By David N. Leff

Like his father and grandfather before him, George Sumner Huntington (1850-1916) was a rural general practitioner in the East Hamptons of Long Island, New York. Fresh from medical school, he began in 1872 to describe the inherited neurological disease that now bears his name. Its three clinical hallmarks include jerky, spasmodic, dance-like movements of the limbs, plus facial grimaces; onset at 30 to 40 years of age; and slowly advancing dementia for the next 10 or 20 years until death.

Anecdotally, Huntington¿s disease (HD) is supposed to have originated with two affected founder brothers, who migrated from England to the U.S. Its inheritance is autosomal and dominant, with complete penetrance, which means that a child of a parent with the disease has a 50-50 chance of acquiring it.

The HD gene, IT-15, was mapped to the short arm of chromosome 4 in the 1980s, and the genetic test for the mutated protein it encodes ¿ huntingtin ¿ was approved in 1993. ¿When that test became available,¿ observed neuropsychiatrist Christopher Ross, ¿we expected a large expression of interest from the 150,000 presymptomatic individuals at risk of HD in the U.S. In fact, only 3,000 asked to be tested, presumably for two reasons: The disease is totally untreatable, so the diagnosis would be useless, and those who tested predictively positive feared they would lose their insurance.¿

Ross heads the Department of Psychiatry and Behavioral Sciences at Johns Hopkins University in Baltimore. He directed a clinical trial of the neurological basis for HD, which appears in today¿s Nature, dated Feb. 3, 2000. Its title: ¿Motor disorder in Huntington¿s disease begins as a dysfunction in error feedback control.¿ The paper¿s co-senior authors are psychiatrist Jason Brandt, in Ross¿s department, and bioengineer Reza Shadmehr, in Hopkins¿ Department of Biomedical Engineering.

¿One of the wonderful things about HD genetic testing,¿ Shadmehr told BioWorld Today, ¿is that we can begin examining people years before the onset of disease. It allows us to look at the nervous system and see ¿ in this early stage ¿ how the disease manifests itself in destroying the nervous system.

¿The brain-imaging scans done previously,¿ he continued, ¿have shown that years before there are any clinical symptoms of HD, one begins to see degradation in the basal part of the brain that¿s particularly affected by HD. But clinically,¿ Shadmehr added, ¿we haven¿t been able to see what kind of function this part of the brain has in the ability to control movements. We wondered: Is there really no effect of this in HD patients?¿

Hunting Brain Jerks In Pre-Symptom Folks

So he and his co-authors turned their attention from the full-blown disease to trying to identify the role of this part of the brain in motor control while individuals at genetic risk are still free of symptoms. ¿We hypothesized, Shadmehr said, ¿that if this automatic response is influenced by the basal ganglia, there might be some defect in this response before there is any clinical symptom. So we tested this and found that there is a really quite remarkable degradation of this fundamental control process in the movement generated genetically in these individuals.

¿We¿re a bunch of engineers here, basically,¿ Shadmehr observed, ¿so we study the brain from the engineering standpoint. We wanted to know in the generation of automatic motor movements what roles are played by different parts of the brain. With regard to the basal ganglia ¿ a deep-brain cluster of neurons at the base of the cerebrum ¿ we knew that people who have developed HD are susceptible to a particular loss of feedback control. They have trouble voluntarily controlling certain aspects of their feedback response to small perturbations.¿

He explained: ¿Imagine you¿re reaching for a cup of coffee, and your hand hits something ¿ say, the wall or the table. Now the normal reaction would be to pull away, and your arm just continues moving toward where it was supposed to go. You do this unconsciously, whereas an HD patient begins right away to overshoot where the cup is, or his arm might come around and hit the table again.

¿We hypothesized that if this automatic response were influenced by the basal ganglia, there might be some defect in its functioning long before there is any clinical symptom.¿

To check out their hunch, the co-authors recruited 42 test subjects: 11 who were known carriers of the HD gene, but asymptomatic; 16 with the clear symptoms of the disease; three individuals who did not have the HD gene, but did have parents with the disease; and 12 age-matched, disease-free controls.

Instead of a coffee cup, they placed these participants in front of a bull¿s eye-like target. Their right hand grasped a robot arm, which the researchers called a manipulendum. ¿Imagine a mechanical system that is designed to look more or less like your arm,¿ Shadmehr recounted, ¿but made out of metal and motors. It allowed us to measure extremely precisely what people [were] doing with their arm. The device has a hand at the end of it, and these subjects were seated in front of it, holding the mechanical hand. They reached with it, while along the way the robot gave their own hand a little bit of perturbation, and measured how they responded to it.

Goal: Train Brain Before HD Hallmarks Emerge

¿In presymptomatic HD individuals, we saw jerky responses to these perturbations. Where the normal persons had a smooth response and pulled away from it, here the movement became destabilizing.¿

Shadmehr reported two kinds of results from this experiment: ¿One has to do with the ability to detect the onset of this disease, five or six years before its clinical diagnosis, and the ability to find something wrong in the brains of the people we thought were presymptomatic ¿ who didn¿t have any symptoms. Secondly, we¿re suggesting that the brain¿s basal ganglia plays a particular role in error feedback control.¿

Shadmehr made the closing point, ¿The brain is fundamentally a plastic system; it can be trained. And our hope is that, now that we think we know that there is a particular deficit in motor control, we could somehow focus rehabilitation early ¿ teach the brain what¿s happening, essentially ¿ years before there is any clinical manifestation of Huntington¿s disease.¿