Left Vagus Stimulation Modulates Contralateral Subthalamic ß Power Improving the Gait in Parkinson's Disease.

BACKGROUND: Transcutaneous vagus nerve stimulation (VNS) showed early evidence of efficacy for the gait treatment of Parkinson's disease (PD). OBJECTIVES: Providing data on neurophysiological and clinical effects of transauricular VNS (taVNS). METHODS: Ten patients with recording deep brain stimulation (DBS) have been enrolled in a within participant design pilot study, double-blind crossover sham-controlled trial of taVNS. Subthalamic local field potentials (ß band power), Unified Parkinson's Disease Rating Scales (UPDRS), and a digital timed-up-and-go test (TUG) were measured and compared with real versus sham taVNS during medication-off/DBS-OFF condition. RESULTS: The left taVNS induced a reduction of the total ß power in the contralateral (ie, right) subthalamic nucleus and an improvement of TUG time, speed, and variability. The taVNS-induced ß reduction correlated with the improvement of gait speed. No major clinical changes were observed at UPDRS. CONCLUSIONS: taVNS is a promising strategy for the management of PD gait, deserving prospective trials of chronic neuromodulation. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Beta-triggered adaptive deep brain stimulation during reaching movement in Parkinson's disease.

Subthalamic nucleus (STN) beta-triggered adaptive deep brain stimulation (ADBS) has been shown to provide clinical improvement comparable to conventional continuous DBS (CDBS) with less energy delivered to the brain and less stimulation induced side effects. However, several questions remain unanswered. First, there is a normal physiological reduction of STN beta band power just prior to and during voluntary movement. ADBS systems will therefore reduce or cease stimulation during movement in people with Parkinson's disease and could therefore compromise motor performance compared to CDBS. Second, beta power was smoothed and estimated over a time period of 400 ms in most previous ADBS studies, but a shorter smoothing period could have the advantage of being more sensitive to changes in beta power, which could enhance motor performance. In this study, we addressed these two questions by evaluating the effectiveness of STN beta-triggered ADBS using a standard 400 ms and a shorter 200 ms smoothing window during reaching movements. Results from 13 people with Parkinson's disease showed that reducing the smoothing window for quantifying beta did lead to shortened beta burst durations by increasing the number of beta bursts shorter than 200 ms and more frequent switching on/off of the stimulator but had no behavioural effects. Both ADBS and CDBS improved motor performance to an equivalent extent compared to no DBS. Secondary analysis revealed that there were independent effects of a decrease in beta power and an increase in gamma power in predicting faster movement speed, while a decrease in beta event related desynchronization (ERD) predicted quicker movement initiation. CDBS suppressed both beta and gamma more than ADBS, whereas beta ERD was reduced to a similar level during CDBS and ADBS compared with no DBS, which together explained the achieved similar performance improvement in reaching movements during CDBS and ADBS. In addition, ADBS significantly improved tremor compared with no DBS but was not as effective as CDBS. These results suggest that STN beta-triggered ADBS is effective in improving motor performance during reaching movements in people with Parkinson's disease, and that shortening of the smoothing window does not result in any additional behavioural benefit. When developing ADBS systems for Parkinson's disease, it might not be necessary to track very fast beta dynamics; combining beta, gamma, and information from motor decoding might be more beneficial with additional biomarkers needed for optimal treatment of tremor.

Evoked resonant neural activity in subthalamic local field potentials reflects basal ganglia network dynamics.

Evoked resonant neural activity (ERNA) is induced by subthalamic deep brain stimulation (DBS) and was recently suggested as a marker of lead placement and contact selection in Parkinson's disease. Yet, its underlying mechanisms and how it is modulated by stimulation parameters are unclear. Here, we recorded local field potentials from 27 Parkinson's disease patients, while leads were externalised to scrutinise the ERNA. First, we show that ERNA in the time series waveform and spectrogram likely represent the same activity, which was contested before. Second, our results show that the ERNA has fast and slow dynamics during stimulation, consistent with the synaptic failure hypothesis. Third, we show that ERNA parameters are modulated by different DBS frequencies, intensities, medication states and stimulation modes (continuous DBS vs. adaptive DBS). These results suggest the ERNA might prove useful as a predictor of the best DBS frequency and lowest effective intensity in addition to contact selection. Changes with levodopa and DBS mode suggest that the ERNA may indicate the state of the cortico-basal ganglia circuit making it a putative biomarker to track clinical state in adaptive DBS.

Subthalamic Nucleus Stimulation-Induced Local Field Potential Changes in Dystonia.

BACKGROUND: Subthalamic nucleus (STN) stimulation is an effective treatment for Parkinson's disease and induced local field potential (LFP) changes that have been linked with clinical improvement. STN stimulation has also been used in dystonia although the internal globus pallidus is the standard target where theta power has been suggested as a physiomarker for adaptive stimulation. OBJECTIVE: We aimed to explore if enhanced theta power was also present in STN and if stimulation-induced spectral changes that were previously reported for Parkinson's disease would occur in dystonia. METHODS: We recorded LFPs from 7 patients (12 hemispheres) with isolated craniocervical dystonia whose electrodes were placed such that inferior, middle, and superior contacts covered STN, zona incerta, and thalamus. RESULTS: We did not observe prominent theta power in STN at rest. STN stimulation induced similar spectral changes in dystonia as in Parkinson's disease, such as broadband power suppression, evoked resonant neural activity (ERNA), finely-tuned gamma oscillations, and an increase in aperiodic exponents in STN-LFPs. Both power suppression and ERNA localize to STN. Based on this, single-pulse STN stimulation elicits evoked neural activities with largest amplitudes in STN, which are relayed to the zona incerta and thalamus with changing characteristics as the distance from STN increases. CONCLUSIONS: Our results show that STN stimulation-induced spectral changes are a nondisease-specific response to high-frequency stimulation, which can serve as placement markers for STN. This broadens the scope of STN stimulation and makes it an option for other disorders with excessive oscillatory peaks in STN. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Balance between competing spectral states in subthalamic nucleus is linked to motor impairment in Parkinson's disease.

Exaggerated local field potential bursts of activity at frequencies in the low beta band are a well-established phenomenon in the subthalamic nucleus of patients with Parkinson's disease. However, such activity is only moderately correlated with motor impairment. Here we test the hypothesis that beta bursts are just one of several dynamic states in the subthalamic nucleus local field potential in Parkinson's disease, and that together these different states predict motor impairment with high fidelity. Local field potentials were recorded in 32 patients (64 hemispheres) undergoing deep brain stimulation surgery targeting the subthalamic nucleus. Recordings were performed following overnight withdrawal of anti-parkinsonian medication, and after administration of levodopa. Local field potentials were analysed using hidden Markov modelling to identify transient spectral states with frequencies under 40 Hz. Findings in the low beta frequency band were similar to those previously reported; levodopa reduced occurrence rate and duration of low beta states, and the greater the reductions, the greater the improvement in motor impairment. However, additional local field potential states were distinguished in the theta, alpha and high beta bands, and these behaved in an opposite manner. They were increased in occurrence rate and duration by levodopa, and the greater the increases, the greater the improvement in motor impairment. In addition, levodopa favoured the transition of low beta states to other spectral states. When all local field potential states and corresponding features were considered in a multivariate model it was possible to predict 50% of the variance in patients' hemibody impairment OFF medication, and in the change in hemibody impairment following levodopa. This only improved slightly if signal amplitude or gamma band features were also included in the multivariate model. In addition, it compares with a prediction of only 16% of the variance when using beta bursts alone. We conclude that multiple spectral states in the subthalamic nucleus local field potential have a bearing on motor impairment, and that levodopa-induced shifts in the balance between these states can predict clinical change with high fidelity. This is important in suggesting that some states might be upregulated to improve parkinsonism and in suggesting how local field potential feedback can be made more informative in closed-loop deep brain stimulation systems.

Combining Multimodal Biomarkers to Guide Deep Brain Stimulation Programming in Parkinson Disease.

BACKGROUND: Deep brain stimulation (DBS) programming of multicontact DBS leads relies on a very time-consuming manual screening procedure, and strategies to speed up this process are needed. Beta activity in subthalamic nucleus (STN) local field potentials (LFP) has been suggested as a promising marker to index optimal stimulation contacts in patients with Parkinson disease. OBJECTIVE: In this study, we investigate the advantage of algorithmic selection and combination of multiple resting and movement state features from STN LFPs and imaging markers to predict three relevant clinical DBS parameters (clinical efficacy, therapeutic window, side-effect threshold). MATERIALS AND METHODS: STN LFPs were recorded at rest and during voluntary movements from multicontact DBS leads in 27 hemispheres. Resting- and movement-state features from multiple frequency bands (alpha, low beta, high beta, gamma, fast gamma, high frequency oscillations [HFO]) were used to predict the clinical outcome parameters. Subanalyses included an anatomical stimulation sweet spot as an additional feature. RESULTS: Both resting- and movement-state features contributed to the prediction, with resting (fast) gamma activity, resting/movement-modulated beta activity, and movement-modulated HFO being most predictive. With the proposed algorithm, the best stimulation contact for the three clinical outcome parameters can be identified with a probability of almost 90% after considering half of the DBS lead contacts, and it outperforms the use of beta activity as single marker. The combination of electrophysiological and imaging markers can further improve the prediction. CONCLUSION: LFP-guided DBS programming based on algorithmic selection and combination of multiple electrophysiological and imaging markers can be an efficient approach to improve the clinical routine and outcome of DBS patients.

Motor Cortex Inputs at the Optimum Phase of Beta Cortical Oscillations Undergo More Rapid and Less Variable Corticospinal Propagation.

Brain oscillations involve rhythmic fluctuations of neuronal excitability and may play a crucial role in neural communication. The human corticomuscular system is characterized by beta activity and is readily probed by transcranial magnetic stimulation (TMS). TMS inputs arriving at the excitable phase of beta oscillations in the motor cortex are known to lead to muscle responses of greater amplitude. Here we explore two other possible manifestations of rhythmic excitability in the beta band; windows of reduced response variability and shortened latency. We delivered single-pulse TMS to the motor cortex of healthy human volunteers (10 females and 7 males) during electroencephalography recordings made at rest. TMS delivered at a particular phase of the beta oscillation benefited from not only stronger, but also less variable and more rapid transmission, as evidenced by the greater amplitude, lower coefficient of variation, and shorter latency of motor evoked potentials. Thus, inputs aligned to the optimal phase of the beta EEG in the motor cortex enjoy transmission amplitude gain, but may also benefit from less variability and shortened latencies at subsequent synapses. Neuronal phase may therefore impact corticospinal communication.SIGNIFICANCE STATEMENT Brain oscillations involve rhythmic fluctuations of neuronal excitability. Therefore, motor responses to transcranial magnetic stimulation are larger when a cortical input arrives at a particular phase of the beta activity in the motor cortex. Here, we demonstrate that inputs to corticospinal neurons which coincide with windows of higher excitability also benefit from more rapid and less variable corticospinal transmission. This shortening of latency and increased reproducibility may confer additional advantage to inputs at specific phases. Moreover, these benefits are conserved despite appreciable corticospinal conduction delays.

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.

Neurophysiological Correlates of Trait Impulsivity in Parkinson's Disease.

BACKGROUND: Impulsivity is common in people with Parkinson's disease (PD), with many developing impulsive compulsive behavior disorders (ICB). Its pathophysiological basis remains unclear. OBJECTIVES: We aimed to investigate local field potential (LFP) markers of trait impulsivity in PD and their relationship to ICB. METHODS: We recorded subthalamic nucleus (STN) LFPs in 23 PD patients undergoing deep brain stimulation implantation. Presence and severity of ICB were assessed by clinical interview and the Questionnaire for Impulsive-Compulsive Disorders in PD-Rating Scale (QUIP-RS), whereas trait impulsivity was estimated with the Barratt Impulsivity Scale (BIS-11). Recordings were obtained during the off dopaminergic states and the power spectrum of the subthalamic activity was analyzed using Fourier transform-based techniques. Assessment of each electrode contact localization was done to determine the topography of the oscillatory activity recorded. RESULTS: Patients with (n = 6) and without (n = 17) ICB had similar LFP spectra. A multiple regression model including QUIP-RS, BIS-11, and Unified PD Rating Scale-III scores as regressors showed a significant positive correlation between 8-13 Hz power and BIS-11 score. The correlation was mainly driven by the motor factor of the BIS-11, and was irrespective of the presence or absence of active ICB. Electrode contact pairs with the highest α power, which also correlated most strongly with BIS-11, tended to be more ventral than contact pairs with the highest beta power, which localize to the dorsolateral motor STN. CONCLUSIONS: Our data suggest a link between α power and trait impulsivity in PD, irrespective of the presence and severity of ICB. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Modulation of Beta Bursts in the Subthalamic Nucleus Predicts Motor Performance.

Considerable evidence suggests a role of beta-band oscillations in voluntary movements. However, most of the studies linking beta power to motor performance are based on data averaged across trials that ignore the fast dynamics of oscillatory activity and trial-to-trial variations in motor responses. Recently, emphasis has shifted from the functional implications of the mean beta power to the presence and nature of episodic bursts of beta activity. Here we test the hypothesis that beta bursts, though short in duration in more physiological state, may help explain spontaneous variations in motor behavior of human adults at the single-trial level. To this end, we recorded local field potential activity from the subthalamic nucleus of parkinsonian patients of both genders whose motor behavior had been normalized as far as possible through treatment with the dopamine prodrug, levodopa. We found that beta bursts present in a time-limited window well before movement onset in the contralateral subthalamic nucleus reduce the peak velocity of that movement and that this effect is further amplified by the amplitude of the burst. Additionally, prolonged reaction times are observed when bursts occur immediately after the GO cue. Together, these results suggest that the modulation of the timing and amplitude of beta bursts might serve to dynamically adapt motor performance. These results offer new insight in the pathology of Parkinson's disease, and suggest that beta bursts whose presence and nature are modulated by context may have a physiological role in modulating behavior.SIGNIFICANCE STATEMENT Beta oscillations (∼13-30 Hz) have been increasingly interpreted as transient bursts rather than as rhythmically sustained oscillations (Feingold et al., 2015). Prolonged and increased probability of beta bursts in the subthalamic nucleus correlates with the severity of motor impairment in Parkinson's disease (Tinkhauser et al., 2017a, b). However, it remains unclear whether beta bursts act to modify motor performance on a trial-by-trial basis under more physiological condition. Here, we found that, according to the time window in which they fall, beta bursts reduced the velocity of the forthcoming movement or prolonged the reaction time. These results offer new insight in the pathology of Parkinson's disease and also suggest that the modulation of beta bursts might serve to dynamically adapt motor performance.

Error-related modulations of the sensorimotor post-movement and foreperiod beta-band activities arise from distinct neural substrates and do not reflect efferent signal processing.

While beta activity has been extensively studied in relation to voluntary movement, its role in sensorimotor adaptation remains largely uncertain. Recently, it has been shown that the post-movement beta rebound as well as beta activity during movement-preparation are modulated by movement errors. However, there are critical functional differences between pre- and post-movement beta activities. Here, we addressed two related open questions. Do the pre- and post-movement error-related modulations arise from distinct neural substrates? Do these modulations relate to efferent signals shaping muscle-activation patterns or do they reflect integration of sensory information, intervening upstream of the motor output? For this purpose, first we exploited independent component analysis (ICA) which revealed a double dissociation suggesting that distinct neural substrates are recruited in error-related beta-power modulations observed before and after movement. Second, we compared error-related beta oscillation responses observed in two bimanual reaching tasks involving similar movements but different interlimb coordination, and in which the same mechanical perturbations induced different behavioral adaptive responses. While the task difference was not reflected in the post-movement beta rebound, the pre-movement beta activity was differently modulated according to the interlimb coordination. Critically, we show an uncoupling between the behavioral and the electrophysiological responses during the movement preparation phase, which demonstrates that the error-related modulation of the foreperiod beta activity does not reflect changes in the motor output from primary motor cortex. It seems instead to relate to higher level processing of sensory afferents, essential for sensorimotor adaptation.

Beta burst coupling across the motor circuit in Parkinson's disease.

Exaggerated activity in the beta band (13-35 Hz) is a hallmark of basal ganglia signals in patients with Parkinson's disease (PD). Beta activity however is not constantly elevated, but comes in bursts. In previous work we showed that the longer beta bursts are maintained, the more the oscillatory synchronisation within the subthalamic nucleus (STN) increases, which is posited to limit the information coding capacity of local circuits. Accordingly, a higher incidence of longer bursts correlates positively with clinical impairment, while the opposite is true for short, more physiological bursts. Here, we test the hypothesis that beta bursts not only indicate local synchronisation within the STN, but also phasic coupling across the motor network and hence entail an even greater restriction of information coding capacity in patients with PD. Local field potentials from the subthalamic nucleus and EEG over the motor cortex area were recorded in nine PD patients after temporary lead externalization after surgery for deep brain stimulation and overnight withdrawal of levodopa. Beta bursts were defined as periods exceeding the 75th percentile of signal amplitude and the coupling between bursts was considered using two distinct measurements, first the % overlapping (%OVL) as a feature of the amplitude coupling and secondly the phase synchrony index (PSI) to measure the phase coupling between regions. %OVL between STN and cortex and between the left and the right STN was higher than expected between the regions than if they had been independent. Similarly, PSI was higher during bursts as opposed to non-bursts periods. In addition, %OVL was greater for long compared to short bursts. Our results support the hypothesis that beta bursts involve long-range coupling between structures in the basal ganglia-cortical network. The impact of this is greater during long as opposed to short duration beta bursts. Accordingly, we posit that episodes of simultaneously elevated coupling across multiple structures in the basal ganglia-cortical circuit further limit information coding capacity and may have further impact upon motor impairment.

Distinct Modulations in Sensorimotor Postmovement and Foreperiod ß-Band Activities Related to Error Salience Processing and Sensorimotor Adaptation.

In a recent study, Tan et al. (2014a,b) showed that the increase in ß-power typically observed after a movement above sensorimotor regions (ß-rebound) is attenuated when movement-execution errors are induced by visual perturbations. Moreover, akin to sensorimotor adaptation, the effect depended on the context in which the errors are experienced. Thus the ß-rebound attenuation might relate to neural processes involved in trial-to-trial adaptive mechanisms. In two EEG experiments with human participants, along with the ß-rebound, we examine ß-activity during the preparation of reaches immediately following perturbed movements. In the first experiment, we show that both foreperiod and postmovement ß-activities are parametrically modulated by the sizes of kinematic errors produced by unpredictable mechanical perturbations (force field) independent of their on-line corrections. In the second experiment, we contrast two types of reach errors: movement-execution errors that trigger trial-to-trial adaptive mechanisms and goal errors that do not elicit sensorimotor adaptation. Movement-execution errors were induced by mechanical or visual perturbations, whereas goal errors were caused by unexpected displacements of the target at movement initiation. Interestingly, foreperiod and postmovement ß-activities exhibit contrasting patterns, pointing to important functional differences of their underlying neuronal activity. While both types of reach errors attenuate the postmovement ß-rebound, only the kinematic errors that trigger trial-to-trial motor-command updates influenced ß-activity during the foreperiod. These findings suggest that the error-related modulation of the ß-rebound may reflect salience processing, independent of sensorimotor adaptation. In contrast, modulations in the foreperiod ß-power might relate to the motor-command adjustments activated after movement-execution errors are experienced. SIGNIFICANCE STATEMENT: The functional significance of sensorimotor ß-band (15-25 Hz) oscillations remains uncertain. Recently ß-power was found to be reduced following erroneous movements. We extend and refine this novel finding in two crucial ways. First, by contrasting the EEG correlates of movement errors driving or not driving adaptation we dissociate error-salience processing from error-based adaptation. Second, in addition to ß-activity in error trials, we examine ß-power during the preparation of the subsequent movements. We find clearly distinct patterns of error-related modulations for ß-activities preceding and succeeding movements, highlighting critical functional differences. Postmovement ß-power may reflect error-salience processing independent of sensorimotor adaptation. In contrast, modulations in the foreperiod ß-band power may directly relate to the motor-command adjustments activated after movement-execution errors are experienced.

Does the processing of sensory and reward-prediction errors involve common neural resources? Evidence from a frontocentral negative potential modulated by movement execution errors.

In humans, electrophysiological correlates of error processing have been extensively investigated in relation to decision-making theories. In particular, error-related ERPs have been most often studied using response selection tasks. In these tasks, involving very simple motor responses (e.g., button press), errors concern inappropriate action-selection only. However, EEG activity in relation to inaccurate movement-execution in more complex motor tasks has been much less examined. In the present study, we recorded EEG while volunteers performed reaching movements in a force-field created by a robotic device. Hand-path deviations were induced by interspersing catch trials in which the force condition was unpredictably altered. Our goal was twofold. First, we wanted to determine whether a frontocentral ERP was elicited by sensory-prediction errors, whose amplitude reflected the size of kinematic errors. Then, we explored whether common neural processes could be involved in the generation of this ERP and the feedback-related negativity (FRN), often assumed to reflect reward-prediction errors. We identified a frontocentral negativity whose amplitude was modulated by the size of the hand-path deviations induced by the unpredictable mechanical perturbations. This kinematic error-related ERP presented great similarities in terms of time course, topography, and potential source-location with the FRN recorded in the same experiment. These findings suggest that the processing of sensory-prediction errors and the processing of reward-prediction errors could involve a shared neural network.

Average power and burst analysis revealed complementary information on drug-related changes of motor performance in Parkinson's disease.

In patients with Parkinson's disease (PD), suppression of beta and increase in gamma oscillations in the subthalamic nucleus (STN) have been associated with both levodopa treatment and motor functions. Recent results suggest that modulation of the temporal dynamics of theses oscillations (bursting activity) might contain more information about pathological states and behaviour than their average power. Here we directly compared the information provided by power and burst analyses about the drug-related changes in STN activities and their impact on motor performance within PD patients. STN local field potential (LFP) signals were recorded from externalized patients performing self-paced movements ON and OFF levodopa. When normalised across medication states, both power and burst analyses showed an increase in low-beta oscillations in the dopamine-depleted state during rest. When normalised within-medication state, both analyses revealed that levodopa increased movement-related modulation in the alpha and low-gamma bands, with higher gamma activity around movement predicting faster reaches. Finally, burst analyses helped to reveal opposite drug-related changes in low- and high-beta frequency bands, and identified additional within-patient relationships between high-beta bursting and movement performance. Our findings suggest that although power and burst analyses share a lot in common they also provide complementary information on how STN-LFP activity is associated with motor performance, and how levodopa treatment may modify these relationships in a way that helps explain drug-related changes in motor performance. Different ways of normalisation in the power analysis can reveal different information. Similarly, the burst analysis is sensitive to how the threshold is defined - either for separate medication conditions separately, or across pooled conditions. In addition, the burst interpretation has far-reaching implications about the nature of neural oscillations - whether the oscillations happen as isolated burst-events or are they sustained phenomena with dynamic amplitude variations? This can be different for different frequency bands, and different for different medication states even for the same frequency band.

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.

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.

Subthalamic beta-targeted neurofeedback speeds up movement initiation but increases tremor in Parkinsonian patients.

Previous studies have explored neurofeedback training for Parkinsonian patients to suppress beta oscillations in the subthalamic nucleus (STN). However, its impacts on movements and Parkinsonian tremor are unclear. We developed a neurofeedback paradigm targeting STN beta bursts and investigated whether neurofeedback training could improve motor initiation in Parkinson's disease compared to passive observation. Our task additionally allowed us to test which endogenous changes in oscillatory STN activities are associated with trial-to-trial motor performance. Neurofeedback training reduced beta synchrony and increased gamma activity within the STN, and reduced beta band coupling between the STN and motor cortex. These changes were accompanied by reduced reaction times in subsequently cued movements. However, in Parkinsonian patients with pre-existing symptoms of tremor, successful volitional beta suppression was associated with an amplification of tremor which correlated with theta band activity in STN local field potentials, suggesting an additional cross-frequency interaction between STN beta and theta activities.

Electrophysiological differences between upper and lower limb movements in the human subthalamic nucleus.

OBJECTIVE: Functional processes in the brain are segregated in both the spatial and spectral domain. Motivated by findings reported at the cortical level in healthy participants we test the hypothesis in the basal ganglia of Parkinson's disease patients that lower frequency beta band activity relates to motor circuits associated with the upper limb and higher beta frequencies with lower limb movements. METHODS: We recorded local field potentials (LFPs) from the subthalamic nucleus using segmented "directional" DBS leads, during which patients performed repetitive upper and lower limb movements. Movement-related spectral changes in the beta and gamma frequency-ranges and their spatial distributions were compared between limbs. RESULTS: We found that the beta desynchronization during leg movements is characterised by a strikingly greater involvement of higher beta frequencies (24-31 Hz), regardless of whether this was contralateral or ipsilateral to the limb moved. The spatial distribution of limb-specific movement-related changes was evident at higher gamma frequencies. CONCLUSION: Limb processing in the basal ganglia is differentially organised in the spectral and spatial domain and can be captured by directional DBS leads. SIGNIFICANCE: These findings may help to refine the use of the subthalamic LFPs as a control signal for adaptive DBS and neuroprosthetic devices.