Parkinsonism: a war without truces

Natalia Ivlieva, "Trinity Variant"

What is Parkinson's disease, or — more broadly — Parkinsonism? Let's turn to Oliver Sacks, who gave a thorough and heartfelt description of the symptoms of the disease at the beginning of his famous book "Awakenings" about the life and struggle with the disease of patients of the clinic in which Sacks worked. (Based on the book, an equally famous film of the same name was shot, in which Robert De Niro and Robin Williams played, perhaps, some of their best roles.)

Parkinson's disease has been called tremor paralysis for several centuries. <...> It is necessary to make a reservation right away that trembling, or tremor, is never an independent manifestation of the disease and generally represents the easiest of the disorders that patients with Parkinsonism have to face. <…>

The second most common symptom of Parkinsonism, besides tremor, is stiffness or rigidity. This rigidity has one notable feature — it is plastic rigidity (characterized by a fairly uniform resistance of the muscles to passive movements. — N. I.), and it is sometimes compared with the plasticity of a bent lead pipe. <...> The main and unique feature of Parkinsonism, detected in all patients without exception, is movement disorders. <…>

The first, described initially, characteristic of Parkinsonism of the patient are fussiness (mincing gait) and propulsions (tremors). Fussiness manifests itself in the acceleration (and simultaneous shortening) of steps, movements, utterance of words and even thoughts — at the same time, the impression of impatience, impulsiveness and haste is created, as if the patient is acutely aware of a lack of time or is late somewhere. Some patients do have a feeling of time deficit and impatience at the same time, although in other cases patients rush against their will. Characteristic features of movements caused by pathological fussiness are speed, sharpness and brevity. <...> I deliberately emphasize these aspects — liveliness, violence and the inevitability of movement — because they represent the "underside" of Parkinsonism, boiling Parkinsonism, Parkinsonism, capable of bursts and explosive reactions, very significant and important, if we keep in mind the numerous "side effects" manifested in patients, less familiar to the general public, taking L-dopa.

The phenomenon opposite to these effects — a kind of slowing down and difficulty of movement — is usually brought to the fore and is designated by the generalizing and very uninformative term "akinesia". There are many forms of akinesia, but a form that is the exact antithesis of thrusts, or propulsions, manifests itself in active inhibition, or resistance, hindering movement, speech, and even thinking, and can lead to their complete stop. Affected in this way, patients discover that as soon as they "wish", or intend, or try to start moving, immediately there is some kind of "opposite desire", or "resistance", in contrast to the original desire. Patients realize that they are driven into an iron system, even immobilized by a special form of physiological conflict — force against force, will against counter will, order against counter-order. Regarding such cornered patients, Sharko writes: "There are no truces in this war." Charcot sees behind the tremor, rigidity and akinesia of these patients the final hopeless outcome of such states of internal struggle as tension and fatigue, which patients with Parkinsonism complain of as a waste of their strength in these senseless internal battles.

Often in the literature, a postural imbalance is also called as a motor symptom, thus highlighting four key signs of the disease in humans: rest tremor, rigidity, slowness of movements and the actual postural imbalance. (Usually Parkinsonism is called the whole group of motor function disorders caused by damage to the dopaminergic system, and Parkinson's disease is a special case of Parkinsonism that develops in the elderly in the absence of obvious triggering factors.)

But Parkinsonism should not be considered a disease characterized exclusively by a lesion of the motor system. In the notes to his book , Sachs writes:

The two main perverted types of will described by James are the "obstructive" will and the "explosive" will. If the first wins, then normal actions become difficult or even impossible. If the second one dominates, then the person is unable to suppress his abnormal actions. Although James uses these terms in application to neurotic perversions of the will and desires, they, of course, are quite applicable to those disorders that we designate as Parkinsonian perversion of the will: parkinsonism, like neurosis, is a volitional disorder.

Oh, this "will", how many copies have been broken in discussions about the validity of this concept in science, in philosophy! "A subject that is indecent even to discuss, a hypothetical revelation of reality in the self under the guise of force or will" (F. G. Bradley). But it is this concept that most accurately expresses our sense of belonging to the world in which we live.

In addition to motor symptoms, we should also mention the so-called non-motor symptoms of Parkinson's disease, which in recent years have been receiving more and more attention in scientific publications: these are cognitive problems, sleep and mood disorders, olfactory disorders, apathy, a wide range of autonomic disorders (1).

Causes of the disease

To date, there is no doubt that the cause of most motor disorders in Parkinson's disease is the death of most of the dopamine neurons of the midbrain, especially in the compact part of the black matter (substantia nigra pars compacta, SNpc). What caused this lesion and why dopamine neurons of the black matter are more vulnerable is still not known, but this problem is being intensively investigated. First of all, the scenario typical for neurodegenerative diseases is discussed, including the interaction of genetic predisposition factors and environmental influences. Several dozen genes have been found that are somehow associated with the risk of developing the disease, some epigenetic changes (modifications of genetic material that lead to a change in the structure, but the work of genes), and the effects of various toxic substances, oxidative stress factors, mechanisms of neuroinflammation, the influence of general metabolic disorders and/or a lack of any substances, including oxygen, and some other factors.

It would be an exaggeration to say that the mechanism of influence of dopamine deficiency on the motor manifestations of the disease is known, but there are ideas that can be called generally accepted.

Where did these ideas come from? After all, multilevel studies of the disease in humans, which can shed light on the mechanism of the disease, are impossible for obvious reasons. Experimental animal models of the disease have served a great service here and continue to serve. There is such a substance — 6-OHDA, a neurotoxin. It began to be used already at the dawn of the study of the functions of dopamine. This substance leads to the death of dopamine neurons, with its use the first models of the disease were created, and it continues to be actively used in modern research. 6-OHDA is injected into the area of the compact part of the black matter of the midbrain and thus provokes the death of selectively dopamine neurons in this area for several hours. With the help of such models, it is possible to study the effects of eliminating dopamine transmission, but it should be well understood that they are not models of the disease itself, primarily because with the natural development of the disease, the death of dopamine neurons occurs gradually. No less important is the fact that even before the start of mass cell death, significant changes occur in their work, transforming the work of the entire system. This difference may turn out to be fundamental, since the adaptation of the body to pathological changes can take place in these cases according to different scenarios and have very different consequences. In this respect, a model based on the neurotoxin MPTP, which, after chemical modification in the nervous system, leads to the gradual death of dopamine neurons, is more close to the natural dynamics of the destruction of dopamine cells. There are other approaches to modeling, now numerous genetic models are being actively developed, especially valuable for studying the mechanisms of disease development in the absence of obvious external influences. But neurotoxic models using MPTP and 6-OHDA are still the most common.

In order to get acquainted with the ideas about the mechanisms of the influence of dopamine deficiency on the motor manifestations of the disease, we need to turn to the scheme of the main connections of the basal ganglia — deep brain structures involved in the organization of movement. It is believed that normally movement is accompanied by the release of dopamine in the striatum, where there are two main types of principal neurons: those on the surface of which there are D1 receptors (they are often called direct pathway neurons - we are talking about the pathway through the basal ganglia), and others with D2 receptors (neurons of the indirect pathway). So, under the influence of dopamine, the excitability of the former increases significantly, they begin to inhibit the neurons of the reticular part of the black substance (substantia nigra, SN) more strongly, and those in turn weaken the inhibition of the stem motor nuclei and motor nuclei of the thalamus, thus allowing movement to begin. Conversely, the excitability of the latter decreases under the influence of dopamine, they inhibit the pale ball (globus pallidus, GP) less, which, when disinhibited, also begins to inhibit the reticular part of the black substance. This structure of the brain is the main output link of the basal ganglia and, according to conventional wisdom, constantly hinders the implementation of movements. And in order for the movement to take place, the reticular part must be temporarily slowed down. And under the influence of dopamine, this happens, and in two ways at once (Fig. 1).

Fig. 1. The estimated activity of the basal ganglia during the initiation of movement in normal (left) and in parkinsonism (right). The arrows indicate exciting influences, T-shaped endings indicate brake inputs. D1 and D2 are schematic representations of direct and indirect pathway neurons in the striatum. A hyper-direct path is also shown. All pathways have their origin in the cerebral cortex, and end in the reticular part of the black matter GP – globus pallidus (pale ball), SN – substantia nigra (black substance, or black matter), STN – subthalamic nucleus (subthalamic nucleus). Marking the links with a dotted line implies the weakening of these links. Reinforced connections are indicated by thickened ones.

Now let's see what happens if dopamine is not released before the start of the movement — for example, because it is simply not enough, as in Parkinsonism (2). In the absence of dopamine modulation, the excitability of neurons of the direct pathway is significantly lower than the excitability of neurons of the indirect pathway, therefore, when activating inputs from the cortex, D2-expressing neurons receive a great advantage (a much greater chance of being excited), and thus the activation of neurons of the indirect pathway is noticeably enhanced. As a result, the activity of the pale ball (GP) is slowed down, which, in turn, leads to disinhibition of the reticular part of the black substance (SN), i.e. its neurons are released from the inhibitory influence of the pale ball. At the same time, the neurons of the direct pathway, whose excitability normally increases significantly under the influence of dopamine, in the absence of dopamine — with Parkinsonism — remain low-excitable, as a result of which, compared with the normal state, the activity of the direct pathway decreases, and it in turn does not inhibit the reticular part of the black matter (SN). As a result, it may turn out that at the moment of the intended movement, the activity of the reticular part of the black matter even increases (remember Sachs's note: "If the <"obstructive" will> prevails, then normal actions become difficult or even impossible"?!).

Since this hypothesis assumes that, at least at the beginning of the disease, the activity of inputs from the cortex is preserved, it also agrees with Sachs' observation that Parkinsonism is a volitional disorder. It can be assumed that the patient, trying to make a movement (which is probably accompanied by activation of the motor areas of the cortex), experiences a feeling of counteraction due to the fact that the motor command is not just "stuck" in the basal ganglia, but rather resembles an active "prohibition" of movement in the form of activation of the reticular part of the black matter.

Recently, this hypothesis has received significant confirmation in an optogenetic study. A group of scientists led by Anatole Kreutzer (3) used genetically modified mice in which the membrane protein channel rhodopsin ChR2 was present in the striatum either only in direct pathway neurons or only in indirect pathway neurons. They showed that bilateral stimulation of neurons of the indirect pathway caused the animal to freeze, slow down movements and a general decrease in motor activity, while stimulation of the direct pathway caused the animal to run more and faster. But the most important thing in this study for us now is that in mice whose dopamine neurons were previously subjected to the destructive action of 6-OHDA, stimulation of the direct pathway led to a weakening of motor disorders. Take another look at the basal ganglia connection diagram and make sure that this result confirms the hypothesis.

But this picture is still too simplistic. And not only because the pathology formed as a result of a long process of degeneration and the accompanying much more complex processes of adaptation and compensation is explained on the basis of a scheme that does not take into account these accompanying processes at all. Here we do not even dare to touch on such problems and only denote their existence. The picture is overly simplified, in particular, because it does not represent another key participant in the process — the hyper-direct path. Let me remind you that its central structure is the subthalamic nucleus, and probably this path, as well as the indirect path, plays a particularly important role for stopping traffic. It is assumed that these two ways of preventing traffic work in slightly different conditions. (Without going into details now, I will suggest imagining very different situations when you need to slow down traffic. For example, one action needs to be stopped just to perform another (stop typing text to scratch your nose), or it is necessary to postpone a deliberate action until a strictly defined moment (so as not to spoil the surprise), or urgently terminate the action if it suddenly turned out to be too dangerous (and the kitten is scratching), or not to reach for marshmallows with both hands at once (this is ugly), or, finally, stop looking for a switch with your hand, which has been on the other side of the door for five years after repair!)

So, it has long been known that the activity of the neurons of the subthalamic nucleus varies greatly with Parkinsonism: it becomes less regular and is characterized as a volley — instead of such a temporary sequence of nerve impulses:
"I I I I I I I I I I I", — becomes, for example, such:
« III    IIII   IIIII».
Neurosurgical interventions aimed at this structure (implantation of electrodes for deep stimulation or removal) can be very effective in relieving the symptoms of the disease. Based on the scheme familiar to us in the previous figure, a fairly simple conclusion could be drawn: since in the absence of dopamine, the activity of the neurons of the pale globe (GP) slows down, they, in turn, have less inhibitory effect on the subthalamic nucleus, i.e. the subthalamic nucleus is disinhibited and prevents movement. But the whole point is that pathological activity in the neurons of the subthalamic nucleus occurs when they are hyperpolarized, that is, in a state rather inhibited (and therefore directly opposite to disinhibited!). There is no consensus yet on what happens to the subthalamic nucleus in Parkinsonism, but I would like to mention one interesting work here.

The authors of this work stimulated (with the help of optogenetics, we have already described this method) the entrances to the subthalamic nucleus from the motor cortex in mice and at the same time investigated what happens to other entrances to the nucleus — from the pale ball — which, it would seem, remained at rest (4). As a result, it was found that the stimulation of these excitatory inputs from the motor cortex leads to an increase in the inhibitory inputs from the pale ball. And this process occurs only with the participation of certain receptors (NMDA receptors, see Fig. 2).

Fig. 2. Stimulation in mice of excitatory inputs to the subthalamic nucleus from the motor cortex leads to an increase in inhibitory inputs from the pale globe.

How do NMDA receptors of one synapse lead to a change in the effectiveness of another? How do the receptors of one excitatory input participate in the amplification of another inhibitory input?

And elegant answers were received to these questions: calcium ions entering the cell through NMDA receptors activate an intracellular enzyme, which in turn mediates the insertion of inhibitory receptors (GABA receptors) into the membrane. All these processes occur normally, but what can happen with Parkinsonism? The researchers injected the experimental animals with the 6-OHDA toxin and found that the normally detected increase in inhibitory connections in mice with Parkinsonism reaches the "ceiling". And in this case, it's not really a figure of speech, but the name of a situation when the process has reached its limit and further change is no longer possible.

This work also attracts attention by the fact that at first glance the paradoxical results are explained by unexpected effects — the interaction of well-known mechanisms, such interactions are ubiquitous, and their role is often underestimated.

Silver lining

Once a man suffering from Parkinson's disease asked his attending physician if there were any positive sides to this disease. The neurologist immediately answered "no", but after thinking about it, he realized that only people living with Parkinson's disease can answer this provocative question. To this end, a study was launched aimed at identifying the "silver lining" of the diagnosis (5). The English saying "every cloud has a silver lining" ("Every cloud has a silver lining"), borrowed from the famous work of the poet John Milton, means that in every misfortune we face, you can find something good (there is no silver lining). Does Parkinson's disease bring something good? This question was addressed by the authors of the study to those who personally encountered the disorder. In response, they heard amazing things:

"I have come to know the true value of life in all its beauty and complexity."

"I have learned patience and how to accept the loss of the illusion that I can control everything. But the most important lesson I have learned is the grace of gratitude for life itself and for everything that has been given to me."

"I started telling my family, friends and complete strangers about my diagnosis in interviews on radio and television, as well as <...> in my podcast "When life presents you with Parkinson's disease." I have changed something for the better in this world <...> in three years with Parkinson's disease, and not in the previous 35 years of working on the radio. I used to have a job, now I have a goal."

"Her husband told her that there are some illnesses that need to be followed through with love, and he will just do it, with her and for her."

"Not exactly an advantage, but an opportunity to grow up."

Obviously, all of this can be attributed to any disease, but do we understand "any", even the simplest disease? Can we say something convincing about the role of the disease in our lives? This seems to be a conversation for adults.

Therapy

Treatment of Parkinsonism now, as half a century ago, is only symptomatic, and L—dopa, which does not look like a panacea at all, still remains the gold therapeutic standard. At the moment, several types of therapeutic effects can be distinguished: firstly, pharmacotherapy, which primarily includes the use of L-dopa and various dopamine receptor agonists, which collectively refer to dopamine replacement therapy, these are neurosurgical effects, including the removal of some structures of the basal ganglia, as well as implantation electrodes for therapeutic intracerebral stimulation. To this list, I would like to add an approach to treatment that looks at first glance as auxiliary or palliative, but before our eyes is gaining grounds to claim more — it is the involvement of patients in physical activity. Special sets of exercises have been used in therapy for a long time, but now it is beginning to become clear that quite intense physical activity relieves the symptoms of the disease, affecting directly the processes in the brain (6). Probably, this approach will not solve all the problems, but instead of severe side effects, it brings general improvement of patients, "has a positive effect on motor skills, the quality of life, cognitive functions and emotions of patients with Parkinson's disease and even animals" (7). In addition, he draws us to the underestimated role that movement plays in our lives.

All these therapeutic effects are now widely used to facilitate the course of the disease. Very methodically sophisticated approaches are also being actively developed: neurotransplantation and gene therapy. But the symptomatic treatment of Parkinsonism can be compared to shooting at a moving target: the disease is progressing and its changing (sometimes very sharply) manifestations require a revision of the approach to treatment. The response to treatment is also changing dramatically. So, Oliver Sacks in "Awakenings" writes:

When we give the patient L-dopa, we first see the release from the disease — AWAKENING. Then a relapse follows, an increase in malaise and the appearance of new complaints — a DISASTER. And finally, perhaps the patient... finds a "balance" with his illness — we can call this an ADAPTATION.

And despite the fact that these words were written a long time ago as a result of observations on one of the very first effects of the use of L-dopa, and the drug was then used mainly in the most severe patients and there was no huge set of modern pharmacological drugs in the arsenal of doctors to correct side effects, despite all this, the problem of side effects of pharmacotherapy is- still very acute. In addition to the rapidly revealed motor, vegetative, mental complications, complex motor stereotypes (punding), disorders of impulse control (or impulses), for example, a passion for buying new things, cognitive disorders, are now described.

Gambling addiction, primarily gambling addiction, is among the most common disorders when using dopamine replacement therapy. The risk group here includes people who are younger, impulsive, often inclined to search for thrills and, among other things, have had experience (personal or family) of alcohol abuse. The relationship between the increase in the prescribed dose of dopamine agonists and the manifestation of craving for gambling is clearly traced in the literature, so gambling addiction can rightfully be considered a side effect of drugs. How does such an unexpected effect occur? The authors, who used slightly different methodological approaches, nevertheless agree on the main conclusions: against the background of the action of dopamine drugs, patients learn much worse from their mistakes. Yes, they master some tasks even faster, but they learn mainly in a situation of success, not defeat. Remember the error of predicting the reward? So, it is assumed that against the background of dopamine replacement therapy, it is negative errors (when the reward is less than expected) that are lost - this natural short decline in dopamine activity is "flooded" by agonists 8.

But there is another unexpected "side effect" of dopamine replacement therapy - craving for creativity. Eugenie Lommi and her colleagues studied patients with Parkinson's disease who were involved in active creative activity (9). These were people who were on dopamine replacement therapy, and the dose of dopamine agonists in their group was higher on average than in the control group of patients who did not show creative activity. Both groups of patients were preparing for surgery to implant electrodes to stimulate the subthalamic nucleus, which should have significantly relieved their symptoms and allowed them to reduce the dose of medications. The authors of the study cite the story of one of the patients:

I've always been drawing and writing. As a teenager, I painted on the walls of my attic. But in 2002 I completely went into drawing. <...> I turned my house into a studio, with tables and canvases everywhere. I was so happy! In 2004, my illness worsened: I stopped working and started taking a new medicine. From that moment on, I started painting from morning to evening and often all night until morning (Fig. 3). I was obsessed with painting. I bought a huge amount of materials and used countless brushes at the same time. I also used knives, forks, sponges. <...> I squeezed the paints onto the canvases directly from the tubes — they were everywhere.

Fig. 3. Creativity of a patient with Parkinson's disease who participated in the studies of Eugenie Lommi and her colleagues.

But I was still able to control it. Then the desire to draw became uncontrollable. I started painting on the walls, on the furniture, even on the washing machine.

I would paint any surface I encountered. I also had a "wall for self-expression," and I couldn't stop painting and repainting that wall every night in a trance-like state. My uncontrolled creativity has turned into something destructive. My partner couldn't take it anymore. People close to me realized that I had crossed some line towards pathology, and in 2006, with their assistance, I was hospitalized. Now my doctors have managed to find me medications, and my creativity has become more calm and structured. It has again become a pleasure that does not upset anyone.

The language of a modern scientific article does not imply emotional assessments, and the authors of the study simply state that after the successful operation and the onset of improvement, the total dose of dopamine replacement drugs was significantly reduced in both groups, and it turned out that the craving for creative activity remained only in one person from the "creative" group.

They further say that patients who plunge headlong into creativity, as a rule, are convinced that their passion is an expression of their own personality and does not depend on the drugs they take to treat Parkinsonism. They value their creativity because it is a source of strong personal enrichment, "awakening", it is appreciated by close people and society. Therefore, before the operation, it is extremely important to warn patients about a very likely loss of craving for creativity. After all, this choice is not easy.

And here the words of John Paul II from his "Message to the People of Art" are very interesting, which Olga Alexandrovna Sedakova drew attention to in the essay "Blessing to Creativity and Parnassian Atheism" (10). These words are about a human artist who works "with an amazing " substance of "his own humanity".

"The substance of humanity" is not a bad name for dopamine.

Literature

1. Armstrong M. J., Okun M. S. Diagnosis and Treatment of Parkinson Disease: A Review // JAMA. 2020 Feb 11; 323(6): 548–560. DOI: 10.1001/jama.2019.22360

2. Wichmann T., Dostrovsky J. O. Pathological basal ganglia activity in movement disorders // Neuroscience. 2011 Dec 15; 198:232–44

3. Kravitz A.V., Freeze B.S., Parker P.R., Kay K., Thwin M.T., Deisseroth K., and Kreitzer A. C. Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry // Nature. 2010. 466, 622–626.

4. Chu H.Y., Atherton J.F., Wokosin D., Surmeier D.J., Bevan M.D. Heterosynaptic regulation of external globus pallidus inputs to the subthalamic nucleus by the motor cortex // Neuron. 2015. 85(2):364-76

5. Alonso-Canovas A., Voeten J., Thomas O., Gifford L., Stamford J.A., Bloem B.R.. The silver linings of Parkinson’s disease // NPJ Parkinsons Dis. 2022 Mar 3;8(1):21. DOI: 10.1038/s41531-022-00283-1

6. Armstrong M.J., Okun M.S. Diagnosis and Treatment of Parkinson Disease: A Review. JAMA. 2020 Feb 11;323(6):548–560. DOI: 10.1001/jama.2019.22360; Sacheli M.A. et al. Exercise increases caudate dopamine release and ventral striatal activation in Parkinson’s disease // Mov Disord. 2019 Dec;34(12):1891–1900. DOI: 10.1002/mds.27865

7. Feng Y.S., Yang S.D., Tan Z.X., Wang M.M., Xing Y., Dong F., Zhang F. The benefits and mechanisms of exercise training for Parkinson’s disease // Life Sci. 2020 Mar 15;245:117345. DOI: 10.1016/j.lfs.2020.117345

8. Piray P., Zeighami Y., Bahrami F., Eissa A.M., Hewedi D.H., Moustafa A.A. Impulse control disorders in Parkinson’s disease are associated with dysfunction in stimulus valuation but not action valuation // J Neurosci. 2014. 34: 7814–7824

9. Lhommée E., Batir A., Quesada J.L., Ardouin C., Fraix V., Seigneuret E., Chabardès S., Benabid A.L., Pollak P., Krack P. Dopamine and the biology of creativity: lessons from Parkinson’s disease // Front Neurol. 2014. 5:55

10. olgasedakova.com/Moralia/276

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