Focused Ultrasound Amygdala Neuromodulation

Affective disorders broadly defined, including the diagnoses of major depression, bipolar disorder, anxiety disorders, and posttraumatic stress disorder, constitute a large portion of the mental health diagnoses worldwide and pose an enormous public health problem. All of these diagnoses are characterized by a common disturbance in affect and emotion, primarily exaggerated and prolonged states of negative affect (e.g., sadness, fear, anxiety, and anger) triggered by reactivity to emotionally provocative stimuli (e.g., a stressful life situation, perceived threat in the environment, etc.). Apropos, all of these diagnoses are similarly characterized by a shared emotion-processing hyperactivity in a subcortical limbic brain structure underlying the detection of salient environmental stimuli-the amygdala. This shared amygdala hyper-reactivity in affective disorders is thought to underlie a common exaggerated emotional reactivity phenotype, consistent with recent conceptualizations of mental illness as reflecting extremes of functioning on trans-diagnostic dimensions of normal bio-behavioral brain processes, i.e. the Research Domain Criteria, which identify the amygdala as a key mediator of all subdomains of negative valence brain systems. Thus, the amygdala remains one of the most promising affective disorder neuromodulatory therapeutic targets.

Although effective psychotherapeutic and pharmacological interventions have been developed for the treatment of affective disorders, a substantial number of individuals fail to respond to such first-line interventions. This inadequacy has led to the development of neuromodulatory therapies for affective disorders, including transcranial electrical (TES)and transcranial magnetic stimulation (TMS), which are believed to exert indirect therapeutic effects on subcortical limbic and ventral prefrontal brain structures via cortical pathways accessible to non-invasive modulation. However, TES/TMS stimulation is critically limited by the fact that focal depth can only reach several centimeters past the skull, thereby limiting the focus of neuromodulation to superficial cortical regions. The investigators propose the inability to directly and non-invasively focally modulate the amygdala, a key locus of affective disorder pathophysiology, is a critical barrier to maximizing the efficacy of neuromodulatory interventions in humans.

Recent advances in brain modulation have identified transcranial low intensity focused ultrasound pulsation (LIFUP) as a novel methodology for reversibly augmenting brain function. LIFUP involves the administration of high frequency sound waves into the brain via a series of transducers placed against the side of the head. This procedure is safe and non-invasive and demonstrates great potential for development as a future neuromodulatory intervention. Importantly, ultrasound has been demonstrated in both animals and humans to have the capability for reversibly up or down-modulating brain function on time scales of seconds to hours.

Crucially, LIFUP has several key advantages over existing non-invasive neuromodulatory interventions. First, it is both focal and depth-compatible, which allows deep subcortical brain structures, e.g., the amygdala, to be directly stimulated non-invasively. Second, it is inherently compatible with functional magnetic resonance imaging (fMRI), the gold-standard methodology for non-invasive brain mapping in humans, which is in contrast to TES/TMS interventions that pose serious risks for deployment in an MR-environment. This allows the modulatory effect of LIFUP to be tracked and quantified in real-time, thereby affording a substantial advancement in stimulation targeting and assessment of target engagement. However, as this technology is very new, there is currently little known regarding its utility as an intervention tool. The investigators will utilize a novel LIFUP device that is capable of directly and non-invasively modulating function of deep subcortical structures such as the amygdala.

In this study, the investigators will test how LIFUP amygdala neuromodulation impacts the function of the amygdala, how this differs in individuals with an affective disorder, and whether repetitive LIFUP targeted to the amygdala (5 days a week for 3 weeks, 15 sessions total) demonstrates any therapeutic benefit on affective disorder symptoms and how such therapeutic benefits might relate to changes observed in brain function.

Inclusion criteria

• Adults ages 18-65
• Willing and able to undergo the MRI and LIFUP procedures and repeated LIFUP for up to 15 sessions
• English language proficiency sufficient to speak to investigators and understand investigator instruction
• Can visit the laboratory several times over the course of 2 to 6 weeks
• Individuals with a primary affective disorder diagnosis (major depression, bipolar disorder, an anxiety disorder, or posttraumatic stress disorder on the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders Diagnosis 5th Edition
• Score of 19 or greater on the general distress subscale of the 30-item Mood and Anxiety Symptom Questionnaire
• Psychiatric medication(s) on a stable dosage and regimen for the past 3 months (including antidepressants, mood stabilizers, atypical antipsychotics, and sedatives/hypnotics)

Exclusion criteria

• Contraindications to LIFUP or MRI including, but not limited to, history of stroke, brain tumors, brain hemorrhages, internal wires, electrodes, pacemakers, implants, irremovable ferromagnetic objects in head that are unsafe for MRI and/or cause large distortions in imaging data, history of seizures (except febrile seizures in childhood), brain surgery, moderate-to-severe head injury or any penetrating head injury, and uncontrolled thyroid disorder.
• Pregnant women or people trying to become pregnant will also be excluded due to the unknown effects of MRI on developing fetuses
• Individuals with serious medical illnesses that are likely to interfere with study: cancer, autism, narcolepsy etc.
• Current active suicidal/homicidal ideation (or suicide attempt in the past 3 months)
• Current substance-use disorder
• Current or recent (within 3 months) psychotic symptoms, or currently meeting diagnostic criteria for a manic episode
• Individuals currently actively engaged in evidence-based or experimental treatments (e.g., weekly cognitive behavioral psychotherapies, transcranial magnetic stimulation, ketamine/esketamine treatment) other than psychiatric medication(s)