Event-related functional magnetic resonance imaging of reward-related brain circuitry in children and adolescents

BACKGROUND: Functional disturbances in reward-related brain systems are thought to play a role in the development of mood, impulse, and substance abuse disorders. Studies in non-human primates have identified brain regions, including the dorsal / ventral striatum and orbital-frontal cortex (OFC), in which neural activity is modulated by reward. Recent studies in adults have concurred with these findings by observing reward-contingent blood oxygen level dependant (BOLD) responses in these regions during functional magnetic resonance imaging (FMRI) paradigms. However no previous studies indicate whether comparable modulations of neural activity exist in the brain reward systems of children and adolescents. METHODS: We used event-related FMRI and a behavioral paradigm modeled on previous work in adults to study brain responses to monetary gains and losses in non-psychiatric children and adolescents as part of a program examining the neural substrates of anxiety and depression in youth. RESULTS: Regions and time-courses of reward-related activity were similar to those observed in adults with condition-dependent BOLD changes in the ventral striatum, lateral and medial OFC; specifically, these regions showed larger responses to positive than to negative feedback. CONCLUSIONS: These results provide further evidence for the value of event-related FMRI in examining reward systems of the brain, demonstrate the feasibility of this approach in children and adolescents, and establish a baseline from which to understand the pathophysiology of reward-related psychiatric disorders in youth

Frontostriatal Maturation Predicts Cognitive Control Failure to Appetitive Cues in Adolescents

Adolescent risk-taking is a public health issue that increases the odds of poor lifetime outcomes. One factor thought to influence adolescents' propensity for risk-taking is an enhanced sensitivity to appetitive cues, relative to an immature capacity to exert sufficient cognitive control. We tested this hypothesis by characterizing interactions among ventral striatal, dorsal striatal, and prefrontal cortical regions with varying appetitive load using fMRI scanning. Child, teen, and adult participants performed a go/no-go task with appetitive (happy faces) and neutral cues (calm faces). Impulse control to neutral cues showed linear improvement with age, whereas teens showed a nonlinear reduction in impulse control to appetitive cues. This performance decrement in teens was paralleled by enhanced activity in the ventral striatum. Prefrontal cortical recruitment correlated with overall accuracy and showed a linear response with age for no-go versus go trials. Connectivity analyses identified a ventral frontostriatal circuit including the inferior frontal gyrus and dorsal striatum during no-go versus go trials. Examining recruitment developmentally showed that teens had greater between-subject ventral-dorsal striatal coactivation relative to children and adults for happy no-go versus go trials. These findings implicate exaggerated ventral striatal representation of appetitive cues in adolescents relative to an intermediary cognitive control response. Connectivity and coactivity data suggest these systems communicate at the level of the dorsal striatum differentially across development. Biased responding in this system is one possible mechanism underlying heightened risk-taking during adolescence

Investigating psychobiological mechanisms underlying dysregulated goal-pursuit across psychiatric disorders

This thesis examines the psychobiological mechanisms contributing to dysregulated reward processing differences in two parts: across psychiatric disorders (Part one), and in bipolar disorder (Part two). Part one comprises a systematic review and meta-analysis examining the extent to which four aspects of reward processing, namely the anticipation and evaluation of rewards and losses, exist transdiagnostically at the psychobiological level. 26 functional magnetic resonance imaging (fMRI) studies that examined whole-brain-based activation during a reward task (monetary incentive delay) and compared between patients and matched controls were included. Results showed that compared to controls, clinical groups exhibit shared increases and decreases in dorsal striatal activity during the evaluation of rewarding outcomes and anticipation of negative outcomes respectively. Part two presents an empirical study, which sought to combine computational modelling and fMRI data to investigate whether momentary changes in mood bias the perception of rewards more strongly in individuals with bipolar disorder than matched controls. Region-of-interest analyses in the ventral striatum, anterior insula and ventromedial prefrontal cortex and exploratory whole-brain analyses were conducted. Although results broadly confirmed previous findings that mood-biased influences on reward learning signals are represented in the reward system, preliminary evidence suggests that individuals with bipolar disorder represent them more strongly than controls in visual processing areas. Part three comprises a critical appraisal of the research process. This includes a discussion of the author’s influences on the research, the relevance of understanding mechanisms in psychological research and treatment and potential challenges of fMRI research, concluding with a summary of recommendations

The Effects of Acute Stress Exposure on Neural Correlates of Pavlovian Conditioning with Monetary Gains and Losses

Pavlovian conditioning involves the association of an inherently neutral stimulus with an appetitive or aversive outcome, such that the neutral stimulus itself acquires reinforcing properties. Across species, this type of learning has been shown to involve subcortical brain regions such as the striatum and the amygdala. It is less clear, however, how the neural circuitry involved in the acquisition of Pavlovian contingencies in humans, particularly in the striatum, is affected by acute stress. In the current study, we investigate the effect of acute stress exposure on Pavlovian conditioning using monetary reinforcers. Participants underwent a partial reinforcement conditioning procedure in which neutral stimuli were paired with high and low magnitude monetary gains and losses. A between-subjects design was used, such that half of the participants were exposed to cold stress while the remaining participants were exposed to a no stress control procedure. Cortisol measurements and subjective ratings were used as measures of stress. We observed an interaction between stress, valence, and magnitude in the ventral striatum, with the peak in the putamen. More specifically, the stress group exhibited an increased sensitivity to magnitude in the gain domain. This effect was driven by those participants who experienced a larger increase in circulating cortisol levels in response to the stress manipulation. Taken together, these results suggest that acute stress can lead to individual differences in circulating cortisol levels which influence the striatum during Pavlovian conditioning with monetary reinforcers

Neural and Behavioral Mechanisms of Interval Timing in the Striatum

To guide behavior and learn from its consequences, the brain must represent time over many scales. Yet, the neural signals used to encode time in the seconds to minute range are not known. The striatum is the major input area of the basal ganglia; it plays important roles in learning, motor function and normal timing behavior in the range of seconds to minutes. We investigated how striatal population activity might encode time. To do so, we recorded the electrical activity from striatal neurons in rats performing the serial fixed interval task, a dynamic version of the fixed Interval schedule of reinforcement. The animals performed in conformity with proportional timing, but did not strictly conform to scalar timing predictions, which might reflect a parallel strategy to optimize the adaptation to changes in temporal contingencies and consequently to improve reward rate over the session. Regarding the neural activity, we found that neurons fired at delays spanning tens of seconds and that this pattern of responding reflected the interaction between time and the animals’ ongoing sensorimotor state. Surprisingly, cells rescaled responses in time when intervals changed, indicating that striatal populations encoded relative time. Moreover, time estimates decoded from activity predicted trial-bytrial timing behavior as animals adjusted to new intervals, and disrupting striatal function with local infusion of muscimol led to a decrease in timing performance. Because of practical limitations in testing for sufficiency a biological system, we ran a simple simulation of the task; we have shown that neural responses similar to those we observe are conceptually sufficient to produce temporally adaptive behavior. Furthermore, we attempted to explain temporal processes on the basis of ongoing behavior by decoding temporal estimates from high-speed videos of the animals performing the task; we could not explain the temporal report solely on basis of ongoing behavior. These results suggest that striatal activity forms a scalable population firing rate code for time, providing timing signals that animals use to guide their actions

Dopamine neurons create Pavlovian conditioned stimuli with circuit-defined motivational properties.

Environmental cues, through Pavlovian learning, become conditioned stimuli that guide animals toward the acquisition of rewards (for example, food) that are necessary for survival. We tested the fundamental role of midbrain dopamine neurons in conferring predictive and motivational properties to cues, independent of external rewards. We found that brief phasic optogenetic excitation of dopamine neurons, when presented in temporal association with discrete sensory cues, was sufficient to instantiate those cues as conditioned stimuli that subsequently both evoked dopamine neuron activity on their own and elicited cue-locked conditioned behavior. Notably, we identified highly parcellated functions for dopamine neuron subpopulations projecting to different regions of striatum, revealing dissociable dopamine systems for the generation of incentive value and conditioned movement invigoration. Our results indicate that dopamine neurons orchestrate Pavlovian conditioning via functionally heterogeneous, circuit-specific motivational signals to create, gate, and shape cue-controlled behaviors

Chronic Variable Stress Induces Avolition and Disrupts Corticoaccumbens Encoding of Approach Cues

Disorders in the ability to process, evaluate, and interact with rewards are hallmarks of a range of mental illnesses. Such disorders are multi-faceted and arise from altered activity throughout diffuse brain regions. Chronic variable stress (CVS) is an oft-used tool for modeling reward-related disorders in preclinical research because it impairs the function of multiple brain regions and causes a range of severe hedonic and motivational deficits. While much research has focused on the former, the latter is poorly characterized. A panel of behavioral tests was used to characterize the effect of CVS exposure on different facets of reward related behaviors in Sprague-Dawley rats. In a subset of animals, in vivo electrophysiology was used to assess the impact of CVS on reward encoding in a primary reward processing region, the nucleus accumbens (NAc). Behavioral deficits occurred in motivational, rather than hedonic, domains, and stress altered the encoding of primary rewards in the Shell subregion of the NAc, an area responsible for encoding value. The prelimbic region of the prefrontal cortex (PL) is known to be sensitive to stress and responsive to reward-predictive cues. The extent to which this area encodes the incentive value of cues has not been characterized. Pavlovian autoshaping is a behavior in which trained animals transfer the incentive value of a primary reward to an associated cue. In vivo electrophysiological recordings of single units in the PL of Sprague-Dawley rats demonstrated that this region was attuned to incentivized cues in the autoshaping paradigm. A projection pathway from the PL targeting the NAc Core (NAcC) subregion has a significant role in promoting motivated approach. However, little is known about how activity in this pathway (1.) changes during associative learning to encode incentivized cues or (2.) may be altered by stress. An intersectional fiber photometry approach used in male Sprague Dawley rats engaged in autoshaping demonstrated that the rapid acquisition of conditioned approach was associated with cue-induced PL-NAcC activity. Prior stress reduced both cue-directed behavior and associated cortical activity. These results support the interpretation that stress disrupts reward processing by altering the attribution of incentive to associated cues

Interactions Between the Basolateral Amygdala and Ventral Striatum During Probabilistic Learning in Children and Associations with Individual Differences in Free Cortisol

Stress can drastically alter the behavioural and functional correlates of feedback learning; however, the functional correlates of these effects are poorly understood, particularly in children. In the present study, typically developing children between the ages of 9- and 11-years-old completed a probabilistic learning task with both appetitive and aversive outcomes in a magnetic resonance imaging scanner. Anticipatory stress to the experimental environment was measured via salivary cortisol at baseline and prior to completion of the task. Although baseline and pre-MRI cortisol values were not reliably different at the group level, subsequent analyses revealed that the basolateral amygdala was less responsive to positive feedback in children with higher pre-MRI cortisol levels. Furthermore, individual differences in feedback-related basolateral amygdala activity were positively associated with differences in striatal activity. Thus, the basolateral amygdala may be particularly sensitive to individual differences in active cortisol levels, and may also modulate striatal feedback sensitivity

Functional connectivity of reward processing in the brain

Controversial results have been reported concerning the neural mechanisms involved in the processing of rewards and punishments. On the one hand, there is evidence suggesting that monetary gains and losses activate a similar fronto-subcortical network. On the other hand, results of recent studies imply that reward and punishment may engage distinct neural mechanisms. Using functional magnetic resonance imaging (fMRI) we investigated both regional and interregional functional connectivity patterns while participants performed a gambling task featuring unexpectedly high monetary gains and losses. Classical univariate statistical analysis showed that monetary gains and losses activated a similar fronto-striatallimbic network, in which main activation peaks were observed bilaterally in the ventral striatum. Functional connectivity analysis showed similar responses for gain and loss conditions in the insular cortex, the amygdala, and the hippocampus that correlated with the activity observed in the seed region ventral striatum, with the connectivity to the amygdala appearing more pronounced after losses. Larger functional connectivity was found to the medial orbitofrontal cortex for negative outcomes. The fact that different functional patterns were obtained with both analyses suggests that the brain activations observed in the classical univariate approach identifi es the involvement of different functional networks in the current task. These results stress the importance of studying functional connectivity in addition to standard fMRI analysis in reward-related studies