On-Off and Proportional Closed-Loop Adaptive Deep Brain Stimulation Reduces Motor Symptoms in Freely Moving Hemiparkinsonian Rats.

OBJECTIVES: Closed-loop adaptive deep brain stimulation (aDBS) continuously adjusts stimulation parameters, with the potential to improve efficacy and reduce side effects of deep brain stimulation (DBS) for Parkinson's disease (PD). Rodent models can provide an effective platform for testing aDBS algorithms and establishing efficacy before clinical investigation. In this study, we compare two aDBS algorithms, on-off and proportional modulation of DBS amplitude, with conventional DBS in hemiparkinsonian rats. MATERIALS AND METHODS: DBS of the subthalamic nucleus (STN) was delivered wirelessly in freely moving male and female hemiparkinsonian (N = 7) and sham (N = 3) Wistar rats. On-off and proportional aDBS, based on STN local field potential beta power, were compared with conventional DBS and three control stimulation algorithms. Behavior was assessed during cylinder tests (CT) and stepping tests (ST). Successful model creation was confirmed via apomorphine-induced rotation test and Tyrosine Hydroxylase-immunocytochemistry. Electrode location was histologically confirmed. Data were analyzed using linear mixed models. RESULTS: Contralateral paw use in parkinsonian rats was reduced to 20% and 25% in CT and ST, respectively. Conventional, on-off, and proportional aDBS significantly improved motor function, restoring contralateral paw use to approximately 45% in both tests. No improvement in motor behavior was observed with either randomly applied on-off or low-amplitude continuous stimulation. Relative STN beta power was suppressed during DBS. Relative power in the alpha and gamma bands decreased and increased, respectively. Therapeutically effective adaptive DBS used approximately 40% less energy than did conventional DBS. CONCLUSIONS: Adaptive DBS, using both on-off and proportional control schemes, is as effective as conventional DBS in reducing motor symptoms of PD in parkinsonian rats. Both aDBS algorithms yield substantial reductions in stimulation power. These findings support using hemiparkinsonian rats as a viable model for testing aDBS based on beta power and provide a path to investigate more complex closed-loop algorithms in freely behaving animals.

Effects of Contralateral Deep Brain Stimulation and Levodopa on Subthalamic Nucleus Oscillatory Activity and Phase-Amplitude Coupling.

BACKGROUND: The modulatory effects of medication and deep brain stimulation (DBS) on subthalamic nucleus (STN) neural activity in Parkinson's disease have been widely studied. However, effects on the contralateral side to the stimulated STN, in particular, changes in local field potential (LFP) oscillatory activity and phase-amplitude coupling (PAC), have not yet been reported. OBJECTIVE: The aim of this study was to examine changes in STN LFP activity across a range of frequency bands and STN PAC for different combinations of DBS and medication on/off on the side contralateral to the applied stimulation. MATERIALS AND METHODS: We examined STN LFPs that were recorded using externalized leads from eight parkinsonian patients during unilateral DBS from the side contralateral to the stimulation. LFP spectral power in alpha (5 to ∼13 Hz), low beta (13 to ∼20 Hz), high beta (20-30 Hz), and high gamma plus high-frequency oscillation (high gamma+HFO) (100-400 Hz) bands were estimated for different combinations of medication and unilateral stimulation (off/on). PAC between beta and high gamma+HFO in the STN LFPs was also investigated. The effect of the condition was examined using linear mixed models. RESULTS: PAC in the STN LFP was reduced by DBS when compared to the baseline condition (no medication and stimulation). Medication had no significant effect on PAC. Alpha power decreased with DBS, both alone and when combined with medication. Beta power decreased with DBS, medication, and DBS and medication combined. High gamma+HFO power increased during the application of contralateral DBS and was unaltered by medication. CONCLUSIONS: The results provide new insights into the effects of DBS and levodopa on STN LFP PAC and oscillatory activity on the side contralateral to stimulation. These may have important implications in understanding mechanisms underlying motor improvements with DBS, including changes on both contralateral and ipsilateral sides, while suggesting a possible role for contralateral sensing during unilateral DBS.

Computational Model of the Effect of Mitochondrial Dysfunction on Excitation-Contraction Coupling in Skeletal Muscle.

It has become well established that mitochondria not only regulate myoplasmic calcium in skeletal muscle, but also use that calcium to stimulate oxidative phosphorylation (OXPHOS). While experimental approaches have allowed for imaging of mitochondrial calcium and membrane potentials in isolated fibers, capturing the role of mitochondria and the impact of mitochondrial impairments on excitation-contraction coupling (ECC) remains difficult to explore in intact muscle. Computational models have been widely used to examine the structure and function of skeletal muscle contraction; however, models of ECC to date lack communication between the myoplasm and mitochondria for regulating calcium and ATP during sustained contractions. To address this, a mathematical model of mitochondrial calcium handling and OXPHOS was integrated into a physiological model of ECC incorporating action potential propagation, calcium handling between the sarcoplasmic reticulum (SR) and the myoplasm, and crossbridge cycling. The model was used to examine the protective role of mitochondria during repeated stimulation and the impact of mitochondrial dysfunction on ECC resulting from progressive OXPHOS inhibition. Pathological myoplasmic calcium accumulation occurred through distinct mechanisms in the model in the case of either electron transport chain, F1F0 ATP synthase, or adenine nucleotide transporter impairments. To investigate the effect of each impairment on force, a model of calcium-stimulated apoptosis was utilized to capture dysfunction-induced reductions in muscle mass, driving whole muscle force loss. The model presented in this study can be used to examine the role of mitochondria in the regulation of calcium, ATP, and force generation during voluntary contraction.

Effects of extracellular potassium on calcium handling and force generation in a model of excitation-contraction coupling in skeletal muscle.

It is well-established that extracellular potassium (Ko+) accumulation reduces muscle fiber excitability, however the effects of Ko+ on the excitation-contraction coupling (ECC) pathway are less understood. In vivo and in vitro studies following fatiguing stimulation protocols are limited in their ability to capture the effects of Ko+ on force production in combination with other simultaneously changing factors. To address this, a computational model of ECC for slow and fast twitch muscle is presented to explore the relative contributions of excitability-induced and metabolic-induced changes in force generation in response to increasing [Formula: see text] . The model incorporates mechanisms previously unexplored in modelling studies, including the effects of extracellular calcium on excitability, calcium-dependent inhibition of calcium release, ATP-dependent ionic pumping, and the contribution of ATP hydrolysis to intracellular phosphate accumulation rate. The model was able to capture the frequency-dependent biphasic Force- [Formula: see text] response observed experimentally. Force potentiation for moderately elevated [Formula: see text] was driven by increased action potential duration, myoplasmic calcium potentiation, and phosphate accumulation rate, while attenuation of force at higher [Formula: see text] was due to action potential failure resulting in reduced calcium release. These results suggest that altered calcium release and phosphate accumulation work together with elevated Ko+ to affect force during sustained contractions.

Methods for Lowering the Power Consumption of OS-Based Adaptive Deep Brain Stimulation Controllers.

The identification of a new generation of adaptive strategies for deep brain stimulation (DBS) will require the development of mixed hardware-software systems for testing and implementing such controllers clinically. Towards this aim, introducing an operating system (OS) that provides high-level features (multitasking, hardware abstraction, and dynamic operation) as the core element of adaptive deep brain stimulation (aDBS) controllers could expand the capabilities and development speed of new control strategies. However, such software frameworks also introduce substantial power consumption overhead that could render this solution unfeasible for implantable devices. To address this, in this work four techniques to reduce this overhead are proposed and evaluated: a tick-less idle operation mode, reduced and dynamic sampling, buffered read mode, and duty cycling. A dual threshold adaptive deep brain stimulation algorithm for suppressing pathological oscillatory neural activity was implemented along with the proposed energy saving techniques on an energy-efficient OS, YetiOS, running on a STM32L476RE microcontroller. The system was then tested using an emulation environment coupled to a mean field model of the parkinsonian basal ganglia to simulate local field potential (LFPs) which acted as a biomarker for the controller. The OS-based controller alone introduced a power consumption overhead of 10.03 mW for a sampling rate of 1 kHz. This was reduced to 12 µW by applying the proposed tick-less idle mode, dynamic sampling, buffered read and duty cycling techniques. The OS-based controller using the proposed methods can facilitate rapid and flexible testing and implementation of new control methods. Furthermore, the approach has the potential to become a central element in future implantable devices to enable energy-efficient implementation of a wide range of control algorithms across different neurological conditions and hardware platforms.

Anatomically accurate model of EMG during index finger flexion and abduction derived from diffusion tensor imaging.

This study presents a modelling framework in which information on muscle fiber direction and orientation during contraction is derived from diffusion tensor imaging (DTI) and incorporated in a computational model of the surface electromyographic (EMG) signal. The proposed model makes use of the principle of reciprocity to simultaneously calculate the electric potentials produced at the recording electrode by charges distributed along an arbitrary number of muscle fibers within the muscle, allowing for a computationally efficient evaluation of extracellular motor unit action potentials. The approach is applied to the complex architecture of the first dorsal interosseous (FDI) muscle of the hand to simulate EMG during index finger flexion and abduction. Using diffusion tensor imaging methods, the results show how muscle fiber orientation and curvature in this intrinsic hand muscle change during flexion and abduction. Incorporation of anatomically accurate muscle architecture and other hand tissue morphologies enables the model to capture variations in extracellular action potential waveform shape across the motor unit population and to predict experimentally observed differences in EMG signal features when switching from index finger abduction to flexion. The simulation results illustrate how structural and electrical properties of the tissues comprising the volume conductor, in combination with fiber direction and curvature, shape the detected action potentials. Using the model, the relative contribution of motor units of different sizes located throughout the muscle under both conditions is examined, yielding a prediction of the detection profile of the surface EMG electrode array over the muscle cross-section.

Quantitative clinical assessment of motor function during and following LSVT-BIG® therapy.

BACKGROUND: LSVT-BIG® is an intensively delivered, amplitude-oriented exercise therapy reported to improve mobility in individuals with Parkinson's disease (PD). However, questions remain surrounding the efficacy of LSVT-BIG® when compared with similar exercise therapies. Instrumented clinical tests using body-worn sensors can provide a means to objectively monitor patient progression with therapy by quantifying features of motor function, yet research exploring the feasibility of this approach has been limited to date. The aim of this study was to use accelerometer-instrumented clinical tests to quantify features of gait, balance and fine motor control in individuals with PD, in order to examine motor function during and following LSVT-BIG® therapy. METHODS: Twelve individuals with PD undergoing LSVT-BIG® therapy, eight non-exercising PD controls and 14 healthy controls were recruited to participate in the study. Functional mobility was examined using features derived from accelerometry recorded during five instrumented clinical tests: 10 m walk, Timed-Up-and-Go, Sit-to-Stand, quiet stance, and finger tapping. PD subjects undergoing therapy were assessed before, each week during, and up to 13 weeks following LSVT-BIG®. RESULTS: Accelerometry data captured significant improvements in 10 m walk and Timed-Up-and-Go times with LSVT-BIG® (p <  0.001), accompanied by increased stride length. Temporal features of the gait cycle were significantly lower following therapy, though no change was observed with measures of asymmetry or stride variance. The total number of Sit-to-Stand transitions significantly increased with LSVT-BIG® (p <  0.001), corresponding to a significant reduction of time spent in each phase of the Sit-to-Stand cycle. No change in measures related to postural or fine motor control was observed with LSVT-BIG®. PD subjects undergoing LSVT-BIG® showed significant improvements in 10 m walk (p <  0.001) and Timed-Up-and-Go times (p = 0.004) over a four-week period when compared to non-exercising PD controls, who showed no week-to-week improvement in any task examined. CONCLUSIONS: This study demonstrates the potential for wearable sensors to objectively quantify changes in motor function in response to therapeutic exercise interventions in PD. The observed improvements in accelerometer-derived features provide support for instrumenting gait and sit-to-stand tasks, and demonstrate a rescaling of the speed-amplitude relationship during gait in PD following LSVT-BIG®.

Beta-band motor unit coherence and nonlinear surface EMG features of the first dorsal interosseous muscle vary with force.

Motor unit firing times are weakly coupled across a range of frequencies during voluntary contractions. Coherent activity within the beta-band (15-35 Hz) has been linked to oscillatory cortical processes, providing evidence of functional connectivity between the motoneuron pool and motor cortex. The aim of this study was to investigate whether beta-band motor unit coherence is altered with increasing abduction force in the first dorsal interosseous muscle. Coherence between motor unit firing times, extracted from decomposed surface electromyography (EMG) signals, was investigated in 17 subjects at 10, 20, 30, and 40% of maximum voluntary contraction. Corresponding changes in nonlinear surface EMG features (specifically sample entropy and determinism, which are sensitive to motor unit synchronization) were also examined. A reduction in beta-band and alpha-band coherence was observed as force increased [F(3, 151) = 32, P < 0.001 and F(3, 151) = 27, P < 0.001, respectively], accompanied by corresponding changes in nonlinear surface EMG features. A significant relationship between the nonlinear features and motor unit coherence was also detected (r = -0.43 ± 0.1 and r = 0.45 ± 0.1 for sample entropy and determinism, respectively; both P < 0.001). The reduction in beta-band coherence suggests a change in the relative contribution of correlated and uncorrelated presynaptic inputs to the motoneuron pool, and/or a decrease in the responsiveness of the motoneuron pool to synchronous inputs at higher forces. The study highlights the importance of considering muscle activation when investigating changes in motor unit coherence or nonlinear EMG features and examines other factors that can influence coherence estimation.NEW & NOTEWORTHY Intramuscular alpha- and beta-band coherence decreased as muscle contraction force increased. Beta-band coherence was higher in groups of high-threshold motor units than in simultaneously active lower threshold units. Alterations in motor unit coherence with increases or decreases in force and with the onset of fatigue were accompanied by corresponding changes in surface electromyography sample entropy and determinism. Mixed-model analysis indicated mean firing rate and number of motor units also influenced the coherence estimate.

Muscle fatigue increases beta-band coherence between the firing times of simultaneously active motor units in the first dorsal interosseous muscle.

Synchronization between the firing times of simultaneously active motor units (MUs) is generally assumed to increase during fatiguing contractions. To date, however, estimates of MU synchronization have relied on indirect measures, derived from surface electromyographic (EMG) interference signals. This study used intramuscular coherence to investigate the correlation between MU discharges in the first dorsal interosseous muscle during and immediately following a submaximal fatiguing contraction, and after rest. Coherence between composite MU spike trains, derived from decomposed surface EMG, were examined in the delta (1-4 Hz), alpha (8-12 Hz), beta (15-30 Hz), and gamma (30-60 Hz) frequency band ranges. A significant increase in MU coherence was observed in the delta, alpha, and beta frequency bands postfatigue. In addition, wavelet coherence revealed a tendency for delta-, alpha-, and beta-band coherence to increase during the fatiguing contraction, with subjects exhibiting low initial coherence values displaying the greatest relative increase. This was accompanied by an increase in MU short-term synchronization and a decline in mean firing rate of the majority of MUs detected during the sustained contraction. A model of the motoneuron pool and surface EMG was used to investigate factors influencing the coherence estimate. Simulation results indicated that changes in motoneuron inhibition and firing rates alone could not directly account for increased beta-band coherence postfatigue. The observed increase is, therefore, more likely to arise from an increase in the strength of correlated inputs to MUs as the muscle fatigues.