Tuning the Brain-TUS
TUS - 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 on 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.
Transcranial ultrasound (TUS) effects on mental states: A pilot study, Brain Stimulation Hameroff S, Trakas M, Duffield C, Annabi E, Gerace MB, Boyle P, Lucas A, Amos Q, Buadu A, Badal JJ Received 21 November 2011; received in revised form 19 February 2012; accepted 6 May 2012. published online 30 May 2012. Brain Stimulation 6: 409-415 Abstract
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. These studies are currently being written up for publication.
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’, 106 to 107 Hz) 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. We propose to determine safety and efficacy of inexpensive and potentially portable TUS technology for improving recovery from TBI, Alzheimer’s disease.
Hypothesis or Objective: 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,4 and promotes their regeneration after injury. Applied at the scalp, low intensity TUS is FDA-approved for brain imaging, though supplanted by CT, MRI etc. TUS 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,11 our group showed that 15 seconds of 8 MHz TUS to fronto-temporal cortex from temporal scalp at 150 mW/cm2 resulted in 40 minutes of improved mood compared to sham exposure. Further studies12 have shown optimal mood improvement with 2 MHz TUS for 30 seconds to 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 level 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). TUS warrants clinical trials for TBI, Alzheimer’s disease and PTSD.
Our previous TUS studies have used a clinical GE Logiq US imaging device, and the U+ single transducer TUS headset from Thync, Tyler’s company (formerly NeuroTrek). Both devices are limited in range of MHz frequencies for testing. We are collaborating with Sterling Cooley (Berkeley Ultrasound, Berkeley, California) who has developed a TUS device called the NeuroResonator 1 (NR1) which we tested and calibrated in October, 2014. Proposed modifications will upgrade to the battery-powered NeuroResonator 2 (‘NR2’) with multiple US piezo transducer/emitters with various lead placements, each emitter controlled individually, able to be aimed at particular brain areas, driven synchronously, sequentially, in any combination and/or pulse modulated, e.g. by music. The NR2 will be calibrated, tested, and reviewed and approved by our Bioengineering and Institutional Review Board. Stimulation sites will be selected based on injured brain area, right fronto-temporal and other areas. We plan pilot studies commencing early spring 2015 and will search for optimal techniques. With the NR2 fitting in an EEG cap, we will also study TUS effects on simultaneous EEG.
- Heimburg T, Jackson AD. On soliton propagation in biomembranes and nerves Proc. Natl. Acad. Sci. U.S.A. 2005, 102 (2): 9790
- Sahu S, Ghosh S, Ghosh B, Aswani K, Hirata K, Fujita D, Bandyopadhyay A. Atomic water channel controlling remarkable properties of a single brain microtubule: correlating single protein to its supramolecular assembly. Biosens Bioelectron. 2013 Sep 15;47:141-8. doi: 10.1016/j.bios.2013.02.050. Epub 2013 Mar 15.
- Sahu S, Ghosh S, Hirata K, Fujita D, Bandyopahyay A. Multi-level memory-switching properties of a single brain microtubule, Applied Physics Letters (Impact Factor: 3.79). 03/2013; 102(12). DOI: 10.1063/1.4793995
- Harvey EN, The effect of high frequency sound waves on heart muscle and other irritable tissues. American Journal of Physiology, 91. 1929 December 1, pp. 284–290
- Raso, VVM, Barbieri CH, Mazzer N, Fazan VPS. Can therapeutic ultrasound influence the regener ation of peripheral nerves? Journal of Neuroscience Methods, v. 142, n.1, p. 185-192, 2005. DOI: 10.1016/j.jneumeth.2004.08.016
- Park SC, Oh SH, Seo TB, Namgung U, Kim JM, Lee JH. Ultrasound-stimulated peripheral nerve regeneration within asymmetrically porous PLGA/Pluronic F127 nerve guide conduit. J Biomed Mater Res B Appl Biomater. 2010 Aug;94(2):359-66. doi: 10.1002/jbm.b.31659.
- Tyler WJ, Tufail Y, Finsterwald M, Tauchmann ML, Olson EJ, et al. (2008) Remote Excitation of Neuronal Circuits Using Low-Intensity, Low-Frequency Ultrasound. PLoS ONE 3(10): e3511. doi:10.1371/journal.pone.0003511
- Pearse A. Keane, Adnan Tufail, Praveen J. Patel. Management of Neovascular Age-Related Macular Degeneration in Clinical Practice: Initiation, Maintenance, and Discontinuation of Therapy, J Ophthalmol. 2011; 2011: 752543. Published online 2011 November 22. doi: 10.1155/2011/752543 PMCID: PMC3228281
- Yoo SS, Bystritsky A, Lee JH, Zhang Y, Fischer K, Min BK, McDannold NJ, Pascual-Leone A, Jolesz FA. Focused ultrasound modulates region-specific brain activity. Neuroimage. 2011 Jun 1; 56(3):1267-75. Doi: 10.1016/j.neuroimage.2011.02.058. Epub2011 Feb 24.
- Legon W, Sato TF, Opitz A, Mueller J, Barbour A, Williams A, Tyler WJ. Transcranial focused ultrasound modulates the activity of primary somatosensory cortex in humans, Nature Neuroscience 17, 322-329 doi:10.1038/nn.3620
- 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. doi: 10.1016/j.brs.2012.05.002. Epub 2012 May 29.
- Tyler WJ, Ultrasound for Neuromodulation? A Continuum Mechanics Hypothesis. The Neuroscientist 17(1), 2011, 25-36.
- Sanguinetti, JL, Smith E, Allen JJB, Hameroff, S (2014). Transcranial Ultrasound (TUS) Affects Mood in Healthy Human Volunteers. Brain Stimulation. [in preparation]
- Raman, U, Gupta S, Parker S , Gupta N, Gupta AK, Duffield C, Ghosh S, Hameroff S. Low-intensity ultrasound (US) stabilizes microtubules and promotes neurite outgrowth. 2014. [in preparation]
Stuart Hameroff administers TUS to a volunteer
Jay Sanguinetti administers brain ultrasound during a clinical trial.