Low-Intensity Focused Ultrasound to the Human Dorsal Anterior Cingulate Attenuates Acute Pain Perception and Autonomic Responses.

The dorsal anterior cingulate cortex (dACC) is a critical brain area for pain and autonomic processing, making it a promising noninvasive therapeutic target. We leverage the high spatial resolution and deep focal lengths of low-intensity focused ultrasound (LIFU) to noninvasively modulate the dACC for effects on behavioral and cardiac autonomic responses using transient heat pain stimuli. A N = 16 healthy human volunteers (6 M/10 F) 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 pain ratings, heart rate variability, EDR response, blood pressure, and the amplitude of the contact heat-evoked potential (CHEP).LIFU reduced pain ratings by 1.09 ± 0.20 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 the blood pressure or EDR. LIFU resulted in a 38.1% reduction in the P2 CHEP amplitude. Results demonstrate LIFU to the dACC reduces pain and alters autonomic responses to acute heat pain stimuli. This has implications for the causal understanding of human pain and autonomic processing in the dACC and potential future therapeutic options for pain relief and modulation of homeostatic signals.

Neuromodulation with single-element transcranial focused ultrasound in human thalamus.

Transcranial focused ultrasound (tFUS) has proven capable of stimulating cortical tissue in humans. tFUS confers high spatial resolutions with deep focal lengths and as such, has the potential to noninvasively modulate neural targets deep to the cortex in humans. We test the ability of single-element tFUS to noninvasively modulate unilateral thalamus in humans. Participants (N = 40) underwent either tFUS or sham neuromodulation targeted at the unilateral sensory thalamus that contains the ventro-posterior lateral (VPL) nucleus of thalamus. Somatosensory evoked potentials (SEPs) were recorded from scalp electrodes contralateral to median nerve stimulation. Activity of the unilateral sensory thalamus was indexed by the P14 SEP generated in the VPL nucleus and cortical somatosensory activity by subsequent inflexions of the SEP and through time/frequency analysis. Participants also under went tactile behavioral assessment during either the tFUS or sham condition in a separate experiment. A detailed acoustic model using computed tomography (CT) and magnetic resonance imaging (MRI) is also presented to assess the effect of individual skull morphology for single-element deep brain neuromodulation in humans. tFUS targeted at unilateral sensory thalamus inhibited the amplitude of the P14 SEP as compared to sham. There is evidence of translation of this effect to time windows of the EEG commensurate with SI and SII activities. These results were accompanied by alpha and beta power attenuation as well as time-locked gamma power inhibition. Furthermore, participants performed significantly worse than chance on a discrimination task during tFUS stimulation.

Effects of transcranial focused ultrasound on human primary motor cortex using 7T fMRI: a pilot study.

BACKGROUND: Transcranial 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. RESULTS: Results 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 or the dorsal premotor cortex. CONCLUSIONS: Single 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. Trial registration ClinicalTrials.gov NCT03634631 08/14/18.

Altered Prefrontal Excitation/Inhibition Balance and Prefrontal Output: Markers of Aging in Human Memory Networks.

Memory impairments and heightened prefrontal cortical (PFC) activity are hallmarks of cognitive and neurobiological human aging. While structural integrity of PFC gray matter and interregional white matter tracts are thought to impact memory processing, the balance of neurotransmitters within the PFC itself is less well understood. We used fMRI to establish whole-brain networks involved in a memory encoding task and dynamic causal models (DCMs) for fMRI to determine the causal relationships between these areas. These data revealed enhanced connectivity from PFC to medial temporal cortex that negatively correlated with recall ability. To better understand the intrinsic activity within the PFC, DCM for EEG was employed after continuous theta burst transcranial magnetic stimulation (TMS) to the PFC to assess the effect on excitatory/inhibitory (E/I) synaptic ratios and behavior. These data revealed that the young cohort had a stable E/I ratio that was unaffected by the TMS intervention, while the aged cohort exhibited lower E/I ratios driven by a greater intrinsic inhibitory tone. TMS to the aged cohort resulted in decreased intrinsic inhibition and a decrement in memory performance. These results demonstrate increased top-down influence of PFC upon medial temporal lobe in healthy aging that is associated with decreased memory and may be due to unstable local inhibitory tone within the PFC.

Vagus Nerve Stimulation and Other Neuromodulation Methods for Treatment of Traumatic Brain Injury.

The objective of this paper is to review the current literature regarding the use of vagus nerve stimulation (VNS) in preclinical models of traumatic brain injury (TBI) as well as discuss the potential role of VNS along with alternative neuromodulation approaches in the treatment of human TBI. Data from previous studies have demonstrated VNS-mediated improvement following TBI in animal models. In these cases, VNS was observed to enhance motor and cognitive recovery, attenuate cerebral edema and inflammation, reduce blood brain barrier breakdown, and confer neuroprotective effects. Yet, the underlying mechanisms by which VNS enhances recovery following TBI remain to be fully elucidated. Several hypotheses have been offered including: a noradrenergic mechanism, reduction in post-TBI seizures and hyper-excitability, anti-inflammatory effects, attenuation of blood-brain barrier breakdown, and cerebral edema. We present other potential mechanisms by which VNS acts including enhancement of synaptic plasticity and recruitment of endogenous neural stem cells, stabilization of intracranial pressure, and interaction with the ghrelin system. In addition, alternative methods for the treatment of TBI including deep brain stimulation, transcranial magnetic stimulation, transcranial direct current stimulation, and focused ultrasound stimulation are discussed. Although the primary source data show that VNS improves TBI outcomes, it remains to be determined if these findings can be translated to clinical settings.

Noninvasive neuromodulation of subregions of the human insula differentially affect pain processing and heart-rate variability: a within-subjects pseudo-randomized trial.

ABSTRACT: The insula is an intriguing target for pain modulation. Unfortunately, it lies deep to the cortex making spatially specific noninvasive access difficult. Here, we leverage the high spatial resolution and deep penetration depth of low-intensity focused ultrasound (LIFU) to nonsurgically modulate the anterior insula (AI) or posterior insula (PI) in humans for effect on subjective pain ratings, electroencephalographic (EEG) contact heat-evoked potentials, as well as autonomic measures including heart-rate variability (HRV). In a within-subjects, repeated-measures, pseudo-randomized trial design, 23 healthy volunteers received brief noxious heat pain stimuli to the dorsum of their right hand during continuous heart-rate, electrodermal, electrocardiography and EEG recording. Low-intensity focused ultrasound was delivered to the AI (anterior short gyrus), PI (posterior longus gyrus), or under an inert Sham condition. The primary outcome measure was pain rating. Low-intensity focused ultrasound to both AI and PI similarly reduced pain ratings but had differential effects on EEG activity. Low-intensity focused ultrasound to PI affected earlier EEG amplitudes, whereas LIFU to AI affected later EEG amplitudes. Only LIFU to the AI affected HRV as indexed by an increase in SD of N-N intervals and mean HRV low-frequency power. Taken together, LIFU is an effective noninvasive method to individually target subregions 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.

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/cm 2 I sppa ) 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/cm 2 to the PLC significantly reduced dopamine release by ∼ 50% for up to 2 hours. However, double the intensity (26 W/cm 2 ) resulted in less inhibition (∼30%), and half the intensity (6.5 W/cm 2 ) 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°C with 13 W/cm 2 , 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.

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

Background: The 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. Objective: Proof-of-concept study to determine whether LIFU modulation of the anterior insula (AI), posterior insula (PI), and dACC influences the HEP. Methods: In 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. Results: Relative 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. Conclusions: These 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.

Physiological observations validate finite element models for estimating subject-specific electric field distributions induced by transcranial magnetic stimulation of the human motor cortex.

Recent evidence indicates subject-specific gyral folding patterns and white matter anisotropy uniquely shape electric fields generated by TMS. Current methods for predicting the brain regions influenced by TMS involve projecting the TMS coil position or center of gravity onto realistic head models derived from structural and functional imaging data. Similarly, spherical models have been used to estimate electric field distributions generated by TMS pulses delivered from a particular coil location and position. In the present paper we inspect differences between electric field computations estimated using the finite element method (FEM) and projection-based approaches described above. We then more specifically examined an approach for estimating cortical excitation volumes based on individualistic FEM simulations of electric fields. We evaluated this approach by performing neurophysiological recordings during MR-navigated motormapping experiments. We recorded motor evoked potentials (MEPs) in response to single pulse TMS using two different coil orientations (45° and 90° to midline) at 25 different locations (5×5 grid, 1cm spacing) centered on the hotspot of the right first dorsal interosseous (FDI) muscle in left motor cortex. We observed that motor excitability maps varied within and between subjects as a function of TMS coil position and orientation. For each coil position and orientation tested, simulations of the TMS-induced electric field were computed using individualistic FEM models and compared to MEP amplitudes obtained during our motormapping experiments. We found FEM simulations of electric field strength, which take into account subject-specific gyral geometry and tissue conductivity anisotropy, significantly correlated with physiologically observed MEP amplitudes (rmax=0.91, p=1.8×10(-5) rmean=0.81, p=0.01). These observations validate the implementation of individualistic FEM models to account for variations in gyral folding patterns and tissue conductivity anisotropy, which should help improve the targeting accuracy of TMS in the mapping or modulation of human brain circuits.

Crossmodal influences on early somatosensory processing: interaction of vision, touch, and task-relevance.

Previous research suggests that somatosensory cortex is subject to modulation based on the relevancy of incoming somatosensory stimuli to behavioural goals. Recent fMRI findings provide evidence for modulation of primary somatosensory cortex when simultaneous visual and tactile stimuli were relevant to the performance of a motor task. The present study aimed to (1) determine the temporal characteristics of this modulation using event-related potentials (ERPs) and (2) investigate the role of task-relevance in mediating such a modulation. Electroencephalography was collected from healthy subjects during visual, vibrotactile or bimodal stimulation as they performed a sensory-guided motor task. Experiment 1 tested the hypothesis that simultaneous bimodal stimuli would be associated with modulation of somatosensory ERPs, and Experiment 2 tested the hypothesis that such effects would only be seen when both modalities are relevant. ERPs were time-locked to stimulus onset, and mean ERP amplitudes and latencies were extracted for the P50, P100, and N140. The bimodal condition in the first experiment was associated with larger amplitudes at both early and mid-latency components. The manipulation of task-relevance under bimodal conditions produced more complex results for the mid-latency components. For the P50, this enhancement was observed only when both stimuli were relevant, whereas the P100 was smallest when the tactile stimuli were not relevant to the response. These results provide evidence that crossmodal stimuli can modulate early somatosensory event-related potentials and that these effects are mediated by stimulus relevance.

Evaluation of a Novel Acoustic Coupling Medium for Human Low-Intensity Focused Ultrasound Neuromodulation Applications.

OBJECTIVE: Single-element low-intensity focused ultrasound (LIFU) is an emerging form of human neuromodulation. Current coupling methods are impractical for clinical bedside use. Here, we evaluate commercially available high-viscosity gel polymer matrices as couplants for human LIFU neuromodulation applications. METHODS: We first empirically tested the acoustic transmission of three densities at 500 kHz and then subjected the gel with the least acoustic attenuation to further tests of the effect of thickness, frequency, de-gassing and production variability. RESULTS: The highest-density gel had the lowest acoustic attenuation (3.3%) with low lateral (<0.5 mm) and axial (<2 mm) beam distortion. Different thicknesses of the gel up to 10 mm did not appreciably affect results. The gel polymers exhibited frequency-dependent attenuation at 1 and 3 MHz up to 86.6%, as well as significant beam distortion >4 mm. Poor de-gassing methods also increased pressure attenuation at 500 kHz up to 59.6%. Standardized methods of making these gels should be established to reduce variability. CONCLUSION: Commercially available de-gassed, high-density gel matrices are a low-cost, easily malleable, low-attenuation and distortion medium for the coupling of single-element LIFU transducers for human neuromodulation applications at 500 kHz.

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.

The Inhibitory Thermal Effects of Focused Ultrasound on an Identified, Single Motoneuron.

Focused ultrasound (US) is an emerging neuromodulation technology that has gained much attention because of its ability to modulate, noninvasively, neuronal activity in a variety of animals, including humans. However, there has been considerable debate about exactly which types of neurons can be influenced and what underlying mechanisms are in play. Are US-evoked motor changes driven indirectly by activated mechanosensory inputs, or more directly via central interneurons or motoneurons? Although it has been shown that US can mechanically depolarize mechanosensory neurons, there are no studies that have yet tested how identified motoneurons respond directly to US and what the underlying mechanism might be. Here, we examined the effects of US on a single, identified motoneuron within a well-studied and tractable invertebrate preparation, the medicinal leech, Hirudo verbana Our approach aimed to clarify single neuronal responses to US, which may be obscured in other studies whereby US is applied across a diverse population of cells. We found that US has the ability to inhibit tonic spiking activity through a predominately thermal mechanism. US-evoked effects persisted after blocking synaptic inputs, indicating that its actions were direct. Experiments also revealed that US-comparable heating blocked the axonal conduction of spontaneous action potentials. Finally, we found no evidence that US had significant mechanical effects on the neurons tested, a finding counter to prevailing views. We conclude that a non-sensory neuron can be directly inhibited via a thermal mechanism, a finding that holds promise for clinical neuromodulatory applications.

Crossmodal influences in somatosensory cortex: Interaction of vision and touch.

Previous research has shown that information from one sensory modality has the potential to influence activity in a different modality, and these crossmodal interactions can occur early in the cortical sensory processing stream within sensory-specific cortex. In addition, it has been shown that when sensory information is relevant to the performance of a task, there is an upregulation of sensory cortex. This study sought to investigate the effects of simultaneous bimodal (visual and vibrotactile) stimulation on the modulation of primary somatosensory cortex (SI), in the context of a delayed sensory-to-motor task when both stimuli are task-relevant. It was hypothesized that the requirement to combine visual and vibrotactile stimuli would be associated with an increase in SI activity compared to vibrotactile stimuli alone. Functional magnetic resonance imaging (fMRI) was performed on healthy subjects using a 3T scanner. During the scanning session, subjects performed a sensory-guided motor task while receiving visual, vibrotactile, or both types of stimuli. An event-related design was used to examine cortical activity related to the stimulus onset and the motor response. A region of interest (ROI) analysis was performed on right SI and revealed an increase in percent blood oxygenation level dependent signal change in the bimodal (visual + tactile) task compared to the unimodal tasks. Results of the whole-brain analysis revealed a common fronto-parietal network that was active across both the bimodal and unimodal task conditions, suggesting that these regions are sensitive to the attentional and motor-planning aspects of the task rather than the unimodal or bimodal nature of the stimuli.

Non-dominant hand movement facilitates the frontal N30 somatosensory evoked potential.

BACKGROUND: Previous literature has shown that the frontal N30 is increased during movement of the hand contralateral to median nerve stimulation. This finding was a result of non-dominant left hand movement in right-handed participants. It is unclear however if the effect depends upon non-dominant hand movement or if this is a generalized phenomenon across the upper-limbs. This study tests the effect of dominant and non-dominant hand movement upon contralateral frontal and parietal somatosensory evoked potentials (SEPs) and further tests if this relationship persists in left hand dominant participants. Median nerve SEPs were elicited from the wrist contralateral to movement in both right hand and left hand dominant participants alternating the movement hand in separate blocks. Participants were required to volitionally squeeze (~20% of a maximal voluntary contraction) a pressure-sensitive bulb every ~3 seconds with the hand contralateral to median nerve stimulation. SEPs were continuously collected during the task and individual traces were grouped into time bins relative to movement according to the timing of components of the Bereitschaftspotential. SEPs were then averaged and quantified from both FCZ and CP3/4 scalp electrode sites during both the squeeze task and at rest. RESULTS: The N30 is facilitated during non-dominant hand movement in both right and left hand dominant individuals. There was no effect for dominant hand movement in either group. CONCLUSIONS: N30 amplitude increase may be a result of altered sensory gating from motor areas known to be specifically active during non-dominant hand movement.

Intermittent theta burst stimulation of the right dorsolateral prefrontal cortex accelerates visuomotor adaptation with delayed feedback.

Implicit adaptation to visual rotations during fast reaching is a well-recognized function of the cerebellum. However, there is still no well-established understanding of the neural underpinnings that support explicit processes during visuomotor adaptation. We tested the causative involvement of dorsolateral prefrontal cortex (DLPFC) in an adaptive reaching task by employing excitatory intermittent theta burst stimulation (iTBS) to left or right DLPFC during learning to adapt to a sudden large visual rotation with delayed terminal feedback. Spontaneous resting-state electroencephalography (EEG) signals were recorded before and immediately after the administration of iTBS. iTBS to right DLPFC, compared to left DLPFC or control, induced faster adaptation to the rotation and had a greater adjustment of aiming directions in early adaptation trials. Moreover, resting-state functional connectivity of EEG of the frontal cortex after iTBS predicted subsequent adaptation rate. These results suggest a critical role of right DLPFC in supporting explicit learning in the adaptive reaching task.

A retrospective qualitative report of symptoms and safety from transcranial focused ultrasound for neuromodulation in humans.

Low intensity transcranial focused ultrasound (LIFU) is a promising method of non-invasive neuromodulation that uses mechanical energy to affect neuronal excitability. LIFU confers 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. Here, we provide an evaluation of the safety of LIFU for human neuromodulation through participant report and neurological assessment with a comparison of symptomology to other forms of non-invasive brain stimulation. Participants (N = 120) that were enrolled in one of seven human ultrasound neuromodulation studies in one laboratory 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 LIFU research (Isppa 11.56-17.12 W/cm2) and the perceived relation of symptoms to LIFU. A total of 64/120 participant (53%) responded to follow-up requests to complete the Participant Report of Symptoms questionnaire. 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 LIFU 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. The profile and incidence of symptoms looks to be similar to other forms of non-invasive brain stimulation.

In vitro and in vivo characterization of a cranial window prosthesis for diagnostic and therapeutic cerebral ultrasound.

OBJECTIVE: The authors evaluated the acoustic properties of an implantable, biocompatible, polyolefin-based cranial prosthesis as a medium to transmit ultrasound energy into the intracranial space with minimal distortion for imaging and therapeutic purposes. METHODS: The authors performed in vitro and in vivo studies of ultrasound transmission through a cranial prosthesis. In the in vitro phase, they analyzed the transmission of ultrasound energy through the prosthesis in a water tank using various transducers with resonance frequencies corresponding to those of devices used for neurosurgical imaging and therapeutic purposes. Four distinct, single-element, focused transducers were tested at fundamental frequencies of 500 kHz, 1 MHz, 2.5 MHz, and 5 MHz. In addition, the authors tested ultrasound transmission through the prosthesis using a linear diagnostic probe (center frequency 5.3 MHz) with a calibrated needle hydrophone in free water. Each transducer was assessed across a range of input voltages that encompassed their full minimum to maximum range without waveform distortion. They also tested the effect of the prosthesis on beam pressure and geometry. In the in vivo phase, the authors performed ultrasound imaging through the prosthesis implanted in a swine model. RESULTS: Acoustic power attenuation through the prosthesis was considerably lower than that reported to occur through the native cranial bone. Increasing the frequency of the transducer augmented the degree of acoustic power loss. The degradation/distortion of the ultrasound beams passing through the prosthesis was minimal in all 3 spatial planes (XY, XZ, and YZ) that were examined. The images acquired in vivo demonstrated no spatial distortion from the prosthesis, with spatial relationships that were superimposable to those acquired through the dura. CONCLUSIONS: The results of the tests performed on the polyolefin-based cranial prosthesis indicated that this is a valid medium for delivering both focused and unfocused ultrasound and obtaining ultrasound images of the intracranial space. The prosthesis may serve for several diagnostic and therapeutic ultrasound-based applications, including bedside imaging of the brain and ultrasound-guided focused ultrasound cerebral procedures.

The relationship between frontal somatosensory-evoked potentials and motor planning.

Performance of efficient and precise movement requires the proper planning of motor parameters as well as the integration of sensory feedback. This study tests the hypothesis that the frontal components of the median nerve somatosensory-evoked potentials are differentially modulated, depending on (i) the stage of motor preparation and (ii) the moving limb. Participants were instructed to make intermittent voluntary contractions with either their right or left hands while receiving median nerve stimulation to the right wrist only. The results indicate that the frontal N30 demonstrated a significant increase in amplitude during the execution, but not the preparation, of a movement contralateral to median nerve stimulation. These data have implications for interhemispheric control of sensory information within the primary and premotor cortices.

Transcranial focused ultrasound neuromodulation of the human primary motor cortex.

Transcranial focused ultrasound is an emerging form of non-invasive neuromodulation that uses acoustic energy to affect neuronal excitability. The effect of ultrasound on human motor cortical excitability and behavior is currently unknown. We apply ultrasound to the primary motor cortex in humans using a novel simultaneous transcranial ultrasound and magnetic stimulation 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). 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). 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. Ultrasound also 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.