Biology subjects

Legon, W.

Publications and source records attributed to Legon, W..

13 recordsLinked to original sources

bioRxiv2026

Focal brain stimulation sites that modify autonomic arousal map to a convergent brain circuit and potential therapeutic target

Causal modulation of autonomic outflow could yield new therapeutic targets for autonomic hyperactivation. We employed three natural experiments in which different brain regions were targeted using transcranial magnetic stimulation (TMS) (n=139 sites, n=14 individuals), deep brain stimulation (n=392 sites, n=58 individuals), or low-intensity focused ultrasound (n=46 sites, n=23 individuals) with subsequent autonomic measurements. Using a human connectome database (n=1000) as a wiring diagram, we identified a convergent brain circuit that, when focally modulated, transiently reduces autonomic arousal. This circuit significantly resembled previously reported causal circuits for posttraumatic stress disorder (PTSD) and anxiety. In independent datasets, TMS to the autonomic arousal circuit reduced laboratory startle in healthy volunteers (n=28), lesions to this circuit reduced exaggerated startle in PTSD (n=193), and TMS to this circuit reduced anxiety-related autonomic symptoms in patients with clinically significant anxiety (n=30). Thus, the convergent circuit may serve as a potential neuromodulation target for autonomic hyperactivation.

neuroscience↗

bioRxiv2025

Wearable Focused Ultrasound Neuromodulation and Electrophysiological Recording Patch for REM Sleep Enhancement

The rise in sleep disease affecting the general population globally in the past decade has been detrimental to individually and socioeconomically. As of now, approaches often are temporary through medication, permanently using invasive implants with surgical complications or neuromodulation therapy. However, non-invasive, state-dependent neuromodulation during sleep is technically challenging, especially with the lack of flexibility, comfortability and robustness for sleep conditions. Here, we introduce a Non-invasive Electrophysiological Recording and Ultrasound Neuromodulation Sleep Patch (NEUSLeeP) in delivering focused ultrasound stimulation to the subthalamic nucleus (STN) overnight with simultaneous stable polysomnography recording. Our sleep patch integrates a custom eight-channel concentric ring transducer array with real-time electroencephalography (EEG), electrooculography (EOG), electromyography (EMG) recording, and individualized line-of-sight targeting to sonicate deep brain areas while preserving mobility. Our platform operated safely and comfortably across the two-nights sleep study. Stimulation of the left STN was delivered every 90 minutes throughout the night and was associated with a 25% increase in REM (Rapid Eye Movement) sleep duration and a 43 minutes reduction in REM sleep latency compared to a sham night in a study of 26 subjects. Blood Oxygen Level Dependent (BOLD) signal attenuation in functional Magnetic Resonance Imaging (fMRI) was localized primarily to a left ipsilateral basal-ganglia-midbrain-temporal circuit, consistent with selective network modulation rather than global arousal changes. Overall, NEUSLeeP demonstrates feasibility by (i) a light weight and wearable ultrasound neuromodulation and sleep recording during natural sleep; (ii) establishing a potential mechanism relating targeted ultrasound stimulation of STN/sleep networks to REM enhancement.

bioengineering↗

bioRxiv2025

Acoustic Coupling for Double-Blind Human Low-Intensity Focused Ultrasound Neuromodulation

ObjectiveLow-intensity focused ultrasound (LIFU) is a non-invasive neuromodulation technique with the potential for precise targeting of small and deep human brain circuitry. To ensure rigorous and reproducible effects, it is necessary to implement double-blinding to mitigate potential experimental biases. This study innovates on previous ultrasound coupling methods by embedding a 3D-printed thermoplastic disc in a high-density gel-polymer matrix to create identical gel-plastic coupling devices that either transmit (verum) or block (sham) ultrasound. MethodsWe evaluated varying thicknesses (1.5 mm, 2,0 mm, 2.5 mm) and infill densities (25%, 50%, 75%, and 100%) of Acrylonitrile Butadiene Styrene (ABS) for insertion loss and effects on beam characteristics across relevant human neuromodulation frequencies from 0.2 - 1 MHz. ResultsABS at 1.5 mm thickness and 50 % infill had the lowest insertion loss at 0.50 MHz of 0.9 {+/-} 0.04 dB demonstrating acoustic transparency suitable for a verum device. For the sham device, we introduced an internal air gap that produced 31 dB insertion loss at 0.50 MHz. The verum device demonstrated minimal effects on the beam shape with a radial peak shift of 0.3 {+/-} 0.2 mm and an average axial shift of 0.5 mm. DiscussionThis novel gel-plastic coupling device can be tailored to most LIFU transducer shapes and is designed to support double-blind protocols by maintaining visual and tactile indistinguishability while controlling transmitted energy. This method provides a cost-effective and easily implementable solution for double-blinding in human LIFU studies to improve the reliability and rigor of experimental outcomes.

neuroscience↗

bioRxiv2024

Examination of low-intensity focused ultrasound parameters for human neuromodulation

BackgroundLow-intensity focused ultrasound (LIFU) is a promising form of non-invasive neuromodulation characterized by a rich parameter space that includes intensity, duration, duty cycle and pulsing strategy. The effect and interaction of these parameters to affect human brain activity is poorly understood. A better understanding of how parameters interact is critical to advance LIFU as a potential therapeutic. Objective/HypothesisTo determine how different parameters, including intensity, duration, and duty cycle interact to produce neuromodulation effects in the human brain. Further, this study assesses the effect of pulsing versus continuous ultrasound. We hypothesize that higher duty cycles will confer excitation. Increasing intensity or duration will increase the magnitude of effect. Pulsing LIFU will not be more effective than continuous wave ultrasound. MethodsN = 18 healthy human volunteers underwent 20 different parameter combinations that included a fully parametrized set of two intensities (ISPPA: 6 & 24 W/cm2), five duty cycles (1, 10, 30, 50, 70%) and two durations (100, 500 msec) with a constant pulse repetition frequency of 1 kHz delivered concurrently with transcranial magnetic stimulation (TMS) to the primary motor cortex (M1). Four of these parameter combinations were also delivered continuously, matched on the number of cycles. Motor-evoked potential (MEP) amplitude was the primary outcome measure. All parameter combinations were collected time-locked to MEP generation. ResultsThere was no evidence of excitation from any parameter combination. 3 of the 24 parameter sets resulted in inhibition. The parameter set that resulted in the greatest inhibition ([~] 30%) was an intensity of 6W/cm2 with a duty cycle of 30% and a duration of 500 msec. A three-way ANOVA revealed an interaction of intensity and duty cycle. The analysis of continuous versus pulsed ultrasound revealed a 3-way interaction of intensity, pulsing, and the number of cycles such that under the 6W/cm2 condition higher cycles of pulsed ultrasound resulted in inhibition whereas lower number of cycles using continuous LIFU resulted in inhibition. ConclusionsLIFU to M1 in humans, in the range employed, either conferred inhibition or had no effect. Significant excitation was not observed. In general, lower intensity looks to be more efficacious for inhibition that depends on duration. Finally, pulsed ultrasound looks to be more effective for inhibition as compared to continuous wave after controlling for total energy delivered.

neuroscience↗

bioRxiv2024

Low-intensity focused ultrasound to the human insular cortex differentially modulates the heartbeat-evoked potential: a proof-of-concept study

BackgroundThe heartbeat evoked potential (HEP) is a brain response time-locked to the heartbeat and a potential marker of interoceptive processing. The insula and dorsal anterior cingulate cortex (dACC) are brain regions that may be involved in generating the HEP. Low-intensity focused ultrasound (LIFU) is a non-invasive neuromodulation technique that can selectively target sub-regions of the insula and dACC to better understand their contributions to the HEP. ObjectiveProof-of-concept study to determine whether LIFU modulation of the anterior insula (AI), posterior insula (PI), and dACC influences the HEP. MethodsIn a within-subject, repeated-measures design, healthy human participants (n=16) received 10 minutes of stereotaxically targeted LIFU to the AI, PI, dACC or Sham at rest during continuous electroencephalography (EEG) and electrocardiography (ECG) recording on separate days. Primary outcome was change in HEP amplitudes. Relationships between LIFU pressure and HEP changes were examined using linear mixed modelling. Peripheral indices of visceromotor output including heart rate and heart rate variability (HRV) were explored between conditions. ResultsRelative to sham, LIFU to the PI, but not AI or dACC, decreased HEP amplitudes; this was partially explained by increased LIFU pressure. LIFU did not affect time or frequency dependent measures of HRV. ConclusionsThese results demonstrate the ability to modulate HEP amplitudes via non-invasive targeting of key interoceptive brain regions. Our findings have implications for the causal role of these areas in bottom-up heart-brain communication that could guide future work investigating the HEP as a marker of interoceptive processing in healthy and clinical populations.

neuroscience↗

bioRxiv2024

Focused Ultrasound modulates dopamine in a mesolimbic reward circuit

Dopamine is a neurotransmitter that plays a significant role in reward and motivation. Dysfunction in the mesolimbic dopamine pathway has been linked to a variety of psychiatric disorders, including addiction. Low-intensity focused ultrasound (LIFU) has demonstrated effects on brain activity, but how LIFU affects dopamine neurotransmission is not known. Here, we applied three different intensities (6.5, 13, and 26 W/cm2 Isppa) of 2-minute LIFU to the prelimbic region (PLC) and measured dopamine in the nucleus accumbens (NAc) core using fast-scan cyclic voltammetry. Two minutes of LIFU sonication at 13 W/cm2 to the PLC significantly reduced dopamine release by [~] 50% for up to 2 hours. However, double the intensity (26 W/cm2) resulted in less inhibition ([~]30%), and half the intensity (6.5 W/cm2) did not result in any inhibition of dopamine. Anatomical controls applying LIFU to the primary somatosensory cortex did not change NAc core dopamine, and applying LIFU to the PLC did not affect dopamine release in the caudate or NAc shell. Histological evaluations showed no evidence of cell damage or death. Modeling of temperature rise demonstrates a maximum temperature change of 0.5{degrees}C with 13 W/cm2, suggesting that modulation is not due to thermal mechanisms. These studies show that LIFU at a moderate intensity provides a noninvasive, high spatial resolution means to modulate specific mesolimbic circuits that could be used in future studies to target and repair pathways that are dysfunctional in addiction and other psychiatric diseases.

neuroscience↗

bioRxiv2024

Low-intensity focused ultrasound to the insula and dorsal anterior cingulate has site-specific and pressure dependent effects on pain during measures of central sensitization

BackgroundThe insula and dorsal anterior cingulate cortex (dACC) are core brain regions involved in pain processing and central sensitization, a shared mechanism across various chronic pain conditions. Methods to modulate these regions may serve to reduce central sensitization, though it is unclear which target may be most efficacious for different measures of central sensitization. Objective/HypothesisInvestigate the effect of low-intensity focused ultrasound (LIFU) pressure to the anterior insula (AI), posterior insula (PI) or dACC on conditioned pain modulation (CPM) and temporal summation of pain (TSP). MethodsN = 16 volunteers underwent TSP and CPM pain tasks pre/post a 10 minute LIFU intervention to either the AI, PI, dACC or Sham stimulation. Pain ratings were collected pre/post LIFU. ResultsLIFU to the PI significantly attenuated pain ratings in both TSP and the CPM protocols. LIFU to the dACC only affected TSP pain ratings. LIFU to AI had no effect on either TSP or CPM pain ratings. LIFU pressure modulated group means but did not affect overall group differences. ConclusionsLIFU to the PI and dACC differentially affected central sensitization. This may, in part, be due to dosing (pressure) of LIFU. Inhibition of the PI with LIFU may be a future potential therapy in chronic pain populations demonstrating central sensitization. The minimal effective dose of LIFU for efficacious neuromodulation will help to translate LIFU for therapeutic options.

neuroscience↗

bioRxiv2023

Non-invasive modulation of the human dorsal anterior cingulate attenuates acute pain perception and homeostatic cardiovascular responses

Homeostasis is the process of maintaining physiologic balance in the body that is critical for maintaining health and is dysfunctional in several disorders like chronic pain. The dorsal anterior cingulate cortex (dACC) is a critical brain area for homeostatic cardiovascular responses and pain processing, making it a promising non-invasive therapeutic target. We leverage the high spatial resolution and deep focal lengths of low-intensity focused ultrasound (LIFU) to non-invasively modulate the dACC for an effect on behavioral and cardiac autonomic responses using a transient heat pain stimulus. N = 16 healthy human volunteers (6M/10F) received transient contact heat pain during either LIFU to the dACC or Sham stimulation. Continuous electroencephalogram (EEG), electrocardiogram (ECG), and electrodermal response (EDR) were recorded. Outcome measures included perceived pain ratings, homeostatic measures including heart-rate variability, blood pressure, EDR response as well as the amplitude of the contact heat-evoked potential (CHEP). LIFU reduced pain ratings by 1.08 {+/-} 0.21 points relative to Sham. LIFU increased heart rate variability indexed by the standard deviation of normal sinus beats (SDNN), low frequency (LF) power, and the low-frequency/high-frequency (LF/HF) ratio. There were no effects on blood pressure or EDR. LIFU resulted in a 25.1% reduction in the N1-P1 CHEP amplitude driven primarily by effects on the P1 amplitude. Our results demonstrate LIFU to the dACC reduces perceived pain and alters homeostatic cardiovascular responses to a transient heat pain stimulus. These results have implications for the causal understanding of human pain and autonomic processing in the dACC and the potential for future therapeutics for pain relief and homeostatic modulation. SIGNIFICANCE STATEMENTNew lines of inquiry now demonstrate cardiac homeostatic signals like heart rate variability (HRV) are aberrant in mental health disorders, addiction, and chronic pain and may contribute to their underlying etiology. The dorsal anterior cingulate cortex (dACC) is a key homeostatic center with direct influences on cardiovascular autonomic function, but its depth precludes direct access without invasive surgery. For the first time in humans, we demonstrate low-intensity focused ultrasound (LIFU) can non-invasively and selectively modulate the dACC to reduce acute pain perception and homeostatic cardiovascular responses as well as pain processing signals. This work helps establish a causal role of the dACC in pain perception and homeostatic signaling with potential future clinical applications in chronic pain and neuropsychological populations.

neuroscience↗

bioRxiv2023

Non-invasive neuromodulation of sub-regions of the human insula differentially affect pain processing and heart-rate variability

The insula is a portion of the cerebral cortex folded deep within the lateral sulcus covered by the overlying opercula of the inferior frontal lobe and superior portion of the temporal lobe. The insula has been parsed into sub-regions based upon cytoarchitectonics and structural and functional connectivity with multiple lines of evidence supporting specific roles for each of these sub-regions in pain processing and interoception. In the past, causal interrogation of the insula was only possible in patients with surgically implanted electrodes. Here, we leverage the high spatial resolution combined with the deep penetration depth of low-intensity focused ultrasound (LIFU) to non-surgically modulate either the anterior insula (AI) or posterior insula (PI) in humans for effect on subjective pain ratings, electroencephalographic (EEG) contact head evoked potentials (CHEPs) and time-frequency power as well as autonomic measures including heart-rate variability (HRV) and electrodermal response (EDR). N = 23 healthy volunteers received brief noxious heat pain stimuli to the dorsum of their right hand during continuous heart-rate, EDR and EEG recording. LIFU was delivered to either the AI (anterior short gyrus), PI (posterior longus gyrus) or under an inert sham condition time-locked to the heat stimulus. Results demonstrate that single-element 500 kHz LIFU is capable of individually targeting specific gyri of the insula. LIFU to both AI and PI similarly reduced perceived pain ratings but had differential effects on EEG activity. LIFU to PI affected earlier EEG amplitudes around 300 milliseconds whereas LIFU to AI affected EEG amplitudes around 500 milliseconds. In addition, only LIFU to the AI affected HRV as indexed by an increase in standard deviation of N-N intervals (SDNN) and mean HRV low frequency power. There was no effect of LIFU to either AI or PI on EDR or blood pressure. Taken together, LIFU looks to be an effective method to individually target sub-regions of the insula in humans for site-specific effects on brain biomarkers of pain processing and autonomic reactivity that translates to reduced perceived pain to a transient heat stimulus. These data have implications for the treatment of chronic pain and several neuropsychological diseases like anxiety, depression and addiction that all demonstrate abnormal activity in the insula concomitant with dysregulated autonomic function.

neuroscience↗

bioRxiv2018

Safety of transcranial focused ultrasound for human neuromodulation

BackgroundLow intensity transcranial focused ultrasound (tFUS) is a new method of non-invasive neuromodulation that uses acoustic energy to affect neuronal excitability. tFUS offers high spatial resolution and adjustable focal lengths for precise neuromodulation of discrete regions in the human brain. Before the full potential of low intensity ultrasound for research and clinical application can be investigated, data on the safety of this technique is indicated.\n\nObjective/HypothesisTo provide an initial evaluation of the safety of tFUS for human neuromodulation through participant report and neurological assessment surrounding pilot investigation of tFUS for neuromodulation.\n\nMethodsParticipants (N = 120) that were enrolled in one of seven human ultrasound neuromodulation studies at the University of Minnesota (2015 - 2017) were queried to complete a follow-up Participant Report of Symptoms questionnaire assessing their self-reported experience and tolerance to participation in tFUS research and the perceived relation of symptoms to tFUS.\n\nResultsA total of 64/120 participant (53%) responded to follow-up requests to complete the Participant Report of Symptoms questionnaire. During the conduct of the seven studies in this report, none of the participants experienced serious adverse effects. From the post-hoc assessment of safety using the questionnaire, 7/64 reported mild to moderate symptoms, that were perceived as possibly or probably related to participation in tFUS experiments. These reports included neck pain, problems with attention, muscle twitches and anxiety. The most common unrelated symptoms included sleepiness and neck pain. There were initial transient reports of mild neck pain, scalp tingling and headache that were extinguished upon follow-up. No new symptoms were reported upon follow up out to 1 month.\n\nConclusions(s)To date, in the literature and including this report, no serious adverse events have been reported as a result of low intensity tFUS for human neuromodulation. Here, we report new data on minor transient events. As currently employed with the parameters used in the studies in this report, tFUS looks to be a safe form of transient neuromodulation in humans.

neuroscience↗

bioRxiv2018

Effects of transcranial focused ultrasound on human primary motor cortex using 7T fMRI

BackgroundTranscranial focused ultrasound (tFUS) is a new non-invasive neuromodulation technique that uses mechanical energy to modulate neuronal excitability with high spatial precision. tFUS has been shown to be capable of modulating EEG brain activity in humans that is spatially restricted, and here, we use 7T MRI to extend these findings. We test the effect of tFUS on 7T BOLD fMRI signals from individual finger representations in the human primary motor cortex (M1) and connected cortical motor regions. Participants (N = 5) performed a cued finger tapping task in a 7T MRI scanner with their thumb, index, and middle fingers to produce a BOLD signal for individual M1 finger representations during either tFUS or sham neuromodulation to the thumb representation.\n\nResultsResults demonstrated a statistically significant increase in activation volume of the M1 thumb representation for the tFUS condition as compared to sham. No differences in percent BOLD changes were found. This effect was spatially confined as the index and middle finger M1 finger representations did not show similar significant changes in either percent change or activation volume. No effects were seen during tFUS to M1 in the supplementary motor area (SMA) or the dorsal premotor cortex (PMd).\n\nConclusionsSingle element tFUS can be paired with high field MRI that does not induce significant artifact. tFUS increases activation volumes of the targeted finger representation that is spatially restricted within M1 but does not extend to functionally connected motor regions.

neuroscience↗

bioRxiv2018

Transcranial focused ultrasound neuromodulation of the human primary motor cortex

Transcranial focused ultrasound is a form of non-invasive neuromodulation that uses acoustic energy to affect neuronal excitability. The effect of ultrasound on human motor cortical excitability is currently unknown. We apply ultrasound to the primary motor cortex in humans using a novel transcranial ultrasound and magnetic stimulation (TUMS) paradigm that allows for concurrent and concentric ultrasound stimulation with transcranial magnetic stimulation (TMS). This allows for non-invasive inspection of the effect of ultrasound on motor neuronal excitability using the motor evoked potential (MEP) generated by TMS. We test the effect of ultrasound on single pulse MEP recruitment curves and paired pulse protocols including short interval intracortical inhibition (SICI) and intracortical facilitation (ICF). We also test the longevity of the effect and the effect of ultrasound on the cortical silent period in a small sub-sample of participants. In addition, we test the effect of ultrasound to motor cortex on a stimulus response reaction time task. Results show ultrasound inhibits the amplitude of single-pulse MEPs and attenuates intracortical facilitation but does not affect intracortical inhibition. Early evidence suggests that ultrasound does not affect cortical silent period duration and that the duration of inhibition may be related to the duration of stimulation. Finally, ultrasound reduces reaction time on a simple stimulus response task. This is the first report of the effect of ultrasound on human motor cortical excitability and motor behavior and confirms previous results in the somatosensory cortex that ultrasound results in effective neuronal inhibition that confers a performance advantage.

neuroscience↗

bioRxiv2017

Ultrasound Produces Extensive Brain Activation via a Cochlear Pathway

Ultrasound (US) can noninvasively activate intact brain circuits, making it a promising neuromodulation technique. However, little is known about the underlying mechanism. Here, we apply transcranial US and perform brain mapping studies in guinea pigs using extracellular electrophysiology. We find that US elicits extensive activation across cortical and subcortical brain regions. However, transection of the auditory nerves or removal of cochlear fluids eliminates the US-induced activity, revealing an indirect auditory mechanism for US neural activation. US likely vibrates the cerebrospinal fluid in the brain, which is continuous with the fluid in the cochlea via cochlear aqueducts; thus, US can activate the ascending auditory pathways and other non-auditory regions through cross-modal projections. This finding of a cochlear fluid-induced vibration mechanism challenges the idea that US can directly activate neurons in the intact brain, suggesting that future US stimulation studies will need to control for this effect to reach reliable conclusions.

neuroscience↗