Task Difficulty Regulates How Conscious and Unconscious Monetary Rewards Boost the Performance of Working Memory: An Event-Related Potential Study

The performance of working memory can be improved by the corresponding high-value vs. low-value rewards consciously or unconsciously. However, whether conscious and unconscious monetary rewards boosting the performance of working memory is regulated by the difficulty level of working memory task is unknown. In this study, a novel paradigm that consists of a reward-priming procedure and N-back task with differing levels of difficulty was designed to inspect this complex process. In particular, both high-value and low-value coins were presented consciously or unconsciously as the reward cues, followed by the N-back task, during which electroencephalogram signals were recorded. It was discovered that the high-value reward elicited larger event-related potential (ERP) component P3 along the parietal area (reflecting the working memory load) as compared to the low-value reward for the less difficult 1-back task, no matter whether the reward was unconsciously or consciously presented. In contrast, this is not the case for the more difficult 2-back task, in which the difference in P3 amplitude between the high-value and low-value rewards was not significant for the unconscious reward case, yet manifested significance for the conscious reward processing. Interestingly, the results of the behavioral analysis also exhibited very similar patterns as ERP patterns. Therefore, this study demonstrated that the difficulty level of a task can modulate the influence of unconscious reward on the performance of working memory.

Behavioral and Gene Regulatory Responses to Developmental Drug Exposures in Zebrafish

Developmental consequences of prenatal drug exposure have been reported in many human cohorts and animal studies. The long-lasting impact on the offspring—including motor and cognitive impairments, cranial and cardiac anomalies and increased prevalence of ADHD—is a socioeconomic burden worldwide. Identifying the molecular changes leading to developmental consequences could help ameliorate the deficits and limit the impact. In this study, we have used zebrafish, a well-established behavioral and genetic model with conserved drug response and reward pathways, to identify changes in behavior and cellular pathways in response to developmental exposure to amphetamine, nicotine or oxycodone. In the presence of the drug, exposed animals showed altered behavior, consistent with effects seen in mammalian systems, including impaired locomotion and altered habituation to acoustic startle. Differences in responses seen following acute and chronic exposure suggest adaptation to the presence of the drug. Transcriptomic analysis of exposed larvae revealed differential expression of numerous genes and alterations in many pathways, including those related to cell death, immunity and circadian rhythm regulation. Differential expression of circadian rhythm genes did not correlate with behavioral changes in the larvae, however, two of the circadian genes, arntl2 and per2, were also differentially expressed at later stages of development, suggesting a long-lasting impact of developmental exposures on circadian gene expression. The immediate-early genes, egr1, egr4, fosab, and junbb, which are associated with synaptic plasticity, were downregulated by all three drugs and in situ hybridization showed that the expression for all four genes was reduced across all neuroanatomical regions, including brain regions implicated in reward processing, addiction and other psychiatric conditions. We anticipate that these early changes in gene expression in response to drug exposure are likely to contribute to the consequences of prenatal exposure and their discovery might pave the way to therapeutic intervention to ameliorate the long-lasting deficits.

Computational approaches to predicting treatment response to obesity using neuroimaging

Obesity is a worldwide disease associated with multiple severe adverse consequences and comorbid conditions. While an increased body weight is the defining feature in obesity, etiologies, clinical phenotypes and treatment responses vary between patients. These variations can be observed within individual treatment options which comprise lifestyle interventions, pharmacological treatment, and bariatric surgery. Bariatric surgery can be regarded as the most effective treatment method. However, long-term weight regain is comparably frequent even for this treatment and its application is not without risk. A prognostic tool that would help predict the effectivity of the individual treatment methods in the long term would be essential in a personalized medicine approach. In line with this objective, an increasing number of studies have combined neuroimaging and computational modeling to predict treatment outcome in obesity. In our review, we begin by outlining the central nervous mechanisms measured with neuroimaging in these studies. The mechanisms are primarily related to reward-processing and include “incentive salience” and psychobehavioral control. We then present the diverse neuroimaging methods and computational prediction techniques applied. The studies included in this review provide consistent support for the importance of incentive salience and psychobehavioral control for treatment outcome in obesity. Nevertheless, further studies comprising larger sample sizes and rigorous validation processes are necessary to answer the question of whether or not the approach is sufficiently accurate for clinical real-world application.

Disrupted reward processing in Parkinson’s disease and its relationship with dopamine state and neuropsychiatric syndromes: a systematic review and meta-analysis

BackgroundNeuropsychiatric symptoms are common in Parkinson’s disease (PD) and predict poorer outcomes. Reward processing dysfunction is a candidate mechanism for the development of psychiatric symptoms including depression and impulse control disorders (ICDs). We aimed to determine whether reward processing is impaired in PD and its relationship with neuropsychiatric syndromes and dopamine replacement therapy.MethodsThe Ovid MEDLINE/PubMed, Embase and PsycInfo databases were searched for articles published up to 5 November 2020. Studies reporting reward processing task performance by patients with PD and healthy controls were included. Summary statistics comparing reward processing between groups were converted to standardised mean difference (SMD) scores and meta-analysed using a random effects model.ResultsWe identified 55 studies containing 2578 participants (1638 PD and 940 healthy controls). Studies assessing three subcomponent categories of reward processing tasks were included: option valuation (n=12), reinforcement learning (n=37) and reward response vigour (n=6). Across all studies, patients with PD on medication exhibited a small-to-medium impairment versus healthy controls (SMD=0.34; 95% CI 0.14 to 0.53), with greater impairments observed off dopaminergic medication in within-subjects designs (SMD=0.43, 95% CI 0.29 to 0.57). Within-subjects subcomponent analysis revealed impaired processing off medication on option valuation (SMD=0.57, 95% CI 0.39 to 0.75) and reward response vigour (SMD=0.36, 95% CI 0.13 to 0.59) tasks. However, the opposite applied for reinforcement learning, which relative to healthy controls was impaired on-medication (SMD=0.45, 95% CI 0.25 to 0.65) but not off-medication (SMD=0.28, 95% CI −0.03 to 0.59). ICD was the only neuropsychiatric syndrome with sufficient studies (n=13) for meta-analysis, but no significant impairment was identified compared tonon-ICD patients (SMD=−0.02, 95% CI −0.43 to 0.39).ConclusionReward processing disruption in PD differs according to subcomponent and dopamine medication state, and warrants further study as a potential treatment target and mechanism underlying associated neuropsychiatric syndromes.

Cell-Type-Specific Adaptions in Striatal Medium-Sized Spiny Neurons and Their Roles in Behavioral Responses to Drugs of Abuse

Drug addiction is defined as a compulsive pattern of drug-seeking- and taking- behavior, with recurrent episodes of abstinence and relapse, and a loss of control despite negative consequences. Addictive drugs promote reinforcement by increasing dopamine in the mesocorticolimbic system, which alters excitatory glutamate transmission within the reward circuitry, thereby hijacking reward processing. Within the reward circuitry, the striatum is a key target structure of drugs of abuse since it is at the crossroad of converging glutamate inputs from limbic, thalamic and cortical regions, encoding components of drug-associated stimuli and environment, and dopamine that mediates reward prediction error and incentive values. These signals are integrated by medium-sized spiny neurons (MSN), which receive glutamate and dopamine axons converging onto their dendritic spines. MSN primarily form two mostly distinct populations based on the expression of either DA-D1 (D1R) or DA-D2 (D2R) receptors. While a classical view is that the two MSN populations act in parallel, playing antagonistic functional roles, the picture seems much more complex. Herein, we review recent studies, based on the use of cell-type-specific manipulations, demonstrating that dopamine differentially modulates dendritic spine density and synapse formation, as well as glutamate transmission, at specific inputs projecting onto D1R-MSN and D2R-MSN to shape persistent pathological behavioral in response to drugs of abuse. We also discuss the identification of distinct molecular events underlying the detrimental interplay between dopamine and glutamate signaling in D1R-MSN and D2R-MSN and highlight the relevance of such cell-type-specific molecular studies for the development of innovative strategies with potential therapeutic value for addiction. Because drug addiction is highly prevalent in patients with other psychiatric disorders when compared to the general population, we last discuss the hypothesis that shared cellular and molecular adaptations within common circuits could explain the co-occurrence of addiction and depression. We will therefore conclude this review by examining how the nucleus accumbens (NAc) could constitute a key interface between addiction and depression.

Prior Methamphetamine Use Disorder History Does Not Impair Interoceptive Processing of Soft Touch in HIV Infection

Introduction: Interoception, defined as the sense of the internal state of one’s body, helps motivate goal-directed behavior. Prior work has shown that methamphetamine (METH) use disorder is associated with altered interoception, and that this may contribute to risky behavior. As people with HIV (PWH) may also experience disrupted bodily sensations (e.g., neuropathy), an important question is whether PWH with a history of METH use disorder might exhibit greater impairment of interoceptive processing. Methods: Eighty-three participants stratified by HIV infection and a past history of methamphetamine use disorder experienced a soft touch paradigm that included slow brush strokes on the left forearm and palm during blood-oxygen level-dependent functional MRI acquisition. To assess differences in interoception and reward, voxelwise analyses were constrained to the insula, a hub for the evaluation of interoceptive cues, and the striatum, which is engaged in reward processing. Results: Overall, individuals with a history of METH use disorder had an attenuated neural response to pleasant touch in both the insula and striatum. Longer abstinence was associated with greater neural response to touch in the insula, suggesting some improvement in responsivity. However, only PWH with no METH use disorder history had lower brain activation in the insula relative to non-using seronegative controls. Conclusions: Our findings suggest that while METH use disorder history and HIV infection independently disrupt the neural processes associated with interoception, PWH with METH use disorder histories do not show significant differences relative to non-using seronegative controls. These findings suggest that the effects of HIV infection and past methamphetamine use might not be additive with respect to interoceptive processing impairment.

Human Primary Olfactory Amygdala Subregions Form Distinct Functional Networks, Suggesting Distinct Olfactory Functions

Three subregions of the amygdala receive monosynaptic projections from the olfactory bulb, making them part of the primary olfactory cortex. These primary olfactory areas are located at the anterior-medial aspect of the amygdala and include the medial amygdala (MeA), cortical amygdala (CoA), and the periamygdaloid complex (PAC). The vast majority of research on the amygdala has focused on the larger basolateral and basomedial subregions, which are known to be involved in implicit learning, threat responses, and emotion. Fewer studies have focused on the MeA, CoA, and PAC, with most conducted in rodents. Therefore, our understanding of the functions of these amygdala subregions is limited, particularly in humans. Here, we first conducted a review of existing literature on the MeA, CoA, and PAC. We then used resting-state fMRI and unbiased k-means clustering techniques to show that the anatomical boundaries of human MeA, CoA, and PAC accurately parcellate based on their whole-brain resting connectivity patterns alone, suggesting that their functional networks are distinct, relative both to each other and to the amygdala subregions that do not receive input from the olfactory bulb. Finally, considering that distinct functional networks are suggestive of distinct functions, we examined the whole-brain resting network of each subregion and speculated on potential roles that each region may play in olfactory processing. Based on these analyses, we speculate that the MeA could potentially be involved in the generation of rapid motor responses to olfactory stimuli (including fight/flight), particularly in approach/avoid contexts. The CoA could potentially be involved in olfactory-related reward processing, including learning and memory of approach/avoid responses. The PAC could potentially be involved in the multisensory integration of olfactory information with other sensory systems. These speculations can be used to form the basis of future studies aimed at clarifying the olfactory functions of these under-studied primary olfactory areas.

Sex Differences in Substance Use Disorders: A Neurobiological Perspective

Clinical studies provide fundamental knowledge of substance use behaviors (substance of abuse, patterns of use, relapse rates). The combination of neuroimaging approaches reveal correlation between substance use disorder (SUD) and changes in neural structure, function, and neurotransmission. Here, we review these advances, placing special emphasis on sex specific findings from structural neuroimaging studies of those dependent on alcohol, nicotine, cannabis, psychostimulants, or opioids. Recent clinical studies in SUD analyzing sex differences reveal neurobiological changes that are differentially impacted in common reward processing regions such as the striatum, hippocampus, amygdala, insula, and corpus collosum. We reflect on the contribution of sex hormones, period of drug use and abstinence, and the potential impact of these factors on the interpretation of the reported findings. With the overall recognition that SUD impacts the brains of females and males differentially, it is of fundamental importance that future research is designed with sex as a variable of study in this field. Improved understanding of neurobiological changes in males and females in SUD will advance knowledge underlying sex-specific susceptibility and the neurobiological impact in these disorders. Together these findings will inform future treatments that are tailor designed for improved efficacy in females and males with SUD.

Extrahypothalamic Control of Energy Balance and Its Connection with Reproduction: Roles of the Amygdala

Body energy and metabolic homeostasis are exquisitely controlled by multiple, often overlapping regulatory mechanisms, which permit the tight adjustment between fuel reserves, internal needs, and environmental (e.g., nutritional) conditions. As such, this function is sensitive to and closely connected with other relevant bodily systems, including reproduction and gonadal function. The aim of this mini-review article is to summarize the most salient experimental data supporting a role of the amygdala as a key brain region for emotional learning and behavior, including reward processing, in the physiological control of feeding and energy balance. In particular, a major focus will be placed on the putative interplay between reproductive signals and amygdala pathways, as it pertains to the control of metabolism, as complementary, extrahypothalamic circuit for the integral control of energy balance and gonadal function.