after evaluation by a multidisciplinary team. Rigorous preoperative and postoperative outcome measures of tics and associated comorbidities should be used. Tics and comorbid neuropsychiatric conditions should be optimally treated per current expert standards, and tics should be the major cause of disability. Psychogenic tics, embellishment, and malingering should be recognized and addressed. We have removed the previously suggested 25‐year‐old age limit, with the specification that a multidisciplinary team approach for screening is employed. A local ethics committee or institutional review board should be consulted for consideration of cases involving persons younger than 18 years of age, as well as in cases with urgent indications. Tourette syndrome patients represent a unique and complex population, and studies reveal a higher risk for post‐DBS complications. Successes and failures have been reported for multiple brain targets; however, the optimal surgical approach remains unknown. Tourette syndrome DBS, though still evolving, is a promising approach for a subset of medication refractory and severely affected patients.

Acute and separate modulation of motor and cognitive performance in parkinsonian rats by bilateral stimulation of the subthalamic nucleus.

The subthalamic nucleus (STN) is involved in motor and cognitive performance through its key role in the basal ganglia-thalamocortical circuits, but how these different modalities (motor and cognition) are controlled (similar vs. dissimilar) has not yet been elucidated. In the present study, the effects of bilateral STN deep brain stimulation (DBS) on motor and cognitive performance were investigated in a rat model of Parkinson disease (PD). After being trained in a choice reaction time (CRT) task, rats received bilateral injections of 6-hydroxydopamine (6-OHDA) into the striatum. One group of 6-OHDA animals was implanted bilaterally with stimulation electrodes at the level of the STN. Stimulations were performed at 130 Hz (frequency), 60 micros (pulse width), and varying amplitudes of 1, 3, 30, and 150 microA during the CRT task. Finally, rats were sacrificed and the brains processed for staining to determine the dopaminergic lesion (TH immunohistochemistry) and localization of the electrode tip (HE histochemistry). Bilateral 6-OHDA infusion significantly decreased (70%) the number of dopaminergic cells in the substantia nigra pars compacta (SNc) and increased motor time (MT), proportion of premature responding (PR), and reaction time (RT). Bilateral STN stimulation with an amplitude of 3 microA normalized 6-OHDA-induced deficits in PR and RT. Simulation with an amplitude of 30 microA reversed the lesion-induced deficits in MT and RT. Our data show for the first time that bilateral STN stimulation differentially affected the 6-OHDA-induced motor and cognitive deficits. This means that basal ganglia-thalamocortical motor and associative circuits responsible for specific motor and cognitive performance, which are processed through the STN, have unique physiological properties that can acutely and separately be modulated by specific electrical stimuli.

Deep Brain Stimulation in Tourette’s Syndrome

SummaryTourette’s Syndrome (TS) is a neuropsychiatric disorder characterized by motor and vocal tics, often associated with behavioral disorders. Symptoms often disappear before or during adulthood. The pathophysiology of TS is still a matter of considerable debate. Current knowledge of cortico—basal ganglia—thalamocortical circuits provide explanations for the beneficial effects of deep brain stimulation (DBS) on tics. When conservative treatment fails in patients with severe TS, DBS may be a therapeutic option. In 1999, thalamic DBS was introduced for intractable TS. Since then, multiple targets have been used in a small number of patients, including the globus pallidus pars interna and the nucleus accumbens. Inclusion and exclusion criteria have been formulated to identify good candidates for DBS.

Impulse control and related disorders in Parkinson’s disease patients treated with bilateral subthalamic nucleus stimulation: A review

Recently, impulse control and related disorders including punding and the dopamine dysregulation syndrome (DDS) have been increasingly recognized in treated patients with Parkinsons disease (PD). Especially the impulse control disorders (ICD) such as pathological gambling, hypersexuality, compulsive eating and buying may have dramatic repercussions on family, personal and professional life. Drug replacement therapy (DRT) is believed to play an important role in the onset of these behavioral disturbances. Although deep brain stimulation (DBS) of the subthalamic nucleus (STN) might be a therapeutic option for those patients with DRT-related behavior, it may also induce ICD. So far, little is known about the relationship between STN DBS and impulse control and related disorders. Our aim was to review the current knowledge on this relationship in PD patients. The available studies showed that stimulation of the STN is associated with both favorable and negative outcome in terms of impulse control and related disorders. Preoperative disorders may resolve or improve after STN DBS, but these can also worsen or show no change at all. Moreover, STN DBS can also reveal or even induce ICD. Possible explanations for this variability are proposed and suggestions for clinical management are given.