The neurobiology of decision making under risk

Risk is a highly salient psychological decision variable, and sensitivity to risk is an evolutionarily ancient attribute. In this thesis I address the neurobiological foundation of risk assessment, and show that behaviour is driven by an underlying distributed neural representation of different elements of risk in the brain. In particular, I show using fMRI (in Chapter 4) and MEG (in Chapter 8) that variance (dispersion) and skewness (asymmetry) of gambles evokes anatomically separable neural responses in a parietal, prefrontal and insula cortical network. I discuss possible theoretical neurobiological mechanisms by which preferences could be imbued to choice, and show that subjective tastes for risk, in terms of behavioural sensitivity to each of these risk dimensions, influences the encoding of risk and subsequent anticipatory responses. In Chapter 5, I show that a representation of prospective outcomes several trials into the future is supported by a dissociated encoding of the statistical information of future states in medial prefrontal cortex; furthermore that this encoding is contingent upon overarching goals or constraints. In Chapter 6, I demonstrate that economic choice is highly susceptible to exogenous biological influences, namely the effect of metabolic state, whilst in Chapter 7 I provide evidence that the encoding of risk is not affected by dopaminergic disruption, suggesting that dopamine might mediate effects on risk-taking via its role in reward feedback representation. In summary, the studies in this thesis elaborate the neural mechanisms underlying how humans make both single-shot and sequential decisions under risk, central elements in decision-making scenarios ranging from foraging to financial investment. This demonstrates that phylogenetically ancient circuitry subserving valuation and reward decompose choice into their salient statistical features, enabling the sophisticated representation of the future and its alternatives

The Affective Impact of Financial Skewness on Neural Activity and Choice

Few finance theories consider the influence of “skewness” (or large and asymmetric but unlikely outcomes) on financial choice. We investigated the impact of skewed gambles on subjects' neural activity, self-reported affective responses, and subsequent preferences using functional magnetic resonance imaging (FMRI). Neurally, skewed gambles elicited more anterior insula activation than symmetric gambles equated for expected value and variance, and positively skewed gambles also specifically elicited more nucleus accumbens (NAcc) activation than negatively skewed gambles. Affectively, positively skewed gambles elicited more positive arousal and negatively skewed gambles elicited more negative arousal than symmetric gambles equated for expected value and variance. Subjects also preferred positively skewed gambles more, but negatively skewed gambles less than symmetric gambles of equal expected value. Individual differences in both NAcc activity and positive arousal predicted preferences for positively skewed gambles. These findings support an anticipatory affect account in which statistical properties of gambles—including skewness—can influence neural activity, affective responses, and ultimately, choice

Free energy, precision and learning: The role of cholinergic neuromodulation

Acetylcholine (ACh) is a neuromodulatory transmitter implicated in perception and learning under uncertainty. This study combined computational simulations and pharmaco-electroencephalography in humans, to test a formulation of perceptual inference based upon the free energy principle. This formulation suggests that ACh enhances the precision of bottom-up synaptic transmission in cortical hierarchies by optimizing the gain of supragranular pyramidal cells. Simulations of a mismatch negativity paradigm predicted a rapid trial-by-trial suppression of evoked sensory prediction error (PE) responses that is attenuated by cholinergic neuromodulation. We confirmed this prediction empirically with a placebo-controlled study of cholinesterase inhibition. Furthermore, using dynamic causal modeling, we found that drug-induced differences in PE responses could be explained by gain modulation in supragranular pyramidal cells in primary sensory cortex. This suggests that ACh adaptively enhances sensory precision by boosting bottom-up signaling when stimuli are predictable, enabling the brain to respond optimally under different levels of environmental uncertainty

Chronic non-freezing cold injury results in neuropathic pain due to a sensory neuropathy

Non-freezing cold injury (NFCI) develops after sustained exposure to cold temperatures, resulting in tissue cooling but not freezing. This can result in persistent sensory disturbance of the hands and feet including numbness, paraesthesia and chronic pain. Both vascular and neurological aetiologies of this pain have been suggested but remain unproven. We prospectively approached patients referred for clinical assessment of chronic pain following non-freezing cold injury between 12 February 2014 and 30 November 2016. Of 47 patients approached 42 consented to undergo detailed neurological evaluations including: questionnaires to detail pain location and characteristics, structured neurological examination, quantitative sensory testing, nerve conduction studies and skin biopsy for intra-epidermal nerve fibre assessment. Of the 42 study participants, all had experienced NFCI whilst serving in the United Kingdom armed services and the majority were of African descent (76.2%) and male (95.2%). Many participants reported multiple exposures to cold. The median time between initial injury and referral was 3.72 years. Pain was principally localised to the hands and the feet, neuropathic in nature and in all study participants associated with cold hypersensitivity. Clinical examination and quantitative sensory testing were consistent with a sensory neuropathy. In all cases large fibre nerve conduction studies were normal. The intra-epidermal nerve fibre density was markedly reduced with 90.5% of participants having a count at or below the 0.05 centile of published normative controls. Using the Neuropathic Pain Special Interest Group (NeuPSIG) of the International Association for the Study of Pain (IASP) grading for neuropathic pain 100% had probable and 95.2% definite neuropathic pain. Chronic non-freezing cold injury is a disabling neuropathic pain disorder due to a sensory neuropathy. Why some individuals develop an acute painful sensory neuropathy on sustained cold exposure is not yet known but individuals of African descent appear vulnerable. Screening tools, such as the DN4 questionnaire, and treatment algorithms for neuropathic pain should now be used in the management of these patients

Dissociable influences of skewness and valence on economic choice and neural activity.

Asymmetry in distributions of potential outcomes (i.e. skewness), and whether those potential outcomes reflect gains or losses (i.e. their valence), both exert a powerful influence on value-based choice. How valence affects the impact of skewness on choice is unknown. Here by orthogonally manipulating the skewness and valence of economic stimuli we show that both have an influence on choice. We show that the influence of skewness on choice is independent of valence, both across and within subjects. fMRI data revealed skew-related activity in bilateral anterior insula and dorsomedial prefrontal cortex, which shows no interaction with valence. Further, the expression of skew-related activity depends on an individual's preference for skewness, and this was again independent of valence-related preference. Our findings highlight the importance of skewness in choice and show that its influence, both behaviourally and neurally, is distinct from an influence of valence

Dissociable influences of skewness and valence on economic choice and neural activity.

Asymmetry in distributions of potential outcomes (i.e. skewness), and whether those potential outcomes reflect gains or losses (i.e. their valence), both exert a powerful influence on value-based choice. How valence affects the impact of skewness on choice is unknown. Here by orthogonally manipulating the skewness and valence of economic stimuli we show that both have an influence on choice. We show that the influence of skewness on choice is independent of valence, both across and within subjects. fMRI data revealed skew-related activity in bilateral anterior insula and dorsomedial prefrontal cortex, which shows no interaction with valence. Further, the expression of skew-related activity depends on an individual's preference for skewness, and this was again independent of valence-related preference. Our findings highlight the importance of skewness in choice and show that its influence, both behaviourally and neurally, is distinct from an influence of valence

Ion channels in EEG: isolating channel dysfunction in NMDA receptor antibody encephalitis

Neurological and psychiatric practice frequently lack diagnostic probes that can assess mechanisms of neuronal communication non-invasively in humans. In N-methyl-D-aspartate (NMDA) receptor antibody encephalitis, functional molecular assays are particularly important given the presence of NMDA antibodies in healthy populations, the multifarious symptomology and the lack of radiological signs. Recent advances in biophysical modelling techniques suggest that inferring cellular-level properties of neural circuits from macroscopic measures of brain activity is possible. Here, we estimated receptor function from EEG in patients with NMDA receptor antibody encephalitis (n = 29) as well as from encephalopathic and neurological patient controls (n = 36). We show that the autoimmune patients exhibit distinct fronto-parietal network changes from which ion channel estimates can be obtained using a microcircuit model. Specifically, a dynamic causal model of EEG data applied to spontaneous brain responses identifies a selective deficit in signalling at NMDA receptors in patients with NMDA receptor antibody encephalitis but not at other ionotropic receptors. Moreover, though these changes are observed across brain regions, these effects predominate at the NMDA receptors of excitatory neurons rather than at inhibitory interneurons. Given that EEG is a ubiquitously available clinical method, our findings suggest a unique re-purposing of EEG data as an assay of brain network dysfunction at the molecular level

Approach-avoidance processes contribute to dissociable impacts of risk and loss on choice

Value-based choices are influenced both by risk in potential outcomes and by whether outcomes reflect potential gains or losses. These variables are held to be related in a specific fashion, manifest in risk aversion for gains and risk seeking for losses. Instead, we hypothesized that there are independent impacts of risk and loss on choice such that, depending on context, subjects can show either risk aversion for gains and risk seeking for losses or the exact opposite. We demonstrate this independence in a gambling task, by selectively reversing a loss-induced effect (causing more gambling for gains than losses and the reverse) while leaving risk aversion unaffected. Consistent with these dissociable behavioral impacts of risk and loss, fMRI data revealed dissociable neural correlates of these variables, with parietal cortex tracking risk and orbitofrontal cortex and striatum tracking loss. Based on our neural data, we hypothesized that risk and loss influence action selection through approach–avoidance mechanisms, a hypothesis supported in an experiment in which we show valence and risk-dependent reaction time effects in line with this putative mechanism. We suggest that in the choice process risk and loss can independently engage approach–avoidance mechanisms. This can provide a novel explanation for how risk influences action selection and explains both classically described choice behavior as well as behavioral patterns not predicted by existing theory

Increased Vitamin D Binding Protein Expression in JIA Patients Suffering Disease Extension

Background: Juvenile idiopathic arthritis (JIA) comprises a poorlyunderstood group of chronic, childhood onset, autoimmune diseaseswith variable clinical presentations, outcomes and therapeuticresponses. Current laboratory tests are unable to flag those patientsat a higher risk of disease spread to multiple joints, who could benefitform earlier therapy to prevent joint damage. This study was focusedon profiling the synovial fluid (SF) proteome associated with diseaseextension from oligo- to polyarticular status by a difference gelelectrophoresis (DIGE) approach.Methods: To construct a discriminant model, SF samples from 55 JIApatients were analysed: 30 oligo-, 8 extended oligo- and 17polyarticular disease. Initial SF samples from each patient werelabeled with Cy dyes and subjected to protein separation by 2-DE. Theability to distinguish patients at risk of disease extension by a selectgroup of proteins was illustrated by multivariate analysis methods.Proteins over expressed with a two-fold difference between patientsubgroups were identified by MALDI-TOF. Specific antibodies wereused to validate putative biomarker expression in synovial fluid bywestern immunoblotting and in synovial membrane (SM) byimmunohistochemistry.Results: Samespots software analysis of SF gel scans was used tohighlight joint-specific proteins which were differentially expressedacross disease classifications. Hierarchical clustering based on theexpression levels of a previously selected set of 40 proteins matchedacross the three clinical subgroups segregates the extended oligoarticularpatients. Proteolytic fragments of apolipoprotein AII, complementcomponent C3c and vitamin D binding protein were identified(