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Putative common pathways in therapeutic brain stimulation for affective disorders.

Brain stimulation methods in the treatment of affective disorder are electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), vagus nerve stimulation (VNS), and deep brain stimulation (DBS). Clinically, ECT is considered the strongest remedy in the treatment of severe depression, especially depression with psychotic features, and in the elderly. TMS, despite positive reports, is somewhat more controversial. VNS has, so far, only been used in treatment-resistant depression with limited results. DBS may be of potential use in rare cases of treatment-resistant cases of affective disorder. This article highlights the similarities and differences between the four stimulation methods. The main difference is the seizures necessary in ECT. A stronger involvement of the hippocampus following experimental seizures compared with effects in that region induced by TMS and VNS might explain the consistent findings of the superiority of ECT in the most severe cases of affective disorder.

Animals↗

Normalizing motor-related brain activity: subthalamic nucleus stimulation in Parkinson disease.

OBJECTIVE: To test whether therapeutic unilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) in patients with Parkinson disease (PD) leads to normalization in the pattern of brain activation during movement execution and control of movement extent. METHODS: Six patients with PD were imaged off medication by PET during performance of a visually guided tracking task with the DBS voltage programmed for therapeutic (effective) or subtherapeutic (ineffective) stimulation. Data from patients with PD during ineffective stimulation were compared with a group of 13 age-matched control subjects to identify sites with abnormal patterns of activation. Conjunction analysis was used to identify those areas in patients with PD where activity normalized when they were treated with effective stimulation. RESULTS: For movement execution, effective DBS caused an increase of activation in the supplementary motor area (SMA), superior parietal cortex, and cerebellum toward a more normal pattern. At rest, effective stimulation reduced overactivity of SMA. Therapeutic stimulation also induced reductions of movement related "overactivity" compared with healthy subjects in prefrontal, temporal lobe, and basal ganglia circuits, consistent with the notion that many areas are recruited to compensate for ineffective motor initiation. Normalization of activity related to the control of movement extent was associated with reductions of activity in primary motor cortex, SMA, and basal ganglia. CONCLUSIONS: Effective subthalamic nucleus stimulation leads to task-specific modifications with appropriate recruitment of motor areas as well as widespread, nonspecific reductions of compensatory or competing cortical activity.

Adult↗

Neurosurgical treatment of spasticity and other pediatric movement disorders.

For children whose spasticity and movement disorders are inadequately treated by oral medications and botulinum toxins, neurosurgical procedures are now available to effectively treat spasticity, tremor, and many cases of dystonia. Spastic diplegia can be treated with selective lumbar rhizotomies, which significantly decrease spasticity, increase range of motion, and improve Gross Motor Function Measure scores. Children with spastic quadriparesis and those with secondary dystonia can be treated with intrathecal baclofen, which diminishes both spasticity and dystonia and is associated with improved function and quality of life. Children with primary dystonia and those with tremor can be treated with deep brain stimulation of the internal globus pallidus and thalamus, respectively. Some children with chorea respond to deep brain stimulation. There are no effective neurosurgical treatments for athetosis or ataxia. The effectiveness of neurosurgical treatments of pediatric movement disorders has increased significantly in the past 15 years.

Athetosis↗

Microelectrode recording-determined subthalamic nucleus length not predictive of stimulation-induced side effects.

OBJECT: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has become a popular treatment for patients with medically refractory Parkinson disease. Many surgeons believe that microelectrode recording (MER) during DBS electrode implantation is needed to optimize placement, whereas stimulation-induced side effects such as paresthesias, dystonic contractions, dyskinesias, and ocular motor signs that become apparent postoperatively may be an indicator of the proximity of the electrode to various boundaries of the STN. This study was performed to evaluate the relationship between mapping of the STN by using MER and postoperative stimulation-induced side effects. METHODS: Eighty-two electrodes implanted in 75 patients between March 1999 and March 2003 were retrospectively examined to evaluate the length of the STN defined by MER, and the number of and threshold for postoperative stimulation-induced side effects. Electrodes were typically tested with increasing stimulation amplitudes (maximum 6 V) by using a monopolar array. The 82 electrodes were associated with 97 stimulation-induced side effects. The mean time between surgery and testing stimulation-induced side effects was 3.9 months. Statistical analysis (two-tailed t-test) revealed no significant difference in the number of stimulation-induced side effects (or the mean threshold for paresthesias, the most common side effect) for electrodes associated with an STN length less than 4.5 mm (13 electrodes) compared with those associated with an STN greater than or equal to 4.5 mm (69 electrodes, p = 0.616). For every electrode, the target adjustment based on MER results was within 2 mm of the image-planned target (usually 1 mm anterior). In the x axis (medial-lateral orientation), there was no systematic difference in adjustments made for the electrodes associated with the shorter compared with the longer STN lengths. In the y axis (anterior-posterior orientation), there was a very small statistically significant difference in the mean adjustment (0.4 mm) between the two groups. CONCLUSIONS: Analysis of these results suggests that a shorter MER-determined STN length alone does not reliably predict the incidence of stimulation-induced side effects.

Chi-Square Distribution↗

Pallidal stimulation for parkinsonism: improved brain activation during sequence learning.

We used (15)O-labeled water and positron emission tomography to assess the effect of deep brain stimulation of the internal globus pallidus on motor sequence learning in Parkinson's disease. Seven right-handed patients were scanned on and off stimulation while they were performing a motor sequence learning task and a kinematically matched motor execution reference task. The scans were performed after a 12-hour medication washout. Stimulation parameters were adjusted for maximal motor improvement; experimental task parameters were held constant across stimulation conditions. Internal globus pallidus stimulation improved motor ratings by 37% (p < 0.01). During the sequence learning task, stimulation improved performance as measured by several correct anticipatory movements (p < 0.01) and by verbal report (p < 0.001). Concurrent positron emission tomography imaging during learning demonstrated significant (p < 0.01) increases in brain activation with stimulation in the left dorsolateral prefrontal cortex, bilaterally in premotor cortex, and in posterior parietal and occipital association areas. Stimulation did not affect the activity of these regions during the performance of the motor execution reference task. These findings suggest that internal globus pallidus deep brain stimulation can enhance the activity of prefrontal cortico-striato-pallidothalamic loops and related transcortical pathways. Improved sequence learning with stimulation may be directly related to these functional changes.

Adult↗

Work toward real-time control of a cortical neural prothesis.

Implantable devices that interact directly with the human nervous system have been gaining acceptance in the field of medicine since the 1960's. More recently, as is noted by the FDA approval of a deep brain stimulator for movement disorders, interest has shifted toward direct communication with the central nervous system (CNS). Deep brain stimulation (DBS) can have a remarkable effect on the lives of those with certain types of disabilities such as Parkinson's disease, Essential Tremor, and dystonia. To correct for many of the motor impairments not treatable by DBS (e.g. quadriplegia), it would be desirable to extract from the CNS a control signal for movement. A direct interface with motor cortical neurons could provide an optimal signal for restoring movement. In order to accomplish this, a real-time conversion of simultaneously recorded neural activity to an online command for movement is required. A system has been established to isolate the cellular activity of a group of motor neurons and interpret their movement-related information with a minimal delay. The real-time interpretation of cortical activity on a millisecond time scale provides an integral first step in the development of a direct brain-computer interface (BCI).

Animals↗

New methods of minimally invasive brain modulation as therapies in psychiatry: TMS, MST, VNS and DBS.

Over the past 20 years, new methods have been developed that have allowed scientists to visualize the human brain in action. Initially positron emission tomography (PET) and now functional magnetic resonance imaging (fMRI) are causing a paradigm shift in psychiatry and the neurosciences. Psychiatry is abandoning the pharmacological model of 'brain as soup', used for much of the past 20 years. Instead, there is new realization that both normal and abnormal behavior arise from chemical processes that occur within parallel distributed networks in specific brain regions. Many of these pathological circuits are becoming well characterized, in disorders ranging from Parkinson's disease, to obsessive-compulsive disorder, to depression. Most recently, there has been an explosion of new techniques that allow for direct stimulation of these brain circuits, without the need for open craniotomy and neurosurgical ablation. The techniques include transcranial magnetic stimulation (TMS), magnetic seizure therapy (MST), vagus nerve stimulation (VNS), and deep brain stimulation (DBS). This review will describe these new tools, and overview their current and future potential for research and clinical neuropsychiatric use. The psychiatry of the future will be better grounded in a firm understanding of neuroanatomy and neurophysiology (as well as pharmacology). These brain stimulation tools, or their next iterations, will play an ever-larger role in clinical neuropsychiatric practice.

Brain↗

Lesion-making surgery versus brain stimulation for treatment of Parkinson's disease.

With the resurgence of interest in neurosurgical intervention for the treatment of drug-resistant Parkinson's disease, posteroventral pallidotomy (internal globus pallidus) has become a procedure widely applied by neurosurgeons. In chronic deep brain stimulation, the stimulation target is the same area as the above lesion-making point: the ventralis intermedius thalamic nucleus, subthalamic nucleus, and internal globus pallidus, since deep brain stimulation does not induce brain damage, and it is possible to control the stimulation (frequency and strength). There is also no recurrence. This procedure has the reversibility, selectivity, and adjustability that is ideal for functional neurosurgery. Such chronic stimulation therapy has thus now become an alternative to lesion-making stereotactic surgery. However, stimulation therapy directed at a particular target has more specific effects on particular symptoms of Parkinson's disease, so that an effective stimulation target needs to be selected depending on the nature of the syndrome to be improved. This article presents a review of the most recent reports on how to perform safer and more effective pallidotomy, and of recent basic and clinical reports concerning pallidal stimulation. Some answers to the question of whether or not stimulation therapy is an alternative to lesion-making surgery at the internal globus pallidus to improve parkinsonian syndrome and levodopa-induced dyskinesias are discussed.

Journal Article↗

Gait and Balance Dysfunction in Adults.

Determining the precise cause of gait dysfunction in adults is often difficult because of the multifactorial nature of the disorder. Additionally, elderly patients have other comorbidities that further complicate their diagnosis. A proper history and physical examination, however, often allow the clinician to arrive at the correct diagnosis. Once a diagnosis is reached, appropriate therapeutic decisions can be made. Patients presenting with Parkinsonism need a thorough evaluation to rule out potentially reversible conditions, such as normal pressure hydrocephalus. Patients with idiopathic Parkinson's disease usually develop gait difficulty and freezing episodes late in the course of the illness. Another important cause of gait disturbance in adults is the cerebellar ataxias. Among the sporadic forms, gluten sensitivity is an important consideration. Identification of this entity is important, because the disease process can be halted with a gluten-free diet. Another group is the paraneoplastic ataxias, which can often be diagnosed in the proper clinical setting. Most of the adult-onset hereditary ataxias are autosomal dominant conditions. Except for the episodic ataxias, treatment of these conditions has been disappointing. Mixed results have been obtained with the use of amantadine, buspirone, and 5-hydroxytryptophan. Physical therapy plays an important role in the gait rehabilitation of these patients. Over the past several years, researchers have developed a greater understanding of motor control and how it relates to freezing. Clinicians can now train patients to use external cues to overcome their motor blocks. Another important advance has been the development of subthalamic nucleus deep brain stimulation in the treatment of patients with troublesome peak dose dyskinesia and other motor fluctuations. Subthalamic nucleus deep brain stimulation should be considered when best medical treatment fails. Cortical myoclonus can be treated with levetiracetam, which has US Food and Drug Administration approval as an antiepileptic agent. It has been quite effective in the treatment of myoclonus and should be considered when other medications fail.

Journal Article↗

Stimulating the human midbrain to reveal the link between pain and blood pressure.

The periaqueductal grey area (PAG) in the midbrain is an important area for both cardiovascular control and modulation of pain. However, the precise relationship between pain and blood pressure is unknown. We prospectively studied 16 patients undergoing deep brain stimulation of the rostral PAG for chronic pain. Pre-operatively, post-operatively, and at 1 year, pain scores were assessed using both visual analogue scores and the McGill Pain Questionnaire. Patients were tested post-operatively to determine whether electrical stimulation of the PAG would modulate blood pressure. We found that the degree of analgesia induced by deep brain stimulation of the rostral PAG in man is related to the magnitude of reduction in arterial blood pressure. We found that this relationship is linear and is related to reduced activity of the sympathetic nervous system. Thus stimulation of the PAG may partly control pain by reducing sympathetic activity as predicted by William James over a century ago.

Adult↗

Control of poststroke involuntary and voluntary movement disorders with deep brain or epidural cortical stimulation.

The effects of deep brain or epidural cortical stimulation on poststroke involuntary and voluntary movement disorders were analyzed in a total of 64 patients. Among them, 22 patients underwent either deep brain or epidural cortical stimulation in order to control their poststroke involuntary movements. The remaining 42 underwent epidural cortical stimulation for the purpose of controlling their poststroke pain. In the latter group of patients, we analyzed the changes in coexistent involuntary or voluntary movement disorders during stimulation for pain control. Stimulation of either the thalamic nucleus ventralis intermedius or the motor cortex proved to be useful in 13 (59%) of the patients who underwent deep brain or epidural cortical stimulation for control of poststroke involuntary movements. Satisfactory control was often achieved in patients with hemiballismus, hemichorea or resting tremor. In 8 (19%) of the patients who underwent epidural cortical stimulation for pain control, stimulation of the motor cortex improved motor performance which had been impaired in association with hemiparesis. Such an effect was independent of pain control and apparently resulted from an inhibition of their rigidity. We believe that these findings justify further clinical studies on deep brain or epidural cortical stimulation for the control of poststroke movement disorders.

Brain↗

Pallidotomy versus pallidal stimulation.

Both posteroventral pallidotomy and pallidal deep brain stimulation (DBS) have a documented effect on Parkinsonian symptoms. DBS is more costly and more laborious than pallidotomy. The aim of this study was to analyse the respective long-term effect of each surgical procedure on contralateral symptoms in the same patients. Five consecutive patients, two women and three men, who at first surgery had a mean age of 64 years and a mean duration of disease of 18 years, received a pallidotomy contralateral to the more symptomatic side of the body. At a mean of 14 months later, the same patients received a pallidal DBS on the side contralateral to the pallidotomy. All patients had on-off phenomena and dyskinesias. There were three left-sided and two right-sided pallidotomies, and, subsequently, two left-sided and three right-sided pallidal DBS. The latest evaluation was performed 37 months (range 22-60) after the pallidotomy and 22 months (range 12-33) after the pallidal DBS. Mean UPDRS motor score pre-operatively was 49 and at last follow-up 33 (32.7% improvement, p<0.05). Appendicular items 20-26 contralateral to pallidotomy remained improved more significantly than contralateral to DBS. Dyskinesia scores were also improved more markedly contralateral to the pallidotomy. Two patients exhibited moderate dysarthria and one patient severe dysphonia following DBS. Symptoms contralateral to the chronologically older pallidotomy, especially dyskinesias, rigidity and tremor, were still more improved than symptoms contralateral to the more recent pallidal DBS, despite numerous post-operative patient visits to optimise stimulation parameters.

Aged↗

Globus pallidus stimulation in advanced Parkinson's disease.

Deep brain stimulation (DBS) of the globus pallidus internus (GPi) has become an accepted therapeutic modality in selected Parkinson's disease (PD) patients with severe levodopa-induced dyskinesias (LID) and on-off motor fluctuations. In comparison to subthalamic nucleus DBS there is a paucity of data on GPi DBS outcomes. We present our experience with a group of 20 PD patients (9 unilateral, 11 bilateral) who underwent GPi stimulation. PD motor symptoms were assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) part III scores and subscores, and dyskinesia using the Abnormal Involuntary Movement Scale (AIMS), UPDRS part IVa, and clinical global impression (CGI). At mean follow-up time of 7 months, bilateral stimulation reduced off-period motor scores by a mean of 46% and on-period motor scores by 18%. Unilateral stimulation reduced off-period motor scores by 18%. Dyskinesia severity was reduced by 76%, which was maintained after a mean follow-up time of 35 months. Antiparkinsonian medication dosage was unchanged. No major adverse effects were seen. Unilateral and bilateral GPi DBS provides lasting benefit in PD patients with severe LID. Beneficial effects on off-period motor symptoms are greater with bilateral stimulation; however, with maintenance of dopaminergic medication, unilateral procedures can also provide important and sustained benefits.

Aged↗

The surgical treatment of Parkinson's disease.

Surgical treatment of Parkinson's disease (PD) can provide gratifying symptomatic improvements for many individuals who suffer from persistent disabling symptoms despite the best available medical management. Current surgical therapies include ablative techniques (thalamotomy and pallidotomy), augmentative techniques (nondestructive) (deep brain stimulation), and restorative techniques (tissue transplantation and gene therapy). Ablative procedures can provide substantial clinical benefit, but the current trend is toward deep brain stimulation, which can provide similar symptomatic improvement in a nondestructive manner. Restorative techniques, such as tissue transplantation and gene therapy, are exciting but have significant obstacles to overcome before their promise can be realized. Until the underlying pathological defect of PD can be identified and treated, surgical intervention is likely to remain important in the symptomatic treatment of this disabling disease.

Electric Stimulation Therapy↗

Stimulation of the posterior hypothalamus for medically intractable impulsive and violent behavior.

OBJECTIVE: To describe the therapeutic effect of deep brain stimulation for the treatment of patients with below-average IQs who are affected by aggressive and disruptive behavior and who are resistant to any drug and/or conservative treatment (including occupational therapy). PATIENTS AND METHODS: Two consecutive patients suffering from mental retardation with aggressive and disruptive behavior and resistant to any pharmacological treatment underwent deep brain stimulation electrode placement in the posteromedial hypothalamus for continuous chronic high-frequency stimulation (HFS). The stereotactic coordinates of the target were chosen according to the study by Sano et al., which involved hypothalamic stereotactic lesions. RESULTS: HFS of the posteromedial hypothalamus demonstrated consistent improvement of disruptive behavior in both patients at the follow-up evaluation 1 year later. CONCLUSIONS: HFS of the posteromedial hypothalamus showed similar results to those obtained by Sano et al. in the 1960s with radiofrequency lesions of the same target volume. The reversibility of neurostimulation allows HFS to control disruptive behavior when conservative treatments are ineffective, and drug therapy is uneventful or causes severe side effects. In conclusion, this neuromodulation procedure improved the quality of life and the range of social relationships for both of the treated patients.

Adult↗