Neural Target Research Articles

Electric hearing and tinnitus suppression by noninvasive ear stimulation

While noninvasive brain stimulation is convenient and cost effective, its utility is limited by the substantial distance between scalp electrodes and their intended neural targets in the head. The tympanic membrane, or eardrum, is a thin flap of skin deep in an orifice of the head that may serve as a port for improved efficiency of noninvasive stimulation. Here we chose the cochlea as a target because it resides in the densest bone of the skull and is adjacent to many deep-brain-stimulation structures. We also tested the hypothesis that noninvasive electric stimulation of the cochlea may restore neural activities that are missing in acoustic stimulation. We placed an electrode in the ear canal or on the tympanic membrane in 25 human adults (10 females) and compared their stimulation efficiency by characterizing the electrically-evoked auditory sensation. Relative to ear canal stimulation, tympanic membrane stimulation was four times more likely to produce an auditory percept, required eight times lower electric current to reach the threshold and produced two-to-four times more linear suprathreshold responses. We further measured tinnitus suppression in 14 of the 25 subjects who had chronic tinnitus. Compared with ear canal stimulation, tympanic membrane stimulation doubled both the probability (22% vs. 55%) and the amount (−15% vs. −34%) of tinnitus suppression. These findings extended previous work comparing evoked perception and tinnitus suppression between electrodes placed in the ear canal and on the scalp. Together, the previous and present results suggest that the efficiency of conventional scalp-based noninvasive electric stimulation can be improved by at least one order of magnitude via tympanic membrane stimulation. This increased efficiency is most likely due to the shortened distance between the electrode placed on the tympanic membrane and the targeted cochlea. The present findings have implications for the management of tinnitus by offering a potential alternative to interventions using invasive electrical stimulation such as cochlear implantation, or other non-invasive transcranial electrical stimulation methods.

Decision value signals in the ventromedial prefrontal cortex and motivational and hedonic symptoms across mood and psychotic disorders

Deficits in motivation and pleasure are common across many psychiatric disorders, and manifest as symptoms of amotivation and anhedonia, which are prominent features of both mood and psychotic disorders. Here we provide evidence for an association between neural value signals and symptoms of amotivation and anhedonia across adults with major depression, bipolar disorder, schizophrenia, or no psychiatric diagnosis. We found that value signals in the ventromedial prefrontal cortex (vmPFC) during intertemporal decision-making were dampened in individuals with greater motivational and hedonic deficits, after accounting for primary diagnosis. This relationship remained significant while controlling for diagnosis-specific symptoms of mood and psychosis, such as depression as well as positive and negative symptoms. Our results demonstrate that dysfunction in the vmPFC during value-based decision-making is specifically linked to motivational and hedonic impairments. These findings provide a quantitative neural target for the potential development of novel treatments for amotivation and anhedonia.

Does export product diversification spur energy demand in the APEC region? Application of a new neural networks experiment and a Decision Tree model

This paper aims to investigate the causal links among export diversification, per capita income, and energy demand for 20 Asia-Pacific Economic Cooperation (APEC) countries. Human capital, industry share, and Foreign Direct Investments (FDI) are included within a multivariate framework. Using data covering the 1995–2018 period, an innovative sequential Artificial Neural Networks experiment is developed. Empirical results highlight that the export diversification index negatively affects the neural target corresponding to energy demand. Conversely, per capita GDP displays a significant influence on the acceleration of the same energy target. Hence, findings suggest that export diversification plays a mitigating role in the demand for energy, which is congruent with the literature. Moreover, economic growth is found to be substantially driven by export diversification, while no evidence of a causal effect is found among export diversification, human capital, and FDI. Such inferences are finally corroborated by a Decision Tree model, conducted as a final robustness check. In line with the Sustainable Development Goals (SDGs), adequate measures are suggested to improve energy savings along the supply chain, without hindering the economic performance of the Asian region.

An improved mask-RCNN algorithm for UAV TIR video stream target detection

In emergency rescue operations, unmanned aerial vehicles (UAVs) equipped with thermal infrared (TIR) sensors are essential to obtain ground information during nighttime operations. However, existing target detection algorithms mainly consider the detection accuracy but not the processing speed and storage space requirements. Furthermore, current neural network target detection algorithms primarily focus on conventional RGB images and are not optimized for UAV-based TIR video stream data. This paper proposes an improved Mask-RCNN algorithm for target detection in UAV TIR video streams to address current research deficiencies. First, MobileNetV3, which is used to process RGB images, is applied to process TIR data for outdoor emergency rescue operations, significantly increasing the time efficiency of the algorithm. Second, prior knowledge such as the projection model of the airborne camera and the target temperature characteristics in the UAV TIR video stream is utilized to filter the detecting results instead of pre-detection temperature masks. Compared with the original Mask-RCNN algorithm, the improved algorithm increases the processing speed, reduces the storage space requirements, and provides detection performances equal or slightly superior to that before the improvement.

Comparison of Spinal Cord Stimulation vs. Dorsal Root Ganglion Stimulation vs. Association of Both in Patients with Refractory Chronic Back and/or Lower Limb Neuropathic Pain: An International, Prospective, Randomized, Double-Blinded, Crossover Trial (BOOST-DRG Study).

While spinal cord stimulation (SCS) is a well-established therapy to address refractory persistent spinal pain syndrome after spinal surgery (PSPS-T2), its lack of spatial selectivity and reported discomfort due to positional effects can be considered as significant limitations. As alternatives, new waveforms, such as burst stimulation and different spatial neural targets, such as dorsal root ganglion stimulation (DRGS), have shown promising results. Comparisons between DRGS and standard SCS, or their combination, have never been studied on the same patients. “BOOST DRG” is the first prospective, randomized, double-blinded, crossover study to compare SCS vs. DRGS vs. SCS+DRGS. Sixty-six PSPS-T2 patients will be recruited internationally in three centers. Before crossing over, patients will receive each stimulation modality for 1 month, using tonic conventional stimulation. After 3 months, stimulation will consist in switching to burst for 1 month, and patients will choose which modality/waveform they receive and will then be reassessed at 6 and 12 months. In addition to our primary outcome based on pain rating, this study is designed to assess quality of life, functional disability, psychological distress, pain surface coverage, global impression of change, medication quantification, adverse events, brain functional imaging and electroencephalography, with the objective being to provide a multidimensional insight based on composite pain assessment.

Environmental and Molecular Modulation of Motor Individuality in Larval Zebrafish.

Innate behavioral biases such as human handedness are a ubiquitous form of inter-individual variation that are not strictly hardwired into the genome and are influenced by diverse internal and external cues. Yet, genetic and environmental factors modulating behavioral variation remain poorly understood, especially in vertebrates. To identify genetic and environmental factors that influence behavioral variation, we take advantage of larval zebrafish light-search behavior. During light-search, individuals preferentially turn in leftward or rightward loops, in which directional bias is sustained and non-heritable. Our previous work has shown that bias is maintained by a habenula-rostral PT circuit and genes associated with Notch signaling. Here we use a medium-throughput recording strategy and unbiased analysis to show that significant individual to individual variation exists in wildtype larval zebrafish turning preference. We classify stable left, right, and unbiased turning types, with most individuals exhibiting a directional preference. We show unbiased behavior is not due to a loss of photo-responsiveness but reduced persistence in same-direction turning. Raising larvae at elevated temperature selectively reduces the leftward turning type and impacts rostral PT neurons, specifically. Exposure to conspecifics, variable salinity, environmental enrichment, and physical disturbance does not significantly impact inter-individual turning bias. Pharmacological manipulation of Notch signaling disrupts habenula development and turn bias individuality in a dose dependent manner, establishing a direct role of Notch signaling. Last, a mutant allele of a known Notch pathway affecter gene, gsx2, disrupts turn bias individuality, implicating that brain regions independent of the previously established habenula-rostral PT likely contribute to inter-individual variation. These results establish that larval zebrafish is a powerful vertebrate model for inter-individual variation with established neural targets showing sensitivity to specific environmental and gene signaling disruptions. Our results provide new insight into how variation is generated in the vertebrate nervous system.

Problem-solving therapy–induced amygdala engagement mediates lifestyle behavior change in obesity with comorbid depression: a randomized proof-of-mechanism trial

Depression hinders obesity treatment; elucidating mechanisms may enable treatment enhancements. The aim was to investigate whether changes in neural targets in the negative affect circuit following psychotherapy mediate subsequent changes in weight and behaviors. Adults (n=108) with obesity and depression were randomly assigned to usual care or an intervention that delivered problem-solving therapy (PST) for depression over 2 mo. fMRI for brain imaging was performed at baseline and 2 mo. BMI, physical activity, and diet were measured at baseline and 12 mo. Mediation analysis assessed between-group differences in neural target changes using t test and correlations between neural target changes and outcome changes (simple and interaction effect) using ordinary least-squares regression. Compared with usual care, PST led to reductions in left amygdala activation (-0.75; 95% CI: -1.49, -0.01) and global scores of the negative affect circuit (-0.43; -0.81, -0.06), engaged by threat stimuli. Increases in amygdala activation and global circuit scores at 2 mo correlated with decreases in physical activity outcomes at 12 mo in the usual-care group; these relations were altered by PST. In relation to change in leisure-time physical activity, standardized β-coefficients were -0.67 in usual care and -0.01 in the intervention (between-group difference: 0.66; 0.02, 1.30) for change in left amygdala activation and -2.02 in usual care and -0.11 in the intervention (difference: 1.92; 0.64, 3.20) for change in global circuit scores. In relation to change in total energy expenditure, standardized β-coefficients were -0.65 in usual care and 0.08 in the intervention (difference: 0.73; 0.29, 1.16) for change in left amygdala activation and -1.65 in usual care and 0.08 in the intervention (difference: 1.74; 0.85, 2.63) for change in global circuit scores. Results were null for BMI and diet. Short-term changes in the negative affect circuit engaged by threat stimuli following PST for depression mediated longer-term changes in physical activity. This trial was registered at www.clinicaltrials.gov as NCT02246413 (https://clinicaltrials.gov/ct2/show/NCT02246413).

Design and Optimization of Ultrasound Phased Arrays for Large-Scale Ultrasound Neuromodulation.

Low-intensity transcranial focused ultrasound stimulation (tFUS), as a noninvasive neuromodulation modality, has shown to be effective in animals and even humans with improved millimeter-scale spatial resolution compared to its noninvasive counterparts. But conventional tFUS systems are built with bulky single-element ultrasound (US) transducers that must be mechanically moved to change the stimulation target. To achieve large-scale ultrasound neuromodulation (USN) within a given tissue volume, a US transducer array should electronically be driven in a beamforming fashion (known as US phased array) to steer focused ultrasound beams towards different neural targets. This paper presents the theory and design methodology of US phased arrays for USN at a large scale. For a given tissue volume and sonication frequency (f), the optimal geometry of a US phased array is found with an iterative design procedure that maximizes a figure of merit (FoM) and minimizes side/grating lobes (avoiding off-target stimulation). The proposed FoM provides a balance between the power efficiency and spatial resolution of a US array in USN. A design example of a US phased array has been presented for USN in a rat's brain with an optimized linear US array. In measurements, the fabricated US phased array with 16 elements (16.7×7.7×2 mm3), driven by 150 V (peak-peak) pulses at f = 833.3 kHz, could generate a focused US beam with a lateral resolution of 1.6 mm and pressure output of 1.15 MPa at a focal distance of 12 mm. The capability of the US phased array in beam steering and focusing from -60o to 60o angles was also verified in measurements.

A New Direction for Closed-Loop Spinal Cord Stimulation: Combining Contemporary Therapy Paradigms with Evoked Compound Action Potential Sensing.

Spinal cord stimulation (SCS) utilizes the delivery of mild electrical pulses via epidural electrodes placed on the dorsal side of the spinal cord, typically to treat chronic pain. The first clinical use of SCS involved the delivery of paresthesia inducing, low-frequency waveforms to the neural targets corresponding to the painful areas. Contemporary SCS therapies now leverage novel therapeutic pathways to limit paresthesia and deliver superior clinical outcomes. Historically, SCS has largely been delivered with fixed stimulation parameters. This approach, referred to as open-loop (OL) SCS, does not account for the fluctuations in spacing—driven by postural changes and activity—between the electrodes and the cord. These fluctuations result in variability in the delivered dose and the volume of tissue activation (VTA) that manifests with each stimulation pulse. Inconsistent dosing may lead to suboptimal therapeutic efficacy and durability. To address this clinical need, closed-loop (CL) SCS systems have been developed to automatically adjust stimulation parameters to compensate for this variability. The evoked compound action potential (ECAP), a biopotential generated by the synchronous activation of dorsal column fibers, is indicative of the VTA resulting from the stimulation pulse. The ECAP may be utilized as a control signal in CL SCS systems to adjust stimulation parameters to reduce variability in the ECAP, and in turn, variability in the VTA. While investigational CL SCS systems with ECAP sensing have so far focused solely on managing paresthesia-based SCS, such systems must also incorporate the stimulation approaches that now define the contemporary clinical practice of SCS. Accordingly, we describe here a flexible, next-generation framework for neural responsive SCS that blends science-based methodologies for pain management with real-time CL control for biophysical variation. We conclude with a clinical example of such a system and the associated performance characteristics.

Input–Output Functions in Human Heads Obtained With Cochlear Implant and Transcranial Electric Stimulation

Electric stimulation is used to treat a number of neurologic disorders such as epilepsy and depression. However, delivering the required current to far-field neural targets is often ineffective because of current spread through low-impedance pathways. Here, the specific aims are to develop an empirical measure for current passing through the human head and to optimize stimulation strategies for targeting deeper structures, including the auditory nerve, by utilizing the cochlear implant (CI). Outward input/output (I/O) functions were obtained by CI stimulation and recording scalp potentials in five CI subjects. Conversely, inward I/O functions were obtained by noninvasive transcranial electric stimulation (tES) and recording intracochlear potentials using the onboard recording capability of the CI. I/O measures indicate substantial current spread, with a maximum of 2.2% gain recorded at the inner ear target during tES (mastoid-to-mastoid electrode configuration). Similarly, CI stimulation produced a maximum of 1.1% gain at the scalp electrode nearest the CI return electrode. Gain varied with electrode montage according to a point source model that accounted for distances between the stimulating and recording electrodes. Within the same electrode montages, current gain patterns varied across subjects suggesting the importance of tissue properties, geometry, and electrode positioning. These results provide a novel objective measure of electric stimulation in the human head, which can help to optimize stimulation parameters that improve neural excitation of deep structures by reducing the influence of current spread. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

In vivo Visualization of Pig Vagus Nerve "Vagotopy" Using Ultrasound.

Background: Placement of the clinical vagus nerve stimulating cuff is a standard surgical procedure based on anatomical landmarks, with limited patient specificity in terms of fascicular organization or vagal anatomy. As such, the therapeutic effects are generally limited by unwanted side effects of neck muscle contractions, demonstrated by previous studies to result from stimulation of (1) motor fibers near the cuff in the superior laryngeal and (2) motor fibers within the cuff projecting to the recurrent laryngeal.Objective: Conventional non-invasive ultrasound, where the transducer is placed on the surface of the skin, has been previously used to visualize the vagus with respect to other landmarks such as the carotid and internal jugular vein. However, it lacks sufficient resolution to provide details about the vagus fascicular organization, or detail about smaller neural structures such as the recurrent and superior laryngeal branch responsible for therapy limiting side effects. Here, we characterize the use of ultrasound with the transducer placed in the surgical pocket to improve resolution without adding significant additional risk to the surgical procedure in the pig model.Methods: Ultrasound images were obtained from a point of known functional organization at the nodose ganglia to the point of placement of stimulating electrodes within the surgical window. Naïve volunteers with minimal training were then asked to use these ultrasound videos to trace afferent groupings of fascicles from the nodose to their location within the surgical window where a stimulating cuff would normally be placed. Volunteers were asked to select a location for epineural electrode placement away from the fascicles containing efferent motor nerves responsible for therapy limiting side effects. 2-D and 3-D reconstructions of the ultrasound were directly compared to post-mortem histology in the same animals.Results: High-resolution ultrasound from the surgical pocket enabled 2-D and 3-D reconstruction of the cervical vagus and surrounding structures that accurately depicted the functional vagotopy of the pig vagus nerve as confirmed via histology. Although resolution was not sufficient to match specific fascicles between ultrasound and histology 1 to 1, it was sufficient to trace fascicle groupings from a point of known functional organization at the nodose ganglia to their locations within the surgical window at stimulating electrode placement. Naïve volunteers were able place an electrode proximal to the sensory afferent grouping of fascicles and away from the motor nerve efferent grouping of fascicles in each subject (n = 3).Conclusion: The surgical pocket itself provides a unique opportunity to obtain higher resolution ultrasound images of neural targets responsible for intended therapeutic effect and limiting off-target effects. We demonstrate the increase in resolution is sufficient to aid patient-specific electrode placement to optimize outcomes. This simple technique could be easily adopted for multiple neuromodulation targets to better understand how patient specific anatomy impacts functional outcomes.

Radar Signal Decomposition in Steering Vector Space for Multi-Target Classification

In automotive frequency-modulated continuous wave radar systems, targets with similar ranges and velocities might be detected as a single target because their target information overlaps on the range-velocity (RV) plane. When the information of multiple targets overlaps on the RV plane, target classification cannot be performed accurately. Therefore, we propose a method to decompose the overlapped target information on the RV plane for effective target classification. To separate each target’s radar signal, we use an orthogonal projection, in which the steering vector formed from the angle information of the desired target is projected onto the kernel space composed of other steering vectors. To verify the performance of the proposed method, a convolutional neural network-based target classification is performed on the decomposed radar signals. Compared to the angle-fast Fourier transform (FFT)-based signal decomposition, the orthogonal projection-based signal decomposition shows higher classification accuracy, which implies that the target information overlapped on the RV plane is effectively separated. When information of two targets is overlapped, the classification accuracy of the proposed method is 5.9%p higher than that of the conventional method. Moreover, when the information of three targets is overlapped, the accuracy is improved by 25.5%p.

An Automated Workflow for the Electric Field Modeling of High-definition Transcranial Direct Current Stimulation (HD-tDCS) in Chronic Stroke with Lesions.

Transcranial Direct Current Stimulation is a popular noninvasive brain stimulation (NIBS) technique that modulates brain excitability by means of low-amplitude electrical current (usually <4mA) delivered to the electrodes on the scalp. The NIBS research has gained significant momentum in the past decade, prompting tDCS as an adjunctive therapeutic tool for neuromuscular disorders like stroke. However, due to stroke lesions and the differences in individual neuroanatomy, the targeted brain region may not show the same response upon NIBS across stroke patients. To this end, we conducted a study to test the feasibility of targeted NIBS. The hand motor hotspot (HMH) for each chronic stroke participant was identified using Neuronavigated Transcranial Magnetic Stimulation (TMS). After identifying the HMH as the neural target site, we applied High-definition TDCS with the current delivered at 2mA for 20 minutes. To simulate the effects of HD-tDCS in the brain, especially with stroke lesions, we used the computational modeling tool (ROAST). The lesion mask was identified using an automated tool (LINDA). This paper demonstrates that the stroke lesions can be incorporated in the computational modeling of electric field distribution upon HD-tDCS without manual intervention.

A narrative review and future considerations of spinal cord stimulation, dorsal root ganglion stimulation and peripheral nerve stimulation.

In recent years, neuromodulation has experienced a renaissance. Novel waveforms and anatomic targets show potential improvements in therapy that may signify substantial benefits. New innovations in peripheral nerve stimulation and dorsal root ganglion stimulation have shown prospective evidence and sustainability of results. Sub-perception physiologic bursting, high-frequency stimulation and feedback loop mechanisms provide significant benefits over traditional tonic spinal cords stimulation (SCS) in peer reviewed investigations. We reviewed the themes associated with novel technology in the context of historical stalwart publications. New innovations have led to better nerve targeting, improvements in disease-based treatment, and opioid alternatives for those in chronic pain. In addition, new neural targets from both structural and cellular perspectives have changed the field of Neurostimulation. For many years, tonic SCS was representative of neuromodulation, but as this review examines, the progression of the field in the past decade has reshaped patient options.

TRANSDIAGNOSTIC APPLICATIONS AND TARGETS OF MINDFULNESS INTERVENTIONS IN YOUTH

Enthusiasm for mindfulness-based interventions (MBIs) has increased immensely over the past decade. In this Symposium, we review the implementation and preliminary results from MBIs, focusing on clinical and neural targets related to emotion dysregulation. Specifically, we present unpublished data from a meta-analysis and 3 studies testing modifications and/or targets of MBIs for youth with and at risk for mental health disorders.

Patterns of brain c-Fos expression in response to feeding behavior in acute and chronic inflammatory pain condition.

Feeding behavior is known to have potential to alleviate pain. We recently demonstrated that both 24 h fasting and 2 h refeeding (food intake after 24 h fasting) induce analgesia in inflammatory pain conditions via different brain mechanisms. However, brain structures that distinctly involved fasting- and refeeding-induced analgesia is still unknown. Hence, this study is aimed to reveal brain structures mediating fasting- and refeeding-induced analgesia. Mice were given intraplantar (i.pl.) injection of formalin and complete Freund's adjuvant into the left hind paw to induce acute and chronic inflammatory pain, respectively. We examined changes in c-Fos expression with 24 h fasting and 2 h refeeding under acute and chronic inflammatory pain conditions in the contralateral brain. Under acute pain condition, c-Fos expression changed with fasting in the anterior cingulate cortex (ACC), central amygdala (CeA), lateral hypothalamus (LH) and nucleus accumbens core (NAcC). Refeeding changed c-Fos expression in the CeA, LH and lateral parabrachial nucleus (lPBN). On the other hand, under chronic inflammatory pain condition, c-Fos expression changed with fasting in the lPBN, medial prefrontal cortex (mPFC) and nucleus accumbens shell (NAcS) while refeeding changed c-Fos expression in the anterior insular cortex, lPBN, mPFC and NAcS. The present results show that brain regions that participated in the fasting- and refeeding-induced analgesia were completely different in acute and chronic inflammatory pain conditions. Also, refeeding recruits more brain regions under chronic inflammatory pain conditions compared to the acute inflammatory pain condition. Collectively, our findings provide novel insights into brain regions involved in fasting- and refeeding-induced analgesia, which can be potential neural circuit-based targets for the development of novel therapeutics.

A Call to Action Toward Optimizing the Electrical Dose Received by Neural Targets in Spinal Cord Stimulation Therapy for Neuropathic Pain.

Spinal cord stimulation has seen unprecedented growth in new technology in the 50 years since the first subdural implant. As we continue to grow our understanding of spinal cord stimulation and relevant mechanisms of action, novel questions arise as to electrical dosing optimization. Programming adjustment — dose titration — is often a process of trial and error that can be time-consuming and frustrating for both patient and clinician. In this report, we review the current preclinical and clinical knowledge base in order to provide insights that may be helpful in developing more rational approaches to spinal cord stimulation dosing. We also provide key conclusions that may help in directing future research into electrical dosing, given the advent of newer waveforms outside traditional programming parameters.

Reversed patterns of resting state functional connectivity for females vs. males in posttraumatic stress disorder

BackgroundPosttraumatic stress disorder (PTSD) is twice as prevalent among females as compared to males following potentially traumatic events. While there is evidence for aberrant functional connectivity between hubs of the central executive network (CEN), salience network (SN), and the default mode network (DMN) in PTSD, little is known regarding sex-specificity of this connectivity. The current study aims to directly examine sex-specific resting-state functional connectivity (rs-FC) in trauma exposed males and females, with and without PTSD. MethodsOne hundred and seventy-eight individuals underwent functional magnetic resonance imaging (fMRI) at rest, of them 85 females (45 with PTSD) and 93 males (57 with PTSD). We conducted whole-brain seed-based analysis using CEN (lateral prefrontal cortex [lPFC]), SN (anterior cingulate cortex [ACC], insula, amygdala [AMG]), and DMN (medial prefrontal cortex [mPFC], posterior parietal cortex [PCC], and hippocampus [HIP]) hubs as seed regions. Group-by-Sex ANOVA was conducted. ResultsThe amygdala-precuneus, ACC-precuneus, and hippocampus-precuneus pathways exhibited significant group-by-sex interaction effects, with females with PTSD consistently differing in connectivity patterns from males with PTSD and from trauma-exposed healthy females. ConclusionsSex-specific neural connectivity patterns were found within and between key nodes of the CEN, DMN, and the SN, suggesting opposite patterns of connectivity in PTSD and trauma-exposed controls as a function of sex as a biological variable (SABV). This may point to mechanistic sex differences in adaptation following trauma and may inform differential neural targets for treatment of females and males with PTSD.

MorphoSONIC: A morphologically structured intramembrane cavitation model reveals fiber-specific neuromodulation by ultrasound

SummaryLow-Intensity Focused Ultrasound Stimulation (LIFUS) holds promise for the remote modulation of neural activity, but an incomplete mechanistic characterization hinders its clinical maturation. Here we developed a computational framework to model intramembrane cavitation (a candidate mechanism) in multi-compartment, morphologically structured neuron models, and used it to investigate ultrasound neuromodulation of peripheral nerves. We predict that by engaging membrane mechanoelectrical coupling, LIFUS exploits fiber-specific differences in membrane conductance and capacitance to selectively recruit myelinated and/or unmyelinated axons in distinct parametric subspaces, allowing to modulate their activity concurrently and independently over physiologically relevant spiking frequency ranges. These theoretical results consistently explain recent empirical findings and suggest that LIFUS can simultaneously, yet selectively, engage different neural pathways, opening up opportunities for peripheral neuromodulation currently not addressable by electrical stimulation. More generally, our framework is readily applicable to other neural targets to establish application-specific LIFUS protocols.

Transcranial direct current stimulation targeting the medial prefrontal cortex modulates functional connectivity and enhances safety learning in obsessive-compulsive disorder: Results from two pilot studies.

Exposed-based psychotherapy is a mainstay of treatment for obsessive-compulsive disorder (OCD) and anxious psychopathology. The medial prefrontal cortex (mPFC) and the default mode network (DMN), which is anchored by the mPFC, promote safety learning. Neuromodulation targeting the mPFC might augment therapeutic safety learning and enhance response to exposure-based therapies. To characterize the effects of mPFC neuromodulation on functional connectivity, 17 community volunteers completed resting-state functional magnetic resonance imaging scans before and after 20 min of frontopolar anodal multifocal transcranial direct current stimulation (tDCS). To examine the effects of tDCS on therapeutic safety learning, 24 patients with OCD completed a pilot randomized clinical trial; they were randomly assigned (double-blind, 50:50) to receive active or sham frontopolar tDCS before completing an in vivo exposure and response prevention (ERP) challenge. Changes in subjective emotional distress during the ERP challenge were used to index therapeutic safety learning. In community volunteers, frontal pole functional connectivity with the middle and superior frontal gyri increased, while connectivity with the anterior insula and basal ganglia decreased (ps < .001, corrected) after tDCS; functional connectivity between DMN and salience network also decreased after tDCS (ps < .001, corrected). OCD patients who received active tDCS exhibited more rapid therapeutic safety learning (ps < .05) during the ERP challenge than patients who received sham tDCS. Frontopolar tDCS may modulate mPFC and DMN functional connectivity and can accelerate therapeutic safety learning. Though limited by small samples, these findings motivate further exploration of the effects of frontopolar tDCS on neural and behavioral targets associated with exposure-based psychotherapies.