Transcranial focused ultrasound (tFUS) is a promising technique for non-invasive brain stimulation. By transmitting low-intensity ultrasound waves, tFUS can target deep brain regions with potentially greater precision than other forms of non-invasive brain stimulation.
As the brain is involved in pain processing and perception, researchers want to learn whether targeting specific brain structures with tFUS stimulation can potentially change how the brain processes pain.
In a preclinical study published in Blood, a collaborative research team designed a new multi-element ultrasound device to target specific brain regions in mice that process pain. The researchers used a genetically engineered mouse model of sickle-cell disease (SCD), a painful human condition characterized by sickle-cell shaped red blood cells. This condition leads to heightened sensitivity to different types of pain and was chosen to determine if this ultrasound approach could impact sensitivity to pain.
Treatment with the new device showed a significant decrease in pain hypersensitivity, particularly in response to heat-induced pain in the mouse model.
“We demonstrated that low-intensity tFUS stimulation altered pain behaviors in a mouse model, and that the effect was sustained and specific to the tFUS stimulation,” said Bin He, Ph.D., corresponding study author and Trustee Professor of Biomedical Engineering at Carnegie Mellon University.
New ultrasound technology and humanized mouse model
The researchers designed a new 128-element ultrasound device that can aim numerous sound waves simultaneously at small mouse brain targets. The number of elements increases the ultrasound focus and precision, making the new device more powerful than conventional ultrasound devices.
The researchers used their device to deliver tFUS in a mouse model of SCD, which expressed nearly 100% of human sickle hemoglobin. In addition to the SCD genetically engineered mice, control mice were genetically engineered with healthy human blood and assessed for their sensitivity to painful stimuli with behavioral measures.
The researchers conducted a series of controlled experiments in the mouse model to determine the impact of tFUS on specific brain circuits involved in pain processing. These brain circuits included the primary somatosensory cortex, a brain circuit that handles initial sensory input, and the thalamus and insula that lie deep within the brain. The thalamus processes pain signals from the spinal cord and brainstem, and the insula is involved in pain perception and modulation.
The specific brain structures were treated with tFUS sessions that lasted a total of 10 minutes, 20 minutes, and one hour.
Since mice can’t communicate pain verbally, the researchers used established behavioral responses to stimuli, including hind paw withdrawal time in response to extreme heat.
The researchers also examined whether gender affected how mice responded to treatment due to reports of higher pain intensity in female mice and female patients with SCD making finding a new pain treatment for females with SCD a priority, said He.
The researchers also used two treatment control groups—no treatment and treatment at a sham brain location──to rule out other factors that could affect treatment outcomes in specific brain locations.
Treatment outcomes
The results of a single 10-minute tFUS session applied to the brain’s primary somatosensory cortex showed a significant suppression of heat pain–related behaviors in SCD mice, regardless of gender. The suppression represented a significant change in the average hind paw withdrawal time for the SCD mice after tFUS treatment compared with their baseline withdrawal times and with both treatment control groups.
The researchers also investigated whether a single 20-minute tFUS session and multiple one-hour tFUS sessions would have a sustained effect on heat pain-related behaviors by targeting different brain circuits in male and female SCD mice.
They found that a single 20-minute treatment session in both male and female SCD mice was only effective in the insula, with a decreased heat pain sensitivity that lasted more than 30 minutes. They also discovered that the treatment effect on heat pain sensitivity was sustained for more than two hours with daily one-hour treatment sessions for 14 days when they targeted the insula or primary somatosensory cortex in only female SCD mice.
“These findings represent important evidence of the effectiveness of tFUS neuromodulation to reduce SCD pain hypersensitivity in mice,” said Moria Bittmann, Ph.D., a program director in the NIBIB Division of Discovery Science and Technology.
A study limitation was that pain-related behavioral measures were used in mice due to the inability to assess pain directly.
Looking ahead
While the study demonstrates the translational potential of this method for pain treatment, He said that further research needs to clarify the mechanisms behind the modulated pain-related behaviors in mice with SCD.
Further research could also investigate whether applying tFUS simultaneously to multiple pain processing brain circuits could generate greater inhibitory effects on pain-associated behaviors than targeting single brain circuits.
For more information on different types of ultrasound and how the technology works, visit the NIBIB science topic page on Ultrasound.
This study was supported in part by NIBIB grant U18EB029354 and is part of the NIH Helping to End Addiction Long-term (HEAL initiative). It was also supported by grants from NINDS (R01NS124564, RF1NS131069), NHLBI (R01HL147562, R01HL147562), and NCI (R01CA263806).
This science highlight describes a basic research finding. Basic research increases our understanding of human behavior and biology, which is foundational to advancing new and better ways to prevent, diagnose, and treat disease. Science is an unpredictable and incremental process—each research advance builds on past discoveries, often in unexpected ways. Most clinical advances would not be possible without the knowledge of fundamental basic research.
Study reference: MG Kim et al. Low-intensity transcranial focused ultrasound suppresses pain by modulating pain-processing brain circuits. Blood, 2024. https://doi.org/10.1182/blood.2023023718