Oxford WINeuro

Drug addiction is a chronically relapsing disorder characterized by compulsive drug use despite catastrophic personal consequences (e.g., loss of family, job) and even when the substance is no longer perceived as pleasurable. In this talk, I will present results of human neuroimaging studies, utilizing a multimodal approach (neuropsychology, functional magnetic resonance imaging, event-related potentials recordings), to explore the neurobiology underlying the core psychological impairments in drug addiction (impulsivity, drive/motivation, insight/awareness) as associated with its clinical symptomatology (intoxication, craving, bingeing, withdrawal). The focus of this talk is on understanding the role of the dopaminergic mesocorticolimbic circuit, and especially the prefrontal cortex, in higher-order executive dysfunction (e.g., disadvantageous decision-making such as trading a car for a couple of cocaine hits) in drug addicted individuals. The theoretical model that guides the presented research is called iRISA (Impaired Response Inhibition and Salience Attribution), postulating that abnormalities in the orbitofrontal cortex and anterior cingulate cortex, as related to dopaminergic dysfunction, contribute to the core clinical symptoms in drug addiction. Specifically, our multi-modality program of research is guided by the underlying working hypothesis that drug addicted individuals disproportionately attribute reward value to their drug of choice at the expense of other potentially but no-longer-rewarding stimuli, with a concomitant decrease in the ability to inhibit maladaptive drug use. In this talk I will also explore whether treatment (as usual) and 6-month abstinence enhance recovery in these brain-behavior compromises in treatment seeking cocaine addicted individuals. Promising neuroimaging studies, which combine pharmacological (i.e., oral methylphenidate, or RitalinTM) and salient cognitive tasks or functional connectivity during resting-state, will be discussed as examples for using neuroimaging for empirically guiding the development of effective neurorehabilitation strategies (encompassing cognitive reappraisal and transcranial direct current stimulation) in drug addiction.

Humans continuously need to learn to make good choices – be it using a new video-conferencing set up, figuring out what questions to ask to successfully secure a reliable babysitter, or just selecting which location in a house is least likely to be interrupted by toddlers during work calls. However, the goals we seek to attain – such as using zoom successfully – are often vaguely defined and previously unexperienced, and in that sense cannot be known by us as being rewarding. We hypothesized that learning to make good choices in such situations nevertheless leverages reinforcement learning processes, and that executive functions in general, and working memory in particular, play a crucial role in defining the reward function for arbitrary outcomes in such a way that they become reinforcing. I will show results from a novel behavioral protocol, as well as preliminary computational and imaging evidence supporting our hypothesis.

The world confronts our senses with a continuous stream of rapidly changing information. Yet, we experience life as a series of episodes or events, and in memory these pieces seem to become even further organized. How do we recall and give structure to this complex information? Recent studies have begun to examine these questions using naturalistic stimuli and behavior: subjects view audiovisual movies and then freely recount aloud their memories of the events. We find brain activity patterns that are unique to individual episodes, and which reappear during verbal recollection; robust generalization of these patterns across people; and memory effects driven by the structure of links between events in a narrative. These findings construct a picture of how we comprehend and recall real-world events that unfold continuously across time.

In many ways, cognitive neuroscience is the attempt to use physiological observation to clarify the mechanisms that shape behavior. Over the past 25 years, fMRI has provided a system-wide and yet somewhat spatially precise view of the response in human cortex evoked by a wide variety of stimuli and task contexts. The current talk focuses on the other direction of inference; the implications of this observed functional organization for behavior. To begin, we must interrogate the methodological and empirical frameworks underlying our derivation of this organization, partially by exploring its relationship to and predictability from gross neuroanatomy. Next, across a series of studies, the implications of two properties of functional organization for behavior will be explored: 1) the co-localization of visual working memory and perceptual processing and 2) implicit learning in the context of distributed responses. In sum, these results highlight the limitations of our current approach and hint at a new general mechanism for explaining observed behavior in context with the neural substrate.

People frequently interpret the same information differently, based on their prior beliefs and views. This may occur in everyday settings, as when two friends are watching the same movie, but also in more consequential circumstances, such as when people interpret the same news differently based on their political views. The role of subjective knowledge in altering how the brain processes narratives has been explored mainly in controlled settings. I will present two projects that examines neural mechanisms underlying narrative interpretation “in the wild” -- how responses differ between two groups of people who interpret the same narrative in two coherent, but opposing ways. In the first project we manipulated participant’s prior knowledge to make them interpret the narrative differently, and found that responses in high-order areas, including the default mode network, language areas and subsets of the mirror neuron system, tend to be similar among people who share the same interpretation, but different from people with an opposing interpretation. In contrast to the active manipulation of participants’ interpretation in the first study, in the second (ongoing) project we examine these processes in a more ecological setting. Taking advantage of people’s natural tendencies to interpret the world through their own (political) filters, we examine these mechanisms while measuring their brain response to political movie clips. These studies are intended to deepen our understanding of the differences in subjective construal processes, by mapping their underlying brain mechanisms.

The hippocampus is implicated in memory formation, and neurons in the hippocampus take part in replay sequences, time-compressed reactivations of trajectories through space the animal has previously explored. These replay sequences have been proposed to be a form of memory for previously experienced places. I will present work exploring how these replays appear and change with experience. By recording from large ensembles of hippocampal neurons as rats explored novel and familiar linear tracks in various experiments, we found that hippocampal replays appear after a single experience and slow down with subsequent experience as greater detail is incorporated. We also investigated hover-and-jump dynamics within replays that are associated with the slow gamma (25-50Hz) oscillation in the LFP and found that replays slow down by adding more hover locations, corresponding to depiction of the behavioral trajectory with increased resolution. Thus, replays can reflect single experiences, and be rapidly modified by subsequent experience to incorporate more detail, consistent with their proposed role as a basic mechanism of hippocampally dependent memory.

Learning the consequences our choices have as we interact with our world is critical for flexible behavior. Relational knowledge of one’s environment gives structure to otherwise-individual one-to-one stimulus-outcome mappings, providing a substrate to globally update behavioral contingencies in the face of changes in the landscape of reward. In the brain, this relational knowledge is thought to be encoded in the hippocampus (HPC) in the form of a cognitive map, while prefrontal regions, such as orbitofrontal cortex (OFC), are thought to instantiate subjective estimates of location on the map, though direct neurophysiological evidence is lacking. In this talk, I will present recent work demonstrating the causal relationship between HPC and OFC as nonhuman primates perform a reward learning task requiring them to learn and maintain knowledge of changing stimulus-outcome associations. I will then provide direct evidence that single primate hippocampal neurons represent an abstract map of the value space defined by the task. Finally, I use behavioral modeling to highlight one possible strategy by which knowledge of value space is exploited by animals to detect changes in choice-outcome mappings and proactively update their behavior in response.

Understanding and remembering realistic experiences in our everyday lives requires activating many kinds of structured knowledge about the world, including spatial maps, temporal event scripts, and semantic relationships. My recent projects have explored the ways in which we build up this schematic knowledge (during a single experiment and across developmental timescales) and can strategically deploy them to construct event representations that we can store in memory or use to make predictions. I will describe my lab's ongoing work developing new experimental and analysis techniques for conducting functional MRI experiments using narratives, movies, poetry, virtual reality, and "memory experts" to study complex naturalistic schemas.

Information that is shared across brains is encoded in idiosyncratic fine-scale functional topographies. Hyperalignment jointly models shared information and idiosyncratic topographies. Pattern vectors for neural responses and connectivities are projected into a common, high-dimensional information space, rather than being aligned in a canonical anatomical space. Hyperalignment calculates individual transformation matrices that preserve the geometry of pairwise dissimilarities between pattern vectors. Individual cortical topographies are modeled as mixtures of overlapping, individual-specific topographic basis functions, rather than as contiguous functional areas. The fundamental property of brain function that is preserved across brains is information content, rather than the functional properties of local features that support that content.