Biology subjects

Hutchison, W. D.

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

11 recordsLinked to original sources

bioRxiv2026

Inhibitory Evoked Potentials as a Spatially Dependent Intraoperative Marker of Clinical Tremor Reduction

Deep brain stimulation (DBS) of the ventral intermediate nucleus (Vim) of the thalamus may be used to treat medication refractory essential tremor. Using recordings from in vivo human Vim neurons, our previous work has suggested that evoked potentials (that we termed quasi-evoked inhibition) ~2 ms following high frequency microstimulation pulses may be related to inhibitory synapses onto the Vim. Here, we investigate whether (i) quasi-evoked inhibition is related to clinical tremor reduction, and (ii) if quasi-evoked inhibition is dependent on the stimulation location within the Vim. By developing an objective determination of the presence or absence of quasi-evoked inhibition and utilizing accelerometer recordings, we showed that recordings with quasi-evoked inhibition at 100 Hz microstimulation exhibit greater tremor reduction than those without (P < 0.05, BF > 30). The number of stimulation pulses with quasi-evoked inhibition is also correlated with tremor reduction (rho = 0.18, P < 0.05) at all stimulation frequencies >=100 Hz. Furthermore, by analyzing microelectrode trajectories reconstructed from structural MRIs, we found that proximity to the ventral caudal border (P < 0.005) and to a previously established sweet spot (P < 0.05) are anti-correlated with the number of stimulation pulses with quasi-evoked inhibition. Our findings suggest that quasi-evoked inhibition is a potential biomarker of tremor reduction by means of network inhibition, and the more posterior regions of the Vim may allow for better recruitment of inhibition. This may be useful for closed-loop stimulation design.

neuroscience↗

bioRxiv2026

Differentiating filter-induced oscillations from physiological stimulation-evoked potentials in intracranial recordings

IntroductionStimulation-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. MethodsWe 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. ResultsFiltering 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. ConclusionsGiven 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.

neuroscience↗

bioRxiv2025

The genome of Istocheta aldrichi (Diptera: Tachinidae), a parasitoid of the Japanese beetle, Popillia japonica (Coleoptera: Scarabaeidae)

Istocheta aldrichi Mesnil 1953 (Diptera: Tachinidae), is native to Japan, and has recently become an important biological control agent of the Japanese beetle, Popillia japonica (Coleoptera: Scarabaeidae), a pest with >300 host plants, including roses, linden trees, and numerous agricultural crops. During the past decade, I. aldrichis range has greatly expanded across North America, particularly in Quebec and Ontario, Canada, and in the Midwest U.S. In many areas, including Minnesota, 15-60% of Japanese beetles are parasitized by I. aldrichi, highlighting its importance as a natural enemy. To facilitate research on I. aldrichi and other tachinid flies we present a reference genome generated from a single individual. The final genome assembly is 875.3 Mbp contained in 1,041 scaffolds, with an N50 of 4.77 Mbp, and 99.5% complete Diptera BUSCOs present. We also present a complete mitogenome and use comparative genomics across 19 tachinid species to identify unique features of I. aldrichi. Specifically, we find that while many tachinid lineages have experienced contractions in gene families, I. aldrichi is characterized by a relatively high number of gene family expansions, many of which are predicted to function in metal ion transport. Tachinids as a whole have undergone rapid copy number changes in 935 gene families, largely related to metabolism and morphogenesis. The I. aldrichi reference genome will further research opportunities on these parasitic flies, including their potential for biocontrol of P. japonica. ARTICLE SUMMARYThe parasitic fly Istocheta aldrichi attacks and kills the Japanese beetle (Popillia japonica), a pest of more than 300 plants. There is potential to leverage I. aldrichi for biological control of the beetle, but application is hindered by a limited understanding of this flys biology. This reference genome for I. aldrichi will enhance research future efforts and our ability to manage P. japonica.

genomics↗

bioRxiv2025

Frequency-dependent Inhibition during Deep Brain Stimulation of Thalamic Ventral Intermediate Nuclei

Deep brain stimulation (DBS) of the thalamic ventral intermediate nucleus (Vim) has been a standard therapy for essential tremor. It has been shown that high frequency ([≥]100Hz) DBS suppresses Vim neuronal firing and tremor activity, however, the underlying mechanisms are not fully understood. Here, we use in vivo recordings (single-unit) of Vim neurons (n=19, people with essential tremor) during different DBS frequencies to investigate whether neuronal suppression during high-frequency DBS occurs at synaptic/cellular levels (e.g., cell inhibition due to synaptic depression/fatigue during high-frequency DBS) or is influenced by network-level effects (e.g., recurrent inhibition). We propose a theoretical framework that explains DBS effects at both cellular and network levels, i.e., (continuous) high-frequency DBS not only depresses synapses projecting to Vim but also enables the recruitment of inhibitory neurons. A transient burst in the spiking activity of Vim during high-frequency DBS, prior to neuronal suppression, is likely providing sufficient network engagement to recruit inhibitory neurons that are silent during low-frequency DBS. Further, we detected a positive-going evoked-field potential effect, hereafter referred to as quasi-evoked inhibition, during high-frequency (100 Hz and 200 Hz) Vim-DBS in four out of 19 recording sites. Interestingly, it was observed that (i) neuronal suppression is stronger in these four neurons (P < 0.05), implying that inhibitory engagement during high-frequency DBS can further suppress neuronal firing, and (ii) quasi-evoked inhibition emerges after the transient burst (P < 1.00 x 10-7), i.e., the latter may give rise to the former. By removing DBS artifacts with a novel algorithm and characterizing the dynamics of quasi-evoked inhibitory activity, we showed that the likelihood of occurrence of this inhibitory activity negatively correlated with the instantaneous firing rate (P < 1.00 x 10-5). These results suggest that an excitatory-inhibitory balance is likely regulating Vim activities during high-frequency DBS. Our findings shed light on potential network mechanisms underlying Vim-DBS, which can provide insight for optimizing DBS by designing new stimulation patterns.

neuroscience↗

bioRxiv2023

Uncovering network mechanism underlying thalamic Deep Brain Stimulation using a novel firing rate model

Thalamic ventral intermediate nucleus (Vim) is the primary surgical target of deep brain stimulation (DBS) for reducing symptoms of essential tremor. High-frequency Vim-DBS ([≥]100Hz) has been clinically effective, generating two experimentally-observed features in Vim spiking activity: 1) a large transient excitatory response (lasting <1s), followed by 2) a suppressed steady-state consisting of oscillations. Yet, mechanisms underlying these observations have not been fully understood by previous studies. In this work, we developed a network rate model and a novel parameter optimization method that accurately fit in-vivo single-unit recordings of Vim in human patients with essential tremor receiving a wide range of DBS frequencies (5[~]200Hz). Our model incorporates both the DBS-induced synaptic plasticity of Vim neurons, and the recurrent connections among excitatory and inhibitory neurons in Vim-network. We hypothesized that besides inducing synaptic depression, the therapeutic mechanism of high-frequency Vim-DBS could be to engage more inhibitory neurons in stabilizing the underlying circuits. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=86 SRC="FIGDIR/small/570924v2_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@1e78cbcorg.highwire.dtl.DTLVardef@c8bde1org.highwire.dtl.DTLVardef@12a3bb3org.highwire.dtl.DTLVardef@1b5a0dd_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

Interrogating basal ganglia circuit function in Parkinson's disease and dystonia

BackgroundThe dichotomy between the hypo-versus hyperkinetic nature of Parkinsons disease (PD) and dystonia, respectively, is thought to be reflected in the underlying basal ganglia pathophysiology. ObjectiveInvestigate differences in globus pallidus internus (GPi) neuronal activity, and short- and long-term plasticity of direct pathway projections. ResultsGPi 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. ConclusionWe 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.

neuroscience↗

bioRxiv2023

Genes associated with fitness and disease severity in the pan-genome of mastitis-associated Escherichia coli

Bovine mastitis caused by Escherichia coli may manifest as subclinical through severe acute disease and can be transient or persistent in nature. Little is known about bacterial factors that impact clinical outcomes or allow some strains to outcompete others in the mammary gland (MG) environment. Mastitis-associated E. coli (MAEC) may have distinctive characteristics which may contribute to the varied nature of the disease. In this study, we sequenced the genomes of 96 MAEC strains isolated from cattle with clinical mastitis (CM). We utilized clinical severity data to perform genome-wide association studies to identify accessory genes associated with strains isolated from mild or severe CM, or with high or low competitive fitness during in vivo competition assays. Genes associated with pathogenic or commensal strains isolated from bovine and avian sources were also identified. A type-2 secretion system (T2SS) and a chitinase (ChiA) exported by this system were strongly associated with pathogenic isolates compared with commensal strains. Strains carrying these genes also had higher competitive fitness during experimental intramammary infections. Deletion of chiA from MAEC isolates decreased their adherence to cultured bovine mammary epithelial cells, suggesting that the increased fitness associated with strains possessing this gene may be due to better attachment in the MG. ImportanceBovine mastitis caused by MAEC compromises animal health and inflicts substantial product losses in dairy farming. Given their high levels of intraspecies genetic variability, virulence factors of commonly used MAEC model strains may not be relevant to all members of this group. Here we analyzed clinical data as well as fitness (quantified in a mouse MG model) of diverse MAEC isolates to identify accessory genes that contribute to infection. We demonstrated a novel role for chitinase in promoting attachment to mammary epithelial cells. Reverse genetic approaches can be applied to the collection of strains and their complete genome sequences that we have presented here. Overall, these results provide a much richer understanding of MAEC and suggest bacterial processes that may underlie the clinical diversity associated with mastitis and their adaptation to this unique environment.

microbiology↗

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↗