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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]

Thalamic deep brain stimulation (DBS) is an effective treatment for tremor, but the mechanisms of action remain unclear. Previous studies of human thalamic neurons to noted transient rebound bursting activity followed by prolonged inhibition after cessation of high frequency extracellular stimulation, and the present study sought to identify the mechanisms underlying this response. Recordings from 13 thalamic neurons exhibiting low threshold spike (LTS) bursting to brief periods of extracellular stimulation were made during surgeries to implant DBS leads in 6 subjects with Parkinson's disease. The response immediately after cessation of stimulation included a short epoch of burst activity, followed by a prolonged period of silence before a return to LTS bursting. A computational model of a population of thalamocortical relay neurons and presynaptic axons terminating on the neurons was used to identify cellular mechanisms of the observed responses. The model included the actions of neuromodulators through inhibition of a non-pertussis toxin sensitive K+ current (IKL), activation of a pertussis toxin sensitive K+ current (IKG), and a shift in the activation curve of the hyperpolarization-activated cation current (Ih). The model replicated well the measured responses, and the prolonged inhibition was associated most strongly with changes in IKG while modulation of IKL or Ih had minimal effects on post-stimulus inhibition suggesting that neuromodulators released in response to high frequency stimulation are responsible for mediating the post-stimulation bursting and subsequent long duration silence of thalamic neurons. The modeling also indicated that the axons of the model neurons responded robustly to suprathreshold stimulation despite the inhibitory effects on the soma. The findings suggest that during DBS the axons of thalamocortical neurons are activated while the cell bodies are inhibited thus blocking the transmission of pathological signals through the network and replacing them with high frequency regular firing. [ABSTRACT FROM AUTHOR]

Abstract: 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 (11–30Hz) 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 (8–20Hz) 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 &y& Elsevier]

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 μA 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM PUBLISHER]

Abstract: Local field potentials (LFPs) were recorded in 13 patients from pairs of microelectrodes driven through thalamus during functional localization prior to implantation of a thalamic deep brain stimulation electrode for treatment of tremor or pain. Six patients had a history of essential tremor (ET), 3 of multiple sclerosis, and the remaining 4 had symptoms of chronic pain. Specific to the ET group was the observation that oscillatory field potentials recorded from the two microelectrodes in the motor thalamus (ventralis intermedius — Vim, ventralis oralis posterior — Vop) were highly coherent at frequencies characteristic of pathological tremor (4–7 Hz). This stands in contrast to the significantly more desynchronized state observed in the somatosensory thalamus (ventralis caudalis — Vc) for that frequency band. In addition, higher frequency coherent oscillations typically associated with physiological tremor (8–12 Hz) were observed in the ET patients in motor thalamus and Vc and in motor thalamus of pain patients. An examination of the inter-frequency correlation of the LFPs in Vim and Vop showed that the low frequency theta waves correlated with high frequency oscillations in the beta and gamma ranges. These findings are consistent with and extend those of other studies suggesting that alterations in thalamic oscillatory activity are involved in the pathophysiology of ET and furthermore suggest that increased synchronization in the 4–7 Hz range is related to the occurrence of tremor in the ET patient group. Furthermore, they support the idea that therapies such as lesions and high frequency stimulation of the motor thalamus are effective in reducing tremor symptoms since they destroy the abnormal low frequency synchronization in motor thalamus. [Copyright &y& Elsevier]

Background: Deep brain stimulation (DBS) administered in the basal ganglia is an effective therapy for movement disorders; however, the mechanism(s) of action remain poorly understood. Objective: Because high-frequency electrical stimulation (HFS) preferentially activates fibers, one hypothesis of DBS action is that local release of transmitters from axon terminals underlies the inhibitory effects on spontaneous spiking observed in human intraoperative recordings. We hypothesize that blocking presynaptic release of transmitters will reduce any stimulation-induced effect and blocking of postsynaptic GABA receptors will reduce the inhibitory effect of HFS. Methods: We recorded neuronal responses after short HFS trains (2-37 μA, 0.5 seconds, 300 Hz) delivered through the recording electrode or via an adjacent electrode in 42 single globus pallidus (GP) units of anesthetized rats before and after injection of the synaptic blockers cobalt chloride (100 mM) and bicuculline methiodide (2 μg/μL). Results: Responses to HFS trains were mainly transient (∼350 milliseconds) inhibition of firing, but a late response (∼1-2 seconds) and rebound burst were also found. Excitation was observed in 4 of 43 neurons studied. Neurons with transient inhibition had the response attenuated by 47% after injection of either synaptic blocker, in part supporting the local gamma-aminobutyric acid release hypothesis. Bicuculline methiodide and cobalt attenuated the late response as well as the rebound burst response, but the late inhibitory response was increased by bicuculline methiodide in one case. HFS-induced excitatory responses were not altered by synaptic blockers suggesting direct stimulation of postsynaptic elements of GP neurons. Conclusions: The results indicate HFS induces the local inhibition of ongoing activity of the somal region of GP neurons as well as the stimulation of axons and active dendrites. These observations serve to shed light on the mechanism(s) of DBS. [Copyright &y& Elsevier]

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 (∼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. [ABSTRACT FROM AUTHOR]

Intraoperative microelectrode single unit recordings are routinely made in the subthalamic nucleus (STN) of awake and alert Parkinson’s disease (PD) patients during surgery for implantation of deep brain stimulation (DBS) electrodes. These recordings not only assist in determining the optimal target for electrode implantation, but also offer the unique opportunity to study movement-evoked responses from the basal ganglia. We report on the responses of human STN neurons to eye movements from eight PD patients (five men and three women). Twenty percent (18/89) of tested STN neurons showed responses to eye movements. Patients made pro-saccades, voluntary saccades or smooth pursuit eye movements in four directions: up, down, left, right. The majority of STN neurons (72% or 13/18), that responded to eye movements were found in the ventral half of the nucleus, while 58% (22/38) of STN neurons that had somatic responses were found in the dorsal half of the nucleus. The firing rate for STN oculomotor neurons was 33±15 Hz ( n=18), which was not different from that reported previously for STN neurons. Most neurons only responded to eye movements in a single direction, but 17% (3/18) showed responses to more than one direction. The majority of responses (17/18) to eye movements were increases in firing rate although one neuron did show a pause in firing with eye movement onset. The phasic changes in firing rate in response to eye movement usually occurred up to 250 ms following eye movement onset. Neurons were found that showed task-specific responses to cued versus self-paced saccades, responded to both passive limb movement and voluntary eye movement, and appeared to show either visual or attentional responses. These human physiological data, in conjunction with previous anatomical studies, suggest that the STN might have an oculomotor role. Although there is no evidence that STN is responsible for driving eye movements, it may have a role in either sensory feedback, corollary discharge, or in focusing the substantia nigra pars reticulata to allow a saccade to occur through disinhibition of the superior colliculus. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is caused by the degeneration of the dopaminergic neurons in the substantia nigra. Loss of dopaminergic innervation leads to hyperactivity in the internal segment of the globus pallidus (GPi), the main output nucleus of the basal ganglia and to a profound disturbance in the function of motor circuits. Lesions of the GPi (or in its upstream modulator, the subthalamic nucleus) can greatly improve the motor symptoms of PD presumably by reducing this pathological activity. Paradoxically, high-frequency electrical stimulation of the GPi (deep brain stimulation, DBS) mimics the effects of pallidotomy and has become an accepted therapeutic technique. The mechanisms underlying the beneficial effects of pallidal DBS are not known. Various mechanisms that might account for inhibiting or disrupting the pathological pallidal outflow by high-frequency DBS have been proposed ranging from depolarization block to stimulation-evoked release of GABA, and these are discussed. [ABSTRACT FROM AUTHOR]

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. • Population activity and single units in the STN and SNr distinguish infrequent from frequent tones. • OB + TM units distinguish infrequent from frequent tones earlier in time compared to pure OB units. • A model-switching analysis suggests that the population code changes over time. • Beta power decreases following oddball tones in the SNr, but not STN. [ABSTRACT FROM AUTHOR]

Abstract Deep brain stimulation of certain target structures within the basal ganglia is an effective therapy for the management of the motor symptoms of Parkinson's disease. However, its mechanisms, as well as the pathophysiology of Parkinson's disease, are varied and complex. The classical model of Parkinson's disease states that symptoms may arise as a result of increased neuronal activity in the basal ganglia output nuclei due to downregulated GABAergic striato-nigral/-pallidal projections. We sought to investigate the stimulation and levodopa induced effects on inhibitory synaptic plasticity in these basal ganglia output nuclei, and to determine the clinical relevance of altered plasticity with respect to patients' symptoms. Two closely spaced microelectrodes were advanced into the substantia nigra pars reticulata (potential novel therapeutic target for axial motor symptoms) or globus pallidus internus (conventional therapeutic target) in each of 28 Parkinson's disease patients undergoing subthalamic or pallidal deep brain stimulation surgery. Sets of 1 Hz test-pulses were delivered at different cathodal pulse widths (25, 50, 100, 150, 250 μs) in randomized order, before and after a train of continuous high frequency stimulation at 100 Hz. Increasing the pulse width led to progressive increases in both the amplitudes of extracellular focally evoked inhibitory field potentials and durations of neuronal silent periods. Both of these effects were augmented after a train of continuous high frequency stimulation. Additionally, reductions in the baseline neuronal firing rate persisted beyond 1 min after high frequency stimulation. We found greater enhancements of plasticity in the globus pallidus internus compared to the substantia nigra pars reticulata, and that intraoperative levodopa administration had a potent effect on the enhancement of nigral plasticity. We also found that lower levels of nigral plasticity were associated with higher severity motor symptoms. The findings of this study demonstrate that the efficacy of inhibitory synaptic transmission may be involved in the pathophysiology of Parkinson's disease, and furthermore may have implications for the development of novel stimulation protocols, and advancement of DBS technologies. Highlights • The output structures of the basal ganglia show inhibitory synaptic plasticity following high frequency stimulation (HFS). • This was shown by increased amplitudes of inhibitory evoked potentials and prolonged silent periods elicited by single pulses. • Additionally, a persistent reduction from the pre-stimulus baseline firing rate persisted for measured ~75 seconds after HFS. • The GPi demonstrated greater enhancements of inhibitory evoked potential amplitudes after HFS compared to the SNr. • Intraoperative administration of levodopa markedly increased plasticity in the SNr compared to the OFF-medication condition. • The degree of plasticity induced in each patient was inversely correlated to the severity of motor symptoms. [ABSTRACT FROM AUTHOR]

Abstract: 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. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To investigate an ocular motor role for the STN in Parkinson’s disease (PD) patients. Methods: Potentials were recorded from deep brain stimulation (DBS) electrodes implanted in the vicinity of STN in five PD patients, while patients simultaneously performed visually cued saccades, self-paced saccades and in two patients self-paced wrist extensions. Results: Premovement potentials related to visually cued saccades were found in 4/5 patients and 56% (5/9) of potentials showed phase reversal indicating a local generator. Onsets of these potentials began closer to saccade initiation from STN contacts (0.88±0.30s) than thalamic ones (1.39±0.28s). Self-paced saccade-related potentials were found in 4/4 patients. Self-paced saccade potential onsets (1.82±0.88s) were not different from self-paced wrist extension onsets (1.27±0.98s), suggesting a non-specific mechanism could be responsible for both potentials. 50% (3/6) of potentials to self-paced saccades and 66% (2/3) of potentials to self-paced wrist extensions showed phase reversal. Potentials could be found either ipsilaterally or contralaterally with respect to saccade direction. Conclusions: These subcortical premovement potentials to saccades are similar to Bereitschaftspotentials and contingent negative variations to limb movements recorded in cortical and subcortical regions. Significance: These studies further support a role of STN in ocular motor control and suggest a common mechanism of motor preparation for both eye and limb movements in the basal ganglia. [Copyright &y& Elsevier]

Objective: To examine the location of deep brain stimulation (DBS) electrode somatosensory evoked potentials (SEPs) and determine the generators of the median nerve SEPs recorded in thalamus and subthalamic nucleus (STN).Methods: SEPs were recorded from contacts of DBS electrodes and microelectrodes in thalamus and STN to establish the latencies of N13, N18 and N20 in 24 patients (8 tremor, 4 chronic pain, 12 Parkinson disease) undergoing chronic DBS.Results: A large SEP with a mean latency of 17.9±1.7ms was recorded from thalamic contacts. Phase reversal occurred at the horizontal level of the anterior commissure-posterior commissure line. Smaller potentials with similar latency but no reversal could be recorded from STN electrodes.Conclusions: We propose that the thalamic SEP is generated by excitatory post-synaptic potentials in sensory relay neurons in nucleus ventrocaudalis. A small potential in STN at a similar latency, may be due to volume conduction from thalamus. Intraoperative and postoperative SEP recordings from DBS electrodes could be used to determine the optimal position of the contacts relative to the sensory pathways and the choice of contacts for chronic stimulation. [Copyright &y& Elsevier]