Carine Karachi

Tourette’s syndrome and deep brain stimulation

In this prospective double blind randomised “N of 1” study, a patient with a severe form of Tourette’s syndrome was treated with bilateral high frequency stimulation of the centromedian-parafascicular complex (Ce-Pf) of the thalamus, the internal part of the globus pallidus (GPi), or both. Stimulation of either target improved tic severity by 70%, markedly ameliorated coprolalia, and eliminated self injuries. Severe forms of Tourette’s syndrome may benefit from stimulation of neuronal circuits within the basal ganglia, thus confirming the role of the dysfunction of limbic striato-pallido-thalamo-cortical systems in this disorder.

Cholinergic mesencephalic neurons are involved in gait and postural disorders in Parkinson disease.

Gait disorders and postural instability, which are commonly observed in elderly patients with Parkinson disease (PD), respond poorly to dopaminergic agents used to treat other parkinsonian symptoms. The brain structures underlying gait disorders and falls in PD and aging remain to be characterized. Using functional MRI in healthy human subjects, we have shown here that activity of the mesencephalic locomotor region (MLR), which is composed of the pedunculopontine nucleus (PPN) and the adjacent cuneiform nucleus, was modulated by the speed of imagined gait, with faster imagined gait activating a discrete cluster within the MLR. Furthermore, the presence of gait disorders in patients with PD and in aged monkeys rendered parkinsonian by MPTP intoxication correlated with loss of PPN cholinergic neurons. Bilateral lesioning of the cholinergic part of the PPN induced gait and postural deficits in nondopaminergic lesioned monkeys. Our data therefore reveal that the cholinergic neurons of the PPN play a central role in controlling gait and posture and represent a possible target for pharmacological treatment of gait disorders in PD.

A three-dimensional, histological and deformable atlas of the human basal ganglia. I. Atlas construction based on immunohistochemical and MRI data.

This paper describes the construction of an atlas of the human basal ganglia. The successive steps of the construction were as follows. First a postmortem specimen was subjected to a MRI acquisition prior to extraction of the brain from the skull. The brain was then cryosectioned (70 microm thickness). One section out of ten (80 sections) was Nissl-stained with cresyl violet, another series of 80 sections was immunostained for the calcium binding protein calbindin. Contours of basal ganglia nuclei including their calbindin-stained functional subdivisions, fiber bundles and ventricles (n=80 structures) were traced from histological sections and digitized. A novelty of this atlas is the MRI acquisition, which represents the core data element of the study. MRI was used for the coregistration of the atlas data and permitted, through multimodal (Nissl, calbindin, images of cryosectioning, T1 and T2 MRI) and 3D optimization, the production of anatomically and geometrically consistent 3D surfaces, which can be sliced through any desired orientation. The atlas MRI is also used for its deformation to provide accurate conformation to the MRI of living patients, thus adding information at the histological level to the patients MRI volume. This latter aspect will be presented in a forthcoming paper.

Internal Pallidal and Thalamic Stimulation in Patients With Tourette Syndrome

BACKGROUND Tourette syndrome (TS) is thought to result from dysfunction of the associative-limbic territories of the basal ganglia, and patients with severe symptoms of TS respond poorly to medication. High-frequency stimulation has recently been applied to patients with TS in open studies using the centromedian-parafascicular complex (CM-Pf) of the thalamus, the internal globus pallidus (GPi), or the anterior limb of the internal capsule as the principal target. OBJECTIVE To report the effect of high-frequency stimulation of the CM-Pf and/or the GPi, 2 associative-limbic relays of the basal ganglia, in patients with TS. DESIGN Controlled, double-blind, randomized crossover study. SETTING Medical research. PATIENTS Three patients with severe and medically refractory TS. INTERVENTION Bilateral placement of stimulating electrodes in the CM-Pf (associative-limbic part of the thalamus) and the GPi (ventromedial part). MAIN OUTCOME MEASURES Effects of thalamic, pallidal, simultaneous thalamic and pallidal, and sham stimulation on neurologic, neuropsychological, and psychiatric symptoms. RESULTS A dramatic improvement on the Yale Global Tic Severity Scale was obtained with bilateral stimulation of the GPi (reduction in tic severity of 65%, 96%, and 74% in patients 1, 2, and 3, respectively). Bilateral stimulation of the CM-Pf produced a 64%, 30%, and 40% reduction in tic severity, respectively. The association of thalamic and pallidal stimulation showed no further reduction in tic severity (60%, 43%, and 76%), whereas motor symptoms recurred during the sham condition. No neuropsychological, psychiatric, or other long-term adverse effect was observed. CONCLUSIONS High-frequency stimulation of the associative-limbic relay within the basal ganglia circuitry may be an effective treatment of patients with TS, thus heightening the hypothesis of a dysfunction in these structures in the pathophysiologic mechanism of the disorder.

Critical Roles for Anterior Insula and Dorsal Striatum in Punishment-Based Avoidance Learning

The division of human learning systems into reward and punishment opponent modules is still a debated issue. While the implication of ventral prefrontostriatal circuits in reward-based learning is well established, the neural underpinnings of punishment-based learning remain unclear. To elucidate the causal implication of brain regions that were related to punishment learning in a previous functional neuroimaging study, we tested the effects of brain damage on behavioral performance, using the same task contrasting monetary gains and losses. Cortical and subcortical candidate regions, the anterior insula and dorsal striatum, were assessed in patients presenting brain tumor and Huntington disease, respectively. Both groups exhibited selective impairment of punishment-based learning. Computational modeling suggested complementary roles for these structures: the anterior insula might be involved in learning the negative value of loss-predicting cues, whereas the dorsal striatum might be involved in choosing between those cues so as to avoid the worst.

The pallidosubthalamic projection : An anatomical substrate for nonmotor functions of the subthalamic nucleus in primates

The subthalamic nucleus (STN) is the best target for correcting motor disability in parkinsonian patients with high‐frequency stimulation. However, STN stimulation has also been reported to modify cognitive, emotional, and motivational functions. The aim of this study was to analyze the topographic organization of the STN according to its inputs coming from the sensorimotor, associative, and limbic territories of the external globus pallidus (GPe) in monkeys, with special reference to the limbic projection. Axonal tracers were injected into the different functional territories of the GPe. Injection performed in the limbic GPe resulted in labeling of cell bodies in the dorsal nucleus accumbens and in a dense labeling of axons in the anterior and medioventral portion of the STN. In comparison, injections in the associative and sensorimotor GPe led to labeling in the central and dorsolateral parts of the STN, respectively. Individual pallidosubthalamic axons ramified into numerous varicose branches, which were restricted to a given territory in the STN. These data provide a functional cartography of this structure in primates and suggest that behavioral disorders observed in stimulated parkinsonian patients could result from a dysfunction of the limbic part of the STN.

Normal and pathological gait: what we learn from Parkinson's disease

Gait and balance disorders represent a major therapeutic challenge in Parkinsons disease (PD). These symptoms respond poorly to dopaminergic treatments, except in the early phase of the disease. Currently, no other treatment is particularly efficient and rehabilitation appears to be the most effective approach. Since these gait and balance deficits are resistant to dopaminergic drugs, their occurrence could be related to the development of extradopaminergic lesions in PD patients. We provide a comprehensive description of the clinical features of gait and balance disorders in PD. We also highlight the brain networks involved in gait and balance control in animals and humans with a particular focus on the relevant structures in the context of PD, such as the mesencephalic locomotor region. We also review other neuronal systems that may be involved in the physiopathology of gait and balance disorders in PD (noradrenergic and serotoninergic systems, cerebellum and cortex). In addition, we review recent evidence regarding functional neurosurgery for gait disorders in PD and propose new directions for future therapeutic research.

Three-dimensional cartography of functional territories in the human striatopallidal complex by using calbindin immunoreactivity

This anatomic study presents an analysis of the distribution of calbindin immunohistochemistry in the human striatopallidal complex. Entire brains were sectioned perpendicularly to the mid‐commissural line into 70‐μm‐thick sections. Every tenth section was immunostained for calbindin. Calbindin labeling exhibited a gradient on the basis of which three different regions were defined: poorly labeled, strongly labeled, and intermediate. Corresponding contours were traced in individual sections and reformatted as three‐dimensional structures. The poorly labeled region corresponded to the dorsal part of the striatum and to the central part of the pallidum. The strongly labeled region included the ventral part of the striatum, the subcommissural part of the external pallidum but also the adjacent portion of its suscommissural part, and the anterior pole of the internal pallidum. The intermediate region was located between the poorly and strongly labeled regions. As axonal tracing and immunohistochemical studies in monkeys show a similar pattern, poorly, intermediate, and strongly labeled regions were considered as the sensorimotor, associative, and limbic territories of the human striatopallidal complex, respectively. However, the boundaries between these territories were not sharp but formed gradients of labeling, which suggests overlapping between adjacent territories. Similarly, the ventral boundary of the striatopallidal complex was blurred, suggesting a structural intermingling with the substantia innominata. This three‐dimensional partitioning of the human striatopallidal complex could help to define functional targets for high‐frequency stimulation with greater accuracy and help to identify new stimulation sites. J. Comp. Neurol. 450:122–134, 2002.

Clinical trial of blood-brain barrier disruption by pulsed ultrasound

An implantable ultrasound device safely disrupts the blood-brain barrier in glioblastoma patients. A sound attack on brain tumors Brain tumors are difficult to treat with chemotherapy because the blood-brain barrier greatly limits the delivery of drugs into the brain. Carpentier et al. have developed a pulsed ultrasound device, which they implanted into the skull of patients with glioblastoma, an aggressive and difficult to treat brain tumor, in a first-in-human trial. At regularly scheduled treatment sessions, the researchers activated the ultrasound device by connecting it to a power source, disrupting the blood-brain barrier long enough for subsequent chemotherapy to reach the brain. The authors confirmed that this approach was well tolerated and showed evidence of effectiveness to disrupt the blood-brain barrier, paving the way for further development of this therapeutic approach. The blood-brain barrier (BBB) limits the delivery of systemically administered drugs to the brain. Methods to circumvent the BBB have been developed, but none are used in standard clinical practice. The lack of adoption of existing methods is due to procedural invasiveness, serious adverse effects, and the complications associated with performing such techniques coincident with repeated drug administration, which is customary in chemotherapeutic protocols. Pulsed ultrasound, a method for disrupting the BBB, was shown to effectively increase drug concentrations and to slow tumor growth in preclinical studies. We now report the interim results of an ultrasound dose-escalating phase 1/2a clinical trial using an implantable ultrasound device system, SonoCloud, before treatment with carboplatin in patients with recurrent glioblastoma (GBM). The BBB of each patient was disrupted monthly using pulsed ultrasound in combination with systemically injected microbubbles. Contrast-enhanced magnetic resonance imaging (MRI) indicated that the BBB was disrupted at acoustic pressure levels up to 1.1 megapascals without detectable adverse effects on radiologic (MRI) or clinical examination. Our preliminary findings indicate that repeated opening of the BBB using our pulsed ultrasound system, in combination with systemic microbubble injection, is safe and well tolerated in patients with recurrent GBM and has the potential to optimize chemotherapy delivery in the brain.

Bilateral Deep Brain Stimulation of the Pallidum for Myoclonus-Dystonia Due to ε-Sarcoglycan Mutations: A Pilot Study

OBJECTIVE To assess the efficacy of bilateral deep brain stimulation of the internal pallidum in patients with myoclonus-dystonia due to genetically proved ε-sarcoglycan (SGCE-M-D) deficiency. DESIGN Patients with documented SGCE-M-D undergoing bilateral deep brain stimulation of the internal pallidum were recruited. Standardized assessments of M-D were videorecorded before surgery and 6 to 9 months and 15 to 18 months after surgery, using the movement and disability subscales of the Burke-Fahn-Marsden Dystonia Rating Scale and the Unified Myoclonus Rating Scale. The analysis was based on blinded evaluation of the recordings. SETTING Movement disorder unit in a university hospital in Paris. PATIENTS Five consecutive patients with documented SGCE-M-D. MAIN OUTCOME MEASURES Myoclonus and dystonia scores at follow-up. RESULTS The median myoclonus score decreased from 76 before surgery (range, 38-116) to 10 at 6 to 9 months after surgery (range, 6-31). The median dystonia score decreased from 30.0 before surgery (range, 18.5-53.0) to 4.5 after surgery (range, 3.5-16.0). Disability was also improved and symptoms remained stable between the postoperative evaluations. No adverse effects occurred. CONCLUSIONS Bilateral deep brain stimulation of the internal pallidum is safe and highly effective in this homogeneous population of patients with SGCE-M-D. This therapeutic option should therefore be considered for patients with severe, drug-resistant forms of the disorder.