Introduction
Following on from our deep dives into dopamine biochemistry, and the role of dopamine cell receptors, in this article we consider the profound implications of dopamine shortages and pragmatic solutions for people with Parkinson’s Disease. We first consider what a new book all about dopamine deficits has to tell us, then look at some further information on the topic provided by Prof. Andrew Huberman, and finally consider the potential roles of a part of the brain called the habenula.
Review of “Dopamine Nation”
A recent book “Dopamine Nation” by Dr Anna Lembke, has some very valuable information for us. Indeed, although this is a book about addiction, my main interest in reading it was as a person with Parkinson's Disease, and hence someone who experiences severe dopamine dysregulation, for the insights which it might bring to managing such conditions.
According to the author, like many of the other regulatory systems of our biology, the dopamine regulation system is inherently one of antagonistic checks and balances, which seek to keep the baseline levels of dopamine in the body and brain at an equilibrium.
For dopamine, this balancing system is pleasure and distraction on one side and pain and discomfort on the other. There is always an inevitable cost to pleasure of some level of subsequent discomfort. For simple pleasures, the discomfort may just be craving for more of what created the pleasurable feelings. The more extreme the pleasure, the more intense and prolonged the pain, as the metaphorical pendulum swings back the other way, whether hangovers after a big night out, or post-orgasmic dopamine crashes experienced by some men. By the same token, enduring simple discomforts can lead to feelings of elation afterward, as the system re-balances by first swinging back to the pleasure side, such as feeling good after a cold shower, or runners' high.
The mechanism for this phenomena of pain following pleasure seems to be due to the way dopamine is created and stored inside neurons, and when called for, is then released by ejecting tiny bubbles of dopamine out of the cell. If a lot of dopamine is called for quickly, such as for a spike of pleasure, these stores are used up fast, and there is then not enough is left to maintain the baseline. Since it takes some time to build up the stores again, the bigger the dopamine spike, then the less stores will be available afterwards, and the longer it will take to get back to baseline levels.
Dr Lembke's main thesis is that we, as a society, have become too driven by pain-avoidance-at-all-costs, that we have totally lost the ability to intuit what our uncomfortable sensations are trying to tell us, are taught to ignore our own bodies' stop signals, have lost our capacity to sit with pain at all, and are told to reach out for pharmaceuticals at the very first hint of any discomfort.
In such a culture, where a wide variety of sources of "junk" dopamine stimulation is also always available everywhere, one very tempting way to try to get rid of pain is by tipping the dopamine regulation system the other way, and to use pleasure and distraction to numb the pain. While this may work at first, because the cost of pleasure is always more pain, this is the one-way road to addictive escalation. The main "take home" message from the book for all of us is that by trying to avoid pain and discomfort through distraction and pleasure, we are just creating even more pain for ourselves.
Indeed, the more we drive our system to extremes of dopamine release, not only the more discomfort we will feel in the aftermath, but also the more we will drive down our baseline of dopamine, permanently tipping the balance ever towards the pain side, requiring ever more extreme forms of pleasure to feel anything at all. Physiologically, this occurs through downregulation or internalization of dopamine cell receptors, as we have discussed before, so that the cells become more insensitive to dopamine. Eventually, the baseline levels of dopamine becomes so low, that we become anhedonistic, unable to feel any comfort, pleasure or joy in everyday things.
Thus the author's more holistic model of addiction, supersedes, yet includes other "single source" hypothesis, such as Dr Gabor Mate's model that is always to do with childhood trauma, via a threshold framework. In such a model, levels of unattended physical, psychic and emotional pain build up through various insults, whether viruses, pathogens, environmental toxins, food intolerances, developmental and shock trauma, injuries and surgeries, socio-economic disadvantages, social injustices, (... name your personal poisons...).
Once the total amount of pain and discomfort builds up beyond a critical level, we start to seek out dopaminergic sources to relieve and distract from our suffering, setting us on the path to hell. Everyone will have different thresholds, and have different and individual collections of insults, but with the same outcome. This brings addiction in to alignment with similar threshold frameworks for chronic illnesses, such as the Cell Danger Response.
The book contains a recipe for addressing addictions, via the author's D.O.P.A.M.I.N.E. model, but basically the moral of the story is that, as a society, we need to learn to listen to our internal sensations, to be able to sit with our discomforts, and to address pain signals as they arise, and not just ignore them and let them build up to overwhelming levels in the first place. We need to keep our baseline or equilibrium levels of dopamine in a healthy range, where we can still enjoy the small pleasures of every day life.
Implications for Parkinson’s Disease
Let us now consider the importance of what we have earned above for people with PD in particular. Clearly, within this framework, people with PD are starting with a very low baseline, so low that it has tipped into the pain and discomfort side of the balance, and we do not have sufficient background dopamine release even for initiating movement. This could be related to not generating enough stores of dopamine, and/or due to insensitivity to dopamine because of too much cell receptor internalization.
First, due to this deficit even at baseline, addictions and addictive behaviours will have much more of a negative impact on us than most. Addressing addictions is therefore probably something we need to be mindful of and attend to. In this regard, it is unfortunate that the dopamine agonist class of drugs tend to cause extreme forms of addictive behaviours, and this may be why they are only a short term solution for many, because they begin to work against themselves?
Secondly, this indicates that we should avoid spiking our dopamine too much, both because the subsequent crash below baseline will likely trigger a symptomatic attack, and because of the longer term prospect of lowering the baseline even more, which would look like progression of the disease or degeneration. The depletion of the already limited stores of dopamine due to a rapid release spike may be doubly problematic for people with PD, because the build up back to baseline may also be slower. This might be due to the normal biochemical generation of dopamine via the phenylalanine and tyrosine pathways being blocked for many of us, and hence why we have to skip these steps by supplementing directly with l-dopa.
The impact of spiking dopamine in people with PD may be similar to the reasons why stress is such anathema to us, when adrenaline is caused to spike, which also causes a rapid depletion of dopamine stores since adrenaline is actually created from dopamine stores. This indicates that perhaps the target for progressive reduction is to avoid extreme excitatory states, but instead to seek to raise the baseline over time, and to maintain equanimity.
On the topic of the mainstay treatment of PD via l-dopa supplementation, I believe the work of Dr Lembke helps explain why it is so biphasic: a little is helpful, but beyond a point, too much makes things even worse. Some amount of supplementation may be necessary to top up the baseline of dopamine to allow movement again, sustained for a couple of hours. Yet too high a dosage results in a massive spike in dopamine, which causes side effects such as dyskinesia (uncontrolled movement) and hallucinations, followed by a massive crash into a totally frozen state. Indeed, according to Prof. Andrew Huberman, even people who are healthy and who choose to supplement with l-dopa via Mucuna Pruriens can experience a crash after a dose wanes.
Spiking dopamine repeatedly by ingesting too much l-dopa at a time will then drive down the baseline further via cell receptor internalization, leading to yet more l-dopa being prescribed, creating even more toxicity, a sudden switching on of movement, followed by severe side-effects, and then a sudden crash. This would present as a neuro-degeneration or disease progression. This is what happened to me, and caused my hospitalization. Hence keeping l-dopa supplementation as low as possible for as long as possible is wise, and taking more is not always the best answer, and may just make things a whole lot worse, leading to entrapment in a vicious circle.
The material of the book also suggests that dealing with physical and emotional pain, and not letting it fester, may be a good idea for people with PD, in part to ameliorate the need for turning to addictions as a coping mechanism. This could involve getting counselling or trauma therapy for emotional issues, and addressing, not just accepting as a necessary symptom, any dystonia, or physical pain. I have found Dr Farias’s Online Dystonia Recovery Program and also Block Therapy, a self-care fascia decompression technique. instrumental for addressing the physical issues directly.
Further Insights
In a podcast interview, Prof. Andrew Huberman provides some further pragmatic advice for how to increase and maintain healthy baseline levels of dopamine, following on from Dr Lembke’s book.
Here is what I gleaned:
dopamine is involved in both motivation (effort, striving, seeking) and reward (achieving a goal, winning);
the problem is that "reward"-type pleasure (quick dopamine hits) without prior requirement for pursuit (effort, seeking, striving) is terrible for us, examples include food at our fingertips without the need to farm, hunt or gather, sex without the romantic courtship, knowledge without the need to actively learn;
the reward version of pleasure has a more opioid bliss character;
celebrating the win (a big, quick peak in dopamine) more than the pursuit rebounds into the pain side of the pleasure-pain balance system, and too much of this will lower baseline levels of dopamine, as per Dr Lembke's work;
we have some control over what we attach dopamine and pleasure to;
to maintain and increase baseline levels of dopamine, we need to learn to take pleasure in the motivating part, in the effort, the seeking and striving;
if addiction is a progressive narrowing of the things that bring pleasure, the alternative is a progressive expansion of the things that bring pleasure, and includes pleasure in the effort part, not just in the win;
like most things, the "no go" or restraint circuits of the brain need to be used often in order to maintain and strengthen them;
restraint or resistance is a practice which can be done daily, by mindfully resisting cravings or impulses, e.g. not checking the smartphone when you have an urge to do so, or not reaching for snacks, even if this resistance is only for a few minutes at first.
This is all very reminiscent of my own workaholic behaviours in the years prior to diagnosis. I was always working flat out, to the exclusion of all else, to complete a task or reach a target, such as the next academic paper, grant application or promotion, whilst never really taking pleasure in the work itself. In fact, I was feeling stressed and angry with my work most of the time. The result would be a very brief win, followed by a crash into feeling flat and disappointed, and then straight on to the next task or target without pause. I see now I was never present to what I was doing, always looking to a future that never realized. So for me, there is much to what Prof. Huberman is saying here, and I do believe my workaholism fed my descent into disease.
I think there is also much we can say about how this applies to how we go about chasing healing too. Perhaps healing can only really happen if we learn to enjoy the healing process itself.
Synchronously, I read an article by Dr Iain McGilchrist, which included the following:
"According to the philosopher James Carse, there are at least two kinds of games. One could be called finite, the other infinite. A finite game is played for the purpose of winning, an infinite game for the purpose of continuing the play."
I think reframing many things in life as infinite games would be in keeping with what Prof. Huberman is recommending.
The Habenula
In the above mentioned interview with Prof. Huberman, he also mentions an area of the brain called the “habenula” being involved. I had never heard of this before, but on researching it, it quickly became apparent to me that this part of the brain is vital to any discussion about Parkinson’s Disease, and indeed may be involved in mediating the freeze stress response. Here is what I learned.
The habenula is a very small area of the brain which neighbours the pineal gland. It receives information from the limbic system and basal ganglia, and sends information to the substantia nigra and the ventral tegmental area, which are both involved with dopamine release. Recall that in the classical view of PD, it is dopamine cell death in the substantia nigra which is the proposed mechanism of the disease. The habenula is a part of the brain which can exert a large and wide influence on dopamine producing cells in the brain.
The activation of the habenula inhibits or deactivates the dopamine neurons in the substantia nigra and ventral tegmental area, and, conversely excites or activates them when it is deactivated. This has profound implications for PD, as this points to the possibility that it is not cell death which causes the issues in PD, but chronic activation of the habenula permanently switching off the cells in the substantia nigra from producing dopamine. This is a more hopeful hypothesis, as it means the cells are just dormant, not dead. If we can figure out how to deactivate the habenula, this could provide significant symptom reduction.
Similarly, if acute activation of the habenula can temporarily switch of dopamine production in the substantia nigra part of the brain, this would cause temporary immobilization, and hence the habenula might be the mechanism by which the Nervous System creates the Freeze or “paying dead” stress response.
The habenula seems to be responsible for the pain part of the pleasure-pain balance of dopamine release highlighted be Dr Lembke, So it is important to understand what can activate the habenula, A very informative article on the habenula reveals that
[... the habenula is involved in encoding information about disappointing (or missing) rewards. The habenula has also been found to be activated in response to punishment and stimuli that we have previously associated with negative experiences. Based on all of this information, it is thought the habenula plays an important role in learning from aversive experiences and in making decisions so as to avoid such unpleasant experiences in the future."
So perhaps the habenula gets stuck on activated, and hence chronic freeze starts manifesting, when one has built up too many negative experiences over a lifetime. Furthermore
“… when the reward is smaller than we expected… dopamine activity in the substantia nigra and ventral tegmental area is inhibited. Smaller-than-expected rewards, however, cause increased activity in the habenula, while larger rewards lead to an inhibition of activity there… when the reward is smaller than we expected, dopamine activity in the substantia nigra and ventral tegmental area is inhibited. Thus, it has been hypothesized that the habenula is involved in encoding information about disappointing (or missing) rewards."
Prof. Huberman refers to this as “reward prediction error”. My disappointment, and feeling flat, after the completion of a task at work, which I described above, is, I think, a good example of this. It is interesting to conjecture how my mindset and behaviours generating a lifetime of disappointments may also have contributed to my PD diagnosis. People with PD also tend to become pessimistic, and this may be a learned adaptive response to avoid disappointments and hence to offset even further activation of the habenula.
"The habenular nuclei are involved in pain processing, reproductive behavior, nutrition, sleep-wake cycles, stress responses, and learning... the function of the lateral habenula with reward processing, in particular with regard to encoding negative feedback or negative rewards.
These are all things also significantly affected by PD.
I wonder if it is possible to create targeted visualization, meditations or hypnotherapy scripts to inform the habenula to de-activate?