Biology subjects

Graham, R. D.

Publications and source records attributed to Graham, R. D..

5 recordsLinked to original sources

bioRxiv2026

FLEX-DBS: a flexible wireless platform for bilateral constant-current deep brain stimulation in freely moving rodents

Background: Preclinical deep brain stimulation (DBS) in rodents is central to understanding how DBS works, but most rodent DBS is delivered through a tether, which constrains behavior, home-cage experiments and uninterrupted stimulation. Most long-runtime wireless mouse stimulators achieve their runtimes by setting stimulation parameters before or around implantation and operating from supplies of about 3 V. New method: FLEX-DBS (Flexible Deep Brain Stimulation) is a head-mounted, battery-powered stimulator that delivers bilateral constant-current stimulation from improved Howland current pumps on +/-5 V rails. Amplitude, pulse width and frequency are programmable in continuous and burst modes from an iOS application over Bluetooth Low Energy, and stimulation continues autonomously after the phone disconnects. The device measures 19.5 x 22.5 x 8.72 mm, weighs 3.71 g in operation and runs on two size-13 zinc-air cells, which are exchanged by briefly detaching the device, pausing stimulation only for the exchange. Results: Into a 1 k{Omega} bench load, delivered current increased approximately linearly with the amplitude setting and was repeatable from pulse to pulse, with an asymmetric biphasic waveform whose recovery phase ran at about one fifth of the stimulating amplitude. Battery current was 1.47-1.89 mA in standby and 3.15-3.42 mA during stimulation at amplitude settings of 60-400 A, giving a projected three days of continuous stimulation per pair of cells. Firmware v0.5 left a net charge of 26-35 % of the stimulating-phase charge per pulse into 1 k{Omega}. Into 47 k{Omega}, within the in vivo load range, stimulating current was compliance-limited at 93 A. Pulse-derived estimates of the effective load presented by five implanted platinum electrodes in three mice had weekly means of 43-54 k{Omega} over eight weeks (32-80 k{Omega} across individual sessions), placing the maximum regulated current near 90 A (81-101 A at the weekly means). Analysis of the current-pump network bounds load-dependent current error at 3-8% for these loads. In vivo, we delivered cingulate FLEX-DBS at high amplitude settings intended to evoke a robust stimulation-associated behavioral phenotype in six mice. Time spent immobile in an open field rose from 46.5% at baseline to 75.7% during stimulation (a 62.7% increase in the group mean) and remained elevated after stimulation ended; without a sham control, this increase cannot be separated from within-session habituation. Comparison with existing methods: Among the published wireless rodent stimulators compared here, several offer some of these capabilities, but none combines bilateral constant current output, real-time wireless control that continues as autonomous stimulation after disconnect, and both continuous and burst modes; FLEX-DBS does so at the cost of runtime measured in days rather than weeks. Conclusions: FLEX-DBS is designed for untethered DBS experiments in which parameters must be set, changed and verified at the cage. Its measured power consumption permits a projected three days of continuous operation per cell pair; firmware v0.5 requires improved charge balancing before prolonged in vivo stimulation. The electrode load, rather than the programmable range, sets the usable stimulation amplitude in vivo. In vivo, stimulation at high amplitude settings was associated with increased immobility, consistent with effective stimulation through implanted electrodes; electrode impedance and delivered current were not measured in these mice.

bioengineering↗

bioRxiv2025

Reduced SK channel control of mesolimbic dopamine neuron firing drives reward seeking adaptations in chronic pain

Patients with chronic neuropathic pain typically experience affective symptoms that drive reduced quality of life and negatively impact pain management. Mesolimbic dopamine is necessary for reward valuation and learning, and the existence of a hypodopaminergic state has been proposed to underlie these affective symptoms of chronic pain. However, direct functional evidence for this hypodopaminergic state is lacking, and the mechanisms underlying its emergence over the acute to chronic pain transition are unknown. Here, we find a selective deficit in the ability of mesolimbic dopamine neurons to sustain burst firing, which is apparent uniquely at chronic timepoints following neuropathic injury. As a result, animals are unable to sustain effortful pursuit of rewards under conditions of high effort or time costs. Convergent biophysical modeling and experimental electrophysiology establish that in a spared nerve injury (SNI) model of chronic neuropathic pain, calcium-activated, small-conductance potassium (SK) channel function is impaired, resulting in lower peak firing and earlier entry into depolarization block of mesolimbic dopamine neurons. Critically, dopamine dependent reward learning, formation of cue-reward associations and locomotor activity remain intact, arguing against the interpretation of a generalized hypodopaminergic state. These results elucidate a circuit-level basis for selective motivational deficits emerging in chronic neuropathic pain.

neuroscience↗

bioRxiv2023

Multiformity of extracellular microelectrode recordings from Aδ neurons in the dorsal root ganglia: A computational modeling study

Microelectrodes serve as a fundamental tool in electrophysiology research throughout the nervous system, providing a means of exploring neural function with a high resolution of neural firing information. We constructed a hybrid computational model using the finite element method and multi-compartment cable models to explore factors that contribute to extracellular voltage waveforms that are produced by sensory pseudounipolar neurons -- specifically, smaller A-type neurons -- and that are recorded by microelectrodes in dorsal root ganglia. The finite element method model included a dorsal root ganglion, surrounding tissues, and a planar microelectrode array. We built a multi-compartment neuron model with multiple trajectories of the glomerular initial segment found in many A-type sensory neurons. Our model replicated both the somatic intracellular voltage profile of A{delta} low-threshold mechanoreceptor neurons and the unique extracellular voltage waveform shapes that are observed in experimental settings. Results from this model indicated that tortuous glomerular initial segment geometries can introduce distinct multiphasic properties into a neurons recorded waveform. Our model also demonstrated how recording location relative to specific microanatomical components of these neurons, and recording distance from these components, can contribute to additional changes in the multiphasic characteristics and peak-to-peak voltage amplitude of the waveform. This knowledge may provide context for research employing microelectrode recordings of pseudounipolar neurons in sensory ganglia, including functional mapping and closed-loop neuromodulation. Further, our simulations gave insight into the neurophysiology of pseudounipolar neurons by demonstrating how the glomerular initial segment aids in increasing the resistance of the stem axon and mitigating rebounding somatic action potentials.

neuroscience↗

bioRxiv2023

Computational modeling of dorsal root ganglion stimulation using an Injectrode

ObjectiveMinimally invasive neuromodulation therapies like the Injectrode, which is composed of a tightly wound polymer-coated platinum/iridium microcoil, offer a low-risk approach for administering electrical stimulation to the dorsal root ganglion (DRG). This flexible electrode is aimed to conform to the DRG. The stimulation occurs through a transcutaneous electrical stimulation (TES) patch, which subsequently transmits the stimulation to the Injectrode via a subcutaneous metal collector. However, effectiveness of stimulation relies on the specific geometrical configurations of the Injectrode-collector-patch system. Hence, there is a need to investigate which design parameters influence the activation of targeted neural structures. ApproachWe employed a hybrid computational modeling approach to analyze the impact of the Injectrode system design parameters on charge delivery and the neural response to stimulation. We constructed multiple finite element method models of DRG stimulation and multi-compartment models of DRG neurons. We simulated the neural responses using parameters based on prior acute preclinical experiments. Additionally, we developed multiple human-scale computational models of DRG stimulation to investigate how design parameters like Injectrode size and orientation influenced neural activation thresholds. Main resultsOur findings were in accordance with acute experimental measurements and indicated that the Injectrode system predominantly engages large-diameter afferents (A{beta}-fibers). These activation thresholds were contingent upon the surface area of the Injectrode. As the charge density decreased due to increasing surface area, there was a corresponding expansion in the stimulation amplitude range before triggering any pain-related mechanoreceptor (A{delta}-fibers) activity. SignificanceThe Injectrode demonstrates potential as a viable technology for minimally invasive stimulation of the DRG. Our findings indicate that utilizing a larger surface area Injectrode enhances the therapeutic margin, effectively distinguishing the desired A{beta} activation from the undesired A{delta}-fiber activation.

bioengineering↗

bioRxiv2021

Augmented Transcutaneous Stimulation Using an Injectable Electrode

Minimally invasive neuromodulation technologies seek to marry the neural selectivity of implantable devices with the low-cost and non-invasive nature of transcutaneous electrical stimulation (TES). The Injectrode(R) is a needle-delivered electrode that is injected onto neural structures under image guidance. Power is then transcutaneously delivered to the Injectrode using surface electrodes. The Injectrode serves as a low-impedance conduit to guide current to the deep on-target nerve, reducing activation thresholds by an order of magnitude compared to using only surface stimulation electrodes. To minimize off-target recruitment of cutaneous fibers, the energy transfer efficiency from the surface electrodes to the Injectrode must be optimized. TES energy is transferred to the Injectrode through both capacitive and resistive mechanisms. Electrostatic finite element models generally used in TES research consider only the resistive means of energy transfer by defining tissue conductivities. Here, we present an electroquasistatic model, taking into consideration both the conductivity and permittivity of tissue, to understand transcutaneous power delivery to the Injectrode. The model was validated with measurements taken from (n=4) swine cadavers. We used the validated model to investigate system and anatomic parameters that influence the coupling efficiency of the Injectrode energy delivery system. Our work suggests the relevance of electroquasistatic models to account for capacitive charge transfer mechanisms when studying TES, particularly when high-frequency voltage components are present, such as those used for voltage-controlled pulses and sinusoidal nerve blocks.

bioengineering↗