Neurobiological theories of bipolar spectrum disorder (BSD) propose that the emotional dysregulation characteristic of BSD stems from disrupted prefrontal control over subcortical limbic structures (Strakowski et al., 2012; Depue & Iacono, 1989). However, existing neuroimaging research on functional connectivity between frontal and limbic brain regions remains inconclusive, and is unable to adequately characterize global functional network dynamics. Graph theoretical analysis provides a framework for understanding the local and global connections of the brain and comparing these connections between groups (Sporns et al., 2004). The purpose of this study was to investigate resting state functional connectivity in individuals at low and high risk for BSD based on moderate versus high reward sensitivity, both with and without a BSD diagnosis, using graph theoretical network analysis. Results demonstrated decreased connectivity in a cognitive control region (dorsolateral prefrontal cortex), but increased connectivity of a brain region involved in the detection and processing of reward (bilateral orbitofrontal cortex), among participants at high risk for BSD. Participants with BSD showed increased inter-module connectivity of the dorsal anterior cingulate cortex (ACC). Reward sensitivity was associated with decreased global and local efficiency, and interacted with BSD risk group status to predict inter-module connectivity. Findings are discussed in relation to neurobiological theories of BSD. / Psychology

Eating disorders involve the inability to appropriately regulate a behavioral response to food due to impaired reward sensitivity, affect regulation and cognitive control, resulting in deleterious effects on the individual's physical and mental well-being. In this way eating disorders may be analogous to addictive disorders (e.g. alcoholism). Furthermore, eating and addictive disorders co-occur at very high rates and appear to have similar contributing mechanisms (impaired reward sensitivity, impaired affect regulation and impaired cognitive control). Overvaluation of weight and shape concerns appears to be one unique characteristic of eating disorders, not shared with addiction. The current study examined the relationship between impaired reward sensitivity, impaired affect regulation and impaired cognitive control with addiction vulnerability. Furthermore, weight and shape concerns were examined as a potential moderator of the relationship between addiction vulnerability and binge eating. A total of 1000 undergraduate students completed self-report measures examining the three posited mechanisms for addiction vulnerability and disordered eating. A subset of 101 students (50 binge-eaters and 51 non-binge eaters) also completed behavioral measures of the three posited mechanisms. The results of this study support the proposed model that weight and shape concerns moderate the relationship between addiction vulnerability and binge eating. Results also demonstrated on a behavioral task that individuals who endorsed binge eating were more likely to act impulsively and quit the PASAT-C task faster than control subjects. Furthermore, they demonstrated a greater increase in irritability while completing the task which may have resulted in their desire to quit the task earlier. No differences were found on behavioral measures of reward sensitivity (delay discount task) or cognitive control (stop signal task). Future studies should continue to examine the construct of addiction vulnerability to provide additional validity for the construct as well as examine it in the context of all forms of disordered eating. / Psychology

Animal models have proven to be useful tools for modeling human neurochemical and behavioral responses to drugs of abuse, including cocaine. Cocaine is a psychomotor stimulant that facilitates monoaminergic neurotransmission by binding to transporters and inhibiting the reuptake of dopamine, serotonin and norepinephrine into presynaptic neurons. Many of the behavioral effects of cocaine, including its locomotor-activating and reinforcing properties, have been attributed to the ability of cocaine to enhance dopaminergic activity. In addition to its direct effects on monoamine neurotransmitters, cocaine impacts other neurotransmitter systems including the endogenous opioid system. The effects of selectively antagonizing mu opioid receptors on cocaine-induced behaviors were evaluated during this research. This research also evaluated the effect of selectively antagonizing dopamine D1 or D2 receptors on cocaine-induced mu opioid receptor occupancy by endogenous opioid ligands. This research furthered our understanding of how the endogenous opioid and dopaminergic systems interact to mediate cocaine-induced behaviors. Although data support the role of mu opioid receptors in modulating cocaine-mediated locomotion and reward, the location of the mu opioid receptors involved has not been established. An evaluation of the effects of a selective mu opioid receptor antagonist administered directly into specific brain regions on cocaine-induced behaviors is important for understanding how the endogenous opioid and dopaminergic systems interact to mediate cocaine-induced behaviors. The studies outlined herein sought to determine the contribution of mu opioid receptors in specific regions of the mesocorticolimbic system to the rewarding and locomotor-activating effects of cocaine in the rat. In addition, to further understand the role of mu opioid receptors in cocaine reward, neuronal activation was studied via cFos activation following the expression of cocaine-induced place preference. Results of the research outlined herein demonstrate the importance of mu opioid receptors in cocaine-induced reward and activity, and demonstrate the anatomical selectivity of mu receptors within the nucleus accumbens, VTA and caudate putamen in this regard. These data suggest that cocaine causes the release of endogenous opioid peptides and that these peptides contribute to the rewarding and locomotor-stimulating effects of cocaine. Further, these data also suggest that opioid peptides are released in the nucleus accumbens shell during the expression of cocaine place preferences and that mu opioid receptors in this region are critical for the manifestation of this behavior. Although data demonstrate that extracellular levels of endogenous opioid peptides are increased following cocaine administration, the time- and dose-dependent occupancy of mu opioid receptors within specific brain regions had not been established in previous studies. The present research sought to determine the time- and dose-dependent occupancy of mu opioid receptors, measured indirectly by displacement of 3H-DAMGO binding, within specific brain regions. 3H-DAMGO binding was measured by in vitro autoradiography. In addition, the contribution of dopamine D1 and D2 receptors in cocaine-induced 3H-DAMGO displacement was evaluated. Results demonstrate that cocaine administration caused a dose- and time-dependent displacement of 3H-DAMGO binding to mu opioid receptors within the nucleus accumbens core and shell. This displacement was attenuated by pretreatment with a selective D2 dopamine receptor antagonist, demonstrating that cocaine, acting via D2 dopamine receptors, can cause the release of an endogenous opioid peptide that binds to mu opioid receptors within the nucleus accumbens core and shell. Previous studies have demonstrated that chronic administration of non-selective mu opioid receptor antagonists has profound effects on mu opioid receptor density and signaling. The research presented herein sought to determine whether chronic treatment with the selective mu opioid receptor antagonist, CTAP, would increase mu opioid receptor density and agonist-stimulated G-protein activation. In addition, this research sought to determine whether chronic CTAP administration would sensitize animals to the locomotor stimulating effects of cocaine. Results outlined herein demonstrate that chronic CTAP treatment sensitized animals to the locomotor effects of cocaine and that this sensitization occurred in conjunction with an increase in mu opioid receptor density within the nucleus accumbens core and shell. / Pharmacology

Posttraumatic stress disorder (PTSD) co-occurs with substance use disorders at high rates, but the neurobiological basis of this relationship remains largely unknown. Identifying mechanisms that underlie this association is necessary, and recognizing pathologies shared by these disorders may provide pertinent information in understanding their functional relationship. Separate lines of evidence suggest that PTSD and drug addiction may share a common feature, that is, dysregulation of the brain's reward circuitry. We hypothesize that PTSD results in reduced dopaminergic neurotransmission which may contribute to deficient reward function and vulnerability to drug-seeking behavior. To address this hypothesis, we combined single-prolonged stress (SPS), a rodent model of PTSD, with a series of behavioral and neuropharmacological assays to assess dopaminergic reward function and cocaine intake. The results of the studies presented herein extend our understanding of the effects of severe stress on drug reinforcement and consumption, and establish a potential mechanism by which PTSD produces deficient reward function through alterations in the dopamine system. A modified SPS procedure consisting of 2 hours of restraint, 20 minutes of group swimming, isoflurane exposure until loss consciousness, and 7 days of isolation was used to induce severe stress in our studies. Initial studies were conducted to examine the effect of SPS on cocaine-conditioned reward and anhedonia-like behavior in adult male Sprague-Dawley rats. Using a biased conditioned place preference paradigm, unstressed controls demonstrated a significant preference for the cocaine-paired context following four pairings with cocaine (5-20 mg/kg, i.p.). Preference for the cocaine-paired side was significantly lower in rats exposed to SPS, suggesting a deficit in the rewarding properties of cocaine following exposure to severe stress. Anhedonia-like behavior was assessed by a two-bottle choice sucrose preference test. Robust consumption of sucrose solution (0.25-1%) was observed in rats that underwent control handling, however, SPS significantly reduced sucrose intake compared to controls. These results suggest an increase in anhedonia-like behavior or a reduction in the rewarding effects of sucrose as a non-drug reinforcer. Finally, basal behavioral activity in SPS rats was compared to unstressed controls in a 24-hour test. Results indicate a significant reduction in spontaneous nocturnal activity following SPS versus control handling. In contrast, hyperlocomotion induced by an acute cocaine injection (5-20 mg/kg, i.p.) was unaltered between rats that underwent SPS or control handling. These data suggest that deficient behavioral activity may be specific to voluntary movements or behavior, and support an increase in anhedonia following exposure to SPS. Intravenous cocaine self-administration was conducted to examine the effect of SPS on the acquisition, motivation, and escalation of cocaine intake. Acquisition of cocaine self-administration was studied using an escalating dose regimen in which rats had sequential access to 0.1875, 0.375, and 0.75 mg/kg/infusion on a fixed-ratio 1 schedule of reinforcement. Rats exposed to SPS did not significantly differ from control handled animals in the latency to meet acquisition criteria (consumption of 6.75 mg/kg/day for 3 consecutive days) or the general pattern and level of cocaine intake at each dose. A subsequent study assessing the breakpoint for cocaine self-administration using a progressive-ratio schedule of reinforcement determined a dose-dependent increase in motivation to work for cocaine (0-1.5 mg/kg/infusion) across both experimental groups. However, motivation to obtain cocaine was similar between SPS and unstressed rats, as there was no significant difference in breakpoint for cocaine self-administration at any dose of cocaine tested. To evaluate potential differences in the transition to escalated cocaine intake, self-administration was measured using an extended-access procedure in which unlimited cocaine (0.375 mg/kg/infusion) was available for six hours daily. Upon extended-access to cocaine, SPS significantly attenuated cocaine intake compared to control handling over 14 sessions. Despite a significant reduction in cocaine intake, rats exposed to SPS still significantly escalated their cocaine intake over the course of 14 days. These results suggest that escalation of cocaine intake occurred in the presence of lower total doses of cocaine in the SPS exposed animals compared to controls. In addition, SPS rats demonstrated a greater percent increase in cocaine consumption compared to controls. This finding suggests that rats exposed to SPS compensated for a decrease in cocaine reinforcement by escalating their intake to a greater magnitude than controls. These studies indicate that SPS may not alter the acquisition of cocaine self-administration or motivation for cocaine. However, the finding of reduced cocaine intake upon extended-access in SPS rats is consistent with a deficit in cocaine-induced reward. The ability of SPS rats to escalate cocaine intake in the presence of less cocaine, or a greater magnitude of escalated cocaine intake than controls, may reflect mechanisms leading to enhanced vulnerability to cocaine abuse. To understand the mechanisms of reduced reward and behavior in the SPS model of PTSD, a series of neurochemical assays was used to assess the ability of SPS to induce dysfunction of dopaminergic neurotransmission. Using high performance liquid chromatography, tissue levels of dopamine and the dopamine metabolites DOPAC and HVA were measured immediately and one week following SPS or control handling. Tissue obtained from SPS rats demonstrated significant decreases in dopamine, DOPAC, and HVA content in both the nucleus accumbens and caudate putamen immediately following SPS and one week later, suggesting a potential deficit in dopaminergic tone. Quantitative autoradiography was used measure the density of dopamine transporters and dopamine D1 and D2 receptors. [3H]WIN35428 binding to dopamine transporters was higher in the nucleus accumbens of SPS rats compared to controls, suggesting an increase in dopamine transporter density following severe stress. The level of [3H]WIN35428 binding in the caudate putamen was not different between groups. [3H]Raclopride binding to D2 receptors was significantly reduced in both the nucleus accumbens and caudate putamen following SPS versus control handling. These results suggest a decrease in the density of striatal D2 receptors. D1 receptor expression was not significantly altered by SPS, as no significant difference in [3H]SCH23390 binding was detected in SPS rats compared to controls. A preliminary functional assessment of dopamine transporters revealed a significant increase in dopamine uptake in the nucleus accumbens of SPS rats compared to controls, whereas uptake in the caudate putamen was unaltered between groups. Enhanced dopamine uptake following SPS is consistent with the increase in dopamine transporter density observed in the nucleus accumbens of SPS rats. Activation of D1 receptors and G-protein mediated transduction was assessed using an adenylyl cyclase assay with the D1 agonist SKF82958. In the caudate putamen, a significant decrease in D1 receptor-stimulated cAMP production was revealed in SPS rats compared to controls, whereas SKF82958-induced cAMP was unchanged in the nucleus accumbens. Finally, the function of D2 dopamine receptors was assessed by D2 receptor-stimulated [35S]GTPγS binding using quinpirole. In the caudate putamen, [35S]GTPγS binding following stimulation of D2 receptors was enhanced by SPS compared to control handling, whereas no difference was observed between groups in the nucleus accumbens. These results indicate increased D2 receptor-mediated activation of G-proteins in the caudate putamen following SPS. In summary, the studies described herein tested the hypothesis that reduced dopaminergic function may be a mechanism for deficient reward and heightened susceptibility to drug use in PTSD. Results demonstrated a significant reduction in cocaine-conditioned reward, as well as attenuated sucrose preference and spontaneous activity in rats exposed to SPS. These findings are consistent with the presence of a dysfunctional reward system which may contribute to anhedonia-like behavior in PTSD. Furthermore, reward deficits may promote altered patterns of cocaine taking behavior and vulnerability to substance abuse. Results demonstrated significant escalation of drug intake following exposure to SPS, which occurred in the presence of less cocaine than controls. A greater increase in cocaine intake was observed in SPS rats over the course of escalation, which may reflect a mechanism for enhanced vulnerability to the development of a substance use disorder in PTSD. Dopaminergic dysfunction may contribute to deficient reward capacity and an altered pattern of cocaine intake in SPS. SPS-induced alterations in dopamine function included a reduction in striatal dopamine content alongside enhanced dopamine transporter levels and function. Mild alterations in D2 receptor density and the function of D1 and D2 receptors were also observed. These findings support the hypothesis that PTSD results in reduced dopaminergic neurotransmission, which may contribute to deficient reward function and altered drug-seeking behavior. Identifying the pathology of PTSD, such as altered dopamine neurotransmission, may lead to enhanced treatment strategies and interventions to prevent substance abuse in persons with PTSD. / Pharmacology

Abuse of psychostimulants including cocaine and new synthetic formulations remains an international public health problem and economic burden. Addiction develops consequential to positive and negative drives that underlie “getting” and “staying” high. Dopamine (DA), arising from ventral tegmental area (VTA), projects to ventral striatal targets to encode reward signals and reward prediction. Mesolimbic DA is implicated in both the immediate rewarding effects of psychostimulants, and its hypoactivity underlies negative affect as drug levels decline. Accordingly, modulating inputs to midbrain DA possesses capacity to mediate positive/rewarding and negative/aversive effects of drugs. Hypocretin/orexin (hcrt/ox) is a family of excitatory hypothalamic peptides that projects widely throughout the central nervous system including to VTA DA cells, and hcrt/ox mediates brain reward function and motivation for self-administered drugs. Notably, the first-in-class hcrt/ox receptor antagonist (suvorexant) was approved for management of insomnia in the summer of 2014. Also within the past decade, the caudal division of VTA (termed “tail of VTA” and “rostromedial tegmental nucleus [RMTg]”) was detailed for its ability to negatively regulate VTA DA. Functionally, stimulation of the GABA-producing RMTg population encodes aversion and responds to aversive cues. Curiously, anatomy work depicts the hypothalamus as a principal input to the RMTg although the cellular phenotypes and functions of hypothalamic projections to RMTg have not been fully resolved. Work in this thesis was designed to map hcrt/ox projections to VTA and RMTg in effort to understand functionally-relevant topographical arrangement. In preliminary assessments, we test for the first time the ability of suvorexant to modulate reward and reinforcement associated with psychostimulant use in rats. Additionally, we profile how self-administered cocaine and “bath salt” synthetic cathinone 3,4-methylenedioxypyrovalerone (MDPV) influence affective states in rats by measuring ultrasonic vocalizations (USVs) and comparing patterns of responding. Subsequently, we test the ability of suvorexant to influence MDPV-taking and affective changes that promote self-administration. Finally, we utilize direct-site pharmacology to assess the degree to which hcrt/ox transmission within VTA and RMTg contributes to motivated responding for and affective processing of self-administered cocaine across two doses. Specifically, we hypothesized that intra-VTA suvorexant would suppress drug-taking by reducing the rewarding value of self-administered cocaine, whereas intra-RMTg hcrt/ox peptide injection would suppress drug-taking by increasing aversive value of self-administered cocaine. We observed that systemic suvorexant effectively reduces motivated cocaine-taking, and that this reduction relates in part to reductions in subjective reward of self-administered cocaine as interpreted by reductions in positively-valenced 50-kHz USVs. Retrograde tracing supports that hcrt/ox projects to both VTA and RMTg without discernible topographical arrangement. Target-site pharmacology finds that intra-VTA suvorexant has no appreciable effects on motivated cocaine-taking but tends to elevate 50-kHz USVs during the pre-drug “anticipation” time epoch in low-dose cocaine self-administering rats (0.375 mg/kg/inf). While intra-RMTg hcrt/ox pre-treatment sparsely affected USVs, 0.3 nmol/hemisphere hcrt/ox significantly enhanced cocaine-taking in low-dose cocaine self-administering rats, and, in high-dose (0.750 mg/kg/inf) cocaine self-administering rats, intra-RMTg hcrt/ox significantly suppressed responding when pre-treated with 1.0 and 3.0 nmol/hemisphere. Collectively, studies within this thesis promote the use of hcrt/ox receptor antagonists as adjunct pharmacotherapy in managing psychostimulant use disorders, although the circuitries through which aberrant motivated behaviors are modulated are not entirely clear. Future work will need to be performed to understand how hcrt/ox transmits to neurochemically-defined cell populations residing within VTA and RMTg—these pathways are recruited for processing stimuli as “rewarding” and “aversive” which are critical contributors in the development of substance use disorders and other psychiatric disorders characterized by dysregulated reward processing. / Biomedical Sciences

Mobile electronic devices such as smartphones are playing an increasingly pervasive role in our daily activities. A growing body of literature is beginning to investigate how mobile technology habits might relate to individual differences in cognitive traits. The present study is an investigation into how individual differences in intertemporal preference, impulse control, and reward sensitivity, are predictive of the degree to which people engage with their smartphones, in two separate experiments. Experiment 1 utilized behavioral and self-reported measures for each of the aforementioned cognitive traits to examine their relationships with Mobile Technology Engagement (MTE) as defined in Wilmer & Chein (2016). The results replicated earlier work demonstrating that mobile technology engagement is positively correlated with a tendency to discount delayed rewards. A positive relationship was also observed between MTE and reward sensitivity. In an attempt to investigate the neural origins of the relationship observed in Experiment 1, Experiment 2 examined the association between mobile technology usage and white matter connectivity from the ventral striatum (vSTR) to the ventromedial prefrontal cortex (vmPFC) and dorsolateral prefrontal cortex (dlPFC), pathways that have been previously implicated as biological markers for individual differences in intertemporal preference. Regression analyses revealed that both pathways predicted delay discounting performance, but only vSTR-vmPFC predicted mobile technology engagement. Taken together, the results of these two experiments provide important foundational evidence for both neural and cognitive factors that predict how individuals engage with mobile technology. / Psychology

The overall research objective was to identify the effects of reward systems (rewards and a penalty) on risk-taking behavior and performance (quality and time) of construction workers from different cultures (American, Asian, and Latin American cultures). This research used the sociotechnical system as the underlying, guiding scientific framework. The research found that Americans and Latin Americans had higher risk-taking behavior than Asians (p<0.01). No difference in risk-taking behavior was found between Americans and Latin Americans (p<0.05). Although culture may influence individuals' risk-taking behavior, the results from this study showed that risk-taking behavior could be altered and suppressed by providing individuals with the proper safety training, education, and safety equipment. Customized safety training for people from different cultures would be useful because the culture elements that contribute to high risk-taking behavior could be addressed. The results also showed that the effects of reward systems on risk-taking behavior were not statistically significant (p>0.1). One possibility that no difference was found may be because the tasks used in this study did not contain enough possibility for participants to take more risk. The effects of reward systems on risk-taking behavior may have been reduced by the low possibility of risky behavior. It is suspected that if the tasks contained more opportunities for participants to take risk, differences in risk-taking behavior would have been significant. The researcher concluded that risk perception is situation-specific and has an influence on the individual's risk-taking behavior on that particular situation but cannot be used to predict risk-taking behavior. Also, general locus of control and general self-efficacy cannot be used to predict risk-taking behaviors. These findings are consistent with many studies that explore locus of control (Iversen & Rundmo, 2002; Rolison & Scherman 2002; Crisp & Barber, 1995), and many researchers that suggested self-efficacy is situation specific (Murdock et al., 2005; Martin et al., 1995; Perraud, 2000; Slanger & Rudestam, 1997). This study also found no relationship between risk-taking behavior and productivity, for both time and quality. / Ph. D.

We develop and analyze a class of CAC algorithms for resource management in wireless networks with the goal not only to satisfy QoS constraints, but also to maximize a value or reward objective function specified by the system. We demonstrate through analytical modeling and simulation validation that the CAC algorithms developed in this research for resource management can greatly improve the system reward obtainable with QoS guarantees, when compared with existing CAC algorithms designed for QoS satisfaction only. We design hybrid partitioning-threshold, spillover and elastic CAC algorithms based on the design techniques of partitioning, setting thresholds and probabilistic call acceptance to use channel resources for servicing distinct QoS classes. For each CAC algorithm developed, we identify optimal resource management policies in terms of partitioning or threshold settings to use channel resources. By comparing these CAC algorithms head-to-head under identical conditions, we determine the best algorithm to be used at runtime to maximize system reward with QoS guarantees for servicing multiple service classes in wireless networks. We study solution correctness, solution optimality and solution efficiency of the class of CAC algorithms developed. We ensure solution optimality by comparing optimal solutions achieved with those obtained by ideal CAC algorithms via exhaustive search. We study solution efficiency properties by performing complexity analyses and ensure solution correctness by simulation validation based on real human mobility data. Further, we analyze the tradeoff between solution optimality vs. solution efficiency and suggest the best CAC algorithm used to best tradeoff solution optimality for solution efficiency, or vice versa, to satisfy the system's solution requirements. Moreover, we develop design principles that remain applicable despite rapidly evolving wireless network technologies since they can be generalized to deal with management of 'resources' (e.g., wireless channel bandwidth), 'cells' (e.g., cellular networks), "connections" (e.g., service calls with QoS constraints), and "reward optimization" (e.g., revenue optimization in optimal pricing determination) for future wireless service networks. To apply the CAC algorithms developed, we propose an application framework consisting of three stages: workload characterization, call admission control, and application deployment. We demonstrate the applicability with the optimal pricing determination application and the intelligent switch routing application. / Ph. D.

The purpose of this study was to examine the relationship between rewards, locus of control and ideational fluency. Forty-three preschool children were initially administered the Revised Peabody Picture Vocabulary Test and the Preschool and Primary Nowicki-Strickland Internal-External Scale. Based on a median split of the locus of control measure, the children were assigned to either a reward or non-reward condition for the second session. In session two the children were administered two ideational fluency tasks, unusual uses and pattern meanings, under the assigned condition. Four separate 2 (external, internal) x 2 (reward, nonreward) analysis of variance were conducted for four ideational fluency scores (popular, original, total fluency and flexibility scores). No significant effects were found in any of the analyses. However, mean differences suggest that rewards limit ideational fluency while internal locus of-control was related to originality. / Master of Science

Yes / The remarkable evolution in the twentieth century has been a result of a new perspective in understanding the importance of investing in individuals and organizational human resources, and the implementation of capacity building strategies in various organizations and in societies. This paper explores the case of ICO, an international consultancy organization, based in the Middle East, specialized in architecture, engineering, planning, environment and economics. This qualitative study, using thirteen selected semi-structured interviews, observations, and secondary data, has been conducted in the Beirut design office of the organization. The paper aims to examine major human resource related capacity building themes in ICO which include employee involvement and motivation, recruitment and selection, in addition to performance appraisal and reward management.