A solution to the paradox of Parkinson’s disease

Parkinson’s disease is a disorder of movement caused by damage to a learning system. Why has been unclear for decades. Now a new study shows us a way out

Source: Wikipedia

I was collecting a poster from the printers. A big, A0 poster, covered in graphics and graphs, for me to take to the gargantuan Society for Neuroscience meeting and add but a drop of new science to the oppressive weight of the 16000 posters that year. The man behind the counter handed me the poster, and gave me a moment to unroll it and check the print quality.

“Excuse me”. I turn. Behind me stand a middle-aged couple, perhaps late 50s, silver-haired, well-dressed, the lady upright and alert, the gentleman looking at his shoes.

She continues, gesturing at my poster: “does that say ‘dopamine’?” “Yes”, I reply, with that flash of wit I’m renowned for. I grope for a clear explanation: “It’s on my research into how dopamine carries a learning signal: the error between what we expect to happen, and what actually happens. So we can learn from those errors.”
“Ah, I see,” she pauses. “We’ve heard a lot about dopamine. My husband has Parkinson’s disease”.

He looks up at me, a trace of a smile in the lines around his eye. “Yes. I’ll shake anyone’s hand, me”.

Beyond a fine example of British humour in the face of adversity, our little exchange succinctly covered the central paradox of Parkinson’s disease. Dopamine is for learning. Losing dopamine causes life-wrecking movement problems. How?

The major symptoms, those used for diagnosis, are all about movement: the tremor of the arms, the slowness of movement, the inability to move. These appear when about 80% of the top group of dopamine neurons die. And they are temporarily fixed by taking a drug — L-DOPA — that produces more dopamine in the brain. Loss of dopamine is inextricably linked to the appearance of movement problems.
 
But in a healthy brain dopamine is inextricably linked to learning. We noted above the “error” theory, in which a burst of dopamine released into the brain is a signal that something is better than expected. Such are the depths of supporting evidence for this theory, that even the sceptics about the details (including myself) acknowledge that there is some sort of error signal.

A new study by Howe and Dombeck offers a vital clue to resolving the paradox. They show there are two types of dopamine neuron. One type releases dopamine in response to an unexpected reward, exactly as the error theory predicts. But the other type — bizarrely, the dominant type — releases dopamine only before and during movement. These neurons send a signal to begin movement, and then to sustain it.

To prove this, Howe and Dombeck made full use of the extraordinary toolbox of modern neuroscience. They used light to cause fast, short dopamine release from these movement neurons; lo and behold, the mice ran!

Like a good thriller, their paper doesn’t reveal the guilty party until the very last. They let the tension build in the reader’s mind: “yes dopamine neurons, yes movement, yes they make the mice run, but, but, but WHERE ARE THEY???” Then, suddenly, on the final figure — they whip the curtain away: the movement and learning neurons are in different parts of the brain. And the movement ones are exactly where we want them to be: in the region that is damaged in human Parkinson’s disease.

A solution to the paradox: fast, short bursts of dopamine signal movement and error, in different groups of neurons. Learning and movement are controlled by different dopamine neurons. The implication? That Parkinson’s disease results from damage to the movement neurons. Beautiful, simple, smart.

There are other solutions to the learning-movement paradox, but none as compelling. Our best contender was the idea that dopamine works at two time-scales. In this idea, fast, short bursts signal error. So they take care of learning. Slow, constant release of dopamine signals motivation, the drive to do things. The idea then is that Parkinson’s disease results from losing just the slow, constant signal — losing the motivation to move. There are problems with this idea. The most obvious is that Parkinson’s disease sufferers don’t lack motivation. They want to move: they just can’t.

And we were building to this solution. The teams of Rui Costa and Henry Yin both reported neurons in the right place that were active just before and during actions, and not (or not just) when getting an unexpected reward. But these studies could not say they were definitely dopamine neurons. Recently, Paul Dodson and colleagues reported neurons that both definitely contained dopamine and definitely paused during running, pointing to a distinct role for dopamine neurons in movement. Science is a collective enterprise, and any breakthrough builds and extends on clues from the work of others.

This is important because any single scientific experiment comes with uncertainties, equivocation, and caveats. A key one here is that Dombeck and Howe measured the amount of calcium in the nerve terminals of these neurons. The amount of calcium in the neuron goes up and down with its activity, so is a good proxy for the neuron’s output. But there are ways in which dopamine can be released which don’t need the neuron to be active. The next generation of these experiments would need to directly measure dopamine release at the same time. But, when we take their evidence together with that of the other teams’, it makes a compelling case.

Hang on, hang on. The title says “a” solution. Not “the” solution. Why?

Because we are hardly short of other mysteries of Parkinson’s disease to solve. We don’t know why these dopamine neurons are lost, and not others. Something makes them uniquely vulnerable, and that unique vulnerability is entirely human — no other animal gets Parkinson’s disease. We don’t know why deep brain stimulation is able to alleviate the movement problems. By sticking an electrode deep in the brain, and sending pulses of electrical current down it at over 100 times per second, clinicians can stop the movement problems. How this somehow repairs or overwrites the loss of dopamine is a deep mystery.

(Seriously, this is about on a par with discovering that rubbing a terrapin on your head cures baldness. And specifically a terrapin: turtles are right out.)

Howe & Dombeck’s study draws a direct link between Parkinson’s disease, dopamine and movement. Let’s be clear: this is “basic science”, driven by curiousity; here, curiousity about what dopamine neurons do for a living. Yet it may hold the keys to solving not just the paradox of Parkinson’s disease, but these other mysteries too. They’ve shone a light along a clear path for others to follow. So let’s follow.

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