Clinical asymmetry in Parkinson's disease is characterized by prevalence of subthalamic pause-burst neurons and alpha-beta oscillations.

OBJECTIVE: We aimed to establish specific biomarkers of Parkinson's disease (PD) by comparing activity of more affected (MA) and less affected (LA) subthalamic nucleus (STN) of patients with prominent clinical asymmetry. METHODS: We recorded single unit activity and local field potentials (LFP) of the STN during deep brain stimulation surgeries. Neuronal firing patterns and discharge rate, as well as oscillatory features of both single cells and LFP, were analyzed. RESULTS: We observed notable differences in proportions of irregular-burst and pause-burst, but not tonic neurons, between the hemispheres. Oscillations of pause-burst neurons correlated significantly with the bradykinesia and rigidity scores of the corresponding hemibody. LFP derived from MA STN featured greater power in 12-15 Hz. CONCLUSIONS: Our results provide evidence that the increased proportion of units with prolonged pauses may be associated with PD. We also speculate that some of them may gain rhythmicity in the alpha-beta range in relation to hypokinetic symptoms, long-term disease, or both. SIGNIFICANCE: Our findings highlight the relation between specific oscillatory features of the STN, predominance of subthalamic pause-burst units and PD pathophysiology.

Pallidal multifractal complexity is a new potential physiomarker of dystonia.

OBJECTIVE: Low-frequency 4-12 Hz pallidal oscillations are being considered as potential physiomarkers for dystonia. We suggest investigating the multifractal properties of pallidal activity as an additional marker. METHODS: We employed local field potentials (LFP) recordings from 23 patients with dystonia who were undergoing deep brain stimulation (DBS) surgery to explore the connection between disease severity and the multifractal characteristics of pallidal activity. Furthermore, we performed an analysis of LFP recordings from four patients, following the externalization of DBS lead electrodes, to investigate the impact of DBS and neck muscle vibration on multifractal parameters. RESULTS: Greater dystonia severity exhibited a correlation with a narrower multifractal spectrum width but higher multifractal spectral asymmetry. Both GPi DBS and muscle vibration in dystonia patients expanded the multifractal spectrum width while restoring multifractal spectral symmetry. Notably, the threshold peak intensities for an increase in multifractal spectrum width substantially overlapped with the optimal volume of tissue activated. A broader multifractal spectrum during DBS corresponded to more favorable clinical outcomes. CONCLUSIONS: Multifractal properties of pallidal neuronal activity serve as indicators of neural dysfunction in dystonia. SIGNIFICANCE: These findings suggest the potential of utilizing multifractal characteristics as predictive factors for the DBS outcome in dystonia.

Proprioceptive Modulation of Pallidal Physiology in Cervical Dystonia.

BACKGROUND: There is a growing body of evidence suggesting that botulinum toxin can alter proprioceptive feedback and modulate the muscle-spindle output for the treatment of dystonia. However, the mechanism for this modulation remains unclear. METHODS: We conducted a study involving 17 patients with cervical dystonia (CD), seven of whom had prominent CD and 10 with generalized dystonia (GD) along with CD. We investigated the effects of neck vibration, a form of proprioceptive modulation, on spontaneous single-neuron responses and local field potentials (LFPs) recorded from the globus pallidum externus (GPe) and internus (GPi). RESULTS: Our findings demonstrated that neck vibration notably increased the regularity of neck-sensitive GPi neurons in focal CD patients. Additionally, in patients with GD and CD, the vibration enhanced the firing regularity of non-neck-sensitive neurons. These effects on single-unit activity were also mirrored in ensemble responses measured through LFPs. Notably, the LFP modulation was particularly pronounced in areas populated with burst neurons compared to pause or tonic cells. CONCLUSION: The results from our study emphasize the significance of burst neurons in the pathogenesis of dystonia and in the efficacy of proprioceptive modulation for its treatment. Moreover, we observed that the effects of vibration on focal CD were prominent in the α band LFP, indicating modulation of pallido-cerebellar connectivity. Moreover, the pallidal effects of vibration in GD with CD involved modulation of cerebro-pallidal θ band connectivity. Our analysis provides insight into how vibration-induced changes in pallidal activity are integrated into the downstream motor circuit. © 2023 International Parkinson and Movement Disorder Society.

Does Pallidal Physiology Determine the Success of Unilateral Deep Brain Stimulation in Cervical Dystonia?

Pallidal deep brain stimulation is a well-known surgical treatment for cervical dystonia. The resolution of dystonia typically requires bilateral pallidal stimulation, but in some instances, unilateral stimulation has been successful. In such instances, generally, the stimulated hemisphere was contralateral to the dystonic sternocleidomastoid, but rarely it was ipsilateral. We sought for the physiological features that determine the basis for success and laterality of deep brain stimulation for cervical dystonia with prominent torticollis. We found that pallidal physiology such as high burst to tonic ratio and significant interhemispheric differences in the neuronal firing rate and regularity are critical determinants of successful treatment with unilateral deep brain stimulation. We also found that higher lateralized differences in pallidal physiological parameters predict more robust improvement. In three out of four patients, the stimulation of the hemisphere ipsilateral to the dystonic sternocleidomastoid muscle was effective. These patients did not have any structural brain abnormalities on clinically available imaging studies. One patient responded to the unilateral deep brain stimulation in the hemisphere contralateral to the dystonic sternocleidomastoid. This patient had a structural putamen lesion on brain MRI. These results provide objective parameters determining the success of pallidal deep brain stimulation for treatment of cervical dystonia. The results also depict differences in the pallidal physiology in patients where ipsilateral versus contralateral deep brain stimulation was effective.

DYT1 dystonia: Neurophysiological properties of the pallidal activity.

OBJECTIVES: The aim of this paper is to find the differences in the physiology of the pallidal neurons in DYT1 and non-DYT1 dystonia. METHODS: We performed microelectrode recording of the single unit activity in both segments of the globus pallidus during stereotactic implantation of electrodes for deep brain stimulation (DBS). RESULTS: We found a reduced firing rate, reduced burst rate, and increased pause index in both pallidal segments in DYT1. Also, in DYT1 the activity in both pallidal segments was similar, but not so in non-DYT1. CONCLUSION: The results suggest a common pathological focus for both pallidal segments, located in the striatum. We also speculate that strong striatal influence on GPi and GPe overrides other input sources to the pallidal nuclei causing similarity in neuronal activity. SIGNIFICANCE: We found significant differences in neuronal activity between DYT1 and non-DYT1 neurons. Our findings shed light on the pathophysiology of DYT-1 dystonia which can be very different from non-DYT1 dystonia and have other efficient treatment tactics.

Excessive α-ß Oscillations Mark Enlarged Motor Sign Severity and Parkinson's Disease Duration.

BACKGROUND: ß Oscillations in the subthalamic nucleus (STN) have been proven to contribute to Parkinson's disease (PD), but the exact borders of ß subbands vary substantially across the studies, and information regarding heterogeneity of ß rhythmic activity is still limited. Recently, α oscillations in the basal ganglia have also become the focus of PD research. OBJECTIVES: The aim was to study rhythmic oscillations in the STN in PD patients to identify different subbands with stable oscillatory peaks within a broad α-ß range and to establish their associations with motor symptoms. METHODS: Local field potentials inside the STN were recorded during deep brain stimulation (DBS) surgeries. After calculating power spectra and extracting an aperiodic component, oscillatory peaks in the 8- to 35-Hz range with amplitude exceeding 90th percentile were clustered into three bands. Peak parameters were estimated for two lower subbands. Clinical features were compared in patients with and without oscillation peaks in the lowest α-ß subband. RESULTS: We isolated α-ß (8-15 Hz), ß (15-25 Hz), and ß-γ (25-35 Hz) subbands within the 8- to 35-Hz spectral range using oscillatory parameters and Ward's hierarchical clustering. Additional α-ß oscillatory peaks were found in about half of patients with ß peaks; they were located more ventrally compared to ß. We have found a significant increase in disease duration, bradykinesia, and rigidity scores in the group with additional α-ß peaks. CONCLUSIONS: Increased α-ß oscillations may emerge as additional phenomena complementing ß oscillations; they may mark disease progression in PD and affect DBS stimulation setup. © 2023 International Parkinson and Movement Disorder Society.

Patients selection for psychiatric neurosurgery: pitfalls and considerations.

Neurosurgical interventions (destructive or neuromodulation) are considered as a therapeutic option for patients with treatment resistant mental disorders. However, the issues of indications and contraindications for psychiatric surgery, method and patient selection remain unresolved. This article discusses possible problems and contradictions in the selection of patients, the need for an interdisciplinary team to work to solve the question of the feasibility of using neurosurgical methods. The authors have identified the main problems that increase the risks of selection and lead to a lack of results or low efficiency of neurosurgical intervention, namely: (1) diagnostic errors or inaccuracies; (2) inconclusive data on therapeutic resistance; (3) lack of a common understanding of the goals and desired results among participants in the selection of patients for neurosurgery. Possible predictors of surgical outcome and ethical issues are also discussed. Neurosurgical interventions as a treatment option for psychiatric disorders are not officially approved in most countries. So an appropriate algorithm for patient selection and clear criteria for outcome measures are needed.

Neurosurgical management of Tourette syndrome: A literature review and analysis of a case series treated with deep brain stimulation.

Tourette syndrome (TS) is a heterogeneous disorder, which clinical presentation includes both multiple motor and vocal tics and commonly associated psychiatric conditions (obsessive-compulsive disorder, attention deficit hyperactivity disorder, depression, anxiety, etc.). Treatment options primarily consist of non-pharmacological interventions (habit reversal training, relaxation techniques, cognitive behavioral therapy, and social rehabilitation) and pharmacotherapy. In case of the intractable forms, neurosurgical treatment may be considered, primarily deep brain stimulation (DBS). DBS appear to be effective in medically intractable TS patients, although, the preferential brain target is still not defined. The majority of studies describe small number of cases and the issues of appropriate patient selection and ethics remain to be clarified. In this article, we review the main points in management of TS, discuss possible indications and contraindications for neurosurgical treatment, and analyze our experience of DBS in a case series of refractory TS patients with the focus on target selection and individual outcomes.

Oscillations of pause-burst neurons in the STN correlate with the severity of motor signs in Parkinson's disease.

BACKGROUND: Oscillatory activity in the subthalamic nucleus (STN) in Parkinson's disease (PD) is under extensive study. While rhythmic features of local field potentials are implicated in the manifestation of PD motor signs, less is known about single unit activity (SUA). SUA parameters inside the STN show significant heterogeneity, and various firing patterns may contribute unequally to PD pathophysiology. OBJECTIVES: We searched for correlations between SUA parameters and PD motor signs, taking neuronal activity patterns into account. METHODS: 829 spike trains for STN SUA were recorded during 25 DBS surgeries. We have isolated three firing patterns (tonic, irregular-burst and pause-burst) and, using mixed linear models, examined several spiking parameters and burst descriptors (for the last two patterns) for their correlation with UPDRS-III PD motor signs in the contralateral hemibody. RESULTS: The predominance of pause-burst as opposed to tonic activity was associated with a higher PD motor sign severity UPDRS-III. Spike synchronization in the alpha and beta range correlated positively with bradykinesia scores only for pause-burst neurons, while spike synchrony in the theta frequency (4-8 Hz) in these neurons showed an inverse correlation with bradykinesia scores. Other patterns showed no correlation with PD motor signs. CONCLUSIONS: Our work demonstrates the PD motor state is associated with distinct changes in firing patterns and oscillatory synchronization that can be associated with PD motor sign severity. Here, pause-burst patterns were identified as most informative, potentially reflecting a progressive shift from tonic to burst to rhythmic activity in the alpha and beta frequency bands in the parkinsonian state.

Pallidal neuron activity determines responsiveness to deep brain stimulation in cervical dystonia.

OBJECTIVE: In patients with cervical dystonia we sought for the differences in neuronal behavior of pallidal regions where deep brain stimulation resulted in favorable therapeutic response compared to those where the response was absent. METHODS: We compared single-unit activity of 564 neurons recorded from deep brain stimulation sensitive and non-sensitive regions in 17 cervical dystonia patients. RESULTS: Globus pallidus internus regions responsive to the deep brain stimulation had lower firing rates and bursting compared to non-responsive areas. The differences were robust in locations where neuronal responses correlated with neck movements. Per the effects of deep brain stimulation, the pallidal regions were classified in weak, intermediate, and excellent responsive. Pallidal regions with weak response to deep brain stimulation had fewer burst neurons and higher firing rate compared to neurons in areas with excellent response. The burst index was significantly decreased in excellent response regions. There was a significant decrease in the alpha band oscillation score but a substantial increase in the gamma band in excellent response neurons. CONCLUSION: The pallidal region that would be responsive to deep brain stimulation has distinct physiology compared to the non-responsive region. SIGNIFICANCE: These results provide novel insights into globus pallidus interna neurons' physiology in cervical dystonia.

Is there a single beta oscillation band interfering with movement in Parkinson's disease?

Beta oscillations in basal ganglia are considered to contribute to motor dysfunction in Parkinson's disease (PD). However, there is a high variety in frequency borders for beta oscillations between studies, which complicates the comparison and interpretation of results. Here we aimed to study the homogeneity of oscillations in the broad "beta" range (8-30 Hz) and their implication to motor functioning in PD. For this purpose, we recorded local field potentials (LFP) in the subthalamic nucleus (STN) during 34 deep brain stimulation surgeries. We identified spectral features of LFP recordings in the range 8-30 Hz to search for candidate sub-regions of stable oscillations and assessed their association with clinical scores on the contralateral side of the body and sensitivity to motor tests. Lower frequency oscillations (8-16 Hz) had a significant positive association with bradykinesia score. During voluntary movements, we observed a significant increase in LFP power in the 12-16 Hz range and a decrease in the 18-26 Hz range. We may conclude that the 8-30 Hz oscillation range includes oscillations with different functional features-sensitivity and responsiveness to movement, and clinical symptoms, which should be taken into account in further studies of beta oscillations association with PD pathophysiology. These data assume the coexistence of several frequency domains within beta range that are modulated in different ways under dopaminergic regulation and motor processing in human STN.

Voluntary movements cause beta oscillations increase and broadband slope decrease in the subthalamic nucleus of parkinsonian patients.

Periodic features of local field potentials (LFP) are extensively studied to establish the pathophysiological features contributing to Parkinson's disease (PD). Pathological LFP synchronization in the subthalamic nucleus (STN) was assumed to link with motor signs of PD. Commonly, the association between oscillations and clinical signs is studied while the patients are at rest. However, changes in LFPs during movement may reflect particular traits of motor processing in the basal ganglia under PD. Recently, the aperiodic 1/f broadband component of LFP spectra has attracted the attention of researchers because it may provide meaningful information about the neural activity in the brain. Here, we compared LFP signals in the STN of parkinsonian patients at rest and during hand movements occasionally followed by leg movements using two approaches, one of which accounts for the aperiodic features of LFP spectra. Using both methods, a significant increase was observed in synchronization in the low beta range during sequent leg but not hand movements. For either movement, there was a significant increase in gamma range synchronization using uncorrected power spectra and a significant decrease in the slope of the aperiodic component for the 1/f-corrected method. These findings may support the claim that the 1/f slope possibly reflects the excitatory/inhibitory projections ratio in the recording site. Only the difference in the slope correlated significantly with motor signs of PD. These data show that the slope of aperiodic component may be a useful measure that is sensitive to the specific state and its changes in the brain.

Pallidal Activity in Cervical Dystonia with and Without Head Tremor.

The relationship between two common movement disorders, dystonia and tremor, is controversial. Both deficits have correlates in the network that includes connections between the cerebellum and the basal ganglia. In order to assess the physiological relationship between tremor and dystonia, we measured the activity of 727 pallidal single-neurons during deep brain stimulation surgery in patients with cervical dystonia without head oscillations, cervical dystonia plus jerky oscillations, and cervical dystonia with sinusoidal oscillations. Cluster analyses of spike-train recordings allowed classification of the pallidal activity into burst, pause, and tonic. Burst neurons were more common, and number of spikes within spike and inter-burst intervals was shorter in pure dystonia and jerky oscillation groups compared to the sinusoidal oscillation group. Pause neurons were more common and irregular in pure tremor group compared to pure dystonia and jerky oscillation groups. There was bihemispheric asymmetry in spontaneous firing discharge in pure dystonia and jerky oscillation groups, but not in sinusoidal oscillation group. These results demonstrate that the physiology of pallidal neurons in patients with pure cervical dystonia is similar to those who have cervical dystonia combined with jerky oscillations, but different from those who have cervical dystonia combined with sinusoidal oscillations. These results imply distinct mechanistic underpinnings for different types of head oscillations in cervical dystonia.

The role of pallidum in the neural integrator model of cervical dystonia.

Dystonia is the third most common movement disorder affecting three million people worldwide. Cervical dystonia is the most common form of dystonia. Despite common prevalence the pathophysiology of cervical dystonia is unclear. Traditional view is that basal ganglia is involved in pathophysiology of cervical dystonia, while contemporary theories suggested the role of cerebellum and proprioception in the pathophysiology of cervical dystonia. It was recently proposed that the cervical dystonia is due to malfunctioning of the head neural integrator - the neuron network that normally converts head velocity to position. Most importantly the neural integrator model was inclusive of traditional proposal emphasizing the role of basal ganglia while also accommodating the contemporary view suggesting the involvement of cerebellum and proprioception. It was hypothesized that the head neural integrator malfunction is the result of impairment in cerebellar, basal ganglia, or proprioceptive feedback that converge onto the integrator. The concept of converging input from the basal ganglia, cerebellum, and proprioception to the network participating in head neural integrator explains that abnormality originating anywhere in the network can lead to the identical motor deficits - drifts followed by rapid corrective movements - a signature of neural integrator dysfunction. We tested this hypothesis in an experiment examining simultaneously recorded globus pallidal single-unit activity, synchronized neural activity (local field potential), and electromyography (EMG) measured from the neck muscles during the standard-of-care deep brain stimulation surgery in 12 cervical dystonia patients (24 hemispheres). Physiological data were collected spontaneously or during voluntary shoulder shrug activating the contralateral trapezius muscle. The activity of pallidal neurons during shoulder shrug exponentially decayed with time constants that were comparable to one measured from the pretectal neural integrator and the trapezius electromyography. These results show that evidence of abnormal neural integration is also seen in globus pallidum, and that latter is connected with the neural integrator. Pretectal single neuron responses consistently preceded the muscle activity; while the globus pallidum internus response always lagged behind the muscle activity. Globus pallidum externa had equal proportion of lag and lead neurons. These results suggest globus pallidum receive feedback from the muscles or the efference copy from the integrator or the other source of the feedback. There was bi-hemispheric asymmetry in the pallidal single-unit activity and local field potentials. The asymmetry correlated with degree of lateral head turning in cervical dystonia patients. These results suggest that bihemispheric asymmetry in the feedback leads to asymmetric dysfunction in the neural integrator causing head turning.