High Frequency Deep Brain Stimulation Research Articles

Model-Based Evaluation of Closed-Loop Deep Brain Stimulation Controller to Adapt to Dynamic Changes in Reference Signal.

High-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) is effective in suppressing the motor symptoms of Parkinson's disease (PD). Current clinically-deployed DBS technology operates in an open-loop fashion, i.e., fixed parameter high-frequency stimulation is delivered continuously, invariant to the needs or status of the patient. This poses two major challenges: (1) depletion of the stimulator battery due to the energy demands of continuous high-frequency stimulation, (2) high-frequency stimulation-induced side-effects. Closed-loop deep brain stimulation (CL DBS) may be effective in suppressing parkinsonian symptoms with stimulation parameters that require less energy and evoke fewer side effects than open loop DBS. However, the design of CL DBS comes with several challenges including the selection of an appropriate biomarker reflecting the symptoms of PD, setting a suitable reference signal, and implementing a controller to adapt to dynamic changes in the reference signal. Dynamic changes in beta oscillatory activity occur during the course of voluntary movement, and thus there may be a performance advantage to tracking such dynamic activity. We addressed these challenges by studying the performance of a closed-loop controller using a biophysically-based network model of the basal ganglia. The model-based evaluation consisted of two parts: (1) we implemented a Proportional-Integral (PI) controller to compute optimal DBS frequencies based on the magnitude of a dynamic reference signal, the oscillatory power in the beta band (13–35 Hz) recorded from model globus pallidus internus (GPi) neurons. (2) We coupled a linear auto-regressive model based mapping function with the Routh-Hurwitz stability analysis method to compute the parameters of the PI controller to track dynamic changes in the reference signal. The simulation results demonstrated successful tracking of both constant and dynamic beta oscillatory activity by the PI controller, and the PI controller followed dynamic changes in the reference signal, something that cannot be accomplished by constant open-loop DBS.

Deep Brain Stimulation in Sub-Thalamic Nucleus in idiopathic Parkinson’s disease – our initial experience in four cases

Parkinson’s Disease ( PD ) is a chronic neurodegenerative disease . It’s cardinal features are resting tremor, Rigidity, Akinesia and postural instability. Idiopathic Parkinson’s disease develops mainly due to degeneration of Dopaminergic neurons of Substantia Nigra. The role of Subthalamic Nucleus ( STN ) in the development of Parkinsonian Tremmor and other cardinal features is not completely understood yet. However previous studies in monkeys , administration of MPTP ( 1-methyl-4-phenyl- 1.2.3.6.-tetrahydropyridine ) proved that sub thalamic nucleus has a direct role in the development of Parkinsonian tremor and other features. We used no Micro Electrode Recording (MER) system,only studied clinically that Parkinsonian tremor stopped immediately after placement of electrode and same thing happened after micro stimulation of the sensorymotor region of the sub thalamic nucleus .Then high frequency deep brain stimulation ( DBS ) of these same four patients were assessed six months after surgery which led to a significant reduction of Parkinsonian tremor as well as other cardinal features of PD ( p< 0.001 ) . Both postural and resting tremor disappeared completely in three cases and significantly reduced in one case
 Bang. J Neurosurgery 2019; 9(1): 78-83

Electrophysiological and imaging evidence of sustained inhibition in limbic and frontal networks following deep brain stimulation for treatment refractory obsessive compulsive disorder.

Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder that arises from a complex interaction of environmental and genetic factors. Despite numerous pharmacological and behavioral interventions, approximately 10% of patients remain refractory. High-frequency deep brain stimulation (HF-DBS) has shown promising results for treatment-refractory OCD. We report the follow-up result of up to 6 years of 4 treatment-refractory OCD patients treated by HF-DBS. Targets of stimulation were the anterior limb of the internal capsule (ALIC) in two cases, and the nucleus accumbens (NAc) in the remaining cohort. The clinical profiles were quantified by the Yale-Brown obsessive-compulsive scale (Y-BOCS). Highly significant reductions in Y-BOCS scores were obtained from all patients during the follow-up period. A greater that 90% reduction in Y-BOCS, observed in the most successful case, was achieved with NAc HF-DBS. Y-BOCS scores in the other patients consistently achieved over 50% reductions in OCD symptoms. FDG-PET imaging indicated post-surgical reductions in metabolism, in not only targeted limbic networks, but also other frontal cortical and subcortical regions, suggesting that large-scale network modulation and inhibitions are associated with functional recovery in OCD. This study demonstrates that HF-DBS targeted to the ALIC and NAc is a safe and effective method for ameliorating intractable, treatment-refractory OCD symptoms. The NAc appeared to be the superior target for symptom reduction, and local inhibition of NAc activity and reduced frontal metabolism are key therapeutic indications.

Acute 5 Hz deep brain stimulation of the lateral habenula is associated with depressive-like behavior in male wild-type Wistar rats

BackgroundChronic high frequency Deep Brain Stimulation (DBS) of the Lateral Habenula (LHb) has been applied in clinical case studies to treat patients with treatment resistant depression. LHb neurons in models of depression were found to have a preferred firing frequency in the theta band. The aim of this study was to determine differential behavioral effects of acute high- and theta band-frequency DBS and whether bilateral DBS electrode insertion may be associated with a lesional effect. MethodsAdult male Wistar rats were implanted with bilateral LHb DBS electrodes and randomly assigned to 100 Hz, 5 Hz or sham stimulation (n = 8 per group). Rats were tested against a control group (n = 8) in a battery of behavioral paradigms. ResultsNo differences between groups were found with regards to locomotor activity in the open field test or anhedonia-like behavior in the novelty suppressed feeding paradigm. 100 Hz stimulation was associated with increased exploratory behavior in the elevated plus maze. In the forced swim test, 5 Hz stimulation was associated with significantly decreased latency to and increased duration of immobility, whereas 100 Hz stimulation significantly increased latency to immobility. No significant behavioral differences between sham stimulation and control group animals were detected. ConclusionAcute theta band frequency DBS in the LHb is associated with depressive-like behavior in wild-type male Wistar rats. This was likely not mediated by a general decrease in locomotor activity or a lesional effect after electrode implantation.

Effect of Microelectrode Recording in Accurate Targeting STN with High Frequency DBS in Parkinson Disease

Parkinson's disease (PD) is a brain disorder with distinct molecular, functional and structural features, causing tremors in elderly-matured-people, which is, differentiated by the convolution of cardinal motoric-symptoms: tremor, Bradykinesia/akinesia rigidity and postural-instability. Though clinical-diagnosis and benefits of deep-brain-stimulation (DBS) in subthalamic-nuclei (STN) have been established, albeit, how its mechanisms augment motoric-symptoms not been fully elucidated. We present a principal component (PC) based tracking method to quantify the efficacy-of-DBS predict UPDRS score objectively. Twelve PD patients were included in this study. Our hypothesis is that whether DBS and innocuous-microelectrodes save STN-neurons and restores-motor-function. In our long study, high-frequency stimulation in PD brain did not dent STN-neurons. Further, it is risk-free to stimulate-STN much prior than it was accepted far so. Intraoperative microelectrode-recording (iMER) for targeting during DBS procedures has been evaluated in 46 successive-patients with advanced idiopathic PD, who received DBS. We extrapolated MER-signals of STN-features with PCs for computing the effects of DBS in PD. The signal-parameters were transformed into a lower dimensional-feature space. In our computation, we obtained 75% variation. We find that MER gives proof of correct-positioning of microelectrode, ensures accurate-detection of STN confines and establishes its exact coordinates in a more objective way. MER boosts safety, accuracy and efficacy of DBS-electrode implementation. Thus, MER confirms the presence of abnormal-STN-neurons. Certainly tranquil MER can confirm clear position-of-electrodes and strengthen the confidence of the neurosurgeons that they are in the right-target. Availability-of-MER results in a vast data vis-á-vis functioning on neurons positioned deep in the brain may further help in untying arcane-of-brain.

Severe seizures as a side effect of deep brain stimulation in the dorsal peduncular cortex in a rat model of depression

Deep brain stimulation (DBS) has shown to have antidepressant effects in both human trials and animal studies. However, the optimal target and the underlying therapeutic mechanisms remain to be determined. In this study, we investigated if high frequency (HF) DBS in the dorsal peduncular cortex (DPC) alleviates depressive-like behavior in an experimental model of depression. Surprisingly, HF DBS in the DPC caused acute induction of seizures in ~40% of animals stimulated with clinically relevant stimulation parameters. Reducing the stimulation's amplitude by 50% did not alter seizure occurrence. Electroencephalographic (EEG) recordings showed seizures up to Racine stage IV lasting up to 4 min after cessation of stimulation. We conclude that HF DBS in the DPC is not suitable for mood-related experiments in rats but could be a potential model for seizure induction.

Mathematical Modeling for Description of Oscillation Suppression Induced by Deep Brain Stimulation.

A mathematical modeling for description of oscillation suppression by deep brain stimulation (DBS) is explored in this paper. High-frequency DBS introduced to the basal ganglia network can suppress pathological neural oscillations that occur in the Parkinsonian state. However, selecting appropriate stimulation parameters remains a challenging issue due to the limited understanding of the underlying mechanisms of the Parkinsonian state and its control. In this paper, we use a describing function analysis to provide an intuitive way to select the optimal stimulation parameters based on a biologically plausible computational model of the Parkinsonian neural network. By the stability analysis using the describing function method, effective DBS parameter regions for inhibiting the pathological oscillations can be predicted. Additionally, it is also found that a novel sinusoidal-shaped DBS may become an alternative stimulation pattern and expends less energy, but with a different mechanism. This paper provides new insight into the possible mechanisms underlying DBS and a prediction of optimal DBS parameter settings, and even suggests how to select novel DBS wave patterns for the treatment of movement disorders, such as Parkinson's disease.

Noise-Induced Improvement of the Parkinsonian State: A Computational Study.

The benefit of noise in improving the basal ganglia (BG) dysfunctions, especially Parkinsonian state, is explored in this paper. High frequency (≥ 100 Hz) deep brain stimulation (DBS), as a clinical effective stimulation method, has compelling and fantastic results in alleviating the motor symptoms of Parkinson's disease (PD). However, the mechanism of DBS is still unclear. And the selection of the DBS waveform parameters faces great challenges to further optimize the stimulation effects and to reduce its energy expenditure. Considering that the desynchronization of the BG neuronal activities is benefited from the forced high frequency regular spikes driven by standard high frequency DBS, we expect to explore a novel stimulation method that has capability of restoring the BG physiological firing patterns without introducing artificial high-frequency fires. In this paper, a colored noise stimulation is used as a neuromodulation method to disrupt the firing patterns of the pathological neuronal activities. A computational model of the BG that exhibits the intrinsic properties of the BG neurons and their interactions with the thalamic (Th) cells is employed. Based on the model, we investigate the effects of noise stimulation and explore the impacts of the noise stimulation parameters on both relay reliability of the Th neurons and energy expenditure of the stimulation. By comparison, it can be found that noise stimulation does not entrain the network to an artificial high-frequency firing state, but induces the pathological increased synchronous activities back to a normal physiological level. Moreover, besides the capability of restoring the neuronal state, the benefits of the noise also include its balanced waveform to avert potential tissue or electrode damage and its ability to reduce the energy expenditure to 50% less than that of the standard DBS, when the noise stimulation has low frequency (≤ 100 Hz) and appropriate intensity. Thus, the exploration of the optimal noise-induced improvement of the BG dysfunction is of great significance in treating symptoms of neurological disorders such as PD.

Pallidal Stimulation Modulates Pedunculopontine Nuclei in Parkinson's Disease.

Background: In advanced Parkinson’s disease, the pedunculopontine nucleus region is thought to be abnormally inhibited by gamma-aminobutyric acid (GABA) ergic inputs from the over-active globus pallidus internus. Recent attempts to boost pedunculopontine nucleus function through deep brain stimulation are promising, but suffer from the incomplete understanding of the physiology of the pedunculopontine nucleus region. Methods: Local field potentials of the pedunculopontine nucleus region and the globus pallidus internus were recorded and quantitatively analyzed in a patient with Parkinson’s disease. In particular, we compared the local field potentials from the pedunculopontine nucleus region at rest and during deep brain stimulation of the globus pallidus internus. Results: At rest, the spectrum of local field potentials in the globus pallidus internus was mainly characterized by delta-theta and beta frequency activity whereas the spectrum of the pedunculopontine nucleus region was dominated by activity only in the delta and theta band. High-frequency deep brain stimulation of the globus pallidus internus led to increased theta activity in the pedunculopontine nucleus region and enabled information exchange between the left and right pedunculopontine nuclei. Therefore, Conclusions: When applying deep brain stimulation in the globus pallidus internus, its modulatory effect on pedunculopontine nucleus physiology should be taken into account.

Initial Unilateral Exposure to Deep Brain Stimulation in Treatment-Resistant Depression Patients Alters Spectral Power in the Subcallosal Cingulate.

Background: High-frequency Deep Brain Stimulation (DBS) of the subcallosal cingulate (SCC) region is an emerging strategy for treatment-resistant depression (TRD). This study examined changes in SCC local field potentials (LFPs). The LFPs were recorded from the DBS leads following transient, unilateral stimulation at the neuroimaging-defined optimal electrode contact. The goal was identifying a putative electrophysiological measure of target engagement during implantation.Methods: Fourteen consecutive patients underwent bilateral SCC DBS lead implantation. LFP recordings were collected from all electrodes during randomized testing of stimulation on each DBS contact (eight total). Analyses evaluated changes in spectral power before and after 3 min of unilateral stimulation at the contacts that later facilitated antidepressant response, as a potential biomarker of optimal contact selection in each hemisphere.Results: Lateralized and asymmetric power spectral density changes were detected in the SCC with acute unilateral SCC stimulation at those contacts subsequently selected for chronic, therapeutic stimulation. Left stimulation induced broadband ipsilateral decreases in theta, alpha, beta and gamma bands. Right stimulation effects were restricted to ipsilateral beta and gamma decreases. These asymmetric effects contrasted with identical white matter stimulation maps used in each hemisphere. More variable ipsilateral decreases were seen with stimulation at the adjacent “suboptimal” contacts, but changes were not statistically different from the “optimal” contact in either hemisphere despite obvious differences in impacted white matter bundles. Change in theta power was, however, most robust and specific with left-sided optimal stimulation, which suggested a putative functional biomarker on the left with no such specificity inferred on the right.Conclusion: Hemisphere-specific oscillatory changes can be detected from the DBS lead with acute intraoperative testing at contacts that later engender antidepressant effects. Our approach defined potential target engagement signals for further investigation, particularly left-sided theta decreases following initial exposure to stimulation. More refined models combining tractography, bilateral SCC LFP, and cortical recordings may further improve the precision and specificity of these putative biomarkers. It may also optimize and standardize the lead implantation procedure and provide input signals for next generation closed-loop therapy and/or monitoring technologies for TRD.

An Invasive Method for the Activation of the Mouse Dentate Gyrus by High-frequency Stimulation.

Electrical high-frequency stimulation (HFS), using implanted electrodes targeting various brain regions, has been proven as an effective treatment for various neurological and psychiatric disorders. HFS in the deep region of the brain, also named deep-brain stimulation (DBS), is becoming increasingly important in clinical trials. Recent progress in the field of high-frequency DBS (HF-DBS) surgery has begun to spread the possibility of utilizing this invasive technique to other situations, such as treatment for major depression disorder (MDD), obsessive-compulsive disorder (OCD), and so on. Despite these expanding indications, the underlying mechanisms of the beneficial effects of HF-DBS remain enigmatic. To address this question, one approach is to use implanted electrodes that sparsely activate distributed subpopulations of neurons by HFS. It has been reported that HFS in the anterior nucleus of the thalamus could be used for the treatment of refractory epilepsy in the clinic. The underlying mechanisms might be related to the increased neurogenesis and altered neuronal activity. Therefore, we are interested in exploring the physiological alterations by the detection of neuronal activity as well as neurogenesis in the mouse dentate gyrus (DG) before and after HFS treatment. In this manuscript, we describe methodologies for HFS to target the activation of the DG in mice, directly or indirectly and in an acute or chronic manner. In addition, we describe a detailed protocol for the preparation of brain slices for c-fos and Notch1 immunofluorescent staining to monitor the neuronal activity and signaling activation and for bromodeoxyuridine (BrdU) labeling to determine the neurogenesis after the HF-DBS induction. The activation of the neuronal activity and neurogenesis after the HF-DBS treatment provides direct neurobiological evidence and potential therapeutic benefits. Particularly, this methodology can be modified and applied to target other interested brain regions such as the basal ganglia and subthalamic regions for specific brain disorders in the clinic.

S2-1. Pathophysiology of involuntary movement based on DBS surgery

A model that explains the pathophysiological condition of involuntary movements as the degree of output levels of the basal ganglia has been proposed. Because high frequency deep brain stimulation (DBS) has an effect similar to ablation, an initial hypothesis regarding the mechanism of DBS was the inhibition of excessive activity at the target site. A recent theory states that an abnormal neural activity pattern such as oscillation in the basal ganglia disrupts motor control. Local field potential recordings for Parkinson disease (PD) have shown increased beta-band oscillations associated with motor symptoms of PD. High-frequency stimulation of the subthalamic nucleus suppresses beta-band oscillations. Meanwhile, at the target site, high-frequency DBS has inhibitory effects on the soma and excitation effects on the axon, thereby influencing the target site and the neural activity of the projection site. DBS possibly acts by modifying or obstructing an abnormal nerve activity pattern in the neural network by combining different effects on the soma and axons, rather than by just suppressing the target site.

Prelimbic Cortex Deep Brain Stimulation Reduces Binge Size in a Chronic Binge Eating Rat Model

Background: Binge eating (BE) involves the consumption of a large amount of food in a short period of time and a loss of control during the binge episode. It is a key feature of the major subtypes of eating disorders like bulimia nervosa, BE disorder, anorexia nervosa binge/purge type. Alterations in the mesocorticolimbic pathway play a crucial role in its pathophysiology. Objectives: We hypothesized that BE rats receiving deep brain stimulation (DBS) in the prelimbic cortex, a functional analog of the dorsolateral prefrontal cortex in humans, would have a reduced binge size compared with those receiving sham stimulation. Methods: Eight male Sprague-Dawley rats were implanted with a DBS electrode in the left prelimbic cortex. A protocol which included limited access to a “sweet-fat” diet was used to achieve a chronic BE state in the rats. After reaching a stable binge size, each rat had undergone sham, low-frequency stimulation (60 Hz), and high-frequency (130 Hz) stimulation for 3 sessions each, and 2 consecutive treatments were separated by at least 2 empty sessions to allow a washout of the effects. A one-way ANOVA was used for the data analysis. Results: Low-frequency (60 Hz) stimulation of the prelimbic cortex significantly reduced the binge size compared to the sham stimulation (p < 0.0001). High-frequency DBS (130 Hz) had no significant influence on this behavior when compared to sham stimulation (p = 0.9). Conclusions: This study suggests that low-frequency prelimbic cortex stimulation in BE would be useful for correcting prefrontal hypofunction which is strongly associated with BE and addiction pathogenesis.

Closed-loop deep brain stimulation by pulsatile delayed feedback with increased gap between pulse phases

Computationally it was shown that desynchronizing delayed feedback stimulation methods are effective closed-loop techniques for the control of synchronization in ensembles of interacting oscillators. We here computationally design stimulation signals for electrical stimulation of neuronal tissue that preserve the desynchronizing delayed feedback characteristics and comply with mandatory charge deposit-related safety requirements. For this, the amplitude of the high-frequency (HF) train of biphasic charge-balanced pulses used by the standard HF deep brain stimulation (DBS) is modulated by the smooth feedback signals. In this way we combine the desynchronizing delayed feedback approach with the HF DBS technique. We show that such a pulsatile delayed feedback stimulation can effectively and robustly desynchronize a network of model neurons comprising subthalamic nucleus and globus pallidus external and suggest this approach for desynchronizing closed-loop DBS. Intriguingly, an interphase gap introduced between the recharging phases of the charge-balanced biphasic pulses can significantly improve the stimulation-induced desynchronization and reduce the amount of the administered stimulation. In view of the recent experimental and clinical studies indicating a superiority of the closed-loop DBS to open-loop HF DBS, our results may contribute to a further development of effective stimulation methods for the treatment of neurological disorders characterized by abnormal neuronal synchronization.

Pulsatile desynchronizing delayed feedback for closed-loop deep brain stimulation.

High-frequency (HF) deep brain stimulation (DBS) is the gold standard for the treatment of medically refractory movement disorders like Parkinson’s disease, essential tremor, and dystonia, with a significant potential for application to other neurological diseases. The standard setup of HF DBS utilizes an open-loop stimulation protocol, where a permanent HF electrical pulse train is administered to the brain target areas irrespectively of the ongoing neuronal dynamics. Recent experimental and clinical studies demonstrate that a closed-loop, adaptive DBS might be superior to the open-loop setup. We here combine the notion of the adaptive high-frequency stimulation approach, that aims at delivering stimulation adapted to the extent of appropriately detected biomarkers, with specifically desynchronizing stimulation protocols. To this end, we extend the delayed feedback stimulation methods, which are intrinsically closed-loop techniques and specifically designed to desynchronize abnormal neuronal synchronization, to pulsatile electrical brain stimulation. We show that permanent pulsatile high-frequency stimulation subjected to an amplitude modulation by linear or nonlinear delayed feedback methods can effectively and robustly desynchronize a STN-GPe network of model neurons and suggest this approach for desynchronizing closed-loop DBS.

Deep Brain Stimulation for Alzheimer's Disease.

High-frequency deep brain stimulation (DBS) was introduced in the late 1980s for the treatment of movement disorders. This reversible, adjustable, and non-ablative therapy has been used to treat more than 100,000 people worldwide. The surgical procedure used to implant the DBS system, as well as the effects of chronic electrical stimulation, have been shown to be safe and effective through many clinical trials. Given the ability to therapeutically modulate the motor circuits of the brain in this manner, clinicians have considered using DBS for other neurodegenerative and neuropsychiatric disorders involving non-motor circuits, including appetite, mood, and cognition. This article highlights several recent studies exploring the feasibility of using DBS to modulate memory, specifically in the context of memory disorders such as Alzheimer disease.

Frequency-dependent, transient effects of subthalamic nucleus deep brain stimulation on methamphetamine-induced circling and neuronal activity in the hemiparkinsonian rat

Methamphetamine-induced circling is used to quantify the behavioral effects of subthalamic nucleus (STN) deep brain stimulation (DBS) in hemiparkinsonian rats. We observed a frequency-dependent transient effect of DBS on circling, and quantified this effect to determine its neuronal basis. High frequency STN DBS (75–260Hz) resulted in transient circling contralateral to the lesion at the onset of stimulation, which was not sustained after the first several seconds of stimulation. Following the transient behavioral change, DBS resulted in a frequency-dependent steady-state reduction in pathological ipsilateral circling, but no change in overall movement. Recordings from single neurons in globus pallidus externa (GPe) and substantia nigra pars reticulata (SNr) revealed that high frequency, but not low frequency, STN DBS elicited transient changes in both firing rate and neuronal oscillatory power at the stimulation frequency in a subpopulation of GPe and SNr neurons. These transient changes were not sustained, and most neurons exhibited a different response during the steady-state phase of DBS. During the steady-state, DBS produced elevated neuronal oscillatory power at the stimulus frequency in a majority of GPe and SNr neurons, and the increase was more pronounced during high frequency DBS than during low frequency DBS. Changes in oscillatory power during both transient and steady-state DBS were highly correlated with changes in firing rates. These results suggest that distinct neural mechanisms were responsible for transient and sustained behavioral responses to STN DBS. The transient contralateral turning behavior following the onset of high frequency DBS was paralleled by transient changes in firing rate and oscillatory power in the GPe and SNr, while steady-state suppression of ipsilateral turning was paralleled by sustained increased synchronization of basal ganglia neurons to the stimulus pulses. Our analysis of distinct frequency-dependent transient and steady-state responses to DBS lays the foundation for future mechanistic studies of the immediate and persistent effects of DBS.

Subthalamic beta oscillations are attenuated after withdrawal of chronic high frequency neurostimulation in Parkinson's disease

Subthalamic nucleus (STN) local field potential (LFP) recordings demonstrate beta (13–30Hz) band oscillations in Parkinson's disease (PD) defined as elevations of spectral power. The amount of attenuation of beta band power on therapeutic levels of high frequency (HF) deep brain stimulation (DBS) and/or dopaminergic medication has been correlated with the degree of improvement in bradykinesia and rigidity from the therapy, which has led to the suggestion that elevated beta band power is a marker of PD motor disability. A fundamental question has not been answered: whether there is a prolonged attenuation of beta band power after withdrawal of chronic HF DBS and whether this is related to a lack of progression or even improvement in the underlying motor disability.Until now, in human PD subjects, STN LFP recordings were only attainable in the peri-operative period and after short periods of stimulation. For the first time, using an investigational, implanted sensing neurostimulator (Activa® PC+S, Medtronic, Inc.), STN LFPs and motor disability were recorded/assessed after withdrawal of chronic (6 and 12month) HF DBS in freely moving PD subjects. Beta band power was similar within 14s and 60min after stimulation was withdrawn, suggesting that “off therapy” experiments can be conducted almost immediately after stimulation is turned off. After withdrawal of 6 and 12months of STN DBS, beta band power was significantly lower (P<0.05 at 6 and 12months) and off therapy UPDRS scores were better (P<0.05 at 12months) compared to before DBS was started. The attenuation in beta band power was correlated with improvement in motor disability scores (P<0.05). These findings were supported by evidence of a gradual increase in beta band power in two unstimulated STNs after 24months and could not be explained by changes in lead impedance. This suggests that chronic HF DBS exerts long-term plasticity in the sensorimotor network, which may contribute to a lack of progression in underlying motor disability in PD.

Hyperhidrosis associated with subthalamic deep brain stimulation in Parkinson's disease: Insights into central autonomic functional anatomy

IntroductionThere is limited evidence regarding the precise location and connections of thermoregulatory centers in humans. We present two patients managed with subthalamic nucleus (STN) Deep Brain Stimulation (DBS) for motor fluctuations in PD that developed reproducible hyperhidrosis with high frequency DBS. ObjectiveTo describe the clinical features and analyze the location of the electrodes leading to autonomic activation in both patients. MethodsWe retrospectively assessed the anatomical localization, electrode programming settings and effects of unilateral STN DBS leading to hyperhidrosis. ResultsUnilateral stimulation of anterior and medially located contacts within the STN and zona incerta (Zi) caused bilateral, consistent, reproducible, and reversible sweating in our patients. Adequate control of motor symptoms without autonomic side effects was accomplished with alternative programming settings. ConclusionStimulation of the medial Zi and medial and anterior STN causes hyperhidrosis in a pattern similar to that described in primates and rats. We speculate that central autonomic fibers originating in the lateral hypothalamic area project laterally to the ventral/medial Zi and then to brainstem nuclei following an medial and posterior trajectory in relationship to STN.

Behavioural effects of basal ganglia rho-kinase inhibition in the unilateral 6-hydroxydopamine rat model of Parkinson's disease.

Parkinson's disease (PD) is one of the most common neurodegenerative disorders, which affects more than six million people in the world. While current available pharmacological therapies for PD in the early stages of the disease usually improve motor symptoms, they cause side effects, such as fluctuations and dyskinesias in the later stages. In this later stage, high frequency deep brain stimulation of the subthalamic nucleus (STN-DBS) is a treatment option which is most successful to treat drug resistant advanced PD. It has previously been demonstrated that activation of Rho/Rho-kinase pathway is involved in the dopaminergic cell degeneration which is one of the main characteristics of PD pathology. In addition, the involvement of this pathway has been suggested in diverse cellular events in the central nervous system; such as epilepsy, anxiety-related behaviors, regulation of dendritic and axonal morphology, antinociception, subarachnoid haemorrhage, spinal cord injury and amyotrophic lateral sclerosis. However, up to date, to our knowledge there are no previous reports showing the beneficial effects of the potent Rho-kinase inhibitor Y-27632 in the 6-hydroxydopamine (6-OHDA) rat model of PD. Therefore, in the present study, we investigated the behavioural effects of basal ganglia Y-27632 microinjections in this PD model. Our results indicated that basal ganglia Y-27632 microinjections significantly decreased the number of contralateral rotations-induced by apomorphine, significantly increased line crossings in the open-field test, contralateral forelimb use in the limb-use asymmetry test and contralateral tape playing time in the somatosensory asymmetry test, which may suggest that Y-27632 could be a potentially active antiparkinsonian agent.