Ultrasound Treatment for Tremors and Parkinsons Disease - Research Paper Example

your the 20 March Ultrasound Treatment for Tremors and Parkinson’s Disease Outline Background of Parkinson’sDisease Therapeutic Ultrasound for Tremors and Parkinson’s Disease History of Therapeutic Ultrasound Ultrasound Techniques and Applications for Parkinson’s Disease and Tremors Limitations of Therapeutic Ultrasound Background of Parkinson’s Disease Parkinson’s disease (PD) is a degenerative disorder of the brain that clinically manifests as a movement disorder. Its prevalence increases with age, and is highest,at around 4%, in individuals above 85 years of age (10). Its pathophysiology involves degeneration of the dopamine-secreting neurons of the substantia nigra, a nucleus in the midbrain. These neurons are normally responsible for an inhibitory and/or excitatory effect on the basal ganglia neurons that control movement; the loss of dopaminergic neurons leads to instability of movement. The resulting classic clinical features in PD include a resting tremor, poverty of facial expressions, difficulty initiating and stopping movements (bradykinesia), muscle rigidity, asymmetric onset, and impairment of postural reflexes. The first complaint may be a difficulty with fine tasks, such as writing and buttoning a shirt (10). Considering the debilitating nature of the disease, many preventive and curative approaches have been used for its treatment. These include medications, botulinum toxin injections, and neurosurgical approaches. Drugs commonly used include those with dopamine agonist activity, such as levodopa and clozapine. Anticholergics are also used, and other second-line drugs include propranolol, amantadine and clonazepam. Although these medications are generally effective, some PD patients’ tremor does not respond to first-line or second-line medications, and surgery- or, in other words, invasive ‘neuromodulation’ - is attempted. Approaches with acceptable success rates include ‘thermocoagulation’ and ‘deep brain stimulation’ at various brain sites, including the thalamus, globus pallidus, and subthalamic nucleus. Other neuromodulation techniques include vagus nerve stimulation, epidural cortical stimulation, repetitive transcranial magnetic stimulation, and many others. Some are invasive, while others are non-invasive procedures. These neuromodulation techniques are reported to achieve good to excellent tremor control while posing minimal risks to the patient (6). However, there are many important limitations with these techniques. For instance, deep brain stimulation involves complex neurosurgery and neurostimulators that require periodic battery replacements. Vagus nerve stimulation and other techniques that are non-invasive have poor spatial resolution. The use of functional MRI has improved the safety and usability of these techniques, however, it is a cumbersome, expensive addition to the procedure. There would be, therefore, many potential benefits of using a non-invasive procedure that did not entail these limitations (1). Therapeutic Ultrasound for Tremors and Parkinson’s Disease Ultrasound technology is widely used in diagnostic imaging. It involves mechanical vibrations above the threshold of human hearing of 16 kHz. Ultrasound can be emitted from a transducer to penetrate tissue and reflect off it, allowing capture of reflected waves and formation of an image. Ultrasound beams can also be focused by transducers to a width of only a few millimeters, and targeted on specific tissue. The following figure demonstrates how a high intensity focused ultrasound (HIFU) transducer is used to target ultrasound onto a selected lesion site (3), (9). History of Therapeutic Ultrasound Therapeutic ultrasound in neurosciences for the treatment of chronic and severe neurologic disorders has been under experiment for decades. One of the earliest reports of ultrasound treatment came in 1948, where Denier treated 3 neurological disease patients, including one with Parkinson’s disease, by focused ultrasound to the diencephalons. The patients subsequently showed clinical improvement (4). Among the most prominent early scientists to work with ultrasound were William and Francis Fry, who initially experimented on animals in the 1950’s, but subsequently succeeded in treating patients with PD and other neurological conditions using high intensity focused ultrasound (Kennedy, Ter Haar and Cranston). During the earliest periods of clinical research into ultrasound, about 200 PD patients were treated. A major limitation of these procedures was the necessity of a craniotomy to provide an acoustic window into the skull, as the cranium did not permit visualization of the brain by ultrasound, the bone also distorted the focused beam and disrupted the transmission of energy. The inability to guide and monitor HIFU at that time made the procedure unacceptable for widespread clinical use. Improvements in visualization techniques, by fMRI and CT have permitted renewed interest in therapeutic ultrasound. Improved techniques and machines – including high-power phased ultrasound arrays and a hemispherical transducer design - overcame the issue of beam distortion and energy absorption by the cranium, making HIFU a non-invasive procedure (3). Ultrasound treatment has also been used for intracranial tumor ablation. The attraction of ultrasound treatment lay in its being a direct and unequivocal treatment approach that directly targets specific diseased neurons. In contrast, pharmacologic therapy can be unpredictable, have only subtle effects, and also causes many undesirable adverse effects. Ultrasound can be low frequency or high frequency. Ultrasound Techniques and Applications for Parkinson’s Disease and Tremors In one of the earliest experiments on the utility of ultrasound in treating movement disorders, ‘ultrasonic irradiation’ of the basal ganglia and related structures was done on patients with intractable Parkinsonian symptoms of chorea, athetosis, and dystonia. Specific structures that were targeted included the head of the caudate nucleus, lentiform nucleus, anterior limb of the internal capsule, oral third of the globus pallidus, and oral third of the putamen (7). They reported encouraging clinical results for nearly all of the patients, with several patients reporting complete relief of the tremor and a marked reduction in rigidity. Importantly, they also established that pallidofugal section and section of the anterior limb of the internal capsule alleviated tremors without causing paresis (limb weakness) or any other movement abnormalities such as dyspraxia or spasticity. These initial treatments were experimental, and reported a trial-and-error approach to determining the frequency and intensity of ultrasound that was most likely to achieve long-term symptom control. A plethora of research has since allowed the development of improvements in imaging and the accuracy and quality of tranducer devices. This has made therapeutic ultrasound a safer and more precise procedure today. A technique that has been developed and widely used is the high intensity focused ultrasound (HIFU), also known as pyrotherapy, which has thermal effect on targeted tissue. It can penetrate the skull and focus on abnormal brain tissue, onto a region as small as approximately 1 mm - 10 mm ellipsoid, without damaging the intervening tissue. It delivers energy that is 4 to 5 orders of magnitude higher than that used in diagnostic ultrasound (2). At the target site, the high intensity acoustic energy is absorbed and converted to heat. The temperature of the targeted tissue rises up to at least 60°C for 1 second, leading to coagulation necrosis and ablation without damaging surrounding normal neuronal tissue. Axonal demyelination with necrosis of Schwann cells at the targeted area has been observed on autopsy in treated cases (2). Acoustic cavitation (the effect of sound fields on microscopic gas bodies to start oscillating and damaging cellular structures) and radiation forces also contribute to the lethal effect (9). Functional MRI is necessary for guidance to the abnormal tissue. HIFU has been used experimentally to treat several disorders, including chronic pain and Parkinson’s disease. As HIFU is a non-invasive procedure, it is considered to be low-risk surgery. General anesthesia is required, and patients must be assessed and cleared by anesthesiology for the procedure. The following image demonstrates one example of a HIFU system that is is coupled with a computerized MRI and CT imaging system for neurosurgical applications (3). Low-intensity focused ultrasound (LIFU) has also been explored in animal studies, and this has been shown to reversibly affect neurons and cause excitation and/or inhibition. It is hypothesized that LIFU acts by non-thermogenic mechanisms to cause action potential changes by mechanical means. LIFU involves very low energy at a frequency of 5.7 Mhz, at which permanent tissue histological damage does not take place. LIFU could potentially be also used to treat PD and other movement disorders, although further experiments are needed. Importantly, LIFU also has the potential to provide brain mapping and replace fMRI use. The image below illustrates how LIFU may be used with fMRI in treating brain disease (1). The MRI shows the sites to be ablated, and the transducer is focused at the sedated patient’s head to deliver the LIFU beam. Therapeutic focused ultrasound requires the use of high-resolution imaging of the lesion, achieved by functional MRI, along with establishment of specific coordinates by using a stereotactic brain atlas. The projection of the 3 coordinates on the intra-operative MR must be precise to a level of 1 mm (8). Ultrasound beams have another effect on the central nervous system – disruption of the blood-brain barrier (BBB). Researchers are currently investigating whether this property of ultrasound can be selectively controlled to create a temporary disruption of the BBB to allow the delivery of therapeutic drugs at the brain sites involved in PD (3). Limitations of Therapeutic Ultrasound Focused ultrasound for neurosurgery has several important limitations of its own. Two major technical challenges are the precise determination of the specific volume of the tissue to be ablated, and to precisely focus a narrow HIFU beam on the determined area. This may be possible through the use of a computerized system involving SPECT/MR imaging and a stereotactic image-guided module. This can provide a precision of up to 2 mm (5). HIFU also involves the artifacts related to ultrasound – refraction, reverberation, and acoustic shadowing. The refraction artifacts could potentially lead to energy deposition in normal tissue near the target. For therapeutic ultrasound involving other body structures such as the liver or prostate, ultrasound imaging for visualization of the lesion can be used. However, due to the nature of the cranium, ultrasound treatment for Parkinson’s is currently dependent on using concomitant imaging procedures such as MRI, SPECT and CT. This makes the procedure expensive, lengthy and more complicated. References 1. Bystritsky, A., et al. "A review of low-intensity focused ultrasound pulsation." Brain Stimul. (2011 ): 125-36. 2. Foley, J.L., S. Vaezy and L.A. Crum. "Applications of high-intensity focused ultrasound in medicine: Spotlight on neurological applications." Applied Acoustics (2007): 245–259. 3. Hynynen, K. and G. Clement. "Clinical applications of focused ultrasound-the brain." Int J Hyperthermia. (2007): 193-202. 4. Jagannathan, J., et al. "High-intensity focused ultrasound surgery of the brain: part 1--A historical perspective with modern applications." Neurosurgery. (2009): 201-10. Kennedy, J.E., G.R. Ter Haar and D. Cranston. "High intensity focused ultrasound: surgery of the future?" British Journal of Radiology. (2003): 590-9. 5. Lee, J.D., et al. "MRI/SPECT-based diagnosis and CT-guided high-intensity focused-ultrasound treatment system in MPTP mouse model of Parkinson's disease." Medical Engineering & Physics (2012). 6. Marjama-Lyons, J. and W. Koller. "Tremor-predominant Parkinson's disease. Approaches to treatment." Drugs Aging. (2000): 273-8. 7. Meyers, R., et al. "Early experiences with ultrasonic irradiation of the pallidofugal and nigral complexes in hyperkinetic and hypertonic disorders." J Neurosurg. (1959): 32-54. 8. Moser, D., et al. "Measurement of targeting accuracy in focused ultrasound functional neurosurgery." Neurosurgury Focus. (2012): E2. 9. Shehata, I.A. "Treatment with high intensity focused ultrasound: secrets revealed." European Jounal of Radiology (2012): 534-41. 10. Weintraub, D., C.L. Comella and S. Horn. "Parkinson's disease--Part 1: Pathophysiology, symptoms, burden, diagnosis, and assessment." Am J Manag Care. (2008): S40-8. Read More