Mental and physical exercise: Alternatives to dopamine treatment in Parkinson’s disease

Several studies have come out recently touting unconventional methods to treat Parkinson’s disease. Parkinson’s is caused by damage to neurons in the substantia nigra (SN), a region of the basal ganglia that is responsible for creating much of the brain’s dopmaine. Dopamine is an essential neurotransmitter implicated in a variety of behavioral and motivational mechanisms, and it is most notably involved in reward and addiction. However, it is also a key component of the motor system. Feedback loops from the cortex to the basal ganglia circulate information about whether to initiate or inhibit a movement, and these cicuits are greased by dopamine, activating the excitatory loop and suppressing the inhibitory one. Without adequate dopamine, the system comes to a stalemate, making the initiation of movement much more difficult and causing the hesitation, trembling, and inertia that are characteristic of Parkinson’s.

Common treatments for Parkinson’s include flooding the brain with dopamine agonists or the dopamine precursor L-DOPA. This boosts dopamine levels in the brain, causing the remaining healthy SN neurons to produce and fire greater amounts of the neurochemical, making up for the deficit from the impairment of the other cells. However, there are currently no treatments that prevent the progressive cell death in the SN, and in advanced stages it is difficult to compensate for the abundant cell loss. Excess “artificial” dopamine in the brain can also result in the downregulation of other dopamine-producing and receiving cells, the brain adjusting to the new flood of dopamine by reducing its endogenous production and receptor sensitivity in an attempt to return to a dopaminergic homeostasis. Additionally, it is impossible to localize dopamine agonists to the motor regions of the brain, meaning that many Parkinson’s patients treated with dopamine come to display symptoms similar to those seen in impulse control disorders, which are also commonly rooted in a widespread dysregulated dopamine system. These can include the development of compulsive gambling and shopping problems, sexually deviant behavior, and drug addiction.

Given the obvious shortcomings in the current treatment options, the need for alternative therapies for Parkinson’s is widely acknowledged. Two labs taking on this problem have recently published results on alternative treatments that do not involve pharmacological challenge and instead target a patient’s motor efficacy, one increasing the patient’s control and the other withdrawing it.

The first, published in the Journal of Neuroscience, suggests that self-regulation of brain activity facilitated by real-time fMRI feedback can increase brain activation and decrease Parkinson’s symptoms. Focusing on the supplementary motor region, an area of cortex that has direct connections with basal ganglia pathways and that is commonly shown to have diminished activity in Parkinson’s, researchers at the University of Cardiff had patients mentally activate this region using motor imagery while in the fMRI scanner. Patients in the experiment group received direct feedback on their activation levels during the trials via a thermometer display, whereas those in the control group did not have any indication of their success at mentally activating the area. The patients who received the real-time feedback were able to activate the supplementary motor region to a greater extent than those who did not, successfully upregulating this area as well as other brain regions associated with the motor system. They also significantly improved their ability on a motor function test and a subjective assessment of Parkinson’s symptoms, whereas control participants did not. Researchers speculate that this increase in activity and subsequent improvement in symptoms is due to a greater excitation of compensatory motor pathways, strengthening these connections and facilitating the activity of the under-utilized basal ganglia circuitry.

The second method, published in Exercise and Sport Sciences Reviews, takes an alternative approach, deliberately taking the control out of the hands (or legs) of the participants. Researchers at the Cleveland Clinic in Ohio are investigating the idea that forced exercise, with exertion levels out of the patient’s control, can be more effective in treating Parkinson’s symptoms than voluntary physical activity. Led by Dr. Jay Alberts, researchers had patients ride on the back of tandem bicycles where the energy output was set at 50% higher than the patients’ comfortable self-selected effort levels. After eight weeks at the greater energy expenditure, patients had a significant decrease in tremors and other motor symptoms, which lasted for approximately one month after treatment was stopped. Additionally, the benefits seen were not just a result of localized increased muscle tone or coordination as has been the case in previous studies investigating the effects of exercise in Parkinson’s. Instead, participants showed improvements in movement throughout the body, as well as increased neural activity during MRI scans of the basal ganglia and cortex. Researchers are as yet unsure of the basis for these improvements, though the emotional and cognitive benefits of exercise are widely known. In an interview with the New York Times, Dr. Alberts speculated that the effects could stem from the release of stress hormones during exercise, which can trigger the neurochemical systems and are more active during forced or very high intensity activities than comfortable voluntary levels of exertion.

While these studies are still only addressing the symptoms rather than the root of the problem, they do provide new evidence for treatment options beyond the standard fair. Importantly, neither of these methods comes with any of the adverse side effects of dopaminergic treatments, which can severely undermine the efficacy and quality of life improvements for patients with Parkinson’s disease. Further research is of course always needed, and certainly these methods would need to be used in tandem with current drug therapies, but these studies present an interesting alternative to complete reliance on pharmacological medication to treat the symptoms of neurological disorders.

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Time warp: Subjective time duration

I got to attend a talk by the dynamic neuroscientist Dr. David Eagleman at the Society for Neuroscience meeting this week, who spoke on temporal expansion and compression (i.e. the subjective speeding up and slowing down of time in our minds) and its possible neural underpinnings. The gist of Dr. Eagleman’s research is that unexpected events seem to last longer (the “oddball effect”), whereas repetitive occurrences seem to speed up and go faster. The classic example of this is when an object is presented to you several times in sequence, you begin to think that the presentation has been sped up. However, if a novel object is introduced it seems to be presented for longer (13% longer to be exact) than the anticipated stimulus.

The initial hypothesis for this phenomenon was that greater attention is paid to these surprising events than the expected ones. However if this were the case, strong salient or attention-grabbing images, such as violent or emotional pictures, should seem to last even longer than unexpected neutral images, as they garner even more attention. However this is not the case, with novel affective images subjectively lasting just as long as novel household items.

Instead the answer seems to lie in a perceptual compression rather than expansion of time, with the repeated images appearing to speed up as they become expected. This is thought to be rooted in an increase in neural efficiency for these events, the neurons and pathways becoming faster and more effective at firing for the expected event, leaving the brain greater capacity to process new information that cannot be predicted in this manner. This is paralleled in the EEG literature where conditioned anticipated events do not elicit the same amplitude of firing from cells that they once did. However, when a novel stimulus is introduced there is an expectation violation, which results in a greater magnitude of neuronal firing in the brain again. This then results in the event seeming longer, or rather no longer being temporally compressed as it had become.

Unfortunately no one is quite certain why increased or decreased cell firing results in this subjective expansion or compression of time, but perhaps we’ll be closer to an answer by next year’s meeting. In the meantime, at least it’s comforting that repetitive (read: potentially boring) events actually seem to go faster than they really are.

SFN 2011

I’m excited to announce that I’m headed to Washington, D.C. today to present my very first poster at Society for Neuroscience!

To all my fellow neuro buffs and brain geeks in attendance, stop by session 192: Dietary influences on obesity mechanisms, Sunday from 10:00-11:00 to say hi and see my poster: Decreased Gray Matter Volume in Overweight and Obese Individuals. It’s got some beautiful brain images and snazzy graphics, and hopefully some cool neuroscience thrown in too.

Also, be sure to check out two of the official SFN blogs, blogs.scientificamerican.com/scicurious and futuredrsciencelady.wordpress.com, for up-to-date posts on all of the neuroscience madness going on this week.

Hope to see many of you there!

Learning from our students

Having just conducted my first round of undergraduate supervisions (similar to an intensive tutoring or teaching assistant session), I have a greater amount of respect for an article published in Science back in June that has been making the rounds in academic discussion forums. In it, researchers conclude from both subjective interviews with students and faculty supervisors, as well as through objective reviews of student research reports, that graduate students who teach or supervise undergraduates come away with better research and analytical skills than those who do not.

This finding is at first counter-intuitive and flies in the face of accepted dogma that students who teach are taken away from their own research and laboratory time, and therefore cannot produce as much or as thorough work as those who do not. However the authors of the report, led by Dr. David Feldon at the University of Virginia, have done a thorough job vetting this claim by objectively assessing graduate students’ research proposals on the quality of their experimental design, hypothesis testability, and general research skills. Based on an empirical set of criteria, the authors of the study determined that students who pursued teaching as well as research assistantships had better research and study design skills than those who did not.

As my fellow graduate students and I can attest, teaching undergraduates takes a significant amount of time, effort, and brain power, all resources that would more preferably be spent (both according to ourselves and our supervisors) on our groundbreaking and earth shattering research. However, in accordance with Dr. Feldon’s report, teaching undergraduates is not without its advantages, though some of the benefits I have experienced are somewhat harder to empirically define.

In a PhD we all too often become absorbed in our own niche research, convinced that it is the most imperative and fascinating topic there is to study. If we did not we would most likely drop out. However, it also means that the articles, discussions, work, patients, and results we see are all geared towards this small facet of our respective subjects, which are at times far away from the more general concerns of the field. Tutoring or supervising undergraduates can bring us back into the larger discussion of our disciplines, reminding us of the history and background that predates our own work. It also provides an opportunity to review some of the seminal papers that we may now take for granted but were groundbreaking at the time of their release. And lastly, it reminds us of information we had learned during our own undergraduate tenures, knowledge and analytical skills that are essential in the wider scope of our fields but that might have been forgotten or discarded in favor of our own passions.

This all happened to me in my first tutoring sessions. I was at first overwhelmed with the information the students were expected to learn and resentful of the distraction from my work. Fortunately, over time I was able to recognize much of the material as familiar and even attempted to provide my own spin on it, combining the fundamentals of the lectures with offshoots from my research. However, it was certainly a humbling reminder of just how much there is I do not know about the brain. I was also impressed by the knowledge and intellect of the students themselves, some of whom I have no doubt are vastly more intelligent than myself. More than anything though, reviewing this material and having to master it all well enough to later disseminate it to others reminded me of just how interesting and exciting some of these topics are, and made me aware of connections in systems pertaining to my own research that I had neglected to make.

While teaching certainly does take up vast quantities of time, it also provides an invaluable medium to refresh us on essential material, to review our field with new eyes, and to make us truly learn the information so that we are later able to provide guidance for others. It is also an important exercise in reminding us of just how little we know, and how seemingly “simple” questions can be far more complex than some of the more nuanced “expert” queries.