Zapping the brain to help ataxia

Written by Dr. Judit M. Perez Ortiz Edited by Dr. Sriram Jayabal

In a new study, scientists have found that “zapping” the brain with an electromagnetic wand may someday help patients with spinocerebellar ataxia.

In an era of ever-evolving technological advances used for personal entertainment and space travel, medical scientists are harnessing the power of electromagnetism to safely penetrate the skull and manipulate brain cells by mimicking their favorite language – electric current.

Clinicians currently have access to powerful and effective tools designed to stimulate brain cells (known as neurons) for various neurological and psychiatric conditions. Spinocerebellar ataxias (SCAs), however, are not yet in the mix. Though several techniques exist, the methods used to stimulate neurons in the brain can be broadly classified into invasive and non-invasive approaches. For instance, Vagus Nerve Stimulation is used for drug-resistant epileptic seizures, while Deep Brain Stimulation is used for Parkinson’s disease and severe depression. In both instances, a surgical procedure is required because the implanted electrodes have to come in direct contact with the target nerve or brain structure. Disadvantages associated with these surgical methods include the risk of infection, bleeding, and hardware malfunction. Non-invasive approaches to stimulate the brain include electroconvulsive (“shock”) therapy, in which electrodes are placed on the scalp surface to provoke a controlled seizure that yields a therapeutic effect. However, shock therapy requires anesthesia, and patients run the risk of memory issues as a side effect. A second non-invasive brain stimulation tool is also available, called repetitive Transcranial Magnetic Stimulation (rTMS). There are many factors that make rTMS clinically appealing: it does not require surgery, it is already FDA-approved (for severe depression), it is painless, and it has been found to be safe. Further, unlike the broad brain stimulation achieved by electroshock therapy, rTMS delivers a more precise stimulation in a defined brain region, which leaves untargeted brain regions untouched.

cartoon of neuronal brain cells and electricity flowing between them
Artist’s depiction of electrical signals in the brain. Image courtesy of flickr.

Besides its circular or figure-eight attachment, the rTMS device looks quite a bit like a magic wand. Though this is no wizard’s tool, you could say that it does cast a powerful spell: the attachments on the end of the rTMS device are electromagnetic coils, which have the power to “zap” specific brain regions. In a remarkably simple procedure, the wand is gently placed over the patient’s scalp, where it delivers electromagnetic pulses that create just enough electric current to stimulate underlying brain cells without adversely affecting them.

A new pilot study conducted at the Beth Israel Deaconess Medical Center found that using rTMS to stimulate the cerebellum of SCA patients is safe and may improve some aspects of ataxia. First, the investigators recorded the study participants’ baseline movement performance using a battery of tests designed to evaluate different features of ataxia, including balance, gait, and posture. Then, half of the study participants were randomly assigned to receive rTMS, while the other half were assigned to the control, or “sham” group.

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Thrift Store Pharmacy: Repurposing a Multiple Sclerosis drug for use in SCA6

Written by Anna Cook Edited by Dr. Monica Banez

Researchers successfully use an existing multiple sclerosis drug to improve performance in an SCA6 mouse model

Spinocerebellar ataxia type 6 (SCA6) is a rare hereditary movement disorder affecting 5 of every 100,000 people worldwide1. The disease is caused by the expansion of a repeating DNA sequence in the CACNA1A gene. The length of this repeat, which is made up of sequential iterations of the code CAG, is normally variable in length, stretching between 4 and 18 repeats in the healthy population. However, in SCA6 patients, something goes wrong and the CAG repeat in the CACNA1A gene is expanded to have 21-33 repeats, causing dysfunction in the brain and motor symptoms for reasons that are not yet fully understood. SCA6 belongs to the group of disorders called polyglutamine diseases, all of which are caused by CAG expansions in different genes. These include disorders like Huntington’s disease and other spinocerebellar ataxias.

five laboratory mice on a rotarod device to test their balance
Laboratory mice on a rotarod device to test motor coordination skills, similar to one of the experiments conducted in this study. Image courtesy of WikiMedia.

SCA6 onset generally occurs at middle age. The characteristic symptoms are difficulties with motor coordination that progressively get worse as patients get older. Current treatment options are limited to managing symptoms rather than addressing the cause of the disease. However, researchers have recently discovered that the FDA-approved drug 4-AP reduces motor symptoms in a mouse model of SCA6, making the drug a promising candidate for the treatment of the disease in humans.

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DNA Damage Repair: A New SCA Disease Paradigm

Written by Dr. Laura Bowie Edited by Dr. Hayley McLoughlin

Researchers use genetics to find new pathways that impact the onset of polyglutamine disease symptoms

The cells of the human body are complex little machines, specifically evolved to fulfill certain roles. Brain cells, or neurons, act differently from skin cells, which, in turn, act differently from muscle cells. The blueprints for all of these cells are encoded in deoxyribonucleic acid (DNA). To carry out the instructions in these cellular blueprints, the DNA must be made into ribonucleic acid (RNA), which carries the instructions from the DNA to the machinery that makes proteins. Proteins are the primary molecules responsible for the structure, function, and regulation of the body’s organs and tissues. A gene is a unit of DNA that encodes instructions for a heritable characteristic – usually, instructions for a making a particular protein. If there is something wrong at the level of the DNA (known as a mutation) then this can translate to a problem at the level of the protein. This could alter the function of a protein in a detrimental manner – possibly even rendering it totally non-functional.

dna-2358911_1280
Artist representation of a DNA molecule. Image courtesy of gagnonm1993 on Pixabay.

DNA is made up of smaller building blocks called nucleotides. There are four different nucleotides: cytosine (C), adenine (A), guanine (G), and thymine (T). Polyglutamine diseases, such as the spinocerebellar ataxias (SCAs) and Huntington’s disease (HD), are caused by a CAG triplet repeat gene expansion, which leads to the expansion of a polyglutamine tract in the protein product of this gene (MacDonald et al., 1993; Zoghbi & Orr, 2000). Beyond a certain tract length, known as the disease “threshold,” the length of this expansion is inversely correlated with age at disease onset. In other words, the longer this expansion is, the earlier those carrying the mutation will develop disease symptoms. However, scientists have determined that onset age is not entirely due to repeat length, since individuals with the same repeat length can have different age of disease symptom onset (Tezenas du Montcel et al., 2014; Wexler et al., 2004). Therefore, other factors must be involved. These factors could be environmental, genetic, or some combination of both.

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