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.

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.

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 1/f asymmetry in patients with cervical dystonia.

Lateralized differences in pallidal outflow are putatively linked to asymmetric tonic contractions of the neck muscles in cervical dystonia (CD). At the population level, the interhemispheric asymmetry has been traditionally studied for the estimation of the spectral power in specified frequency bands. Broadband spectral features, however, were not taken into consideration. The contemporary analysis revealed that the aperiodic (1/f) broadband activity could be a neurophysiological marker of the excitation/inhibition ratio. During deep brain stimulation (DBS) surgery, we measured bilateral pallidal local field potentials (LFP) in nine CD patients, examining the effects of lateralized asymmetry on 1/f broadband activity. All patients showed a trend towards an asymmetric difference in the 1/f broadband activity. The ipsilateral 1/f slope was significantly higher in internal (GPi) segment of the globus pallidus that is on the contralateral side of the direction of the dystonia. We also found lateralized differences in the beta oscillations for GPi and in the alpha oscillations for GPe. Our findings emphasize the importance of mainstreaming broadband activity in the estimation of LFP spectral features together with periodic features and provide further evidence for the pallidal asymmetry in CD patients.

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.

Implications of asymmetric neural activity patterns in the basal ganglia outflow in the integrative neural network model for cervical dystonia.

Cervical dystonia (CD) is characterized by abnormal twisting and turning of the head with associated head oscillations. It is the most common form of dystonia, which is a third most common movement disorder. Despite frequent occurrence there is paucity in adequate therapy, much of which is attributed to its uncertain pathophysiology. Recently we proposed a unifying network model highlighting the role of head neural integrator (hNI) for the pathophysiology of CD. According to our hypothesis the CD is due to abnormal output of hNI; the latter itself is not affected but its dysfunction is secondary to abnormal feedback. We hypothesized that asymmetry in the feedback to hNI is associated with severity in CD; the feedback asymmetry is greater in CD with lateralized head postures, such as turning of head in yaw plane (torticollis) or roll plane (laterocollis). The hypothesis also specifies that feedback to hNI-cerebellum, proprioception, and basal ganglia outflow (pallidus) are connected in a network; thus asymmetry is distributed through the feedback network. In 15 CD patients undergoing deep brain stimulation (DBS) surgery, with their informed consent, we used the opportunity to collect single unit neural responses and local field potential from the globus pallidus to measure whether feedback to hNI is asymmetric. Using machine learning algorithms developed to analyze single unit data, we found: (1) globus pallidus interna (GPi) firing rate, discharge pattern and gamma oscillation were asymmetric in patients with robust torticollis; (2) there was no asymmetry in these parameters in retrocollis; and (3) in those patients with oppositely directed laterocollis and torticollis. Firing rate was higher in GPi cells ipsilateral to the direction of head rotation; the asymmetry was more pronounced in tonic cells compared to burst neurons. In addition to confirming that CD is associated with an asymmetric pallidal activity, our data showed that neuronal asymmetry correlated with the degree of involuntary head turning. We propose that asymmetric pallidal activity results in asymmetric feedback to hNI causing its dysfunction.

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.

Neuronal activity patterns in the ventral thalamus: Comparison between Parkinson's disease and cervical dystonia.

OBJECTIVE: The aim of this study was to distinguish neuronal activity patterns in the human ventral thalamus and reveal common and disease-specific features in patients with Parkinson's disease (PD) and cervical dystonia (CD). METHODS: Single unit activity of neurons was recorded during microelectrode-guided thalamotomies. We classified neurons of surgical target and surrounding area into patterns and compared their characteristics and responsiveness to voluntary movement between PD and CD patients. RESULTS: We distinguished five patterns of neuronal activity: single, LTS burst, mixed, non-LTS burst and longburst patterns. The burst and mixed patterns showed significant differences in several basic and burst characteristics. We showed that there were no disease-specific patterns or significant differences in pattern distribution between studied patients. However, burst patterns had an unbalanced distribution between disease conditions. In addition, we found difference in LTS burst characteristics between surgical targets and surrounding nuclei. All identified patterns, except the long burst pattern, were reactive to the motor tasks and to contraction of the pathological muscles. CONCLUSIONS: The ventral thalamus was characterised by common neuronal activity patterns which differed in characteristics between PD and CD. SIGNIFICANCE: Our findings highlight patterns of neuronal activity of the human ventral thalamus and specific pathological features.

Participation of the thalamic CM-Pf complex in movement performance in patients with dystonia.

INTRODUCTION: The centrum medianum- parafascicular complex of the human thalamus has a critical influence on cortical activity and significantly influences somatosensory function, arousal, and attention. In addition to its cortical connections, this region of the intralaminar thalamic nuclei is also connected to motor areas of the basal ganglia and the brain stem. OBJECTIVE: The goal of this study was to identify movement-related neurons in the centrum medianum-parafascicular complex and analyze the changes in their activity during voluntary movements in patients with cervical dystonia. METHODS: Single-unit activity was recorded during the micro-electrode-guided surgical ablation procedures in patients with cervical dystonia. The neural responses and synchronous electromyographic signals of the neck and finger flexor muscles were simultaneously recorded. RESULTS: We found the following 3 types of movement-sensitive neurons in the centrum medianum-parafascicular complex: neurons that responded selectively to voluntary hand movement (hand-only neurons), neurons that selectively responded to neck movements (neck-only neurons), neurons responding to both hand and neck movements (combined neurons). We discovered the following 3 patterns of movement-related changes in neural activity: an increase in the firing rate, a reduction in the bursting activity, and short-term oscillations and synchronization with neighboring neurons. The most pronounced and prolonged responses were observed during movements involving neck muscles as well as during involuntary dystonic movements. CONCLUSION: The centrum medianum-parafascicular complex of the thalamus is a component of the subcortical network that participates in motor behavior and may be involved in the pathophysiology of cervical dystonia. © 2016 International Parkinson and Movement Disorder Society.