Leo Chi U Seak’s research while affiliated with University of Cambridge and other places

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Publications (15)


Studying neural responses for multi-component economic choices in human and non-human primates using concept-based behavioral choice experiments
  • Article

June 2023

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21 Reads

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1 Citation

STAR Protocols

Alexandre Pastor-Bernier

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Konstantin Volkmann

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Leo Chi U Seak

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[...]

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Wolfram Schultz

Realistic, everyday rewards contain multiple components, such as taste and size. However, our reward valuations and the associated neural reward signals are single dimensional (vector to scalar transformation). Here, we present a protocol to identify these single-dimensional neural responses for multi-component choice options in humans and monkeys using concept-based behavioral choice experiments. We describe the use of stringent economic concepts to develop and implement behavioral tasks. We detail regional neuroimaging in humans and fine-grained neurophysiology in monkeys and describe approaches for data analysis. For complete details on the use and execution of this protocol, please refer to our work on humans Seak et al.¹ and Pastor-Bernier et al.² and monkeys Pastor-Bernier et al. ³, Pastor-Bernier et al.⁴, and Pastor-Bernier et al.⁵.


Figure 1. Experimental design.
Figure 2. Differential risk attitude across reward probabilities in the Marschak-Machina triangle.
Figure 3. General Linear Models (GLM's) of human data (probability of safer choices) predict monkeys'
Figure 4. Violations of independence axiom in monkeys and humans displayed in the Marschak-Machina
Systematic comparison of risky choices in humans and monkeys
  • Preprint
  • File available

February 2023

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100 Reads

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1 Citation

The past decades have seen tremendous progress in fundamental studies on economic choice in humans. However, elucidation of the underlying neuronal processes requires invasive neurophysiological studies that are met with difficulties in humans. Monkeys as evolutionary closest relatives offer a solution. The animals display sophisticated and well-controllable behavior that allows to implement key constructs of proven economic choice theories. However, the similarity of economic choice between the two species has never been systematically investigated. We investigated compliance with the independence axiom (IA) of expected utility theory as one of the most demanding choice tests and compared IA violations between humans and monkeys. Using generalized linear modeling and cumulative prospect theory (CPT), we found that humans and monkeys made comparable risky choices, although their subjective values (utilities) differed. These results suggest similar fundamental choice mechanism across these primate species and encourage to study their underlying neurophysiological mechanisms.

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Risky choice: Probability weighting explains independence axiom violations in monkeys

July 2022

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131 Reads

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3 Citations

Journal of Risk and Uncertainty

Unlabelled: Expected Utility Theory (EUT) provides axioms for maximizing utility in risky choice. The Independence Axiom (IA) is its most demanding axiom: preferences between two options should not change when altering both options equally by mixing them with a common gamble. We tested common consequence (CC) and common ratio (CR) violations of the IA over several months in thousands of stochastic choices using a large variety of binary option sets. Three monkeys showed consistently few outright Preference Reversals (8%) but substantial graded Preference Changes (46%) between the initial preferred gamble and the corresponding altered gamble. Linear Discriminant Analysis (LDA) indicated that gamble probabilities predicted most Preference Changes in CC (72%) and CR (88%) tests. The Akaike Information Criterion indicated that probability weighting within Cumulative Prospect Theory (CPT) explained choices better than models using Expected Value (EV) or EUT. Fitting by utility and probability weighting functions of CPT resulted in nonlinear and non-parallel indifference curves (IC) in the Marschak-Machina triangle and suggested IA non-compliance of models using EV or EUT. Indeed, CPT models predicted Preference Changes better than EV and EUT models. Indifference points in out-of-sample tests were closer to CPT-estimated ICs than EV and EUT ICs. Finally, while the few outright Preference Reversals may reflect the long experience of our monkeys, their more graded Preference Changes corresponded to those reported for humans. In benefitting from the wide testing possibilities in monkeys, our stringent axiomatic tests contribute critical information about risky decision-making and serves as basis for investigating neuronal decision mechanisms. Supplementary information: The online version contains supplementary material available at 10.1007/s11166-022-09388-7.


Experimental design and measures of risky and riskless choices. a Binary choice task. The monkeys chose one of two gambles with a left–right motion joystick. They received the blackcurrant juice reward associated with the chosen stimuli after each trial. Time, in seconds, indicate the duration of each of the task’s main events. b Schema of visual stimuli. Rewards were visually represented by horizontal lines (one or two) set between two vertical ones. The vertical position of these lines signalled the magnitude of said rewards. The width of these lines, the probability that these rewards would be realized). c Estimating certainty equivalents from risky choices. Monkeys chose between a safe reward and a risky gamble on each trial. The safe rewards alternated pseudo-randomly on every trial—they could be of any magnitude between 0 and 0.5 ml in 0.05 ml increments. Each point is a measure of choice ratio: the probability of choosing the gamble option over various safe rewards. Psychometric softmax functions (Eq. 1) were fitted to these choice ratios, then used to measure the certainty equivalents (CEs) of individual gambles (the safe magnitude for which the probability of either choice was 0.5; black arrow). The solid vertical line indicates the expected value (EV) of the gamble represented in the box. d Estimating the strength of preferences from riskless choices. Riskless safe rewards were presented against one another, the probability of choosing the higher magnitude option (A) is plotted on the y-axis as a function of the difference in magnitude between the two options presented (Δ\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\Delta$$\end{document} magnitude). The differences in magnitude tested were 0.02 ml, 0.04 ml, 0.06 ml, and a psychometric curve, anchored with its inflection anchored at a Δ\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\Delta$$\end{document} magnitude of 0, were fitted on the choice ratios measured (Eq. 2). These functions were fitted to different magnitude levels, and the temperature of each curve was linked to the strength of preferences at each of these different levels
Estimating risky utilities using the fractile procedure. a Fixed utilities are mapped onto different reward magnitudes. The gambles that monkeys experienced are defined from bisections of the range of possible reward magnitudes. For each step the gambles were held fixed; safe magnitudes varied by 0.05 ml increments. b Estimation of utility using the stepwise, fractile method. In step 1, the monkeys were presented with an equivariant gamble comprised of the maximum and minimum magnitudes in the tested reward range. The CE of the gamble was estimated and assigned a utility of 50%. In step 2, two new equivariant gambles were defined from the CE elicited in step 1. The CEs of these gambles were elicited and assigned a utility of 25% and 75%. Two more gambles are defined in step 3, from the CEs elicited in step 2. Their CEs were then assigned a utility of 12.5% and 87.5%. Parametric utility functions, anchored at 0 and 1, were fitted on these utility estimates (see methods). c Utility functions estimated from choices. Data points represent daily CEs (semi-transparent) and their median values (red filled circles) tied to specific utility levels, as estimated through the fractile procedure. Both monkeys exhibit risk-seeking behaviour for low-magnitude rewards, and risk-aversion for high-magnitude ones. The data represent individual utility estimates gathered over 22 sessions for monkey A, and 7 sessions for monkey B. The red curves were obtained by fitting piecewise polynomial functions to the measured CEs (cubic splines with three knots)
Estimating riskless utilities from the stochasticity in safe–safe choices. a Measuring stochasticity in choices between safe two reward options. Example visual stimuli (top) representing choices between safe rewards (A: low, B: high) resulting in different percentage of choices for the high option (bottom; black dots). This was repeated for different reward option sets, centered at different increments (midpoints). For each midpoint, the likelihoods were fitted with a softmax curve (dashed), used to estimate the probability of choosing the larger option for a gap of 0.03 ml (gray dot). b Choice ratios as differences in utility. The likelihoods that monkeys would pick the better reward were transformed using the inverse cumulative distribution function (iCDF) of a logistic distribution. The utility of different rewards took the form of equally noisy distributions centered at the true utilities. The output of iCDFs is the distance between these random utilities (i.e. the marginal utility). c From marginal utilities to utility. The cumulative sum of marginal utilities approximated a direct utility measure for each midpoint. These measurements were normalized whereby the utility of the highest midpoint was 1, and the starting midpoint had a utility of 0. d Daily strength of preference estimates. Each point represented the temperature of the softmax curve fitted on the choice ratios (blue points: average across days). The lower the temperature parameter, the steeper was the softmax curve and the more separable were the random utilities. Lower values meant higher marginal utility measurement (steeper utility function), higher ones meant lower marginal utility (flatter function). e Daily choice ratio estimates from softmax fits. Estimates from the same day are linked by grey lines. Ratios of 0.5 meant that the random utility of the two options were fully overlapping (i.e. flat utility function); choice ratios closer to 1 meant random utilities that were fully dissociated and non-overlapping. f Utility functions. Utilities estimated in single days (grey lines) and averages (blue), normalized relative to the minimum and maximum midpoint
Discrete choice estimates differ between risky and riskless choices. a Utility functions in risky choice. Median parametric estimates for utility functions and probability weighting functions fitted to risky choices. Shaded area: 95% C.I. on the median of these functions. Two versions of the discrete choice model were fitted: the expected utility theory (EUT) model predicted choices solely based on reward options’ utilities (without probability weighting); the prospect theory (PT) model, predicted choices based on utilities and probability weighting. An expected value (EV) based model was included for comparison. Monkeys were risk-seeking, but where the PT model accounted for this mainly through probability weighting, the EUT model accounted for it through a more convex utility. b Comparison of risky choice models. The PT model described individual choices better than EUT and EV. Bayesian information criterions (BIC) were calculated from the log likelihoods of the daily best-fitting PT and EUT discrete choice models. c Utility functions in riskless choice. Median parametric estimates for utility functions fitted to riskless choices (shaded area: 95% C.I. on the median). The discrete choice model predicted choices from the expected utilities of rewards (no probability weighting). Utilities were mostly linear, though slightly concave
Risky utilities do not predict riskless ones, and vice versa. a Median utility function estimates for risky and riskless choices. The shaded area represents the 95% C.I. on the median of these functions. For riskless choices, utility estimates were mostly linear (though slightly concave). For risky utilities, the two different versions of the discrete choice model predicted S-shaped utilities, but risky EUT utility functions were more convex than PT utility functions. b Absence of correlation for utility parameters in risky vs. riskless choices. Pearson’s correlations were run on the parameters from risky and riskless scenarios. Red squares highlight Pearson’s R for the correlation of the α and inflection parameters between risky and riskless choices. Asterisks (*) indicate significant correlations (p < 0.05)
Comparing utility functions between risky and riskless choice in rhesus monkeys

April 2022

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170 Reads

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7 Citations

Animal Cognition

Decisions can be risky or riskless, depending on the outcomes of the choice. Expected utility theory describes risky choices as a utility maximization process: we choose the option with the highest subjective value (utility), which we compute considering both the option’s value and its associated risk. According to the random utility maximization framework, riskless choices could also be based on a utility measure. Neuronal mechanisms of utility-based choice may thus be common to both risky and riskless choices. This assumption would require the existence of a utility function that accounts for both risky and riskless decisions. Here, we investigated whether the choice behavior of two macaque monkeys in risky and riskless decisions could be described by a common underlying utility function. We found that the utility functions elicited in the two choice scenarios were different from each other, even after taking into account the contribution of subjective probability weighting. Our results suggest that distinct utility representations exist for risky and riskless choices, which could reflect distinct neuronal representations of the utility quantities, or distinct brain mechanisms for risky and riskless choices. The different utility functions should be taken into account in neuronal investigations of utility-based choice.


Fig. 1. Western Blot analysis on different laccases. A) Western blot analysis on the expression of NSP4-Lac1326, BPUL Laccase, and NSP4-tvel5 laccase B) Relative expression level of laccases under 1 mM IPTG induction. Recombinant proteins containing C-terminal His-tagged residues were expressed in E. coli BL21 (DE3), followed by purification by HEPES solution. Anti-RNA polymerase beta was used as a loading control. Error Bar represented SD of the mean.
Fig. 2. Expression and secretion of laccases under different culturing conditions. A) Western blot analysis of Laccases purified from the lysed cells. B) Western blot analysis of Laccases purified from the cell-free medium.
Fig. 3. Decolorization of indigo carmine by different recombinant laccases at 37 • C. (A) Decolorization of the indigo carmine dye across 4 days as measured with OD (610 nm). The experiment was triplicated with mean and SD was shown in the error bar. (B) Enzyme activity of the three laccases, estimated with indigo carmine decolorization, under 37 • C incubation in a 96-h interval.
Fig. 4. LC-MS analysis of β-estradiol degradation by recombinant laccases. A) Chromatogram of β-estradiol by NSP4-Lac1326 and NSP4-tvel5 Laccase from cell lysates and cell-free medium extraction, with pET-11a as control B) LC-MS analysis of β-estradiol degradation by different laccases. Protein expression from cell lysed and cell free medium (Ni: Nickle Pulldown Assay) was from E. coli induced under the condition of OD 600 = 0.4, IPTG = 0.4 mM and 25 • C.
Plasmids used in this study.
Expression, secretion and functional characterization of three laccases in E. coli

March 2022

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91 Reads

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10 Citations

Synthetic and Systems Biotechnology

Endocrine Disrupting Chemicals (EDCs) are a group of molecules that can influence hormonal balance, causing disturbance of the reproductive system and other health problems. Despite the efforts to eliminate EDC in the environment, all current approaches are inefficient and expensive. In previous research, studies revealed that laccase-producing microorganisms may be a potential candidate for EDC degradation, as laccases have been found to be able to degrade many kinds of EDCs effectively and steadily. Here, we created two recombinant laccases, each fused with secretion peptide, Novel Signal Peptide 4 (NSP4), and expressed them in Escherichia coli (E. coli, BL21), together with one laccase without secretion peptide. We first optimized the culture condition of expressing these laccases. Then, we test the activity of the recombinant laccases of decolorizing of a synthetic dye, indigo carmine. Finally, we confirmed the secreted can degrade one of the EDCs, β-estradiol, showing the potential of using the laccase secretion system to degrade toxic compounds.



Using recombinant adhesive proteins as durable and green flame-retardant coatings

December 2021

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104 Reads

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32 Citations

Synthetic and Systems Biotechnology

Current fire retardants are known to be toxic to humans and our environment. As environmental-friendly flame retardants (FRs), protein-based flame retardants have been studied extensively recently, even though they are not durable. In this study, we designed, synthesized and tested a durable protein-based FR through the fusion of the adhesion domain from either mussel foot protein-5 (mfp-5) or cellulose-binding domain (CBD) with flame retardant protein (SR protein and alpha casein). We first verified the expression of the recombinant proteins in Escherichia coli using Western blot. Then, we coated the fusion protein (carrying cell lysates) to cotton fabrics and wood and verified with Infrared (IR) spectroscopy. Using a vertical burning test and wood flammability test, we confirmed the flame retardancy of the materials after the protein coating. In the vertical burning test, the SR protein and alpha casein flame retardant proteins with the CBD adhesion domain showed a 50.0% and 43.3% increase in flame retardancy. The data is also consistent in the wood flame retardancy test. Confocal imaging experiments also suggested these new fire retardants can be preserved on the materials well even after washing. Overall, our results showed that flame-retardant proteins with adhesion domains are high potential candidates of green alternative flame retardants.


Probability weighting explains Independence Axiom violations of Expected Utility Theory in monkeys

November 2021

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23 Reads

Expected Utility Theory (EUT) provides axioms for maximizing utility in risky choice. The independence axiom (IA) is its most demanding axiom: preferences between two options should not change when altering both options equally by mixing them with a common gamble. We tested common consequence (CC) and common ratio (CR) violations of the IA in thousands of stochastic choice over several months using a large variety of binary option sets. Three monkeys showed few outright Preference Reversals (8%) but substantial graded Preference Changes (46%) between the initial preferred gamble and the corresponding altered gamble. Linear Discriminant Analysis (LDA) indicated that gamble probabilities predicted most Preference Changes in CC (72%) and CR (87%) tests. The Akaike Information Criterion indicated that probability weighting within Cumulative Prospect Theory (CPT) explained choices better than models using Expected Value (EV) or EUT. Fitting by utility and probability weighting functions of CPT resulted in nonlinear and non-parallel indifference curves (IC) in the Marschak-Machina triangle and suggested IA non-compliance of models using EV or EUT. Indeed, CPT models predicted Preference Changes better than EV and EUT models. Indifference points in out-of-sample tests were closer to CPT-estimated ICs than EV and EUT ICs. Finally, while the few outright Preference Reversals may reflect the long experience of our monkeys, their more graded Preference Changes corresponded to those reported for humans. In benefitting from the wide testing possibilities in monkeys, our stringent axiomatic tests contribute critical information about risky decision-making and serves as basis for investigating neuronal decision mechanisms.


Fig. 1C). The progress of matching the genetic regulators can be done by correlation analyses
Next-generation biocomputing: mimicking artificial neural network with genetic circuits

March 2021

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193 Reads

Artificial neural network (ANN) is nowadays one of the most used and researched computational methods. In the field of biocomputing, however, synthetic biologists are still using logic gate technologies to design genetic circuits. We here propose and computationally validate a novel method to mimic ANN with genetic circuits. We first describe the flow and the mathematical expression of this genetic circuit design and then we provide in silico proof to support the functionality of our method in regression and classification analyses. We believe that this de novo genetic circuit design method would have wide applications in biotechnology.


Citations (5)


... The way RS was measured in the present study was unique in several ways making it useful as a novel approach, but also difficult to match with previous work on RS. The paradigm differs from typical work on preference using intertemporal choice (Bujold et al., 2022;Seak et al., 2023) by evaluating preference from 'imperative' or forced choice trials. Relative reward functioning is a part of all choice paradigms, but only behavioral tasks that provide a clear reference and compare relative and absolute reward contexts can directly gauge reward updating (Flaherty, 1996). ...

Reference:

Altered reward sensitivity to sucrose outcomes prior to drug exposure in alcohol preferring rats
Systematic comparison of risky choices in humans and monkeys

... Recent research has revealed that laccase heterologous expression and secretion may be accomplished using modified E. coli. When expressing extracellular enzymes, however, E. coli easily forms inclusion bodies and preserves part of the produced enzyme in these inclusions, heterologous laccase expression in E. coli offers a possible strategy for PE biodegradation 87,88 . Microalgae as phototrophic microorganisms are so advantageous for use as microbial cell factories because of their high growth rates, scalability, easy and low-cost cultivation, and potentially suitable for genetic manipulation. ...

Expression, secretion and functional characterization of three laccases in E. coli

Synthetic and Systems Biotechnology

... Casein required further enhancement to modify its durability and concomitantly its flame retardancy. A method reported by Leong et al. [176] enhanced the durability of casein by fusion of the mussel foot protein-5 (mfp-5) or cellulose-binding adhesion domain where the casein remained even after washing, confirmed by the confocal imaging. ...

Using recombinant adhesive proteins as durable and green flame-retardant coatings

Synthetic and Systems Biotechnology

... These two abilities can depend on how memory interacts with reward value processing. Timing intervals between food experiences are encoded automatically as a part of reward sensitivity (Bouton et al., 2013;Bujold et al., 2022;Vestergaard and Schultz, 2015) and alterations in encoding reward value dependent upon the time interval (seconds to minutes versus 24 h.) could reflect impairments that impact short-term versus long-term memory retrieval or altered interactions between memory and sensory processing (Plowright, 1993;Sargisson and White, 2004;Sargisson and White, 2007). Finding limited within-session discrimination might be related to the fact that discrete stimuli were not implemented in this study, and that predictive cues (test chamber and the houselight stimulus) were not specific to particular outcomes and their related values. ...

Comparing utility functions between risky and riskless choice in rhesus monkeys

Animal Cognition

... With these properties, the IA provides for a stringent test framework for investigating brain mechanisms of economic choice. So far, human fMRI studies demonstrate subjective value coding in reward-related brain regions, including the ventral striatum, midbrain, amygdala, and orbitofrontal and ventromedial prefrontal cortex (Gelskov et al., 2015;Hsu et al., 2009;Seak et al., 2021;Wu et al., 2011). Neurophysiological studies in monkeys demonstrate the coding of subjective value in midbrain dopamine neurons and orbitofrontal cortex (Kobayashi & Schultz, 2008;Lak et al., 2014;Padoa-Schioppa & Assad, 2006;Stauffer et al., 2014;Tremblay & Schultz, 1999) and formal utility coding in dopamine neurons . ...

Single-Dimensional Human Brain Signals for Two-Dimensional Economic Choice Options

The Journal of Neuroscience : The Official Journal of the Society for Neuroscience