Behavioral impulsivity and hallucinations : insights from Parkinson's disease

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, September 2011.Cataloged from PDF version of thesis. "September 2011."Includes bibliographical references (p. 125-156).Parkinson's disease (PD) is an age-related degenerative disease of the brain, characterized by motor, cognitive, and psychiatric symptoms. Neurologists and neuroscientists now understand that several symptoms of the disease, including hallucinations and impulse control behaviors, stem from the dopaminergic medications used to control the motor aspects of PD. Not all patients experience these nonmotor symptoms and tools that can predict a priori which patients are likely to have an adverse response to medication do not exist. This thesis begins to fill this gap by elucidating the mechanisms underlying the adverse effects of dopaminergic medications. Converging evidence from animals and humans shows that individual differences in particular genes that affect the dopamine system may alter the response of PD patients to dopaminergic medication. We examined the hypothesis that patients taking dopamine replacement therapy who carry candidate alleles that increase dopamine signaling experience a dopamine overdose, causing unwanted psychiatric symptoms.by Paymon Ashourian.Ph.D

Bayesian Inference Underlies the Contraction Bias in Delayed Comparison Tasks

Delayed comparison tasks are widely used in the study of working memory and perception in psychology and neuroscience. It has long been known, however, that decisions in these tasks are biased. When the two stimuli in a delayed comparison trial are small in magnitude, subjects tend to report that the first stimulus is larger than the second stimulus. In contrast, subjects tend to report that the second stimulus is larger than the first when the stimuli are relatively large. Here we study the computational principles underlying this bias, also known as the contraction bias. We propose that the contraction bias results from a Bayesian computation in which a noisy representation of a magnitude is combined with a-priori information about the distribution of magnitudes to optimize performance. We test our hypothesis on choice behavior in a visual delayed comparison experiment by studying the effect of (i) changing the prior distribution and (ii) changing the uncertainty in the memorized stimulus. We show that choice behavior in both manipulations is consistent with the performance of an observer who uses a Bayesian inference in order to improve performance. Moreover, our results suggest that the contraction bias arises during memory retrieval/decision making and not during memory encoding. These results support the notion that the contraction bias illusion can be understood as resulting from optimality considerations

Effect of noise on the response curve.

<p><b>A</b>, Subjects performed a modified experiment where a secondary task had to be performed between the presentations of the two bars on randomly selected 50% of the trials. Top row depicts sequence of events in trials with interference: a sequence of 4 colors was presented on the screen 500 msec after the presentation of <i>L</i>₁. Each color was presented for 400 msec and subjects were instructed to memorize the sequence. 400 msec after the disappearance of the last color, a number from 1 to 4 appeared on the screen. Subjects were instructed to recall the color that corresponded to the number. <b>B</b>, Percentage correct in bar length comparison in the standard (black) and modified (red) trials. The ability to memorize the length of <i>L</i>₁ was impaired in the modified trials compared to the standard unperturbed trials, in both the easy (±30%, left), intermediate (±15%, center) and hard (±7.5%, right) trials. These results suggest that the secondary task increased uncertainty in the memory of the length of <i>L</i>₁. <b>C</b>, Response curve in the standard (filled circles) and modified trials (open circles). The larger slope of the response curve on the modified trials compared to the standard trials suggests that the secondary task caused an enhancement of the contraction bias. Each data point corresponds to 6 impossible trials per subject. Error bars depict SEM. Lines are the best fit of the Bayesian model, see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0019551#s4" target="_blank">Materials and Methods</a>.</p

Bayesian inference and the contraction bias.

<p><b>A</b>, Response curve of a Bayesian model with infinite noise in the representation of <i>L</i>₁ (no memory of <i>L</i>₁) and no noise in representation of <i>L</i>₂. The model reports ‘<i>L</i>₁><i>L</i>₂’ in trials where <i>L</i>₂ is smaller than the median of the prior distribution, and ‘<i>L</i>₁<<i>L</i>₂’ in trials in which <i>L</i>₂ is larger than the median. This behavior arises because the posterior distribution of <i>L</i>₁ is the same as the prior distribution of the bar lengths, whereas the posterior distribution of <i>L</i>₂ is not influenced by the prior at all. <b>B</b>, Response curve of the Bayesian model with equal noise in the representations of <i>L</i>₁ and of <i>L</i>₂. The contribution of the prior to the posteriors of <i>L</i>₁ and <i>L</i>₂ is identical because the levels of noise in the two representations are equal. Thus, in trials where <i>L</i>₁ = <i>L</i>₂, the model reports ‘<i>L</i>₁><i>L</i>₂’ at chance level independently of the length of the bars. <b>C</b>, Response curve of the Bayesian model assuming that there is more noise in the representation of <i>L</i>₁ than in representation of <i>L</i>₂. Response curve is a combination of <b>A</b> and <b>B</b>.</p

Ideal decision maker solution to the task in <b>Figure 1A</b>.

<p><b>A</b>, The likelihood of a representation <i>R_i</i> given a particular length (here <i>L_i</i> = 0.85, <i>σ_i</i> = 0.24) assuming . <b>B</b>, The prior distribution of bar lengths. <b>C</b>, The posterior distribution of <i>L_i</i> given a particular measurement (here <i>R_i</i> = 0.85), calculated using Bayes' rule. <b>D</b>, The probability that <i>L</i>₁><i>L</i>₂ for different values of <i>R</i>₁ and <i>R</i>₂, computed using the posteriors. The black line corresponds to the values of <i>R</i>₁ and <i>R</i>₂ such that Pr(<i>L</i>₁><i>L</i>₂|<i>R</i>₁,<i>R</i>₂) = 0.5 (here, and ). <b>E</b>, Response curve of the model on the impossible trials in which <i>L</i>₁ = <i>L</i>₂.</p

The delayed comparison task and subjects' performance.

<p><b>A</b>, The standard task. Subjects viewed a horizontal bar (<i>L</i>₁) on a computer screen for 1 sec and memorized its length. After a delay period of 1 sec, during which the screen remained blank, the subjects viewed a second bar (<i>L</i>₂) and were instructed to report which of the two bars was longer. The second bar, <i>L</i>₂ remained visible until subjects made a response. The difference in length between <i>L₁</i> and <i>L₂</i> varied between −30% and +30%. Unbeknownst to the subjects, on roughly 50% of the trials, the lengths of the first and second bars were equal (<i>L</i>₁ = <i>L</i>₂). <b>B</b>, The average psychometric curve of 9 subjects. The abscissa corresponds to the difference between the two bar lengths, and the ordinate corresponds to the fraction of trials in which subjects chose <i>L</i>₁ as longer than <i>L</i>₂. Error bars depict standard error of the mean (SEM). Line is a least-square fit of an error function: where and . <b>C</b>, Average response curve of 9 subjects. Fraction of times in which subjects reported ‘<i>L</i>₁><i>L</i>₂’ on the impossible trials are plotted as a function of bar length. Subjects overestimated the magnitude of the memorized <i>L</i>₁ bar when it was relatively small and underestimated <i>L</i>₁ when it was relatively long, consistent with the contraction bias. Each data point corresponds to 21 impossible trials per subject. Error bars depict SEM.</p

Substantia nigra volume loss before basal forebrain degeneration in early Parkinson disease

Objective: To test the hypothesis that degeneration of the substantia nigra pars compacta (SNc) precedes that of the cholinergic basal forebrain (BF) in Parkinson disease (PD) using new multispectral structural magnetic resonance (MR) imaging tools to measure the volumes of the SNc and BF. Design: Matched case-control study. Setting: The Athinoula A. Martinos Imaging Center at the McGovern Institute for Brain Research, Massachusetts Institute of Technology (MIT), and the Massachusetts General Hospital/MIT Morris Udall Center of Excellence in Parkinson Disease Research. Patients: Participants included 29 patients with PD (Hoehn and Yahr [H&Y] stages 1-3) and 27 matched healthy control subjects. Main Outcome Measures: We acquired multiecho T1-weighted, multiecho proton density, T2-weighted, and T2-weighted fluid-attenuated inversion recovery (FLAIR) sequences from each participant. For the SNc, we created a weighted mean of the multiple echoes, yielding a single volume with a high ratio of contrast to noise. We visualized the BF using T2-weighted FLAIR images. For each participant, we manually labeled the 2 structures and calculated their volumes. Results: Relative to the controls, 13 patients with H&Y stage 1 PD had significantly decreased SNc volumes. Sixteen patients with H&Y stage 2 or 3 PD showed little additional volume loss. In contrast, the BF volume loss occurred later in the disease, with a significant decrease apparent in patients having H&Y stage 2 or 3 PD compared with the controls and the patients having H&Y stage 1 PD. The latter group did not differ significantly from the controls. Conclusion: Our results support the proposed neuropathological trajectory in PD and establish novel multispectral methods as MR imaging biomarkers for tracking the degeneration of the SNc and BF