Memory of Time May Be Factor in Parkinson's

Bad timing, not nerves, may explain the irregular motions of Parkinson's Disease patients, research led at Columbia has found.

Any body movement involves a timed sequence of motions, and "evidence is accumulating that a central problem in Parkinson's is memory for time, a cognitive function in the brain, not a neuromuscular function," said John Gibbon, professor of psychology at Columbia. "Even simple movements require complex temporal sequencing."

The timing function is analogous to an internal stopwatch. It tells humans a stop light is broken or that the end of a television commercial is approaching.

Gibbon, who is also director of the department of biopsychology at the New York State Psychiatric Institute, presented the research at the recent annual meeting of the American Association for the Advancement of Science in Baltimore, Md. His work, and that of collaborators, has shown which parts of the brain allow humans and animals to sense intervals of time and why that sense is so important.

Gibbon, with Chara Malapani, a scientist with the French research organization INSERM U-289 and the Hôpital de la Salpetrière in Paris, discovered that Parkinson's patients have difficulty estimating and remembering timed intervals. Gibbon and his colleagues hypothesize that the jerky motions of Parkinson's may result from a patient's inability to time smooth, fluid movement, like a turn of the head or a wave of the arm, creating instead a series of separate, stop-and-go motions.

In the research at the Hôpital de la Salpetrière, which began in 1994 and is ongoing, Parkinson's patients were asked to watch a computer image of a rectangle that changed color after 8 seconds or after 21 seconds and then reproduce the experience by estimating when the rectangle would change color again. The patients were unable to accurately remember the interval, consistently guessing too late on the short interval and too early on the long one. A control group of matched-age subjects was quite accurate on both.

Parkinson's is a degenerative disease that often manifests itself late in life and is marked by abrupt motions, muscle tremors and a peculiar gait. People who suffer from this disease, once thought to be strictly neuromuscular, lose neurons from a part of the brain called the substantia nigra that produces the neurotransmitter dopamine, which helps brain cells communicate with one another. Parkinson's patients also experience a slowing of some cognitive functions and have difficulty with complex tasks.

Treatment with levodopa, which when metabolized by the body increases the level of dopamine, is effective in treating motor problems but less so with cognitive ones, and is less effective as the disease progresses. In the Paris experiments, patients were tested after stopping their medication. Putting patients back on the drug restored their sense of time. The work is the first to indicate that damage to the basal ganglia, a region of the brain that coordinates voluntary muscle movements, results in temporal memory deficiencies that may cause the ill-timed motor sequences of Parkinson's.

Gibbon has studied humans' sense of passing time, and how, for example, we know how long a red light should last or how long to snack while a television commercial is on. He has found, in both animals and humans, that if an individual perceives a time interval incorrectly, i.e., as too long or too short, he or she will perceive other intervals - whether longer or shorter - in the same way, as too long or too short, and by the same percentage of the original interval. Gibbon has named this phenomenon the scalar time sense, and has found it effective at periods ranging from milliseconds to hours.

That sense must be based in a cellular or molecular mechanism that operates subconsciously and allows memories of timed intervals to be recorded and later retrieved, the scientists say. The next research question for interval timing researchers is how people and animals remember the intervals that their internal stopwatch measures, Gibbon said.

The Columbia biopsychologist is beginning experiments with the Paris research group to determine whether the impairment in Parkinson's occurs during storage or retrieval of temporal memory.

That work could well give scientists the insights that will give Parkinson's patients back their sense of time and movement.

Gibbon and Malapani, with Warren Meck, associate professor of experimental psychology at Duke and former associate professor of psychology at Columbia, are working to isolate nerve connections--called striato-cortical loops--between the basal ganglia and the frontal cortex, where time is consciously observed.

Scientists believe identifying those connections that serve memory functions will help pinpoint the neural mechanisms that observe, record and retrieve memories of timed intervals. Knowing how that system works might some day allow researchers to design therapies to overcome these impairments.

In related discoveries with animals, also reported at AAAS, Gibbon and two colleagues described components of the interval timing mechanism, located in the basal ganglia, that act as the body's stopwatch.

Collaborators on the work were Meck and Russell Church, professor of psychology at Brown.

Increasing or decreasing the level of dopamine in the brain speeds up or slows down an individual's sense of the passage of time, Meck and Church had found in the early 1980's.

The three psychologists hypothesized that the brain must record nerve impulses facilitated by dopamine; the more such impulses registered, the more subjective time an individual thinks has passed.

They have isolated different components of the timing mechanism, controlled by different structures in the basal ganglia. Severe damage to the substantia nigra stops all timing, as it cuts off the dopamine supply.

Damage to the caudate and putamen, major structures in the basal ganglia, appears to impair communication between the clock mechanism and the frontal cortex, where time is consciously perceived.

But therapeutic lesions to the globus pallidus, a way station in the striato-cortical loops, sometimes improve dopamine regulation and may improve interval timing as well.

Columbia University Record -- April 5, 1996 -- Vol. 21, No. 22