Subthalamic stimulation modulates context-dependent effects of beta bursts during fine motor control.

Increasing evidence suggests a considerable role of pre-movement beta bursts for motor control and its impairment in Parkinson's disease. However, whether beta bursts occur during precise and prolonged movements and if they affect fine motor control remains unclear. To investigate the role of within-movement beta bursts for fine motor control, we here combine invasive electrophysiological recordings and clinical deep brain stimulation in the subthalamic nucleus in 19 patients with Parkinson's disease performing a context-varying task that comprised template-guided and free spiral drawing. We determined beta bursts in narrow frequency bands around patient-specific peaks and assessed burst amplitude, duration, and their immediate impact on drawing speed. We reveal that beta bursts occur during the execution of drawing movements with reduced duration and amplitude in comparison to rest. Exclusively when drawing freely, they parallel reductions in acceleration. Deep brain stimulation increases the acceleration around beta bursts in addition to a general increase in drawing velocity and improvements of clinical function. These results provide evidence for a diverse and task-specific role of subthalamic beta bursts for fine motor control in Parkinson's disease; suggesting that pathological beta bursts act in a context dependent manner, which can be targeted by clinical deep brain stimulation.

Perspectives of Implementation of Closed-Loop Deep Brain Stimulation: From Neurological to Psychiatric Disorders.

BACKGROUND: Deep brain stimulation (DBS) is a highly efficient, evidence-based therapy to alleviate symptoms and improve quality of life in movement disorders such as Parkinson's disease, essential tremor, and dystonia, which is also being applied in several psychiatric disorders, such as obsessive-compulsive disorder and depression, when they are otherwise resistant to therapy. SUMMARY: At present, DBS is clinically applied in the so-called open-loop approach, with fixed stimulation parameters, irrespective of the patients' clinical state(s). This approach ignores the brain states or feedback from the central nervous system or peripheral recordings, thus potentially limiting its efficacy and inducing side effects by stimulation of the targeted networks below or above the therapeutic level. KEY MESSAGES: The currently emerging closed-loop (CL) approaches are designed to adapt stimulation parameters to the electrophysiological surrogates of disease symptoms and states. CL-DBS paves the way for adaptive personalized DBS protocols. This review elaborates on the perspectives of the CL technology and discusses its opportunities as well as its potential pitfalls for both clinical and research use in neuropsychiatric disorders.

Clinical neurophysiological interrogation of motor slowing: A critical step towards tuning adaptive deep brain stimulation.

OBJECTIVE: Subthalamic nucleus (STN) beta activity (13-30 Hz) is the most accepted biomarker for adaptive deep brain stimulation (aDBS) for Parkinson's disease (PD). We hypothesize that different frequencies within the beta range may exhibit distinct temporal dynamics and, as a consequence, different relationships to motor slowing and adaptive stimulation patterns. We aim to highlight the need for an objective method to determine the aDBS feedback signal. METHODS: STN LFPs were recorded in 15 PD patients at rest and while performing a cued motor task. The impact of beta bursts on motor performance was assessed for different beta candidate frequencies: the individual frequency strongest associated with motor slowing, the individual beta peak frequency, the frequency most modulated by movement execution, as well as the entire-, low- and high beta band. How these candidate frequencies differed in their bursting dynamics and theoretical aDBS stimulation patterns was further investigated. RESULTS: The individual motor slowing frequency often differs from the individual beta peak or beta-related movement-modulation frequency. Minimal deviations from a selected target frequency as feedback signal for aDBS leads to a substantial drop in the burst overlapping and in the alignment of the theoretical onset of stimulation triggers (to âˆ¼ 75% for 1 Hz, to âˆ¼ 40% for 3 Hz deviation). CONCLUSIONS: Clinical-temporal dynamics within the beta frequency range are highly diverse and deviating from a reference biomarker frequency can result in altered adaptive stimulation patterns. SIGNIFICANCE: A clinical-neurophysiological interrogation could be helpful to determine the patient-specific feedback signal for aDBS.

Dynamic modulation of subthalamic nucleus activity facilitates adaptive behavior.

Adapting actions to changing goals and environments is central to intelligent behavior. There is evidence that the basal ganglia play a crucial role in reinforcing or adapting actions depending on their outcome. However, the corresponding electrophysiological correlates in the basal ganglia and the extent to which these causally contribute to action adaptation in humans is unclear. Here, we recorded electrophysiological activity and applied bursts of electrical stimulation to the subthalamic nucleus, a core area of the basal ganglia, in 16 patients with Parkinson's disease (PD) on medication using temporarily externalized deep brain stimulation (DBS) electrodes. Patients as well as 16 age- and gender-matched healthy participants attempted to produce forces as close as possible to a target force to collect a maximum number of points. The target force changed over trials without being explicitly shown on the screen so that participants had to infer target force based on the feedback they received after each movement. Patients and healthy participants were able to adapt their force according to the feedback they received (P < 0.001). At the neural level, decreases in subthalamic beta (13 to 30 Hz) activity reflected poorer outcomes and stronger action adaptation in 2 distinct time windows (Pcluster-corrected < 0.05). Stimulation of the subthalamic nucleus reduced beta activity and led to stronger action adaptation if applied within the time windows when subthalamic activity reflected action outcomes and adaptation (Pcluster-corrected < 0.05). The more the stimulation volume was connected to motor cortex, the stronger was this behavioral effect (Pcorrected = 0.037). These results suggest that dynamic modulation of the subthalamic nucleus and interconnected cortical areas facilitates adaptive behavior.

The aperiodic exponent of subthalamic field potentials reflects excitation/inhibition balance in Parkinsonism.

Periodic features of neural time-series data, such as local field potentials (LFPs), are often quantified using power spectra. While the aperiodic exponent of spectra is typically disregarded, it is nevertheless modulated in a physiologically relevant manner and was recently hypothesised to reflect excitation/inhibition (E/I) balance in neuronal populations. Here, we used a cross-species in vivo electrophysiological approach to test the E/I hypothesis in the context of experimental and idiopathic Parkinsonism. We demonstrate in dopamine-depleted rats that aperiodic exponents and power at 30-100 Hz in subthalamic nucleus (STN) LFPs reflect defined changes in basal ganglia network activity; higher aperiodic exponents tally with lower levels of STN neuron firing and a balance tipped towards inhibition. Using STN-LFPs recorded from awake Parkinson's patients, we show that higher exponents accompany dopaminergic medication and deep brain stimulation (DBS) of STN, consistent with untreated Parkinson's manifesting as reduced inhibition and hyperactivity of STN. These results suggest that the aperiodic exponent of STN-LFPs in Parkinsonism reflects E/I balance and might be a candidate biomarker for adaptive DBS.

Dynamic control of decision and movement speed in the human basal ganglia.

To optimally adjust our behavior to changing environments we need to both adjust the speed of our decisions and movements. Yet little is known about the extent to which these processes are controlled by common or separate mechanisms. Furthermore, while previous evidence from computational models and empirical studies suggests that the basal ganglia play an important role during adjustments of decision-making, it remains unclear how this is implemented. Leveraging the opportunity to directly access the subthalamic nucleus of the basal ganglia in humans undergoing deep brain stimulation surgery, we here combine invasive electrophysiological recordings, electrical stimulation and computational modelling of perceptual decision-making. We demonstrate that, while similarities between subthalamic control of decision- and movement speed exist, the causal contribution of the subthalamic nucleus to these processes can be disentangled. Our results show that the basal ganglia independently control the speed of decisions and movement for each hemisphere during adaptive behavior.

Treadmill training in Parkinson's disease is underpinned by the interregional connectivity in cortical-subcortical network.

Treadmill training (TT) has been extensively used as an intervention to improve gait and mobility in patients with Parkinson's disease (PD). Regional and global effects on brain activity could be induced through TT. Training effects can lead to a beneficial shift of interregional connectivity towards a physiological range. The current work investigates the effects of TT on brain activity and connectivity during walking and at rest by using both functional near-infrared spectroscopy and functional magnetic resonance imaging. Nineteen PD patients (74.0 ± 6.59 years, 13 males, disease duration 10.45 ± 6.83 years) before and after 6 weeks of TT, along with 19 age-matched healthy controls were assessed. Interregional effective connectivity (EC) between cortical and subcortical regions were assessed and its interrelation to prefrontal cortex (PFC) activity. Support vector regression (SVR) on the resting-state ECs was used to predict prefrontal connectivity. In response to TT, EC analysis indicated modifications in the patients with PD towards the level of healthy controls during walking and at rest. SVR revealed cerebellum related connectivity patterns that were associated with the training effect on PFC. These findings suggest that the potential therapeutic effect of training on brain activity may be facilitated via changes in compensatory modulation of the cerebellar interregional connectivity.

Gait Abnormalities in Parkinson's Disease Are Associated with Extracellular Free-Water Characteristics in the Substantia Nigra.

BACKGROUND: Gait impairments are common in Parkinson's disease (PD). The pathological mechanisms are complex and not thoroughly elucidated, thus quantitative and objective parameters that closely relate to gait characteristics are critically needed to improve the diagnostic assessments and monitor disease progression. The substantia nigra is a relay structure within basal ganglia brainstem loops that is centrally involved in gait modulation. OBJECTIVE: We tested the hypothesis that quantitative gait biomechanics are related to the microstructural integrity of the substantia nigra and PD-relevant gait abnormalities are independent from bradykinesia-linked speed reductions. METHODS: Thirty-eight PD patients and 33 age-matched control participants walked on a treadmill at fixed speeds. Gait parameters were fed into a principal component analysis to delineate relevant features. We applied the neurite orientation dispersion and density imaging (NODDI) model on diffusion-weighted MR-images to calculate the free-water content as an advanced marker of microstructural integrity of the substantia nigra and tested its associations with gait parameters. RESULTS: Patients showed increased duration of stance phase, load response, pre-swing, and double support time, as well as reduced duration of single support and swing time. Gait rhythmic alterations associated positively with the free-water content in the right substantia nigra in PD, indicating that patients with more severe neurodegeneration extend the duration of stance phase, load response, and pre-swing. CONCLUSION: The results provide evidence that gait alterations are not merely a byproduct of bradykinesia-related reduced walking speed. The data-supported association between free-water and the rhythmic component highlights the potential of substantia nigra microstructure imaging as a measure of gait-dysfunction and disease-progression.

Deciphering the Network Effects of Deep Brain Stimulation in Parkinson's Disease.

INTRODUCTION: Deep brain stimulation of the subthalamic nucleus (STN-DBS) is an established therapy for Parkinson's disease (PD). However, a more detailed characterization of the targeted network and its grey matter (GM) terminals that drive the clinical outcome is needed. In this direction, the use of MRI after DBS surgery is now possible due to recent advances in hardware, opening a window for the clarification of the association between the affected tissue, including white matter fiber pathways and modulated GM regions, and the DBS-related clinical outcome. Therefore, we present a computational framework for reconstruction of targeted networks on postoperative MRI. METHODS: We used a combination of preoperative whole-brain T1-weighted (T1w) and diffusion-weighted MRI data for morphometric integrity assessment and postoperative T1w MRI for electrode reconstruction and network reconstruction in 15 idiopathic PD patients. Within this framework, we made use of DBS lead artifact intensity profiles on postoperative MRI to determine DBS locations used as seeds for probabilistic tractography to cortical and subcortical targets within the motor circuitry. Lastly, we evaluated the relationship between brain microstructural characteristics of DBS-targeted brain network terminals and postoperative clinical outcomes. RESULTS: The proposed framework showed robust performance for identifying the DBS electrode positions. Connectivity profiles between the primary motor cortex (M1), supplementary motor area (SMA), and DBS locations were strongly associated with the stimulation intensity needed for the optimal clinical outcome. Local diffusion properties of the modulated pathways were related to DBS outcomes. STN-DBS motor symptom improvement was highly associated with cortical thickness in the middle frontal and superior frontal cortices, but not with subcortical volumetry. CONCLUSION: These data suggest that STN-DBS outcomes largely rely on the modulatory interference from cortical areas, particularly M1 and SMA, to DBS locations.

Deficient Interhemispheric Connectivity Underlies Movement Irregularities in Parkinson's Disease.

BACKGROUND: Movement execution is impaired in patients with Parkinson's disease. Evolving neurodegeneration leads to altered connectivity between distinct regions of the brain and altered activity at interconnected areas. How connectivity alterations influence complex movements like drawing spirals in Parkinson's disease patients remains largely unexplored. OBJECTIVE: We investigated whether deteriorations in interregional connectivity relate to impaired execution of drawing. METHODS: Twenty-nine patients and 31 age-matched healthy control participants drew spirals with both hands on a digital graphics tablet, and the regularity of drawing execution was evaluated by sample entropy. We recorded resting-state fMRI and task-related EEG, and calculated the time-resolved partial directed coherence to estimate effective connectivity for both imaging modalities to determine the extent and directionality of interregional interactions. RESULTS: Movement performance in Parkinson's disease patients was characterized by increased sample entropy, corresponding to enhanced irregularities in task execution. Effective connectivity between the motor cortices of both hemispheres, derived from resting-state fMRI, was significantly reduced in Parkinson's disease patients in comparison to controls. The connectivity strength in the nondominant to dominant hemisphere direction in both modalities was inversely correlated with irregularities during drawing, but not with the clinical state. CONCLUSION: Our findings suggest that interhemispheric connections are affected both at rest and during drawing movements by Parkinson's disease. This provides novel evidence that disruptions of interhemispheric information exchange play a pivotal role for impairments of complex movement execution in Parkinson's disease patients.

Increased migraine-free intervals with multifocal repetitive transcranial magnetic stimulation.

INTRODUCTION: Episodic migraine is a debilitating condition associated with vast impairments of health, daily living, and life quality. Several prophylactic treatments exist, having a moderate ratio of action related to side effects and therapy costs. Repetitive transcranial magnetic stimulation (rTMS) is an evidence based therapy in several neuropsychiatric conditions, showing robust efficacy in alleviating specific symptoms. However, its efficacy in migraine disorders is unequivocal and might be tightly linked to the applied rTMS protocol. We hypothesized that multifocal rTMS paradigm could improve clinical outcomes in patients with episodic migraine by reducing the number of migraine days, frequency and intensity of migraine attacks, and improve the quality of life. METHODS: We conducted an experimental, double-blind, randomized controlled study by applying a multifocal rTMS paradigm. Patients with episodic migraine with or without aura were enrolled in two centers from August 2018, to December 2019, and randomized to receive either real (n = 37) or sham (sham coil stimulation, n = 28) multifocal rTMS for six sessions over two weeks. Patients, physicians, and raters were blinded to the applied protocol. The experimental multifocal rTMS protocol included two components; first, swipe stimulation of 13 trains of 140 pulses/train, 67 Hz, 60% of RMT, and 2s intertrain interval and second, spot burst stimulation of 33 trains of 15 pulses/train, 67 Hz, 85% of RMT, and 8s intertrain interval. Reduction >50% from the baseline in migraine days (as primary outcome) and frequency and intensity of migraine attacks (as key secondary outcomes) over a 12-week period were assessed. To balance the baseline variables between the treatment arms, we applied the propensity score matching through the logistic regression. RESULTS: Among 65 randomized patients, sixty (age 39.7 ± 11.6; 52 females; real rTMS n = 33 and sham rTMS n = 27) completed the trial and five patients dropped out. Over 12 weeks, the responder's rate in the number of migraine days was significantly higher in the real rTMS compared to the sham group (42% vs. 26%, p < 0.05). The mean migraine days per month decreased from 7.6 to 4.3 days in the real rTMS group and from 6.2 to 4.3 days in the sham rTMS group, resulting in a difference with real vs. sham rTMS of -3.2 days (p < 0.05). Similarly, over the 12-week period, the responder's rate in the reduction of migraine attacks frequency was higher in the real rTMS compared to the sham group (42% vs 33%, p < 0.05). No serious adverse events were observed. CONCLUSION: Our pilot study shows compelling evidence in a double placebo-controlled trial that multifocal rTMS is an effective and well-tolerated preventive treatment in patients with episodic migraine.

Cross-frequency coupling between gamma oscillations and deep brain stimulation frequency in Parkinson's disease.

The disruption of pathologically enhanced beta oscillations is considered one of the key mechanisms mediating the clinical effects of deep brain stimulation on motor symptoms in Parkinson's disease. However, a specific modulation of other distinct physiological or pathological oscillatory activities could also play an important role in symptom control and motor function recovery during deep brain stimulation. Finely tuned gamma oscillations have been suggested to be prokinetic in nature, facilitating the preferential processing of physiological neural activity. In this study, we postulate that clinically effective high-frequency stimulation of the subthalamic nucleus imposes cross-frequency interactions with gamma oscillations in a cortico-subcortical network of interconnected regions and normalizes the balance between beta and gamma oscillations. To this end we acquired resting state high-density (256 channels) EEG from 31 patients with Parkinson's disease who underwent deep brain stimulation to compare spectral power and power-to-power cross-frequency coupling using a beamformer algorithm for coherent sources. To show that modulations exclusively relate to stimulation frequencies that alleviate motor symptoms, two clinically ineffective frequencies were tested as control conditions. We observed a robust reduction of beta and increase of gamma power, attested in the regions of a cortical (motor cortex, supplementary motor area, premotor cortex) and subcortical network (subthalamic nucleus and cerebellum). Additionally, we found a clear cross-frequency coupling of narrowband gamma frequencies to the stimulation frequency in all of these nodes, which negatively correlated with motor impairment. No such dynamics were revealed within the control posterior parietal cortex region. Furthermore, deep brain stimulation at clinically ineffective frequencies did not alter the source power spectra or cross-frequency coupling in any region. These findings demonstrate that clinically effective deep brain stimulation of the subthalamic nucleus differentially modifies different oscillatory activities in a widespread network of cortical and subcortical regions. Particularly the cross-frequency interactions between finely tuned gamma oscillations and the stimulation frequency may suggest an entrainment mechanism that could promote dynamic neural processing underlying motor symptom alleviation.

The Cumulative Effect of Transient Synchrony States on Motor Performance in Parkinson's Disease.

Bursts of beta frequency band activity in the basal ganglia of patients with Parkinson's disease (PD) are associated with impaired motor performance. Here we test in human adults whether small variations in the timing of movement relative to beta bursts have a critical effect on movement velocity and whether the cumulative effects of multiple beta bursts, both locally and across networks, matter. We recorded local field potentials from the subthalamic nucleus (STN) in 15 PD patients of both genders OFF-medication, during temporary lead externalization after deep brain stimulation surgery. Beta bursts were defined as periods exceeding the 75th percentile amplitude threshold. Subjects performed a visual cued joystick reaching task, with the visual cue being triggered in real time with different temporal relationships to bursts of STN beta activity. The velocity of actions made in response to cues prospectively triggered by STN beta bursts was slower than when responses were not time-locked to recent beta bursts. Importantly, slow movements were those that followed multiple bursts close to each other within a trial. In contrast, small differences in the delay between the last burst and movement onset had no significant impact on velocity. Moreover, when the overlap of bursts between the two STN was high, slowing was more pronounced. Our findings suggest that the cumulative, but recent, history of beta bursting, both locally and across basal ganglia networks, may impact on motor performance.SIGNIFICANCE STATEMENT Bursts of beta frequency band activity in the basal ganglia are associated with slowing of voluntary movement in patients with Parkinson's disease. We show that slow movements are those that follow multiple bursts close to each other and bursts that are coupled across regions. These results suggest that the cumulative, but recent, history of beta bursting, both locally and across basal ganglia networks, impacts on motor performance in this condition. The manipulation of burst dynamics may be a means of selectively improving motor impairment.