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.

Advanced target identification in STN-DBS with beta power of combined local field potentials and spiking activity.

BACKGROUND: In deep brain stimulation of the subthalamic nucleus (STN-DBS) for Parkinson's Disease (PD), often microelectrode recordings (MER) are used for STN identification. However, for advanced target identification of the sensorimotor STN, it may be relevant to use local field potential (LFP) recordings. Then, it is important to assure that the measured oscillations are coming from the close proximity of the electrode. NEW METHOD: Through multiple simultaneous recordings of LFP and neuronal spiking, we investigated the temporal relationship between local neuronal spiking and more global LFP. We analyzed the local oscillations in the LFP by calculating power only over specific frequencies that show a significant coherence between LFP and neuronal spiking. Using this 'coherence method', we investigated how well measurements in the sensorimotor STN could be discriminated from measurements elsewhere in the STN. RESULTS/COMPARISON WITH EXISTING METHODS: The 'sensorimotor power index' (SMPI) of beta frequencies, representing the ability to discriminate sensorimotor STN measurements based on the beta power, was significantly larger using the 'coherence method' for LFP spectral analysis compared to other methods where either the complete LFP beta spectrum or only the prominent peaks in the LFP beta spectrum were used to calculate beta power. CONCLUSIONS: The results suggest that due to volume conduction of beta frequency oscillations, proper localization of the sensorimotor STN with only LFP recordings is difficult. However, combining recordings of LFP and neuronal spiking and calculating beta power over the coherent parts of the LFP spectrum can be beneficial in discriminating the sensorimotor STN.

Cortically evoked potentials in the human subthalamic nucleus.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) alleviates motor symptoms in Parkinson's disease (PD) patients. However, in a substantial number of patients the beneficial effects of STN DBS are overshadowed by psychiatric side effects. We hypothesize that stimulation of the STN motor area will provide the optimal effect on the motor symptoms without inducing these side effects, and expect that motor cortex stimulation (MCS) evokes a spatially specific response within the STN, which identifies the STN motor area. We previously showed that MCS evokes responses in the unit activity specifically within certain areas of the STN. Unit activity is generally considered a measure of the output activity. To gain more insight into the neuronal input into the STN, we describe the results of cortically evoked subthalamic local field potentials (LFPs). We show that the cortically evoked LFPs follow a certain temporal and spatial pattern. The significant peaks of the evoked LFPs coincide with the timing of some of the inhibitions and excitations present in the unit responses. The spatial resolution of responses measured in the LFP to MCS is not high enough to identify the STN motor region. However, we believe that optimizing targeting techniques and the development of novel DBS electrodes will improve STN DBS therapy for PD patients.

Motor cortex stimulation for Parkinson's disease: a modelling study.

Chronic motor cortex stimulation (MCS) is currently being investigated as a treatment method for Parkinson's disease (PD). Unfortunately, the underlying mechanisms of this treatment are unclear and there are many uncertainties regarding the most effective stimulation parameters and electrode configuration. In this paper, we present a MCS model with a 3D representation of several axonal populations. The model predicts that the activation of either the basket cell or pyramidal tract (PT) type axons is involved in the clinical effect of MCS. We propose stimulation protocols selectively targeting one of these two axon types. To selectively target the basket cell axons, our simulations suggest using either cathodal or bipolar stimulation with the electrode strip placed perpendicular rather than parallel to the gyrus. Furthermore, selectivity can be increased by using multiple cathodes. PT type axons can be selectively targeted with anodal stimulation using electrodes with large contact sizes. Placing the electrode epidurally is advisable over subdural placement. These selective protocols, when practically implemented, can be used to further test which axon type should be activated for clinically effective MCS and can subsequently be applied to optimize treatment. In conclusion, this paper increases insight into the neuronal population involved in the clinical effect of MCS on PD and proposes strategies to improve this therapy.

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.

Mild dopaminergic lesions are accompanied by robust changes in subthalamic nucleus activity.

The subthalamic nucleus (STN) is a major player in the input and output of the basal ganglia motor circuitry. The neuronal regular firing pattern of the STN changes into a pathological bursting mode in both advanced Parkinson's disease (PD) and in PD animals models with severe dopamine depletion. One of the current hypothesis, based on clinical and experimental evidence, is that this typical burst activity is responsible for some of the principal motor symptoms. In the current study we tested whether mild DA depletion, mimicking early stages of PD, induced deficits in motor behaviour and changes in STN neuronal activity. The present study demonstrated that rats with a mild lesion (20-40% loss of DA neurons) and a slowed motor response, but without gross motor abnormalities already have an increased number of bursty STN neurons under urethane anaesthesia. These findings indicate that the early increase in STN burst activity is a compensatory mechanism to maintain the dopamine homeostasis in the basal ganglia.

Ambulatory monitoring of activities and motor symptoms in Parkinson's disease.

Ambulatory monitoring of motor symptoms in Parkinsons disease (PD) can improve our therapeutic strategies, especially in patients with motor fluctuations. Previously published monitors usually assess only one or a few basic aspects of the cardinal motor symptoms in a laboratory setting. We developed a novel ambulatory monitoring system that provides a complete motor assessment by simultaneously analyzing current motor activity of the patient (e.g. sitting, walking) and the severity of many aspects related to tremor, bradykinesia, and hypokinesia. The monitor consists of a set of four inertial sensors. Validity of our monitor was established in seven healthy controls and six PD patients treated with deep brain stimulation (DBS) of the subthalamic nucleus. Patients were tested at three different levels of DBS treatment. Subjects were monitored while performing different tasks, including motor tests of the Unified Parkinsons Disease Rating Scale (UPDRS). Output of the monitor was compared to simultaneously recorded videos. The monitor proved very accurate in discriminating between several motor activities. Monitor output correlated well with blinded UPDRS ratings during different DBS levels. The combined analysis of motor activity and symptom severity by our PD monitor brings true ambulatory monitoring of a wide variety of motor symptoms one step closer..