Biology subjects

Hutchison, W. D.

Publications and source records attributed to Hutchison, W. D..

4 recordsLinked to original sources

bioRxiv2022

Modelling Instantaneous Firing Rate of DBS Target Neuronal Ensembles in Basal Ganglia and Thalamus

ObjectiveDeep Brain Stimulation (DBS) is an effective treatment for movement disorders, including Parkinsons disease and essential tremor. However, the underlying mechanisms of DBS remain elusive. Despite the capability of existing models in interpreting experimental data qualitatively, there are very few unified computational models that quantitatively capture the dynamics of the neuronal activity of varying stimulated nuclei--including subthalamic nucleus (STN), substantia nigra pars reticulata (SNr) and ventral intermediate nucleus (Vim)--across different DBS frequencies. Materials and MethodsBoth synthetic and experimental data were utilized in the model fitting; the synthetic data were generated by an established spiking neuron model that was reported in our previous work 1, and the experimental data were provided using single-unit microelectrode recordings (MER) during DBS (microelectrode stimulation). Based on these data, we developed a novel mathematical model to represent the firing rate of neurons receiving DBS, including neurons in STN, SNr and Vim--across different DBS frequencies. In our model, the DBS pulses were filtered through a synapse model and a nonlinear transfer function to formulate the firing rate variability. For each DBS-targeted nucleus, we fitted a single set of optimal model parameters consistent across varying DBS frequencies. ResultsOur model accurately reproduced the firing rates observed and calculated from both synthetic and experimental data. The optimal model parameters were consistent across different DBS frequencies. ConclusionThe result of our model fitting were in agreement with experimental single-unit microelectrode recording data during DBS. Reproducing neuronal firing rates of different nuclei of the basal ganglia and thalamus during DBS can be helpful to further understand the mechanisms of DBS, and to potentially optimize stimulation parameters based on their actual effects on neuronal activity.

neuroscience↗

bioRxiv2022

Single-neuron bursts encode pathological oscillations in Parkinson's disease and essential tremor

Deep brain stimulation procedures offer an invaluable opportunity to study disease through intracranial recordings from awake patients. Herein, we address the relationship between singleneuron and aggregate-level (local field potential; LFP) activities in the subthalamic nucleus (STN) and thalamic ventral intermediate nucleus (Vim) of patients with Parkinsons 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 (13-33Hz; STN) and tremor (4-10Hz; 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 phasecoupling relationship between LFP and high-frequency oscillation (HFO) signals closely resembled the relationships between the LFP and single-neuron bursting. This suggests that periodic singleneuron 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 Parkinsons disease and shed light onto the single-neuron basis and origin of pathophysiological oscillations in movement disorders. SignificanceIn surgical patients with Parkinsons disease and essential tremor, we leverage intracranial recordings to establish a link between pathophysiological phenomena across various scales of observation (spatio-temporal resolutions). We provide insights and reconcile theories about aberrant neurocircuit phenomena which underly theses debilitating, medically refractory movement disorders. Furthermore, our connectivity analyses between single-neuron and local field potential activities may shed light on the origin of the deleterious neural oscillations underlying these disorders. Ultimately, our findings may aid in the development or investigation of targeted therapies to address or correct underlying neurocircuit dysfunction, which can include neuropharmaceuticals, but also novel neuromodulatory strategies like closed-loop deep brain stimulation targeting pathophysiological oscillations and phase-dependent stimulation methods seeking to stimulate "at the right time/phase."

neuroscience↗

bioRxiv2021

Persistent synaptic inhibition of the subthalamic nucleus by high frequency stimulation

BackgroundDeep brain stimulation (DBS) provides symptomatic relief in a growing number of neurological indications, but local synaptic dynamics in response to electrical stimulation that may relate to its mechanism of action have not been fully characterized. ObjectiveThe objectives of this study were to (1) study local synaptic dynamics during high frequency extracellular stimulation of the subthalamic nucleus (STN), and (2) compare STN synaptic dynamics with those of the neighboring substantia nigra pars reticulata (SNr). MethodsTwo microelectrodes were advanced into the STN and SNr of patients undergoing DBS surgery for PD. Neuronal firing and evoked field potentials (fEPs) were recorded with one microelectrode during stimulation from an adjacent microelectrode. ResultsExcitatory and inhibitory fEPs could be discerned within the STN and their amplitudes predicted bidirectional effects on neuronal firing (p = .007). There were no differences between STN and SNr inhibitory fEP dynamics at low stimulation frequencies (p > .999). However, inhibitory neuronal responses were sustained over time in STN during high frequency stimulation, but not SNr (p < .001) where depression of inhibitory input was coupled with a return of neuronal firing (p = .003). InterpretationPersistent inhibitory input to the STN suggests a local synaptic mechanism for the suppression of subthalamic firing during high frequency stimulation. Moreover, differences in the resiliency versus vulnerability of inhibitory inputs to the STN and SNr suggest a projection source- and frequency-specificity for this mechanism. The feasibility of targeting electrophysiologically-identified neural structures may provide insight into how DBS achieves frequency-specific modulation of neuronal projections.

neuroscience↗

bioRxiv2020

A theoretical framework for the site-specific and frequency-dependent neuronal effects of deep brain stimulation

With the growing interest in the expansion of deep brain stimulation indications, we aimed to provide experimental and computational insights into the brain-region-specific and frequency-dependent effects of extracellular stimulation on human neuronal activity. Experimentally, we demonstrated microstimulation-evoked excitatory neuronal responses in the ventral intermediate nucleus and reticular thalamus, and inhibitory responses in the subthalamic nucleus and substantia nigra pars reticulata; hypothesized to be the result of simultaneous activations of convergent afferent inputs. Higher stimulation frequencies led to a loss of site-specificity and convergence towards neuronal suppression; hypothesized to be mediated by synaptic depression. These experimental findings were reproduced by a computational framework in which relative distributions of convergent excitatory/inhibitory afferents were embedded within a model of short-term synaptic plasticity for the prediction of site-specific and frequency-dependent responses to extracellular stimulation. This theoretical framework may aid in the design of physiologically-informed stimulation paradigms in existing or prospective deep brain stimulation indications.

neuroscience↗