Faulty brakes

After reading my last post, you may be wondering if it’s just a coincidence that lesions in the cerebellum mimic many of the disinhibited behavioral features of PSP.  It’s no coincidence, and here’s why.

The motor role of the cerebellum in effect acts as a “brake” on the actions of the cerebral motor cortex and basal ganglia.  The “ataxic” gait of cerebellar disease is characterized by unchecked lateral movement of the center of gravity.  Once the proprioceptive (joint position sense) and visual functions perceive that one is reeling to one side, a voluntary check and corrective action occur.  But that correction, similarly, goes too far, producing a reeling in the other direction.  This is the familiar gait of the drunk, as alcohol is an acute cerebellar toxin. 

The same goes for other cerebellar motor deficits.  The uncoordinated hand movements consist of overshooting a goal followed by a correction that itself overshoots, and the process repeats, producing a kind of tremor or wavering.  The speech, besides its slurring, is degraded by an unintended, rapid grouping of syllables followed by a long pause. Try it — if you want to mimic drunkenness.  The eyes exhibit a slow, involuntary movement of a few degrees to one side followed by a rapid correction.  This is called “nystagmus” and can produce a constant jittering of the visual scene that may be described by the patient as “double vision.”

The behavioral aspects of cerebellar dysfunction are analogous.  Just as they cause a loss of inhibition of an ongoing motor action, so do they cause a loss of inhibition on behavior, with inappropriate or repetitive comments, compulsive thoughts and incontinent laughter or crying.

So, yes, it makes sense.

In through the back door?

One of my retirement activities is giving an occasional lecture to the neurology residents in my old department at Rutgers Robert Wood Johnson Medical School.  In March, my topic will be the anatomy of the cerebellum.  I’ve never lectured specifically on that before, so I’ve been updating my knowledge and preparing slides.  That led me to something very interesting. 

It turns out that one or more discrete lesions, typically small strokes, of the posterior half of the cerebellum (hence the anatomical connection) can produce behavioral and cognitive abnormalities.  Mind you, the cerebellum has classically been considered only a center of motor control.  But in 1997, Dr. Jeremy Schmahmann, a neurologist at Harvard, and his psychologist colleague Dr. Janet Sherman described what they called the “cerebellar cognitive affective syndrome.” 

This is a mouthful, and “Schmahmann-Sherman syndrome” would have been shorter but more of a tongue-twister.  So the world, as usual, decided to recognize the contribution of the man over that of the woman, and the condition is usually called “Schmahmann’s syndrome.”  In protest, I’ll call it CCAS. 

From: Stoodley CJ, MacMore JP, Makris N, Sherman JC, Schmahmann JD. Location of lesion determines motor vs. cognitive consequences in patients with cerebellar stroke. NeuroImage Clin. 2016;12:765–75.
The Roman numerals are areas of the cerebellum. X, y and z are the three axes of space and the numerical values are the distance of the image plane from a standard reference plane for that axis. Each color is arbitrarily chosen and represents one patient’s stroke(s).

It’s not clear why CCAS arises from disruption of only the back half of the cerebellum, as both halves have pretty much the same kind of circuitry, as far as we know.  The features of CCAS include loss of:

  • executive functions (difficulty with shifting tasks or multitasking, problem solving, planning, organizing, and sequencing)
  • some aspects of affect (disinhibition of speech or behavior, making inappropriate jokes, behaving childishly, inability to suppress laughter or crying, being obsessive or compulsive) 
  • some language functions (loss of fluency of speech, grammatical rule-breaking)
  • some visuospatial skills (inability to copy or understand pictures or to distinguish two objects presented at the same time)

Ring a bell (especially the first two)?  Sound something like PSP? 

We’ve known since its original 1964 description of PSP by Steele, Richardson and Olszewski that the cerebellum, specifically in an important part called the dentate nucleus (because its layers are in a saw-tooth pattern), is a site of tau deposits and cell damage.  But the balance problems and dizziness produced by dentate damage may be swamped by the symptoms from the degeneration in the cerebrum, specifically the basal ganglia.  So, the symptoms of PSP have never been considered to arise importantly from the cerebellum damage.

But now, thanks to Drs. Schmahmann and Sherman, we know that cerebellar problems can cause cognitive and behavioral problems, and that they look like those of PSP.  True, the well-known loss of function in the frontal lobes can explain those symptoms as well.  But here’s the rub:  Cerebellar symptoms in PSP might be amenable to treatment by transcranial magnetic stimulation (TMS).

TMS involves the painless, nearly harmless (as far as we know) application of magnetic fields to the scalp.  It’s an emerging field for a wide variety of neurological problems and has been FDA-approved for depression and migraine.  The European Union has approved it for several other conditions as well, including Alzheimer’s, Parkinson’s, autism, bipolar disorder, epilepsy, chronic pain and PTSD. Adverse effects are very rare, with the most common being fainting.  Some others are seizures, pain, confusion, hearing loss and hyperactivity.  Caution must be exercised in the presence of pacemakers or other implanted or worn devices.  The procedure is typically repeated once or twice a month for six to 12 months.  Unfortunately, Medicare and commercial insurance do not yet cover it, and the cost is several thousand dollars for a course.

In PSP, seven studies of TMS have been published, involving a total of only 47 patients.  Two of the seven were single cases reports.  Three of the seven, involving 32 patients, stimulated over the cerebellum. They all reported modest improvement in motor symptoms, and two studied reported speech improvements.  None found side effects, at least over short-term follow-up.  Unfortunately, none of the three studies evaluated cognition or behavior in detail.

A closely related technique is transcranial direct current stimulation. Its advantage over magnetic stimulation is that it can reach more deeply into the brain, but with more side effects. It has not been studied as well in PSP as TMS. My November 8, 2021 post was about one such study. I’ll return to TDCS in another post.

So we have work to do.  The frequency of the magnetic impulses, their strength, temporal pattern and precise location could make big differences in the outcome, so this will not be simple.  But if careful study shows that the benefit amounts to even a modest improvement in quality of life for those with PSP, and if Medicare eventually decides to pay for it, let’s get busy.

My idea of art

Here’s something I’ve been working on sporadically for months. It’s a diagram providing a quick-and-easy guide to the major neurodegenerative diseases from the standpoint of PSP and CBD. It’s designed to show laypersons that while PSP and CBD are rare, they can provide researchers important insights into the more frequent diseases. It’s kind of like how an advertisement for a retail business shows how centrally located it is through careful centering of the map.

The diagram’s overall concept should be self-explanatory, though most people will have to hit Wikipedia to learn what many of these specific diseases are. At the lower left is a key showing which colors are diseases and which are commonalities and differences (with respect to PSP/CBD).

Don’t interpret the relative positions of the diseases to mean that one disease is a variant or subtype of the other. The lines only indicate similarity, not necessarily classification. The area where classification is justified, but only incidentally, is that “frontotemporal disorders” is an umbrella term for all of the diseases to which that label is connected, including PSP and CBD.

Also, please be aware that the “Genetic” label means “single genetic causation.” In the case of trisomy 21, it’s a whole chromosome and for NPC, it’s a mutation in one gene acting via a recessive mechanism. Many of these disorders have more subtle contributions to their causation from multiple variant genes in the same individual, each mutation contributing a slight degree of risk.