Near-infrared stimulation on globus pallidus and subthalamus.

Near-infrared stimulation (NIS) is an emerging technique used to evoke action potentials in nervous systems. Its efficacy of evoking action potentials has been demonstrated in different nerve tissues. However, few studies have been performed using NIS to stimulate the deep brain structures, such as globus pallidus (GP) and subthalamic nucleus (STN). Male Sprague-Dawley rats were randomly divided into GP stimulation group (n=11) and STN stimulation group (n=6). After introducing optrodes stereotaxically into the GP or STN, we stimulated neural tissue for 2 min with continuous near-infrared light of 808 nm while varying the radiant exposure from 40 to 10 mW. The effects were investigated with extracellular recordings and the temperature rises at the stimulation site were also measured. NIS was found to elicit excitatory responses in eight out of 11 cases (73%) and inhibitory responses in three cases in the GP stimulation group, whereas it predominantly evoked inhibitory responses in seven out of eight cases (87.5%) and an excitatory response in one case in STN stimulation group. Only radiation above 20 mW, accompanying temperature increases of more than 2°C, elicited a statistically significant neural response (p<0.05). The responsiveness to NIS was linearly dependent on the power of radiation exposure.

GFAP expression in the rat brain following sub-chronic exposure to a 900 MHz electromagnetic field signal.

PURPOSE: The rapid development and expansion of mobile communications contributes to the general debate on the effects of electromagnetic fields emitted by mobile phones on the nervous system. This study aims at measuring the glial fibrillary acidic protein (GFAP) expression in 48 rat brains to evaluate reactive astrocytosis, three and 10 days after long-term head-only sub-chronic exposure to a 900 MHz electromagnetic field (EMF) signal, in male rats. METHODS: Sprague-Dawley rats were exposed for 45 min/day at a brain-averaged specific absorption rate (SAR) = 1.5 W/kg or 15 min/day at a SAR = 6 W/kg for five days per week during an eight-week period. GFAP expression was measured by the immunocytochemistry method in the following rat brain areas: Prefrontal cortex, cerebellar cortex, dentate gyrus of the hippocampus, lateral globus pallidus of the striatum, and the caudate putamen. RESULTS: Compared to the sham-treated rats, those exposed to the sub-chronic GSM (Global System for mobile communications) signal at 1.5 or 6 W/kg showed an increase in GFAP levels in the different brain areas, three and ten days after treatment. CONCLUSION: Our results show that sub-chronic exposures to a 900 MHz EMF signal for two months could adversely affect rat brain (sign of a potential gliosis).

Quantifying the neural elements activated and inhibited by globus pallidus deep brain stimulation.

Deep brain stimulation (DBS) of the globus pallidus pars interna (GPi) is an effective therapy option for controlling the motor symptoms of medication-refractory Parkinson's disease and dystonia. Despite the clinical successes of GPi DBS, the precise therapeutic mechanisms are unclear and questions remain on the optimal electrode placement and stimulation parameter selection strategies. In this study, we developed a three-dimensional computational model of GPi-DBS in nonhuman primates to investigate how membrane channel dynamics, synaptic inputs, and axonal collateralization contribute to the neural responses generated during stimulation. We focused our analysis on three general neural elements that surround GPi-DBS electrodes: GPi somatodendritic segments, GPi efferent axons, and globus pallidus pars externa (GPe) fibers of passage. During high-frequency electrical stimulation (136 Hz), somatic activity in the GPi showed interpulse excitatory phases at 1-3 and 4-5.5 ms. When including stimulation-induced GABA(A) and AMPA receptor dynamics into the model, the somatic firing patterns continued to be entrained to the stimulation, but the overall firing rate was reduced (78.7 to 25.0 Hz, P < 0.001). In contrast, axonal output from GPi neurons remained largely time-locked to each pulse of the stimulation train. Similar entrainment was also observed in GPe efferents, a majority of which have been shown to project through GPi en route to the subthalamic nucleus. The models suggest that pallidal DBS may have broader network effects than previously realized and the modes of therapy may depend on the relative proportion of GPi and/or GPe efferents that are directly affected by the stimulation.

Treatment of dystonia with deep brain stimulation.

Pallidal deep brain stimulation (DBS) is an established treatment option for medically refractive dystonia. The mechanism by which globus pallidus pars interna (GPi) DBS improves dystonia is still unclear. Primary generalized dystonia usually responds well to this therapy, as recently confirmed in two well-designed, double-blind, controlled trials; however, predictors of outcome within this population are not well known. The role of GPi DBS in idiopathic cervical dystonia resistant to treatment with botulinum toxin, in tardive dystonia, and in some types of secondary dystonia are emerging as populations of patients who may also benefit, but outcomes are not well documented. Serious complications from this therapy are rare. Future research will likely continue to address the most appropriate programming settings for various populations of dystonia, the mechanism by which DBS affects dystonia, and the possibility of alternative brain targets that might have less associated side effects or greater efficacy than the GPi.

Human central nervous system circuits examined through the electrodes implanted for deep brain stimulation.

High-frequency repetitive electrical stimulation of deep brain structures through stereotactically implanted electrodes is a well established procedure for symptomatic treatment of patients with Parkinson's disease and other neurological conditions involving dysfunction of basal ganglia circuits. Target nuclei have mainly three structures: the nucleus ventrointermedius externus of the thalamus (Vim), the globus pallidus internum (GPi) and the subthalamic nucleus (STN). Having an electrode implanted in deep brain tissue offers a unique opportunity for carrying out neurophysiological studies on the neural structures and pathways that are within the area of influence of the electrode. This possibility has been used by many researchers in the field that either recorded the activity from, or applied stimulation to, the electrode implanted in the target nuclei. The results of these studies have brought improvement on our knowledge of human brain circuitry and provided cues for understanding better the effects of deep brain stimulation (DBS). We present here a review of the literature on the use of DBS electrodes for externally controlled recording or stimulation. The results reported show some of the possibilities of this new dimension of neurophysiological studies and are, most likely, a preliminary account of future major interventions on human brain.

Deep brain stimulation in the globus pallidus to treat dystonia: electrophysiological characteristics and 2 years' follow-up in 10 patients.

Deep brain stimulation (DBS) was applied in the internal segment of the globus pallidus (GPi) to treat dystonia in 10 patients. One year after surgery the Burke-Fahn-Marsden movement scores were significantly lower than preoperative values (P=0.01). Two years after surgery the mean decrease reached 65% (P=0.001) with no motor symptoms worsening. Single unity activity was recorded in the operating room: GPi cells discharged with tonic (n=19; 29%), irregular (n=32; 48%), or burst-like activity (n=15; 23%) and fired with a mean discharge rate of 39 Hz+/-22. Some neurons demonstrated an oscillatory activity with periods lasting several seconds. Pairs of pallidal cells (n=8) recorded simultaneously displayed discharge synchronization. Movement modulated 64.4% of the cells tested, with increases in firing in 89% of cells and decreases in firing in 10% of cells. GPi cells responded to flexion and extension movements and to several passive manipulations indicating an important sensory role in dystonia. GPi neurons fired in advance of the electromyography (EMG) when the surface EMG was recorded simultaneously with the neuronal activity. Spectral analysis of the co-contracting muscles during dystonia demonstrated prominent high peaks at a low frequency band (20 Hz) during involuntary and voluntary movements. The high amplitude EMG profile recorded at rest diminished to very low values with GPi stimulation, allowing an ease of voluntary contractions. We conclude that DBS in the GPi is a reliable surgical technique for dystonia. GPi cells discharge with distinct electrophysiological characteristics that may explain some of the symptoms in dystonia. EMG recording in the operating room helps to determine which DBS contacts produce the best benefit.

Low-pass filter properties of basal ganglia cortical muscle loops in the normal and MPTP primate model of parkinsonism.

Oscillatory bursting activity is commonly found in the basal ganglia (BG) and the thalamus of the parkinsonian brain. The frequency of these oscillations is often similar to or higher than that of the parkinsonian tremor, but their relationship to the tremor and other parkinsonian symptoms is still under debate. We studied the frequency dependency of information transmission in the cortex-BG and cortex-periphery loops by recording simultaneously from multiple electrodes located in the arm-related primary motor cortex (MI) and in the globus pallidus (GP) of two vervet monkeys before and after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment and induction of parkinsonian symptoms. We mimicked the parkinsonian bursting oscillations by stimulating with 35 ms bursts given at different frequencies through microelectrodes located in MI or GP while recording the evoked neuronal and motor responses. In the normal state, microstimulation of MI or GP does not modulate the discharge rate in the other structure. However, the functional-connectivity between MI and GP is greatly enhanced after MPTP treatment. In the frequency domain, GP neurons usually responded equally to 1-15 Hz stimulation bursts in both states. In contrast, MI neurons demonstrated low-pass filter properties, with a cutoff frequency above 5 Hz for the MI stimulations, and below 5 Hz for the GP stimulations. Finally, muscle activation evoked by MI microstimulation was markedly attenuated at frequencies higher than 5 Hz. The low-pass properties of the pathways connecting GP to MI to muscles suggest that parkinsonian tremor is not directly driven by the BG 5-10 Hz burst oscillations despite their similar frequencies.

Exacerbation of blepharospasm associated with craniocervical dystonia after placement of bilateral globus pallidus internus deep brain stimulator.

To report a case of exacerbation of blepharospasm after bilateral globus pallidus internus (GPi) deep brain stimulator (DBS) placement. A 69-year-old male presented after bilateral GPi DBS placement for blepharospasm and craniocervical dystonia with worsening eyelid spasms and associated apraxia of lid opening (ALO). Numerous attempts to adjust DBS parameters were ineffective. Consequently, bilateral upper eyelid myectomy was performed. Myectomy surgery was free of complications. The patient had significant improvement of blepharospasm and ALO. Although early success has been reported with DBS placement in a small number of patients with focal dystonias, further studies and longer follow-up are needed to demonstrate whether this will prove to be a useful approach in the treatment of blepharospasm. Upper eyelid myectomy can provide an effective means for treating blepharospasm and associated ALO.

Cortical evoked potentials from pallidal stimulation in patients with primary generalized dystonia.

Deep brain stimulation (DBS) of globus pallidus internus (GPi) has emerged as an effective treatment for primary generalized dystonia. However, the physiological mechanisms of improvement are not fully understood. Cortical activity in response to pallidal stimulation was recorded in 6 patients with primary generalized dystonia >6 months after bilateral GPi DBS. Scalp electroencephalogram was recorded using 60 surface electrodes during 10 Hz bipolar pallidal DBS at each electrode contact pair. Anatomical position of the electrode contacts in relation to the GPi, medial medullary lamina and globus pallidus externus (GPe) was determined from the postoperative stereotactic MRI. In all six patients an evoked potential (EP) was observed with average onset latency of 10.9 ms +/- 0.77, peak latency 26.6 ms +/- 1.6, distributed mainly over the ipsilateral hemisphere, maximal centrally. The mean amplitude of this potential was larger with stimulation in posteroventral GPi than in GPe (3.36 microV vs. 0.50 microV, P < 0.0001). The EP was absent in one patient-side, ipsilateral to a previous thalamotomy. Low frequency GPi stimulation produces an EP distributed centrally over the ipsilateral hemisphere. The latency and distribution of the EP are consistent with stimulation of pallidothalamic neurons projecting to the sensorimotor cortex. Because the EP is larger and more consistently present with stimulation of posteroventral GPi than GPe, it may provide a physiological tool to identify contacts within the optimal surgical target.

Multicenter study on deep brain stimulation in Parkinson's disease: an independent assessment of reported adverse events at 4 years.

Ongoing adverse events (AEs) at 4-years postsurgery in 69 patients with advanced Parkinson's disease (PD) who received deep brain stimulation (DBS) of the subthalamic nucleus (STN) (n = 49) or the internal globus pallidus (GPi) (n = 20), in the framework of a subset of eight centers of a multicenter study, were analyzed by an independent ad hoc committee. At baseline, the patients' age, sex, disease duration, and clinical condition were virtually identical, as was the duration of follow-up. There were 64 AEs reported in 53% of STN DBS patients and eight AEs reported in 35% of GPi DBS patients. Most of the AEs were not deemed severe and were reported to be present "both with and without stimulation." The majority of the AEs affected patients' cognitive, psychiatric and behavioral status, as well as speech, gait, and balance, and most of these AEs occurred in STN DBS patients. When comparing patients who exhibited AEs with those who did not, it was found that in the STN DBS group, the patients with AEs had a longer disease duration, as well as more gait disorders and psychiatric disturbances at baseline.

Deep brain stimulation for Parkinson's disease: prevalence of adverse events and need for standardized reporting.

Deep brain stimulation (DBS) has assumed a prominent role in the treatment of Parkinson's disease (PD). In this manuscript, we attempt to estimate the prevalence and categorize adverse events (AEs) of DBS in PD, based on efficacy studies published over the last decade. We conclude that reliable categorization and quantification of AEs based on available data poses many challenges and argue that a standardized scheme for reporting AEs should be created. This would provide a foundation for a meaningful risk/benefit analysis, for comparison of results between centers and, ultimately, for a well informed decision by physicians and patients as to whether surgery should be pursued.

Pallidal stimulation for dystonia in pantothenate kinase-associated neurodegeneration.

Patients with generalized dystonia secondary to pantothenate kinase-associated neurodegeneration are traditionally treated palliatively with medical therapy. Therapeutic advances include stereotactic basal ganglia ablative techniques and, more recently, pallidal deep-brain stimulation. We report the course of dystonia in a teenage male. Bilateral microelectrode-guided pallidal deep-brain stimulators were placed while the patient was awake. Three parasagittal microelectrodes were inserted simultaneously. Two anterior microelectrodes were relatively quiet. The posterior electrode demonstrated a pattern of frequent bursts with high-frequency activity. The stimulator was therefore placed in the posterior location, which resulted in symptomatic improvement. Pallidal deep-brain stimulation appears to create a functional correction that may alter globus pallidus internus inhibitory output to the motor thalamus. The prominent, noisy bursting patterns observed in the globus pallidus internus suggests that high-frequency stimulation may improve signs of dystonia by normalizing thalamic discharge patterns.

Antero-ventral internal pallidum stimulation improves behavioral disorders in Lesch-Nyhan disease.

The Lesch-Nyhan syndrome is an X-linked recessive disorder caused by a deficiency in hypoxanthine-guanine phosphoribosyl transferase, a purine salvage enzyme. Affected individuals exhibit a characteristic neurobehavioral disorder with delayed acquisition of motor skills, dystonia, severe self-mutilations, and aggressive behavior. Deep brain stimulation has been previously proposed for controlling isolated involuntary movements and psychiatric disorders. We applied a double bilateral simultaneous stimulation to limbic and motor internal pallidum in one patient for controlling both behavioral and movement disorders, respectively. The injurious compulsions disappeared; dystonia and dyskinesia were decreased at 28 months follow-up.

Deep brain stimulation for torsion dystonia.

Deep brain stimulation (DBS) at the globus pallidus pars internus (GPi) is an effective treatment for some patients with medically refractory torsion dystonia. In this chapter we review the classification and treatment of torsion dystonia including the current indications for DBS surgery. Details of the DBS procedure and programming of the DBS devices are discussed. Pallidal DBS is most effective in patients with primary generalized dystonia. Children and adolescents possessing the DYT1 gene mutation may respond best of all. Patients with cervical dystonia may also improve with pallidal DBS but definitive clinical evidence is lacking. As a group, patients with secondary dystonias respond less well to DBS than do patients with primary dystonia; however, patients with dystonia secondary to anoxic brain injury who have grossly intact basal ganglia anatomy, and patients with tardive dystonia may represent secondary dystonia subtypes for whom pallidal DBS is a viable option.

First case of X-linked dystonia-parkinsonism ("Lubag") to demonstrate a response to bilateral pallidal stimulation.

"Lubag" or X-linked dystonia-parkinsonism (XDP) is a genetic syndrome afflicting Filipino men. Intracranial surgical procedures for Lubag have been unsuccessful. We report a 45-year-old Filipino male with genetically confirmed XDP who underwent bilateral pallidal deep brain stimulation (DBS) surgery. The patient started to exhibit improvement on initial programming, most notably of his severe jaw-opening dystonia. At 1-year follow-up, his Burke-Fahn-Marsden dystonia score and motor Unified Parkinson's Disease Rating Scale score were improved by 71% and 62%, respectively, with the stimulators on compared to stimulators off state. Bilateral pallidal DBS may be a viable option for Lubag patients with medically refractory symptoms.

Lower stimulation frequency can enhance tolerability and efficacy of pallidal deep brain stimulation for dystonia.

We report the case of a patient with medically refractory primary dystonia who was treated with bilateral pallidal deep brain stimulation. Stimulation at 130 Hz or higher, by means of the more ventral contacts generated capsular side effects, which made their use impractical. Consequently, the patient was treated for 9 months at 130 to 185 Hz, by means of the more dorsal contacts, achieving modest results. By reducing the stimulation frequency to 80 Hz, we were able to activate the ventral contacts without inducing side effects. Within days, the patient experienced a dramatic improvement in function that has persisted for 1 year. A further reduction in stimulation frequency to 60 Hz resulted in a worsening of his symptoms. We conclude that chronic stimulation at frequencies of <100 Hz may be efficacious in dystonia and may enhance the tolerability of stimulation by means of contacts that are positioned posteroventrally within the internal globus pallidus, nearer the internal capsule.

Mood improvement after deep brain stimulation of the internal globus pallidus for tardive dyskinesia in a patient suffering from major depression.

Deep brain stimulation (DBS) has the unique characteristic to very precisely target brain structures being part of functional brain circuits in order to reversibly modulate their function. It is an established adjunctive treatment of advanced Parkinson's disease and has virtually replaced ablative techniques in this indication. Several cases have been published relating effectiveness in neuroleptics-induced tardive dyskinesia. It is also investigated as a potential treatment of mood disorders. We report on the case of a 62 years old female suffering from a treatment refractory major depressive episode with comorbid neuroleptic-induced tardive dyskinesia. She was implanted a deep brain stimulation treatment system bilaterally in the globus pallidus internus and stimulated for 18 months. As well the dyskinesia as also the symptoms of depression improved substantially as measured by the Hamilton Rating Scale of Depression (HRSD) score and the Burke-Fahn-Marsden-Dystonia-Rating-Scale (BFMDRS) score. Scores dropped for HRSD from 26 at baseline preoperatively to 13 after 18 months; and for BFMDRS from 27 to 17.5. This case illustrates the potential of deep brain stimulation as a technique to be investigated in the treatment of severe and disabling psychiatric and movement disorders. DBS at different intracerebral targets being actually investigated for major depression might have similar antidepressant properties because they interact with the same cortico-basal ganglia-thalamocortical network found to be dysfunctional in major depression.

Effects of GPi stimulation on human thalamic neuronal activity.

OBJECTIVE: Determine the effects of globus pallidus interna (GPi) deep brain stimulation (DBS) on ventral oralis posterior nucleus of the thalamic (Vop) neuronal activity. METHODS: Microelectrode recordings in Vop during high frequency DBS GPi in a patient with dystonia. RESULTS: Twelve (48%) of 25 neurons in five locations neurons decreased their average discharge frequency, 2 (8%) increased and 11(44%) demonstrated no overall change. The patterns of responses were complex with periods of increase and decreased activity. All neurons were inhibited for the time period 3.5-5ms following the DBS pulse. Eighty-eight percent of neurons showed brief but highly consistent increases in the first 1ms following stimulation, 52% showed increased activities from 1.5 to 3ms. Twenty-four percent of neurons increased activity following inhibition. CONCLUSIONS: These findings are consistent with DBS activation of GPi axons to Vop and probable antidromic activation of Vop axons. SIGNIFICANCE: The physiological effects of DBS are far more complicated and will escape any theory that does not address the mechanisms of DBS as stimulation of a complex network of interactions. Further, the findings of post-inhibitory rebound increased raises questions about the role in inhibition in the current concepts of basal ganglia physiology.

A dominant bursting electromyograph pattern in dystonic conditions predicts an early response to pallidal stimulation.

Although chronic pallidal deep brain stimulation (DBS) is effective in the treatment of medically intractable dystonia, there is no way of predicting the variations in clinical outcome, partly due to our limited understanding of the pathophysiological mechanisms underlying this condition. We recorded electromyographic (EMG) activity from the most severely affected muscle groups in seven dystonia patients before and after pallidal DBS. Patient EMG recordings could be classified into two groups: one consisting of patients who at rest demonstrated a dominant low frequency component of activity on power spectral analysis (ranging from 2 to 5 Hz), and one group in which this dominant pattern was absent. Early postoperative improvements (within 2-3 days) were observed in the former group, whereas the latter group benefited more gradually (over several months). Analysis of EMG activity may provide a sensitive means of identifying dystonic patients who are likely to be most responsive to functional neurosurgical intervention.