Modulation of neuronal activity in human centromedian nucleus during an auditory attention and working memory task.

Centromedian nucleus (CM) is one of several intralaminar nuclei of the thalamus and is thought to be involved in consciousness, arousal, and attention. CM has been suggested to play a key role in the control of attention, by regulating the flow of information to different brain regions such as the ascending reticular system, basal ganglia, and cortex. While the neurophysiology of attention in visual and auditory systems has been studied in animal models, combined single unit and LFP recordings in human have not, to our knowledge, been reported. Here, we recorded neuronal activity in the CM nucleus in 11 patients prior to insertion of deep brain stimulation electrodes for the treatment of epilepsy while subjects performed an auditory attention task. Patients were requested to attend and count the infrequent (p = 0.2) odd or "deviant" tones, ignore the frequent standard tones and report the total number of deviant tones at trial completion. Spikes were discriminated, and LFPs were band pass filtered (5-45 Hz). Average peri­stimulus time histograms and spectra were constructed by aligning on tone onsets and statistically compared. The firing rate of CM neurons showed selective, multi-phasic responses to deviant tones in 81% of the tested neurons. Local field potential analysis showed selective beta and low gamma (13-45 Hz) modulations in response to deviant tones, also in a multi-phasic pattern. The current study demonstrates that CM neurons are under top-down control and participate in the selective processing during auditory attention and working memory. These results, taken together, implicate the CM in selective auditory attention and working memory and support a role of beta and low gamma oscillatory activity in cognitive processes. It also has potential implications for DBS therapy for epilepsy and non-motor symptoms of PD, such as apathy and other disorders of attention.

The tidyomics ecosystem: Enhancing omic data analyses.

The growth of omic data presents evolving challenges in data manipulation, analysis, and integration. Addressing these challenges, Bioconductor1 provides an extensive community-driven biological data analysis platform. Meanwhile, tidy R programming2 offers a revolutionary standard for data organisation and manipulation. Here, we present the tidyomics software ecosystem, bridging Bioconductor to the tidy R paradigm. This ecosystem aims to streamline omic analysis, ease learning, and encourage cross-disciplinary collaborations. We demonstrate the effectiveness of tidyomics by analysing 7.5 million peripheral blood mononuclear cells from the Human Cell Atlas3, spanning six data frameworks and ten analysis tools.

Cortical modulations before lower limb motor blocks are associated with freezing of gait in Parkinson's disease: an EEG source localization study.

BACKGROUND: Freezing of gait (FOG) is a debilitating symptom of Parkinson's disease (PD) characterized by paroxysmal episodes in which patients are unable to step forward. A research priority is identifying cortical changes before freezing in PD-FOG. METHODS: We tested 19 patients with PD who had been assessed for FOG (n=14 with FOG and 5 without FOG). While seated, patients stepped bilaterally on pedals to progress forward through a virtual hallway while 64-channel EEG was recorded. We assessed cortical activities before and during lower limb motor blocks (LLMB), defined as a break in rhythmic pedaling, and stops, defined as movement cessation following an auditory stop cue. This task was selected because LLMB correlates with FOG severity in PD and allows recording of high-quality EEG. Patients were tested after overnight withdrawal from dopaminergic medications ("off" state) and in the "on" medications state. EEG source activities were evaluated using individual MRI and standardized low resolution brain electromagnetic tomography (sLORETA). Functional connectivity was evaluated by phase lag index between seeds and pre-defined cortical regions of interest. RESULTS: EEG source activities for LLMB vs. cued stops localized to right posterior parietal area (Brodmann area 39), lateral premotor area (Brodmann area 6), and inferior frontal gyrus (Brodmann area 47). In these areas, PD-FOG (n=14) increased alpha rhythms (8-12 Hz) before LLMB vs. typical stepping, whereas PD without FOG (n=5) decreased alpha power. Alpha rhythms were linearly correlated with LLMB severity, and the relationship became an inverted U-shape when assessing alpha rhythms as a function of percent time in LLMB in the "off" medication state. Right inferior frontal gyrus and supplementary motor area connectivity was observed before LLMB in the beta band (13-30 Hz). This same pattern of connectivity was seen before stops. Dopaminergic medication improved FOG and led to less alpha synchronization and increased functional connections between frontal and parietal areas. CONCLUSIONS: Right inferior parietofrontal structures are implicated in PD-FOG. The predominant changes were in the alpha rhythm, which increased before LLMB and with LLMB severity. Similar connectivity was observed for LLMB and stops between the right inferior frontal gyrus and supplementary motor area, suggesting that FOG may be a form of "unintended stopping." These findings may inform approaches to neurorehabilitation of PD-FOG.

The tidyomics ecosystem: enhancing omic data analyses.

The growth of omic data presents evolving challenges in data manipulation, analysis and integration. Addressing these challenges, Bioconductor provides an extensive community-driven biological data analysis platform. Meanwhile, tidy R programming offers a revolutionary data organization and manipulation standard. Here we present the tidyomics software ecosystem, bridging Bioconductor to the tidy R paradigm. This ecosystem aims to streamline omic analysis, ease learning and encourage cross-disciplinary collaborations. We demonstrate the effectiveness of tidyomics by analyzing 7.5 million peripheral blood mononuclear cells from the Human Cell Atlas, spanning six data frameworks and ten analysis tools.

Auditory oddball responses in the human subthalamic nucleus and substantia nigra pars reticulata.

The auditory oddball is a mainstay in research on attention, novelty, and sensory prediction. How this task engages subcortical structures like the subthalamic nucleus and substantia nigra pars reticulata is unclear. We administered an auditory OB task while recording single unit activity (35 units) and local field potentials (57 recordings) from the subthalamic nucleus and substantia nigra pars reticulata of 30 patients with Parkinson's disease undergoing deep brain stimulation surgery. We found tone modulated and oddball modulated units in both regions. Population activity differentiated oddball from standard trials from 200 ms to 1000 ms after the tone in both regions. In the substantia nigra, beta band activity in the local field potential was decreased following oddball tones. The oddball related activity we observe may underlie attention, sensory prediction, or surprise-induced motor suppression.

Continental-scale migration patterns and origin of Helicoverpa zea (Lepidoptera: Noctuidae) based on a biogeochemical marker.

Insect migrations have ecological and economic impacts, particularly in agriculture. However, there is limited knowledge about the migratory movements of pests at the continental scale, which is an important factor influencing the spread of resistance genes. Understanding the migratory patterns of economic pests, like Helicoverpa zea (Boddie), is essential for improving Integrated Pest Management (IPM) and Insect Resistance Management (IRM) strategies. In this study, we used stable hydrogen isotopic ratios in wing tissue as a biogeochemical marker to examine migratory patterns and estimate the native origins of H. zea individuals collected across a wide latitudinal gradient in North America. Samples collected at higher latitudes (Ontario, Canada and Minnesota, USA) exhibited a greater proportion (60%-96%) of nonlocal individuals, with an increased probability of origin from the southeastern United States. Populations from mid-latitudes (Florida, North Carolina, and South Carolina) showed a blend of local and nonlocal (40%-60%) individuals. Finally, 15% of the southernmost population individuals (Puerto Rico) were classified as migratory, with some having a probability of origin at higher latitudes (>30°). Overall, our results provide evidence of a northward spring/summer migration of H. zea in North America and underscore the significance of the southeastern United States as a hub for genetic flow. In addition, based on stable hydrogen isotopic ratios, there is strong evidence of reverse (southward) migration of H. zea from the continental United States to Puerto Rico. Our study highlights the implications for IPM and IRM programs and the need for management strategies that account for both northward and southward migration patterns.

Modeling Instantaneous Firing Rate of Deep Brain Stimulation Target Neuronal Ensembles in the Basal Ganglia and Thalamus.

OBJECTIVE: Deep brain stimulation (DBS) is an effective treatment for movement disorders, including Parkinson 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 METHODS: Both synthetic and experimental data were used in the model fitting; the synthetic data were generated by an established spiking neuron model that was reported in our previous work, and the experimental data were provided using single-unit microelectrode recordings (MERs) 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. RESULTS: Our 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. CONCLUSIONS: The result of our model fitting was in agreement with experimental single-unit MER 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.

Subthalamic and pallidal neurons are modulated during externally cued movements in Parkinson's disease.

External sensory cues can reduce freezing of gait in people with Parkinson's disease (PD), yet the role of the basal ganglia in these movements is unclear. We used microelectrode recordings to examine modulations in single unit (SU) and oscillatory local field potentials (LFP) during auditory-cued rhythmic pedaling movements of the feet. We tested five blocks of increasing cue frequencies (1 Hz, 1.5 Hz, 2 Hz, 2.5 Hz, and 3 Hz) in 24 people with PD undergoing deep brain stimulation surgery of the subthalamic nucleus (STN) or globus pallidus internus (GPi). Single unit firing and beta band LFPs (13-30 Hz) in response to movement onsets or cue onsets were examined. We found that the timing accuracy of foot pedaling decreased with faster cue frequencies. Increasing cue frequencies also attenuated firing rates in both STN and GPi neurons. Peak beta power in the GPi and STN showed different responses to the task. GPi beta power showed persistent suppression with fast cues and phasic modulation with slow cues. STN beta power showed enhanced beta synchronization following movement. STN beta power also correlated with rate of pedaling. Overall, we showed task-related responses in the GPi and STN during auditory-cued movements with differential roles in sensory and motor control. The results suggest a role for both input and output basal ganglia nuclei in auditory rhythmic pacing of gait-like movements in PD.

Hail netting excludes key insect pests and protects from fruit damage in a commercial Minnesota apple orchard.

Exclusion netting in some European and North American apple (Malus domestica Borkhausen, Rosaceae, Rosales) orchards has been documented to be an effective method of control for multiple insect pest species. By minimizing reliance on insecticides, these orchards have reduced costs, risks to the environment and non-target species, and reduced the risk of insecticide resistance. This study examined the use of commercially available hail netting (DrapeNet®; Prosser, WA) as a pest exclusion strategy under conditions in Minnesota, USA. In 2021 and 2022, we assessed the efficacy of hail netting as a tool for pest suppression in orchards by monitoring pest species in netted and open plots crossed with and without insecticide applications. Our findings show that both of the major pest species in Minnesota, the codling moth (Cydia pomonella L.; Lepidoptera: Tortricidae) and the apple maggot (Rhagoletis pomonella Walsh; Diptera: Tephritidae), were significantly reduced inside the netting compared to open plots by 94% and 96%, respectively. For a secondary pest, the red-banded leafroller (Argyrotaenia velutinana Walker; Lepidoptera: Tortricidae), moth populations were reduced by 56%. We also found that insecticide application alone did not significantly reduce pest pressure in these species. Additionally, we investigated the subsequent effects of hail netting on fruit quality and yield. The use of hail netting and insecticide application resulted in significantly higher proportions of high-quality fruit at harvest. However, netting did not significantly influence yield. These findings suggest that hail netting can be used to control Midwest apple insect pests with limited insecticide applications while maintaining high fruit quality.

Extended Sentinel Monitoring of Helicoverpa zea Resistance to Cry and Vip3Aa Toxins in Bt Sweet Corn: Assessing Changes in Phenotypic and Allele Frequencies of Resistance.

Transgenic corn and cotton that produce Cry and Vip3Aa toxins derived from Bacillus thuringiensis (Bt) are widely planted in the United States to control lepidopteran pests. The sustainability of these Bt crops is threatened because the corn earworm/bollworm, Helicoverpa zea (Boddie), is evolving a resistance to these toxins. Using Bt sweet corn as a sentinel plant to monitor the evolution of resistance, collaborators established 146 trials in twenty-five states and five Canadian provinces during 2020-2022. The study evaluated overall changes in the phenotypic frequency of resistance (the ratio of larval densities in Bt ears relative to densities in non-Bt ears) in H. zea populations and the range of resistance allele frequencies for Cry1Ab and Vip3Aa. The results revealed a widespread resistance to Cry1Ab, Cry2Ab2, and Cry1A.105 Cry toxins, with higher numbers of larvae surviving in Bt ears than in non-Bt ears at many trial locations. Depending on assumptions about the inheritance of resistance, allele frequencies for Cry1Ab ranged from 0.465 (dominant resistance) to 0.995 (recessive resistance). Although Vip3Aa provided high control efficacy against H. zea, the results show a notable increase in ear damage and a number of surviving older larvae, particularly at southern locations. Assuming recessive resistance, the estimated resistance allele frequencies for Vip3Aa ranged from 0.115 in the Gulf states to 0.032 at more northern locations. These findings indicate that better resistance management practices are urgently needed to sustain efficacy the of corn and cotton that produce Vip3Aa.

Beta band oscillations in the motor thalamus are modulated by visuomotor coordination in essential tremor patients.

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.

Tissue-specific transcriptome analyses in Drosophila provide novel insights into the mode of action of the insecticide spinosad and the function of its target, nAChRα6.

BACKGROUND: The insecticides spinosad and imidacloprid are neurotoxins with distinct modes of action. Both target nicotinic acetylcholine receptors (nAChRs), albeit different subunits. Spinosad is an allosteric modulator, that upon binding initiates endocytosis of its target, nAChRα6. Imidacloprid binding triggers excessive neuronal ion influx. Despite these differences, low-dose effects converge downstream in the precipitation of oxidative stress and neurodegeneration. RESULTS: Using RNA-sequencing, we compared the transcriptional signatures of spinosad and imidacloprid, at low-dose exposures. Both insecticides cause up-regulation of glutathione S-transferase and cytochrome P450 genes in the brain and down-regulation in the fat body, whereas reduced expression of immune-related genes is observed in both tissues. Spinosad shows unique impacts on genes involved in lysosomal function, protein folding, and reproduction. Co-expression analyses revealed little to no correlation between genes affected by spinosad and nAChRα6 expressing neurons, but a positive correlation with glial cell markers. We also detected and experimentally confirmed nAChRα6 expression in fat body cells and male germline cells. This led us to uncover lysosomal dysfunction in the fat body following spinosad exposure, and a fitness cost in spinosad-resistant (nAChRα6 null) males - oxidative stress in testes, and reduced fertility. CONCLUSION: Spinosad and imidacloprid share transcriptional perturbations in immunity-, energy homeostasis-, and oxidative stress-related genes. Low doses of other neurotoxic insecticides should be investigated for similar impacts. While target-site spinosad resistance mutation has evolved in the field, this may have a fitness cost. Our findings demonstrate the power of tissue-specific transcriptomics approach and the use of single-cell transcriptome data. © 2023 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Top-down control of human motor thalamic neuronal activity during the auditory oddball task.

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.

Long-Term Recording of Subthalamic Aperiodic Activities and Beta Bursts in 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.

The importance of time in nutrient regulation: a case study with spotted-wing Drosophila (Drosophila suzukii).

Introduction: The ability of living organisms to acquire the nutrients needed to carry out required physiological functions has important consequences for fitness. However, an organism must not simply meet the requirements for individual nutrients, but must ingest an optimal balance of multiple nutrients. Despite this, animals rarely consume truly balanced resources, and instead commonly feed selectively across multiple unbalanced resources to reach an optimal balance, i.e., intake target. Nutritional research has predominantly focused on the behavioral strategies employed during nutrient regulation, as well as the fitness consequence of failing to meet intake targets, but little work has been done on the temporal aspects of this process. For instance, within what timeframe must organisms reach their intake target before a fitness cost is incurred? Hours, days, weeks? Methods: In this study, we investigated how nutrient regulation interval impacts consumption and performance in adult female spotted-wing Drosophila (Drosophila suzukii). Females were constrained to either a protein- orcarbohydrate-biased diet over different time intervals and at different schedules, while control flies were constrained to one diet for the entire feeding period. Results: Regulation interval had a significant impact on feeding behavior and consumption. Total consumption was highest on the shorter interval treatments, where diets were alternated more frequently, and declined as the interval period increased. The relative consumption of both diets was statistically-different across intervals and was higher for the carbohydrate-biased diet. Consumption of the protein-biased diet was more variable across intervals and was more strongly impacted by the daily timing of diet switches. Performance data showed that shorter regulation intervals led to longer fly lifespans, a result commonly observed in studies exploring the impacts of diet macronutrient ratio variability on performance. Discussion: These results show that the temporal aspects of nutrition, such as feeding intervals and the timing of resource availability, can have strong impacts on feeding behavior, nutrient regulation, and fitness. These results provide an insight into how consumers may deal with changes in host phenology, the availability of hosts, and changes in nutrient availability within hosts. Understanding these mechanisms will be important for predicting responses to changes in nutrient cycling and resource availability mediated by natural and anthropogenic habitat modifications, such as global climate change.

Hail netting: an economically competitive IPM alternative to insecticides for Midwest apple production.

Apple orchards are highly managed agricultural ecosystems where growers typically rely on insecticides to minimize the risk of pest-related fruit losses. Apple growers practicing integrated pest management require cost-effective alternatives to conventional insecticides for control of major pests such as codling moth (Cydia pomonella L.) and apple maggot (Rhagoletis pomonella Walsh). Exclusion netting has been shown to effectively control multiple insect pest species, limit fruit damage and reduce the use of insecticides while also conferring consumer and environmental benefits. In this study, partial budgeting was applied to explore the financial efficacy of using a hail netting (DrapeNet®) system as a sustainable pest management strategy for Midwest U.S. apple (Malus x domestica). The cost of the hail netting was compared to a common Midwest insecticide spray regimen for apples using yield and quality data from a field study at two Minnesota apple orchards in 2021-2022. The PB analysis indicated that the netting system was an economically competitive alternative to conventional insecticide applications. The economic results were robust across a range of apple prices and yields suggesting that Minnesota apple growers can benefit economically from the application of hail netting for sustainable pest management.

Corrigendum: Modeling-informed Engineered Genetic Incompatibility strategies to overcome resistance in the invasive Drosophila suzukii.

[This corrects the article DOI: 10.3389/finsc.2022.1063789.].

Long-Term Follow-Up on Bilateral Posterior Hypothalamic Deep Brain Stimulation for Treating Refractory Aggressive Behavior in a Patient with Cri du Chat Syndrome: Analysis of Clinical Data, Intraoperative Microdialysis, and Imaging Connectomics.

Posterior hypothalamic-deep brain stimulation (pHyp-DBS) has been reported as a successful treatment for reducing refractory aggressive behaviors in patients with distinct primary diagnoses. Here, we report on a patient with cri du chat syndrome presenting severe self-injury and aggressive behaviors toward others, who was treated with pHyp-DBS. Positive results were observed at long-term follow-up in aggressive behavior and quality of life. Intraoperative microdialysis and imaging connectomics analysis were performed to investigate possible mechanisms of action. Our results suggest the involvement of limbic and motor areas and alterations in main neurotransmitter levels in the targeted area that are associated with positive results following treatment.

Persistent synaptic inhibition of the subthalamic nucleus by high frequency stimulation.

BACKGROUND: Deep 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. OBJECTIVE: The 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). METHODS: Two microelectrodes were advanced into the STN and SNr of patients undergoing DBS surgery for Parkinson's disease (PD). Neuronal firing and evoked field potentials (fEPs) were recorded with one microelectrode during stimulation from an adjacent microelectrode. RESULTS: Inhibitory fEPs could be discerned within the STN and their amplitudes predicted bidirectional effects on neuronal firing (p = .013). 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 in SNr (p < .001) where depression of inhibitory input was coupled with a return of neuronal firing (p = .003). INTERPRETATION: Persistent 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.