1. Focused Ultrasound Neuromodulation in Humans
Alexander Korb PhD, John Stern MD, Mark Cohen PhD, Patricia Walshaw PhD, William Yong MD, Alexander Bystritsky MD, PhD
UCLA - Semel Institute for Neuroscience and Human Behavior
ABSTRACT
MATERIALS & METHODS
RESULTS
CONCLUSIONS
The hypothalamus and ventral striatum both play a role in diabetes and obesity, and modulating neural activity in these regions could have a therapeutic effect. However, current methods for neurmodulation do not allow for non-invasive, targeted stimulation of deep brain structures. By contrast, low-intensity focused ultrasound pulsations (LIFUP) does offer the possibility of non-invasive neuromodulation of deep brain structures. Therefore, a pilot study was conducted on the safety and feasibility of LIFUP in the human brain. For the purposes of safety the study only included participants (n=2) with temporal lobe epilepsy who were about to undergo surgical resection of the temporal lobe. To determine neuromodulatory effects, LIFUP was conducted simultaneously with fMRI. Neuropsychological measures and EEG, as well as histological analysis of resected tissue, were conducted to examine for potential safety risks of LIFUP. fMRI analysis revealed strong evidence of effective neuromodulation in one participant. Analysis of neuropsychological testing, EEG and histology did not reveal any evidence of adverse effects. LIFUP may provide a safe and effective means of modulating activity in deep brain structures, but further refinement of the method is needed.
Participants (n=2) were recruited from a pool of patients with temporal lobe epilepsy treated by the UCLA Seizure Disorder Center who had elected to undergo temporal lobe surgery.
The study used a custom transducer with a focal length of 61mm and center frequency of 650kHz (Blatek, Inc., State College, PA). In the week prior to the scheduled surgery, participants underwent simultaneous LIFUP and fMRI using various LIFUP pulsing paradigms to excite (PRF - 10Hz; PW – 50ms; Duration 1s) or suppress (PRF - 100Hz; PW – 0.5ms; Duration 30s) neural tissue. Activation scans lasted 4 minutes and consisted of 5 one-second sonications, each separated by 39s. Suppression scans lasted 7 minutes, and consisted of two thirty-second sonications separated by 2.5 minutes. Activation scans were conducted at 3 different intensities (250mW/cm2, 500mW/cm2 and 720mW/cm2), while only 1 suppression scan was conducted at the highest intensity.
fMRI data was processed with FSL version (Oxford Centre for Functional Magnetic Resonance Imaging of the Brain (FMRIB), Oxford University, U.K.), and standard pre-processing steps were applied (e.g. brain extraction, motion, spatial smoothing with a Gaussian kernel of FWHM 5 mm, high-pass filtering of 100s).
The brain response to LIFUP was modeled using the general linear model by performing a convolution of the timing of LIFUP sonication with the canonical hemodynamic response function. Cluster thresholding was used, with a voxel threshold of Z>1.9, a cluster significance of p<0.05.
To test the safety of LIFUP, participants also underwent pre- and post-EEG and neuropsychological testing. Post-surgery histological analysis was conducted on resected tissue. Epileptiform discharge frequency was calculated from the EEG.
Safety:
Histology of resected tissue did not reveal any tissue damage that could be readily ascribed to the focused ultrasound procedure. For example, the pathologist noted of participant 1, “There are focal microhemorrhages in brain parenchyma and subarachnoid space but these are commonly seen in epilepsy surgery specimens.” Neuropsychological testing did not show any large consistent differences between visit 1 and visit 2, although it was not possible to do statistical analysis on neuropsychological testing, due to small sample size and missing forms. No adverse events were reported. EEG did not reveal any evidence of increased seizures. Epileptiform discharge frequency could not be calculated for participant 1 due to artifact, and for participant 2 there was no change.
fMRI:
Activation scans did not show any evidence of significant increase in BOLD signal in either participant. Suppression scans showed a significant reduction (p<0.05) in the BOLD signal in one participant (Figure 2).
LIFUP did not cause any measureable tissue damage, nor result in any other unwanted effects in the two participants studied, and thus is likely safe for use in humans.
Significant neuromodulatory effects were seen in one participant. More testing is needed to determine the most effective parameters, including increasing intensity.
The evidence suggests that LIFUP may be capable of modulating deep brain structures in a safe and targeted manner, but further refinement of the technology is necessary.
Figure 1. Setup
A B C
REFERENCES
Fig. 1 The experimental setup is displayed with A) the LIFUP stimulation unit B) the transducer and holder and C) an MRI of a participant with attached transducer and holder.
Sani, S, et al. (2007). Deep brain stimulation for treatment of obesity in rats. J Neurosurg 107,
2. Mantione, M, et al. (2010). Smoking cessation and weight loss after chronic deep brain stimulation of the nucleus accumbens: therapeutic and research implications: case report. Neurosurgery 66, E218; discussion E218.
3. Whiting, DM, et al. (2013). Lateral hypothalamic area deep brain stimulation for refractory obesity: a pilot study with preliminary data on safety, body weight, and energy metabolism. J Neurosurg 119,
4. Min, BK, et al. (2011). Focused ultrasound-mediated suppression of chemically-induced acute epileptic EEG activity. BMC Neurosci 12, 23.
5. Yoo, SS, et al. (2011). Focused Ultrasound Modulates Region-specific Brain Activity. Neuroimage 56,
6. Lee, W, et al. (2015). Image-guided transcranial focused ultrasound stimulates human primary somatosensory cortex. Scientific reports 5, 8743.
7. Legon, W, et al. (2014). Transcranial focused ultrasound modulates the activity of primary somatosensory cortex in humans. Nature neuroscience 17,
BACKGROUND
As the hypothalamus is a target for insulin and plays a role, along with the ventral striatum, in appetite and satiety, modulating neural activity in these regions could have a therapeutic effect on diabetes and obesity. For example, Deep Brain Stimulation (DBS) of the lateral hypothalamus has been shown to cause weight loss in rats1. Limited results in humans also show the positive potential of neuromodulation2,3. Unfortunately, DBS requires invasive brain surgery, and current forms of non-invasive neuromodulation, such as TMS, cannot adequately target deep brain structures.
Low-intensity focused ultrasound pulsations (LIFUP) may provide a safe, non-invasive and targeted approach to neuromodulation of deep brain structures. The neuromodulatory effects of LIFUP have been safely demonstrated numerous times in multiple animal models4,5. While other studies have documented the neuromodulatory effects of LIFUP in humans, these studies have only targeted superficial cortices6,7.
The current study aimed to determine whether LIFUP could safely modulate activity in the human temporal lobe. To ensure safety, the participants recruited suffered from medically refractory temporal lobe epilepsy and were scheduled for temporal lobe resective surgery.
Figure 2. fMRI Results
z =
Transducer
ACKNOWLEDGMENTS
Thank-you to the Gerald J. and Dorothy R. Friedman NY Foundation for Medical Research for their generous support of this project.
Conflict of Interest Statement:
Dr. Bystritsky is the founder of Brainsonix Inc, and Dr. Korb is a consultant for Brainsonix and owns shares in the company.
Fig 2. Significant (p<0.05) reduction in BOLD signal in the temporal lobe of one participant.