Incentive Processing and Inhibitory Control in Adolescents and Young Adults

Adolescents are known to demonstrate normative increases in risk-taking behaviors. Understanding the interaction between incentive (reward, punishment) processing and basic cognitive control abilities, both of which are still maturing into adolescence, may provide insight on the basic mechanisms contributing to this complex behavioral phenomenon. In this dissertation, we present a compilation of papers aimed at characterizing the influence of potential reward gain or loss on response inhibition performance and supporting brain circuitry in adolescents and adults. In study 1, we use fast, event-related functional magnetic resonance imaging (fMRI) to examine the neural circuitry supporting perfomance on an antisaccade task with reward or neutral contingencies added to each trial. Results indicate that components of the adolescent reward system exhibit an initially sluggish, then eventually overactive response to rewards, as well as limited recruitment in regions supporting the executive assessment of rewards. In study 2, the effects of different magnitudes of potential gains and losses on antisaccade task performance were examined. Results indicate that higher compared to lower magnitude reward contingencies differentially affect adolescent, but not adult, response suppression abilities. Furthemore, both age groups performed consistently well (low error rates) on punishment trials. In study 3, adolescents and adults underwent fast, event-related fMRI as they performed a rewarded antisaccade task with fixed-magnitude reward and punishment stimuli, previously determined to result in equivalent levels of behavioral performance across the age groups (study 2). Additionally, auditory, performance-based feedback was provided on each trial. fMRI results indicate that during detection of reward cues, adolescents do not show the same early recruitment of oculomotor control regions evident in adults. Furthermore, adolescents demonstrated temporally extended responses in several brain regions (e.g., orbitofrontal cortex, supplementary eye field) during the preparatory period of potential punishment trials, reflecting possible immaturities in mechanisms underlying potential loss or 'risk' anticipation. Finally, adults demonstrated enhanced activity in the ventral striatum and cortical eye fields during the response/feedback epoch, suggesting more mature consummatory processing. Collectively, the results of these studies demonstrate protracted development of higher-order executive aspects of reward processing and its interaction with response inhibition abilites into adolescence

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

The Motivation-Based Promotion of Proactive Control: The Role of Salience Network

It has been shown that reward motivation can facilitate proactive control, a cognitive control mode that is characterized of prior preparation and sustained holding of the goal-relevant information in working memory. However, it remains to be established the neural networks that may be involved in this promotion effect. In this study, participants underwent the AX-Continuous Performance Task (AX-CPT) that measures relative proactive control during functional magnetic resonance imaging (fMRI) scanning. We employed independent component analysis to decompose multiple brain networks and identified the task related network. Results showed that the salience network (SN) was engaged in the AX-CPT protocol. Importantly, our data demonstrated that reward modulated the association between task engagement of SN and proactive control, whereby the positive correlation was particularly observed in the reward condition. Moreover, reward modulated task engagement of the SN in a proactive manner, which may contribute to the behavioral proactive performance. Overall, our data suggest the involvement of SN in the reward facilitation effect of proactive control

Towards an integrated account of the development of self-regulation from a neurocognitive perspective: A framework for current and future longitudinal multi-modal investigations

Self-regulation is the ability to monitor and modulate emotions, behaviour, and cognition in order to adapt to changing circumstances. Developing adequate self-regulation is associated with better social coping and higher educational achievement later in life; poor self-regulation has been linked to a variety of detrimental developmental outcomes. Here, we focus on the development of neurocognitive processes essential for self-regulation. We outline a conceptual framework emphasizing that this is inherently an integrated, dynamic process involving interactions between brain maturation, child characteristics (genetic makeup, temperament, and pre- and perinatal factors) and environmental factors (family characteristics, parents and siblings, peers, and broader societal influences including media development). We introduce the Consortium of Individual Development (CID), which combines a series of integrated large-scale, multi-modal, longitudinal studies to take essential steps towards the ultimate goal of understanding and supporting this process

Development of Motivational Influences on Monitoring and Control Recruitment in the Context of Proactive and Reactive Control in Adolescent Males

Adolescence and the onset of puberty is a time period of physiological and behavioral changes that include a heightened reward sensitivity, but underdeveloped cognitive control. Cognitive control involves monitoring for salient stimuli and recruiting control to adapt behavior advantageously to reach a specific goal and is supported by the three domains of executive functioning (EF): inhibitory control, set-shifting, and working memory. Proactive control is engaged after an informative cue in preparation for an upcoming stimulus, while reactive control can be employed when preparation is not possible and you need to respond to a stimulus. Oscillations in the theta frequency (4-8Hz) during both cue presentation and stimulus presentation are implicated in proactive and reactive control processes. While reward has been shown to upregulate proactive control in adults, little work has assessed how reward influences theta oscillations during both proactive and reactive control throughout adolescence and pubertal development. Further, no work has sought to understand how EF abilities bolster reward-related changes in proactive or reactive control. Here, 68 adolescent males (Meanage=13.61, SDage=2.52) aged 9 – 17 years old completed a rewarded cued flanker paradigm while electroencephalogram (EEG) was collected. They also completed tasks from the NIH toolbox that tap the three EF domains. Behaviorally, reward hindered performance on proactive trials, particularly in mid-puberty, while enhancing performance on reactive trials. Reward was associated with increases in cue-locked theta power, but with overall reductions in cue-locked theta ICPS. Stim-locked theta power increased on reactive trials with increasing age, while stim-locked theta ICPS peaked in mid-adolescence for rewarded trials. Increased cue theta power was associated with worse performance on proactive trials. On proactive trials, adolescents with low levels of inhibitory control experience more reward-related interference, while reward-related interference was mitigated by better set-shifting abilities only in younger and older adolescents. In conclusion, reward differentially impacts proactive and reactive control throughout adolescent development and EF influences the impact of reward on proactive control throughout adolescence

Neuroenhancement in Military Personnel::Conceptual and Methodological Promises and Challenges

Military personnel face harsh conditions that strain their physical and mental well-being, depleting resources necessary for sustained operational performance. Future operations will impose even greater demands on soldiers in austere environments with limited support, and new training and technological approaches are essential. This report highlights the progress in cognitive neuroenhancement research, exploring techniques such as neuromodulation and neurofeedback, and emphasizes the inherent challenges and future directions in the field of cognitive neuroenhancement for selection, training, operations, and recovery

BIOLOGICAL BASIS OF VARIABILITY IN DOPAMINE AVAILABILITY ON FRONTOSTRIATAL BRAIN FUNCTION IN ADOLESCENCE

Neurodevelopmental studies indicate a protracted development through adolescence of brain systems underlying incentive-driven behaviors including prefrontal cortex (PFC) and the striatum. These systems support the executive control of behavior as well as motivationally driven behaviors and may contribute to vulnerabilities in the emergence of psychopathology. The PFC and striatum may support cognition and motivation through the function of the neurotransmitter dopamine. Dopamine (DA) availability is increased during the adolescent period in human and animals and play an important role in mediating individual differences in risk-taking behaviors. This dissertation seeks to examine the moderating role of genetically mediated DA availability on frontostriatal brain function in adolescence. To this end, we genotyped individuals between the ages of 10 and 20 for common functional polymorphisms in three genes that have a direct influence on synaptic DA availability. In addition, we calculated a multilocus composite score in order to assess additive effects of our three genetic loci. We used functional magnetic resonance imaging (fMRI) to assess brain function. The purpose of our first study was to examine the integrity of frontostriatal networks using resting state functional connectivity. We then look more directly at the role of frontostriatal brain function on incentive-driven behaviors using a rewarded inhibitory control task that has a known developmental signature . Overall we found a moderating influence of DA availability on age-related changes in key frontostriatal circuitry suggesting that the maturation of brain function in adolescence may in part be mediated by inter-individual variability in DA signaling. Overall, the genotypes by age interactions highlight a unique DA-driven brain profile in adolescence. This suggests that a genetically mediated brain phenotype characterized in adolescence may differ significantly from that in adulthood. This has strong implications regarding the variability observed in adolescent risk-taking behaviors as well as predictions of later adult behavior

Effects Of Brief And Prolonged Emotion On Cognitive And Neural Processes Across Development

Emotional experiences are pervasive in everyday life and can influence our thoughts and actions. Dysregulation of cue triggered emotions and emotional mood states are core features of several mental illnesses, such as anxiety and mood disorders, that peak in prevalence during adolescence— a time of heightened sensitivity to social and emotional cues in the environment. During this period of development, emergence of exploratory and criminal behaviors is reflected in the “age-crime curve” whereby these behaviors emerge during the teen years and subsequently decline by the mid-twenties. Often when young people come in contact with the law, it is under emotionally charged situations, further highlighting the importance of understanding the impact of emotions on brain and behavior across development. We developed a novel behavioral paradigm for use with functional MRI to examine the impact of emotions on cognitive control and the neural circuitry. We incorporated brief and sustained positive and negative emotional states to distinguish effects of arousal versus valence. We first tested for dissociable effects of both positive and negative emotional cues and states on cognitive performance and neural processes. We find that in adults, brief emotional triggers or cues, whether positive or negative, similarly influence cognitive control. In contrast, sustained emotional states differentially impact cognitive control. Specifically, positive states enhance performance while negative state diminishes performance. Behavioral differences were paralleled by differential recruitment of fronto-parietal and fronto-striatal circuitry. Central to our primary question, we next examined the impact of these emotions on behavior and brain during the transition from adolescence to adulthood, in teens 13 to 17, young adults 18 to 21, and over 21 years-old. We show protracted development of cognitive control in both brief and prolonged potentially threatening situations into the early twenties. This behavioral pattern was paralleled by developmental changes in prefrontal circuitry. The question remains as to how reactivity to emotional information during adolescence may impacts subsequent memory for this information. We show preliminary evidence that temporal dynamics of memory processes may be changing across development. Together these studies begin to dissociate complex influences of emotions on behavioral and neural processes across development and how they may differentially lead to changes in behavior and actions

Topography of Extracellular Matrix Mediates Vascular Morphogenesis and Migration Speeds in Angiogenesis

The extracellular matrix plays a critical role in orchestrating the events necessary for wound healing, muscle repair, morphogenesis, new blood vessel growth, and cancer invasion. In this study, we investigate the influence of extracellular matrix topography on the coordination of multi-cellular interactions in the context of angiogenesis. To do this, we validate our spatio-temporal mathematical model of angiogenesis against empirical data, and within this framework, we vary the density of the matrix fibers to simulate different tissue environments and to explore the possibility of manipulating the extracellular matrix to achieve pro- and anti-angiogenic effects. The model predicts specific ranges of matrix fiber densities that maximize sprout extension speed, induce branching, or interrupt normal angiogenesis, which are independently confirmed by experiment. We then explore matrix fiber alignment as a key factor contributing to peak sprout velocities and in mediating cell shape and orientation. We also quantify the effects of proteolytic matrix degradation by the tip cell on sprout velocity and demonstrate that degradation promotes sprout growth at high matrix densities, but has an inhibitory effect at lower densities. Our results are discussed in the context of ECM targeted pro- and anti-angiogenic therapies that can be tested empirically