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Principal Investigator: Noah Stephen Philip
Organization: OCEAN STATE RESEARCH INSTITUTE, INC.
Fiscal Year: 2024
Award: $585,279
Funding agency: National Institute of Mental Health
PROJECT SUMMARY/ABSTRACT
Current treatments for depression and anxiety are often limited by partial efficacy and significant side effects.
These disorders constitute serious public health challenges due to significant burden of illness, and the lack of
more effective treatments contributes to substantial suicide risks. To address these unmet needs, non-invasive
brain stimulation is a circuit-based treatment with minimal side effects; it is clinically available for major
depression and obsessive-compulsive disorder, with evidence for efficacy in anxiety and posttraumatic stress
disorder. One of the core brain regions involved in these disorders, among others, is the amygdala, with its
critical role in salience detection and emotion processing. This region demonstrates pathological activation in
nearly all depressive and anxiety disorders, and pathological activity changes with successful treatment. Yet,
because the amygdala is distal to the cortical surface it is not directly accessible with current technologies. Our
challenge is to find a way to focally and non-invasively modulate the amygdala, with the broader hypothesis
that direct engagement will yield treatments with superior clinical outcomes.
Low intensity pulsed focused ultrasound (LIFU) applies non-invasive acoustic energy to safely
modulate neural activity in translational models and non-human primates. Unlike transcranial magnetic or
electrical stimulation and related technologies, LIFU is able to directly and focally modulate activity within deep
brain structures. LIFU can safely modulate human somatosensory and motor cortex and safely suppress
thalamic activity; recent data indicates it can suppress amygdala activity. Furthermore, an MRI-compatible
LIFU system is now available (Brainsonix, Inc. LA, USA), thus permitting simultaneous fMRI-LIFU experiments.
These factors create a compelling argument to develop LIFU as a treatment for depression and anxiety by
testing whether it can safely modulate the amygdala.
To set the stage for future clinical trials, we must first test how LIFU engages the amygdala in patients
with depression and anxiety. In accordance with the U01 RFA, we propose several pilot experiments. We will
systematically assess safety (Aim 1) as we evaluate spatial specificity of target engagement, using online and
offline approaches (Aims 2-3) using a randomized, anatomically controlled, experimental design, and explore
the impact of LIFU on clinical symptoms. We obtained an Investigational Device Exemption (IDE) from the FDA
for this proposal as it is written.
If successful, this first-in-human proposal will provide the necessary data to support a broad and
programmatic research focus on clinically applied LIFU for depression and anxiety. Resulting data will inform
future studies, including improvement of individual-level modeling for LIFU, informing optimal targets to
engage, refinement of LIFU shams, and evaluating effects of varied LIFU parameters or multiple sessions.
Terms: <Acoustics><Active Follow-up><Acute><Address><Amygdala><Amygdaloid Body><Amygdaloid Nucleus><Amygdaloid structure><Anatomic Sites><Anatomic structures><Anatomy><Anxiety><Anxiety Disorders><Brain><Brain Nervous System><Brain region><Cephalic><Clinical><Clinical Trials><Clinical Trials Design><Contralateral><Controlled Study><Cranial><Cross-Over Designs><Crossover Design><Data><Depressive Syndromes><Depressive disorder><Detection><Devices><Diagnostic><Disease><Disorder><Distal><Domestic Rabbit><E-stim><Electric Stimulation><Electromagnetics><Emotional><Emotions><Encephalon><Evaluation><Experimental Designs><Face><Family suidae><Focused Ultrasound><Functional MRI><Functional Magnetic Resonance Imaging><Future><Grant><Human><Individual><Intervention><Intervention Strategies><Left><MR Imaging><MR Tomography><MRI><MRIs><Magnetic Resonance Imaging><Magnetism><Major Depressive Disorder><Measures><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Mental Depression><Mice><Mice Mammals><Modeling><Modern Man><Motor Cortex><Murine><Mus><NMR Imaging><NMR Tomography><Neurologic><Neurological><Nuclear Magnetic Resonance Imaging><Obsessive-Compulsive Disorder><Obsessive-Compulsive Neurosis><Oryctolagus cuniculus><Outcome><PTSD><Participant><Pathologic><Patients><Persons><Physiologic pulse><Pigs><Post-Traumatic Neuroses><Post-Traumatic Stress Disorders><Posttraumatic Neuroses><Public Health><Pulsar><Pulse><Rabbits><Rabbits Mammals><Randomized><Research><Research Design><Risk><Role><Safety><Somatosensory Cortex><Sonication><Specificity><Structure><Study Type><Suidae><Surface><Swine><Symptoms><System><Technology><Testing><Thalamic structure><Thalamus><Writing><Zeugmatography><active followup><amygdaloid nuclear complex><burden of disease><burden of illness><clinical depression><depression><design><designing><disease burden><effective therapy><effective treatment><electrostimulation><experience><experiment><experimental research><experimental study><experiments><fMRI><faces><facial><first in man><first-in-human><follow up><follow-up><followed up><followup><improve symptom><improved><insight><interest><interventional strategy><magnetic><major depression><major depression disorder><neural><non-human primate><non-invasive brain stimulation><nonhuman primate><noninvasive brain stimulation><porcine><post-trauma stress disorder><posttrauma stress disorder><randomisation><randomization><randomly assigned><rational design><recruit><safety assessment><safety testing><side effect><social role><somesthetic sensory cortex><study design><suicidal risk><suicide rate><suicide risk><suid><symptom improvement><symptomatic improvement><thalamic><translational model><traumatic neurosis><ultrasound>