|University of Illinois at Urbana-Champaign | Department of Electrical and Computer Engineering | Department of Bioengineering
Department of Statistics | Coordinated Science Laboratory | Beckman Institute | Food Science and Human Nutrition | Division of Nutritional Sciences | College of Engineering
|Monday, May 20th, 2019|
Treating MS with Focused Ultrasound
Multiple sclerosis (MS) is a prevalent and debilitating neurological disease effecting as many as 500,000 adults in the United States and 2.5 million adults worldwide (Kobelt et al., 2006, Mayr et al., 2003). It is hypothesized that the characteristic inflammatory response of MS is due an autoimmune response involving lymphocytes attacking nerve fibers in the brain spinal cord, and optic nerve.
Recent studies have suggested that the cervical lymph nodes (located superficially in the neck) are involved in the entrance and exit of lymphocytes in the central nervous system (Louveau et al. 2015). In related studies, cervical lymphadenectomy was employed using the associated animal model experimental autoimmune encephalomyelitis (EAE). Following excision of the cervical lymph nodes, cerebral EAE lesions in rats were reduced by 40% relative to sham treated control animals (Phillips et al., 1997), while a reduction in EAE incidence and delay in relapse was observed in a related experiment in mice (van Zwam et al., 2009). However, such a procedure is particularly invasive and may be overly aggressive when translated to human patients. For this reason, minimally invasive, targeted therapy is desirable for the treatment of autoimmune diseases such as MS.
In a recent, proof-of concept, pilot study, our lab employed focused ultrasound (FUS) therapy as an alternative mechanism for attenuating cervical lymph node activity in rats with EAE. FUS (also known as high-intensity focused ultrasound or HIFU) is a form of medical therapy in which tissues are exposed to high intensity ultrasound fields in order to non-invasively induce treatment by localized heating or mechanical action.
In order to provide proof of concept evidence on the efficacy of FUS treatment of the cervical lymph nodes, a short pilot study was conducted on 13 dark agouti rats with EAE symptoms. Each rat was injected at the base of the tail with a 50/50 mixture (by-volume) of myelin oligodendrocyte glycoprotein (MOG, AnaSpec, Inc., Fremont, CA, USA) and complete Freund’s adjuvant (CFA, Sigma-Aldrich, St. Louis, MO) to induce symptoms of EAE. Clinical signs of disease progression were monitored daily starting at day 5 using a 5-point scale described in the table below.
EAE Score Clinical Symptoms 0 Healthy; No observable disease symptoms 1 Loss of tip-of-tail reflex, loss of tail tonus, and or unsteady gait 2 Partial paralysis of hind legs 3 Complete hind leg paralysis 4 Complete paralysis of the lower part of the body 5 Death due to EAE
First onset of symptoms typically occurred around 7-8 days post injection, and consequently FUS treatments were scheduled to occur on days 9 and 12. A 500 kHz, 1 inch diameter weakly focused (f/3) ultrasound transducer was suspended above in a water filled plastic bowl with a Saran-wrap covered cutout to act as an acoustic window. This experimental apparatus was lowered down onto the anesthetized rat’s neck (after shaving and chemically removing all hair in the treatment zone) and coupled with mineral oil to ensure efficient energy transfer. Two target locations on the left and right side of the rat’s neck were chosen as treatment sites. Individual treatments lasted for 20 minutes on each side, and acoustic settings were adjusted to keep the temperature between 37-44°C for each of the seven treated rats as monitored by a subcutaneous needle thermocouple. The remaining six rats were designated as shams and underwent every step of the procedure with the FUS system turned off. A diagram of the setup is shown below.
Illustration of rat exposure.
Following treatment, the rats continued to be monitored daily until euthanasia on day 21 post-injection or earlier if EAE symptoms significantly impacted the rat’s quality of life. At the conclusion of the study, the average EAE score of the treated rats dropped by almost a full point by day 16 as shown in the figure below. In contrast, remittance in the sham treated rats didn’t occur until day 19, and the effect was only marginal at best. Statistically significant (p=0.037) differences were observed in the peak remittance score (defined as max(EAE)-min(EAE after max)), which were 1.14 ± 0.48 and 0.33 ± 0.27 for the treated and sham treated rats respectively. These results suggest that the ultrasound treatment induced remission among those rats that received it, and could be a powerful future treatment alternative for MS patients in the years to come.
This work is supported by a grant from the NIH (NIH R21NS098174).
Average EAE Score for FUS-treated and Sham-treated rats .
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