Subthalamic dynamic neural states correlate with motor symptoms in Parkinson’s Disease

ObjectiveThis study aims to discriminate the dynamic synchronization states from the subthalamic local field potentials and investigate their correlations with the motor symptoms in Parkinson’s Disease (PD).MethodsThe resting-state local field potentials of 10 patients with PD were recorded from the subthalamic nucleus. The dynamic neural states of multiple oscillations were discriminated and analyzed. The Spearman correlation was used to investigate the correlations between occurrence rate or duration of dynamic neural states and the severity of motor symptoms.ResultsThe proportion of long low-beta and theta synchronized state was significantly correlated with the general motor symptom and tremor, respectively. The duration of combined low/high-beta state was significantly correlated with rigidity, and the duration of combined alpha/high-beta state was significantly correlated with bradykinesia.ConclusionsThis study provides evidence that motor symptoms are associated with the neural states coded with multiple oscillations in PD.SignificanceThis study may advance the understanding of the neurophysiological mechanisms of the motor symptoms and provide potential biomarkers for closed-loop deep brain stimulation in PD.     

Timing and direction selectivity of subthalamic and pallidal neurons in patients with Parkinson disease

Current models of basal ganglia function suggest that some manifestations of Parkinson disease (PD) arise from abnormal activity and decreased selectivity of neurons in the subthalamic nucleus (STN) and globus pallidus internus (Gpi). Our goal was to examine the timing and direction selectivity of neuronal activity relative to visually guided movements in the STN and Gpi of patients with PD. Recordings were made from 152 neurons in the STN and 33 neurons in the Gpi of awake subjects undergoing surgery for PD. Corresponding EMG data were obtained for half the cells. We employed a structured behavioral task in which the subjects used a joystick to guide a cursor to one of four targets displayed on a monitor. Each direction was tested over multiple trials. Movement-related modulation of STN activity began on average 264±10 ms before movement initiation and 92±13 ms before initial EMG activity, while modulation of Gpi activity began 204±21 ms before overt movement initiation. In the STN, 40% of cells demonstrated perimovement activity, and of these 64% were directionally selective. In Gpi, 45% of cells showed perimovement activity of which 80% were selective. In both nuclei, directionally selective cells had significantly lower baseline firing rates than nonselective cells (41±5 vs 59±4 spikes/s in STN, and 50±9 vs 74±15 spikes/s in Gpi). These results suggest that STN activity occurs earlier than previously reported, and that higher neuronal firing rates maybe associated with decreased direction selectivity in PD patients.     

Projections of the precentral motor cortex and other cortical areas of the frontal lobe to the subthalamic nucleus in the monkey

Summary Corticofugal projections were examined by means of the autoradiographic tracer method in 21 macaca fascicularis. The labeled material was injected into the main body representation areas of the precentral motor cortex and into various regions of Brodmann's areas 6, 8 and 9 of the frontal lobe. The ipsilateral subthalamic nucleus receives a moderately strong and somato-topically organized projection from Woolsey's precentral motor cortex. This projection is mainly restricted to the lateral moiety. The remaining nucleus is occupied by less intensive projections from premotor and prefrontal areas. It is concluded that the subthalamic nucleus is a convergence site of pallidal and corticomotor and frontal projections. Cortical afferents may exert an influence on the pallido-subthalamic-pallidal inhibitory feedback loop.     

Excitation of rat subthalamic nucleus neurones in vitro by activation of a group I metabotropic glutamate receptor

The subthalamic nucleus (SThN) provides a glutamate mediated excitatory drive to several other component nuclei of the basal ganglia, thereby significantly influencing locomotion and control of voluntary movement. We have characterised functionally the metabotropic glutamate (mGlu) receptors in the SThN using extracellular single unit recording from rat midbrain slices. SThN neurones fired action potentials spontaneously at a rate of 10 Hz which was increased by the group I/II mGlu receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate (1S,3R-ACPD; 1–30 μM) and the group I selective agonist (S,R)-dihydroxyphenylglycine (DHPG; 1–30 μM). However, both the group II selective agonist (1S,1′R,2′R,3′R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV; 1 μM) and the group III selective agonist (S)-2-amino-4-phosphonobutanoic acid (L-AP4; 10 μM) were without effect, indicating that the excitation was mediated by a group I mGlu receptor. The excitation caused by DHPG (3 μM) was reversed by co-application of the mGlu receptor antagonist (+)-α-methyl-4-carboxyphenylglycine (MCPG; 500 μM). Thus a group I mGlu receptor mediates excitation of SThN neurones, and suggests a use for group I mGlu receptor ligands for treatment of both hypo- and hyperkinetic disorders of basal ganglia origin, such as Parkinson's disease and Huntington's disease.     

Effect of subthalamic nucleus deep brain stimulation on visual scanning

Objective

Deep brain stimulation (DBS) can provide insights into the workings of the basal ganglia (BG) by interfering with their function. In patients with Parkinson's disease (PD) treated with DBS of the subthalamic nucleus, we studied the effect of DBS on scanning eye movements.

Non-motor outcomes of subthalamic stimulation in Parkinson's disease depend on location of active contacts

Background

Subthalamic nucleus (STN) deep brain stimulation (DBS) improves quality of life (QoL), motor, and non-motor symptoms (NMS) in Parkinson's disease (PD). Few studies have investigated the influence of the location of neurostimulation on NMS.

Pallidal deep brain stimulation modulates excessive cortical high β phase amplitude coupling in Parkinson disease

Objective

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and globus pallidus internus (GPi) are equally efficacious in the management of Parkinson disease (PD). Studies of STN-DBS have revealed a therapeutic reduction in excessive cortical β-γ phase-amplitude coupling (PAC). It is unclear whether this is specific to STN-DBS and potentially mediated by modulation of the hyperdirect pathway or if it is a generalizable mechanism seen with DBS of other targets. Moreover, it remains unclear how cortical signals are differentially modulated by movement versus therapy. To clarify, the effects of GPi-DBS and movement on cortical β power and β-γ PAC were examined.

Voice acoustic changes during bilateral subthalamic stimulation in patients with Parkinson's disease

Objectives

The purpose of this study was to investigate the effects of bilateral subthalamic nucleus deep brain stimulation on the phonation of patients with Parkinson's disease in three drug-free conditions: (1) stimulation off, (2) with clinically optimised stimulation parameters, and (3) subthreshold overstimulation, in order to detect differences following voice analysis.

Patients and methods

Conversational speech and sustained vowel sounds /a/, /i/, /o/, /u/ and high /i/ were recorded from 22 PD patients. Perceptual analysis, perturbation jitter, shimmer, noise-to-harmonics ratio, and nonlinear dynamic analysis (NDA) with detrended fluctuation analysis and recurrence period density entropy were measured and compared to the above conditions. Quadratic discriminant analysis (QDA) was used to investigate stimulation conditions for given acoustic data.

Results

The changes of perturbation measurements for the above conditions were not significant. With differences between vowels, NDA showed more significant changes and more powerful correlation with perceptual scores than perturbation measurements. NDA was significantly more sensitive during the QDA of the conditions.

Conclusions

Acoustic voice analysis of sustained vowels can help with recognizing the overstimulated condition, and, with an appropriate test battery and software package including nonlinear dynamic analysis, it can be a valuable tool for fine adjustments of stimulation parameters.     

Intra-operative STN DBS attenuates the prominent beta rhythm in the STN in Parkinson's disease

Power spectra from local field potentials (LFPs) recorded post-operatively from the deep brain stimulation (DBS) macroelectrode show prominence of the beta rhythm (11-30 Hz) in untreated Parkinson's disease (PD). Dopaminergic medication and movement attenuate this beta band in PD. In this pilot study of six sides in four patients, we recorded LFPs from the DBS electrode in untreated PD patients in the operating room. In all cases, there was a peak in the time-frequency spectrogram in the beta frequency range when the patients were at rest, which was associated with attenuation in the same range with movement. The actual frequency range and the strength of the beta peak varied among cases. In two patients, intra-operative constraints permitted recording of LFPs at rest, before and immediately after subthalamic nucleus (STN) DBS. In both patients we documented that STN DBS caused a significant attenuation in power in the beta band at rest that persisted for 15-25 s after DBS had been turned off (P < 0.01). From one case, our data suggest that the beta rhythm attenuation was most prominent within the STN itself. This study shows for the first time that STN DBS attenuates the power in the prominent beta band recorded in the STN of patients with PD. These pilot findings raise the interesting possibility of using this biomarker for closed loop DBS or neuromodulation.     

“Sukeroku sign” and “dent internal-capsule sign”—identification guide for targeting the subthalamic nucleus for placement of deep brain stimulation electrodes

Introduction  The purpose of this study was to assess the usefulness of signs (“Sukeroku sign” and “dent internal-capsule sign”) for the recognition of subthalamic nucleus (STN). Materials and methods  Five Parkinson’s disease cases in which there was a successful placement of deep brain stimulation (DBS) electrodes at the STN were retrospectively reviewed. Five radiologists who were not engaged in localization of STNs in clinical practice were asked to locate the STNs before and after instructions on the signs. We evaluated the deviation between the reader-located points and the location of the DBS electrode for which there had been a successful installation. Results  After instruction, there was a significant reduction in the deviation between the reader-located points and the DBS electrode. The time required for localization was also reduced after the instructions. Conclusion  Sukeroku sign and dent internal-capsule sign are feasible indicators of STN and seem to be useful in helping to identify the STN.