William Duncan Hutchison

Introduction: Stimulation-evoked potentials (SEPs), recorded both during and after deep brain stimulation (DBS) surgery, have shown promise for guiding DBS targeting and programming. However, filtering protocols applied to stimulation trains produce an artifact we call a filter-induced oscillation (FIO) which closely mimics physiological SEPs. Hence, we outline the mechanistic origins of this distortion and describe a means of differentiating it from valid SEP activity. Methods: We recorded in 18 patients undergoing DBS surgery targeting the subthalamic nucleus or globus pallidus internus. We stimulated target nuclei with cathode-first (CF) and anode-first (AF) pulses to record native SEPs, and in white matter tracts (null condition). Recordings were subsequently filtered to illustrate FIO. Next, we filtered harmonic frequencies of an artificial stimulation train to demonstrate FIO origins. Finally, FIO was deliberately generated in white matter recordings with a notch filter, and its behaviour contrasted with SEPs during AF and CF stimulation. Results: Filtering stimulation trains produced FIOs that depended on filter order and corner frequency. We also showed that FIO emerges from filter-induced attenuations of harmonic frequencies which compose stimulation trains, producing oscillations of like frequency around pulses. Finally, FIOs reverse in polarity depending on AF or CF stimulation, whereas SEPs do not. Conclusions: Given the potential for widespread adoption of SEPs in DBS targeting and programming, safe analytical protocols are imperative to avoid the induction of processing-related artifacts which can be misinterpreted as biological signals. Here we establish the necessary theory for identifying FIOs and tuning analytical pipelines to avoid their generation.

Background Deep brain stimulation (DBS) is used to treat neurological and psychiatric disorders by modulating neuronal circuits. However, other mechanisms of DBS, such as the effects of electrical stimulation on the neurovascular unit remain poorly understood due to limitations of capturing microvascular changes near implanted leads. This motivated us to investigate electrophysiological surrogates of vascular dynamics in response to intraoperative microstimulation. Methods Microelectrode recordings (n = 193; 108 patients) were obtained during DBS implantation surgery from two electrodes (∼600 µm apart) before and after microstimulation through one electrode. Linear mixed models assessed cardioballistic waveform (CBW) amplitude changes following low-frequency (LFS, 1 Hz) or high-frequency stimulation (HFS, 100 Hz), with comparisons across basal ganglia regions and in white matter. An analytical model interpreted CBW amplitudes as pressure-driven vessel wall expansion, enabling estimation of stimulation-evoked vasodilation and cerebral blood flow. Results CBW amplitudes increased significantly after HFS at the stimulating electrode, but not at the non-stimulating electrode or after LFS. Significant region-specific effects were observed in the ventral intermediate nucleus (Vim; 107 ± 13%), subthalamic nucleus (STN; 79 ± 7%), and globus pallidus internus (GPi; 78 ± 8%), but not in white matter (50 ± 14%) or substantia nigra (45 ± 8%). Modelling showed that the mean 88% CBW increase across Vim, STN, and GPi corresponds to an acute increase in cerebral blood flow. Conclusion Intracranial CBW recordings reveal that high-frequency DBS evokes region-specific vascular responses which can be modelled as substantial increases in local blood flow, establishing CBW amplitude as a novel biomarker of subcortical hemodynamics, and a potential therapeutic modality.

Parkinson’s disease (PD) has been associated with pathological neural activity within the basal ganglia. Herein, we analyzed resting-state single-neuron and local field potential (LFP) activities from people with PD who underwent awake deep brain stimulation surgery of the subthalamic nucleus (STN; n = 125) or globus pallidus internus (GPi; n = 44), and correlated rate-based and oscillatory features with UPDRSIII off-medication subscores. Rate-based single-neuron features did not correlate with PD symptoms. STN single-neuron and LFP low-beta (12–21 Hz) power and burst dynamics showed modest correlations with bradykinesia and rigidity severity, while STN spiketrain theta (4–8 Hz) power correlated modestly with tremor severity. GPi low- and high-beta (21–30 Hz) power and burst dynamics correlated moderately with bradykinesia and axial symptom severity. These findings suggest that elevated single-neuron and LFP oscillations may be linked to symptoms, though modest correlations imply that the pathophysiology of PD may extend beyond resting-state beta oscillations.

Background: The dichotomy between the hypo- versus hyperkinetic nature of Parkinson’s disease (PD) and dystonia, respectively, is thought to be reflected in the underlying basal ganglia pathophysiology. In this study, we investigated differences in globus pallidus internus (GPi) neuronal activity, and short- and long-term plasticity of direct pathway projections.Methods: Using microelectrode recording data collected from the GPi during deep brain stimulation surgery, we compared neuronal spiketrain features between people with PD and those with dystonia, as well as correlated neuronal features with respective clinical scores. Additionally, we characterized and compared readouts of short- and long-term synaptic plasticity using measures of inhibitory evoked field potentials.Results: GPi neurons were slower, burstier, and less regular in dystonia. In PD, symptom severity positively correlated with the power of low-beta frequency spiketrain oscillations. In dystonia, symptom severity negatively correlated with firing rate and positively correlated with neuronal variability and the power of theta frequency spiketrain oscillations. Dystonia was moreover associated with less long-term plasticity and slower synaptic depression.Conclusions: We substantiated claims of hyper- versus hypofunctional GPi output in PD versus dystonia, and provided cellular-level validation of the pathological nature of theta and low-beta oscillations in respective disorders. Such circuit changes may be underlain by disease-related differences in plasticity of striato-pallidal synapses.Funding: This project was made possible with the financial support of Health Canada through the Canada Brain Research Fund, an innovative partnership between the Government of Canada (through Health Canada) and Brain Canada, and of the Azrieli Foundation (LM), as well as a grant from the Banting Research Foundation in partnership with the Dystonia Medical Research Foundation (LM).

Background: A randomized trial suggested that reducing left‐sided subthalamic stimulation amplitude could improve axial dysfunction.Objectives: To explore open‐label tolerability and associations between trial outcomes and asymmetry data.Methods: We collected adverse events in trial participants treated with open‐label lateralized settings for ≥3 months. We explored associations between trial outcomes, location of stimulation and motor asymmetry.Results: 14/17 participants tolerated unilateral amplitude reduction (left‐sided = 10, right‐sided = 4). Two hundred eighty‐four left‐sided and 1113 right‐sided stimulated voxels were associated with faster gait velocity, 81 left‐sided and 22 right‐sided stimulated voxels were associated with slower gait velocity. Amplitude reduction contralateral to shorter step length was associated with 2.4‐point reduction in axial MDS‐UPDRS. Reduction contralateral to longer step length was associated with 10‐point increase in MDS‐UPDRS.Conclusions: Left‐sided amplitude reduction is potentially more tolerable than right‐sided amplitude reduction. Right‐sided more than left‐sided stimulation could be associated with faster gait velocity. Shortened step length might reflect contralateral overstimulation.

Introduction: Beta oscillations in sensorimotor structures contribute to the planning, sequencing, and stopping of movements, functions that are typically associated with the role of the basal ganglia. The presence of beta oscillations (13–30 Hz) in the cerebellar zone of the thalamus (the ventral intermediate nucleus – Vim) indicates that this rhythm may also be involved in cerebellar functions such as motor learning and visuomotor adaptation.Methods: To investigate the possible role of Vim beta oscillations in visuomotor coordination, we recorded local field potential (LFP) and multiunit activity from the Vim of essential tremor (ET) patients during neurosurgery for the implantation of deep brain stimulation (DBS) electrodes. Using a computer, patients performed a visuomotor adaptation task that required coordinating center-out movements with incongruent visual feedback imposed by inversion of the computer display.Results: The results show that, in ET, Vim beta oscillations of the LFP were lower during the incongruent center-out task than during the congruent orientation. Vim firing rates increased significantly during periods of low beta power, particularly on approach to the peripheral target. In contrast, beta power in the subthalamic nucleus of Parkinson’s disease (PD) patients did not differ significantly between the incongruent and the congruent orientation of the center-out task.Discussion: The findings support the hypothesis that beta oscillations of the Vim are modulated by novel visuomotor tasks. The inverse relationship between the power of Vim-LFP beta oscillations and Vim firing rates suggest that the suppression of beta oscillations may facilitate information throughput to the thalamocortical circuit by modulation of Vim firing rates.

The neurophysiology of selective attention in visual and auditory systems has been studied in animal models but not with single unit recordings in human. Here, we recorded neuronal activity in the ventral intermediate nucleus as well as the ventral oral anterior, and posterior nuclei of the motor thalamus in 25 patients with parkinsonian (n = 6) and non-parkinsonian tremors (n = 19) prior to insertion of deep brain stimulation electrodes while they performed an auditory oddball task. In this task, patients were requested to attend and count the randomly occurring odd or “deviant” tones, ignore the frequent standard tones and report the number of deviant tones at trial completion. The neuronal firing rate decreased compared to baseline during the oddball task. Inhibition was specific to auditory attention as incorrect counting or wrist flicking to the deviant tones did not produce such inhibition. Local field potential analysis showed beta (13–35 Hz) desynchronization in response to deviant tones. Parkinson’s disease patients off medications had more beta power than the essential tremor group but less neuronal modulation of beta power to the attended tones, suggesting that dopamine modulates thalamic beta oscillations for selective attention. The current study demonstrated that ascending information to the motor thalamus can be suppressed during auditory attending tasks, providing indirect evidence for the searchlight hypothesis in humans. These results taken together implicate the ventral intermediate nucleus in non-motor cognitive functions, which has implications for the brain circuitry for attention and the pathophysiology of Parkinson’s disease.

Background: Local field potentials (LFPs) represent the summation of periodic (oscillations) and aperiodic (fractal) signals. Although previous studies showed changes in beta band oscillations and burst characteristics of the subthalamic nucleus (STN) in Parkinson's disease (PD), how aperiodic activity in the STN is related to PD pathophysiology is unknown.Objectives: The study aimed to characterize the long‐term effects of STN–deep brain stimulation (DBS) and dopaminergic medications on aperiodic activities and beta bursts.Methods: A total of 10 patients with PD participated in this longitudinal study. Simultaneous bilateral STN‐LFP recordings were conducted in six separate visits during a period of 18 months using the Activa PC + S device in the off and on dopaminergic medication states. We used irregular‐resampling auto‐spectral analysis to separate oscillations and aperiodic components (exponent and offset) in the power spectrum of STN‐LFP signals in beta band.Results: Our results revealed a systematic increase in both the exponent and the offset of the aperiodic spectrum over 18 months following the DBS implantation, independent of the dopaminergic medication state of patients with PD. In contrast, beta burst durations and amplitudes were stable over time and were suppressed by dopaminergic medications.Conclusions: These findings indicate that oscillations and aperiodic activities reflect at least partially distinct yet complementary neural mechanisms, which should be considered in the design of robust biomarkers to optimize adaptive DBS. Given the link between increased gamma‐aminobutyric acidergic (GABAergic) transmission and higher aperiodic activity, our findings suggest that long‐term STN‐DBS may relate to increased inhibition in the basal ganglia. © 2022 International Parkinson and Movement Disorder Society.

Deep brain stimulation procedures offer an invaluable opportunity to study disease through intracranial recordings from awake patients. Here, we address the relationship between single-neuron and aggregate-level (local field potential; LFP) activities in the subthalamic nucleus (STN) and thalamic ventral intermediate nucleus (Vim) of patients with Parkinson’s disease ( n = 19) and essential tremor ( n = 16), respectively. Both disorders have been characterized by pathologically elevated LFP oscillations, as well as an increased tendency for neuronal bursting. Our findings suggest that periodic single-neuron bursts encode both pathophysiological beta (13 to 33 Hz; STN) and tremor (4 to 10 Hz; Vim) LFP oscillations, evidenced by strong time-frequency and phase-coupling relationships between the bursting and LFP signals. Spiking activity occurring outside of bursts had no relationship to the LFP. In STN, bursting activity most commonly preceded the LFP oscillation, suggesting that neuronal bursting generated within STN may give rise to an aggregate-level LFP oscillation. In Vim, LFP oscillations most commonly preceded bursting activity, suggesting that neuronal firing may be entrained by periodic afferent inputs. In both STN and Vim, the phase-coupling relationship between LFP and high-frequency oscillation (HFO) signals closely resembled the relationships between the LFP and single-neuron bursting. This suggests that periodic single-neuron bursting is likely representative of a higher spatial and temporal resolution readout of periodic increases in the amplitude of HFOs, which themselves may be a higher resolution readout of aggregate-level LFP oscillations. Overall, our results may reconcile “rate” and “oscillation” models of Parkinson’s disease and shed light on the single-neuron basis and origin of pathophysiological oscillations in movement disorders.