Tag Archives: Epilepsy

Set points, a mechanism for one at last.

Human biology is full of set points.  Despite our best efforts few can lose weight and keep it off.  Yet few count calories and try to eat so their weight is constant.  Average body temperature is pretty constant (despite daily fluctuations).  Neuroscientists are quite aware of synaptic homeostasis.

And yet until now, despite their obvious existence, all we could do is describe setpoints, not explain the mechanisms behind them.  Most ‘explanations’ of them were really descriptions.

Here is an example:

Endocrinology was pretty simple in med school back in the 60s. All the target endocrine glands (ovary, adrenal, thyroid, etc.) were controlled by the pituitary; a gland about the size of a marble sitting an inch or so directly behind the bridge of your nose. The pituitary released a variety of hormones into the blood (one or more for each target gland) telling the target glands to secrete, and secrete they did. That’s why the pituitary was called the master gland back then.  The master gland ruled.

Things became a bit more complicated when it was found that a small (4 grams or so out of 1500) part of the brain called the hypothalamus sitting just above the pituitary was really in control, telling the pituitary what and when to secrete. Subsequently it was found that the hormones secreted by the target glands (thyroid, ovary, etc.) were getting into the hypothalamus and altering its effects on the pituitary. Estrogen is one example. Any notion of simple control vanished into an ambiguous miasma of setpoints, influences and equilibria. Goodbye linearity and simple notions of causation.

As soon as feedback (or simultaneous influence) enters the picture it becomes like the three body problem in physics, where 3 objects influence each other’s motion at the same time by the gravitational force. As John Gribbin (former science writer at Nature and now prolific author) said in his book ‘Deep Simplicity’, “It’s important to appreciate, though, that the lack of solutions to the three-body problem is not caused by our human deficiencies as mathematicians; it is built into the laws of mathematics.” The physics problem is actually much easier than endocrinology, because we know the exact strength and form of the gravitational force.

A recent paper [ Neuron vol. 102 pp. 908 – 910, 1009 – 1024 ’19 ] is the first to describe a mechanism behind any setpoint and one of particular importance to the brain (and possibly to epilepsy as well).

The work was done at significant remove from the brain — hippocampal neurons grown in culture.  They synapse with each other, action potentials are fired and postsynaptic responses occur.  The firing rate is pretty constant.  Block a neurotransmitter receptor, and the firing rate increases to keep postsynaptic responses the same.  Increase the amount of neurotransmitter released by an action potential (neuronal firing) and the firing rate descreases.  This is what synaptic homeostasis is all about.  It’s back to baseline transmission across the synapse regardless of what we do, but we had no idea how this happened.

Well we still don’t but at least we know what controls the rate at which hippocampal neurons fire in culture (e.g. the setpoint).  It has to do with an enzyme (DHODH) and mitochondrial calcium levels.

DHODH stands for Di Hydro Orotate DeHydrogenase, an enzyme in mitochondria involved in electron transfer (and ultimately energy production).   Inhibit the enzyme (or decrease the amount of DHODH around) and the neurons fire less.  What is interesting about this, that all that is changed is the neuronal firing rate (e.g. the setpoint is changed).  However, there is no change in the intrinsic excitability of the neurons (to external electrical stimulation), the postsynaptic response to transmitter, the number of mitochondria, presynaptic ATP levels etc.

Even better, synaptic homeostasis is preserved.  Manipulations increasing or decreasing the firing rate are never permanent, so that changes back to the baseline rate occur.

Aside from its intrinsic intellectual interest, this work is potentially quite useful.  The firing rate of neurons in people with epilepsy is increased.  It is conceivable that drugs inhibiting DHODH would treat epilepsy.  Such drugs (teriflunomide) are available for the treatment of multiple sclerosis.

The paper has some speculation of how DHODH inhibition would lead to decreased neuronal firing (changes in mitochondrial calcium levels etc. etc) which I won’t go into here as it’s just speculation (but at least plausible spectulation).

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Hillary’s health — you can see a lot by looking

Last night’s debates should put two suggestions about Hillary’s health to rest and gives some evidence for two others. First, she does not have Parkinson’s disease. Second, she does not have epilepsy. Third, her eye movements still show some residua from the stroke of December 2012. Fourth, she may have a mild proximal myopathy.

Now to elaborate.

Parkinson’s disease: Two great things happened in September 1970 — I finished my two years in the Air Force and L – DOPA was released for use in the USA. American neurologists had been reading about the great things it was doing for the disease in Europe for almost 10 years. So when I went back to complete the last two years of my residency, the chief put me in charge of the L – DOPA clinic he’d just set up. So until retirement in 2000, I treated lots of people with it.

As the chief said — Parkinson’s disease is a Yellow Cab disease. If you see a Yellow Cab on the street, you don’t write down the license number, go down to city hall and find that it was registered as a Yellow Cab. You look at it and say “that’s a Yellow Cab”.

Parkinsonians have a rather immobile face (masklike) — Hillary’s face is quite mobile. Their speech lacks the normal musicality of speech (prosody), Hillary’s speech has normal inflection. Parkinsonians have a slow, stiff gait with difficulty initiating it. Hillary has none of this. Finally there is no sign of any tremor.

Epilepsy: Videos of purported seizures are out and about on the internet, particularly one during an interview. I thought that the ones I saw looked rather edited, as though some individual frames had been deleted from the videos. Fortunately last night we had an opportunity to see for ourselves. Toward the end of the debate, she had another episode, during which she shook her head and her shoulders for a few seconds. This happened in real time, so we could run the video recording backwards and forwards. At no time did she appear to be out of contact, and she then continued on with what she was saying without pause. So it’s just something she voluntarily does. It isn’t epilepsy.

Eye movements: Recall that after the stroke in December 2012, Hillary had double vision and had to wear Fresnel lenses to correct it for a few weeks afterwards — pictures of her testifying in congress January 2013 show this. So last night there was a 90 minute opportunity to watch the way her eyes move. They aren’t quite normal – on looking to her left the right eye lags and doesn’t bury the white. Even though Trump was to her right, she turned her head rather than her eyes to look at him, so I only saw her look to her right on a few occasions, but when she did her eyes appeared to move together. No other residua of a brainstem stroke were present such as slurred speech (dysarthria), facial weakness, facial asymmetry.

Proximal muscle weakness: The internist referred to in a previous post noted the following:

“There were shots a month or so ago of her needing help to get up outdoor stairs and also needing a small step-stool to get up into a Secret Service Suburban. My wife and I hop in and out of a Yukon and do not need any step device (they are of comparable age). After a photo of her doing that was published, she started getting in and out of vehicles on the side away from cameras and was also switched to a taller van with a step mounted on the vehicle. In February, press was forbidden by her staff from filming her climbing the stairs to board her private jet.”

He wondered if she could have something like limb girdle dystrophy.

Well, such a dystrophy is certainly possible. Although Hillary  had no difficulty standing for 90 minutes, at the end, she appeared to waddle as she walked toward the moderator.. There wasn’t really enough time to definitely say that she waddled.  It’s worth carefully watching the way she walks in the future.

Why is waddling a sign of mild weakness of the muscles of the pelvic girdle? Believe it or not the buttocks are not a secondary sexual characteristic. The main buttock muscle (gluteus maximus) is so big because it has so much work to do.

Think about what you do when you take a step forward with your right foot. To remain stable, your entire upper body weight must  be strongly plastered to your left hip. You need a strong, large muscle to do this (the gluteus maximus). What happens if the muscle is weak? Your upper body would fall to the right. How would you prevent this? By throwing your upper body to the left, putting its center of gravity there, so it presses on the left hip with greater force. A similar thing happens when stepping forward with the left foot. The net effect is that you waddle, which is what Hillary appeared to do.

It’s worth watching her walk in the future.

Stamina: she was under 90 minutes of stress, and showed no sign of fatigue.

Now, hopefully, back to the science, with a very long (over 1,000 Angstroms) allosteric effect.