Neural and computational representations of decision variables

These studies explore how, where, and when representations of variables critical to decision-making are represented in the brain. In order to produce a decision, humans must first determine the relevant stimuli, actions, and possible outcomes before applying an algorithm that will select an action from those available. When choosing amongst alternative stimuli, the framework of value-based decision-making proposes that values are assigned to the stimuli and that these values are then compared in an abstract “value space” in order to produce a decision. Despite much progress, in particular regarding the pinpointing of ventromedial prefrontal cortex (vmPFC) as a region that encodes the value, many basic questions remain. In Chapter 2, I show that distributed BOLD signaling in vmPFC represents the value of stimuli under consideration in a manner that is independent of the type of stimulus it is. Thus the open question of whether value is represented in abstraction, a key tenet of value-based decision-making, is confirmed. However, I also show that stimulus-dependent value representations are also present in the brain during decision-making and suggest a potential neural pathway for stimulus-to-value transformations that integrates these two results.

More broadly speaking, there is both neural and behavioral evidence that two distinct control systems are at work during action selection. These two systems compose the “goal-directed system”, which selects actions based on an internal model of the environment, and the “habitual” system, which generates responses based on antecedent stimuli only. Computational characterizations of these two systems imply that they have different informational requirements in terms of input stimuli, actions, and possible outcomes. Associative learning theory predicts that the habitual system should utilize stimulus and action information only, while goal-directed behavior requires that outcomes as well as stimuli and actions be processed. In Chapter 3, I test whether areas of the brain hypothesized to be involved in habitual versus goal-directed control represent the corresponding theorized variables.

The question of whether one or both of these neural systems drives Pavlovian conditioning is less well-studied. Chapter 4 describes an experiment in which subjects were scanned while engaged in a Pavlovian task with a simple non-trivial structure. After comparing a variety of model-based and model-free learning algorithms (thought to underpin goal-directed and habitual decision-making, respectively), it was found that subjects’ reaction times were better explained by a model-based system. In addition, neural signaling of precision, a variable based on a representation of a world model, was found in the amygdala. These data indicate that the influence of model-based representations of the environment can extend even to the most basic learning processes.

Knowledge of the state of hidden variables in an environment is required for optimal inference regarding the abstract decision structure of a given environment and therefore can be crucial to decision-making in a wide range of situations. Inferring the state of an abstract variable requires the generation and manipulation of an internal representation of beliefs over the values of the hidden variable. In Chapter 5, I describe behavioral and neural results regarding the learning strategies employed by human subjects in a hierarchical state-estimation task. In particular, a comprehensive model fit and comparison process pointed to the use of "belief thresholding". This implies that subjects tended to eliminate low-probability hypotheses regarding the state of the environment from their internal model and ceased to update the corresponding variables. Thus, in concert with incremental Bayesian learning, humans explicitly manipulate their internal model of the generative process during hierarchical inference consistent with a serial hypothesis testing strategy.

Single cell proteomics microchip to profile immune function, with applications in stem cell biology, translational disease mechanism study and clinical therapeutics monitoring

In response to infection or tissue dysfunction, immune cells develop into highly heterogeneous repertoires with diverse functions. Capturing the full spectrum of these functions requires analysis of large numbers of effector molecules from single cells. However, currently only 3-5 functional proteins can be measured from single cells. We developed a single cell functional proteomics approach that integrates a microchip platform with multiplex cell purification. This approach can quantitate 20 proteins from >5,000 phenotypically pure single cells simultaneously. With a 1-million fold miniaturization, the system can detect down to ~100 molecules and requires only ~104 cells. Single cell functional proteomic analysis finds broad applications in basic, translational and clinical studies. In the three studies conducted, it yielded critical insights for understanding clinical cancer immunotherapy, inflammatory bowel disease (IBD) mechanism and hematopoietic stem cell (HSC) biology.

To study phenotypically defined cell populations, single cell barcode microchips were coupled with upstream multiplex cell purification based on up to 11 parameters. Statistical algorithms were developed to process and model the high dimensional readouts. This analysis evaluates rare cells and is versatile for various cells and proteins. (1) We conducted an immune monitoring study of a phase 2 cancer cellular immunotherapy clinical trial that used T-cell receptor (TCR) transgenic T cells as major therapeutics to treat metastatic melanoma. We evaluated the functional proteome of 4 antigen-specific, phenotypically defined T cell populations from peripheral blood of 3 patients across 8 time points. (2) Natural killer (NK) cells can play a protective role in chronic inflammation and their surface receptor – killer immunoglobulin-like receptor (KIR) – has been identified as a risk factor of IBD. We compared the functional behavior of NK cells that had differential KIR expressions. These NK cells were retrieved from the blood of 12 patients with different genetic backgrounds. (3) HSCs are the progenitors of immune cells and are thought to have no immediate functional capacity against pathogen. However, recent studies identified expression of Toll-like receptors (TLRs) on HSCs. We studied the functional capacity of HSCs upon TLR activation. The comparison of HSCs from wild-type mice against those from genetics knock-out mouse models elucidates the responding signaling pathway.

In all three cases, we observed profound functional heterogeneity within phenotypically defined cells. Polyfunctional cells that conduct multiple functions also produce those proteins in large amounts. They dominate the immune response. In the cancer immunotherapy, the strong cytotoxic and antitumor functions from transgenic TCR T cells contributed to a ~30% tumor reduction immediately after the therapy. However, this infused immune response disappeared within 2-3 weeks. Later on, some patients gained a second antitumor response, consisted of the emergence of endogenous antitumor cytotoxic T cells and their production of multiple antitumor functions. These patients showed more effective long-term tumor control. In the IBD mechanism study, we noticed that, compared with others, NK cells expressing KIR2DL3 receptor secreted a large array of effector proteins, such as TNF-α, CCLs and CXCLs. The functions from these cells regulated disease-contributing cells and protected host tissues. Their existence correlated with IBD disease susceptibility. In the HSC study, the HSCs exhibited functional capacity by producing TNF-α, IL-6 and GM-CSF. TLR stimulation activated the NF-κB signaling in HSCs. Single cell functional proteome contains rich information that is independent from the genome and transcriptome. In all three cases, functional proteomic evaluation uncovered critical biological insights that would not be resolved otherwise. The integrated single cell functional proteomic analysis constructed a detail kinetic picture of the immune response that took place during the clinical cancer immunotherapy. It revealed concrete functional evidence that connected genetics to IBD disease susceptibility. Further, it provided predictors that correlated with clinical responses and pathogenic outcomes.

Essays on cooperation and reciprocity

This dissertation comprises three essays that use theory-based experiments to gain understanding of how cooperation and efficiency is affected by certain variables and institutions in different types of strategic interactions prevalent in our society.

Chapter 2 analyzes indefinite horizon two-person dynamic favor exchange games with private information in the laboratory. Using a novel experimental design to implement a dynamic game with a stochastic jump signal process, this study provides insights into a relation where cooperation is without immediate reciprocity. The primary finding is that favor provision under these conditions is considerably less than under the most efficient equilibrium. Also, individuals do not engage in exact score-keeping of net favors, rather, the time since the last favor was provided affects decisions to stop or restart providing favors.

Evidence from experiments in Cournot duopolies is presented in Chapter 3 where players indulge in a form of pre-play communication, termed as revision phase, before playing the one-shot game. During this revision phase individuals announce their tentative quantities, which are publicly observed, and revisions are costless. The payoffs are determined only by the quantities selected at the end under real time revision, whereas in a Poisson revision game, opportunities to revise arrive according to a synchronous Poisson process and the tentative quantity corresponding to the last revision opportunity is implemented. Contrasting results emerge. While real time revision of quantities results in choices that are more competitive than the static Cournot-Nash, significantly lower quantities are implemented in the Poisson revision games. This shows that partial cooperation can be sustained even when individuals interact only once.

Chapter 4 investigates the effect of varying the message space in a public good game with pre-play communication where player endowments are private information. We find that neither binary communication nor a larger finite numerical message space results in any efficiency gain relative to the situation without any form of communication. Payoffs and public good provision are higher only when participants are provided with a discussion period through unrestricted text chat.

Extraction of CP Properties of the H(125) Boson Discovered in Proton-Proton Collisions at sqrt(s) = 7 and 8 TeV with the CMS Detector at the LHC

In this thesis we build a novel analysis framework to perform the direct extraction of all possible effective Higgs boson couplings to the neutral electroweak gauge bosons in the H → ZZ^(*) → 4l channel also referred to as the golden channel. We use analytic expressions of the full decay differential cross sections for the H → VV' → 4l process, and the dominant irreducible standard model qq ̄ → 4l background where 4l = 2e2μ,4e,4μ. Detector effects are included through an explicit convolution of these analytic expressions with transfer functions that model the detector responses as well as acceptance and efficiency effects. Using the full set of decay observables, we construct an unbinned 8-dimensional detector level likelihood function which is con- tinuous in the effective couplings, and includes systematics. All potential anomalous couplings of HVV' where V = Z,γ are considered, allowing for general CP even/odd admixtures and any possible phases. We measure the CP-odd mixing between the tree-level HZZ coupling and higher order CP-odd couplings to be compatible with zero, and in the range [−0.40, 0.43], and the mixing between HZZ tree-level coupling and higher order CP -even coupling to be in the ranges [−0.66, −0.57] ∪ [−0.15, 1.00]; namely compatible with a standard model Higgs. We discuss the expected precision in determining the various HVV' couplings in future LHC runs. A powerful and at first glance surprising prediction of the analysis is that with 100-400 fb^-1, the golden channel will be able to start probing the couplings of the Higgs boson to diphotons in the 4l channel. We discuss the implications and further optimization of the methods for the next LHC runs.

Lock Acquisition and Sensitivity Analysis of Advanced LIGO Interferometers

Laser interferometer gravitational wave observatory (LIGO) consists of two complex large-scale laser interferometers designed for direct detection of gravitational waves from distant astrophysical sources in the frequency range 10Hz - 5kHz. Direct detection of space-time ripples will support Einstein's general theory of relativity and provide invaluable information and new insight into physics of the Universe.

Initial phase of LIGO started in 2002, and since then data was collected during six science runs. Instrument sensitivity was improving from run to run due to the effort of commissioning team. Initial LIGO has reached designed sensitivity during the last science run, which ended in October 2010.

In parallel with commissioning and data analysis with the initial detector, LIGO group worked on research and development of the next generation detectors. Major instrument upgrade from initial to advanced LIGO started in 2010 and lasted till 2014.

This thesis describes results of commissioning work done at LIGO Livingston site from 2013 until 2015 in parallel with and after the installation of the instrument. This thesis also discusses new techniques and tools developed at the 40m prototype including adaptive filtering, estimation of quantization noise in digital filters and design of isolation kits for ground seismometers.

The first part of this thesis is devoted to the description of methods for bringing interferometer to the linear regime when collection of data becomes possible. States of longitudinal and angular controls of interferometer degrees of freedom during lock acquisition process and in low noise configuration are discussed in details.

Once interferometer is locked and transitioned to low noise regime, instrument produces astrophysics data that should be calibrated to units of meters or strain. The second part of this thesis describes online calibration technique set up in both observatories to monitor the quality of the collected data in real time. Sensitivity analysis was done to understand and eliminate noise sources of the instrument.

Coupling of noise sources to gravitational wave channel can be reduced if robust feedforward and optimal feedback control loops are implemented. The last part of this thesis describes static and adaptive feedforward noise cancellation techniques applied to Advanced LIGO interferometers and tested at the 40m prototype. Applications of optimal time domain feedback control techniques and estimators to aLIGO control loops are also discussed.

Commissioning work is still ongoing at the sites. First science run of advanced LIGO is planned for September 2015 and will last for 3-4 months. This run will be followed by a set of small instrument upgrades that will be installed on a time scale of few months. Second science run will start in spring 2016 and last for about 6 months. Since current sensitivity of advanced LIGO is already more than factor of 3 higher compared to initial detectors and keeps improving on a monthly basis, upcoming science runs have a good chance for the first direct detection of gravitational waves.