Low Intensity Focused Ultrasound Pulses (LIFUP) to Modulate Pain
Condition: Healthy Adults
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): LIFUP; Sham LIFUP
Intervention type(s): Device; Device
Intervention description(s): Low Intensity Focused Ultrasound Pulsation (LIFUP) is an interesting new form of brain stimulation that may be possible to stimulate non-invasively, safely, deep in the brain with focal precision.; The same as LIFUP but the device is not turned on and the subject does not receive any ultrasound.
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Basic Science