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The auditory oddball is a mainstay in research on attention, novelty, and sensory prediction. How this task engages subcortical structures like the subthalamic nucleus and substantia nigra pars reticulata is unclear. We administered an auditory OB task while recording single unit activity (35 units) and local field potentials (57 recordings) from the subthalamic nucleus and substantia nigra pars reticulata of 30 patients with Parkinson's disease undergoing deep brain stimulation surgery. We found tone modulated and oddball modulated units in both regions. Population activity differentiated oddball from standard trials from 200 ms to 1000 ms after the tone in both regions. In the substantia nigra, beta band activity in the local field potential was decreased following oddball tones. The oddball related activity we observe may underlie attention, sensory prediction, or surprise-induced motor suppression., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Deep brain stimulation (DBS) is an effective treatment for movement disorders, including Parkinson disease and essential tremor. However, the underlying mechanisms of DBS remain elusive. Despite the capability of existing models in interpreting experimental data qualitatively, there are very few unified computational models that quantitatively capture the dynamics of the neuronal activity of varying stimulated nuclei-including subthalamic nucleus (STN), substantia nigra pars reticulata (SNr), and ventral intermediate nucleus (Vim)-across different DBS frequencies., Materials and Methods: Both synthetic and experimental data were used in the model fitting; the synthetic data were generated by an established spiking neuron model that was reported in our previous work, and the experimental data were provided using single-unit microelectrode recordings (MERs) during DBS (microelectrode stimulation). Based on these data, we developed a novel mathematical model to represent the firing rate of neurons receiving DBS, including neurons in STN, SNr, and Vim-across different DBS frequencies. In our model, the DBS pulses were filtered through a synapse model and a nonlinear transfer function to formulate the firing rate variability. For each DBS-targeted nucleus, we fitted a single set of optimal model parameters consistent across varying DBS frequencies., Results: Our model accurately reproduced the firing rates observed and calculated from both synthetic and experimental data. The optimal model parameters were consistent across different DBS frequencies., Conclusions: The result of our model fitting was in agreement with experimental single-unit MER data during DBS. Reproducing neuronal firing rates of different nuclei of the basal ganglia and thalamus during DBS can be helpful to further understand the mechanisms of DBS and to potentially optimize stimulation parameters based on their actual effects on neuronal activity., Competing Interests: Conflict of Interest Suneil K. Kalia reports consulting fees from Boston Scientific, Medtronic, and Abbott. Andres M. Lozano reports consulting fees from Abbott, Boston Scientific, Medtronic, and Insightec. The remaining authors reported no conflict of interest., (Copyright © 2023 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

External sensory cues can reduce freezing of gait in people with Parkinson's disease (PD), yet the role of the basal ganglia in these movements is unclear. We used microelectrode recordings to examine modulations in single unit (SU) and oscillatory local field potentials (LFP) during auditory-cued rhythmic pedaling movements of the feet. We tested five blocks of increasing cue frequencies (1 Hz, 1.5 Hz, 2 Hz, 2.5 Hz, and 3 Hz) in 24 people with PD undergoing deep brain stimulation surgery of the subthalamic nucleus (STN) or globus pallidus internus (GPi). Single unit firing and beta band LFPs (13-30 Hz) in response to movement onsets or cue onsets were examined. We found that the timing accuracy of foot pedaling decreased with faster cue frequencies. Increasing cue frequencies also attenuated firing rates in both STN and GPi neurons. Peak beta power in the GPi and STN showed different responses to the task. GPi beta power showed persistent suppression with fast cues and phasic modulation with slow cues. STN beta power showed enhanced beta synchronization following movement. STN beta power also correlated with rate of pedaling. Overall, we showed task-related responses in the GPi and STN during auditory-cued movements with differential roles in sensory and motor control. The results suggest a role for both input and output basal ganglia nuclei in auditory rhythmic pacing of gait-like movements in PD., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Local field potentials (LFPs) represent the summation of periodic (oscillations) and aperiodic (fractal) signals. Although previous studies showed changes in beta band oscillations and burst characteristics of the subthalamic nucleus (STN) in Parkinson's disease (PD), how aperiodic activity in the STN is related to PD pathophysiology is unknown., Objectives: The study aimed to characterize the long-term effects of STN-deep brain stimulation (DBS) and dopaminergic medications on aperiodic activities and beta bursts., Methods: A total of 10 patients with PD participated in this longitudinal study. Simultaneous bilateral STN-LFP recordings were conducted in six separate visits during a period of 18 months using the Activa PC + S device in the off and on dopaminergic medication states. We used irregular-resampling auto-spectral analysis to separate oscillations and aperiodic components (exponent and offset) in the power spectrum of STN-LFP signals in beta band., Results: Our results revealed a systematic increase in both the exponent and the offset of the aperiodic spectrum over 18 months following the DBS implantation, independent of the dopaminergic medication state of patients with PD. In contrast, beta burst durations and amplitudes were stable over time and were suppressed by dopaminergic medications., Conclusions: These findings indicate that oscillations and aperiodic activities reflect at least partially distinct yet complementary neural mechanisms, which should be considered in the design of robust biomarkers to optimize adaptive DBS. Given the link between increased gamma-aminobutyric acidergic (GABAergic) transmission and higher aperiodic activity, our findings suggest that long-term STN-DBS may relate to increased inhibition in the basal ganglia. © 2022 International Parkinson and Movement Disorder Society., (© 2022 International Parkinson and Movement Disorder Society.)

Background: Deep brain stimulation (DBS) provides symptomatic relief in a growing number of neurological indications, but local synaptic dynamics in response to electrical stimulation that may relate to its mechanism of action have not been fully characterized., Objective: The objectives of this study were to (1) study local synaptic dynamics during high frequency extracellular stimulation of the subthalamic nucleus (STN), and (2) compare STN synaptic dynamics with those of the neighboring substantia nigra pars reticulata (SNr)., Methods: Two microelectrodes were advanced into the STN and SNr of patients undergoing DBS surgery for Parkinson's disease (PD). Neuronal firing and evoked field potentials (fEPs) were recorded with one microelectrode during stimulation from an adjacent microelectrode., Results: Inhibitory fEPs could be discerned within the STN and their amplitudes predicted bidirectional effects on neuronal firing (p = .013). There were no differences between STN and SNr inhibitory fEP dynamics at low stimulation frequencies (p > .999). However, inhibitory neuronal responses were sustained over time in STN during high frequency stimulation but not in SNr (p < .001) where depression of inhibitory input was coupled with a return of neuronal firing (p = .003)., Interpretation: Persistent inhibitory input to the STN suggests a local synaptic mechanism for the suppression of subthalamic firing during high frequency stimulation. Moreover, differences in the resiliency versus vulnerability of inhibitory inputs to the STN and SNr suggest a projection source- and frequency-specificity for this mechanism. The feasibility of targeting electrophysiologically-identified neural structures may provide insight into how DBS achieves frequency-specific modulation of neuronal projections., Competing Interests: Declaration of competing interest S.K.K., M.H., W.D.H. have received honoraria, travel funds, and/or grant support from Medtronic (not related to this work). A.M.L. has received honoraria, travel funds, and/or grant support from Medtronic, Boston Scientific, St. Jude-Abbott, and Insightec (not related to this work). A.M.L. is a co-founder of Functional Neuromodulation Ltd. A.A.K. has received honoraria and/or travel funds from Medtronic, Boston Scientific, St. Jude-Abbott, and Stada Pharm (not related to this work). M.R.P. is a co-founder and a shareholder in MyndTec Inc. L.M., L.A.S., H.A., J.R.P.G. have no financial disclosures., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Patients with Parkinson's disease might develop treatment-resistant axial dysfunction after bilateral subthalamic stimulation., Objectives: To study whether lateralized stimulation (unilateral 50% amplitude reduction) for ≥21 days results in ≥0.13 m/s faster gait velocity in the dopaminergic ON state in these patients, and its effects on motor and axial function, quantitative gait and speech measures, quality of life, and selected cognitive tasks., Methods: Randomized, double-blinded, double-crossover trial., Results: In 22 participants (51-79 years old, 15 women), there were no significant changes in gait velocity, quality of life, cognitive, and speech measures. Reducing left-sided amplitude resulted in a 2.5-point improvement in axial motor Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) (P = 0.005, uncorrected) and a 1.9-point improvement in the Freezing of Gait Questionnaire (P = 0.024, uncorrected)., Conclusions: Lateralized subthalamic stimulation does not result in meaningful improvement in gait velocity in patients with Parkinson's disease who develop treatment-resistant axial dysfunction after bilateral subthalamic stimulation. Left subthalamic overstimulation may contribute to axial deterioration in these patients. © 2022 International Parkinson and Movement Disorder Society., (© 2022 International Parkinson and Movement Disorder Society.)

Parkinson's disease can be associated with significant cognitive impairment that may lead to dementia. Deep brain stimulation (DBS) of the subthalamic nucleus is an effective therapy for motor symptoms but is associated with cognitive decline. DBS of globus pallidus internus (GPi) poses less risk of cognitive decline so may be the preferred target. A research priority is to identify biomarkers of cognitive decline in this population, but efforts are hampered by a lack of understanding of the role of the different basal ganglia nuclei, such as the globus pallidus, in cognitive processing. During deep brain stimulation (DBS) surgery, we monitored single units, beta oscillatory LFP activity as well as event related potentials (ERPs) from the globus pallidus internus (GPi) of 16 Parkinson's disease patients, while they performed an auditory attention task. We used an auditory oddball task, during which one standard tone is presented at regular intervals and a second deviant tone is presented with a low probability that the subject is requested to count and report at the end of the task. All forms of neuronal activity studied were selective modulated by the attended tones. Of 62 neurons studied, the majority (51 or 82%) responded selectively to the deviant tone. Beta oscillatory activity showed an overall desynchronization during both types of attended tones interspersed by bursts of beta activity giving rise to peaks at a latency of around 200 ms after tone onset. cognitive ERPs recorded in GPi were selective to the attended tone and the right-side cERP was larger than the left side. The averages of trials showing a difference in beta oscillatory activity between deviant and standard also had a significant difference in cERP amplitude. In one block of trials, the random occurrence of 3 deviant tones in short succession silenced the activity of the GPi neuron being recorded. Trial blocks where a clear difference in LFP beta was seen were twice as likely to yield a correct tone count (25 vs 11). The data demonstrate strong modulation of GPi neuronal activity during the auditory oddball task. Overall, this study demonstrates an involvement of GPi in processing of non-motor cognitive tasks such as working memory and attention, and suggests that direct effects of DBS in non-motor GPi may contribute to cognitive changes observed post-operatively., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Deep brain stimulation is an established therapy for several neurological disorders; however, its effects on neuronal activity vary across brain regions and depend on stimulation settings. Understanding these variable responses can aid in the development of physiologically-informed stimulation paradigms in existing or prospective indications., Objective: Provide experimental and computational insights into the brain-region-specific and frequency-dependent effects of extracellular stimulation on neuronal activity., Methods: In patients with movement disorders, single-neuron recordings were acquired from the subthalamic nucleus, substantia nigra pars reticulata, ventral intermediate nucleus, or reticular thalamus during microstimulation across various frequencies (1-100 Hz) to assess single-pulse and frequency-response functions. Moreover, a biophysically-realistic computational framework was developed which generated postsynaptic responses under the assumption that electrical stimuli simultaneously activated all convergent presynaptic inputs to stimulation target neurons. The framework took into consideration the relative distributions of excitatory/inhibitory afferent inputs to model site-specific responses, which were in turn embedded within a model of short-term synaptic plasticity to account for stimulation frequency-dependence., Results: We demonstrated microstimulation-evoked excitatory neuronal responses in thalamic structures (which have predominantly excitatory inputs) and inhibitory responses in basal ganglia structures (predominantly inhibitory inputs); however, higher stimulation frequencies led to a loss of site-specificity and convergence towards neuronal suppression. The model confirmed that site-specific responses could be simulated by accounting for local neuroanatomical/microcircuit properties, while suppression of neuronal activity during high-frequency stimulation was mediated by short-term synaptic depression., Conclusions: Brain-region-specific and frequency-dependant neuronal responses could be simulated by considering neuroanatomical (local microcircuitry) and neurophysiological (short-term plasticity) properties., Competing Interests: Declaration of competing interest S.K.K., M.H., W.D.H. have received honoraria, travel funds, and/or grant support from Medtronic (not related to this work). A.M.L. has received honoraria, travel funds, and/or grant support from Medtronic, Boston Scientific, St. Jude-Abbott, and Insightec (not related to this work). M.R.P. is a shareholder in MyndTec Inc. A.M.L. is a co-founder of Functional Neuromodulation Ltd. L.M. and M.L. have no financial disclosures., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Microelectrode recordings (MERs) are used during deep brain stimulation surgery (DBS) to optimize patient outcomes and provide a unique method of collecting data regarding neurological conditions. However, MERs can be affected by anesthetics such as dexmedetomidine. Little is known about the effects of dexmedetomidine (DEX) on the globus pallidus interna (GPi), a common target for DBS. The primary aim of this study is to investigate the hypothesis that DEX is associated with alterations in GPi MERs., Methods: We conducted a retrospective analysis comparing MERs from patients with Parkinson's disease (PD) and dystonia who underwent insertion of DBS of the GPi under DEX sedation with those who went through the same procedure without DEX (No DEX)., Results: Firing rates for GPi neurons in the DEX group were lower (57.44 ± 2.04; mean ± SEM, n = 163 cells) than the No DEX group (69.53 ± 2.06, n = 112 cells, P < 0.0001). Overall, DEX was associated with a greater proportion of GPi cells classified as firing in bursty pattern compared to our No DEX group. (29.41%, n = 153 vs 14.81%, n = 108, P = 0.008). This effect was present for both PD and dystonia patients who underwent the procedure. High doses of DEX were associated with lower firing rates than low doses., Conclusions: Our results suggest that DEX is associated with a decrease in GPi firing rates and are associated with an increase in burstiness. Furthermore, these effects are similar between dystonia and PD patients. Lastly, the effects of DEX may differ between high doses and low doses.

Parkinson's disease is a neurodegenerative disease affecting the supply of dopamine to basal ganglia nuclei, leading to pathological beta band (13-35 Hz) oscillations in the subthalamic nucleus (STN). STN and beta activity are recognized in motoric functions but their role in cognitive functions remains elusive. We examined single unit and beta local field potential (LFP) activity in the STN during a visual choice preference task in PD patients (n = 12) undergoing deep brain stimulation surgery. Patients viewed 2 of 5 possible animal picture-pairs and were instructed to choose their favorite ("fav") picture by clicking the left or right mouse key. A block of trials consisted of 50-75 picture-pair presentations. Single unit histograms and LFP spectrograms were aligned to picture presentation and point of decision for pairs that included the fav and non-fav pictures, respectively. A total of 58 neurons from 26 blocks of trials were analyzed. Thirty of 58 neurons showed a selective change in spiking activity 0.20-0.65 s to fav picture presentation, which preceded the shortest recorded reaction time (=0.7 s), and 17/58 neurons showed no significant response in our task. Beta LFP significantly desynchronized in response to fav but not non-fav pictures in all trials, and in 14/26 blocks of trials, the desynchronization was followed by a "beta burst" and ramp-up to baseline activity. Neurons with choice preference responses were found throughout the dorsoventral extent of the STN. STN single units and beta activity are modulated during visual choice preference, and this suggests a role for STN beta activity in cognitive processing., (© 2020 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Objective: Many lines of evidence suggest that response conflict recruits brain regions in the cortical-basal ganglia system. Within the basal ganglia, deep brain recordings from the subthalamic nucleus (STN) have shown that conflict triggers a transient increase in low-frequency oscillations (LFOs; 2-8Hz). Here, we deployed a new method of delivering short trains of event-related deep brain stimulation (DBS) to the STN to test the causal role of the STN and its associated circuits in conflict-related processing., Methods: In a double-blind design, we stimulated the STN in patients with Parkinson disease by locking brief trains of DBS to specific periods of the trial within a Stroop task., Results: Stimulation had a specific effect on conflict compared to nonconflict trials by relatively speeding responses on conflict trials (ie, reducing the Stroop effect, defined as the difference in reaction time between conflict and nonconflict trials) when it was delivered in the preresponse period in the preparation phase. Stimulation also increased errors when it was delivered early in the response window. This latter result corresponded to the timing of the conflict-induced increase in LFOs observed in the absence of stimulation but was not directly related to the reduction in the Stroop effect., Interpretation: These results support the theory that the time of LFO increase recorded from the STN corresponds to a conflict-processing function. They also provide one of the first demonstrations of event-related DBS of the STN in humans during a cognitive control paradigm. Ann Neurol 2018;84:515-526., (© 2018 American Neurological Association.)

Ventral intermediate thalamic deep brain stimulation is a standard therapy for the treatment of medically refractory essential tremor and tremor-dominant Parkinson's disease. Despite the therapeutic benefits, the mechanisms of action are varied and complex, and the pathophysiology and genesis of tremor remain unsubstantiated. This intraoperative study investigated the effects of high frequency microstimulation on both neuronal firing and tremor suppression simultaneously. In each of nine essential tremor and two Parkinson's disease patients who underwent stereotactic neurosurgery, two closely spaced (600 µm) microelectrodes were advanced into the ventral intermediate nucleus. One microelectrode recorded action potential firing while the adjacent electrode delivered stimulation trains at 100 Hz and 200 Hz (2-5 s, 100 µA, 150 µs). A triaxial accelerometer was used to measure postural tremor of the contralateral hand. At 200 Hz, stimulation led to 68 ± 8% (P < 0.001) inhibition of neuronal firing and a 53 ± 5% (P < 0.001) reduction in tremor, while 100 Hz reduced firing by 26 ± 12% (not significant) with a 17 ± 6% (P < 0.05) tremor reduction. The degree of cell inhibition and tremor suppression were significantly correlated (P < 0.001). We also found that the most ventroposterior stimulation sites, closest to the border of the ventral caudal nucleus, had the best effect on tremor. Finally, prior to the inhibition of neuronal firing, microstimulation caused a transient driving of neuronal activity at stimulus onset (61% of sites), which gave rise to a tremor phase reset (73% of these sites). This was likely due to activation of the excitatory glutamatergic cortical and cerebellar afferents to the ventral intermediate nucleus. Temporal characteristics of the driving responses (duration, number of spikes, and onset latency) significantly differed between 100 Hz and 200 Hz stimulation trains. The subsequent inhibition of neuronal activity was likely due to synaptic fatigue. Thalamic neuronal inhibition seems necessary for tremor reduction and may function in effect as a thalamic filter to uncouple thalamo-cortical from cortico-spinal reflex loops. Additionally, our findings shed light on the gating properties of the ventral intermediate nucleus within the cerebello-thalamo-cortical tremor network, provide insight for the optimization of deep brain stimulation technologies, and may inform controlled clinical studies for assessing optimal target locations for the treatment of tremor.

Background: Deep brain stimulation of the ventro-intermedius nucleus of the thalamus is an established treatment for tremor of differing etiologies but factors that may predict the short- and especially long-term outcome of surgery are still largely unknown., Methods: We retrospectively investigated the clinical, pharmacological, electrophysiological and anatomical features that might predict the initial response and preservation of benefit in all patients who underwent deep brain stimulation for tremor. Data were collected at the following time points: baseline (preoperative), one-year post-surgery, and most recent visit. Tremor severity was recorded using the Fahn-Tolosa-Marin Tremor Rating Scale and/or the Unified Parkinson's Disease Rating Scale., Results: A total of 52 patients were included in the final analysis: 31 with essential tremor, 15 with cerebellar tremor of different etiologies, and 6 with Parkinson's disease. Long-term success (mean follow-up duration 34.7 months, range 1.7-121.1 months) was reported in 63.5%. Predictors of long-term benefit were: underlying tremor etiology (best outcome in Parkinson's disease, worst outcome in cerebellar tremor); age at surgery (the older the better); baseline tremor severity (the greater the better); lack of response to benzodiazepines; a more anterior electrode placement and single-unit beta power (the greater the better)., Conclusions: Specific patients' features (including single unit beta activity) and electrode locations may predict the short- and long-term benefit of thalamic stimulation for tremor. Future prospective studies enrolling a much larger sample of patients are needed to substantiate the associations detected by this retrospective study., (Copyright © 2018 Elsevier Inc. All rights reserved.)

OBJECTIVE Deep brain stimulation (DBS) of the posterior hypothalamus (PH) has been reported to be effective for aggressive behavior in a number of isolated cases. Few of these case studies have analyzed single-unit recordings in the human PH and none have quantitatively analyzed single units in the red nucleus (RN). The authors report on the properties of ongoing neuronal discharges in bilateral trajectories targeting the PH and the effectiveness of DBS of the PH as a treatment for aggressive behavior. METHODS DBS electrodes were surgically implanted in the PH of 1 awake patient with Sotos syndrome and 3 other anesthetized patients with treatment-resistant aggressivity. Intraoperative extracellular recordings were obtained from the ventral thalamus, PH, and RN and analyzed offline to discriminate single units and measure firing rates and firing patterns. Target location was based on the stereotactic coordinates used by Sano et al. in their 1970 study and the location of the dorsal border of the RN. RESULTS A total of 138 units were analyzed from the 4 patients. Most of the PH units had a slow, irregular discharge (mean [± SD] 4.5 ± 2.7 Hz, n = 68) but some units also had a higher discharge rate (16.7 ± 4.7 Hz, n = 15). Two populations of neurons were observed in the ventral thalamic region as well, one with a high firing rate (mean 16.5 ± 6.5 Hz, n = 5) and one with a low firing rate (mean 4.6 ± 2.8 Hz, n = 6). RN units had a regular firing rate with a mean of 20.4 ± 9.9 Hz and displayed periods of oscillatory activity in the beta range. PH units displayed a prolonged period of inhibition following microstimulation compared with RN units that were not inhibited. Patients under anesthesia showed a trend for lower firing rates in the PH but not in the RN. All 4 patients displayed a reduction in their aggressive behavior after surgery. CONCLUSIONS During PH DBS, microelectrode recordings can provide an additional mechanism to help identify the PH target and surrounding structures to be avoided such as the RN. PH units can be distinguished from ventral thalamic units based on their response to focal microstimulation. The RN has a characteristic higher firing rate and a pattern of beta oscillations in the spike trains. The effect of the anesthetic administered should be considered when using microelectrode recordings. The results of this study, along with previous reports, suggest that PH DBS may be an effective treatment for aggression.

Deep brain stimulation (DBS) of the subgenual cingulate gyrus (SCG) has been used to treat patients with treatment-resistant depression. As in humans, DBS applied to the ventromedial prefrontal cortex of rats induces antidepressant-like responses. Physiological interactions between structures that play a role in depression and antidepressant treatment are still unknown. The present study examined the effect of DBS on inter-region communication by measuring the coherence of local field potentials in the rat infralimbic cortex (IL; homologue of the SCG) and one of its major afferents, the ventral hippocampus (VH). Rats received daily IL DBS treatment (100 μA, 90 μs, 130 Hz; 8h/day). Recordings were conducted in unrestrained, behaving animals on the day before treatment, after 1 and 10 days of treatment, and 10 days stimulation offset. VH-IL coherence in the 2-4 Hz range was reduced in DBS-treated animals compared with shams after 10 days, but not after only 1 day of treatment. No effect of DBS was observed in the 6-10 Hz (theta) range, where coherence was generally high and could be further evoked with a loud auditory stimulus. Finally, coherence was not affected by fluoxetine (10mg/kg), suggesting that the effects of DBS were not likely mediated by increased serotonin levels. While these data support the hypothesis that DBS disrupts communication between regions important for expectation-based control of emotion, they also suggest that lasting physiological effects require many days of treatment and, furthermore, may be specific to lower-frequency patterns, the nature and scope of which await further investigation., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Increased oscillations in the beta band are thought to be related to motor symptoms of Parkinson's disease (PD). Previous studies have shown that beta-band desynchronization in the subthalamic nucleus (STN) is reduced just before and during limb movements. While the STN is part of the basal ganglia (BG)-thalamocortical circuit controlling limb movements, it is also part of the BG-brainstem projection controlling saccadic eye movements. Late-stage PD patients have deficits in saccades in addition to difficulties with limb movements arising from impaired functions of the BG. We investigated saccade-related changes in beta-band (15-30 Hz) oscillatory activities in the human STN while PD patients performed visually guided prosaccades and antisaccades, the latter requiring suppression of reflexive responses and volitional initiation of saccades. We recorded local field potentials from deep brain stimulation electrodes implanted in the STN in human PD patients 1-5 d after surgery and compared prosaccades and antisaccades with these and with limb movements. Saccade-related beta-band desynchronizations were observed just before and during saccades in all subjects, suggesting that reduction of beta-band oscillatory activity in the STN is related to preparation and execution of saccades. Furthermore, beta-band desynchronizations for antisaccades started earlier, were sustained for longer periods, were of greater magnitude, and were observed more often than prosaccades. Beta-band desynchronization in the STN may reflect the additional processes associated with suppression of reflexive responses and volitional execution of saccades in the opposite direction.

Background: The efficacy of bilateral globus pallidus internus (GPi) deep brain stimulation (DBS) for medically refractory idiopathic generalized dystonia has been demonstrated repeatedly. More variable outcomes have been reported in the treatment of secondary dystonia with GPi DBS., Objectives: The present study seeks to examine the pallidal physiology and clinical outcome of GPi DBS in a case of secondary dystonia., Methods: We report on a 43-year-old man who at the age of 9 suffered a left basal ganglia stroke and at the age of 21 developed severe disabling hemidystonia. Following unsuccessful medical management for many years and an axial involvement of the dystonia, he underwent bilateral GPi DBS with dual microelectrode mapping of cell firing and evoked field potentials (fEP)., Results: On the intact side we found regular firing of pallidal neurons and normal fEP indicative of functioning striatopallidal pathways. The affected side was found to include a higher frequency of bursting pallidal neurons. fEP could not be evoked on the affected side, suggesting their origin to be striatal GABAergic afferents., Conclusions: The patient had marked benefit from bilateral GPi DBS, which suggests that the therapeutic effects of DBS were mediated by the intact pathways in this case of hemidystonia., (Copyright © 2013 S. Karger AG, Basel.)

Background: Pedunculopontine nucleus (PPN) DBS has emerged as a potential intervention for patients with gait and balance disorders. However, targeting this nucleus can be challenging. We report on the first neuropathological analyses after PPN-DBS surgery in advanced progressive supranuclear palsy (PSP)., Methods: Two patients with PSP underwent unilateral PPN-DBS surgery and were clinically followed to autopsy. Both patients underwent postmortem neuropathological analysis, including choline acetyltransferase immunohistochemistry, to ascertain PPN boundaries and electrode location., Results: Both patients experienced partial improvement in some motor and nonmotor domains postintervention, but died shortly of other complications. Postmortem neuropathological analysis of each patient confirmed the electrode in a region of cholinergic neuronal loss corresponding to the PPN., Conclusions: We provide histopathological evidence for the validity of our stereotactic approach to target the PPN and correlate electrode location with clinical outcomes., (Copyright © 2012 Movement Disorder Society.)

Deep brain stimulation (DBS) in the globus pallidus internus (GPi) has been shown to improve dystonia, a movement disorder of repetitive twisting movements and postures. DBS at frequencies above 60 Hz improves dystonia, but the mechanisms underlying this frequency dependence are unclear. In patients undergoing dual-microelectrode mapping of the GPi, microstimulation has been shown to reduce neuronal firing, presumably due to synaptic GABA release. This study examined the effects of different microstimulation frequencies (1-100 Hz) and train length (0.5-20 s), with and without prior high-frequency stimulation (HFS) on neuronal firing and evoked field potentials (fEPs) in 13 dystonia patients. Pre-HFS, the average firing decreased as stimulation frequency increased and was silenced above 50 Hz. The average fEP amplitudes increased up to frequencies of 20-30 Hz but then declined and at 50 Hz, were only at 75% of baseline. In some cases, short latency fiber volleys and antidromic-like spikes were observed and followed high frequencies. Post-HFS, overall firing was reduced compared with pre-HFS, and the fEP amplitudes were enhanced at low frequencies, providing evidence of inhibitory synaptic plasticity in the GPi. In a patient with DBS electrodes already implanted in the GPi, recordings from four neurons in the subthalamic nucleus showed almost complete inhibition of firing with clinically effective but not clinically ineffective stimulation parameters. These data provide additional support for the hypothesis of stimulation-evoked GABA release from afferent synaptic terminals and reduction of neuronal firing during DBS and additionally, implicate excitation of GPi axon fibers and neurons and enhancement of inhibitory synaptic transmission by high-frequency GPi DBS as additional putative mechanisms underlying the clinical benefits of DBS in dystonia.

Objective: Deep brain stimulation in the globus pallidus internus (GPi) is used to alleviate the motor symptoms of both Parkinson's disease (PD) and dystonia. We tested the hypothesis that PD and dystonia are characterized by different temporal patterns of synchronized oscillations in the GPi, and that the dopaminergic loss in PD makes the basal ganglia more susceptible to oscillatory activity., Methods: Neuronal firing and local field potentials (LFPs) were simultaneously recorded from the GPi in four PD patients and seven dystonia patients using two independently driven microelectrodes., Results: In the PD patients, beta (11-30 Hz) oscillations were observed in the LFPs and the firing activity of ∼30% of the neurons was significantly coherent with the LFP. However, in the dystonia group, the peak frequency of LFP oscillations was lower (8-20 Hz) and there was a significantly smaller proportion of neurons (∼10%) firing in coherence with the LFP (P<0.001)., Conclusions: These findings suggest that synchronization of neuronal firing with LFP oscillations is a more prominent feature in PD than in dystonia., Significance: This study adds to the growing evidence that dopaminergic loss in PD may increase the sensitivity of the basal ganglia network to rhythmic oscillatory inputs., (Copyright © 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Bilateral deep brain stimulation of the globus pallidus pars interna (GPi) is the favored neuromodulation procedure in cases of cervical dystonia. The authors report on a case of unilateral GPi implantation that resulted in sustained benefit with marked improvement in pain and dystonia.

Background: Tremor is an important cause of disability in patients with multiple sclerosis (MS). Deep brain stimulation (DBS) in the ventral intermediate nucleus (VIM) of the thalamus is said to be beneficial for MS tremor., Objective: To assess the long-term efficacy of VIM DBS for MS disabling tumor., Methods: We treated 10 patients (4 men and 6 women) with advanced MS-related medication-resistant tremor with DBS at the VIM thalamic nucleus. DBS was unilateral in 9 patients and bilateral in 1 patient in 2 stages. Contralateral arm tremor was assessed with the Fahn-Tolosa-Marin tremor rating scale., Results: At 1 year, 5 of 10 patients (5 of 11 hemispheres) had a reduction in tremor scores with stimulation compared with baseline; in 3 patients, the reduction was > 50%. After 36 months, 3 patients continued benefiting from stimulation, 2 having > 50% improvement. Of the 6 symptomatic sides that did not benefit at 1 year, 3 failed to have even initial benefit, and 3 had a transient improvement lasting < 1 year. One patient stopped using stimulation because of a lack of improvement at 5 months after surgery and was lost to follow-up., Conclusion: Approximately one-half of the patients derived some benefit from VIM DBS 1 year after surgery, but this benefit reached a > 50% reduction in only 30% of the patients. This level of improvement may be related to the variability of the demyelinating lesions and the superimposition of ataxia in the MS patients. Developing better treatments for MS tremor continues to be a challenge.

Deep brain stimulation (DBS) of the anterior thalamic nucleus (AN), an important relay in the circuitry of memory, is currently being proposed as a treatment for epilepsy. Despite the encouraging results with the use of this therapy, potential benefits and adverse effects are yet to be determined. We show that AN stimulation at relatively high current disrupted the acquisition of contextual fear conditioning and impaired performance on a spatial alternating task in rats. This has not been observed at parameters generating a charge density that approximated the one used in clinical practice. At settings that impaired behavior, AN stimulation induced a functional depolarization block nearby the electrode, increased c-Fos expression in cerebral regions projecting to and receiving projections from the AN, and influenced hippocampal activity. This suggests that complex mechanisms might be involved in the effects of AN DBS, including a local target inactivation and the modulation of structures at a distance. Though translating data from animals to humans has to be considered with caution, our study underscores the need for carefully monitoring memory function while selecting stimulation parameters during the clinical evaluation of AN DBS., (Copyright 2010 Elsevier Inc. All rights reserved.)

Deep brain stimulation of the basal ganglia and other brain regions has been used successfully to treat a variety of neurological disorders. However, the mechanisms by which it works, remain unclear. In a previous study, we showed that locally delivered single current pulses delivered from a nearby microelectrode are sufficient to inhibit firing in the internal globus pallidus for tens of milliseconds. The GPi and the substantia nigra pars reticulata are the output nuclei of the basal ganglia and share many anatomical and physiological features. The goal of the current study was to examine the after-effects of trains of high-frequency microstimulation on neuronal firing in the GPi of Parkinson's disease and dystonia patients as well as in the SNr of PD patients. Microelectrode recordings and microstimulation were performed in a total of 57 patients during stereotactic surgery. We found that firing in the GPi and SNr is inhibited for several hundreds of milliseconds following the end of a short, 200 Hz high-frequency train delivered through the recording electrode (e.g., on average 618 ms when stimulating in the SNr with a 0.5 s train of 4 microA pulses at 200 Hz). Inhibition duration usually increased with increasing current intensity, train frequency and generally peaked for trains of 1-2 s, while it decreased with increasing train durations. Statistical analysis with general linear models revealed a significant linear relationship between current intensity and inhibition duration in all nuclei and patient groups. There was also a significant relationship between train frequency and inhibition duration in the SNr and GPi of PD patients and between train duration and inhibition duration in the GPi of PD patients. There was no significant difference in inhibition duration across patient groups but the current threshold for inhibition was significantly different in the SNr compared to the GPi. The characteristics of the inhibition observed are consistent with stimulation-induced GABA release following activation of the GABAergic afferents in the SNr and GPi. The findings suggest that high-frequency microstimulation of the GPi and SNr depresses local neuronal activity and synaptic transmission, and such mechanisms may contribute to the therapeutic effects of DBS.

Despite improvements in anatomic imaging of the basal ganglia, microelectrode recording is still an invaluable tool in locating appropriate targets for neurosurgical intervention. These recording also provide an unparalleled opportunity to study the pathophysiological aspects of diseases. This article reviews the principles of microelectrode recording in functional neurosurgery and discusses the pathologic neurophysiologic findings commonly encountered. It also highlights some of the potential mechanisms of action of both dopaminergic drugs and deep brain stimulation. In addition we review the recent work on pedunculopontine nucleus neurophysiology and trials of deep brain stimulation in that region for gait disturbances in Parkinson's disease.

Postural instability and falls are a major source of disability in patients with advanced Parkinson's disease. These problems are currently not well addressed by either pharmacotherapy nor by subthalamic nucleus deep-brain stimulation surgery. The neuroanatomical substrates of posture and gait are poorly understood but a number of important observations suggest a major role for the pedunculopontine nucleus and adjacent areas in the brainstem. We conducted a double-blinded evaluation of unilateral pedunculopontine nucleus deep-brain stimulation in a pilot study in six advanced Parkinson's disease patients with significant gait and postural abnormalities. There was no significant difference in the double-blinded on versus off stimulation Unified Parkinson's Disease Rating Scale motor scores after 3 or 12 months of continuous stimulation and no improvements in the Unified Parkinson's Disease Rating Scale part III scores compared to baseline. In contrast, patients reported a significant reduction in falls in the on and off medication states both at 3 and 12 months after pedunculopontine nucleus deep-brain stimulation as captured in the Unified Parkinson's Disease Rating Scale part II scores. Our results suggest that pedunculopontine nucleus deep-brain stimulation may be effective in preventing falls in patients with advanced Parkinson's disease but that further evaluation of this procedure is required.

Object: The aim of the current study was to examine and compare the aftereffects of local high-frequency microstimulation through the recording electrode on the firing of neurons in the subthalamic nucleus (STN) and the substantia nigra pars reticulata (SNr) in patients undergoing surgery for deep brain stimulation. Deep brain stimulation has been playing an increasing role in the treatment of Parkinson disease, with the subthalamic nucleus (STN) being the preferred implantation target. Changes in cellular activity indicative of the borders of the STN are typically used during surgery to determine the extent of the STN and locate the optimal target, but in some cases borders may be difficult to identify. In this study the authors compared the effects of microstimulation in the SNr and STN. In previous studies they have shown that microstimulation in the internal globus pallidus, which is functionally similar to the SNr, inhibits firing, whereas similar microstimulation in the STN has minimal effect. The presence of inhibition in the SNr but not in the STN could be used as an additional criterion to help identify the location of the border between the STN and SNr., Methods: Dual microelectrode recordings were performed during stereotactic surgery in 4 patients. Well-isolated high-amplitude units were stimulated extracellularly through the recording microelectrode with 0.5-second trains of high frequency (200 Hz) and low current (

Animal studies suggest that rapid eye movement (REM) sleep is governed by the interaction of REM-promoting and REM-inhibiting nuclei in the pontomesencephalic tegmentum. The pedunculopontine nucleus is proposed to be REM promoting. Using polysomnography, we studied sleep in five parkinsonian patients undergoing unilateral pedunculopontine nucleus deep brain stimulation (DBS). We demonstrated a near doubling of nocturnal REM sleep between the DBS "off" and DBS "on" states, without significant changes in other sleep states. This represents the first demonstration that DBS can selectively modulate human sleep, and it supports an important role for the pedunculopontine nucleus region in modulating human REM sleep. Ann Neurol 2009;66:110-114.

The pedunculopontine nucleus (PPN) lies within the brainstem reticular formation and is involved in the motor control of gait and posture. Interest has focused recently on the PPN as a target for implantation of chronic deep brain stimulation (DBS) electrodes for Parkinson's disease (PD) and progressive supranuclear palsy (PSP) therapy. The aim of this study was to examine the neurophysiology of the human PPN region and to identify neurophysiological landmarks that may aid the proper placement of DBS electrodes in the nucleus for the treatment of PD and PSP. Neuronal firing and local field potentials were recorded simultaneously from two independently driven microelectrodes during stereotactic neurosurgery for implantation of a unilateral DBS electrode in the PPN in five PD patients and two PSP patients. Within the PPN region, the majority (57%) of the neurons fired randomly while about 21% of the neurons exhibited 'bursty' firing. In addition, 21% of the neurons had a long action potential duration and significantly lower firing rate suggesting they were cholinergic neurons. A change in firing rate produced by passive and/or active contralateral limb movement was observed in 38% of the neurons that were tested in the PPN region. Interestingly, oscillatory local field potential activity in the beta frequency range ( approximately 25 Hz) was also observed in the PPN region. These electrophysiological characteristics of the PPN region provide further support for the proposed role of this region in motor control. It remains to be seen to what extent the physiological characteristics of the neurons and the stimulation-evoked effects will permit reliable identification of PPN and determination of the optimal target for DBS therapy.

Objectives: To examine the influence of deep brain stimulation on hippocampal neurogenesis in an adult rodent model., Methods: Rats were anesthetized and treated for 1 hour with electrical stimulation of the anterior nucleus of the thalamus (AN) or sham surgery. The animals were injected with 5'-bromo-2'-deoxyuridine (BrdU) 1-7 days after surgery and killed 24 hours or 28 days later. The authors counted the BrdU-positive cells in the dentate gyrus (DG) of the hippocampus. To investigate the fate of these cells, they also stained sections for doublecortin, NeuN, and GFAP and analyzed the results with confocal microscopy. In a second set of experiments they assessed the number of DG BrdU-positive cells in animals treated with corticosterone (a known suppressor of hippocampal neurogenesis) and sham surgery, corticosterone and AN stimulation, or vehicle and sham surgery., Results: Animals receiving AN high-frequency stimulation (2.5 V, 90 musec, 130 Hz) had a 2- to 3-fold increase in the number of DG BrdU-positive cells compared with nonstimulated controls. This increase was not seen with stimulation at 10 Hz. Most BrdU-positive cells assumed a neuronal cell fate. As expected, treatment with corticosterone significantly reduced the number of DG BrdU-positive cells. This steroid-induced reduction of neurogenesis was reversed by AN stimulation., Conclusions: High-frequency stimulation of the AN increases the hippocampal neurogenesis and restores experimentally suppressed neurogenesis. Interventions that increase hippocampal neurogenesis have been associated with enhanced behavioral performance. In this context, it may be possible to use electrical stimulation to treat conditions associated with impairment of hippocampal function.

Subthalamic nucleus deep brain stimulation (STN-DBS) is effective in advanced Parkinson's disease (PD), but its effects on the levodopa response are unclear. We studied the levodopa response after long-term STN-DBS, STN-DBS efficacy and predictive value of preoperative levodopa response to long-term DBS benefit in 33 PD patients with bilateral STN-DBS. Patients were assessed using the Unified Parkinson's Disease Rating Scale preoperatively (with and without medications) and postoperatively (without medications or stimulation, with only medications or stimulation, and with both medications and stimulation). Levodopa response significantly decreased postoperatively by 31.1% at 3 years and 32.3% at 5 years, possibly related to the reduction in medication requirement, direct STN stimulation effect or PD progression. STN-DBS alone significantly improved motor scores (37.2% at 3 years and 35.1% at 5 years) and activities of daily living scores (27.1% at 3 years and 19.2% at 5 years). Anti-PD drugs were significantly reduced by 47.9% at 3 years and 39.8% at 5 years. However, the magnitude of the preoperative response to levodopa did not predict DBS benefit at 3 and 5 years., ((c) 2007 Movement Disorder Society.)

Objective: To improve functional stereotactic microelectrode localization of small deep brain structures by developing and evaluating a recording system with two closely separated independently controlled microelectrodes., Methods: Data were obtained from 52 patients using this dual microelectrode technique and 38 patients using the standard single microelectrode technique for subthalamic nucleus localization in patients with Parkinson's disease., Results: There was a decrease in the incidence of noncontributory trajectories, defined as a single penetration made by the pair of closely spaced parallel microelectrodes, owing to microelectrode failure (from 7.2% to <1%), an improved localization and verification of nuclear borders, and a significant decrease in the number of trajectories used to localize the subthalamic nucleus from a median of three to two per initial operative side (P < 0.001). The technique also provides the novel opportunity to examine population activity by correlating the discharge between two closely spaced simultaneously recorded neurons and can be used to monitor the electrophysiological effects of local electrical stimulation or microinjections of pharmacological agents., Conclusion: Our experience indicates that the use of two closely spaced microelectrodes improves the utility of microelectrode localization in minimally invasive functional neurosurgery.

Deep brain stimulation (DBS) of the globus pallidus internus (GPi) is being evaluated as a potential new therapy for patients with Huntington's disease (HD). In addition to skeletal movement disorders, HD patients have difficulty initiating voluntary saccades and have difficulty in suppressing rapid saccades toward newly appearing stimuli. We measured several saccade parameters in an HD patient who had marked improvement of clinical symptoms with bilateral GPi DBS to determine whether oculomotor performance improved in parallel with clinical scores. Oculomotor performance was assessed using three testing paradigms: pro-saccades, anti-saccades, and memory-guided saccades. The data from the HD patient was also compared to that of two healthy controls. Pallidal DBS decreased pro-saccade latency, total movement time, and the number of correctly executed trials, as well as increasing saccade gain. Memory-saccade performance was negatively affected with stimulation: saccade gain decreased, latency increased, and the patient's ability to suppress unwanted saccades decreased with stimulation. Our data demonstrate a task-specific improvement of oculomotor deficits in this HD patient with pallidal DBS, supporting a role of GPi in oculomotor control., ((c) 2004 Movement Disorder Society.)

Introduction: Beta oscillations in sensorimotor structures contribute to the planning, sequencing, and stopping of movements, functions that are typically associated with the role of the basal ganglia. The presence of beta oscillations (13-30 Hz) in the cerebellar zone of the thalamus (the ventral intermediate nucleus - Vim) indicates that this rhythm may also be involved in cerebellar functions such as motor learning and visuomotor adaptation. Methods: To investigate the possible role of Vim beta oscillations in visuomotor coordination, we recorded local field potential (LFP) and multiunit activity from the Vim of essential tremor (ET) patients during neurosurgery for the implantation of deep brain stimulation (DBS) electrodes. Using a computer, patients performed a visuomotor adaptation task that required coordinating center-out movements with incongruent visual feedback imposed by inversion of the computer display. Results: The results show that, in ET, Vim beta oscillations of the LFP were lower during the incongruent center-out task than during the congruent orientation. Vim firing rates increased significantly during periods of low beta power, particularly on approach to the peripheral target. In contrast, beta power in the subthalamic nucleus of Parkinson's disease (PD) patients did not differ significantly between the incongruent and the congruent orientation of the center-out task. Discussion: The findings support the hypothesis that beta oscillations of the Vim are modulated by novel visuomotor tasks. The inverse relationship between the power of Vim-LFP beta oscillations and Vim firing rates suggest that the suppression of beta oscillations may facilitate information throughput to the thalamocortical circuit by modulation of Vim firing rates. [ABSTRACT FROM AUTHOR]

Deep brain stimulation procedures offer an invaluable opportunity to study disease through intracranial recordings from awake patients. Here, we address the relationship between single-neuron and aggregate-level (local field potential; LFP) activities in the subthalamic nucleus (STN) and thalamic ventral intermediate nucleus (Vim) of patients with Parkinson's disease (n = 19) and essential tremor (n = 16), respectively. Both disorders have been characterized by pathologically elevated LFP oscillations, as well as an increased tendency for neuronal bursting. Our findings suggest that periodic singleneuron bursts encode both pathophysiological beta (13 to 33 Hz; STN) and tremor (4 to 10 Hz; Vim) LFP oscillations, evidenced by strong time-frequency and phasecoupling relationships between the bursting and LFP signals. Spiking activity occurring outside of bursts had no relationship to the LFP. In STN, bursting activity most commonly preceded the LFP oscillation, suggesting that neuronal bursting generated within STN may give rise to an aggregate-level LFP oscillation. In Vim, LFP oscillations most commonly preceded bursting activity, suggesting that neuronal firing may be entrained by periodic afferent inputs. In both STN and Vim, the phase-coupling relationship between LFP and high-frequency oscillation (HFO) signals closely resembled the relationships between the LFP and single-neuron bursting. This suggests that periodic single-neuron bursting is likely representative of a higher spatial and temporal resolution readout of periodic increases in the amplitude of HFOs, which themselves may be a higher resolution readout of aggregate-level LFP oscillations. Overall, our results may reconcile "rate" and "oscillation" models of Parkinson's disease and shed light on the single-neuron basis and origin of pathophysiological oscillations in movement disorders. [ABSTRACT FROM AUTHOR]

Tremor is a well-known side effect from many psychiatric medications, including lithium and dopamine antagonists. In patients whose psychiatric symptoms are stabilized and only respond to certain medications, deep brain stimulation may offer relief of the consequent motor complications. We report the case of an elderly male with disabling tremor related to lithium therapy for bipolar affective disorder, who was subsequently treated with deep brain stimulation. In this patient, we obtained recordings from the substantia nigra pars reticulata and performed a high-frequency stimulation protocol that robustly elicits long-term potentiation (LTP)-like changes in patients with Parkinson's disease. We hypothesized that in this patient, who did not have Parkinson's disease, the levels of inhibitory plasticity would be much greater. However, we found an unanticipated lack of plasticity in the patient with lithium-induced tremor, compared with two de novo control patients with Parkinson's disease. This patient was successfully treated with deep brain stimulation in the vicinity of the ventral oral posterior nucleus, an area of the thalamus that receives inputs from the basal ganglia. We postulate that the lithium-induced blockade of LTP may bring about motor complications such as tremor while simultaneously contributing to the therapeutic mechanism for treating the symptoms of psychiatric disorders such as bipolar affective disorder. [ABSTRACT FROM AUTHOR]

Ventral intermediate thalamic deep brain stimulation is a standard therapy for the treatment of medically refractory essential tremor and tremor-dominant Parkinson's disease. Despite the therapeutic benefits, the mechanisms of action are varied and complex, and the pathophysiology and genesis of tremor remain unsubstantiated. This intraoperative study investigated the effects of high frequency microstimulation on both neuronal firing and tremor suppression simultaneously. In each of nine essential tremor and two Parkinson's disease patients who underwent stereotactic neurosurgery, two closely spaced (600 µm) microelectrodes were advanced into the ventral intermediate nucleus. One microelectrode recorded action potential firing while the adjacent electrode delivered stimulation trains at 100 Hz and 200 Hz (2-5 s, 100 µA, 150 µs). A triaxial accelerometer was used to measure postural tremor of the contralateral hand. At 200 Hz, stimulation led to 68 ± 8% (P < 0.001) inhibition of neuronal firing and a 53 ± 5% (P < 0.001) reduction in tremor, while 100 Hz reduced firing by 26 ± 12% (not significant) with a 17 ± 6% (P < 0.05) tremor reduction. The degree of cell inhibition and tremor suppression were significantly correlated (P < 0.001). We also found that the most ventroposterior stimulation sites, closest to the border of the ventral caudal nucleus, had the best effect on tremor. Finally, prior to the inhibition of neuronal firing, microstimulation caused a transient driving of neuronal activity at stimulus onset (61% of sites), which gave rise to a tremor phase reset (73% of these sites). This was likely due to activation of the excitatory glutamatergic cortical and cerebellar afferents to the ventral intermediate nucleus. Temporal characteristics of the driving responses (duration, number of spikes, and onset latency) significantly differed between 100 Hz and 200 Hz stimulation trains. The subsequent inhibition of neuronal activity was likely due to synaptic fatigue. Thalamic neuronal inhibition seems necessary for tremor reduction and may function in effect as a thalamic filter to uncouple thalamo-cortical from cortico-spinal reflex loops. Additionally, our findings shed light on the gating properties of the ventral intermediate nucleus within the cerebello-thalamo-cortical tremor network, provide insight for the optimization of deep brain stimulation technologies, and may inform controlled clinical studies for assessing optimal target locations for the treatment of tremor. [ABSTRACT FROM AUTHOR]

Deep brain stimulation of the subthalamic nucleus is an effective treatment for Parkinson's disease symptoms. The therapeutic benefits of deep brain stimulation are frequency-dependent, but the underlying physiological mechanisms remain unclear. To advance deep brain stimulation therapy an understanding of fundamental mechanisms is critical. The objectives of this study were to (i) compare the frequency-dependent effects on cell firing in subthalamic nucleus and substantia nigra pars reticulata; (ii) quantify frequency-dependent effects on short-term plasticity in substantia nigra pars reticulata; and (iii) investigate effects of continuous long-train high frequency stimulation (comparable to conventional deep brain stimulation) on synaptic plasticity. Two closely spaced (600 µm) microelectrodes were advanced into the subthalamic nucleus (n = 27) and substantia nigra pars reticulata (n = 14) of 22 patients undergoing deep brain stimulation surgery for Parkinson's disease. Cell firing and evoked field potentials were recorded with one microelectrode during stimulation trains from the adjacent microelectrode across a range of frequencies (1-100 Hz, 100 µA, 0.3 ms, 50-60 pulses). Subthalamic firing attenuated with ≥20 Hz (P < 0.01) stimulation (silenced at 100 Hz), while substantia nigra pars reticulata decreased with ≥3 Hz (P < 0.05) (silenced at 50 Hz). Substantia nigra pars reticulata also exhibited a more prominent increase in transient silent period following stimulation. Patients with longer silent periods after 100 Hz stimulation in the subthalamic nucleus tended to have better clinical outcome after deep brain stimulation. At ≥30 Hz the first evoked field potential of the stimulation train in substantia nigra pars reticulata was potentiated (P < 0.05); however, the average amplitude of the subsequent potentials was rapidly attenuated (P < 0.01). This is suggestive of synaptic facilitation followed by rapid depression. Paired pulse ratios calculated at the beginning of the train revealed that 20 Hz (P < 0.05) was the minimum frequency required to induce synaptic depression. Lastly, the average amplitude of evoked field potentials during 1 Hz pulses showed significant inhibitory synaptic potentiation after long-train high frequency stimulation (P < 0.001) and these increases were coupled with increased durations of neuronal inhibition (P < 0.01). The subthalamic nucleus exhibited a higher frequency threshold for stimulation-induced inhibition than the substantia nigra pars reticulata likely due to differing ratios of GABA:glutamate terminals on the soma and/or the nature of their GABAergic inputs (pallidal versus striatal). We suggest that enhancement of inhibitory synaptic plasticity, and frequency-dependent potentiation and depression are putative mechanisms of deep brain stimulation. Furthermore, we foresee that future closed-loop deep brain stimulation systems (with more frequent off stimulation periods) may benefit from inhibitory synaptic potentiation that occurs after high frequency stimulation. [ABSTRACT FROM AUTHOR]