The mind is one of nature’s most complex entities. It is difficult to grasp just how many 100 billion neurons, the number that makes the average human brain, really is. If you consider each neuron in the human brain lined up end to end, the structure would wrap around the earth two full times [1]. This highlights the sheer complexity of the organ. Generally, the more complex an entity, the higher the probability that an error occurs. Biology is not perfect, evidenced by atypical uncontrolled cell growth in cancers; extremely complex organs such as the brain have an increased likelihood for error. Neurodegenerative diseases are such errors that lead to neural cell death. One, in particular, that is ravaging the human population with an accelerating diagnosis rate is Alzheimer’s.

What is Alzheimer’s?

     Alzheimer’s disease (AD) is the sixth leading cause of death in the United States and the only disease in the top ten without any form of treatment. Currently 5.3 million Americans live with the condition, and it is projected that more than 16 million Americans will have a diagnosis by 2050 [2]. AD is the most common form of dementia, and it leads to a loss of cognitive abilities, memory loss, and impaired ability to speak [3]. Since the disease primarily affects older individuals, as the population of the United States ages, the prevalence of the disease will only grow. Clearly, it is essential to study this disease extensively. The effects of AD are initially associated with the medial temporal lobe, particularly the hippocampus, the memory center of the brain. The disease spreads throughout the temporal and parietal cortex areas, encroaching into the frontal cortex. Eventually, nearly every part of the brain is affected.  At the cellular level, AD involves the death of both cortical and non-cortical neurons in the brain, especially those dealing with higher cognitive function and memory.  The mass and volume of the brain are in turn reduced in advanced AD cases, illustrating the damaging effects on the brain [3].
     A widely-held theory about the cause of AD deals with an abnormal accumulation of amyloid-beta protein (Aβ) [4]. The brain responds to Aβ accumulation by mobilizing microglia and astrocytes to separate damaged areas and clear out protein. However, neuronal death still occurs. In addition to abnormal plaque buildup, it is widely believed that neurofibrillary tangles (NFT) of tau, a microtubule binding protein, can inadvertently interfere with the transport of components crucial for proper neuron function. For example, tau is involved in the trafficking of vesicles containing neurotransmitters [4]. While many of the disease mechanisms remain unclear, a recent breakthrough has occurred in the search for a treatment. Focused ultrasound therapy combined with microbubbles, the newest attempt to tackle AD, could be the key to mitigating or totally eliminating the effects of the neurodegenerative disease.

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How Focused Ultrasound Therapy is used in areas other than the Brain

     Focused ultrasound therapy is providing a revolutionary non-invasive technology that allows for treatment of damaged tissue. Similar to burning a hole through a piece of paper with a light source and a magnifying glass, an acoustic lens focuses beams of ultrasound waves together at a focal point. At this convergence point, these beams can precisely raise the temperature of the desired tissue, destroying unhealthy cells, a process known as thermal ablation. No incisions or radiation are required to implement this treatment, minimizing invasive practices; furthermore, MRI imaging can serve both as a map for delivery and a readout of temperature achieved by the dose [5]. This focused ultrasound technology has been used to treat maladies such as bone tumors, prostate cancer, and uterine fibroids [5]. Furthermore, a modified low-frequency version of focused ultrasound has impactful implications for Alzheimer’s and the brain [6].

How Focused Ultrasound Combined with Microbubbles has Implications in Treating the Brain

The Blood Brain Barrier (BBB) is a complex membrane structure created by endothelial cells that attach to blood vessels inside the brain. The barrier is impermeable due to the tight junctions lining the endothelial cells. The junctions make it difficult to administer drugs to the brain, as they have trouble getting in. However, combining focused ultrasound therapy with microbubbles, in an approach called acoustic cavitation, allows the blood brain barrier to be temporarily opened [7]. A microbubble is a molecule about the size of a red blood cell with an inner gas core surrounded by an outer layer of proteins, lipids, and polymers. They are coveted for their small size, which makes maneuvering through the circulatory system easy, and for their ability to be easily manipulated by researchers [8]. The patient is initially injected with the desired chemical medication through an intravenous (IV) delivery into the circulatory system. Microbubbles are then injected through the same mechanism. Next, the patient is placed in an MRI machine fitted with a helmet attached to the patient table. Focused ultrasound waves are then directed through the headgear to the desired location in the brain [9]. 
     As focused ultrasound waves hit microbubbles in the targeted region, acoustic pressure causes them to expand and contract [10]. As microbubbles grow, tight junctions and other areas of the membrane open, allowing diffusion of the chemical treatment across the BBB. Mouse studies have demonstrated that opening of the Blood Brain Barrier by itself can result in a decrease in Aβ plaques in the brain and can allow for hippocampal neurogenesis [11]. Specifically, pre-clinical studies at the Queensland Brain Institute of Australia, headed by Jurgen Götz and Gerhard Leinenga, and at the Sunnybrook Research Institute, led by Kullervo Hynynen, independently showed the potential of focused ultrasound and microbubbles in attacking plaques in Alzheimer’s [12].
     The first instance the treatment was used on a patient was in 2015 at the Sunnybrook Health Sciences Centre. This demonstrated success in brain absorption of chemotherapy drugs which specifically attacked tumor tissue in a cancer patient [13]. Now, in an ongoing Phase 1 clinical trial, six patients will have two sessions of focused ultrasound treatment and multiple tests to assess the therapy [14]. The opening of the Blood Brain Barrier has proved a major success, and now the main focus for researchers will be on drug therapies that can diffuse across the BBB with the assistance of acoustic cavitation. A multitude of drugs could have efficacy in treating Alzheimer’s by breaking up plaques, among other things, once they diffuse across the BBB with the use of this new approach. The technology is emerging, but the opportunities it introduces provide hope for millions affected by Alzheimer’s and other neurodegenerative diseases.
     This treatment could be seen as the neuroscientist’s version of the Apollo 11 mission. NASA’s operation broke past barriers never thought possible, leading to an advanced understanding of our moon in a relatively short period of time. Now, science has both figuratively and literally broken past another barrier. In the coming years, if this approach proves effective, the world may not only see a decrease in the number of deaths from Alzheimer’s, but also from many other neurodegenerative diseases. Science is in a prime place to revolutionize treatment for the brain forevermore.

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1. “The Human Brain is the Most Complex Structure in the Universe. Let’s do All We Can to Unravel its Mysteries New Techniques are Producing Great Excitement Among Neuroscientists.”Http:// April 4, 2014. Accessed October 28, 2017

2. “2017 Alzheimer’s Disease Facts And Figures.” 2017. Accessed October 28, 2017.

3. MacGill, Markus. “Alzheimer’s Disease: Causes, Symptoms and Treatments.” April 29, 2016. Accessed October 29, 2017.

4. Querfurth HW, LaFerla FM. Alzheimer’s disease. N Engl J Med 2010; 362: 329 44. doi: 10.1056/NEJMra0909142,Norfray JF, Provenzale JM. Alzheimer’s disease: neuro-pathologic findings and recent advances in imaging. AJR Am J Roentgenol 2004; 182: 3 13. doi: 10.2214/ajr.182.1.1820003

5. Fornell, Dave. “High-intensity Focused Ultrasound Offers New Opportunities.” Imaging Technology News. March 02, 2017. Accessed October 29, 2017.

6. First Alzheimer’s patient treated with focused ultrasound to open the blood-brain barrier.” Sunnybrook Hospital. May 2, 2017. Accessed October 31, 2017.

7. Burgess A., Hynynen K. (2016) Microbubble-Assisted Ultrasound for Drug Delivery in the Brain and Central Nervous System. In: Escoffre JM., Bouakaz A. (eds) Therapeutic Ultrasound. Advances in Experimental Medicine and Biology, vol 880. Springer, Cham

8. Sirsi, Shashank, and Mark Borden. “Microbubble Compositions, Properties and Biomedical Applications.” Bubble science engineering and technology 1.1-2 (2009): 3–17. PMC. Web. 31 Oct. 2017.

9. World first: blood-brain barrier opened non-invasively to deliver chemotherapy.” Sunnybrook Hospital. November 8, 2015. Accessed October 31, 2017.

10. Science Translational Medicine  11 Mar 2015:Vol. 7, Issue 278, pp. 278ra33DOI: 10.1126/scitranslmed.aaa2512

11. Meng, Ying, Matthew Volpini, Sandra Black, Andres M. Lozano, Kullervo Hynynen, and Nir Lipsman. “Focused ultrasound as a novel strategy for Alzheimer disease therapeutics.” Annals of Neurology. May 04, 2017. Accessed October 31, 2017.

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12. “Pre-Clinical Research Validates Potential for Focused Ultrasound in Alzheimer’s.” Imaging Technology News. March 27, 2015. Accessed October 31, 2017.

13. “Blood-Brain Barrier Opened Non-invasively With Focused Ultrasound For The First Time.” Focused Ultrasound Foundation. November 5, 2015. Accessed October 31, 2017.

14. “First Alzheimer’s patient treated with focused ultrasound to open the blood-brain barrier.” Sunnybrook Hospital. May 2, 2017. Accessed October 31, 2017.