Neuropsychiatric features of punding and hobbyism in Parkinson's disease

And they described a behavioral abnormality, which was quite common among amphetamine addicts, which is characterized by complex stereotyped, NoGo-orientated, behavior, which could be continuous sorting, handling, manipulation of objects, tinkering with electronical equipment pointless driving, walkabouts, hoarding behavior, and et cetera.

The paper from California, actually, they found this behavior in one quarter of all patients addicted to amphetamine. It's Interesting, because the term punding was initially coined in Sweden and it could be translated to "Blockheads." When you think about Parkinson's disease, the first description was published in 1994 by Friedman. So, he described a 65-year-old male PD patient who started shuffling and sorting papers, senselessly for hours and hours, and also singing uncontrollably. And this was quite dramatic because it happened immediately after an increase in levodopa.

As soon as they decreased levodopa back to the previous dosage, their behaviors were completely gone.
 

[00:02:56] (Host) Dr. Hugo Morales:
Interesting. So we learn from these studies and observations of patients who use amphetamines they start to develop these abnormal behaviors that may look like an exaggerated normal repertoire movement. And it's telling because of these drugs that can enhance the dopaminergic system.

But I wonder about the phenomenology in Parkinson's disease. And especially with punding, the context in which these patients develop the behaviors. Is it just any movement, any special specific motor behavior? Do they tend to recapitulate where they used to do in the past, or is it something new?
 

[00:03:40] Dr. Pedro Barbosa:
Oh, that's quite an interesting point because punding tends to be idiosynchratic. So, previous hobbies or occupations or anything that the patient used to do. So some motor programs from previous routines can be incorporated into the punding routine. And this can be simple or more complex, but it's interesting to notice that punding is, is meaningless.

It can appear to be purposeful, but it's not. So for instance if you have a musician that has a large collection of CDs, the punding behavior could be sorting CDs the whole night and in the morning, he would end up with chaos and nothing organized. So a writer could spend hours writing words devoid of meaning, actually. And so on. So one of the classic descriptions is a seamstress that would organize buttons the whole night, which was published by professor Lee's group actually before.
 

[00:04:42] (Host) Dr. Hugo Morales:
And just out of interest, when these patients are punding, are they in their best motor response or they can be either off or on, or this doesn't matter.
 

[00:04:55] Dr. Pedro Barbosa:
A great question. Actually, they tend to be on. And also punding has been associated with dyskinesias. There is a higher proportion of patients with punding presenting with dyskinesias. Also, you have to be suspicious of patients with punding if they are on higher doses of dopamine treatment, because if you're looking to the prevalence of punding, previous studies have shown that approximately 2% to 4% of patients in a general population of PD patients have punding behavior.

But if you look into individuals with a high dosage of dopamine replacement therapy, the prevalence actually goes all the way up to 14%. And these are individuals using more than 800 levodopa equivalent units per day of dopamine replacement therapy.
 

[00:05:48] (Host) Dr. Hugo Morales:
On the same topic of the phenomenology of punding, I wonder if there's any difference between men and women in the way they do this punding. Have you seen any differences in the patients you have studied?
 

[00:06:02] Dr. Pedro Barbosa:
Yes. So several authors have reported that there is a difference between male and female patients. So male patients would dismantle electronic equipment, work with tools at home, while women would spend more time in organizing, tidying up — which it's quite difficult to ascertain if this is biochemical or cultural, actually, because as we said before punding is actually motor programs from before or motor routines being repeated excessively because of dopaminergic stimulation.
 

[00:06:40] (Host) Dr. Hugo Morales:
With these repetitive and complex behaviors, are they really successful in the task? Are they actually completing the tasks properly, or do they have deficits underlying these motor tasks?
 

[00:06:52] Dr. Pedro Barbosa:
Yeah, that's quite interesting because one of the ways that helps you identify if a behavior as punding is that it usually tends to leave chaos behind. Tidying up never tides up the place, actually. So patients spent the whole night tidying up the place, but they end up leaving a big mess.

 There are a few patients that used to be construction workers that started to break the walls, just to check where the wiring was placed and actually pretending to be renovating their home, but actually never, never ending the renovation. And it's quite common also for patients to dismantle electronic equipment and never assemble them back together. So that's an interesting point that the clinician can always look for: if chaos is left behind, it's a nonproductive activity, it's probably punding.
 

[00:07:49] (Host) Dr. Hugo Morales:
Yeah, that's a good clinical pointer. In your study you and your co-authors, they compare Parkinson's disease patient with punding and hobbyism, and without it, and just emphasizing the neuropsychiatric aspects, namely mood disorders and frontal cognitive function. Tell us, what you find in this study.
 

[00:08:10] Dr. Pedro Barbosa:
Well the problem is that there's too much we don't know about punding. So we had the opportunity to assess 21 PD patients with punding behavior and compare them with 26 patients with excessive hobbies, but no punding behavior. We also compare a control group of 25 PD controls without punding or any other impulsive compulsive behaviors.

So what we found was increased anxiety levels in patients with punding and hobbyism. And if you look into patients with punding, actually, there was a higher burden of motor symptoms measured by the UPDRS3 and worse frontal lobe function compared to excessive hobbyisms. Frontal function was actually measured with the frontal assessment battery. We also did the Montreal cognitive assessment. So, as with any paper, these findings need to be replicated by other studies. But the interesting thing is that what appears to separate these patients with excessive hobbies from punding is the frontal dysfunction.

If you allow me to diverge a little bit to the nomenclature, because we talk about impulsive-compulsive behaviors and some clinicians also, when they will go to PubMed to study, they will see sometimes impulse control disorders, dopamine dysregulation syndrome. So there are a few behavioral abnormalities in Parkinson's disease that are a consequence of the use of dopaminergic replacement therapy. And this falls into two categories. The first is the impulse control disorders, which are hypersexuality, pathological gambling, compulsive shopping, and eating. And they have the behaviors that fall on the compulsive side of the spectrum, which is dopamine dysregulation syndrome, addiction to levodopa tablets, and punding behavior, which what we're talking about. So impulse control disorders are more frequently seen with the use of dopamine agonists, especially the oral, non-ergolinic agonists, which tends to be also very strong dopaminergic D3 receptor agonists, while compulsive behaviors, they are more associated with a medication that stimulates dopamenergic D1 and D2 receptor, such as levodopa and apomorphine.

This is major difference between the behaviors. Usually, the way the brain signals a rewarding activity is by shifting dopamine release into the nucleus accumbens, which is part of the ventral striatum. The nucleus accumbens has connections with the prefrontal cortex, so too much dopamine in the nucleus accumbens will signal a reward. And at the same time through dopaminergic inhibitory connections, will decrease the input from the prefrontal cortex. The prefrontal cortex task is to shift attention to another activity. So too much dopamine, it's a reward. Also the prefrontal cortex will leave t he brain to enjoy that reward activity for awhile.

So if you have too much dopamine, the prefrontal cortex input will be reduced. And also if you're already on the top of a reduced frontal striatal inhibition, which we found in our patients with punding, this could explain punding behavior.

So it's too much dopamine in a frontal prefrontal cortex, perhaps that is already not in the best shape, let's say. So this could be the main mechanism behind the punding behavior.
 

[00:12:10] (Host) Dr. Hugo Morales:
So, this is highly relevant for clinical practice. I think also based on what you have found in your previous studies, there seems to be at least a pathophysiology in this punding mechanism and different from the impulse control disorders based on the segregation of the pathways. And what you mentioned is that the ventral pathway with the nucleus accumbens being hybrid, dopaminergic, and then having an effect on the prefrontal cortex and then the prefrontal cortex not working that well, to prevent repetitive behavior or stop signals. This is very interesting.

I guess the other question that is relevant as well for a clinical practice is how patients with punding should be managed in terms of medical therapy and what is the long-term outcome of these patients?
 

[00:13:07] Dr. Pedro Barbosa:
One other thing that I think is important when you are suspicious that, your patient has punding in is to have a high index of suspicion. It's quite common for patients to under report. And not only punding, but all impulse control disorders and also dopamine dysregulation syndrome. And there's probably many factors to explain this. Lack of insights is probably one important factor. Patients fail to associate their behavior with Parkinson's or the treatment. Concealment, embarrassment — the clinician needs to have a high index of suspicion, particularly in patients with dyskinesias and/ or high doses of dopaminergic replacement therapy. If you're looking to treatments there are no randomized clinical trials to guide the treatment here. But what we know from many reports before is that the most important point is to reduce dopamine replacement therapy. One way to start doing this is to stop rescue doses, which has been suggested by many authors because these patients are at high risk of dopamines regulation syndrome as well. So if you stop rescue doses, it's a good beginning, but most of them will need further reduction in the amount of treatment they are receiving.

What I usually do is try to clean up or maybe simplify the treatment regime. And I tend to try to reduce or stop dopamine agonists. Even though dopamine agonists are associated with impulse control disorders, we know from patients with dopamine dysregulation syndrome that reducing dopamine agonist is an effective measure to improve their behavior, and also it helps reducing the total amount of the dopaminergic replacement therapy. And then you can simplify levodopa regime, you can also review if a patient is on apomorphine, try to avoid rescue doses of apomorphine — not every place in the world has apomorphine yet.

Another important thing that needs to be considered is selegiline. Selegiline is a MAO inhibitor that has amphetamine-like metabolites. And as we saw before, amphetamine has been associated with punding-like behavior. So if possible, if your patient uses selegiline, stop selegiline as well, remember that. And then we go to the anti-psychotics... there are contradictory data, actually. The only anti-psychotic that's been reported to improve punding is quetiapine. And this was done actually after the reduction of dopamine replacement therapy was not successful, either because the patients were already, let's say, motor symptoms were too prevalent, so because of motor handicap. And you can use quetiapine to allow the patients to remain on the same medication.

So there are case reports of improvements, but there are also, I think a couple of case reports of patients developing punding on quetiapine. But this could be a coincidence since patients were already using high doses of dopamine treatment. Another contradictory drug is a amantadine. Amantadine has been correlated with impulse control disorders in a large study, but also there are quite a few reports of amantadine improving pathological gambling and impulse control disorders. Medication-wise, I think the main goal is to reduce dopamine replacement therapy. If your patient gets too impaired, you can also use quetiapine. And also remember to involve family members and carers.
 

[00:16:53] (Host) Dr. Hugo Morales:
The other question, and this is also along the lines of management, in this patient where you have done everything adjusting medication, selegiline adjustment or preventing the use of this — it's extremely useful, but what about continued dopaminogenic therapy with either apomorphine infusion, with levodopa intestinal gel infusion, or even deep brain stimulation? Have you had experience with these therapies in patients with punding?
 

[00:17:23] Dr. Pedro Barbosa:
Yes. So interesting question. We know more about the impulse control disorders and dopamine regulation syndrome. In theory, if you provide a more continuous stimulation of dopamine receptors that can be achieved by infusion therapies, such as apomorphine and duodopa intestinal gel, dopamine could be less reinforcing. This could probably be beneficial in patients with punding, but we lack the data.

When I was in the UK working with professor Tom Warner, I actually had a few patients who used apomorphine, which started all the way back with Professor Angeles as well. So they tend to improve, actually. All impulse compulsive behaviors we saw apomorphine is actually more associated with punding behavior.

But if you do provide a continuous stimulation and you reduce the total amount of medication that you receive, they actually benefit from improve impulse control disorders, dopamine dysregulation syndrome, and punding. But I have to say my impression is that you have to reduce the total amount of dopamine replacement therapy they are getting.

And regarding deep brain stimulation, it could be effective. It has be show that in a long-term scenario, despite subthalamic nucleus deep brain stimulation, increasing impulsivity in the immediate post-op, after operation, in the medium and long-term scenario, the patients tend to improve the impulsive compulsive behaviors because they are able to reduce significantly the total amount of medication they receive.
 

[00:19:05] (Host) Dr. Hugo Morales:
Now just for future research and clinical studies, what are the questions that remain unanswered in punding in a patients with Parkinson's disease?
 

[00:19:16] Dr. Pedro Barbosa:
We had the opportunity to look into the long-term scenario of individuals with all types of impulse control disorders, impulsive compulsive behaviors, actually. And we found that despite early reports of a significant improvement in impulse control disorders in a medium term scenario — if you're looking to a longer-term scenario, a high proportion of patients remain symptomatic.

However, nearly all of them improve. So their behaviors are no longer as disruptive as they were. But as much as 50% of patients with dopamine dysregulation syndrome and impulsive compulsive behaviors in general could be symptomatic in the long-term scenario.

But we still need more data on the long-term scenario. So this is one of the unanswered questions.

The other questions about punding is why some individuals developed punding and others not. And this can also extrapolate to every impulsive-compulsive behavior in Parkinson's disease. So what we know: There is a strong association with dopamine replacement therapy, but not all individuals will develop punding.

And what is the relationship between punding and dyskinesias, as well. Is punding akin to dyskinesias, meaning that dyskinesias is an excessive simplified motor program that originates in the dorsal striatum, and is punding excessive complex motor program that originates in a different part of the brain?

We also need to understand the other neurotransmitters, what are the roles for the other neurotransmitters? Because when we talk about dopamine, this is a simplification. Dopamine is the main neurotransmitter in the dopaminergic reward system.

But these have input from many other neurotransmitters, such as opioids, serotonin, even cannabinoid systems. So this is quite an interesting topic because. It makes you wonder about voluntary control, free will as well, and how patients can have a dramatic shift in personality or behaviors. I'm not talking only about punding, but all the impulsive-compulsive behaviors and what's happening to the brain of these people. We need more awareness of people's compulsive behavior. We need more studies as well, but hopefully with time, this will come.
 

[00:21:50] (Host) Dr. Hugo Morales:
I'm pretty sure after listening to this interview, more listeners and researcher will have more interest in this topic and certainly will spark more ideas for research. But I would like to thank you again, Pedro for sharing your insights into the phenomenology and features of punding in Parkinson's disease.
 

[00:22:15] Dr. Pedro Barbosa:
Well, I appreciate the invitation. It has really been a delight to talk to you.
 

[00:22:20] (Host) Dr. Hugo Morales:
I invite our listeners to go read the paper "Neuropsychiatric Features of Punding and Hobbyism in Parkinson's Disease" in this January issue of Movement Disorders Clinical Practice, and to stay alert for the upcoming episodes of the MDS podcast.