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

A variety of studies have arisen recently touting unconventional methods for treating Parkinson's disease. Parkinson's is caused by damage to the 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 in a variety of behavioral and motivational mechanisms, often implicated 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. However, without adequate dopamine the system comes to a stalemate, making the initiation of movement much more difficult and causing the hesitation, trembling, and inertia characteristic of Parkinson's. Common treatments for Parkinson's include flooding the brain with dopamine agonists or the dopamine precursor L-DOPA. This helps to boost dopamine levels in the brain, causing the remaining healthy SN neurons to produce and fire greater amounts of the neurochemical, attempting to make up for the deficit from the impairment of the other cells. However, there are currently no treatments to 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 attempts 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.

The cookie monster in all of us: Sugar addiction

Having quite a large sweet tooth myself, I feel a bit hypocritical writing on the subject of excessive sugar consumption. However the importance of this message, not to mention the sheer fascinating nature of the topic, has prompted me to press on. There are reasons to believe that certain hedonic foods, namely those high in sugar, can qualify as substances that are at risk for addictive abuse, not just in the colloquial but also in the clinical sense of the term. Psychologists at Princeton University, lead by Dr. Nicole Avena, research sugar addiction using a sucrose solution in rats, and they have discovered several similarities between the neurochemical effects of sugar and addictive drugs on the brain. Researchers fed rats on an intermittent feeding schedule, depriving them for 12 hours before allowing them to eat from a sucrose solution in addition to their regular food chow. After a month of this schedule rats began to show binge, craving and withdrawal-like behaviors for the sucrose, whereas rats who had received only the food chow on this intermittent schedule, or had unrestricted access to food and sucrose, did not show these effects. The scheduling of the sucrose availability is crucial as it prompts them to develop binge-like behaviors, and is similar to the schedule used to develop cocaine dependency in rats. This means that after being deprived of the food or drug the rat will self-administer extremely large quantities of the substance once it is available again. This behavior tapers off once the animals are sated, but these binges will consistently occur after each period of deprivation.

Due to these sucrose binges adaptations similar to those that occur in cocaine addicted animals were seen in the rats' brains. The binges resulted in surges of dopamine being released in the nucleus accumbens, a key facet of drug addiction, and one that is linked to feelings of reward and novelty. Over time mutations can occur in these dopamine receptors, increasing the sensitivity of some types (D1 and D3) while simultaneously decreasing the sensitivity and overall levels of others (D2). This results in larger doses of the substance being required to achieve the same level of arousal and decreases the sensitivity of this region to other types of natural rewards. This occurs after abuse of both sugar and drugs and seems to be linked to the bingeing nature of compulsive consumption.

An increase in craving was also seen in the test animals, demonstrated by an increase in sucrose-seeking in rats deprived of the solution. This behavior was resistant to extinction, remaining over a month after the last exposure to sucrose, and was also maintained in the face of adverse consequences, a principle criterion for compulsive behaviors.

In addition to craving, researchers discovered that mice seemed to go through withdrawal-like symptoms when deprived of sugar. These included tremors, head shakes, and signs of anxiety and aggression, all symptoms seen in animals going through opiate withdrawal. These effects stem from a crash in striatal dopamine, accompanied by decreases in opioid receptor activation, as well as an increase in acetylcholine, a neurochemical that has been linked to depression. One explanation for the similarity between sugar and opiate withdrawal is the activation of the opioid system by both substances. High fat/high sugar foods have been found to stimulate the release of endogenous opioids in the brain, which is thought to be due to their rewarding and pleasurable characteristics and causes effects similar to the administration of synthetic opiates, though on a much smaller scale.

This overlap between opiates and sugary foods has also been seen in abstinent heroin users, who often quickly develop a strong affinity for sweets while in recovery. Candy and junk food come to replace heroin as recovering users' preferred drug of abuse, indirectly activating the opioid system, and ex-heroin users are known to hoard, binge, and go to extremes to seek out sweets after going off drugs. This phenomenon is referred to as "consummatory cross-sensitization", and occurs when dependence upon one substance leads to the rapid acquisition of increased intake or dependence on another. It suggests that the brain and these neurotransmitter receptors can become primed after frequent activation, and will therefore become increasingly responsive to other sorts of excitatory stimuli.

After the New York Time's recent embarrassing op-ed publication on "iPhone addiction" and the resulting backlash, I'm reluctant to use the term in reference to anything other than drugs. However, given the evidence above, I believe there is a convincing argument that our brains and bodies process large quantities of sugar in much the same way as we do drugs of abuse. This does not mean that anyone who eats a slice of cake will develop sugar cravings, just as not everyone who takes drugs becomes addicted to them. However, for individuals who suffer from binge eating disorder or other eating problems it may be possible that their brains and bodies have adapted to put them at a disadvantage for trying to cut back on unhealthy foods or lose weight.

This is your brain on music

A great bit of research conducted by neuroscientists at Columbia University for the PBS program NOVA looks at the emotional implications of music and what happens in your brain as you listen to your favorite song. Using the famous neuroscientist and writer Oliver Sacks as a test subject, researchers played Dr. Sacks two pieces of music while he lay in an fMRI scanner. The first was from his lifelong favorite composer, Bach, and the other was by Beethoven, a talented adversary, but one who didn't resonate with Sacks quite as much. While listening to both pieces, areas in the auditory cortex and other regions typically associated with music lit up as expected. However, during the Bach piece the amygdala was also activated, signifying the emotional connection Sacks felt to the music. Even at moments when Sacks could not identify which composer he was hearing, his brain still demonstrated greater emotional responding to the Bach pieces.

Music is a universal human characteristic. We are born with the innate ability to hear and appreciate it, and all cultures create and celebrate their own styles. Our speech reflects the cadence and intonations of our society's popular music, as do the cries of even very young infants. According to a new book out by Elena Mannes, The Power of Music, music activates more areas of our brain than any other sensory experience, ranging from the auditory and motor cortices, to the executive control center in the frontal cortex, to older subcortical structures and the cerebellum. In her book she cites examples of music being used as a tool in speech therapy for individuals who experience verbal aphasia after suffering from a stroke in the left temporal lobe (the language center in the brain), and music or singing has long been used as a therapeutic instrument for chronic stutterers (just see The King's Speech for brilliant performances by Colin Firth and Geoffrey Rush).

Psychologists and neurologists have also begun using music as a form of therapy in a number of neurological disorders and are seeing encouraging results. In individuals with Parkinson's disease, music has proven to help patients with both their gross mobility and fine motor control. This phenomenon is wonderfully demonstrated in this video, where a man suffering from Parkinson's struggles to walk fluidly, jolting and hesitating across his living room. After putting on music though, his gait and demeanor entirely changes, and he triumphantly begins strutting and dancing around the room.

Dr. Sacks writes in his book Awakenings about patients suffering from encephalitis lethargica, or sleepy sickness, a rare disease with unknown origin, but believed to involve cells in the basal ganglia. This subcortical neural structure is involved in fine motor movements and is at the center of dopamine production in the brain. Patients with encephalitis lethargica demonstrate symptoms similar to patients with Parkinson's, as well as profound muscle weakness, catatonia and lethargy. In the 1960s Sacks discovered that encephalitis patients responded to treatment with L-DOPA, a precursor to dopamine used in Parkinson's patients to stimulate dopamine production and stimulate motor ability in the basal ganglia. However, Sacks also made the profound revelation that these same patients also responded to music, miraculously rousing them out of their catatonic state for a brief period to dance and sing.

The similarities between Parkinson's and encephalitis lethargica, both in their etiology and pathology, as well as their amazing assistance by music, suggests that the dopamine system is intrinsically involved in our experience and appreciation of music. One possible explanation is the ability of music to release endogenous dopamine into the brain via the cortico-striatal reward circuitry. However, many different stimuli have this ability, including food, sex, drugs and other hedonic pleasures, without having the therapeutic effects that music has in these patient populations. This suggests that there is something deeper and more inherent in the association between music and dopamine release that goes beyond pleasure, potentially implicating the motor system of the basal ganglia rather than the proximal nucleus accumbens, which is closely tied to reward. This could also explain why dancing is such a natural reaction to hearing beat or melody, as the movement could stem from the natural release of dopamine in the basal ganglia.

The powerful effect of music on the brain, with its broad reaching activations and emotional and physical implications, suggests that there is something very special about our relationship to it, and should be pursued as a potential source of therapy in other dopamine deficient disorders, such as drug addiction or depression.