Functional organisation of behavioural inhibitory control mechanisms in cortico-basal ganglia circuitry: implications for stimulant use disorder.

The neural and psychological mechanisms of inhibitory control processes were investigated, focusing on the cortico-basal ganglia circuits in rats and humans. These included behavioural flexibility, ‘waiting’ and ‘stopping’ impulsivity and involved serial spatial reversal learning task in rodents, and in humans, premature responses in the Monetary Incentive Delay (MID) task and the stop-signal reaction time task. Chapter 2 and Chapter 3 focus on individual differences in behavioural flexibility in rats while Chapter 4, Chapter 5 and Chapter 6 consider how inhibitory control mechanisms are affected by the psychostimulant drug cocaine in both rats and humans. As reported in Chapter 2, systemic modulation of monoaminergic transmission by monoamine oxidase A (MAO-A) inhibitors enhanced reversal learning performance, selectively by decreasing the lose-shift probability, thereby implicating a role for dopamine, serotonin and noradrenaline in facilitating learning from negative feedback. Resting state functional magnetic resonance imaging (fMRI) revealed enhanced functional connectivity of the orbitofrontal and motor cortices as a correlate of flexible reversal learning performance, consistent with elevated levels of monoamines in these region (Chapter 3). Having clarified the mechanisms underlying behavioural flexibility in rats, Chapter 4 reports that escalation of intravenous cocaine self-administration induces behavioural inflexibility in rats even after a relatively short period of cocaine intake. Computational models, including a reinforced and Bayesian learner, revealed a lack of exploitation of the learned response-outcome relationships in cocaine-exposed rats. Chapter 5 focused on impulse control in human volunteers, identifying the striatal and cingulo-opercular networks as substrates of impulsive, premature responding in healthy 4 volunteers, stimulant-dependent individuals and their unaffected siblings. Loss of impulse control was elicited by different incentives for drug-free participants as opposed to drug users. Drug cues elicited striatal activation and increased premature responses in the stimulant-dependent group compared with the control group. In contrast, the ventral striatum was linked to incentive specific activation to reward anticipation. Task-based fMRI demonstrated that interactions between dorsal striatum and cingulo-opercular “cold cognition” networks underlie failures of impulse control in the control, at-risk and stimulant-dependent groups. However, whereas the cingulo-opercular networks were associated with premature responding in all groups, the reward system was activated specifically by the drug incentive cues in the stimulant group, and by monetary incentive cues in the drug-free groups. Chapter 6 presents evidence that corticostriatal functional and effective connectivity in an overlapping network that includes the anterior cingulate and inferior frontal cortices as well as motor cortex, the subthalamic nucleus and dorsal striatum, is critical to stopping impulse control in both control and cocaine individuals. No stopping efficiency impairments were observed in the cocaine-dependent group. Nevertheless, lower structural corticostriatal connectivity measured using diffusion MRI was associated with response execution impairments in cocaine participants performing a stop-signal reaction time task. Further, response execution was rescued by the selective noradrenaline reuptake inhibitor atomoxetine, which also increased corticostriatal effective connectivity. Finally, increased impulsivity and behavioural inflexibility seen in stimulant use disorder in Chapter 5 and Chapter 4, respectively, were not observed in the endophenotype at risk for developing stimulant abuse but were rather a consequence of stimulant abuse. These results further clarify the monoaminergic substrates of behavioural flexibility and specify the neural and computational impairments in inhibitory control induced by stimulant dependence.Pinsent Darwin Studentship from the Dept of Physiology, Development and Neuroscienc

Functional Organization of the Human Brain: How We See, Feel, and Decide.

The human brain is responsible for constructing how we perceive, think, and act in the world around us. The organization of these functions is intricately distributed throughout the brain. Here, I discuss how functional magnetic resonance imaging (fMRI) was employed to understand three broad questions: how do we see, feel, and decide? First, high-resolution fMRI was used to measure the polar angle representation of saccadic eye movements in the superior colliculus. We found that eye movements along the superior-inferior visual field are mapped across the medial-lateral anatomy of a subcortical midbrain structure, the superior colliculus (SC). This result is consistent with the topography in monkey SC. Second, we measured the empathic responses of the brain as people watched a hand get painfully stabbed with a needle. We found that if the hand was labeled as belonging to the same religion as the observer, the empathic neural response was heightened, creating a strong ingroup bias that could not be readily manipulated. Third, we measured brain activity in individuals as they made free decisions (i.e., choosing randomly which of two buttons to press) and found the activity within fronto-thalamic networks to be significantly decreased compared to being instructed (forced) to press a particular button. I also summarize findings from several other projects ranging from addiction therapies to decoding visual imagination to how corporations are represented as people. Together, these approaches illustrate how functional neuroimaging can be used to understand the organization of the human brain

Effective Connectivity of Functionally Anticorrelated Networks Under Lysergic Acid Diethylamide

Background: Classic psychedelic-induced ego dissolution involves a shift in the sense of self and a blurring of the boundary between the self and the world. A similar phenomenon is identified in psychopathology and is associated with the balance of anticorrelated activity between the default mode network, which directs attention inward, and the salience network, which recruits the dorsal attention network to direct attention outward. Methods: To test whether changes in anticorrelated networks underlie the peak effects of lysergic acid diethylamide (LSD), we applied dynamic causal modeling to infer effective connectivity of resting-state functional magnetic resonance imaging scans from a study of 25 healthy adults who were administered 100 μg of LSD or placebo. Results: We found that inhibitory effective connectivity from the salience network to the default mode network became excitatory, and inhibitory effective connectivity from the default mode network to the dorsal attention network decreased under the peak effect of LSD. Conclusions: The effective connectivity changes we identified may reflect diminution of the functional anticorrelation between resting-state networks that may be a key neural mechanism of LSD and underlie ego dissolution. Our findings suggest that changes to the sense of self and subject-object boundaries across different states of consciousness may depend upon the organized balance of effective connectivity of resting-state networks

A unified model of ketamine’s dissociative and psychedelic properties

OKKetamine is an N-methyl-d-aspartate antagonist which is increasingly being researched and used as a treatment for depression. In low doses, it can cause a transitory modification in consciousness which was classically labelled as ‘dissociation’. However, ketamine is also commonly classified as an atypical psychedelic and it has been recently reported that ego dissolution experiences during ketamine administration are associated with greater antidepressant response. Neuroimaging studies have highlighted several similarities between the effects of ketamine and those of serotonergic psychedelics in the brain; however, no unified account has been proposed for ketamine’s multi-level effects – from molecular to network and psychological levels. Here, we propose that the fast, albeit transient, antidepressant effects observed after ketamine infusions are mainly driven by its acute modulation of reward circuits and sub-acute increase in neuroplasticity, while its dissociative and psychedelic properties are driven by dose- and context-dependent disruption of large-scale functional networks. Computationally, as nodes of the salience network (SN) represent high-level priors about the body (‘minimal’ self) and nodes of the default-mode network (DMN) represent the highest-level priors about narrative self-experience (‘biographical’ self), we propose that transitory SN desegregation and disintegration accounts for ketamine’s ‘dissociative’ state, while transitory DMN desegregation and disintegration accounts for ketamine’s ‘psychedelic’ state. In psychedelic-assisted psychotherapy, a relaxation of the highest-level beliefs with psychotherapeutic support may allow a revision of pathological self-representation models, for which neuroplasticity plays a permissive role. Our account provides a multi-level rationale for using the psychedelic properties of ketamine to increase its long-term benefits.publishersversionepub_ahead_of_prin

Biological Mechanisms Linking Stress and Anhedonia

Evidence from research across species suggests that stress exposure is linked with anhedonia (loss of pleasure and/or decreased motivation). However, the mechanisms through which stress might impact anhedonia remain unclear. Chapters 1 and 2 of this dissertation review putative etiological pathways from stress to anhedonia and discuss stressor characteristics that could inform experimental models of stress-induced anhedonia. Chapter 3 describes an attempt to identify which types of stress are most associated with anhedonia using stress interview data from multiple datasets. Unexpectedly, we found no credible effects on anhedonic symptoms for stressor chronicity, severity, dependence on behavior, or interpersonal focus. Instead, number of stressors endorsed was the best predictor of anhedonic symptoms. Next, Chapters 4 and 5 report on two studies that tested possible biological mediators of the stress-anhedonia link. Chapter 4 describes an analysis of the UK Biobank dataset aimed at evaluating frontostriatal functional connectivity as a mechanism of stress-induced anhedonia. Although stress exposure predicted anhedonia, analyses uncovered no stable relation between frontostriatal connectivity and anhedonia, and no support for the proposed mediation model. Chapter 5 details a study that implemented a laboratory-based stressor to assess its potential impact on motivated behavior (thought to be a key component of anhedonia), and whether any such effects might be mediated by inflammatory responding. Low concentrations of salivary cytokines suggested questionable validity of inflammatory assessment, and no effect of stress on inflammatory responding was observed. Additionally, stress produced no measurable changes in motivated behavior. Thus, analyses revealed no evidence consistent with inflammation as a mechanism of stress-induced anhedonia. Finally, Chapter 6 discusses conclusions and implications of the current findings, and provides ideas for future directions