Transcranial Ultrasound

Ultrasound consists of megahertz mechanical vibrations, and is widely used for medical imaging. As microtubules have megahertz vibrations, we have been studying ultrasound effects on the brain, delivered non-invasively from the scalp – ‘transcranial ultrasound’ (‘TUS’). We performed the first clinical trial of transcranial ultrasound (TUS) on mental states in human volunteers, finding that 15 seconds of sub-thermal 8 MHz ultrasound applied at the fronto-temporal scalp resulted in 40 minutes of mood improvement compared with placebo.

With the discovery of coherent megahertz vibrations in microtubules (2012, Anirban Bandyopadhyay group in Japan), Hameroff proposed that low intensity, non-invasive megahertz vibrations – ultrasound – to the brain could therapeutically stimulate microtubule resonance and polymerization, and improve mental and cognitive states. He and UA Anesthesiology colleagues performed and published the first clinical trial showing mood enhancement by non-invasive transcranial ultrasound (‘TUS’) in human volunteers in 2013 in Brain Stimulation. Now collaborating with Psychology professor John JB Allen, Jay Sanguinetti, and, in the College of Medicine, Bellal Joseph (Surgery), Rich Amini (Emergency Medicine), and Todd Vanderah (Pharmacology), and with funding from the Penrose Institute, the group is planning TUS clinical studies for Alzheimer’s.

Enhancing Mindfulness Training — SEMA Lab (CCS-UA)

The SEMA lab at the Center for Consciousness Studies focuses on accelerating mindfulness training with ultrasound (or other technologies). Dr. Jay Sanguinetti, Co-Director of SEMA Lab and Associate Director of the Center for Consciousness Studies, is a research assistant professor in the College of Social and Behavioral Sciences. Sanguinetti specializes in psychophysiological measures (EEG, fMRI, eye-tracking) of visual perception, emotion, and mindfulness meditation. His current research includes using noninvasive brain stimulation to enhance cognition and well-being. Sanguinetti co-launched the Sonication Enhanced Mindful Awareness (SEMA) lab to develop accelerated mindfulness protocols for therapeutic interventions to treat addiction, chronic pain, and depression. (semalab.arizona.edu)

At the SEMA Lab we seek to solve a common obstacle faced when applying mindfulness practice to clinical populations: mindfulness meditation is sometimes simply too difficult for those that could benefit the most from it. Mindfulness has been shown to improve outcomes for a whole host of disorders — chronic pain, depression, anxiety, eating disorders, addiction. Despite its effectiveness, compliance with mindfulness protocols in clinical populations tends to be low, perhaps due to the immense effort and time it takes to start seeing benefits of the practice.

How can we make mindfulness more rewarding? We’re using a new form of noninvasive brain stimulation called transcranial ultrasound (TUS). TUS uses low-intensity ultrasound to safely and reversibly modulate brain activity and is quickly gaining traction as a tool for neuroscience. When we ultrasound a part of the brain, we call that “sonicating” the brain. TUS can be focused, allowing us to sonicate relatively specific parts of the brain. We are aiming the ultrasound at a part of the brain that we think should help enhance the acquisition of meditation skills (like equanimity, concentration, and sensory clarity), and participants receive sonication while they meditate. We are not seeking to replace meditation — participants will still have to do the hard work — but we hope this paradigm will help them learn the techniques quicker and benefit from the practice sooner.

This research is in the early stages. So far, we have run encouraging pilot experiments, but we must do more to validate these results. In SEMA lab at the University of Arizona, we are currently launching several experiments to examine the efficacy and safety of sonication enhanced mindfulness, and will submit the results to peer-reviewed journals as the experiments are completed.

The science: TUS for mood, TBI and Alzheimer’s

Non-invasive brain stimulation techniques aimed at mental and neurological conditions include transcranial magnetic stimulation (TMS) for depression, and transcranial direct current (electrical) stimulation (tDCS), shown to improve memory. Transcranial ultrasound stimulation (TUS) has also shown promise.

Mood disorders, Alzheimer’s disease, traumatic brain injury (TBI) and post-traumatic stress disorders (PTSD) are enormous problems for those afflicted, their families, caregivers and society in general. Current treatments for these disorders are modestly effective at best, and new, more effective and inexpensive approaches are needed. A major hurdle in treatment is the lack of understanding in mainstream approaches as to how the brain works normally — how mood, cognition, memory and consciousness derive from synaptic computation among neurons. However, evidence now suggests mental states may depend, to some extent at least, on vibrations — e.g. sound wave solitons in neuronal membranes, and megahertz (‘MHz’) resonances in microtubule networks inside neurons. In TBI and Alzheimer’s disease, microtubules are disrupted and release ‘tau’, a microtubule-associated protein. Under normal circumstances, microtubules are directly responsible for neuronal and synaptic growth, repair and plasticity.

Ultrasound (US) consists of mechanical oscillations, e.g. in MHz. ‘Transcranial ultrasound’ (‘TUS’) passes low intensity, sub-thermal US through the skull into the brain, safely and painlessly. In clinical trials, TUS improves human mood and cognition, and in lab studies megahertz stimulation promotes microtubule assembly.

High intensity US can heat, cavitate and ablate kidney stones, brain tumors and other tissue. Mid-intensity US (‘diathermy’) causes mild heating, useful for musculoskeletal problems. Low intensity, ‘sub-thermal’ US (<720 mW/cm² by FDA guidelines) excites peripheral neurons and promotes their regeneration after injury. Applied at the scalp, low intensity TUS is FDA-approved for brain imaging, and is still used to image brains of newborn babies through boneless fontanelles, and can be focused anywhere in the adult brain. WJ Tyler and others first showed low intensity TUS caused behavioral and electrophysiological changes in animals, and more recently cognitive enhancement in humans.

In the first TUS study on human mental states, our group showed that 15 seconds of 8 MHz TUS to fronto-temporal cortex from the temporal scalp at 150 mW/cm² resulted in 40 minutes of improved mood compared to sham exposure. Further studies have shown optimal mood improvement with 2 MHz TUS for 30 seconds to the right fronto-temporal cortex. In some cases, vertex stimulation (targeting cingulate cortex) resulted in uncontrolled laughter, “out of body” experiences and feelings of being “more in the moment”. High frequency (gamma synchrony) EEG was increased near the TUS stimulation site.

Regarding cellular and molecular mechanisms, Tyler suggested TUS promotes vibrations in a mechanical continuum of extracellular, intra-membrane and intra-neuronal structures. Among these are microtubules, self-assembling polymers of tubulin, the brain’s most prevalent protein. TUS might act by tuning or enhancing endogenous microtubule megahertz resonances. Cellular damage in TBI is attributed to biochemical cascades, apoptosis, inflammation, free radicals, glutamate excitotoxicity, blood-brain barrier breakdown, axon shearing, and cytoskeletal disruption. Regardless, neuronal recovery and synaptic formation require microtubule-dependent extension of axonal and dendritic ‘neurites’. TUS may stimulate neuronal repair (e.g. for TBI) and memory turnover (PTSD), and warrants clinical trials for TBI, Alzheimer’s disease and PTSD.

First clinical trial

CCS pioneered brain ultrasound therapy. When Anirban Bandyopadhyay discovered megahertz and other frequencies in microtubules, Hameroff wondered whether ultrasound (megahertz mechanical vibrations) into the brain might be beneficial. It turned out to be safe and painless at reasonable exposure, and the group performed and published the first clinical trial of transcranial ultrasound (TUS) on chronic pain and mood (Hameroff et al, 2013). Hameroff later worked with Jay Sanguinetti and John Allen in psychology on TUS (Sanguinetti et al, 2020), and hopes to continue and expand clinical trials of TUS — e.g. for dementia, TBI, depression, anxiety, PTSD and addiction.

Microtubules within brain neurons are thought to resonate at megahertz frequencies, precisely where ultrasound acts. The aim is to enhance mood, and treat various neurological disorders, by stimulating brain microtubule dynamics through TUS. Two subsequent TUS studies done in collaboration with UA professor of psychology John Allen and post-doc Jay Sanguinetti have shown similar mood improvement from brief, sub-thermal TUS.

Peer-reviewed publications

• Sanguinetti JL, Hameroff S, Smith EE, Sato T, Daft CMW, Tyler WJ, Allen JJB. Transcranial Focused Ultrasound to the Right Prefrontal Cortex Improves Mood and Alters Functional Connectivity in Humans. Frontiers in Human Neuroscience, 2020 Feb 28. doi
• Hameroff S, Trakas M, Duffield C, Annabi E, Gerace MB, Boyle P, Lucas A, Amos Q, Buadu A, Badal JJ. Transcranial ultrasound (TUS) effects on mental states: a pilot study. Brain Stimul. 2013 May;6(3):409-15. PubMed
• Sanguinetti JL, Smith E, Allen JJB, Hameroff S. Human Brain Stimulation with Transcranial Ultrasound: Potential Applications for Mental Health. In Bioelectromagnetic and Subtle Energy Medicine, 2nd ed., CRC Press, 2014, pp. 355–360. Link
• Gibson BC, Sanguinetti JL, Badran BW, Yu AB, Klein EP, Abbott CC, Hansberger JT, Clark VP. Increased Excitability Induced in the Primary Motor Cortex by Transcranial Ultrasound Stimulation. Front. Neurol., 2018 Nov 28. Frontiers

Press & media

• Good Vibrations: Mediating Mood Through Brain Ultrasound. Science Daily, July 18, 2013. Link
• Hacking enlightenment: can ultrasound help you transcend reality? The Guardian, June 29, 2021 (feature on SEMA lab).