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Pulsed TUS and Its Applications in Treatment of Focal Cerebral Ischemia and Depression

Saturday, February 24, 2018

8:30 PM-10:30 PM

BIOMED PhD Thesis Defense (DU-SJTU Dual PhD)

Pulsed Transcranial Ultrasound Stimulation and Its Applications in Treatment of Focal Cerebral Ischemia and Depression

Hangdao Li, Dual PhD Candidate, School of Biomedical Engineering, Science and Health Systems, Drexel University, and Shanghai Jiao Tong University (SJTU)

Peter A. Lewin, PhD, Richard B. Beard Distinguished University Professor, School of Biomedical Engineering, Science and Health Systems, Drexel University

Shanbao Tong, PhD, Professor, Shanghai Jiao Tong University (SJTU)

The aims of this thesis were to investigate the therapeutic effects of pulsed transcranial ultrasound stimulation (pTUS) on focal cerebral ischemia and depression, respectively, in rodent models. Neurological and psychiatric disorders, such as Parkinson's disease, epilepsy, Alzheimer's disease, stroke (vascular disorder that results in neurological defects), depression, and etc., present an increasing challenge and a substantial social and economic burden for an aging and stressed population. However, conventional treatments, especially pharmacologic interventions, have significant limitations, such as nonspecific effects, insufficient tailoring to the individual, adverse effects such as drowsiness, weight gain and nausea, or inadequate uptake into the brain due to the blood-brain-barrier (BBB). In contrast, neuromodulation techniques have gained more attention, which are able to enhance or inhibit the neural activities in specific cortex, such as motor, somatosensory or other areas related to cognition. Neuromodulation thus could potentially restore the disrupted neural network due to neurological disorders. Capitalizing on its noninvasiveness, high precision (in the scale of mm) and penetration depth (several centimeters), low-intensity (typically <1 W/cm2 spatial-peak-pulse-average intensity-ISPTA) low-frequency (typically <1MHz), pulsed transcranial ultrasound stimulation (pTUS) has been emerging as a promising therapeutic tool for neurological and psychiatric disorders. This thesis provided the first in-vivo demonstrations that pTUS might serve as neuroprotective preconditioning of ischemic brain injury and treatment of depression. Additionally, it also proposed a novel optical imaging-based technique to characterize the neuromodulatory effect of pTUS, which facilitates the parameter optimization of therapeutic pTUS in practice.

Both suppressive and excitatory pTUS are applied in this thesis. The corresponding pTUS parameters were: (a) suppressive pTUS (or pTUSS): ISPPA = 8W/cm2, frequency (f) = 0.5 MHz, pulse repetition frequency (PRF) = 100 Hz, and duty cycle (DC) =5%, and (b) excitatory pTUS (or pTUSE): ISPPA = 8W/cm2, f = 0.5MHz, PRF = 1.5 kHz, and DC = 60%, respectively. Before the therapeutic experiments, the neuromodulatory effects of both pTUSS and pTUSE were examined using laser speckle imaging(LSCI) and multispectral reflectance imaging (MSRI) in aspect of the neurovascular responses. Specifically, this thesis consists of:

(1) Study on the neurovascular response to pTUS. Compared with other methods, such as pTUS-triggered motor response and visual evoked potentials (VEP), optical imaging allows to measure the neurovascular change at high spatiotemporal resolution (in the scale of μm and ms), including cortical suppression without evoked output. LSCI and MSRI were used to monitor the primary somatosensory response (Chapter 2) to hind limb electrical stimulation before, immediately, and 1 h after 5-min application of pTUSS and pTUSE, respectively. Several indicators, including Response Index, Peak Response, Latency and Response Duration, were derived from optical images to characterize the neuromodulatory effects of pTUS on primary somatosensory cortex. Our results showed that pTUSS could suppress the primary somatosensory cortex across all rats whereas pTUSE only presented excitatory effects in 5 out of 11 rats. The neuromodulatory effects of pTUS were correlated with the baseline cortical excitability. The results showed that: (i) pTUSs could serve in investigating cognitive function by silencing the neurons in the target region; (ii) pTUSE exposure should be treated with caution due to individual differences in neuromodulatory effects, which were associated with the initial brain state of rats; and (iii) optical imaging was useful in evaluating the pTUS neuromodulatory effects.

(2) Neuroprotection of preconditioning pTUS. By applying suppressive pTUS, it was investigated whether the severity of stroke could be minimized or alleviated by prior exposure to ultrasound stimulation (Chapter 3). Preconditioning was supposed to increase the tolerance of brain to subsequent ischemic insult. It can potentially be used to prevent the perioperative stroke in patients undergoing cardiovascular surgeries with a series of complications. Considering the noninvasiveness and safety of ultrasound, pTUS may provide a novel preconditioning method. To test the effectiveness of preconditioning pTUS, rats were randomly assigned to control (n=12) and preconditioning pTUS (pTUS-PC) groups (n=14). The pTUS-PC animals received ultrasound stimulation before the induction of photothrombotic stroke, whereas control animals were handled identically except the ultrasound stimulation. The cerebral blood flow was monitored using LSCI in both groups during stroke induction, as well as 24 hours and 48 hours after stroke, respectively. Also, infarct volumes and edema were measured at 48 hours after euthanatizing the rats. Results showed that pTUS-PC rats had smaller ischemic volume during stroke induction, as well as 24 hours and 48 hours after the stroke than the controls. Moreover, the pTUS-PC group showed lower volume of brain edema than the control group.

(3) Antidepressant-like effect by pTUS. The potential antidepressant-like effects of pTUS were further investigated in a rat model of depression with excitatory pTUS. Stimulating the left prefrontal cortex (PFC) by TMS has been clinically used for depression treatment, it was thus hypothesize that pTUSE on PFC would act similarly with TMS and result in antidepressant-like effect. To test this hypothesis, pTUS was applied for 2 weeks daily to the left PFC of depressed rats induced by 48-hour restraint. The long-term (3 weeks) efficacy of the depression model as well as the antidepressant-like effects of pTUS were investigated with a group of behavioral tests. In addition, the hippocampal BDNF was measured by western blot to study the mechanisms underlying antidepressant-like effects of pTUS. The safety of long-term (2 weeks) pTUS was assessed by histologic analysis. Results showed that 48-hour-restraint stress could stably lead to at least 3-week reduction of exploratory behavior and protracted anhedonia, whereas pTUSE treatment could successfully reverse the depression-like phenotypes and promote the BDNF expression in the left hippocampus. In addition, H&E staining of brain tissues confirmed the safety of the long-term pTUS treatment.

In conclusion, the results in this work suggested that pTUS could serve as preconditioning of perioperative stroke and therapeutics for depression. Additionally, the results also demonstrated that optical neurovascular imaging could measure the neuromodulatory effect of pTUS. This study documented more evidence that pTUS is a promising tool for basic neuroscience and therapeutic applications.

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Ken Barbee

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Med-X Building, Room 218, Shanghai Jiao Tong University (SJTU), Shanghai, China


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