Know your brain: Parkinson's disease


In 1817, James Parkinson published an essay titled An Essay on the Shaking Palsy. In it, Parkinson described 6 patients who suffered from tremors, abnormalities in gait, balance problems, and a number of other symptoms. Parkinson, a physician in a village outside of London, hypothesized that these symptoms were characteristic of one overarching disease. His meticulously detailed account of these cases provided a clearer picture of the disorder than anyone before him had been able to produce.

Parkinson's precise descriptions and insightful conclusions led his essay to become recognized as an important step forward in understanding this collection of symptoms. Later in the 19th century, the influential neurologist Martin Charcot suggested the disorder that Parkinson had described should be called Parkinson's disease (PD).

What are the symptoms of Parkinson's disease?

The most noticeable symptoms of PD are movement-related, and the hallmark symptoms are: bradykinesia, resting tremor, and rigidity.

Watch this 2-Minute Neuroscience video for a summary of Parkinson’s disease symptoms, neurobiology, and treatment.

Bradykinesia refers to slowness of movement---especially slowness of the initiation of movement. PD patients will often have trouble getting their body to transition from a resting state to an active state. When they finally do get moving, their movement may be much slower than a healthy patient's.

Resting tremor indicates a tremor that is worse when the patient is at rest. When the patient makes a voluntary movement, the intensity of the tremor often subsides. These tremors typically start in the hands or arms and then spread to the legs as the disease progresses.

Rigidity describes a state of generally elevated muscle tone where the patient displays inflexibility and resistance to movement (try to reach for something while keeping your arm muscles contracted and you can see how this can result in rigid and difficult movement).

Although these movement-related symptoms are the most familiar signs of PD, there are a number of other common symptoms (both movement-related and non-movement-related) that occur as well. For example, later in the disease, postural instability becomes common, making falls more likely. Some of the non-motor symptoms include constipation, deficits in the sense of smell, sleep abnormalities, mood disorders like depression and anxiety, cognitive impairment, and dementia. 

What happens in the brain in Parkinson's disease?

Although there are many changes that occur in the brain during PD, there are two pathological changes that are considered hallmark signs of the disease. One is the degeneration and death of dopamine neurons in a dopamine-rich region of the brainstem called the substantia nigra. By the time a PD patient dies, she may have lost up to 70% of the dopamine neurons in this region. Neuronal loss in PD is most prominent in the substantia nigra, but as the disease progresses neurons in other areas of the brain and brainstem, like the amygdala, hypothalamus, locus coeruleus, and median raphe nucleus (among others) begin to die as well.

The basal ganglia (surrounded by red box).

How exactly the death of dopamine neurons in the substantia nigra leads to the most common symptoms of PD is still not completely clear, but current hypotheses focus on the role of dopamine neurons in the substantia nigra in facilitating movement. The substantia nigra is part of a collection of structures known as the basal ganglia, which are extremely important for movement (among other things). The basal ganglia are thought to both be involved in helping us to move when a movement is desired, and inhibiting movement when it's not wanted.

To get a better understanding of how this balance of movement and movement inhibitions works, think for a moment about what's going on in your body right now as you remain relatively still to read this text (if you are moving right now while you're reading this, then think of another time when your body was at rest). As you're reading, if you want to move your hand to the screen or mouse, the movement is initiated by your brain. But when you're not aiming to make a movement, and are trying to stay relatively motionless, your brain is also intensively involved in keeping you that way. In other words, as you're remaining still, your brain has to intentionally inhibit any undesired movements---like your head suddenly turning in a different direction, your hand involuntarily jerking up in the air, and so on.

The basal ganglia are thought to be integral to this type of inhibition, as circuits within them constantly quiet the activity of neurons that project to the motor cortex to initiate voluntary movement. Dopamine neurons in the substantia nigra play a role in the release of that inhibition. In other words, without dopamine, your basal ganglia have a difficult time stopping their inhibition of your movement. They become like a switch that can't be turned off, and in this case the switch controls a device that constantly applies force to keep another device from being turned on.

Thus, when those dopamine neurons degenerate and die, it becomes more difficult to stop your basal ganglia from inhibiting movement. Then, even desired movements can be inhibited, providing an explanation for why the initiation of movement for a PD patient requires so much effort, and why it is slow and labored even after it starts.

What causes the death of dopamine neurons in the substantia nigra, however, is still unclear. Some research suggests their death is linked to abnormal protein deposits, which are the other hallmark sign of a PD brain. These deposits consist primarily of a protein called alpha-synuclein, which in PD and several other disorders (e.g. Alzheimer's disease, dementia) can clump together in abnormal aggregates inside neurons. These protein aggregates are known as Lewy bodies, named after Fritz Lewy, who discovered them in 1910. Lewy bodies are thought to be able to interfere with cell structure and function in a number of ways, ranging from damaging DNA to the destruction of mitochondria.

Regardless, the connection between Lewy bodies and cell death is still not completely clear, and some researchers point to evidence of cell death in areas where no Lewy bodies are typically seen as proof that other factors are at play in causing neurons to die in PD.

All neurons in the brain express alpha-synuclein and rely on the same mechanisms thought to fail in neurons that die during PD pathology, so it's still unclear why PD preferentially affects the substantia nigra and a select few other areas of the brain. Some have proposed that PD is capable of spreading throughout the brain using a prion-like mechanism, and the path of spreading is dictated by the connections of neurons. Others suggest that certain neurons are simply more susceptible to the pathology that causes damage in PD, and thus they are the ones most likely to be affected. As of yet, the exact reasons for the tendency of PD pathology to preferentially affect certain areas of the brain are still unclear.

It's also uncertain what causes the disease process to begin in the first place. In most cases, it is thought to be linked to a combination of genetic and environmental factors. But exactly which genes and environmental influences are involved likely differs from case to case, and although a number of potential genes and environmental risks (e.g. pesticide exposure, repetitive head injuries) have been identified as potential contributing factors, more research needs to be done to develop a better understanding what exactly causes the initiation of the disease.

L-DOPA for Parkinson's disease

Although there are now several viable treatments for PD, the most common---and often the most effective treatment initially---is a precursor to dopamine called levodopa, or L-DOPA. When your brain produces dopamine, it starts with the amino acid tyrosine, which it can either get directly from the diet or through the conversion of another amino acid (phenylalanine). Tyrosine is then converted into L-DOPA, which can be converted into dopamine.

While it might seem that the most logical treatment for PD would be to administer dopamine to the patient to replenish depleted levels of the neurotransmitter in the basal ganglia, this would prove fruitless because dopamine cannot cross the blood-brain barrier, a structure that generally helps to keep unwanted substances circulating in the bloodstream from entering the brain. This barrier is usually beneficial, as it prevents things like pathogens from getting into the brain. Unfortunately, however, the blood-brain barrier can also thwart attempts to get potentially therapeutic substances into the brain.

L-DOPA, on the other hand, can cross the blood-brain barrier. Thus, when L-DOPA is administered to a PD patient, the brain can use the excess levels of the precursor to produce more dopamine, replenishing depleted levels of the neurotransmitter (at least this is what the role of L-DOPA typically is assumed to be---see below). This can, in less than an hour after administration, produce some astonishing improvements in motor function. Take a look at the video to the right as an example. In it, you'll see a PD patient before L-DOPA therapy displaying all of the classic signs of PD (e.g. tremor, bradykinesia, postural instability). Then, at around 1:00 into the video, you'll see that same patient after L-DOPA administration, and all of the symptoms have disappeared.

While the hypothesis that L-DOPA improves PD symptoms by acting as a precursor the brain can turn into more dopamine is taught as fact in most neuroscience courses, researchers are actually still a bit unclear on exactly how L-DOPA works. Some evidence suggests it can act as a neurotransmitter on its own, and there are also indications it can be converted into other active compounds (besides dopamine), which may be capable of influencing dopamine activity.

Regardless of how it works, when L-DOPA was first discovered it seemed like a miracle drug. But problems with L-DOPA treatment soon became apparent. One problem is that, over time, the effectiveness of L-DOPA seems to diminish. In the early days of L-DOPA treatment, the medication can sometimes completely control a patient's symptoms. Later in treatment, however, patients may experience a return of symptoms between doses, and the time they experience relief from their PD symptoms can gradually decrease with continued time on the drug.

Additionally, long-term use of L-DOPA is associated with movement-related side effects itself. These movement problems are often called L-DOPA-induced dyskinesias, and include symptoms like involuntary movements and sustained muscle contractions. It's still not fully understood why these side effects occur, but researchers have hypothesized that chronic L-DOPA therapy can lead to excessive dopamine activity in the basal ganglia, essentially creating the opposite effect (excessive movement) from what the paucity of dopamine typically causes in PD (a lack of movement). This perspective has been challenged, however, by evidence that suggests the development of dyskinesias may not be dependent on increases in dopamine levels.

Since the discovery of L-DOPA, there have been a number of other drugs discovered that can increase the effectiveness of L-DOPA or have their own effects to improve PD symptoms. New surgical methods like deep brain stimulation also offer some promise in treating cases of the disorder that have become resistant to other types of treatment. None of these approaches, however, has the ability to stop the progression of neuronal death that leads to Parkinsonian symptoms to begin with. L-DOPA, for example, may be able to replenish dopamine levels, but it can't stop dopamine neurons from dying. Thus, L-DOPA and other PD treatments are ways of managing symptoms, but they do not remedy the underlying pathology of the disease. Because of this, researchers continue to fervently look for better alternatives for treating PD.

Reference (in addition to linked text above):

Obeso JA, et al. Past, present, and future of Parkinson's disease: A special essay on the 200th Anniversary of the Shaking Palsy. Mov Disord. 2017 Sep;32(9):1264-1310. doi: 10.1002/mds.27115.

Want to learn more about Parkinson's disease? Try these articles:

Deep brain stimulation in Parkinson's disease: Uncovering the mechanism

The unsolved mysteries of protein misfolding in common neurodegenerative diseases

2-Minute Neuroscience: Parkinson's Disease


In this video, I discuss Parkinson's disease---the second most common neurodegenerative disease behind Alzheimer's disease. Parkinson's disease is associated with the degeneration and death of dopamine neurons in the substantia nigra. The substantia nigra is a region of the brain that is part of a collection of structures known as the basal ganglia, which are important to movement. Parkinson's disease patients experience severe movement difficulties that become more problematic as the degeneration of substantia nigra neurons becomes more extensive. The most common treatment for Parkinson's disease involves the administration of L-DOPA, a precursor to dopamine that allows the brain to synthesize more of the neurotransmitter to replenish depleted dopamine levels.

Deep brain stimulation in Parkinson's disease: Uncovering the mechanism

Parkinson's disease (PD) belongs to a group of diseases that are referred to as neurodegenerative because they involve the degeneration and death of neurons. In PD a group of structures called the basal ganglia, which play a role in facilitating movement, are predominantly affected. The substantia nigra, one of the basal ganglia nuclei as well as one of the most dopamine-rich areas in the brain, is severely impacted; by the end stages of the disease patients have often lost 50-70% of the dopamine neurons in this region. This excessive loss of dopamine neurons and the accompanying depletion of dopamine levels in the basal ganglia are associated with increasingly debilitating movement-related symptoms, such as rigidity, tremor, bradykinesia (slow movement), and postural impairment.

The most common method of treating PD involves the administration of L-DOPA. L-DOPA is a precursor to dopamine that the brain can use to synthesize more of the neurotransmitter; thus, it works to increase the dopamine levels that are being continuously reduced by the disease. PD, however, is progressive, meaning that neurodegeneration will continue once it has begun. L-DOPA isn't capable of halting neurodegeneration, and eventually the dopamine synthesized from L-DOPA is not enough to replace all that has been lost due to the disorder; with time L-DOPA begins to lose its effectiveness. Especially in the later stages of PD, L-DOPA provides diminishing returns, and the side effects of chronic L-DOPA treatment start to make its continued use more detrimental than beneficial.

Therefore, we continue to seek out treatments for PD that will be more effective in the advanced stages of the disease (while maintaining a manageable side effect profile). In the early 1990s, it was observed in non-human primates that lesions of the subthalamic nucleus (STN) appeared to effectively eradicate Parkinsonian symptoms. Although the reason for this was not fully understood, a hypothesis was formulated based on the understanding that one of the functions of the STN seems to be to inhibit unwanted movements. Normally, this suppression of movement should only occur when a movement is not desired, and thus the interference should be removed with the attempt to initiate movement. In PD, decreased dopamine levels may prevent another structure in the basal ganglia, the globus pallidus, from moderating activity in the STN. This can lead to excessive STN activity, which serves to overly-inhibit movements and may cause the difficulty in making movements that characterizes PD. Based on this rationale and related experimental evidence, the STN was identified as a potential therapeutic target in PD. At that point, though, the only way to reduce activity in the STN was through a surgical procedure that irreversibly destroyed the nucleus.

However, not long after the STN was identified as playing a role in PD symptoms, a new method of influencing activity in the STN (and other brain areas) was developed: deep brain stimulation (DBS). This method was tested in patients with PD for the first time in the mid-1990s. The results were encouraging, as in some cases symptoms improved drastically and the patients were able to reduce their dose of L-DOPA and related drugs significantly. An example of the marked improvements that can occur after DBS is initiated can be seen in the video to the right. Since the first experimental DBS procedures, the method has been used with thousands of patients, making it an established therapeutic approach for the treatment of advanced PD.

Deep brain stimulation procedure

DBS involves the insertion of an electrode into the brain. Thus, it requires an invasive surgical procedure that necessitates making one or two holes in the skull. An electrode is placed in the desired region of the brain (in the case of PD usually the STN but also sometimes the globus pallidus); the electrode is connected to a wire that runs under the skin to a device called a pulse generator, which is usually implanted under the collar bone.

When the pulse generator is turned on, it emits electrical impulses that seem to disrupt neural functioning. This can be used to cause changes in brain activity that resemble what happens when a lesion has been created. Thus, implanting an electrode near the STN and turning on the pulse generator reduces excessive activity in the STN; the abatement of STN activity is associated with an improvement of symptoms.

Although the DBS procedure has seen some success in alleviating symptoms in patients with advanced PD, the mechanism by which it achieves those effects is still unclear. DBS in the STN does reduce STN activity in patients with PD, but it is uncertain why stimulation of a brain region would have effects similar to the ablation of that brain region. Several hypotheses have been put forth to explain the mechanism of DBS, ranging from the assertion that DBS causes changes in neurotransmitter and hormone levels to the proposition that DBS disrupts abnormal neural oscillations in the brains of PD patients. This latter hypothesis has perhaps received the most research attention as a mechanism of DBS, and is considered by some to be the most viable explanation.

Neural oscillations and phase-amplitude coupling

The term neural oscillations describes rhythmic changes in the electrical activity of neurons and can involve fluctuations in the membrane potential of an individual neuron (i.e. action potential) or a small population of neurons (i.e. local field potential). These neural oscillations in certain areas of the brain tend to exhibit patterns of synchronization, which means that the activity of different neural populations becomes regulated on a similar timescale. In other words, synchronized neural populations may (on average) fire action potentials at the same time, then be at rest at the same time. It is thought that these synchronized patterns of neural activity are used to facilitate communication and integrate activity among groups of neurons from different parts of the brain, and thus normal oscillatory behavior may be essential for diverse functions ranging from sensory perception to motor movements

There are several different rhythms of oscillatory activity that can be detected throughout the brain; they range from low frequency delta oscillations (1-4 Hz) to high frequency gamma oscillations (>30 Hz). What makes understanding the effects of neural oscillations even more complicated is that these different frequencies of oscillations can be linked, or coupled, together in such a way that different areas of the brain with different patterns of oscillatory activity seem to work in concert with one another by coordinating their disparate oscillatory behavior. For example, a peak in the activity in one region might coincide with a valley in the activity of another. This mechanism, known as phase-amplitude coupling (PAC) may allow for the syncing of activity across a variety brain regions in a dynamic manner, and is becoming recognized as a key feature of healthy cognition.

Deep brain stimulation as a correction to abnormal oscillatory activity

Patients with PD display abnormally increased oscillatory activity in the STN in the beta frequency (13-30 Hz), which has been hypothesized to disrupt the normal functioning of the basal ganglia in such a way as to impair movement. And, some studies have found that the reduction of this oscillatory activity may be one mechanism by which DBS alleviates the symptoms of PD. However, the signal for voluntary movement originates in the motor areas of the cerebral cortex, and it remains unclear how abnormal beta oscillations in the basal ganglia might influence the motor cortex in such a way as to produce the movement-related symptoms of PD. Thus, it is also unknown how the stimulation provided by DBS might affect the motor cortex to alleviate those symptoms.

In a recent study published in Nature Neuroscience, de Hemptinne et al. (2015) explored the hypothesis that DBS helps to improve the symptoms of PD by reducing excessive coupling of neural oscillations in the motor cortex. In non-PD patients, PAC between high- and low-frequency oscillations in motor areas of the brain occurs when at rest and is reduced when movements are made. It has been suggested that this coupling may inhibit neural activity until movement is initiated; at that point the coupling is diminished so movement can occur. de Hemptinne et al. hypothesized that in PD patients, the PAC is exaggerated and continues to inhibit movement even when a movement is desired. DBS, however, may act to reduce PAC and increase the possibility of movement execution. To test this hypothesis, they used a procedure called electrocorticography in PD patients before, during, and after DBS stimulation of the STN.

Electrocorticography (ECoG), also sometimes called intracranial electroencephalogram (iEEG), involves the placement of electrodes directly on the surface of the brain to record the electrical activity of neurons. Although this is an invasive surgical procedure, the patients in the study by de Hemptinne et al. were already undergoing surgery for the placement of the DBS electrode and thus an additional surgical procedure wasn't required. In this study, the electrodes for ECoG were placed directly on the sensorimotor cortex.

As the authors hypothesized, the ECoG recording before the DBS device was turned on showed excessive beta frequency activity in the STN as well as exaggerated coupling of beta activity with gamma frequency oscillations in the motor cortex. Patients at this point displayed characteristic PD symptoms like rigidity, tremor, and bradykinesia. When the DBS device was turned on, however, the abnormal PAC in the motor cortex was reduced and symptoms were alleviated. Additionally, the degree to which PAC was reduced was associated with the degree to which the patients' symptom severity was mitigated. Thus, it appears plausible that DBS reduces PD symptoms in part by reducing PAC in the motor cortex.

DBS is still considered a last-resort option for most PD patients, as it does involve invasive surgery and all the associated risks, and it is not successful for everyone. However, if we can come to fully understand the mechanism by which it works, we may be able to refine the method and improve its success rate. For example, if PAC in the motor cortex is to blame for the severity of some of the symptoms of PD, future DBS devices could incorporate real-time monitoring of PAC and the automatic adjustment of stimulation to most effectively reduce it.

As we uncover more information about the mechanism of DBS, it may become a treatment for PD that can eventually replace L-DOPA which, despite its therapeutic value, remains a temporary solution to the problem. Regardless of the improvements we make to DBS, however, it still does not seem it will be capable of permanently arresting the neurodegeneration that occurs in PD. Thus, the search will continue for a therapeutic approach to treating the symptoms of PD that can at the same time either slow or stop the relentless loss of basal ganglia neurons that defines the disease.

de Hemptinne, C., Swann, N., Ostrem, J., Ryapolova-Webb, E., San Luciano, M., Galifianakis, N., & Starr, P. (2015). Therapeutic deep brain stimulation reduces cortical phase-amplitude coupling in Parkinson's disease Nature Neuroscience, 18 (5), 779-786 DOI: 10.1038/nn.3997