Introduction: Biochemical Disruptions
For those of us who spend a lot of time in the Dorsal Vagus Nerve activated freeze/immobilization/death feigning stress response,
THE DORSAL VAGUS NERVE AND PARKINSON'S DISEASE,
a number of otherwise vital biochemical reactions in our brains and bodies can go awry. We may stop producing healthy levels of particular enzymes, peptides, hormones and neurotransmitters, or make too much of these, or else stop being able to remove toxic by-products, that are necessarily created as part of the chemical steps in the creation and degradation of these substances, fast enough.
For example, our bodies may become depleted of specific chemicals called “co-factors”, required for proper functioning of detoxification biochemistry, lacking now perhaps due to long years of overburden exposure to ingested or internally created personal poisons. We have already explored an example of this which arises as part of Dopamine biochemistry, whereby the metabolic steps in the breakdown of this neurotransmitter creates a toxic aldehyde called DOPAL.
DOPAMINE, ALDEHYDE POISONING AND PARKINSON'S DISEASE.
The “cofactor” in this case is molybdenum, which is required for an enzyme to be able to break down the poisonous DOPAL fast enough. If molybdenum is depleted or exhausted in our system, Dopamine production and degradation becomes self-poisoning, and our systems response can be inherently wise: to stop producing Dopamine.
However, there are many other important biochemical steps which can get severely disrupted when we are stuck in freeze or the Fear (Withdrawal) Paraylsis Reflex for long times. This is because immobilization is mediated by Dorsal Vagus Nerve activation in the gut. This stress signal causes the digestive system to shut down, and breaks the communication between gut and brain. The Enteric Nervous System is put into a state of shock or into “survival mode”, from the ongoing threat signals coming from the Dorsal Vagus activation. In this emergency state, healthy digestive chemistry goes offline and the gut stops producing some enzymes, peptides, hormones and neurotransmitters, stops absorbing some nutrients from food, and may even stop being an environment in which good microbiota can survive. .A large portion of our biochemicals are synthesised in the gut: 50% for Dopamine, and 95% for Serotonin, for example. The digestive system also directly affects the biochemistry of the brain, which we now know relies on gut signalling to the brain or healthy functioning too.
If we are stuck in freeze for long times, self-poisoning and increasing sensitivity or reactivity to environmental chemicals and food can occur due to the disruption of the Enteric Nervous System. It can even be the case that specific "health foods" or "beneficial supplements" can become toxic to us individually, because we simply no longer have the ability to complete their chemical processing fully.
Through long years of very careful elimination and re-introduction trials of food, supplement and environmental chemical exposures, I have discovered that I have a number of seriously haywire biochemical reactions, due to my prolonged Dorsal Vagus activation/Enteric Nervous System disruptions which are part and parcel of my rigidity dominant form of Idiopathic Parkinson's Disease. Often, these have only made sense after stumbling on research on specific biochemical disruptions which can occur in chronic illnesses, with sudden "ah ha!" realizations of why specific foods and chemicals affect me so detrimentally. Exposure to these presents itself in my case as markedly increased symptoms, especially pain, rigidity, immobility, anxiety and brain fog, while avoiding these at all costs has led to progressive symptom reduction over time, presumably as this gives time for my system to detoxify.
I do seem to be more prone to these biochemical issues than most people with PD, and indeed, it seems everyone has different reactivities (highly personalized) depending on precisely which parts of their biochemistry are broken. Thus there is no one size fits all solutions to any of this, and I believe with chronic illnesses of many kinds, we need to carefully test and observe the effects of diet and environment for ourselves, to work out what increases our symptoms on an individual basis.
In this article, I cover in depth what I’ve learned along the way for one specific biochemical pathway, in particular the production of Dopamine, perhaps the most relevant consideration for people with Parkinson’s Disease.
Basic Dopamine Biochemistry
Before proceeding, we need to a little of background on the biochemical pathway by which Dopamine is actually produced in our bodies and brains. The fundamental steps in this Dopamine production chain are:
PHENYLALANINE (from food) -> TYROSINE (from food or made in body from Phenylalanine) -> L-DOPA (from food or made in the body from Tyrosine, L-Dopa supplementation is also currently the mainstay medical intervention for Parkinson's Disease) -> DOPAMINE.
Any disruption at any stage of this biochemical chain, e.g. due to existing in Survival Mode or a stressed state for prolonged periods which shuts down healthy digestion, may result in a lack of Dopamine in our system.
Learnings from Black Urine Disease
I believe that some of the disruptions due to prolonged Dorsal Vagus activation may resemble or mimic genetically inherited problems, and I feel it is worth exploring what we can learn from these.
When I started using a urination bottle as a practical way to make going to the bathroom easier, less stressful and less messy while in an "off" (immoblized) state, I noticed that although my urine was quite clear at the time of passing water, frequently in the morning the little bit which was left in the bottom of the bottle would have turned dark brown or even black overnight (as exampled by the image at the top of this article). I emphasise here the changing of the color in the air-exposed bottle, some hours after passing perfectly clear wee, and not just coming out dark in the first place, which may be due to quite different reasons (e.g. dehydration, medications).
I then began to notice that I could also correlate the severity my symptoms and ineffectiveness of my PD meds during the day with the darker the urine had turned overnight - the darker, the worse I was likely to feel. So I began to investigate what this phenomena may signify in earnest. In doing so, I discovered a genetic biochemical disruption called "Alkaptonuria". This mechanism for urine to turn black when exposed to air is due to the body not being able fully break down two protein building blocks (amino acids) called Tyrosine and Phenylalanine, resulting in a build-up of a toxic chemical called Homogentisic Acid in the system. Given their central role in the Dopamine production chain outlined above, this direct link to a malfunction in the Phenylalanine and Tyrosine conversion steps set a number of light bulbs off in my head, and set me on a path of research, the outcomes of which I will attempt to cover here.
We immediately see that disruption of the Phenylalanine and Tyrosine steps can cause key steps in the biochemistry of Dopamine to be shut off, and hence the possible link to issues such as Alkpatonuria (aka "Black Urine Disease") with Parkinson's Disease: if our biochemistry is disrupted such that we can no longer convert enough Phenylalanine and/or Tyrosine to the L-Dopa stage, we cannot, in turn, synthesize enough Dopamine. Indeed, there are some significant overlaps in symptoms between the two conditions, for example, Black Urine Disease can result in lower back pain and stiffness, knee, hip and shoulder pain, and eventually, fascia may become brittle. If the bones and muscles around the lungs become stiff, it can prevent the chest expanding and lead to shortness of breath or difficulty breathing.
It is also telling that the mainstay medical treatment for PD remains supplementation of high levels of L-Dopa, and not of Phenylalanine and Tyrosine. This points to the need to skip the Phenylalanine and Tyrosine steps, because their conversion to L-Dopa and then Dopamine is not working properly or disrupted in some way in people with PD, requiring direct intervention at the L-Dopa stage instead. Apart from seeing my urine having turned black, I found further evidence that the early stages of Dopamine production are broken in my own biochemistry, because I’ve tried Tyrosine supplementation several times, but it has never worked to reduce my symptoms nor to switch my movement back on. In fact, it not only always gives me a headache, but also blocks the L-Dopa supplementation from being effective too. We will return to this blocking of L-Dopa medication by amino acids later in this research trail, as I believe it is important to understand how food-medicine interactions can prevent effective treatment.
Learnings from Phenylketonuria
More clues pointing to possible roles of disruption of proper biochemical processing of Phenylalanine, the building block of Tyrosine, and hence of L-Dopa and Dopamine too, arise from exploring another [mainly genetic] issue: Phenylketonuria or "PKU". People with PKU can't break down the amino acid Phenylalanine, which then builds up to toxic levels in the blood and brain. This can lead to brain damage.
Again, interesting overlaps exist between the symptoms of PKU and Parkinson's Disease, including: behavioural difficulties, mental health issues, skin problems, jerking movements in arms and legs, tremors. Also associated with PKU is a musty smell on the breath, skin and urine, which is intriguing given that is known that PD has its own musky smell, detectable by both humans and dogs. Also interesting is the fact that people with PKU have to avoid food products that contain aspartame, because this is converted to Phenylalanine in the body, and there are also strong associations with aspartame and PD made in the science literature.
The main version of Phenylketonuria is an inherited genetic disorder, due to mutations in which results in low levels of the enzyme "Phenylalanine Hydroxylase" (PH), the chemical catalyst required to remove the amino acid by converting it into the next step of the Dopamine production chemical train, Tyrosine. Without sufficient PH, this enzymatic conversion step cannot take place fast enough, resulting in the systematic build up of by-products of dietary Phenylalanine to potentially toxic levels.
Moreover, like most biochemical enzyme reactions, the PH enzyme also requires the presence of special chemicals itself, called “co-factors”, to work, and without which the enzyme still cannot do its detoxification job even if present in sufficient quantities. Indeed, another form of PKU is known, and this is due to "Tetrahydrobiopterin Deficiency" which occurs even when the Phenylalanine Hydroxylase enzyme levels are actually normal, because Tetrahydrobiopterin (BH4) is the co-factor which is required for the PH enzyme to work. Low levels of Dopamine are associated with this type of PKU, but not with the genetic version of PKU. This is because Tertrahydrobiopterin also turns out to be the co-factor for the next step in the Dopamine production chain, converting Tyrosine into L-Dopa, made viable by the enzyme “Tyrosine Hydroxylase”. A lack of BH4 is thus a “double whammy” which results in the disruption of both the Phenylanaline and Tyrosine conversion steps, blocking both as useful chemical building blocks of Dopamine. Indeed, one of the primary conditions that can result from BH4 deficiency is known to be Dopamine-responsive Dystonia.
One answer would be to supplement with BH4 when deficiency of this co-factor is the main issue. However, there seems to be serious problems with the production of BH4 as a supplement. First, it appears that it is already patented as a drug:
"Tetrahydrobiopterin is available as a tablet for oral administration in the form of Tetrahydrobiopterin Dihydrochloride, which is FDA approved under the trade name Kuvan. The typical cost of treating a patient with Kuvan is $100,000 per year. BioMarin holds the patent for Kuvan until at least 2024, but Par Pharmaceutical has a right to produce a generic version by 2020".
However, Life Extension, a company which supplies supplements, also state
"Seven years ago, Life Extension researchers identified a critical compound (Tetrahydrobiopterin) that is an essential cofactor. We spent several hundred thousand dollars trying to develop an affordable way to manufacture this compound as it offered tremendous promise. We failed to find an affordable way to make Tetrahydrobiopterin".
Thus the main way to manage BH4 deficiency and PKU-like biochemical disruption is through a special diet that avoids ingestion of Phenylalanine (and potentially Tyrosine), namely a low-protein diet that completely avoids foods such as meat, eggs and dairy products, and controls the intake of many other foods, such as potatoes and cereals. In addition, people with PKU issues may need take supplements of other specific amino acids to ensure they are getting all of the nutrients required for normal growth and good health.
Tyrosine Hydroxylase
Tyrosine can also be obtained from certain foods, especially meat and diary (in fact the word Tyrosine is derived from the Greek for cheese), or produced internally though biochemical conversion of Phenylalanine. If the Tyrosine conversion step into L-Dopa is blocked in some way, then the body and brain can only normally create enough Dopamine through ingested L-Dopa, allowing the Tyrosine step to be bypassed. L-Dopa is contained in specific foods too, famously high in a certain type of bean called mucuna pruriens, for example. Many people with PD have found benefit through ingesting mucuna pruriens. Meanwhile, synthetic L-Dopa supplementation is still the mainstay pharmaceutical intervention for Parkinson's Disease. Tyrosine supplementation doesn't appear to benefit many people with PD in the same way, and again this points to the Tyrosine biochemistry being disrupted in some way in some forms of PD and Dystonias.
The conversion of Tyrosine to L-Dopa is a relatively slow chemical reaction, and limits the rate at which Dopamine can be produced even in healthy people. It requires the presence of the enzyme Tyrosine Hydroxylase (TH) for it to occur fast enough at all, and TH in turn requires the "co-factor" chemical BH4 to work, as explained above. So two possible ways in which Tyrosine conversion towards Dopamine might get blocked are insufficient quantities of the TH enzyme in the body or insufficient availability of its co-factor BH4.
Interestingly, "Tyrosine Hydroxylase Staining" is a technique used on biological laboratory samples which shows up whether TH was present when the sample was part of a living animal . When a lack of TH is apparent in regions where it was expected, this has been used to infer that the dopamine producing cells there were dead when the animal was alive. In particular, TH Staining has been used in post-mortem brains of people with PD to infer that Dopamine producing cells in a region of the brain die off in people with PD. However, for me this is a leap too far: while such experiments on dead tissue show that TH levels are low in the PD brain, this does not necessarily mean that the Dopamine producing cells themselves were already dead, and it could be that they were simply not getting the TH supplies needed to create Dopamine. Indeed, according to the scientific journal article
Tyrosine Hydroxylase and Regulation of Dopamine Synthesis,
“Tyrosine Hydroxylase activity and Dopamine levels are decreased in the Parkinson brain more than would be expected simply from the loss of the Dopaminergic neurons. Therefore, chemical modifications to TH consistent with etiology of Parkinson Disease are of great interest".
A very recent piece of science,
Nigrostriatal dopamine transporter availability in early Parkinson's disease,
also confirms my perspective that PD does not necessarily mean cell death:
“ ‘These results suggest that in the early stages of the disease dopamine cells are still viable and that, given the correct treatment, it should be possible to restore their function,’ says Andrea Varrone, senior lecturer in nuclear medicine at Karolinska Institutet's Department of Clinical Neuroscience who led the study. “
Also, several other papers in the scientific literature, such as
Overview of tyrosine hydroxylase in Parkinson's disease,
Tyrosine hydroxylase and Parkinson's disease.
have even ascribed depletion of TH as causal in PD,
"Reduction of TH expression results in diminished Dopamine synthesis and leads to PD; thus TH is essential in the pathogenesy of PD."
Interactions with Medication
More learnings can be gleaned by considering how the chemical building blocks of Dopamine, which are mainly sourced through ingesting food, actually get out of the gut [small intestine], into the blood stream, and from the blood into the brain through the blood-brain-barrier. Indeed, researching PKU disease further, I discovered:
"Phenylalanine is a large, neutral amino acid (LNAA). Other LNAA's compete with it for specific carrier proteins that transport LNAAs across the intestinal mucosa into the blood and across the blood–brain barrier into the brain. If Phenylalanine is in excess in the blood, it will saturate the transporter. Excessive levels of Phenylalanine therefore tend to decrease the levels of other LNAAs in the brain. As these amino acids are necessary for protein and neurotransmitter synthesis, Phenylalanine buildup hinders the development of the brain, causing intellectual disability."
and
"It was recently suggested that PKU may resemble amyloid diseases, such as Alzheimer's disease and Parkinson's disease, due to the formation of toxic amyloid-like assemblies of Phenylalanine."
Importantly, Tyrosine is itself one of these other large, neutral amino acids, and hence too much Phenylalnine build up can block it getting to the brain, yet another mechanism by which the production of Dopamine through conversion of Tyrosine to L-Dopa in the brain could be disrupted, even if Tyrosine chemistry itself is healthy in this case.
Interestingly, it also appears that L-Dopa is transported across these membranes via the same type of proteins. Importantly, this means that getting supplemental L-Dopa from the gut into the brain could also be a competitive process with other amino acids, e.g.
High- and low-affinity transport of L-leucine and L-DOPA by the hetero amino acid exchangers,
complex transports L-DOPA across the blood-brain barrier,
and the chemicals which may compete with L-Dopa for transport include both Phenylalanine and Tyrosine. This would match my own experience mentioned above that, for myself, supplementation by Tyrosine not only wasn’t helpful, but also significantly blocked the effectiveness of my L-Dopa based PD meds. Thus a further complication is that, if either Phenylalanine or Tyrosine conversion towards Dopamine are disrupted in some way, such that these become saturated in the body, this could have significant impact on the effectiveness of PD drugs, blocking their uptake.
Another important drug interaction may occur with Tyrosine and the so-called Monoamine Oxidase Inhibitors (MAOIs) class of pharmaceutical interventions. MAOIs slow the breakdown of Dopamine in the body and brain, which can help make L-Dopa supplementation work for longer periods or more effectively.
The link to Tyrosine arises, because not only can Tyrosine be biochemically converted to L-Dopa, but also to a chemical called Tyramine, in the gut via a different chemical pathway. If Tyrosine conversion to L-Dopa is disrupted, therefore, this alternative pathway may become over-activated, resulting in excessive levels of Tyramine. This seems important, because
"Tyramine is an amino acid that helps regulate blood pressure. It occurs naturally in the body [through conversion of Tyrosine], and it's found in certain foods. MAOIs block monoamine oxidase, which is an enzyme that breaks down excess Tyramine in the body, helps relieve depression. If taking an MAOI and eating high-Tyramine foods [or presumably are converting a build up of Tyrosine to Tyramine], Tyramine can quickly reach dangerous levels. This can cause a serious spike in blood pressure and require emergency treatment. Avoid consuming foods that are high in Tyramine if you take an MAOI. You may need to continue following a low-Tyramine diet for a few weeks after you stop the medication."
MAOIs themselves can be naturally found in some foods. Life Extension supplies a natural MAOI as a supplement called "Dopa-Mind“ based on Wild Green Oat extract.
Interactions with Gut Bacteria
While I was researching this area, a very timely article appeared in "Nature":
Gut bacterial tyrosine decarboxylases restrict levels of levodopa in the treatment of Parkinson’s disease.
Interestingly, the paper highlights a phenomenon in which bacteria in our small intestines may produce, as by-products of their life cycles, very similar chemicals as those involved in the innate bio-chemical production of neurotransmitters. In particular, the researchers discovered how specific types of bacteria in the gut create chemicals called Tyrosine Decarboxylases (TD). TD is actually the enzyme which catalyses the conversion of Tyrosine in to Tyramine, but it can also catalyses the conversion of L-Dopa into Dopamine.
The outcome of this is that the high levels of these bacteria in the gut, found in people with PD who rely on L-Dopa supplementation, can cause significant amounts of the L-Dopa to be converted directly to Dopamine in the small intestine, before it is absorbed into the blood stream and can get across the blood-brain-barrier. This results in not enough of the L-Dopa reaching the brain, requiring ever increasing dosages.
Actually, this conversion of L-Dopa in the gut to Dopamine due to the presence of the natural TD enzyme, was a problem known from the early days of L-Dopa supplementation for PD. This is why the PD medications are not just straight L-Dopa supplements, but also contain another chemical: a TD inhibitor, which stops the enzyme working on the L-Dopa component before it escapes the gut, increasing the chances that more of the drug gets to the brain. In Sinemet, the TD inhibitor is called Cardidopa, and in Madopar it is Benserazide. Intriguingly, however, the above article also finds that these inhibitor chemicals additives in PD drugs, while blocking the action of natural (human) TD, are highly ineffective at inhibiting the action of the bacterially generated forms of TD!
Another issue with excessive TD in the gut is then that Tyrosine will also be effectively converted to Tyramine more competitively with the conversion of Tyrsosine to naturally (bio-chemically) produced L-Dopa. This could be another way that the Tyrosine pathway to Dopamine is effectively cut off, and another reason why Tyrosine supplementation doesn't appear to provide the same benefits as L-Dopa for some people with PD, because then the Tyrosine is preferentially feeding the production of Tyramine rather than that of L-Dopa.
Interactions with Fungi
In sharing this series, fellow persons with Parkinson's Disease, David Spry and Glen Petitbone, pointed out some important and profound information about how fungal factors could interfere with the Dopamine biochemical production pathway, too. For example, according to the Wikipedia article on a fungal toxin called “Ochratoxin A”:
"Ochratoxin is a toxin produced by different Aspergillus and Penicillium species, one of the most-abundant food-contaminating mycotoxins. It is also a frequent contaminant of water-damaged houses and of heating ducts. Human exposure can occur through consumption of contaminated food products, particularly contaminated grain and pork products, as well as coffee, wine grapes, and dried grapes. The toxin has been found in the tissues and organs of animals, including human blood and breast milk."
Furthermore,
"Ochratoxin A has a strong affinity for the brain, especially the cerebellum. Ochratoxin causes acute depletion of striatal dopamine, [as in] Parkinson's disease, but it did not cause cell death in any of brain regions examined."
The impact of the fungal toxin on Dopamine appears to occur by once more disrupting the biochemical reaction pathway of the neurotransmitter. In particular, it inhibits the enzyme Phenylalanine Hydroxylase, the chemical catalyst required for fast enough conversion of Phenylalanine into Tyrosine, creating PKU-like effects,
Studies of ochratoxin A-induced inhibition of phenylalanine hydroxylase and its reversal by phenylalanine.
David then suggested I looked up “Malassezia” and L-Dopa.
"Malassezia is a genus of fungi, naturally found on the skin surfaces of many animals, including humans. Allergy tests for this fungus are available."
Moreover,
"Investigations show that the Malassezia species causing most skin disease in humans, including the most common cause of dandruff and seborrhoeic dermatitis. As the fungus requires fat to grow, it is most common in areas with many sebaceous glands: on the scalp, face, and upper part of the body. When the fungus grows too rapidly, the natural renewal of cells is disturbed, and dandruff appears with itching (a similar process may also occur with other fungi or bacteria)."
This is interesting, because such skin issues are very prevalent in Parkinson's Disease. Indeed, David makes one more extremely important connection. Malassezia feeds on L-Dopa,
The Role of L-DOPA on Melanization and Mycelial Production in Malassezia Furfur,
which infers overgrowth of this fungus may deplete natural or supplemental sources of L-Dopa in the body, preventing enough getting into the brain, and hence this could presumably contribute to PD symptoms, as well as impact on the effectiveness of L-Dopa supplementation.
Even more intriguing, as mentioned above, PD is now known to have a musky specific smell, which both dogs and humans can detect, and this smell has been linked directly to Malassezia:
"The change of neurotransmitters secreted by the neurons affected by PD could stimulate sebum production by exocrine glands. This change in sebum could be the perfect media for certain lipophilic bacteria and yeast (Malassezia yeasts for example) to thrive, changing the person’s skin microbiome. Changes in the microbiome, in turn, create the unique smell of PD and explain why the smell gets stronger each year, as microbial colonies proliferate with the worsening of the disease.”
This may help explain why people with PD need more and L-Dopa as time goes on, because the L-Dopa is feeding the fungus, and as it proliferates it consumes more and more of the L-Dopa supplement before it can reach the brain.
Links between Malassezia infections and PD have also been directly, e.g.
A laboratory-based study on patients with Parkinson’s disease and seborrheic dermatitis: the presence and density of Malassezia yeasts, their different species and enzymes production.
Pragmatic Conclusions
It is difficult to make any generic, one-size fits all recommendations for the short or medium term steps which people with PD can take, because, as the above outlines, there are a myriad of ways and complex interactions by which Dopamine biochemistry can be disrupted, and the problems, and hence solutions, are likely to be very individualistic. Certainly, the above highlights the role of food and supplements in addressing these disruptions. It would certainly be worth monitoring any changes in urine samples overnight, especially if it turns from clear to black. Indeed, addressing this observation in myself, mainly through cutting down on Phenlyalanine and Tyrosine containing foods (a low meat and cow’s dairy diet), has cleared it up in my case (apart from when I eat too much protein), and I definitely feel better for it. I continue to monitor my urine.
It is also clear to me from all the research presented in this article that the solutions depend on whether we are already habitualized on L-Dopa supplementation. There seems little benefit in ingesting Phenylalanine or Tyrosine in this case, because this natural biochemical pathway to L-Dopa will not only be redundant (too slow and limited in comparison to the action of the supplemental L-Dopa), but these amino acids may interfere with the L-Dopa medication effectiveness in several ways. For those at early stages of PD, however, and/or not yet reliant on L-Dopa supplements, it might be worth seeking carefully to re-establish the Tyrosine pathway. In either case, I feel it may be worth very carefully undertaking trials of eliminating and re-introducing high Phenlyalanine, and/or Tyrosine containing foods and supplements, to assess if avoiding or increasing ingesting these might help.
In terms of the potential interactions with bacteria and fungi, this provides another reason for people to PD to stick to an anti-inflammatory or anti-fungal diet, such as that recommended in
Role of Diet and Nutritional Supplements in Parkinson’s Disease Progression.
However, my experience and research points to a long term solution: seek to decrease the disruptive effect on digestion and the Enteric Nervous System due to over-activation of the Dorsal Vagus Nerve, by regulating and calming the Nervous System, and increase Ventral Vagal and Parasympathetic Nervous System tone. This includes learning to how relax, reconnecting body and mind and establishing healthy sleep cycles. The many other articles on this website document the practical steps I have been undertaking towards this goal. Interestingly, I am currently experiencing a phase in which the effectiveness of my L-Dopa supplementation is becoming more effective again, such that it is much more likely that a dose will actually switch my movement back on, with significantly more “on” time, and less severe side-effects, such as Dyskinesia, overall.