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Thalamic stimulation and functional magnetic resonance imaging: localization of cortical and subcortical activation with implanted electrodes. Technical note.

The utility of functional magnetic resonance (fMR) imaging in patients with implanted thalamic electrodes has not yet been determined. The aim of this study was to establish the safety of performing fMR imaging in patients with thalamic deep brain stimulators and to determine the value of fMR imaging in detecting cortical and subcortical activity during stimulation. Functional MR imaging was performed in three patients suffering from chronic pain and two patients with essential tremor. Two of the three patients with pain had undergone electrode implantation in the thalamic sensory ventralis caudalis (Vc) nucleus and the other had undergone electrode implantation in both the Vc and the periventricular gray (PVG) matter. Patients with tremor underwent electrode implantation in the ventralis intermedius (Vim) nucleus. Functional MR imaging was performed during stimulation by using a pulse generator connected to a transcutaneous extension lead. Clinically, Vc stimulation evoked paresthesias in the contralateral body, PVG stimulation evoked a sensation of diffuse internal body warmth, and Vim stimulation caused tremor arrest. Functional images were acquired using a 1.5-tesla MR imaging system. The Vc stimulation at intensities provoking paresthesias resulted in activation of the primary somatosensory cortex (SI). Stimulation at subthreshold intensities failed to activate the SI. Additional stimulation-coupled activation was observed in the thalamus, the secondary somatosensory cortex (SII), and the insula. In contrast, stimulation of the PVG electrode did not evoke paresthesias or activate the SI, but resulted in medial thalamic and cingulate cortex activation. Stimulation in the Vim resulted in thalamic, basal ganglia, and SI activation. An evaluation of the safety of the procedure indicated that significant current could be induced within the electrode if a faulty connecting cable (defective insulation) came in contact with the patient. Simple precautions, such as inspection of wires for fraying and prevention of their contact with the patient, enabled the procedure to be conducted safely. Clinical safety was further corroborated by performing 86 MR studies in patients in whom electrodes had been implanted with no adverse clinical effects. This is the first report of the use of fMR imaging during stimulation with implanted thalamic electrodes. The authors' findings demonstrate that fMR imaging can safely detect the activation of cortical and subcortical neuronal pathways during stimulation and that stimulation does not interfere with imaging. This approach offers great potential for understanding the mechanisms of action of deep brain stimulation and those underlying pain and tremor generation.

Chronic Disease↗

[Newer treatment of epilepsy--brain pacemakers and transcranial magnetic stimulation].

The antiepileptic medication and surgical treatment had brought many patients with epilepsy to be seizure free, however, one third of the patients continue to experience seizures. There has recently been an explosion of research into brain stimulation for treating these intractable epilepsy patients. This is largely due to the success of deep brain stimulation of movement disorders. The intelligent cardiac pacemakers also stimulated the neurosurgeons to utilize the implantable devices. In this paper, brain stimulations with vagus nerve stimulator (VNS), depth electrodes, subdural electrodes, external responsive neuro-stimulator, implantable brain stimulator and transcranial magnetic stimulator are reviewed. The VNS had been approved in Europe and United States for clinical use. The efficacy of the VNS has already proven by the controlled trials. Stimulation of the thalamus, subthalamic nucleus and hippocampus showed some efficacy in a small number of patients, however, large scale traials remains to be undertaken. External responsive neurostimulator has shown efficacy and safety to justify further studies with implantable brain stimulators. The multi-center cooperative study is ongoing in the US to examine the usefulness of the implantable stimulator. Animal studies showed efficacy of the transcranial magnetic stimulation for the treatment and prevention of the seizures and status epilepticus.

Animals↗

Bilateral stimulation of the subthalamic nucleus in patients with Parkinson disease: a study of efficacy and safety.

OBJECT: Palliative neurosurgery has reemerged as a valid therapy for patients with advanced Parkinson disease (PD) that is complicated by severe motor fluctuations. Despite great enthusiasm for long-term deep brain stimulation (DBS) of the subthalamic nucleus (STN), existing reports on this treatment are limited. The present study was designed to investigate the safety and efficacy of bilateral stimulation of the STN for the treatment of PD. METHODS: In 12 patients with severe PD, electrodes were stereotactically implanted into the STN with the assistance of electrophysiological conformation of the target location. All patients were evaluated preoperatively during both medication-off and -on conditions, as well as postoperatively at 3, 6, and 12 months during medication-on and -off states and stimulation-on and -off conditions. Tests included assessments based on the Unified Parkinson's Disease Rating Scale (UPDRS) and timed motor tests. The stimulation effect was significant in patients who were in the medication-off state, resulting in a 47% improvement in the UPDRS Part III (Motor Examination) score at 12 months, compared with preoperative status. The benefit was stable for the duration of the follow-up period. Stimulation produced no additional benefit during the medication-on state, however, when compared with patient preoperative status. Significant improvements were made in reducing dyskinesias, fluctuations, and duration of off periods. CONCLUSIONS: This study demonstrates that DBS of the STN is an effective treatment for patients with advanced, medication-refractory PD. Deep brain stimulation of the STN produced robust improvements in motor performance in these severely disabled patients while they were in the medication-off state. Serious adverse events were common in this cohort; however, only two patients suffered permanent sequelae.

Aged↗

Essential Tremor.

Multiple pharmacologic treatments have been studied, but propranolol and primidone have proven to be the most effective medications. It is unlikely that a patient will respond miraculously to another medication if his or her response to propranolol and primidone is minimal. Some subsets of essential tremor, however, such as the kinetic predominant type, may respond better to other medications. Mildly affected patients may not need treatment at all, and the potential benefits must always be weighed against the possible side effects. The main benefit of botulinum toxin injection is for head tremor, whereas its efficacy in hand tremor is variable. If a patient does not respond to adequate doses of propranolol or primidone, deep brain stimulation should be considered because it carries the lowest risk of the available surgical procedures; usually, it should be given preference over thalamotomy. It is important for the physician to realize the multitude of symptomatic treatments available. Beyond the conventional and often effective oral medications, use of newer treatments such as botulinum toxin, thalamotomy, and deep brain stimulation can often reduce tremor and lead to a greater quality of life for patients with ET.

Journal Article↗

New strategies for the treatment of Parkinson's disease hold considerable promise for the future management of neurodegenerative disorders.

Neurodegenerative diseases are often considered incurable with no efficient therapies to modify or halt the progress of disease, and ultimately lead to reduced quality of life and to death. Our knowledge of the nervous system in health and disease has, however, increased considerably during the last fifty years and today, neuroscience reveals promising new strategies to deal with disorders of the nervous system. Some of these results have been implemented with success in the treatment of Parkinson's disease, a common neurodegenerative illness affecting approximately 1% of the population aged seventy or more. Parkinson's disease is characterized by a massive loss of dopaminergic neurons in the substantia nigra, leading to severe functional disturbance of the neuronal circuitry in the basal ganglia. A thorough description of basal ganglia circuitry in health and disease is presented. We describe how the functional disturbances seen in Parkinson's disease may be corrected at specific sites in this circuitry by medical treatment or, in advanced stages of Parkinson's disease, by neurosurgical methods. The latter include lesional surgery, neural transplantation and deep brain stimulation, together with future treatment strategies using direct or indirect implantation of genetically modified cell-lines capable of secreting neurotrophic factors or neurotransmitters. Advantages and disadvantages are briefly mentioned for each strategy and the implications for the future and the possible use of these interventions in other neurodegenerative diseases are discussed, with special emphasis on deep brain stimulation.

Animals↗

Quantifying motion in dystonic syndromes: the bare essentials.

Quantifying movement disorders is becoming crucially important in neurosurgery units to evaluate the efficacy of new therapeutic interventions such as deep brain stimulation. Kinematic analysis, available for more than a century, may represent an adequate solution to this problem. However, quantifying movement disorders poses a number of technical problems. To help clinicians quantify movement disorders, the authors present data recorded in patients with dystonic syndromes and explore the question of movement "normality" in these patients when they receive deep brain stimulation of the internal globus pallidus. In particular, they show that when one control group (n = 11) and a group of dystonic patients (n = 11) are compared, it is possible to detect subtle changes in the performance of a double-handed finger to nose test. These differences persist in the absence of differences in the clinical evaluation of these patients. Suggestions regarding the compromises to make and pitfalls to avoid when quantifying movement disorders are discussed.

Dystonic Disorders↗

Treatment of motor dysfunction in Parkinson's disease: an overview.

Levodopa remains the most effective treatment for Parkinson's disease (PD). However, the use of this drug is complicated by several adverse effects, in particular motor fluctuations and dyskinesias. Drugs providing more continuous dopaminergic stimulation and surgical approaches, such as deep-brain stimulation, have an important ameliorative effect on these problems. Despite these advances, the progression of the disease remains unaffected and strategies that slow or stop the neurodegenerative process are currently not available. Nevertheless, several compounds or surgical procedures are candidates for being neuroprotective and some of them are under evaluation.

Animals↗

Relationship between oscillations in the basal ganglia and synchronization of cortical activity.

The functions of oscillations within the basal ganglia are poorly understood. We discuss in the present paper, the possible physiological or pathological roles of oscillatory activities within the basal ganglia, and their relationship to cortical oscillations. Three aspects are presented: 1. What do we know from animal studies? 2. What do we know from neurophysiological studies in parkinsonian patients? 3. What is the effect of L-dopa treatment and electrical stimulation within basal ganglia circuits on cortical oscillations? Animal studies suggest that neuronal oscillations are spontaneously generated within the basal ganglia system, especially from the GPE and the subthalamic nucleus (STN), but are mainly synchronized by cortical activity via the striatal inputs. Dopamine depletion results in a global increase of oscillations within the whole basal ganglia system, particularly in the GP-NST network. Oscillations within the basal ganglia may, in part, be related to tremor since they are enhanced, especially in the globus pallidus internus (GPI) and the STN, in human and animal dopaminergic depletion. However, they also play a role in the physiology of movement as revealed by coherence analysis between cortex, muscles and GPI/STN in parkinsonian patients undergoing deep brain stimulation. It is known that the basal ganglia may influence cortico-muscular oscillations such as the Piper rhythm and other rhythms in the beta band. In off-drug parkinsonian patients, low frequency oscillations (4-10 Hz) are favoured, presumably resulting in bradykinesia and low force. When medically (Ldopa) or surgically (deep brain stimulation) treated, these low frequency oscillations are replaced by high frequency (70 Hz) oscillations that are important for motor programs to be correctly executed. Studies of cortical reactivity related to planning of voluntary movement in parkinsonian patients provide evidence that it is possible to influence cortical reactivity through the basal ganglia system.

Animals↗

The basal ganglia: an overview of circuits and function.

The technique of electrical stimulation of brain tissue-known clinically as deep brain stimulation (DBS)-is at the fore of treatment of human neurological disease. Here we provide a general overview highlighting the anatomy and circuitry of the basal ganglia (BG). We introduce common disease states associated with BG dysfunction and current hypotheses of BG function. Throughout this introductory review we direct the reader to other reviews in this special issue of Neuroscience and Biobehavioral Reviews highlighting the interaction between basic science and clinical investigation to more fully understand the BG in both health and disease.

Animals↗

From psychosurgery to neuromodulation and palliation: history's lessons for the ethical conduct and regulation of neuropsychiatric research.

As we contemplate the emerging era of neuromodulation and imagine the utility of deep brain stimulation for disease entities in neurology and psychiatry, our enthusiasm is immediately tempered by history. Just a generation ago, other confident investigators were heralding invasive somatic therapies like prefrontal lobotomy to treat psychiatric illness. That era of psychosurgery ended with widespread condemnation, congressional calls for a ban, and avow that history should never repeat itself. Now, just 30 years later, neurologists, neurosurgeons, and psychiatrists are implanting deep brain stimulators for the treatment of Parkinson's disease and contemplating their use for severe psychiatric illnesses, such as obsessive-compulsive disorder and the modulation of consciousness in traumatic brain injury.

Biomedical Research↗

Stimulation of the caudal zona incerta is superior to stimulation of the subthalamic nucleus in improving contralateral parkinsonism.

Deep brain stimulation (DBS) has an increasing role in the treatment of idiopathic Parkinson's disease. Although, the subthalamic nucleus (STN) is the commonly chosen target, a number of groups have reported that the most effective contact lies dorsal/dorsomedial to the STN (region of the pallidofugal fibres and the rostral zona incerta) or at the junction between the dorsal border of the STN and the latter. We analysed our outcome data from Parkinson's disease patients treated with DBS between April 2002 and June 2004. During this period we moved our target from the STN to the region dorsomedial/medial to it and subsequently targeted the caudal part of the zona incerta nucleus (cZI). We present a comparison of the motor outcomes between these three groups of patients with optimal contacts within the STN (group 1), dorsomedial/medial to the STN (group 2) and in the cZI nucleus (group 3). Thirty-five patients with Parkinson's disease underwent MRI directed implantation of 64 DBS leads into the STN (17), dorsomedial/medial to STN (20) and cZI (27). The primary outcome measure was the contralateral Unified Parkinson's Disease Rating Scale (UPDRS) motor score (off medication/off stimulation versus off medication/on stimulation) measured at follow-up (median time 6 months). The secondary outcome measures were the UPDRS III subscores of tremor, bradykinesia and rigidity. Dyskinesia score, L-dopa medication reduction and stimulation parameters were also recorded. The mean adjusted contralateral UPDRS III score with cZI stimulation was 3.1 (76% reduction) compared to 4.9 (61% reduction) in group 2 and 5.7 (55% reduction) in the STN (P-value for trend <0.001). There was a 93% improvement in tremor with cZI stimulation versus 86% in group 2 versus 61% in group 1 (P-value = 0.01). Adjusted 'off-on' rigidity scores were 1.0 for the cZI group (76% reduction), 2.0 for group 2 (52% reduction) and 2.1 for group 1 (50% reduction) (P-value for trend = 0.002). Bradykinesia was more markedly improved in the cZI group (65%) compared to group 2 (56%) or STN group (59%) (P-value for trend = 0.17). There were no statistically significant differences in the dyskinesia scores, L-dopa medication reduction and stimulation parameters between the three groups. Stimulation related complications were seen in some group 2 patients. High frequency stimulation of the cZI results in greater improvement in contralateral motor scores in Parkinson's disease patients than stimulation of the STN. We discuss the implications of this finding and the potential role played by the ZI in Parkinson's disease.

Aged↗

Pharmacological treatment of disabling tremor.

Tremor is often a disabling primary condition or secondary to another disorder. No universally effective pharmacological agent exists for the treatment of essential tremor, and patients differ greatly in their response to therapies, thus requiring individualised regimens. Deep brain stimulation is the best option for patients with disabling, drug-resistant essential tremor. Resting tremor in Parkinson's disease is usually not the primary disabling feature, and in most cases, levodopa/carbidopa is satisfactory for many years. Young Parkinson's patients with dominant, disabling tremor benefit from anticholinergics in addition to dopaminergic therapies. However, older Parkinson's patients with more disabling tremor may suffer from dose-dependent side effects, and deep brain stimulation should be considered. This article outlines the available pharmacological agents and treatment considerations for various disabling tremors, including essential tremor and Parkinson's disease.

Botulinum Toxins, Type A↗

[Imaging in Parkinson disease surgery].

Parkinson's disease is a progressive degenerative disease of the central nervous system frequently becoming motor disabling. Deep brain stimulation is one more therapeutic option. The authors describe the different steps of this therapeutic procedure with detail on imaging protocol to the precise and exact targeting of subthalamic nucleus. MR and CT imaging on stereotactic conditions are the imaging support to the determination of the anatomic target allowing also the choose of trajectory for the surgical procedure. Neurophysiologic exploration and clinical evaluation during the surgery give us the functional target. Deep brain stimulation has been revealing as a safe and effective therapy on some cases of Parkinson's disease with a significant improvement on quality of life of those patients. The brain imaging is a fundamental tool on target determination.

Humans↗

[Delayed central pain associated with a sub-insular hematoma followed by parieto-occipital tumor. Favorable effects of chronic stimulation of the ventral posterior thalamic nucleus].

INTRODUCTION: Déjerine and Roussy reported thalamic syndrome, chronic pain after a vascular lesion in the thalamus, in 1906. Posterior clinical observations allowed know that the same clinical picture can be observed after lesions in other parts of the central nervous system. Due to the fact that the more frequent etiology is vascular, nowadays the term central poststroke pain syndrome is preferred. CLINICAL CASE: We report a patient who suffered a left subinsular hematoma when he was 62 years old. Four years later he started complaining burning constant pain in the right side of the body with crisis of lancinating pain. Also allodynia was observed in the face and right arm. MRI disclosed a necrotic lesion at the level of the left subinsular region. CONCLUSIONS: The lancinating pain and the allodynia were properly controlled by deep brain stimulation with an electrode placed stereotactically at the level of VPL nucleus of the left thalamus. Five months later there was a recurrence of the pain, a CT disclosed a tumour in the parietal region with an important shift of the midline and migration of the electrode out the thalamus. A biopsy disclosed tumoral necrosis. The pathophysiology of the central poststroke pain and effectivity of the deep brain stimulation in this cases are discussed.

Biopsy↗

Pain in Parkinson's Disease.

Pain is reported by nearly 50% of patients with Parkinson's disease. In some patients, it can be more debilitating than the motor deficits. In order to identify the appropriate treatment strategy for each patient, it is useful to categorize pain syndromes as follows: 1) low DOPA (end of dose wearing off, diphasic, or early morning) painful states are associated with inadequate levels of dopamine receptor stimulation; 2) high DOPA (peak dose) painful states occur at times of maximum levodopa efficacy; and 3) many patients report pain that has no obvious relation to dopaminergic medications or may even be caused by other conditions. Low DOPA painful states are best treated by trying to provide more continuous dopaminergic stimulation and thereby reduce or prevent the number and duration of "off" periods. Adding or increasing the dose of direct-acting dopamine receptor agonists or of catechol-o-methyl transferase inhibitors is the best first-line strategy. Other approaches include increasing the frequency of immediate-release levodopa preparations or using controlled-release preparations. More invasive approaches should be considered only when simpler methods fail. These include deep brain stimulation to the pallidum or the subthalamic nucleus, or direct duodenal continuous infusion of levodopa in patients who are unable to undergo surgery. Pain associated with excessive dopaminergic stimulation usually is a result of dystonia or severe chorea. Reduction of levodopa is the first step in attempting to diminish high DOPA states, followed by reduction or cessation of other dopaminergic agents such as selegiline, catechol-o-methyl transferase inhibitors, or direct-acting dopamine receptor agonists. Adding amantadine can reduce chorea significantly and it should be tried if the potential and actual side effects are tolerable to the patient. Deep brain stimulation is a good final option if medication adjustments are ineffective. Nonspecific pains of Parkinson's disease can be difficult to treat. The effective use of central pain suppressant or analgesics is anecdotal and difficult to verify. In untreated early disease, generalized pain or pain related to joint or muscle immobility may be reduced by effective treatment of the underlying Parkinson's disease.

Journal Article↗

Center median-parafascicular complex and pain control. Review from a neurosurgical perspective.

The center median-parafascicular (CM-Pf) complex, which constitutes the major portion of the intralaminar thalamus in man, has long been known to be involved in the processing of pain under normal and pathological conditions. Yet, these 'forgotten' nuclei with their rich connectivity to other thalamic nuclei, the basal ganglia and cortical areas have received only relatively little attention over the past two decades. With regard to the recent reinterest in functional stereotactic neurosurgery as a treatment option for chronic refractory pain, the CM-Pf complex has been reconsidered as a target. This review provides a systematic overview on the current knowledge about the anatomy and connectivity of the CM-Pf complex, neurophysiological studies, and on concepts of its role in pain processing under various conditions. We also review the previous experience with ablative surgery and deep brain stimulation of the CM-Pf complex. Studies in men and experimental animals indicate that the CM-Pf complex is part of a medial pain system, which appears to be involved primarily in affective and motivational dimensions of pain. Single-unit recordings from the CM-Pf complex have shown that the activity of CM-Pf cells is modified by painful stimuli. Under pathological conditions, bursting firing patterns and altered discharge rates were found. Thalamotomies targeting at the CM-Pf complex yielded beneficial results for chronic pain, but interpretation of the results is limited. With bifocal deep brain stimulation, short-term effects of CM-Pf stimulation were superior to those of somatosensory thalamic stimulation in neuropathic pain. There is evidence, that the CM-Pf complex might also be involved in the mediation of the beneficial effects of somatosensory thalamic stimulation and periventricular grey stimulation.

Animals↗

High-frequency stimulation in Parkinson's disease: more or less?

Deep-brain stimulation at high frequency is now considered the most effective neurosurgical therapy for movement disorders. An electrode is chronically implanted in a particular area of the brain and, when continuously stimulated, it significantly alleviates motor symptoms. In Parkinson's disease, common target nuclei of high-frequency stimulation (HFS) are ventral thalamic nuclei and basal ganglia nuclei, such as the internal segment of the pallidum and the subthalamic nucleus (STN), with a preference for the STN in recent years. Two fundamental mechanisms have been proposed to underlie the beneficial effects of HFS: silencing or excitation of STN neurons. Relying on recent experimental data, we suggest that both are instrumental: HFS switches off a pathological disrupted activity in the STN (a 'less' mechanism) and imposes a new type of discharge in the upper gamma-band frequency that is endowed with beneficial effects (a 'more' mechanism). The intrinsic capacity of basal ganglia and particular STN neurons to generate oscillations and shift rapidly from a physiological to a pathogenic pattern is pivotal in the operation of these circuits in health and disease.

Animals↗

Future and current surgical therapies in Parkinson's disease.

PURPOSE OF REVIEW: The mainstay of treatment for Parkinson's disease remains medical therapy. With improved surgical precision and decreased morbidity, stereotactic lesioning and deep brain stimulation have become more popular. New therapies currently in clinical trials include gene therapy and direct drug delivery to the brain. The present review discusses surgical therapies for the treatment of Parkinson's disease and the status of experimental strategies currently in preclinical and clinical testing. RECENT FINDINGS: Both stereotactic ablation and deep brain stimulation of the thalamus, globus pallidus interna, and subthalamic nucleus are discussed and compared in the current literature. New therapies such as drug infusions into the brain, gene therapy, and neural transplantation are in clinical trials and have been tested extensively in animals. Safety and efficacy of such therapies are discussed in recent literature. SUMMARY: Although medication remains the first and main line of treatment and the mainstay for Parkinson's disease, advances in techniques and safety of operations have made surgical interventions more popular. Thalamic surgery remains helpful only in a limited subset of patients with predominent tremor that is unresponsive to medication. Bilateral subthalamic nucleus DBS holds the most promising results for patients with tremor, severe motor fluctuations and dyskinesias from L-dopa, with the best improvements seen in daily activities and quality of life. Newer therapies currently in clinical trial include gene therapy to replace lost gamma-aminobutyric acid inputs to the subthalamic nucleus and globus pallidus interna/substantia nigra pars reticulata, and infusion of recombinant glial derived neurotrophic factor to support at-risk nigrostriatal neurons. Further developments in these areas, along with evolution in stem cell science that hopefully will permit replacement of lost neurons, may alter the nature of surgical practice in Parkinson's disease patients in the not too distant future.

Corpus Striatum↗