Subthalamic and pallidal neurons are modulated during externally cued movements in Parkinson's disease.

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.

Differences in Olivo-Cerebellar Circuit and Cerebellar Network Connectivity in Essential Tremor: a Resting State fMRI Study.

The olivo-cerebellar circuit is thought to play a crucial role in the pathophysiology of essential tremor (ET). Whether olivo-cerebellar circuit dysfunction is also present at rest, in the absence of clinical tremor and linked voluntary movement, remains unclear. Assessing this network in detail with fMRI is challenging, considering the brainstem is close to major arteries and pulsatile cerebrospinal fluid-filled spaces obscuring signals of interest. Here, we used methods tailored to the analysis of infratentorial structures. We hypothesize that the olivo-cerebellar circuit shows altered intra-network connectivity at rest and decreased functional coupling with other parts of the motor network in ET. In 17 ET patients and 19 healthy controls, we investigated using resting state fMRI intracerebellar functional and effective connectivity on a dedicated cerebellar atlas. With independent component analysis, we investigated data-driven cerebellar motor network activations during rest. Finally, whole-brain connectivity of cerebellar motor structures was investigated using identified components. In ET, olivo-cerebellar pathways show decreased functional connectivity compared with healthy controls. Effective connectivity analysis showed an increased inhibitory influence of the dentate nucleus towards the inferior olive. Cerebellar independent component analyses showed motor resting state networks are less strongly connected to the cerebral cortex compared to controls. Our results indicate the olivo-cerebellar circuit to be affected at rest. Also, the cerebellum is "disconnected" from the rest of the motor network. Aberrant activity, generated within the olivo-cerebellar circuit could, during action, spread towards other parts of the motor circuit and potentially underlie the characteristic tremor of this patient group.

Validation of Soft Multipin Dry EEG Electrodes.

Current developments towards multipin, dry electrodes in electroencephalography (EEG) are promising for applications in non-laboratory environments. Dry electrodes do not require the application of conductive gel, which mostly confines the use of gel EEG systems to the laboratory environment. The aim of this study is to validate soft, multipin, dry EEG electrodes by comparing their performance to conventional gel EEG electrodes. Fifteen healthy volunteers performed three tasks, with a 32-channel gel EEG system and a 32-channel dry EEG system: the 40 Hz Auditory Steady-State Response (ASSR), the checkerboard paradigm, and an eyes open/closed task. Within-subject analyses were performed to compare the signal quality in the time, frequency, and spatial domains. The results showed strong similarities between the two systems in the time and frequency domains, with strong correlations of the visual (ρ = 0.89) and auditory evoked potential (ρ = 0.81), and moderate to strong correlations for the alpha band during eye closure (ρ = 0.81-0.86) and the 40 Hz-ASSR power (ρ = 0.66-0.72), respectively. However, delta and theta band power was significantly increased, and the signal-to-noise ratio was significantly decreased for the dry EEG system. Topographical distributions were comparable for both systems. Moreover, the application time of the dry EEG system was significantly shorter (8 min). It can be concluded that the soft, multipin dry EEG system can be used in brain activity research with similar accuracy as conventional gel electrodes.

Intermittent cortical involvement in the preservation of tremor in essential tremor.

Cortical involvement in essential tremor, an involuntary action tremor supposedly of subcortical origin, is uncertain. Conflicting results of corticomuscular coherence studies in essential tremor suggest an intermittent corticomuscular coupling. On the basis of the literature, we hypothesized that corticomuscular coupling is influenced by bilateral motor synchronization and "cognitive states" such as awareness of tremor. In the present study, we investigated 1) the existence of intermittent corticomuscular coherence (CMC) in essential tremor and 2) factors that influence CMC strength. In 18 essential tremor patients and 18 healthy controls, who mimicked tremor, we simultaneously recorded 64-channel EEG and 6-channel bipolar surface EMG from right and left wrist extensors and flexors. Right-sided (mimicked) hand tremor was recorded with and without a cognitive arithmetic task and with left-sided (mimicked) hand tremor. CMC values per task were compared within and between groups. Changes in CMC strength during tasks were calculated. Our main findings are 1) significant CMC around the (mimicked) tremor frequency across all tasks in both groups; 2) significant differences in CMC between unilateral tasks, with the highest values during the cognitive task only in the essential tremor group; and 3) significant fluctuations of CMC strength over time, independent of the tremor intensity, only in the essential tremor group. Our results suggest a limited role, and certainly not a continuous steering role, of sensorimotor cortical neurons in the generation of tremor. In clinical practice, these findings might help to standardize tremor registration and the interpretation of the analysis.NEW & NOTEWORTHY The part of the motor cortex involved in essential tremor is uncertain. The current electrophysiological study is the first to assess corticomuscular coherence systematically. The study shows a dynamic nature of corticomuscular coherence and a possible influence of cognitive states. The results elucidate the involvement of the motor cortex in tremor and help interpret the varying results in the literature. In clinical practice, the findings may guide in standardizing tremor registration and its interpretation.

High-frequency electrical stimulation suppresses cholinergic accumbens interneurons in acute rat brain slices through GABA(B) receptors.

The nucleus accumbens is selected as a surgical target in deep brain stimulation for treating refractory obsessive-compulsive disorder (OCD). One of the therapeutic benefits of this procedure is that the abnormal hyper-functioning prefrontal cortex of patients with OCD is restored during stimulation. One hypothesis regarding the mechanism of deep brain stimulation is that the neuronal electrophysiological properties are directly altered by electrical stimulation; another hypothesis assumes that the stimulation induces selective neuron transmitter release, such as γ-aminobutyric acid (GABA). In this study, we used multi-electrode arrays with electrode size of 40 × 40 µm to record electrophysiological signals from the large nucleus accumbens neurons in acute rat brain slices while applying electrical stimulation simultaneously. We revealed that high-frequency stimulation (HFS, 140 Hz) suppressed the spontaneous neuronal firing rate significantly, whereas low-frequency stimulation (LFS, 10 Hz) did not. Both HFS and LFS have no effect on neuronal firing pattern or on neuronal oscillation synchrony. GABAB receptor antagonism reversed the HFS-provoked neuronal inhibition, whereas GABAA receptor blockade failed to affect it. The recorded neurons were pharmacologically identified to be cholinergic interneurons. We propose that HFS has a direct suppressive effect on the identified accumbal acetylcholine (ACh) interneurons by enhancing GABA release in the stimulated region. Potentially, suppressed ACh interneurons decrease the disinhibiting function of medium-sized spiny neurons in the striato-thalamo-cortical circuit. This finding might give an indication of the mechanism of the therapeutic effect of HFS in nucleus accumbens on restoring the abnormal hyperactive prefrontal cortex status in OCD.

Pallidal gap junctions-triggers of synchrony in Parkinson's disease?

Although increased synchrony of the neural activity in the basal ganglia may underlie the motor deficiencies exhibited in Parkinson's disease (PD), how this synchrony arises, propagates through the basal ganglia, and changes under dopamine replacement remains unknown. Gap junctions could play a major role in modifying this synchrony, because they show functional plasticity under the influence of dopamine and after neural injury. In this study, confocal imaging was used to detect connexin-36, the major neural gap junction protein, in postmortem tissues of PD patients and control subjects in the putamen, subthalamic nucleus (STN), and external and internal globus pallidus (GPe and GPi, respectively). Moreover, we quantified how gap junctions affect synchrony in an existing computational model of the basal ganglia. We detected connexin-36 in the human putamen, GPe, and GPi, but not in the STN. Furthermore, we found that the number of connexin-36 spots in PD tissues increased by 50% in the putamen, 43% in the GPe, and 109% in the GPi compared with controls. In the computational model, gap junctions in the GPe and GPi strongly influenced synchrony. The basal ganglia became especially susceptible to synchronize with input from the cortex when gap junctions were numerous and high in conductance. In conclusion, connexin-36 expression in the human GPe and GPi suggests that gap junctional coupling exists within these nuclei. In PD, neural injury and dopamine depletion could increase this coupling. Therefore, we propose that gap junctions act as a powerful modulator of synchrony in the basal ganglia.

Effects of STN DBS and auditory cueing on the performance of sequential movements and the occurrence of action tremor in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) patients show a higher ability to perform repetitive movements when they are cued by external stimuli, suggesting that rhythmic synchronization with an auditory timekeeper can be achieved in the absence of intact basal ganglia function. Deep brain stimulation (DBS) is another therapeutic method that improves movement performance in PD and may suppress or enhance action tremor. However, the combined effect of these therapies on action tremor has not been studied yet. In this pilot study, we thus test the effect of both DBS in the subthalamic nucleus (STN) and auditory cueing on movement performance and action tremor. METHODS: 7 PD patients treated with (bilateral) STN DBS were asked to move one hand or foot between two dots, separated by 30 cm as indicated on the table or the floor. The movement frequency was dictated by a metronome with a frequency in the range of 1.6 to 4.8 Hz. Each test was repeated three times for each extremity, with different stimulation settings applied during each repetition. The power spectral density patterns of recorded movements were studied. Tremor intermittency was taken into account by classifying each 2-second window of the recorded angular velocity signals as a tremor or non-tremor window. By determining the phase locking value it was tested whether movement or tremor was synchronized with the auditory cue. RESULTS: While action tremor presence or absence did not affect the level of synchronization of the movement signal with the auditory cue for the different metronome frequencies, the number of extremities showing action tremor was significantly reduced under external cueing conditions in combination with DBS. In this respect the cueing frequencies of 1.6 and 4.8 Hz showed similar effects, suggesting that the frequency of the cueing signal is not that critical. CONCLUSION: The combination of deep brain stimulation and auditory cueing, which both are proposed to involve the activation of cerebellar circuits, shows an enhanced action tremor reduction in Parkinson's disease.

Power spectral density analysis of physiological, rest and action tremor in Parkinson's disease patients treated with deep brain stimulation.

BACKGROUND: Observation of the signals recorded from the extremities of Parkinson's disease patients showing rest and/or action tremor reveal a distinct high power resonance peak in the frequency band corresponding to tremor. The aim of the study was to investigate, using quantitative measures, how clinically effective and less effective deep brain stimulation protocols redistribute movement power over the frequency bands associated with movement, pathological and physiological tremor, and whether normal physiological tremor may reappear during those periods that tremor is absent. METHODS: The power spectral density patterns of rest and action tremor were studied in 7 Parkinson's disease patients treated with (bilateral) deep brain stimulation of the subthalamic nucleus. Two tests were carried out: 1) the patient was sitting at rest; 2) the patient performed a hand or foot tapping movement. Each test was repeated four times for each extremity with different stimulation settings applied during each repetition. Tremor intermittency was taken into account by classifying each 3-second window of the recorded angular velocity signals as a tremor or non-tremor window. RESULTS: The distribution of power over the low frequency band (<3.5 Hz - voluntary movement), tremor band (3.5-7.5 Hz) and high frequency band (>7.5 Hz - normal physiological tremor) revealed that rest and action tremor show a similar power-frequency shift related to tremor absence and presence: when tremor is present most power is contained in the tremor frequency band; when tremor is absent lower frequencies dominate. Even under resting conditions a relatively large low frequency component became prominent, which seemed to compensate for tremor. Tremor absence did not result in the reappearance of normal physiological tremor. CONCLUSION: Parkinson's disease patients continuously balance between tremor and tremor suppression or compensation expressed by power shifts between the low frequency band and the tremor frequency band during rest and voluntary motor actions. This balance shows that the pathological tremor is either on or off, with the latter state not resembling that of a healthy subject. Deep brain stimulation can reverse the balance thereby either switching tremor on or off.

Subthalamic neuronal responses to cortical stimulation.

BACKGROUND: Deep brain stimulation of the subthalamic nucleus alleviates motor symptoms in Parkinson's disease patients. However, some patients suffer from cognitive and emotional changes. These side effects are most likely caused by current spread to the cognitive and limbic territories in the subthalamic nucleus. The aim of this study was to identify the motor part of the subthalamic nucleus to reduce stimulation-induced behavioral side effects, by using motor cortex stimulation. METHODS: We describe the results of subthalamic nucleus neuronal responses to stimulation of the hand area of the motor cortex and evaluate the safety of this novel technique. RESULTS: Responses differed between regions within the subthalamic nucleus. In the anterior and lateral electrode at dorsal levels of the subthalamic nucleus, an early excitation (∼5-45 ms) and subsequent inhibition (45-105 ms) were seen. The lateral electrode also showed a late excitation (∼125-160 ms). Focal seizures were observed following motor cortex stimulation. CONCLUSIONS: To prevent seizures the current density should be lowered, so that motor cortex stimulation-evoked responses can be safely used during deep brain stimulation surgery.

Intraoperative Quantification of MDS-UPDRS Tremor Measurements Using 3D Accelerometry: A Pilot Study.

The most frequently used method for evaluating tremor in Parkinson's disease (PD) is currently the internationally standardized Movement Disorder Society­Unified PD Rating Scale (MDS-UPDRS). However, the MDS-UPDRS is associated with limitations, such as its inherent subjectivity and reliance on experienced raters. Objective motor measurements using accelerometry may overcome the shortcomings of visually scored scales. Therefore, the current study focuses on translating the MDS-UPDRS tremor tests into an objective scoring method using 3D accelerometry. An algorithm to measure and classify tremor according to MDS-UPDRS criteria is proposed. For this study, 28 PD patients undergoing neurosurgical treatment and 26 healthy control subjects were included. Both groups underwent MDS-UPDRS tests to rate tremor severity, while accelerometric measurements were performed at the index fingers. All measurements were performed in an off-medication state. Quantitative measures were calculated from the 3D acceleration data, such as tremor amplitude and area-under-the-curve of power in the 4−6 Hz range. Agreement between MDS-UPDRS tremor scores and objective accelerometric scores was investigated. The trends were consistent with the logarithmic relationship between tremor amplitude and MDS-UPDRS score reported in previous studies. The accelerometric scores showed a substantial concordance (>69.6%) with the MDS-UPDRS ratings. However, accelerometric kinetic tremor measures poorly associated with the given MDS-UPDRS scores (R2 < 0.3), mainly due to the noise between 4 and 6 Hz found in the healthy controls. This study shows that MDS-UDPRS tremor tests can be translated to objective accelerometric measurements. However, discrepancies were found between accelerometric kinetic tremor measures and MDS-UDPRS ratings. This technology has the potential to reduce rater dependency of MDS-UPDRS measurements and allow more objective intraoperative monitoring of tremor.

Comparison of methodologies for modeling directional deep brain stimulation electrodes.

Deep brain stimulation (DBS) is an established clinical therapy, and directional DBS electrode designs are now commonly used in clinical practice. Directional DBS leads have the ability to increase the therapeutic window of stimulation, but they also increase the complexity of clinical programming. Therefore, computational models of DBS have become available in clinical software tools that are designed to assist in the identification of therapeutic settings. However, the details of how the DBS model is implemented can influence the predictions of the software. The goal of this study was to compare different methods for representing directional DBS electrodes within finite element volume conductor (VC) models. We evaluated 15 different DBS VC model variants and quantified how their differences influenced estimates on the spatial extent of axonal activation from DBS. Each DBS VC model included the same representation of the brain and head, but the details of the current source and electrode contact were different for each model variant. The more complex VC models explicitly represented the DBS electrode contacts, while the more simple VC models used boundary condition approximations. The more complex VC models required 2-3 times longer to mesh, build, and solve for the DBS voltage distribution than the more simple VC models. Differences in individual axonal activation thresholds across the VC model variants were substantial (-24% to +47%). However, when comparing total activation of an axon population, or estimates of an activation volume, the differences between model variants decreased (-7% to +8%). Nonetheless, the technical details of how the electrode contact and current source are represented in the DBS VC model can directly affect estimates of the voltage distribution and electric field in the brain tissue.

The Beneficial Effects of Conventional Visual Cues Are Retained When Augmented Reality Glasses Are Worn.

Wearing smart glasses may be distracting and thus annihilate the beneficial effects of cues on freezing of gait in Parkinson's disease. Furthermore, augmented reality cues might be effective in reducing FOG specifically in cueing-responsive patients. We present a single-patient study in which a patient with Parkinson's disease traversed a doorway under different cueing conditions. Wearing augmented reality (AR) glasses did not deteriorate FOG nor affect the beneficial effects of cues. The AR visual cues did not improve FOG. This single-patient study implies that the current design of AR glasses does not stand in the way of the development of augmented reality visual cues. However, the effectivity of augmented reality visual cues remains to be proven.

The Effects of Augmented Reality Visual Cues on Turning in Place in Parkinson's Disease Patients With Freezing of Gait.

Background: Turning in place is particularly bothersome for patients with Parkinson's disease (PD) experiencing freezing of gait (FOG). Cues designed to enforce goal-directed turning are not yet available. Objectives: Assess whether augmented reality (AR) visual cues improve FOG and turning in place in PD patients with FOG. Methods: Sixteen PD patients with FOG performed a series of 180° turns under an experimental condition with AR visual cues displayed through a HoloLens and two control conditions (one consisting of auditory cues and one without any cues). FOG episodes were annotated by two independent raters from video recordings. Motion data were measured with 17 inertial measurement units for calculating axial kinematics, scaling, and timing of turning. Results: AR visual cues did not reduce the percent time frozen (p = 0.73) or the number (p = 0.73) and duration (p = 0.78) of FOG episodes compared to the control condition without cues. All FOG parameters were higher with AR visual cues than with auditory cues [percent time frozen (p = 0.01), number (p = 0.02), and duration (p = 0.007) of FOG episodes]. The AR visual cues did reduce the peak angular velocity (visual vs. uncued p = 0.03; visual vs. auditory p = 0.02) and step height (visual vs. uncued p = 0.02; visual vs. auditory p = 0.007), and increased the step height coefficient of variation (visual vs. uncued p = 0.04; visual vs. auditory p = 0.01) and time to maximum head-pelvis separation (visual vs. uncued p = 0.02; visual vs. auditory p = 0.005), compared to both control conditions. Conclusions: The AR visual cues in this study did not reduce FOG, and worsened some measures of axial kinematics, and turn scaling and timing. Stimulating goal-directed turning might, by itself, be insufficient to reduce FOG and improve turning performance. Trial Registration: This study was registered in the Dutch trial registry (NTR6409; 2017-02-16).

Frequency-selectivity of a thalamocortical relay neuron during Parkinson's disease and deep brain stimulation: a computational study.

In this computational study, we investigated (i) the functional importance of correlated basal ganglia (BG) activity associated with Parkinson's disease (PD) motor symptoms by analysing the effects of globus pallidus internum (GPi) bursting frequency and synchrony on a thalamocortical (TC) relay neuron, which received GABAergic projections from this nucleus; (ii) the effects of subthalamic nucleus (STN) deep brain stimulation (DBS) on the response of the TC relay neuron to synchronized GPi oscillations; and (iii) the functional basis of the inverse relationship that has been reported between DBS frequency and stimulus amplitude, required to alleviate PD motor symptoms [A. L. Benabid et al. (1991)Lancet, 337, 403-406]. The TC relay neuron selectively responded to and relayed synchronized GPi inputs bursting at a frequency located in the range 2-25 Hz. Input selectivity of the TC relay neuron is dictated by low-threshold calcium current dynamics and passive membrane properties of the neuron. STN-DBS prevented the TC relay neuron from relaying synchronized GPi oscillations to cortex. Our model indicates that DBS alters BG output and input selectivity of the TC relay neuron, providing an explanation for the clinically observed inverse relationship between DBS frequency and stimulus amplitude.

Single-Cell Recordings to Target the Anterior Nucleus of the Thalamus in Deep Brain Stimulation for Patients with Refractory Epilepsy.

Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is a promising treatment for patients with refractory epilepsy. However, therapy response varies and precise positioning of the DBS lead is potentially essential for maximizing therapeutic efficacy. We investigate if single-cell recordings acquired by microelectrode recordings can aid targeting of the ANT during surgery and hypothesize that the neuronal firing properties of the target region relate to clinical outcome. We prospectively included 10 refractory epilepsy patients and performed microelectrode recordings under general anesthesia to identify the change in neuronal signals when approaching and transecting the ANT. The neuronal firing properties of the target region, anatomical locations of microelectrode recordings and active contact positions of the DBS lead along the recorded trajectory were compared between responders and nonresponders to DBS. We obtained 19 sets of recordings from 10 patients (five responders and five nonresponders). Amongst the 403 neurons detected, 365 (90.6%) were classified as bursty. Entry into the ANT was characterized by an increase in firing rate while exit of the ANT was characterized by a decrease in firing rate. Comparing the trajectories of responders to nonresponders, we found differences neither in the neuronal firing properties themselves nor in their locations relative to the position of the active contact. Single-cell firing rate acquired by microelectrode recordings under general anesthesia can thus aid targeting of the ANT during surgery, but is not related to clinical outcome in DBS for patients with refractory epilepsy.

The subthalamic nucleus part II: modelling and simulation of activity.

Part I of The Subthalamic Nucleus (volume 198) (STN) accentuates the gap between experimental animal and human information concerning subthalamic development, cytology, topography and connections.The light and electron microscopical cytology focuses on the open nucleus concept and the neuronal types present in the STN. The cytochemistry encompasses enzymes, NO, glial fibrillary acidic protein (GFAP), calcium binding proteins, and receptors (dopamine, cannabinoid, opioid, glutamate, gamma-aminobutyric acid (GABA), serotonin, cholinergic, and calcium channels). The ontogeny of the subthalamic cell cord is also reviewed. The topography concerns the rat, cat, baboon and human STN. The descriptions of the connections are also given from a historical point of view. Recent tracer studies on the rat nigro-subthalamic connection revealed contralateral projections. This monograph (Part II of the two volumes) on the subthalamic nucleus (STN) starts with a systemic model of the basal ganglia to evaluate the position of the STN in the direct, indirect and hyperdirect pathways. A summary of in vitro studies is given, describing STN spontaneous activity as well as responses to depolarizing and hyperpolarizing inputs and high-frequency stimulation. STN bursting activity and the underlying ionic mechanisms are investigated. Deep brain stimulation used for symptomatic treatment of Parkinson's disease is discussed in terms of the elements that are influenced and its hypothesized mechanisms. This part of the monograph explores the pedunculopontine-subthalamic connections and summarizes attempts to mimic neurotransmitter actions of the pedunculopontine nucleus in cell cultures and high-frequency stimulation on cultured dissociated rat subthalamic neurons. STN cell models - single- and multi-compartment models and system-level models are discussed in relation to subthalamic function and dysfunction. Parts I and II are compared.

The subthalamic nucleus. Part I: development, cytology, topography and connections.

This monograph (Part I of two volumes) on the subthalamic nucleus (STN) accentuates the gap between experimental animal and human information concerning subthalamic development, cytology, topography and connections. The light and electron microscopical cytology focuses on the open nucleus concept and the neuronal types present in the STN. The cytochemistry encompasses enzymes, NO, glial fibrillary acidic protein (GFAP), calcium binding proteins, and receptors (dopamine, cannabinoid, opioid, glutamate, gamma-aminobutyric acid (GABA), serotonin, cholinergic, and calcium channels). The ontogeny of the subthalamic cell cord is also reviewed. The topography concerns the rat, cat, baboon and human STN. The descriptions of the connections are also given from a historical point of view. Recent tracer studies on the rat nigro-subthalamic connection revealed contralateral projections. Part II of the two volumes (volume 199) on the subthalamic nucleus (STN) starts with a systemic model of the basal ganglia to evaluate the position of the STN in the direct, indirect and hyperdirect pathways. A summary of in vitro studies is given, describing STN spontaneous activity as well as responses to depolarizing and hyperpolarizing inputs and high-frequency stimulation. STN bursting activity and the underlying ionic mechanisms are investigated. Deep brain stimulation used for symptomatic treatment of Parkinson's disease is discussed in terms of the elements that are influenced and its hypothesized mechanisms. This part of the monograph explores the pedunculopontine-subthalamic connections and summarizes attempts to mimic neurotransmitter actions of the pedunculopontine nucleus in cell cultures and high-frequency stimulation on cultured dissociated rat subthalamic neurons. STN cell models--single- and multi-compartment models and system-level models are discussed in relation to subthalamic function and dysfunction. Parts I and II are compared.

Usability of Three-dimensional Augmented Visual Cues Delivered by Smart Glasses on (Freezing of) Gait in Parkinson's Disease.

External cueing is a potentially effective strategy to reduce freezing of gait (FOG) in persons with Parkinson's disease (PD). Case reports suggest that three-dimensional (3D) cues might be more effective in reducing FOG than two-dimensional cues. We investigate the usability of 3D augmented reality visual cues delivered by smart glasses in comparison to conventional 3D transverse bars on the floor and auditory cueing via a metronome in reducing FOG and improving gait parameters. In laboratory experiments, 25 persons with PD and FOG performed walking tasks while wearing custom-made smart glasses under five conditions, at the end-of-dose. For two conditions, augmented visual cues (bars/staircase) were displayed via the smart glasses. The control conditions involved conventional 3D transverse bars on the floor, auditory cueing via a metronome, and no cueing. The number of FOG episodes and percentage of time spent on FOG were rated from video recordings. The stride length and its variability, cycle time and its variability, cadence, and speed were calculated from motion data collected with a motion capture suit equipped with 17 inertial measurement units. A total of 300 FOG episodes occurred in 19 out of 25 participants. There were no statistically significant differences in number of FOG episodes and percentage of time spent on FOG across the five conditions. The conventional bars increased stride length, cycle time, and stride length variability, while decreasing cadence and speed. No effects for the other conditions were found. Participants preferred the metronome most, and the augmented staircase least. They suggested to improve the comfort, esthetics, usability, field of view, and stability of the smart glasses on the head and to reduce their weight and size. In their current form, augmented visual cues delivered by smart glasses are not beneficial for persons with PD and FOG. This could be attributable to distraction, blockage of visual feedback, insufficient familiarization with the smart glasses, or display of the visual cues in the central rather than peripheral visual field. Future smart glasses are required to be more lightweight, comfortable, and user friendly to avoid distraction and blockage of sensory feedback, thus increasing usability.

Cortico-subthalamic inputs from the motor, limbic, and associative areas in normal and dopamine-depleted rats are not fully segregated.

The subthalamic nucleus (STN) receives monosynaptic glutamatergic afferents from different areas of the cortex, known as the "hyperdirect" pathway. The STN has been divided into three distinct subdivisions, motor, limbic, and associative parts in line with the concept of parallel information processing. The extent to which the parallel information processing coming from distinct cortical areas overlaps in the different territories of the STN is still a matter of debate and the proposed role of dopaminergic neurons in maintaining the coherence of responses to cortical inputs in each territory is not documented. Using extracellular electrophysiological approaches, we investigated to what degree the motor and non-motor regions in the STN are segregated in control and dopamine (DA) depleted rats. We performed electrical stimulation of different cortical areas and recorded STN neuronal responses. We showed that motor and non-motor cortico-subthalamic pathways are not fully segregated, but partially integrated in the rat. This integration was mostly present through the indirect pathway. The spatial distribution and response latencies were the same in sham and 6-hydroxydopamine lesioned animals. The inhibitory phase was, however, less apparent in the lesioned animals. In conclusion, this study provides the first evidence that motor and non-motor cortico-subthalamic pathways in the rat are not fully segregated, but partially integrated. This integration was mostly present through the indirect pathway. We also show that the inhibitory phase induced by GABAergic inputs from the external segment of the globus pallidus is reduced in the DA-depleted animals.

Spatial Localization of Sources in the Rat Subthalamic Motor Region Using an Inverse Current Source Density Method.

Objective: In this study we introduce the use of the current source density (CSD) method as a way to visualize the spatial organization of evoked responses in the rat subthalamic nucleus (STN) at fixed time stamps resulting from motor cortex stimulation. This method offers opportunities to visualize neuronal input and study the relation between the synaptic input and the neural output of neural populations. Approach: Motor cortex evoked local field potentials and unit activity were measured in the subthalamic region, with a 3D measurement grid consisting of 320 measurement points and high spatial resolution. This allowed us to visualize the evoked synaptic input by estimating the current source density (CSD) from the measured local field potentials, using the inverse CSD method. At the same time, the neuronal output of the cells within the grid is assessed by calculating post stimulus time histograms. Main results: The CSD method resulted in clear and distinguishable sources and sinks of the neuronal input activity in the STN after motor cortex stimulation. We showed that the center of the synaptic input of the STN from the motor cortex is located dorsal to the input from globus pallidus. Significance: For the first time we have performed CSD analysis on motor cortex stimulation evoked LFP responses in the rat STN as a proof of principle. Our results suggest that the CSD method can be used to gain new insights into the spatial extent of synaptic pathways in brain structures.