The anterior nuclei of the thalamus in addition to periaqueductal gray (PAG) and rostral ventromedial medulla (RVM) are integral regions of a supraspinal opioidergic structure that regulate pain perception. With the capability to influence deep neurological tissues, low intensity frequency ultrasound pulsation (LIFUP) can likely modulate this circuit and induce analgesia. LIFUP deep brain modulation is achieved by induction of focused mechanical waveforms that traverse the cranium and underlying brain tissue. The low frequency of the ultrasonic wave consequently alters neuronal transmission and causes action potential variations through mechanical means, rather than thermal.

The purpose of this study is to examine whether stimulation of the anterior nuclei of the thalamus via LIFUP induces analgesia. We hypothesize that suppression of the anterior nuclei of the thalamus will induce a temporary increase in pain tolerance. Moreover, the behavioral changes in pain will correlate with specific regional BOLD changes during pain.

LIFUP uses a single large concave, or multiple ultrasound transducers in a cap placed on the scalp to produce high frequency (100Hz) sonications for 30 seconds at a time for 10 trains of pulses. Unlike traditional diagnostic ultrasound, which constantly transmits ultrasound and 'listens' to the echo to form an image, LIFUP delivers the ultrasound in packets or pulses. For reasons that are not clear, pulsed ultrasound causes neurons to depolarize and fire. Bones typically block ultrasound waves. Cleverly, however, one can deliver the ultrasound from multiple sources and use the skull as a lens, to actually shape and focus the convergent beam deeper in the brain.

The clinical use of LIFUP thus uses MRI scans taken before stimulation to position and calculate how multiple ultrasonic pulsations will converge at a location in the brain (taking into account the bone dispersion of the beam from the skull). Since a small transducer like in diagnostic ultrasound cannot individually cause neuronal discharge, with LIFUP neuronal firing can be focused both deep (2-12cm under the cap; for comparison, traditional TMS can stimulate 1-3.4cm2 deep(9, 10)) and focally (as small as 0.5mm in diameter, and up to 1000mm; the facility of a standard, commercially-available 70mm figure-of-8 TMS coil is roughly 50mm2; (9, 10)). Interestingly, the pulse width of the carrying frequency of LIFUP (0.5ms) is strikingly similar to that used in all other pulsed neuromodulation therapies (DBS: 0.6ms, ECT: 0.5ms; TMS: 0.2ms; VNS: 0.5ms), suggesting that this timeframe is mechanistically meaningful. This is a good example of the common background science of brain stimulation that transcends the individual methods.

Researchers have examined the effects of LIFUP in preclinical and clinical settings, confirming its ability to safely stimulate neural tissue(11-14), proposing cellular mechanisms for its efficacy(13-19), and now using LIFUP in human patients(20). Monti et al. (2016) described a case study in which they used LIFUP to stimulate a comatose patient's thalamus.(20). Two pre-LIFUP assessments rated the patient as being in minimally conscious state (MCS). After sonication, the patient recovered motor and oromotor functions the next day, advancing to full language comprehension and communication by nodding and shaking his head. Five days post-LIFUP, the patient attempted to walk. While this study was neither blinded nor sham-controlled, the first application of therapeutic LIFUP in a human patient was encouraging and we expect more therapeutic applications of LIFUP and potential clinical trials in the future. If LIFUP continues to show clinical potential, it has the potential to supplant the role of DBS without the need for surgery. The key barrier to LIFUP replacing DBS for clinical applications is that by and large, DBS is used in a manner where the device is inserted and turned constantly on without attempting to fundamentally change circuit dynamics or behavior so that you could remove the device. Obviously, patients cannot permanently wear a LIFUP helmet. However, to the degree that we learn how to stimulate in ways that permanently change circuit behavior (LTD or LTP) without ablation, we may be able to substitute several sessions of LIFUP that can train and rewire the brain instead of permanently implanting hardware. LIFUP can certainly stimulate deep and focal and noninvasively and thus may be a key next step in the field of brain stimulation.

Information on the intervention to be studied. We will be using the Brainsonix Low intensity focused ultrasound pulsation device. (BX Pulsar 1001). Please see the manufacturers description (Technical Summary) along with appendixes about the actual safety of the device itself.

Inclusion Criteria:

• 18-45 years of age
• Healthy volunteer

Exclusion Criteria:

• seizure history (individual or family)
• history of depression
• hospitalizations or surgeries in the previous 6 months
• currently experiencing pain
• history of chronic pain
• metal implants or objects (e.g. pacemakers, metal plates, wires)
• pregnant
• alcohol dependence
• illicit drug use in the previous 6 months
• known allergy to capsaicin
• history of brain surgery or brain lesions
• history of loss of consciousness (greater than 15 min)
• on stimulants or medications that lower seizure threshold.

yes. After the initial data analysis is complete and the primary papers are submitted, we will release anonymized data to other credible researchers who ask.

1 year

LIFUP is a safe form of brain stimulation with no risk of adverse events when administered at this intensity