Decision-Making under Conditions of Uncertainty in Parkinson’s Disease
Michele A. Basso, Ph.D.
University of California Los Angeles, Los Angeles, CA, Brain Research Institute UCLA
Website
Grant Program:
Clinical Neuroscience Research
Funded in:
December 2011, for 3 years
Funding Amount:
$300,000
Lay Summary
Decision-Making under Conditions of Uncertainty in Parkinson's Disease
Investigators will explore whether patients with Parkinson’s disease (PD) make impaired visual perception decisions, and whether deep brain stimulation (DBS) treatment for PD enables patients to access prior memory to help guide perceptual choice.
PD is a degenerative brain disease. Dopamine-transmitting cells die in the substantia nigra, a part of the basal ganglia, relentlessly impairing motor and cognitive functioning. As an example, PD patients experience “paradoxical movement.” They initiate normal patterns of walking when aided by sensory information such as horizontal lines on floor. Without such cues, though, PD patients use short, shuffling steps, don’t swing their arms, and keep their heads down. Their eye movements show similar patterns of defects in the absence of sensory stimuli. The UCLA investigators’ studies in non-human primates suggest that networks in the basal ganglia normally give rise not only to visual perception but also to perceptual decisions. They used psychophysics, electrophysiology and statistical modeling methods to study how monkeys decide whether an arrow on a screen is pointing to the left or the right in repeated tests as the contrast between arrow and background diminishes. They found that when there was little contrast to guide choice, monkeys relied on prior memory of the statistical probability that the arrow would be pointing to the left or the right.
Recently, the investigators translated this research into PD patients, who have damaged basal ganglia, to assess the effects of this damage on visual perception and perceptual decision-making. Four of the PD patients were being treated with the drug L-DOPA, and three (severely affected) PD patients were being treated with DBS. When contrast between arrow and background was sharp, patients performed relatively well. But when the contrast was weak and patients had to rely on memory of prior probability, their performance dropped substantially. Surprisingly, though, the DBS-treated patients performed significantly better than those being treated with L-DOPA. This finding suggests that DBS-treated patients had access to prior memory of probability. Now, investigators will expand the study to 36 people: 12 DBS-treated PD patients; 12 L-DOPA-treated PD patients and 12 healthy volunteers. They hypothesize that PD patients will have more difficulty making correct visual perceptual decisions than healthy volunteers when faced with sensory uncertainty, but that DBS-treated patients will show ability to use memory to guide their choices.
Significance: If confirmed, the findings would provide new evidence that the basal ganglia is involved in making perceptual decisions, and that DBS can help to restore cognitive functioning by enabling patients to retrieve memory. This would confer a potentially major therapeutic benefit for patients with PD and perhaps those with other degenerative diseases, such as Alzheimer’s.
Investigator Biographies
Michele A. Basso, Ph.D.
Michele A. Basso received her Ph.D. working with Dr. Craig Evinger at Stony Brook University in 1995. It was during this time that her interest in Parkinson’s disease developed. For her thesis work, Dr. Basso used a rodent model of Parkinson’s disease and revealed the anatomical and physiological pathways that underlie a prominent and early symptom of Parkinson’s disease called the glabellar tap sign. This symptom appears as a loss of control of blinking in response to blink-evoking stimuli such as puffs of air or taps on the forehead. In healthy humans and other animals, blinks normally occur in response to taps on the forehead. With repeated taps, however, the blinks diminish. In Parkinson’s disease in contrast, the habituation of blinking fails to occur. In fact, the response of the system controlling blinks can be so extreme that some patients develop severe spams of the eyelid muscle rendering them functionally blind. This extreme symptom is a focal dystonia referred to as blepharospasm. Dr. Basso’s Ph.D. work was the first to show how damage to a brain region that is involved in Parkinson’s disease (the basal ganglia) can lead to this symptom.
After completing her Ph.D., Dr. Basso moved to the National Eye Institute at the National Institutes of health for post-doctoral training. In the Laboratory of Sensorimotor Research she worked with Dr. Robert Wurtz studying how the brain makes choices about where to look when faced with options. During this time, Dr. Basso explored how the basal ganglia, together with one of its major target structures the superior colliculus, work together to determine action choices. Her work during this time led her to begin thinking about cognitive symptoms associated with movement disorders such as Parkinson’s disease and dystonia. After completing her post-doctoral fellowship in 2000, Dr. Basso moved to the University of Wisconsin where she accepted her first faculty position in the Department of Neuroscience. In 2012, she moved to UCLA as Professor of Psychiatry and Biobehavioral Sciences at the Jane and Terry Semel Institute for Neuroscience and Human Behavior where she has assumed the position of Director of the Fuster Laboratory of Cognitive Neuroscience. At UCLA, Dr. Basso and members of her laboratory study how the brain converts visual images into commands to move and the neuronal processes that intervene between seeing and acting. These processes include learning, memory and decision-making. Her focus is in understanding the brain mechanisms of these processes in the healthy brain and how they go awry in diseases such as Parkinson’s disease and dystonia.
The work performed by Basso and her colleagues in the Fuster Laboratory of Cognitive Neuroscience spans a large range from in vitro studies exploring the cellular mechanisms of neuronal circuits giving rise to behavior, to psychophysical and electrophysiological studies in non-human primates to psychophysical studies in both healthy humans and in clinical populations. Her experiments in clinical populations are performed in collaboration with neurologists, neurosurgeons and neuropsychologists. Her most recent work translates directly the experiments performed in non-human primates to patients with Parkinson’s disease to assess how well patients make decisions when placed in conditions of uncertainty and how well they can use their memories to guide their decision-making. By performing such a range of studies, Dr. Basso’s work bridges the large gap between cellular and systems neuroscience and she is hopeful that this work will shed light on the neuronal basis of higher mental function leading to better diagnostics as well as treatments in the future.
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