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1.  The problem with value 
Neural correlates of value have been extensively reported in a diverse set of brain regions. However, in many cases it is difficult to determine whether a particular neural response pattern corresponds to a value-signal per se as opposed to an array of alternative non-value related processes, such as outcome-identity coding, informational coding, encoding of autonomic and skeletomotor consequences, alongside previously described “salience” or “attentional” effects. Here, I review a number of experimental manipulations that can be used to test for value, and I identify the challenges in ascertaining whether a particular neural response is or is not a value signal. Finally, I emphasize that some non-value related signals may be especially informative as a means of providing insight into the nature of the decision-making related computations that are being implemented in a particular brain region.
doi:10.1016/j.neubiorev.2014.03.027
PMCID: PMC4332826  PMID: 24726573
Reward; neuroeconomics; decision-making; learning
2.  [No title available] 
PMCID: PMC3944001  PMID: 24374383
3.  Inflammation and the Two-Hit Hypothesis of Schizophrenia 
The high societal and individual cost of schizophrenia necessitates finding better, more effective treatment, diagnosis, and prevention strategies. One of the obstacles in this endeavor is the diverse set of etiologies that comprises schizophrenia. A substantial body of evidence has grown over the last few decades to suggest that schizophrenia is a heterogeneous syndrome with overlapping symptoms and etiologies. At the same time, an increasing number of clinical, epidemiological, and experimental studies have shown links between schizophrenia and inflammatory conditions. In this review, we analyze the literature on inflammation and schizophrenia, with a particular focus on comorbidity, biomarkers, and environmental insults. We then identify several mechanisms by which inflammation could influence the development of schizophrenia via the two-hit hypothesis. Lastly, we note the relevance of these findings to clinical applications in the diagnosis, prevention, and treatment of schizophrenia.
doi:10.1016/j.neubiorev.2013.11.006
PMCID: PMC3896922  PMID: 24247023
Schizophrenia; Inflammation; Infection; Biomarkers; Comorbidity; Animal Models
5.  Ventral–striatal responsiveness during reward anticipation in ADHD and its relation to trait impulsivity in the healthy population: A meta-analytic review of the fMRI literature 
A review of the existing functional magnetic resonance imaging (fMRI) studies on reward anticipation in patients with attention-deficit/hyperactivity disorder (ADHD) is provided. Meta-analysis showed a significant medium effect size (Cohen’s d = 0.48–0.58) in terms of ventral–striatal (VS)-hyporesponsiveness in ADHD.
Studies on VS-responsiveness and trait impulsivity in the healthy population demonstrate the opposite relationship, i.e. impulsivity-scores positively correlated with VS activation during reward processing.
Against the background that ADHD may represent an extreme on a continuum of normal variability, the question arises as to how these contrasting findings can be integrated. We discuss three theoretical approaches, each of which integrates the opposing findings: (1) an inverted-u-shape model; (2) a (genetic) moderator model; and (3) the “unrelated model”. We conclude that at the present stage the number of existing studies in the healthy population as well as in ADHD groups is too small for a final answer. Therefore, our presented integrative approaches should be understood as an attempt to frame future research directions by generating testable hypotheses and giving practical suggestions for future studies.
doi:10.1016/j.neubiorev.2013.07.012
PMCID: PMC3989497  PMID: 23928090
ADHD; Impulsivity; Ventral–striatal hypoactivation; Hyporesponsiveness; Ventral striatum; Reward
6.  Intellectual Disability and Autism Spectrum Disorders: Causal Genes and Molecular Mechanisms 
Intellectual disability (ID) and Autism Spectrum disorder (ASD) are the most common developmental disorders present in humans. Combined, they affect between 3-5% of the population. Additionally, they can be found together in the same individual thereby complicating treatment.
The causative factors (genes, epigenetic and environmental) are quite varied and likely interact so as to further complicate the assessment of an individual patient. Nonetheless, much valuable information has been gained by identifying candidate genes for ID or ASD. Understanding the etiology of either ID or ASD is of utmost importance for families. It allows a determination of the risk of recurrence, the possibility of other comorbidity medical problems, the molecular and cellular nature of the pathobiology and hopefully potential therapeutic approaches.
doi:10.1016/j.neubiorev.2014.02.015
PMCID: PMC4185273  PMID: 24709068
Intellectual Disability; Autism Spectrum Disorders; Synaptic plasticity; Neurodevelopmental disorder; Molecular pathways
7.  Innovative solutions to novel drug development in mental health 
Neuroscience and biobehavioral reviews  2013;37(10 0 1):10.1016/j.neubiorev.2013.03.022.
There are many new advances in neuroscience and mental health which should lead to a greater understanding of the neurobiological dysfunction in neuropsychiatric disorders and new developments for early, effective treatments. To do this, a biomarker approach combining genetic, neuroimaging, cognitive and other biological measures is needed. The aim of this article is to highlight novel approaches for pharmacological and non-pharmacological treatment development. This article suggests approaches that can be taken in the future including novel mechanisms with preliminary clinical validation to provide a toolbox for mechanistic studies and also examples of translation and back-translation. The review also emphasizes the need for clinician-scientists to be trained in a novel way in order to equip them with the conceptual and experimental techniques required, and emphasizes the need for private-public partnership and pre-competitive knowledge exchange. This should lead the way for important new holistic treatment developments to improve cognition, functional outcome and well-being of people with neuropsychiatric disorders.
doi:10.1016/j.neubiorev.2013.03.022
PMCID: PMC3788850  PMID: 23563062
translation; back-translation; pharmacological tool box; cognitive and psychosocial treatments; novel drug development; biomarkers; neurobiological mechanisms; neuropsychiatric disorders
8.  Age, Plasticity, and Homeostasis In Childhood Brain Disorders 
Neuroscience and biobehavioral reviews  2013;37(10 0 2):10.1016/j.neubiorev.2013.09.010.
It has been widely accepted that the younger the age and/or immaturity of the organism, the greater the brain plasticity, the young age plasticity privilege. This paper examines the relation of a young age to plasticity, reviewing human pediatric brain disorders, as well as selected animal models, human developmental and adult brain disorder studies. As well, we review developmental and childhood acquired disorders that involve a failure of regulatory homeostasis. Our core arguments are: Plasticity is neutral with respect to outcome. Although the effects of plasticity are often beneficial, the outcome of plasticity may be adaptive or maladaptive.The young age plasticity privilege has been overstated.Plastic change operates in concert with homeostatic mechanisms regulating change at every point in the lifespan.The same mechanisms that propel developmental change expose the immature brain to adverse events, making it more difficult for the immature than for the mature brain to sustain equilibrium between plasticity and homeostasis.Poor outcome in many neurodevelopmental disorders and childhood acquired brain insults is related to disequilibrium between plasticity and homeostasis.
doi:10.1016/j.neubiorev.2013.09.010
PMCID: PMC3859812  PMID: 24096190
Plasticity; homeostasis; neurodevelopmental disorders; childhood-acquired brain damage; age at brain injury; time since brain injury
9.  Common and distinct neural targets of treatment: changing brain function in substance addiction 
Neuroscience and biobehavioral reviews  2013;37(10 0 2):10.1016/j.neubiorev.2013.10.002.
Neuroimaging offers an opportunity to examine the neurobiological effects of therapeutic interventions for human drug addiction. Using activation likelihood estimation, the aim of the current meta-analysis was to quantitatively summarize functional neuroimaging studies of pharmacological and cognitive-based interventions for drug addiction, with an emphasis on their common and distinct neural targets. More exploratory analyses also contrasted subgroups of studies based on specific study and sample characteristics. The ventral striatum, a region implicated in reward, motivation, and craving, and the inferior frontal gyrus and orbitofrontal cortex, regions involved in inhibitory control goal-directed behavior, were identified as common targets of pharmacological and cognitive-based interventions; these regions were observed when the analysis was limited to only studies that used established or efficacious interventions, and across imaging paradigms and types of addictions. Consistent with theoretical models, cognitive-based interventions were additionally more likely to activate the anterior cingulate cortex, middle frontal gyrus, and precuneus, implicated in self-referential processing, cognitive control, and attention. These results suggest that therapeutic interventions for addiction may target the brain structures that are altered across addictions and identify potential neurobiological mechanisms by which the tandem use of pharmacological and cognitive-based interventions may yield synergistic or complementary effects. These findings could inform the selection of novel functional targets in future treatment development for this difficult-to-treat disorder.
doi:10.1016/j.neubiorev.2013.10.002
PMCID: PMC3859814  PMID: 24140399
addiction; therapeutic intervention; pharmacotherapy; pharmacological challenge; cognitive-behavioral therapy; craving regulation; functional neuroimaging; functional magnetic resonance imaging (fMRI); Positron emission tomography (PET); activation likelihood estimation (ALE) meta-analysis
10.  Critical Involvement of the Motor Cortex in the Pathophysiology and Treatment of Parkinson’s Disease 
Neuroscience and biobehavioral reviews  2013;37(10 0 2):10.1016/j.neubiorev.2013.09.008.
This review examines the involvement of the motor cortex in Parkinson’s disease (PD), a debilitating movement disorder typified by degeneration of dopamine cells of the substantia nigra. While much of PD research has focused on the caudate/putamen, many aspects of motor cortex function are abnormal in PD patients and in animal models of PD, implicating motor cortex involvement in disease symptoms and their treatment. Herein, we discuss several lines of evidence to support this hypothesis. Dopamine depletion alters regional metabolism in the motor cortex and also reduces interneuron activity, causing a breakdown in intracortical inhibition. This leads to functional reorganization of motor maps and excessive corticostriatal synchrony when movement is initiated. Recent work suggests that electrical stimulation of the motor cortex provides a clinical benefit for PD patients. Based on extant research, we identify a number of unanswered questions regarding the motor cortex in PD and argue that a better understanding of the contribution of the motor cortex to PD symptoms will facilitate the development of novel therapeutic approaches.
doi:10.1016/j.neubiorev.2013.09.008
PMCID: PMC3859864  PMID: 24113323
Parkinson’s Disease; Motor Cortex; Supplementary Motor Area; Premotor Cortex; Dopamine; Functional Imaging; Transcranial Magnetic Stimulation; Deep Brain Stimulation; Plasticity
11.  Cognitive Unbinding: A Neuroscientific Paradigm of General Anesthesia and Related States of Unconsciousness 
Neuroscience and biobehavioral reviews  2013;37(10 0 2):10.1016/j.neubiorev.2013.09.009.
“Cognitive unbinding” refers to the impaired synthesis of specialized cognitive activities in the brain and has been proposed as a mechanistic paradigm of unconsciousness. This article draws on recent neuroscientific data to revisit the tenets and predictions of cognitive unbinding, using general anesthesia as a representative state of unconsciousness. Current evidence from neuroimaging and neurophysiology supports the proposition that cognitive unbinding is a parsimonious explanation for the direct mechanism (or “proximate cause”) of anesthetic-induced unconsciousness across multiple drug classes. The relevance of cognitive unbinding to sleep, disorders of consciousness, and psychological processes is also explored. It is concluded that cognitive unbinding is a viable neuroscientific framework for unconscious processes across the fields of anesthesiology, sleep neurobiology, neurology and psychoanalysis.
doi:10.1016/j.neubiorev.2013.09.009
PMCID: PMC3870022  PMID: 24076246
consciousness; unconsciousness; cognitive binding; cognitive unbinding; information integration; anesthesia; vegetative state; sleep; psychoanalysis
12.  Foreign language training as cognitive therapy for age-related cognitive decline: A hypothesis for future research 
Neuroscience and biobehavioral reviews  2013;37(10 0 2):2689-2698.
Over the next fifty years, the number of older adults is set to reach record levels. Protecting older adults from the age-related effects of cognitive decline is one of the greatest challenges of the next few decades as it places increasing pressure on families, health systems, and economies on a global scale. The disease-state of age-related cognitive decline—Alzheimer's disease and other dementias—hijacks our consciousness and intellectual autonomy. However, there is evidence that cognitively stimulating activities protect against the adverse effects of cognitive decline. Similarly, bilingualism is also considered to be a safeguard. We propose that foreign language learning programs aimed at older populations are an optimal solution for building cognitive reserve because language learning engages an extensive brain network that is known to overlap with the regions negatively affected by the aging process. It is recommended that future research should test this potentially fruitful hypothesis.
doi:10.1016/j.neubiorev.2013.09.004
PMCID: PMC3890428  PMID: 24051310
aging; language learning; cognitive decline; cognitive reserve; training
13.  The Downward Spiral of Chronic Pain, Prescription Opioid Misuse, and Addiction: Cognitive, Affective, and Neuropsychopharmacologic Pathways 
Neuroscience and biobehavioral reviews  2013;37(10 0 2):2597-2607.
Prescription opioid misuse and addiction among chronic pain patients are emerging public health concerns of considerable significance. Estimates suggest that more than 10% of chronic pain patients misuse opioid analgesics, and the number of fatalities related to nonmedical or inappropriate use of prescription opioids is climbing. Because the prevalence and adverse consequences of this threat are increasing, there is a pressing need for research that identifies the biobehavioral risk chain linking chronic pain, opioid analgesia, and addictive behaviors. To that end, the current manuscript draws upon current neuropsychopharmacologic research to provide a conceptual framework of the downward spiral leading to prescription opioid misuse and addiction among chronic pain patients receiving opioid analgesic pharmacotherapy. Addictive use of opioids is described as the outcome of a cycle initiated by chronic pain and negative affect and reinforced by opioidergic-dopamingeric interactions, leading to attentional hypervigilance for pain and drug cues, dysfunctional connectivity between self-referential and cognitive control networks in the brain, and allostatic dysregulation of stress and reward circuitry. Implications for clinical practice are discussed; multimodal, mindfulness-oriented treatment is introduced as a potentially effective approach to disrupting the downward spiral and facilitating recovery from chronic pain and opioid addiction.
doi:10.1016/j.neubiorev.2013.08.006
PMCID: PMC3967721  PMID: 23988582
chronic pain; opioid misuse; addiction; allostasis; reward; attentional bias; default mode; mindfulness
14.  Measuring reinforcement learning and motivation constructs in experimental animals: relevance to the negative symptoms of schizophrenia 
Neuroscience and biobehavioral reviews  2013;37(9 0 0):10.1016/j.neubiorev.2013.08.007.
The present review article summarizes and expands upon the discussions that were initiated during a meeting of the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS; http://cntrics.ucdavis.edu). A major goal of the CNTRICS meeting was to identify experimental procedures and measures that can be used in laboratory animals to assess psychological constructs that are related to the psychopathology of schizophrenia. The issues discussed in this review reflect the deliberations of the Motivation Working Group of the CNTRICS meeting, which included most of the authors of this article as well as additional participants. After receiving task nominations from the general research community, this working group was asked to identify experimental procedures in laboratory animals that can assess aspects of reinforcement learning and motivation that may be relevant for research on the negative symptoms of schizophrenia, as well as other disorders characterized by deficits in reinforcement learning and motivation. The tasks described here that assess reinforcement learning are the Autoshaping Task, Probabilistic Reward Learning Tasks, and the Response Bias Probabilistic Reward Task. The tasks described here that assess motivation are Outcome Devaluation and Contingency Degradation Tasks and Effort-Based Tasks. In addition to describing such methods and procedures, the present article provides a working vocabulary for research and theory in this field, as well as an industry perspective about how such tasks may be used in drug discovery. It is hoped that this review can aid investigators who are conducting research in this complex area, promote translational studies by highlighting shared research goals and fostering a common vocabulary across basic and clinical fields, and facilitate the development of medications for the treatment of symptoms mediated by reinforcement learning and motivational deficits.
doi:10.1016/j.neubiorev.2013.08.007
PMCID: PMC3849135  PMID: 23994273
reinforcement; reward; motivation; learning; cognition
15.  Animal models and measures of perceptual processing in Schizophrenia 
Neuroscience and biobehavioral reviews  2013;37(9 0 0):10.1016/j.neubiorev.2013.06.016.
This paper summarizes the discussions regarding animal paradigms for assessing perception at the seventh meeting of the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS). A breakout group at the meeting addressed candidate tests in animals that might best parallel the human paradigms selected previously in the CNTRICS program to assess two constructs in the domain of perception: gain control and visual integration. The perception breakout group evaluated the degree to which each of the nominated tasks met pre-specified criteria: comparability of tasks across multiple species; construct validity; neuroanatomical homology between species; and dynamic range across parametric variation.
doi:10.1016/j.neubiorev.2013.06.016
PMCID: PMC3849201  PMID: 23867801
Prepulse inhibition of startle; Event related potentials; Mismatch negative; Visual integration
16.  Individual variation in resisting temptation: implications for addiction 
Neuroscience and biobehavioral reviews  2013;37(0):10.1016/j.neubiorev.2013.02.008.
When exposed to the sights, sounds, smells and/or places that have been associated with rewards, such as food or drugs, some individuals have difficulty resisting the temptation to seek out and consume them. Others have less difficulty restraining themselves. Thus, Pavlovian reward cues may motivate maladaptive patterns of behavior to a greater extent in some individuals than in others. We are just beginning to understand the factors underlying individual differences in the extent to which reward cues acquire powerful motivational properties, and therefore, the ability to act as incentive stimuli. Here we review converging evidence from studies in both human and non-human animals suggesting that a subset of individuals are more “cue reactive”, in that certain reward cues are more likely to attract these individuals to them and motivate actions to get them. We suggest that those individuals for whom Pavlovian reward cues become especially powerful incentives may be more vulnerable to impulse control disorders, such as binge eating and addiction.
doi:10.1016/j.neubiorev.2013.02.008
PMCID: PMC3732519  PMID: 23438893
rat; human; sign-tracking; goal-tracking; addiction; binge eating; obesity; motivation; dopamine; individual differences; learning; accumbens; Pavlovian; relapse
17.  Adjusting Behavior to Changing Environmental Demands with Development 
Neuroscience and biobehavioral reviews  2013;37(9 0 0):10.1016/j.neubiorev.2013.03.003.
Plasticity refers to changes in the brain that enable an organism to adapt its behavior in the face of changing environmental demands. The evolutionary role of plasticity is to provide the cognitive flexibility to learn from experiences, to monitor the world based on learned predictions, and adjust actions when these predictions are violated. Both progressive (myelination) and regressive (synaptic pruning) brain changes support this type of adaptation. Experience-driven changes in neural connections underlie the ability to learn and update thoughts and behaviors throughout life. Many cognitive and behavioral indices exhibit nonlinear life-span trajectories, suggesting the existence of specific sensitive developmental periods of heightened plasticity. We propose that age-related differences in learning capabilities and behavioral performance reflect the distinct maturational timetable of subcortical learning systems and modulatory prefrontal regions. We focus specifically on the developmental transition of adolescence, during which individuals experience difficulty flexibly adjusting their behavior when confronted with unexpected and emotionally salient events. In this article, we review the findings illustrating this phenomenon and how they vary by individual.
doi:10.1016/j.neubiorev.2013.03.003
PMCID: PMC3751996  PMID: 23518271
adolescence; development; individual differences; learning; plasticity; reward; self-control
18.  Conflation of Cocaine Seeking and Cocaine Taking Responses in IV Self-administration Experiments in Rats: Methodological and Interpretational Considerations 
Neuroscience and biobehavioral reviews  2013;37(0):10.1016/j.neubiorev.2013.04.017.
IV drug self-administration is a special case of an operant task. In most operant experiments, the instrumental response that completes the schedule requirement is separate and distinct from the consumptive response (e.g. eating or drinking) that follows the delivery of the reinforcing stimulus. In most IV self-administration studies drug seeking and drug taking responses are conflated. The instrumental lever press or nose poke is also a consumptive response. The conflation of these two response classes has important implications for interpretation of the data as they are differentially regulated by dose and price. The types of pharmacological pretreatments that affect appetitive responses are not necessarily the same as those that affect consumptive responses suggesting that the neurobiology of the two response classes are to some extent controlled by different mechanisms. This review discusses how schedules of reinforcement and behavioral economic analyses can be used to assess the regulation of drug seeking and drug taking separately. New methods are described that allow the examination of appetitive or consumptive responding in isolation and provide subjects with greater control over the self-administered dose. These procedures provide novel insights into the regulation of drug intake. Cocaine intake patterns that result in large, intermittent spikes in cocaine levels are shown to produce increases in appetitive responding (i.e. drug seeking). The mechanisms that control drug intake should be considered distinct from appetitive and motivational processes and should be taken into consideration in future IV self-administration studies.
doi:10.1016/j.neubiorev.2013.04.017
PMCID: PMC3838507  PMID: 23669047
cocaine; self-administration; addiction; consummatory behavior; appetitive behavior; drug seeking; drug taking; schedules of reinforcement; motivation; reward
19.  CNTRICS final animal model task selection: Control of attention 
Neuroscience and biobehavioral reviews  2012;37(9 0 0):10.1016/j.neubiorev.2012.05.009.
Schizophrenia is associated with impaired attention. The top-down control of attention, defined as the ability to guide and refocus attention in accordance with internal goals and representations, was identified by the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) initiative as an important construct for task development and research. A recent CNTRICS meeting identified three tasks commonly used with rodent models as having high construct validity and promise for further development: The 5-choice serial reaction time task, the 5-choice continuous performance task, and the distractor condition sustained attention task. Here we describe their current status, including data on their neural substrates, evidence for sensitivity to neuropharmacological manipulations and genetic influences, and data from animal models of the cognitive deficits of schizophrenia. A common strength is the development of parallel human tasks to facilitate connections to the neural circuitry and drug development research done in these animal models. We conclude with recommendations for the steps needed to improve testing so that it better represents the complex biological and behavioral picture presented by schizophrenia.
doi:10.1016/j.neubiorev.2012.05.009
PMCID: PMC3490036  PMID: 22683929
CNTRICS; attention; schizophrenia; top-down attention; cognitive control; 5CSRTT; 5C-CPT; dSAT
20.  Consideration of species differences in developing novel molecules as cognition enhancers 
Neuroscience and biobehavioral reviews  2012;37(9 0 0):10.1016/j.neubiorev.2012.10.002.
The NIH-funded CNTRICS initiative has coordinated efforts to promote the vertical translation of novel procognitive molecules from testing in mice, rats and non-human primates, to clinical efficacy in patients with schizophrenia. CNTRICS highlighted improving construct validation of tasks across species to increase the likelihood that the translation of a candidate molecule to humans will be successful. Other aspects of cross-species behaviors remain important however. This review describes cognitive tasks utilized across species, providing examples of differences and similarities of innate behavior between species, as well as convergent construct and predictive validity. Tests of attention, olfactory discrimination, reversal learning, and paired associate learning are discussed. Moreover, information on the practical implication of species differences in drug development research is also provided. The issues covered here will aid in task development and utilization across species as well as reinforcing the positive role preclinical research can have in developing procognitive treatments for psychiatric disorders.
doi:10.1016/j.neubiorev.2012.10.002
PMCID: PMC3594426  PMID: 23064177
Species; differences; mice; rats; non-human primates; monkeys; human primates; CNTRICS; cognitive; attention; reversal learning; impulsivity
21.  The contribution of brain reward circuits to the obesity epidemic 
Neuroscience and biobehavioral reviews  2012;37(0):10.1016/j.neubiorev.2012.12.001.
One of the defining characteristics of the research of Ann E. Kelley was her recognition that the neuroscience underlying basic learning and motivation processes also shed significant light upon mechanisms underlying drug addiction and maladaptive eating patterns. In this review, we examine the parallels that exist in the neural pathways that process both food and drug reward, as determined by recent studies in animal models and human neuroimaging experiments. We discuss contemporary research that suggests that hyperphagia leading to obesity is associated with substantial neurochemical changes in the brain. These findings verify the relevance of reward pathways for promoting consumption of palatable, calorically dense foods, and lead to the important question of whether changes in reward circuitry in response to intake of such foods serve a causal role in the development and maintenance of some cases of obesity. Finally, we discuss the potential value for future studies at the intersection of the obesity epidemic and the neuroscience of motivation, as well as the potential concerns that arise from viewing excessive food intake as an “addiction”. We suggest that it might be more useful to focus on overeating that results in frank obesity, and multiple health, interpersonal, and occupational negative consequences as a form of food “abuse”.
doi:10.1016/j.neubiorev.2012.12.001
PMCID: PMC3604128  PMID: 23237885
Obesity; feeding; reward; reinforcement; mesolimbic dopamine system; opioids; food addiction; drug addiction; food abuse
22.  Striatal ups and downs: Their roles in vulnerability to addictions in humans 
Neuroscience and biobehavioral reviews  2013;37(0):10.1016/j.neubiorev.2013.01.018.
Susceptibility to addictive behaviors has been related to both increases and decreases in striatal function. Both profiles have been reported in humans as well as in animal models. Yet, the mechanisms underlying these opposing effects and the manner in which they relate to the behavioral development and expression of addiction remain unclear. In the present review of human studies, we describe a number of factors that could influence whether striatal hyper- or hypo-function is observed and propose a model that integrates the influence of these opposite responses on the expression of addiction related behaviors. Central to this model is the role played by the presence versus absence of addiction related cues and their ability to regulate responding to abused drugs and other rewards. Striatal function and incentive motivational states are increased in the presence of these cues and decreased in their absence. Alternations between these states might account for the progressive narrowing of interests as addictions develop and point to relevant processes to target in treatment.
doi:10.1016/j.neubiorev.2013.01.018
PMCID: PMC3743927  PMID: 23333263
Basal ganglia; Conditioning; Dopamine; Drug addiction; Drug self-administration; Functional magnetic resonance imaging; Positron emission tomography; Sensitization; Striatum
23.  Using Conditioned Place Preference to Identify Relapse Prevention Medications 
Neuroscience and biobehavioral reviews  2013;37(0):10.1016/j.neubiorev.2013.05.002.
Stimuli, including contexts, which predict the availability or onset of a drug effect, can acquire conditioned incentive motivational properties. These conditioned properties endure after withdrawal, and can promote drug-seeking which may result in relapse. Conditioned place preference (CPP) assesses the associations between drugs and the context in which they are experienced. Here, we review the potential utility of CPP procedures in rodents and humans to evaluate medications that target conditioned drug-seeking responses. We discuss the translational potential of the CPP procedure from rodents to humans, and review findings with FDA-approved treatments that support the use of CPP to develop relapse-reduction medications. We also discuss challenges and methodological questions in applying the CPP procedure to this purpose. We argue that an efficient and valid CPP procedure in humans may reduce the burden of full clinical trials with drug-abusing patients that are currently required for testing promising treatments.
doi:10.1016/j.neubiorev.2013.05.002
PMCID: PMC3815959  PMID: 23680702
Conditioned place preference; amphetamine; methamphetamine; mirtazapine; baclofen; varenicline; naltrexone; addiction therapy; rodents; humans
24.  The clinical relevance of neuroplasticity in corticostriatal networks during operant learning 
Neuroscience and biobehavioral reviews  2013;37(0):10.1016/j.neubiorev.2013.03.019.
Dopamine and glutamate serve crucial functions in neural plasticity, learning and memory, and addiction. Contemporary theories contend that these two, widely-distributed neurotransmitter systems play an integrative role in motivational and associative information processing. Combined signaling of these systems, particularly through the dopamine (DA) D1 and glutamate (Glu) N-methyl-D-aspartate receptors (NMDAR), triggers critical intracellular signaling cascades that lead to changes in chromatin structure, gene expression, synaptic plasticity, and ultimately behavior. Addictive drugs also induce long-term neuroadaptations at the molecular and genomic levels causing structural changes that alter basic connectivity. Indeed, evidence that drugs of abuse engage D1- and NMDA-mediated neuronal cascades shared with normal reward learning provides one of the most important insights from contemporary studies on the neurobiology of addiction. Such drug-induced neuroadaptations likely contribute to abnormal information processing and behavior, resulting in the poor decision-making, loss of control, and compulsivity that characterize addiction. Such features are also common to many other neuropsychiatric disorders. Behavior problems, construed as difficulties associated with operant learning and behavior, present compelling challenges and unique opportunities for their treatment that require further study. The present review highlights the integrative work of Ann E. Kelley and colleagues, demonstrating a critical role not only for NMDAR, D1 receptors (D1R), and their associated signaling cascades, but also for other Glu receptors and protein synthesis in operant learning throughout a cortico-striatal-limbic network. Recent work has extended the impact of appetitive learning to epigenetic processes. A better understanding of these processes will likely assist in discovering therapeutics to engage neural plasticity-related processes and promote functional behavioral adaptations.
doi:10.1016/j.neubiorev.2013.03.019
PMCID: PMC3830626  PMID: 23567518
25.  Amygdalostriatal projections in the neurocircuitry for motivation: A neuroanatomical thread through the career of Ann Kelley 
Neuroscience and biobehavioral reviews  2012;37(0):10.1016/j.neubiorev.2012.11.019.
In MacLean’s triune brain, the amygdala putatively subserves motivated behavior by modulating the “reptilian” basal ganglia. Accordingly, Ann Kelley, with Domesick and Nauta, influentially showed that amygdalostriatal projections are much more extensive than were appreciated. Caudal of the anterior commissure, the entire striatum receives afferents from deep basal nuclei of the amygdala. They highlighted that amygdalar projections to the rostral ventromedial striatum converged with projections from the ventral tegmental area and cingulate cortex, forming a “limbic striatum”. Orthologous topographic projections subsequently were observed in fish, amphibians, and reptiles. Subsequent functional studies linked acquired value to action via this neuroanatomical substrate. From Dr. Kelley’s work evolved insights into components of the distributed, interconnected network that subserves motivated behavior, including the nucleus accumbens shell and core and the striatal-like extended amygdala macrostructure. These heuristic frameworks provide a neuroanatomical basis for adaptively translating motivation into behavior. The ancient amygdala-to-striatum pathways remain a current functional thread not only for stimulus–response valuation, but also for the psychopathological plasticity that underlies addictionrelated memory, craving and relapse.
doi:10.1016/j.neubiorev.2012.11.019
PMCID: PMC3838492  PMID: 23220696
Basolateral or medial or lateral or basomedial or central nucleus of the amygdala; Striatum; Extended amygdala; Bed nucleus of the stria terminalis; Nucleus accumbens; Caudate; Putamen; Afferent or efferent or projection or circuit; Incentive salience or motivation or reward; Pavlovian or classical or instrumental or operant conditioning; Addiction; Obesity

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