Transcranial focused ultrasound (tFUS) is an innovative non-invasive neuromodulation technique that uses low-intensity ultrasound waves to modulate brain activity. This method allows for precise targeting of specific brain regions, offering several advantages over traditional stimulation techniques including transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). Tina Chou, PhD and Darin Dougherty, MD and their colleagues in the Division of Neurotherapeutics at Mass General have been conducting pioneering research on the use of transcranial focused ultrasound (tFUS) for neuromodulation.
Overview of Transcranial Focused Ultrasound
With tFUS, it is currently theorized that focused ultrasound waves may modulate neuronal activity by creating mechanical pressure effects on neuronal membranes and ion channels. Depending on the parameters of the ultrasound applied, tFUS can either excite or inhibit neuronal activity. Compared to TMS and tDCS, tFUS provides greater spatial resolution and therefore can target brain structures with high precision, allowing for effective neuromodulation at a millimeter scale.
While other non-invasive neuromodulation techniques act on more superficial structures of the brain, tFUS can reach deeper brain areas without significant loss of intensity, making it suitable for targeting regions that are otherwise difficult to access.
Research indicates that tFUS is safe for use in humans, with studies showing no lasting neurological effects or tissue damage when appropriate parameters of use are applied. The technique’s non-invasive nature makes it an attractive option for both research and therapeutic purposes.
Research studies using tFUS have demonstrated its ability to alter neuronal activity in several brain regions, including the somatosensory cortex, visual cortex, and thalamus. In this setting tFUS has been used to better understand brain function and connectivity.
There is growing interest in how tFUS may be used for treating neuropsychiatric disorders. Potential applications include:
- Modulating mood and emotional regulation by targeting specific areas of the prefrontal cortex
- Improving cognitive functioning in neurodegenerative conditions, such as Alzheimer’s disease and Parkinson’s disease
- Reducing anxiety by targeting the amygdala
- Treating obsessive-compulsive disorder (OCD) by targeting the ventral capsule/ventral striatum (VC/VS) in comparison to the entorhinal cortex (ErC) as an active control region
Targeting Anxiety: Amygdala Modulation Study
Chou and colleagues conducted a study targeting the amygdala to explore the effects of tFUS on anxiety. In this investigation, 30 healthy participants were randomly assigned to receive either active or sham tFUS targeting the left amygdala. The results showed that individuals receiving active tFUS exhibited decreased activation of the amygdala during a fear-inducing task, as compared to those receiving sham stimulation. Additionally, active tFUS reduced activation in the hippocampus and dorsal anterior cingulate cortex, regions of the brain that are key players in the fear and anxiety circuits.
Clinically, decreased amygdala activation was correlated with reduced subjective anxiety. This finding was further supported by the observation that active tFUS altered resting-state functional connectivity between the amygdala and other brain regions involved in fear processing.
The current study demonstrates that tFUS can effectively modulate amygdala activity and connectivity associated with fear and anxiety, suggesting promising therapeutic potential for treating anxiety disorders.
Targeting OCD Symptoms: Ventral Capsule/Ventral Striatum (VC/VS) Stimulation Study
In another study, Chou and colleagues explored the effects of tFUS targeting theVentral Capsule/Ventral Striatum or VC/VS, a region implicated in obsessive-compulsive disorder (OCD). Previous studies from Dougherty and colleagues have demonstrated that deep brain stimulation (DBS) of the VC/VS is effective for treatment-resistant obsessive-compulsive disorder (OCD); however, DBS requires surgical implication of a stimulation device and thus is associated with neurosurgical risks.
This study examined the impact of different tFUS protocols targeting the VC/VS and the entorhinal cortex (ErC), in healthy individuals without OCD. The VC/VS is a critical component of the cortico-striatal-thalamo-cortical (CSTC) circuitry, which plays a significant role in regulating mood, cognition, and motor functions. This circuitry is often implicated in psychiatric conditions such as OCD, where abnormalities in CSTC connectivity are thought to contribute to OCD symptomatology.
The researchers investigated how varying tFUS parameters affected mood, energy, and brain activity during a reward task. They found that one of the VC/VS tFUS protocols was associated with increased putamen activation during the reward task, suggesting engagement of the CSTC circuitry. However, no significant effects on mood or energy were observed.
In contrast, a different tFUS protocol targeting the entorhinal cortex (ErC) was associated with decreased putamen activation and local perfusion changes, suggesting downstream effects on CSTC regions. The ErC, which is involved in memory and reward processing, is part of a broader network that shows altered structural connectivity with the VC/VS and prefrontal regions in patients with OCD. These findings imply that tFUS targeting of the ErC may indirectly influence CSTC circuitry, which could have implications for understanding and potentially modulating circuits relevant to OCD pathology.
Overall, this preliminary study provides valuable insights into the safety and potential efficacy of tFUS for modulating brain circuits implicated in OCD. Future research should focus on optimizing tFUS parameters and exploring additional target sites within the brain to enhance therapeutic outcomes and further understand its clinical potential.
Model-Based Navigation Advances tFUS Targeting
One of the major challenges in translating tFUS to humans has been the human skull itself. The skull’s thickness and density scatter and absorb ultrasound waves, reducing the acoustic dose reaching the brain and making precise targeting more difficult.
To address this problem, researchers at MGH have been developing a new tool: model-based navigation (MBN). This approach uses personalized, precomputed models of ultrasound wave propagation through each individual’s skull to improve targeting accuracy.
MBN starts with an MRI scan of an individual and, using advanced computational techniques, maps thousands of virtual ultrasound transducers. The resulting beam patterns are calculated in advance and embedded into a real-time neuronavigation system connected to an optical tracking camera. This setup allows clinicians to see a live display of the ultrasound beam (~10 Hz refresh rate) as they move the transducer across the scalp, enabling more precise delivery to deep brain targets.
Unlike previous optical tracking methods, MBN accounts for how each individual’s skull absorbs and scatters ultrasound energy. Thanks to high-speed simulation software, the precomputation process takes approximately 30 minutes per subject, which is fast enough to allow for imaging, modeling, and tFUS delivery within a single study session.
Preliminary studies suggest that MBN can significantly improve targeting accuracy and increase the acoustic dose delivered to deep brain structures compared to traditional line-of-sight targeting methods, while also reducing variability in dose deposition between subjects. By improving both precision and consistency, MBN represents an important step toward making tFUS a more reliable tool for clinical neuromodulation research and ultimately treatment.
Transcranial focused ultrasound (tFUS) represents a promising frontier in non-invasive neuromodulation, offering new possibilities for treating complex neuropsychiatric disorders. Researchers like Tina Chou, PhD, Darin Dougherty, MD, and their colleagues in the Division of Neurotherapeutics at Mass General are at the forefront of this innovation, combining sophisticated brain targeting strategies like model-based navigation to enhance precision and therapeutic impact. As tFUS technology continues to evolve, it holds the potential to transform how clinicians approach an array of neuropsychiatric disorders, ultimately paving the way for safer, more effective, and highly personalized brain therapies.
Read More
Chou T, Kochanowski BJ, Hayden A, Borron BM, Barbeiro MC, Xu J, Kim JW, Zhang X, Bouchard RR, Phan KL, Goodman WK, Dougherty DD. A Low-Intensity Transcranial Focused Ultrasound Parameter Exploration Study of the Ventral Capsule/Ventral Striatum. Neuromodulation. 2025 Jan; 28(1):146-154.
Chou T, Deckersbach T, Guerin B, Sretavan Wong K, Borron BM, Kanabar A, Hayden AN, Long MP, Daneshzand M, Pace-Schott EF, Dougherty DD. Transcranial focused ultrasound of the amygdala modulates fear network activation and connectivity. Brain Stimul. 2024 Mar-Apr;17(2):312-320.
Daneshzand M, Guerin B, Kotlarz P, Chou T, Dougherty DD, Edlow BL, Nummenmaa A. Model-based navigation of transcranial focused ultrasound neuromodulation in humans: Application to targeting the amygdala and thalamus. Brain Stimul. 2024 Jul-Aug;17(4):958-969.
Tina Chou, PhD is the former Director of Research of the Division of Neurotherapeutics at Massachusetts General Hospital and an Assistant Professor of Psychology at Harvard Medical School. Her research involves utilizing clinical neuroimaging methods to develop novel brain stimulation-based interventions and optimize treatments for mood and anxiety disorders. She is also a psychologist with a PhD in clinical psychology from Harvard University who specializes in mood and anxiety disorders.
Darin Dougherty, MD is the Director of the Division of Neurotherapeutics in the Department of Psychiatry and is an Associate Professor of Psychiatry at Harvard Medical School. His research focuses on neurotherapeutic interventions for severe, treatment-resistant psychiatric illnesses, particularly for PTSD, eating disorders, major depressive disorder and obsessive compulsive disorder. His studies span both mechanistic studies, clinical trials, and device-based interventions employing a variety of techniques, including neuroimaging and electrophysiology. We also provide clinical services and surgical treatments for psychiatric illness.
