WOOHOO! I am finally done with my senior paper. As you may surmise from the title I chose to write it on the neuro-mechanics involved with CI therapy. It’s written with a more informal tone but nonetheless it still landed me high marks. Comments, questions, and retweets (#revfrost) are always welcome. Enjoy!
ABSTRACT: The human brain is capable of extraordinary change. The impact of strokes can be devastating and often times seen as refractory. Constraint Induced (CI) therapy has proved beneficial in alleviating common symptoms caused by strokes. Recent evidence provides an insight in identifying the biological mechanisms exploited by CI-therapy: neurogenesis, gliosis, and synaptogenesis.
History of the Brain
The human brain has long been an object of deep-seated misunderstanding. In the times of the early Greeks it was believed to have been a cooling system for the body and thus a fever was the organ malfunctioning. Whereas some cultures such as the Egyptians believed it was completely useless aside from motor function and thus disregarded it in their preparation for the afterlife. Early followers of Christianity dismissed any notion of the brain’s importance as it contradicted the church’s teachings of the soul. The main shift from archaic to secular thinking of the brain came about in the 1600s under the influence of Thomas Willis (Zimmer, 2005). Until this time it was uncommon to even remove the brain before exploring its anatomy. Neurology only truly obtained its standing in the 19th century with the advent of modern medical equipment. All things considered, neurology as a whole is still a very young science. It is because of this that so many inaccuracies about the field have been allowed to propagate.
Society has a tradition of trusting Old Wives and the tales they tell. Yet, it would seem that most are in need of remedial instruction on scientific literature. There is a popular notion that neural development is limited to the childhood years and that one must “use it or lose it” to prevent a permanent future deficit. Beliefs such as this persist because they are essentially half-truths. People see remarkable change in children and only minute amounts in adults. People see marked development in children, simply stated, because there is vast amount of change in children. One study gives evidence that younger is not always better in terms of growth. In children afflicted with head trauma, the age of injury negatively correlates with the outcome of recovery (Anderson et al., 2005). To contrast, adults have been documented to overcome great neural damage such as full recovery after a 97% loss in the pyramidal tract (Bach-Y-Rita, 2004a)
In the early 1960s Dr. Bach-Y-Rita helped set the stage for the eventual phenomenon known as neuroplasticity. His work contributed to the practical applications of neuroscience, inventing a chair that would allow the blind to crudely see objects by detecting vibration pulses (Bach-Y-Rita, 2004b), and further calling attention to the growing field. Additionally, Dr. Merzenich began in the late 1970s to put focus on the behavioral aspects of neurology and would eventually help create the cochlear implant we use today. While both men had their own specialty, their work is solidly grounded in neuroplasticity and gives example to how widely ranging the field can be.
Neuroplasticity translates to change occurring within the brain (Doidge, 2007). While greatly important, a universal framework neither has yet to be agreed upon nor is it well defined. This word is generally used as a blanket term encompassing various smaller processes within the brain that facilitate change (Shaw and McEachern, 2001). Here we will be looking at the underlying mechanisms of neural restructuring and how operant behavior plays a vital role.
Essentially every action that a human can engage in can be said to have a hand in plasticity. Every action and thought causes some form of change within the brain. Most changes could be said to be so trivial that essentially zero variation in physiology could be detected. Yet, changes still occur and can build substantially with enough repetition. There are two ways that one could interpret behavioral action: passively and actively.
A simple way to envision passive behavior is by examining vision. Even when not focusing at an object in particular, the eyes are feeding the occipital lobe with information every second. The visual pathway (Figure 1) consists of information from the left or right field of each eye crossing the corpus callosum to its respective side in the posterior of the brain, the occipital lobe. From the occipital lobe the information is then sent back to the prefrontal cortex for analysis (Molavi, 1997).
In the event that a one-sided lesion disrupts the processing abilities of the prefrontal cortex, what happens? In a static environment you could assume that the side affected by the lesion would lose greater processing for that side of the brain (opposite field of vision due to crisscross). However, if the brain were dynamic and could re-route the circuit, information from that field could have the potential to return. It would seem that brain does just that (Voytek et al., 2010). In a study that tested memory and attention in visual fields affected by lesion, the researchers discovered a very beneficial change in circuitry. The sensory information directed at the nonoperational, lesioned area would start toward the initial destination then become redirected to the active processing site on the other hemisphere. The researchers found that this only holds true as long as the operational lobe was currently analyzing the other field. Although neurologically dynamic, the input is passive as the observer makes no additional effort aside from keeping the eyes open. With this form of action, behavioral influence is minimal and all change associated is unconscious.
The other method by which neuroplasticity arises is via active behavior. This is the same phenomenon which accounts for learning and rehabilitation. An individual performs repetitions of the same task until the task itself becomes gradually easier (Merzenich et al., 1996). This change in difficulty comes from restructuring at the cellular level induced by the actions of the operator.
Mechanisms of Neuroplastic Change
Neurogenesis is the process by which new neurons are produced. Unlike reptiles, mammalian neuronal growth is severely halted after development with the exception of a few critical areas such as the hippocampus and the olfactory system (Kempermann et al., 2004). Previously held assumptions regarding neurogenesis were that: it did not occur in humans, it could not occur in situ, and that even if it did the new neural tissues would not be functional. Neurogenesis had never been observed in mammals prior to 1962 (Altman, 1962; Altman and Chorover, 1963) and not in humans until 1998 (Eriksson et al., 1998). The 1998 findings began to raise several questions. If this could occur naturally, then can we induce it? Initial studies on mice proved the answer to be a resounding yes whether caused by artificial apoptotic degeneration (Magavi et al., 2000), via inducing a stroke (Kolb et al., 2007), or by utilizing motor skill rehabilitation methods on impaired limbs (Wurm et al., 2007). Researchers then directed the question toward humans only to be met by similar answers. New, functional (Kempermann et al., 2004) neural tissues can be induced naturally by precursors produced following a stroke (Arvidsson et al., 2002).
Gliosis, another form of cellular change, is the process by which astrocytes multiply across a damaged area, much similar to scabbing of skin cells, and may eventually lead to a glial scar. Glial cells, once thought to be primarily for support purposes, have been identified in complex roles such as breathing regulation (Gourine et al., 2010). However, gliosis is also highly involved in neurological disorders such as Alzheimer’s, multiple sclerosis, and Mad Cow Disease. In response to motor skill rehabilitation, astrocytes have been seen to increase cell volume and reduce proliferation while being mirrored with an increase in synapse number (Kleim et al., 2007).
The addition and formation of new synapses between neural cells is known as synaptogenesis. Frequent and continual activity in one area of function may induce the growth of more synaptic connections associated with the task (Kleim et al., 2002). In many cases of injury, the brain’s built-in repair system will respond to the insult with physiological changes that decrease the overall strain upon the system. However, the changes seen are not limited to the damaged area. Studies have found that synapse increase can present not only in tissues surrounding the lesion site (Jones, 1999), but increase in the respected area on the other hemisphere (Allred and Jones, 2004) and also in various areas of the brain tied to the behavior of the affected area (Chu and Jones, 2000). Additionally, motor skill (Jones et al., 1999) training and active, intentional behavioral stimuli further enhance this process.
Patients suffering from dysfunction within the vestibular regions of the inner ear often suffer from balance-associated conditions, posture, and gait abnormalities. Due to the severity of impairment these balance disorders can reach, sufferers are sometimes referred to as Wobblers. Dysfunction within the vestibular, and even peripheral pathways, causes the patient to lose nearly all sense of balance and as a result feel a continuous sense of falling and spinning (Robin Technologies, 2011). Bach-Y-Rita and colleagues created a rehabilitation device, BrainPort, which contains an accelerometer and senses the position of the patient’s head. This information is then sent to an electrode placed on the tongue where it establishes connection to the nervous system via the facial nerve. With training, the patients can use this accessory system to reestablish balance (Danilova et al., 2007). The novel aspect of the device is the residual effects after the device has been removed. With increased exposure to the device the patient would experience increased durations of symptom relief when the device was no longer in use. It is believed that simultaneous exposure to both the device and vestibular signals allowed for a “rewiring” of neural circuitry that bypassed the damaged area causing the symptoms (Doidge, 2007).
Much like the vision example detailed previously, a dysfunction is present within a sensory system. In this case, the vestibular system is sending either null or erroneous information. In conjunction with the device, the brain learns to tune out false or missing information and rely upon the working sensory input or even the visual system for data. This neuromodulation accounts for the perpetually increasing amounts of symptom relief as new pathways are being formed and strengthened (Wildenberg et al., 2010).
Another neurological dysfunction with profound effects on motor skills is hemiparesis. Hemiparesis is a condition marked by mild to severe weakness of the body one on side, in most cases caused by neural damage to the opposing hemisphere. While many conditions can present this symptom, one illness that has recently received large attention is the stroke. Caused by an occluded blood vessel or hemorrhagic bleed, strokes are often seen from a treatment perspective as refractory once an allotted time-period has passed. This view is beginning to become more widely dismissed as plastic treatments are on the rise. One treatment that has become well known for its efficacy, as well as its controversial creator, is Constraint-Induced Therapy.
Constraint-Induced (CI) Therapy
A man known and vilified for his media-imposed “unethical” use of lab animals, Edward Taub has become one of the most influential neuroscientists of the last century. His early work focused on deafferentation experiments in macaques. Deafferentation entails surgically disrupting sensory nerves so that while sensation past the disruption ceases, motor function remains intact. Taub discovered that if one arm were deafferented the animals would cease use entirely and solely use the unaffected arm. However, if both arms were deafferented then the macaque would continue its use of both as if nothing had occurred. In the case of the single arm deafferentation, the monkey would ultimately experience an initial period of self-testing. Upon discovering the arm to feel foreign in comparison to the unaffected arm, the macaque would then abandon the arm entirely. Taub termed this phenomena learned non-use, as the monkey would unintentionally learn not to use the limb (Carlson et al., 1994).
In an attempt to reverse the process of learned non-use, Taub restrained the unaffected arm of the macaque so that only the deafferented limb remained free. In doing so, the monkey was forced to use the remaining arm despite having no sensation (Taub et al., 1994). It was from this experiment that Taub crafted the concept of Constraint-Induced therapy. The treatment would be focused on an individual with a side-favored motor impairment, such as hemiparesis. The individual would spend the next two weeks engaging in active rehabilitation exercises with the unaffected limb bound to inhibit use (Taub et al., 1999)
Since its inception CI therapy has been utilized in countless studies from treatment of stroke patients to those with cerebral palsy with remarkable success (Huang et al., 2009; Miltner et al., 1999). However, despite the remarkable success following the therapy, the follow-up to these experiments yielded mixed results of the efficacy of the treatment. The patients would perform well in the clinic but upon return to their homes the activities would decrease substantially. Finally, a new component was added to the therapy termed “the transfer package.” The premise behind the transfer package was to incorporate therapeutical techniques into everyday tasks to ensure continued use. In addition, the patients would undergo brief behavioral therapy prior to exiting the program to solidify the desire behind continuation of treatment. The resulting improvement was 2.88 times greater (P<0.0001) than those without the transfer package (Gauthier et al., 2008). Behind CI therapy and overcoming learned non-use lays the foundation of neuroplasticity, repetition of an action without counter-productive measures (use of other arm). In allowing for greater use of the affected limb, operant conditioning is able to play a role in sustaining the behavior leading to further use (Gauthier and Taub, 2009)
Studies of CI therapy on the cellular level indicate significant changes in tissue volume of patients treated. Application of CI therapy also yields a reduction of overall volume loss while increasing synaptic growth and reorganization (DeBow et al., 2003). Additionally, the level of improvement upon completion remains independent of lesion location in the patient (Gauthier et al., 2009).
The field of neuroplasticity is rapidly growing. With an ever increasing geriatric population stroke rates are likely to be on the rise. By understanding the mechanisms behind plastic therapies such as Constraint-Induced, researchers are better able to gain insight and develop further treatments that can exploit these benefits. In addition, this treatment can be further applied to a wide array of neurological diseases, injuries obtained from blunt trauma, and even dysfunction resulting from surgical procedures such as hemispherectomies. Deafferentation studies have always been unpopular due to objections whether from extremist animal rights’ groups, researcher’s ethical quandaries, or simply the unpleasantness for test animals involved. The information gained from this style of research proves invaluable in our quest to understand the human mind. The potential gain that could be achieved for both humans and the primates studied greatly outweighs any costs incurred.
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