Counterfactual Choice and Learning in a Neural Network Centered on Human Lateral Frontopolar Cortex

Decision making and learning in a real-world context require organisms to track not only the choices they make and the outcomes that follow but also other untaken, or counterfactual, choices and their outcomes. Although the neural system responsible for tracking the value of choices actually taken is increasingly well understood, whether a neural system tracks counterfactual information is currently unclear. Using a three-alternative decision-making task, a Bayesian reinforcement-learning algorithm, and fMRI, we investigated the coding of counterfactual choices and prediction errors in the human brain. Rather than representing evidence favoring multiple counterfactual choices, lateral frontal polar cortex (lFPC), dorsomedial frontal cortex (DMFC), and posteromedial cortex (PMC) encode the reward-based evidence favoring the best counterfactual option at future decisions. In addition to encoding counterfactual reward expectations, the network carries a signal for learning about counterfactual options when feedback is available—a counterfactual prediction error. Unlike other brain regions that have been associated with the processing of counterfactual outcomes, counterfactual prediction errors within the identified network cannot be related to regret theory. Furthermore, individual variation in counterfactual choice-related activity and prediction error-related activity, respectively, predicts variation in the propensity to switch to profitable choices in the future and the ability to learn from hypothetical feedback. Taken together, these data provide both neural and behavioral evidence to support the existence of a previously unidentified neural system responsible for tracking both counterfactual choice options and their outcomes

Ventromedial Prefrontal and Anterior Cingulate Cortex Adopt Choice and Default Reference Frames during Sequential Multi-Alternative Choice

Although damage to the medial frontal cortex causes profound decision-making impairments, it has been difficult to pinpoint the relative contributions of key anatomical subdivisions. Here we use function magnetic resonance imaging to examine the contributions of human ventromedial prefrontal cortex (vmPFC) and dorsal anterior cingulate cortex (dACC) during sequential choices between multiple alternatives— two key features of choices made in ecological settings. By carefully constructing options whose current value at any given decision was dissociable from their longer term value, we were able to examine choices in current and long-term frames of reference. We present evidence showing that activity at choice and feedback in vmPFC and dACC was tied to the current choice and the best long-term option, respectively. vmPFC, mid-cingulate, and posterior cingulate cortex encoded the relative value between the chosen and next best option at each sequential decision, whereas dACC encoded the relative value of adapting choices from the option with the highest value in the longer term. Furthermore, at feedback we identify temporally dissociable effects that predict repetition of the current choice and adaptation away from the long-term best option in vmPFC and dACC, respectively. These functional dissociations at choice and feedback suggest that sequential choices are subject to competing cortical mechanisms

Ibrutinib inhibits SDF1/CXCR4 mediated migration in AML

Pharmacological targeting of BTK using ibrutinib has recently shown encouraging clinical activity in a range of lymphoid malignancies. Recently we reported that ibrutinib inhibits human acute myeloid leukemia (AML) blast proliferation and leukemic cell adhesion to the surrounding bone marrow stroma cells. Here we report that in human AML ibrutinib, in addition, functions to inhibit SDF1/CXCR4-mediated AML migration at concentrations achievable in vivo. It has previously been shown that SDF1/CXCR4-induced migration is dependent on activation of downstream BTK in chronic lymphocytic leukaemia (CLL) and multiple myeloma. Here we show that SDF-1 induces BTK phosphorylation and downstream MAPK signalling in primary AML blast. Furthermore, we show that ibrutinib can inhibit SDF1-induced AKT and MAPK activation. These results reported here provide a molecular mechanistic rationale for clinically evaluating BTK inhibition in AML patients and suggests that in some AML patients the blasts count may initially rise in response to ibrutinib therapy, analgous to similar clinical observations in CLL

Neural activity tracking identity and confidence in social information

Humans learn about the environment either directly by interacting with it or indirectly by seeking information about it from social sources such as conspecifics. The degree of confidence in the information obtained through either route should determine the impact that it has on adapting and changing behaviour. We examined whether and how behavioural and neural computations differ during non-social learning as opposed to learning from social sources. Trial-wise confidence judgements about non-social and social information sources offered a window into this learning process. Despite matching exactly the statistical features of social and non-social conditions, confidence judgements were more accurate and less changeable when they were made about social as opposed to non-social information sources. In addition to subjective reports of confidence, differences were also apparent in the Bayesian estimates of participants' subjective beliefs. Univariate activity in dorsomedial prefrontal cortex and posterior temporoparietal junction more closely tracked confidence about social as opposed to non-social information sources. In addition, the multivariate patterns of activity in the same areas encoded identities of social information sources compared to non-social information sources

On the relationship between the “default mode network” and the “social brain”

The default mode network (DMN) of the brain consists of areas that are typically more active during rest than during active task performance. Recently however, this network has been shown to be activated by certain types of tasks. Social cognition, particularly higher-order tasks such as attributing mental states to others, has been suggested to activate a network of areas at least partly overlapping with the DMN. Here, we explore this claim, drawing on evidence from meta-analyses of functional MRI data and recent studies investigating the structural and functional connectivity of the social brain. In addition, we discuss recent evidence for the existence of a DMN in non-human primates. We conclude by discussing some of the implications of these observations

Viewing ambiguous social interactions increases functional connectivity between frontal and temporal nodes of the social brain.

Social behaviour is coordinated by a network of brain regions, including those involved in the perception of social stimuli and those involved in complex functions like inferring perceptual and mental states and controlling social interactions. The properties and function of many of these regions in isolation is relatively well-understood, but less is known about how these regions interact whilst processing dynamic social interactions. To investigate whether the functional connectivity between brain regions is modulated by social context, we collected functional MRI (fMRI) data from male monkeys (Macaca mulatta) viewing videos of social interactions labelled as "affiliative", "aggressive", or "ambiguous". We show activation related to the perception of social interactions along both banks of the superior temporal sulcus, parietal cortex, medial and lateral frontal cortex, and the caudate nucleus. Within this network, we show that fronto-temporal functional connectivity is significantly modulated by social context. Crucially, we link the observation of specific behaviours to changes in functional connectivity within our network. Viewing aggressive behaviour was associated with a limited increase in temporo-temporal and a weak increase in cingulate-temporal connectivity. By contrast, viewing interactions where the outcome was uncertain was associated with a pronounced increase in temporo-temporal, and cingulate-temporal functional connectivity. We hypothesise that this widespread network synchronisation occurs when cingulate and temporal areas coordinate their activity when more difficult social inferences are being made.SIGNIFICANCE STATEMENT:Processing social information from our environment requires the activation of several brain regions, which are concentrated within the frontal and temporal lobes. However, little is known about how these areas interact to facilitate the processing of different social interactions. Here we show that functional connectivity within and between the frontal and temporal lobes is modulated by social context. Specifically, we demonstrate that viewing social interactions where the outcome was unclear is associated with increased synchrony within and between the cingulate cortex and temporal cortices. These findings suggest that the coordination between the cingulate and temporal cortices is enhanced when more difficult social inferences are being made

Manipulation of subcortical and deep cortical activity in the primate brain using transcranial focused ultrasound stimulation

Publisher’s embargo period: Embargo set on 04.03.2019 by SR (TIS).The causal role of an area within a neural network can be determined by interfering with its activity and measuring the impact. Many current reversible manipulation techniques have limitations preventing their application, particularly in deep areas of the primate brain. Here, we demonstrate that a focused transcranial ultrasound stimulation (TUS) protocol impacts activity even in deep brain areas: a subcortical brain structure, the amygdala (experiment 1), and a deep cortical region, the anterior cingulate cortex (ACC, experiment 2), in macaques. TUS neuromodulatory effects were measured by examining relationships between activity in each area and the rest of the brain using functional magnetic resonance imaging (fMRI). In control conditions without sonication, activity in a given area is related to activity in interconnected regions, but such relationships are reduced after sonication, specifically for the targeted areas. Dissociable and focal effects on neural activity could not be explained by auditory confounds

Changing connectivity between premotor and motor cortex changes inter-areal communication in the human brain.

The ventral premotor cortex (PMv) is an important component of cortico-cortical pathways mediating prefrontal control over primary motor cortex (M1) function. Paired associative stimulation (ccPAS) is known to change PMv influence over M1 in humans, which manifests differently depending on the behavioural context. Here we show that these changes in influence are functionally linked to PMv-M1 phase synchrony changes induced by repeated paired stimulation of the two areas. PMv-to-M1 ccPAS leads to increased phase synchrony in alpha and beta bands, while reversed order M1-to-PMv ccPAS leads to decreased theta phase synchrony. These changes are visible at rest but are predictive of changes in oscillatory power in the same frequencies during movement execution and inhibition, respectively. The results unveil a link between the physiology of the motor network and the resonant frequencies mediating its interactions and provide a putative mechanism underpinning the relationship between synaptic efficacy and brain oscillations