Frequency Deep Brain Stimulation Research Articles

Effects of high frequency stimulation of nucleus accumbens shell subregion on food intake in obesity rats and regulation of appetite-related hormones

Objective To explore the effects of chronic high frequency deep brain stimulation (DBS) of nucleus accumbens shell subregion on food intake and regulation of appetite-related hormones. Methods High-fat diet induced obesity rats were randomly divided into two groups, namely DBS group and sham-DBS group.Stimulating electrodes were implanted in the bilateral shell subregion of nucleus accumbens. The amount of food intake was measured before and during stimulation.Peripheral concentrations of ghrelin, NPY, and leptin were tested before and after DBS or sham-DBS. Results The amount of food intake began to significantly decrease once stimulation was on. After 7 days'continuous stimulation, peripheral concentrations of NPY and leptin decreased significantly (Leptin: pre-DBS: 32±10 vs.post-DBS: 20±10pg/ml, P<0.05; NPY: pre-DBS: 1 302±287 vs. post-DBS: 926±299 pg/ml, P<0.05), and ghrelin increased significantly (Pre-DBS: 1066±310 vs. Post-DBS: 1603±848 pg/ml, P<0.05). Conclusions NAc shell subregion is an effective DBS target to decrease food intake in obesity rats. NAc-shell DBS seems to temporarily inhibit the hypothalamic secretion of NPY. Increase of ghrelin levels maybe a second result of decreased food intake caused by NAc-shell stimulation. Key words: Deep brain stimulation; Nucleus accumbens; Obesity; Ghrelin; Leptin; Neuropeptide Y; Rats

Combined auditory and visual cueing provided by eyeglasses influence gait performance in Parkinson Disease patients submitted to deep brain stimulation: a pilot study

Background: Auditory-visual cueing using portable cueing devices has been effective for gait training in rehabilitation programs with Parkinson patients. However, it is possible that some gait problems arise due to interference from chronic high frequency stimulation with the gait and balance neural networks in patients with Parkinson Disease. Thus, it should be useful to test whether advanced Parkinson Disease patients experiencing gait problems (despite the treatment with medication and high frequency deep brain stimulation) would benefit from therapy using cueing. Methods: Eyeglasses combining auditory-visual cueing were used with 18 patients with advanced Parkinson Disease and treated with medication and deep brain stimulation. Patients were assessed using the Dynamic Gait Index, Timed Up and Go and Six-Minute Walking Test and performance was measured with and without the cueing (with and without eyeglasses on). Results: One way ANOVA on the performance measures indicated that Dynamic Gait Index and Six-Minute Walking Test significantly improved in the cued condition. Since cueing was task specific, and Timed Up and Go includes subtasks such sitting and standing, the combined auditory-visual cueing did not improve performance on such tasks. Conversely, the combined cueing may have worked as distractors during these subtasks. Conclusion: Combined auditory-visual cueing provided by this wearable technology may have practical applicability in rehabilitation therapy. It provided additional benefits on gait in patients with advanced Parkinson Disease with deep brain stimulation in the subthalamic nucleus.

Therapeutic Significance of Frequency of Deep Brain Stimulation in Intractable Epilepsy

In addition to the exact placement of electrodes in the target site, the successful outcome of DBS depends largely upon correct choice of its stimulation parameters (especially voltage, frequency, pulsewidth and mode of stimulation) and optimal stimulation parameters (SPs) are those that reduce seizures optimally with minimum side effects and minimum consumption of the device-battery. The DBS in the patients with IE is commonly delivered at initial SP settings of 5-6 voltage in the frequency range of 130-180 Hz and pulse width varying from 60-90 microseconds by a monopolar intermittent mode of stimulation (1-min ON and 5-min OFF). The frequency of stimulation (FOS) selected is invariably in the high range for reasons outlined below. In the authors’ opinion, the FOS is of utmost importance in the determination of success and efficacy of the DBS as changes in FOS can potentially exercise maximum impact on the seizure profile (frequency, duration, severity of seizures and interictal epileptiform discharge rates) of the patients. It is generally agreed that analogous to vagal nerve stimulation (VNS), DBS is also effective at highfrequency stimulation (HFS) in reducing seizures [1-3], whereas low-frequency stimulation (LFS) is generally ineffective and can even exacerbate existing seizures [2]. The main objectives of selection of SPs for a successful DBS that have been postulated earlier also [4] are induction of EEGdesynchronization with reduction (or even possibly abolishment) of interictal epileptiform discharges (IEDs). This is in keeping with the generally accepted electrophysiological concept that EEGdesynchronization is associated with seizure resistance and reduction in the occurrence of IEDs and seizures. It has been suggested that LFS induces EEG synchronization, whereas HFS is associated with desynchronization, which might have a therapeutic effect in epilepsy as it has been found to be effective in both animal models and patients with epilepsy [5,6]; LFS is assumed to have anti-epileptic properties but the efficacy is highly debated [5,6] and from their study [5], the researchers have concluded that HFS at 130Hz is more effective than LFS (5Hz) in affecting excitability in epileptic rats. In 2007, a study by Boex et al. [3] also identified that HFS, but not LFS, was associated with a reduction of the interictal discharges and seizures. In Parkinson’s disease also, another neurological disorder characterized by abnormal neuronal synchrony, the usual FOS of the subthalamic nucleus is in the range of 130-180 Hz [7] and in one study [8], FOS at 90 Hz or more yielded the best results, whereas, FOS at 10 Hz or even 50 Hz failed to yield the required clinical effect. From a previous study also [9], the researchers have suggested that the effects of hippocampal DBS depend upon the frequency and topography of stimulation and a patterned stimulation with LFS and HFS resulted in desynchronization and exhibited anti-kindling effects in animal models of epilepsy. Thus, in view of the above electrophysiological findings, we suggest that the FOS in DBS plays a crucial role in determining the clinical outcome of DBS therapy in IE and the selection of optimal FOS may be based on its ability to induce EEG-desynchronization that can be assessed with a simultaneous EEG monitoring. This is especially in view of the observations that the optimal FOS may vary from patient to patient and therefore require individual settings. Admittedly, larger well-designed prospective studies are recommended that may in the course of time validate the therapeutic significance of the FOS and the utility of EEG monitoring in determining the optimal FOS.

Deep Brain Stimulation Frequency Modulation in Parkinson's Disease - One Size May Not Fit All

Deep Brain Stimulation (DBS) is an effective therapeutic modality for patients with Parkinson’s Disease who have developed complications from longstanding levodopa such as dyskinesias and motor fluctuations. It produces robust responses to segmental symptoms (ie, bradykinesia, tremor, rigidity) while attenuating involuntary dyskinetic movements and smoothing out ‘on’ and ‘off’ period cycling. The subthalamic nucleus and the globus pallidus interna are widely accepted surgical targets for stimulation therapy, with STN more commonly used, though superiority has not been established [1-4]. Long-term outcome studies reveal sustained stable responses to rigidity, tremor, motor fluctuations, and dyskinesias among patients with bilateral DBS, mostly STN based [3,5-7]. Bradykinesia improvement also persisted but trended upwards as time went on, though remaining below preoperative baseline. Axial symptoms such as gait, postural stability, freezing of gait, and speech oftentimes transiently responded to stimulation and continued to deteriorate over time. Despite many of the DBS outcome studies having been conducted in patients with short disease duration, Merola and colleagues [8] described the development of progressive axial symptoms in patients treated with STN-DBS with more than 20 years disease duration. These symptoms globally lose any levodopa responsiveness and the synergism of stimulation ON/medication ON condition wanes as well, underscoring the likely contribution of nondopaminergic systems in their phenotype.

2014 Lasker-DeBakey Clinical Medical Research Award.

2014 Lasker-DeBakey Clinical Medical Research Award.

Origins and suppression of oscillations in a computational model of Parkinson's disease.

Efficacy of deep brain stimulation (DBS) for motor signs of Parkinson's disease (PD) depends in part on post-operative programming of stimulus parameters. There is a need for a systematic approach to tuning parameters based on patient physiology. We used a physiologically realistic computational model of the basal ganglia network to investigate the emergence of a 34Hz oscillation in the PD state and its optimal suppression with DBS. Discrete time transfer functions were fit to post-stimulus time histograms (PSTHs) collected in open-loop, by simulating the pharmacological block of synaptic connections, to describe the behavior of the basal ganglia nuclei. These functions were then connected to create a mean-field model of the closed-loop system, which was analyzed to determine the origin of the emergent 34Hz pathological oscillation. This analysis determined that the oscillation could emerge from the coupling between the globus pallidus external (GPe) and subthalamic nucleus (STN). When coupled, the two resonate with each other in the PD state but not in the healthy state. By characterizing how this oscillation is affected by subthreshold DBS pulses, we hypothesize that it is possible to predict stimulus frequencies capable of suppressing this oscillation. To characterize the response to the stimulus, we developed a new method for estimating phase response curves (PRCs) from population data. Using the population PRC we were able to predict frequencies that enhance and suppress the 34Hz pathological oscillation. This provides a systematic approach to tuning DBS frequencies and could enable closed-loop tuning of stimulation parameters.

Maximizing relaxation time in oscillator networks with implications for neurostimulation.

High frequency deep brain stimulation (HF-DBS) is a pervasive clinical neurostimulation paradigm in which rapid (> 100Hz) pulses of electrical current are invasively delivered to the brain. Here, we use dynamical systems analysis to provide hypotheses regarding the frequency-specificity of the therapeutic effects of HF-DBS. Using phase oscillator-based models, we study the relaxation time of a synchronized network following impulsive stimulation. In particular, by approximating a standard DBS pulse by a finite-energy (Dirac) delta function, we show the existence of a minimum bound on the frequency of stimulation necessary to keep the network in a desynchronized regime. If, as evidence suggests, pathological synchronization is central to the pathology in DBS-responsive disorders, then the analysis gives conceptual insight into why lower frequency and/or randomized stimulation therapy is less effective, and provides a way to study alternative design strategies.

Deep brain stimulation of the prelimbic medial prefrontal cortex: quantification of the effect on glucose metabolism in the rat brain using [(18) F]FDG microPET.

Prefrontal cortex (PFC) deep brain stimulation (DBS) has been proposed as a therapy for addiction and depression. This study investigates changes in rat cerebral glucose metabolism induced by different DBS frequencies using μPET. One hour DBS of the prelimbic area (PL) of the medial PFC (mPFC) (60 Hz, 130 Hz or sham) in rats (n = 9) was followed by 2-deoxy-2-[(18) F] fluoro-D-glucose ([(18) F]FDG) μPET. Sixty Hz DBS elicited significant hypermetabolism in the ipsilateral PL ([(18) F]FDG uptake +5.2 ± 2.3 %, p < 0.05). At 130 Hz, hypometabolism was induced in the ipsilateral PL (-2.5 ± 2.6 %, non-significant). Statistical parametric mapping revealed hypo and hypermetabolism clusters for both 60 and 130 Hz versus sham and show a certain state of alertness (increased activity in sensory and motor-related regions) mainly for 60 Hz. This study suggests the potential of 60 Hz PL mPFC DBS for the treatment of disorders associated with prefrontal hypofunction.

Treatment of depression with deep brain stimulation works by altering in specific ways the conscious perception of the core symptoms of sadness or anhedonia, not by modulating network circuitry

An important advance in the management of treatment-resistant depression has recently been reported: deep brain stimulation (DBS) of the subgenual cingulate (Brodmann area 25 or Cg 25) or the nucleus accumbens (NAcc). These treatments produce a response rate, meaning significant clinical improvement, of about 50%, but only a few patients are returned completely to normal. The authors of these papers generally attribute the therapeutic response to restoration of an altered or perturbed neural network. In contrast, the idea advanced here is that DBS works by altering conscious perception of the core symptoms of sadness and anhedonia, not by modulating network circuitry. In the case of Cg25, the crucial thing about this site is that it is where conscious perception of sadness localizes. However, the stimulus frequency of DBS (130Hz) was too fast to support consciousness, which is associated with gamma frequencies (35–85Hz). Therefore, the imposed rapid frequency instantaneously blocked the subjective experience of sadness. In the case of the NAcc, the treatment worked by stimulating hot zones in the NAcc, which, in animal models, are known to intensify the perception of pleasure. This magnifier effect on the perception of pleasure was able to alleviate anhedonia. The response was not instantaneous but could begin within hours. In both cases, patients’ realization that a core symptom had been relieved led to a moderate overall improvement in other symptoms.

Effects of antidromic and orthodromic activation of STN afferent axons during DBS in Parkinson's disease: a simulation study

Recent studies suggest that subthalamic nucleus (STN)-Deep Brain Stimulation (DBS) may exert at least part of its therapeutic effect through the antidromic suppression of pathological oscillations in the cortex in 6-OHDA treated rats and in parkinsonian patients. STN-DBS may also activate STN neurons by initiating action potential propagation in the orthodromic direction, similarly resulting in suppression of pathological oscillations in the STN. While experimental studies have provided strong evidence in support of antidromic stimulation of cortical neurons, it is difficult to separate relative contributions of antidromic and orthodromic effects of STN-DBS. The aim of this computational study was to examine the effects of antidromic and orthodromic activation on neural firing patterns and beta-band (13-30 Hz) oscillations in the STN and cortex during DBS of STN afferent axons projecting from the cortex. High frequency antidromic stimulation alone effectively suppressed simulated beta activity in both the cortex and STN-globus pallidus externa (GPe) network. High frequency orthodromic stimulation similarly suppressed beta activity within the STN and GPe through the direct stimulation of STN neurons driven by DBS at the same frequency as the stimulus. The combined effect of both antidromic and orthodromic stimulation modulated cortical activity antidromically while simultaneously orthodromically driving STN neurons. While high frequency DBS reduced STN beta-band power, low frequency stimulation resulted in resonant effects, increasing beta-band activity, consistent with previous experimental observations. The simulation results indicate effective suppression of simulated oscillatory activity through both antidromic stimulation of cortical neurons and direct orthodromic stimulation of STN neurons. The results of the study agree with experimental recordings of STN and cortical neurons in rats and support the therapeutic potential of stimulation of cortical neurons.

Effects of deep brain stimulation frequency on bradykinesia of Parkinson's disease

Deep brain stimulation (DBS) in Parkinson's disease (PD) is frequency-dependent. Past studies of the effect of DBS frequency, however, involved scrutiny of too few frequencies to eliminate risk of undersampling. Also, these studies presented averaged measures across subjects; high intersubject variability makes these measures problematic. In this study, 6 subjects with PD were tested in a drug-minimal state. Following 10 minutes of stimulation at the new frequency, all available frequencies were tested. Hand-opening and hand-closing amplitude and frequency were measured in 3 epochs of 15 seconds each. Multiple frequencies (low and high) resulted in peaks of increased movement amplitudes. Peaks were specific and varied among individuals. No clear relationship between stimulation frequency and movement frequency was discovered. In light of the findings, a wider range of stimulation frequencies should be examined, particularly lower frequencies. Most current theories of PD pathophysiology and DBS mechanisms of action fail to explain results of the kind demonstrated herein.

The functional role of beta oscillations in Parkinson's disease

Modulations of beta oscillations (13-30 Hz) during normal motor control suggest that they may act to promote current motor set at the expense of new movements. These oscillations are greatly enhanced in Parkinson's disease (PD) and there is strong correlative evidence linking beta activity at rest and beta changes in response to treatment with bradykinesia and rigidity. Some evidence that this link may be mechanistically important or causal comes from studies in which either cortical or subcortical sites have been stimulated in the beta frequency range causing modest but significant slowing of movements. However, recent trials in which high frequency deep brain stimulation (DBS) has only been delivered during periods of elevated beta activity have demonstrated major clinical effects that even exceed those of standard continuous high frequency DBS. These studies suggest that beta activity may be both causally and quantitatively important in the motor impairment of PD, and demonstrate how improvements in the understanding of the pathophysiology of PD can lead to enhanced therapeutic interventions in this condition.

Phase dependent modulation of tremor amplitude in essential tremor through thalamic stimulation

High frequency deep brain stimulation of the thalamus can help ameliorate severe essential tremor. Here we explore how the efficacy, efficiency and selectivity of thalamic deep brain stimulation might be improved in this condition. We started from the hypothesis that the effects of electrical stimulation on essential tremor may be phase dependent, and that, in particular, there are tremor phases at which stimuli preferentially lead to a reduction in the amplitude of tremor. The latter could be exploited to improve deep brain stimulation, particularly if tremor suppression could be reinforced by cumulative effects. Accordingly, we stimulated 10 patients with essential tremor and thalamic electrodes, while recording tremor amplitude and phase. Stimulation near the postural tremor frequency entrained tremor. Tremor amplitude was also modulated depending on the phase at which stimulation pulses were delivered in the tremor cycle. Stimuli in one half of the tremor cycle reduced median tremor amplitude by ∼10%, while those in the opposite half of the tremor cycle increased tremor amplitude by a similar amount. At optimal phase alignment tremor suppression reached 27%. Moreover, tremor amplitude showed a non-linear increase in the degree of suppression with successive stimuli; tremor suppression was increased threefold if a stimulus was preceded by four stimuli with a similar phase relationship with respect to the tremor, suggesting cumulative, possibly plastic, effects. The present results pave the way for a stimulation system that tracks tremor phase to control when deep brain stimulation pulses are delivered to treat essential tremor. This would allow treatment effects to be maximized by focussing stimulation on the optimal phase for suppression and by ensuring that this is repeated over many cycles so as to harness cumulative effects. Such a system might potentially achieve tremor control with far less power demand and greater specificity than current high frequency stimulation approaches, and may lower the risk for tolerance and rebound.

Axonal and synaptic failure suppress the transfer of firing rate oscillations, synchrony and information during high frequency deep brain stimulation

High frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a widely used treatment for Parkinson's disease, but its effects on neural activity in basal ganglia circuits are not fully understood. DBS increases the excitation of STN efferents yet decouples STN spiking patterns from the spiking patterns of STN synaptic targets. We propose that this apparent paradox is resolved by recent studies showing an increased rate of axonal and synaptic failures in STN projections during DBS. To investigate this hypothesis, we combine in vitro and in vivo recordings to derive a computational model of axonal and synaptic failure during DBS. Our model shows that these failures induce a short term depression that suppresses the synaptic transfer of firing rate oscillations, synchrony and rate-coded information from STN to its synaptic targets. In particular, our computational model reproduces the widely reported suppression of parkinsonian β oscillations and synchrony during DBS. Our results support the idea that short term depression is a therapeutic mechanism of STN DBS that works as a functional lesion by decoupling the somatic spiking patterns of STN neurons from spiking activity in basal ganglia output nuclei.

More than meets the Eye—Myelinated axons crowd the subthalamic nucleus

High frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a successful treatment for patients with advanced Parkinson's disease (PD). Although its exact mechanism of action is unknown, it is currently believed that the beneficial effects of the stimulation are mediated either by alleviating pathological basal ganglia output patterns of activity or by activation of the axons of passage that arise from the cerebral cortex and other sources. In this study, we show that the anatomical composition of the primate STN provides a substrate through which DBS may elicit widespread changes in brain activity via stimulation of fibers of passage. Using quantitative high-resolution electron microscopy, we found that the primate STN is traversed by numerous myelinated axons, which occupy as much as 45% of its sensorimotor territory and 36% of its associative region. In comparison, myelinated axons occupy only 27% of the surface areas of the sensorimotor and associative regions of the internal segment of the globus pallidus (GPi), another target for therapeutic DBS in PD. We also noted that myelinated axons in the STN, on average, have a larger diameter than those in GPi, which may render them more susceptible to electrical stimulation. Because axons are more excitable than other neuronal elements, our findings support the hypothesis that STN DBS, even when carried out entirely within the confines of the nucleus, mediates some of its effects by activating myelinated axons of passage.

Predicting deep-brain stimulation frequencies to suppress pathological population oscillations in a network model of Parkinson's disease

Deep-brain stimulation (DBS) is used to treat medication-refractory Parkinson's disease (PD). However, tuning stimulation parameters requires time intensive visits with a clinician using a trial-and-error process until therapy is achieved with minimal side effects [1]. There is a need for a systematic approach to determining DBS parameters from the patient's physiological response to the stimulus. It is hypothesized that oscillations in the basal ganglia are responsible for many motor signs of PD [2] and that DBS works by disrupting these pathological oscillations. These oscillations arise from the excitatory-inhibitory loop between subthalamic nucleus (STN) and globus pallidus external (GPe) [3]. Periodic forcing of an oscillating system can induce chaos at certain frequencies [4]. When the system is chaotic it behaves aperiodically thereby suppressing the pathological oscillations. From a system's phase response curve (PRC), it is possible to determine at which stimulus frequencies and amplitudes chaotic responses will occur. Here we measure PRCs and predict optimal stimulation frequencies in a physiologically realistic computational model of STN DBS [5]. The model consists of 300 neurons in GPe and 100 neurons in STN and was tuned to reproduce non-human primate data. In the PD state, GPe activity produces a strong 32 Hz oscillation similar to the beta oscillations observed in the animal model. DBS pulses are applied to the STN and its efferent connections. Stimulation at 136 Hz, commonly used clinically, suppresses the beta oscillation. From low frequency stimulation (2 Hz) we are able to estimate the PRC of the population oscillation to the DBS pulse. From the measured PRC the stimulus frequencies that induce chaos in the STN-GPe loop are predicted. The STN was then stimulated over a range of frequencies and the power of the 32 Hz population oscillation measured. There is a strong correlation between the stimulus frequencies predicted to produce chaos from the PRC and the simulations where beta is suppressed. This indicates that it may be possible to predict DBS frequencies to successfully eliminate pathological oscillations based on a PRC measured from a patient using low frequency stimulation. Novel contributions of this work are methods of measuring PRCs from population activity and utilizing them to accurately predict stimulus frequencies that suppress oscillations in a model of the basal ganglia. We propose that this approach can be applied to patients in which electrophysiology measurements can be made simultaneously with stimulation. This approach to tuning stimulation parameters may dramatically reduce tuning time and improve efficacy for treatment of PD.

Interaction of Oscillations, and Their Suppression via Deep Brain Stimulation, in a Model of the Cortico-Basal Ganglia Network

Growing evidence suggests that synchronized neural oscillations in the cortico-basal ganglia network may play a critical role in the pathophysiology of Parkinson's disease. In this study, a new model of the closed loop network is used to explore the generation and interaction of network oscillations and their suppression through deep brain stimulation (DBS). Under simulated dopamine depletion conditions, increased gain through the hyperdirect pathway resulted in the interaction of neural oscillations at different frequencies in the cortex and subthalamic nucleus (STN), leading to the emergence of synchronized oscillations at a new intermediate frequency. Further increases in synaptic gain resulted in the cortex driving synchronous oscillatory activity throughout the network. When DBS was added to the model a progressive reduction in STN power at the tremor and beta frequencies was observed as the frequency of stimulation was increased, with resonance effects occurring for low frequency DBS (40 Hz) in agreement with experimental observations. The results provide new insights into the mechanisms by which synchronous oscillations can arise within the network and how DBS may suppress unwanted oscillatory activity.

Medial Septal Nucleus Theta Frequency Deep Brain Stimulation Improves Spatial Working Memory after Traumatic Brain Injury

More than 5,000,000 survivors of traumatic brain injury (TBI) live with persistent cognitive deficits, some of which likely derive from hippocampal dysfunction. Oscillatory activity in the hippocampus is critical for normal learning and memory functions, and can be modulated using deep brain stimulation techniques. In this pre-clinical study, we demonstrate that lateral fluid percussion TBI results in the attenuation of hippocampal theta oscillations in the first 6 days after injury, which correlate with deficits in the Barnes maze spatial working memory task. Theta band stimulation of the medial septal nucleus (MSN) results in a transient increase in hippocampal theta activity, and when delivered 1 min prior to training in the Barnes maze, it significantly improves spatial working memory. These results suggest that MSN theta stimulation may be an effective neuromodulatory technique for treatment of persistent learning and memory deficits after TBI.

A Point Process Model-based Framework Reveals Reinforcement Mechanisms in Striatum during High Frequency STN DBS.

Striatum is a major stage of the motor loop but, despite a pivotal role in the execution of movements, it has been poorly studied thus far under Parkinsonian conditions and Deep Brain Stimulation (DBS). We propose a computational framework to analyze the spiking activity of striatal neurons under several conditions. This framework combines point process models and single unit recordings, and separately evaluates the effects of the spiking history, DBS frequency, and other cells on the neuronal discharge pattern, thus giving a full characterization of non-stationary neuronal dynamics and inter-neuronal dependencies. We applied this framework to 166 striatal neurons collected in a monkey both at rest and during DBS (30-130 Hz). Our analysis was conducted both before and after treatment of the animal with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which evoked Parkinsonian-like motor disorders. We reported that high frequency (≥100 Hz) DBS reduces non-stationary dynamics and inter-neuronal dependencies by regularizing the discharge patterns both in MPTP and normal striatum, while the combination of MPTP and low frequency (30-80 Hz) DBS enhances these features, thus suggesting that pattern regularization in striatum might contribute to the therapeutic effect of high frequency DBS and presumably results from the overlap of feed-forward and feedback activation along the motor loop (reinforcement).

Resting Beta Hypersynchrony in Secondary Dystonia and Its Suppression During Pallidal Deep Brain Stimulation in DYT3+ Lubag Dystonia

1) To characterize patterns of globus pallidus interna neural synchrony in patients with secondary dystonia; 2) to determine whether neural hypersynchrony in the globus pallidus externa (GPe) and interna (GPi) is attenuated during high frequency deep brain stimulation (HF DBS) in a patient with DYT3+ dystonia and in a patient with secondary dystonia due to childhood encephalitis. We recorded local field potentials from the DBS lead in the GPi of four patients (seven hemispheres) with secondary dystonia and from one patient (two hemispheres) with primary DYT3+ dystonia. In two patients, we also recorded pallidal local field potentials during the administration of 10 sec epochs of HF DBS. Power spectral densities during rest demonstrated visible peaks in the beta band in seven out of nine cases. In DYT3+ dystonia, power in the alpha and beta bands, but not theta band, was attenuated during HF DBS in the GPe and in GPi, and attenuation was most prominent in the high beta band. This patient demonstrated an early and maintained improvement in dystonia. There was no beta peak and the power spectrum was not attenuated during HF DBS in a patient with secondary dystonia due to childhood encephalitis. These results suggest that beta hypersynchrony, demonstrated now in both primary and secondary dystonia, may play a pathophysiological role in pathological hyperkinesis. Further investigation is needed in a larger cohort of well-characterized primary and secondary dystonia patients.