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1.  Neuroimaging of Parkinson’s Disease: Expanding views 
Advances in molecular and structural and functional neuroimaging are rapidly expanding the complexity of neurobiological understanding of Parkinson’s disease (PD). This review article begins with an introduction to PD neurobiology as a foundation for interpreting neuroimaging findings that may further lead to more integrated and comprehensive understanding of PD. Diverse areas of PD neuroimaging are then reviewed and summarized, including positron emission tomography, single photon emission computed tomography, magnetic resonance spectroscopy and imaging, transcranial sonography, magnetoencephalography, and multimodal imaging, with focus on human studies published over the last five years. These included studies on differential diagnosis, co-morbidity, genetic and prodromal PD, and treatments from L-DOPA to brain stimulation approaches, transplantation and gene therapies. Overall, neuroimaging has shown that PD is a neurodegenerative disorder involving many neurotransmitters, brain regions, structural and functional connections, and neurocognitive systems. A broad neurobiological understanding of PD will be essential for translational efforts to develop better treatments and preventive strategies. Many questions remain and we conclude with some suggestions for future directions of neuroimaging of PD.
doi:10.1016/j.neubiorev.2015.09.007
PMCID: PMC4763948  PMID: 26409344
Parkinson’s disease; Brain imaging; Neuroimaging; PET; SPECT; MRS; MRI; TCS; MEG; DTI; fMRI; Magnetic resonance imaging; Positron emission tomography; Diffusion tensor imaging; Functional connectivity
2.  Empathy: Gender effects in brain and behavior 
Neuroscience and biobehavioral reviews  2014;46(Pt 4):604-627.
Evidence suggests that there are differences in the capacity for empathy between males and females. However, how deep do these differences go? Stereotypically, females are portrayed as more nurturing and empathetic, while males are portrayed as less emotional and more cognitive. Some authors suggest that observed gender differences might be largely due to cultural expectations about gender roles. However, empathy has both evolutionary and developmental precursors, and can be studied using implicit measures, aspects that can help elucidate the respective roles of culture and biology. This article reviews evidence from ethology, social psychology, economics, and neuroscience to show that there are fundamental differences in implicit measures of empathy, with parallels in development and evolution. Studies in nonhuman animals and younger human populations (infants/children) offer converging evidence that sex differences in empathy have phylogenetic and ontogenetic roots in biology and are not merely cultural byproducts driven by socialization. We review how these differences may have arisen in response to males’ and females’ different roles throughout evolution. Examinations of the neurobiological underpinnings of empathy reveal important quantitative gender differences in the basic networks involved in affective and cognitive forms of empathy, as well as a qualitative divergence between the sexes in how emotional information is integrated to support decision making processes. Finally, the study of gender differences in empathy can be improved by designing studies with greater statistical power and considering variables implicit in gender (e.g., sexual preference, prenatal hormone exposure). These improvements may also help uncover the nature of neurodevelopmental and psychiatric disorders in which one sex is more vulnerable to compromised social competence associated with impaired empathy.
doi:10.1016/j.neubiorev.2014.09.001
PMCID: PMC5110041  PMID: 25236781
Ontogeny; Gender; Sex; Contagion; Mimicry; Prosocial; Helping; Emotion; Mirror neuron system; Development; Evolution
3.  Found in translation: understanding the biology and behavior of experimental traumatic brain injury 
BONDI, C.O., B.D. Semple, L.J. Noble-Haeusslein, N.D. Osier, S.W. Carlson, C.E. Dixon, C.C. Giza and A.E. Kline. Found in translation: understanding the biology and behavior of experimental traumatic brain injury. NEUROSCI BIOBEHAV REV. The aim of this review is to discuss in greater detail the topics covered in the recent symposium entitled “Traumatic brain injury: laboratory and clinical perspectives,” presented at the 2014 International Behavioral Neuroscience Society annual meeting. Herein we review contemporary laboratory models of traumatic brain injury (TBI) including common assays for sensorimotor and cognitive behavior. New modalities to evaluate social behavior after injury to the developing brain, as well as the attentional set-shifting test (AST) as a measure of executive function in TBI, will be highlighted. Environmental enrichment (EE) will be discussed as a preclinical model of neurorehabilitation, and finally, an evidence-based approach to sports-related concussion will be considered. The review consists predominantly of published data, but some discussion of ongoing or future directions is provided.
doi:10.1016/j.neubiorev.2014.12.004
PMCID: PMC4465064  PMID: 25496906
Attentional set-shifting test (AST); closed head injury; concussion; controlled cortical impact (CCI); environmental enrichment (EE); fluid percussion (FP); neurorehabilitation; pediatrics; social behavior
4.  Toward sophisiticated basal ganglia neuromodulation: review on basal gaglia deep brain stimulation 
This review presents state-of-the-art knowledge about the roles of the basal ganglia (BG) in action-selection, cognition, and motivation, and how this knowledge has been used to improve deep brain stimulation (DBS) treatment of neurological and psychiatric disorders. Such pathological conditions include Parkinson’s disease, Huntington’s disease, Tourette syndrome, depression, and obsessive-compulsive disorder. The first section presents evidence supporting current hypotheses of how the cortico-BG circuitry works to select motor and emotional actions, and how defects in this circuitry can cause symptoms of the BG diseases. Emphasis is given to the role of striatal dopamine on motor performance, motivated behaviors and learning of procedural memories. Next, the use of cutting-edge electrochemical techniques in animal and human studies of BG functioning under normal and disease conditions is discussed. Finally, functional neuroimaging studies are reviewed; these works have shown the relationship between cortico-BG structures activated during DBS and improvement of disease symptoms.
doi:10.1016/j.neubiorev.2015.02.003
PMCID: PMC4534367  PMID: 25684727
deep brain stimulation; striatum; subthalamic nucleus; globus pallidus; substantia nigra; electrochemistry; voltammetry; functional magnetic resonance imaging; pig; human
5.  Negative affective states and cognitive impairments in nicotine dependence 
Smokers have substantial individual differences in quit success in response to current treatments for nicotine dependence. This observation may suggest that different underlying motivations for continued tobacco use across individuals and nicotine cessation may require different treatments in different individuals. Although most animal models of nicotine dependence emphasize the positive reinforcing effects of nicotine as the major motivational force behind nicotine use, smokers generally report that other consequences of nicotine use, including the ability of nicotine to alleviate negative affective states or cognitive impairments, as reasons for continued smoking. These states could result from nicotine withdrawal, but also may be associated with premorbid differences in affective and/or cognitive function. Effects of nicotine on cognition and affect may alleviate these impairments regardless of their premorbid or postmorbid origin (e.g., before or after the development of nicotine dependence). The ability of nicotine to alleviate these symptoms would thus negatively reinforce behavior, and thus maintain subsequent nicotine use, contributing to the initiation of smoking, the progression to dependence and relapse during quit attempts. The human and animal studies reviewed here support the idea that self-medication for pre-morbid and withdrawal-induced impairments may be more important factors in nicotine addiction and relapse than has been previously appreciated in preclinical research into nicotine dependence. Given the diverse beneficial effects of nicotine under these conditions, individuals might smoke for quite different reasons. This review suggests that inter-individual differences in the diverse effects of nicotine associated with self-medication and negative reinforcement are an important consideration in studies attempting to understand the causes of nicotine addiction, as well as in the development of effective, individualized nicotine cessation treatments.
Graphical abstract
Affective and Cognitive impairments, either premorbid in origin, or associated with nicotine withdrawal (as described above) contribute to nicotine dependence. Greater consideration of these processes, and the potential role of negative reinforcement, needs to be incorporated into animal models of nicotine dependence.
doi:10.1016/j.neubiorev.2015.06.004
PMCID: PMC4670824  PMID: 26054790
Nicotine; negative affect; cognitive impairment; negative reinforcement
6.  Chronic stress and brain plasticity: mechanisms underlying adaptive and maladaptive changes and implications for stress-related CNS disorders 
Stress responses entail neuroendocrine, autonomic, and behavioral changes to promote effective coping with real or perceived threats to one’s safety. While these responses are critical for the survival of the individual, adverse effects of repeated exposure to stress are widely known to have deleterious effects on health. Thus, a considerable effort in the search for treatments to stress-related CNS disorders necessitates unraveling the brain mechanisms responsible for adaptation under acute conditions and their perturbations following chronic stress exposure. This paper is based upon a symposium from the 2014 International Behavioral Neuroscience Meeting, summarizing some recent advances in understanding the effects of stress on adaptive and maladaptive responses subserved by limbic forebrain networks. An important theme highlighted in this review is that the same networks mediating neuroendocrine, autonomic, and behavioral processes during adaptive coping also comprise targets of the effects of repeated stress exposure in the development of maladaptive states. Where possible, reference is made to the similarity of neurobiological substrates and effects observed following repeated exposure to stress in laboratory animals and the clinical features of stress-related disorders in humans.
doi:10.1016/j.neubiorev.2015.06.018
PMCID: PMC4684432  PMID: 26116544
7.  Investigating the underlying mechanisms of aberrant behaviors in bipolar disorder from patients to models 
Psychiatric patients with bipolar disorder suffer from states of depression and mania, during which a variety of symptoms are present. Current treatments are limited and neurocognitive deficits in particular often remain untreated. Targeted therapies based on the biological mechanisms of bipolar disorder could fill this gap and benefit patients and their families. Developing targeted therapies would benefit from appropriate animal models which are challenging to establish, but remain a vital tool. In this review, we summarize approaches to create a valid model relevant to bipolar disorder. We focus on studies that use translational tests of multivariate exploratory behavior, sensorimotor gating, decision-making under risk, and attentional functioning to discover profiles that are consistent between patients and rodent models. Using this battery of translational tests, similar behavior profiles in bipolar mania patients and mice with reduced dopamine transporter activity have been identified. Future investigations should combine other animal models that are biologically relevant to the neuropsychiatric disorder with translational behavioral assessment as outlined here. This methodology can be utilized to develop novel targeted therapies that relieve symptoms for more patients without common side effects caused by current treatments.
doi:10.1016/j.neubiorev.2015.08.008
PMCID: PMC4684462  PMID: 26297513
Bipolar disorder; translational; animal model; dopamine transporter
8.  Brains in the City: Neurobiological effects of urbanization 
With a majority of humans now living in cities, strategic research is necessary to elucidate the impact of this evolutionarily unfamiliar habitat on neural functions and well-being. In this review, both rodent and human models are considered in the evaluation of the changing physical and social landscapes associated with urban dwellings. Animal models assessing increased exposure to artificial physical elements characteristic of urban settings, as well as exposure to unnatural sources of light for extended durations, are reviewed. In both cases, increased biomarkers of mental illnesses such as major depression have been observed. Additionally, applied human research emphasizing the emotional impact of environmental threats associated with urban habitats is considered. Subjects evaluated in an inner-city hospital reveal the impact of combined specific genetic vulnerabilities and heightened stress responses in the expression of posttraumatic stress disorder. Finally, algorithm-based models of cities have been developed utilizing population-level analyses to identify risk factors for psychiatric illness. Although complex, the use of multiple research approaches, as described herein, results in an enhanced understanding of urbanization and its far-reaching effects--confirming the importance of continued research directed toward the identification of putative risk factors associated with psychiatric illness in urban settings.
doi:10.1016/j.neubiorev.2015.04.007
PMCID: PMC4774049  PMID: 25936504
Urbanization; Psychiatric illness; Natural environment; Light pollution; Depression; Socioeconomic Disadvantage; Intercity violence; PTSD; Self-efficacy; Collective Efficacy; Animal models; Agent-based models
9.  Identifying the role of pre-and postsynaptic GABAB receptors in behavior 
Although many reviews exist characterizing the molecular differences of GABAB receptor isoforms, there is no current review of the in vivo effects of these isoforms. The current review focuses on whether the GABAB1a and GABAB1b isoforms contribute differentially to behaviors in isoform knockout mice. The roles of these receptors have primarily been characterized in cognitive, anxiety, and depressive phenotypes. Currently, the field supports a role of GABAB1a in memory maintenance and protection against an anhedonic phenotype, whereas GABAB1b appears to be involved in memory formation and a susceptibility to developing an anhedonic phenotype. Although GABAB receptors have been strongly implicated in drug abuse phenotypes, no isoform-specific work has been done in this field. Future directions include developing site-specific isoform knockdown to identify the role of different brain regions in behavior, as well as identifying how these isoforms are involved in development of behavioral phenotypes.
doi:10.1016/j.neubiorev.2015.08.007
PMCID: PMC4548832  PMID: 26283074
GABAB receptor; isoform; knockout; cognition; depression; drugs of abuse
10.  Implications of cortical balanced excitation and inhibition, functional heterogeneity, and sparseness of neuronal activity in fMRI 
Blood-oxygenation-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) studies often report inconsistent findings, probably due to brain properties such as balanced excitation and inhibition and functional heterogeneity. These properties indicate that different neurons in the same voxels may show variable activities including concurrent activation and deactivation, that the relationships between BOLD signal and neural activity (i.e., neurovascular coupling) are complex, and that increased BOLD signal may reflect reduced deactivation, increased activation, or both. The traditional general-linear-model-based-analysis (GLM-BA) is a univariate approach, cannot separate different components of BOLD signal mixtures from the same voxels, and may contribute to inconsistent findings of fMRI. Spatial independent component analysis (sICA) is a multivariate approach, can separate the BOLD signal mixture from each voxel into different source signals and measure each separately, and thus may reconcile previous conflicting findings generated by GLM-BA. We propose that methods capable of separating mixed signals such as sICA should be regularly used for more accurately and completely extracting information embedded in fMRI datasets.
doi:10.1016/j.neubiorev.2015.08.018
PMCID: PMC4623927  PMID: 26341939
independent component analysis; neuroimaging; general linear model; neurovascular coupling; hemodynamic response function; magnetic resonance imaging
11.  Thyroid hormone signaling: Contribution to neural function, cognition, and relationship to nicotine 
Cigarette smoking is common despite its adverse effects on health, such as cardiovascular disease and stroke. Understanding the mechanisms that contribute to the addictive properties of nicotine makes it possible to target them to prevent the initiation of smoking behavior and/or increase the chance of successful quit attempts. While highly addictive, nicotine is not generally considered to be as reinforcing as other drugs of abuse. There are likely other mechanisms at work that contribute to the addictive liability of nicotine. Nicotine modulates aspects of the endocrine system, including the thyroid, which is critical for normal cognitive functioning. It is possible that nicotine’s effects on thyroid function may alter learning and memory, and this may underlie some of its addictive potential. Here, we review the literature on thyroid function and cognition, with a focus on how nicotine alters thyroid hormone signaling and the potential impact on cognition. Changes in cognition are a major symptom of nicotine addiction. Current anti-smoking therapies have modest success at best. If some of the cognitive effects of nicotine are mediated through the thyroid hormone system, then thyroid hormone agonists may be novel treatments for smoking cessation therapies. The content of this review is important because it clarifies the relationship between smoking and thyroid function, which has been ill-defined in the past. This review is timely because the reduction in smoking rates we have seen in recent decades, due to public awareness campaigns and public smoking bans, has leveled off in recent years. Therefore, novel treatment approaches are needed to help reduce smoking rates further.
doi:10.1016/j.neubiorev.2015.09.001
PMCID: PMC4624048  PMID: 26344666
Nicotine; Thyroid; Acetylcholine; Cognition; Learning and memory
12.  The Prosocial Effects of 3,4-methylenedioxymethamphetamine (MDMA): Controlled Studies in Humans and Laboratory Animals 
Users of ±3,4-Methylenedioxymethamphetamine (MDMA; ‘ecstasy’) report prosocial effects such as sociability and empathy. Supporting these apparently unique social effects, data from controlled laboratory studies indicate that MDMA alters social feelings, information processing, and behavior in humans, and social behavior in rodents. Here, we review this growing body of evidence. In rodents, MDMA increases passive prosocial behavior (adjacent lying) and social reward while decreasing aggression, effects that may involve serotonin 1A receptor mediated oxytocin release interacting with vasopressin receptor 1A. In humans, MDMA increases plasma oxytocin and produces feelings of social affiliation. It decreases identification of negative facial expressions (cognitive empathy) and blunts responses to social rejection, while enhancing responses to others’ positive emotions (emotional empathy) and increasing social approach. Thus, consistent with drug folklore, laboratory administration of MDMA robustly alters social processing in humans and increases social approach in humans and animals. Effects are consistent with increased sociability, with mixed evidence about enhanced empathy. These neurobiologically-complex prosocial effects likely motivate recreational ecstasy use.
doi:10.1016/j.neubiorev.2015.08.016
PMCID: PMC4678620  PMID: 26408071
MDMA; ecstasy; molly; sociability; prosocial; social reward; social threat; empathy
13.  The basolateral amygdala in reward learning and addiction 
Sophisticated behavioral paradigms partnered with the emergence of increasingly selective techniques to target the basolateral amygdala (BLA) have resulted in an enhanced understanding of the role of this nucleus in learning and using reward information. Due to the wide variety of behavioral approaches many questions remain on the circumscribed role of BLA in appetitive behavior. In this review, we integrate conclusions of BLA function in reward-related behavior using traditional interference techniques (lesion, pharmacological inactivation) with those using newer methodological approaches in experimental animals that allow in vivo manipulation of cell type-specific populations and neural recordings. Secondly, from a review of appetitive behavioral tasks in rodents and monkeys and recent computational models of reward procurement, we derive evidence for BLA as a neural integrator of reward value, history, and cost parameters. Taken together, BLA codes specific and temporally dynamic outcome representations in a distributed network to orchestrate adaptive responses. We provide evidence that experiences with opiates and psychostimulants alter these outcome representations in BLA, resulting in long-term modified action.
doi:10.1016/j.neubiorev.2015.08.017
PMCID: PMC4681295  PMID: 26341938
basolateral amygdala; orbitofrontal cortex; outcome devaluation; discounting; reversal learning; amphetamine; opiate
14.  NR2B subunit in the prefrontal cortex: A double-edged sword for working memory function and psychiatric disorders 
The prefrontal cortex (PFC) is a brain region featured with working memory function. The exact mechanism of how working memory operates within the PFC circuitry is unknown, but persistent neuronal firing recorded from prefrontal neurons during a working memory task is proposed to be the neural correlate of this mnemonic encoding. The PFC appears to be specialized for sustaining persistent firing, with N-methyl-D-aspartate (NMDA) receptors, especially slow-decay NR2B subunits, playing an essential role in the maintenance of sustained activity and normal working memory function. However, the NR2B subunit serves as a double-edged sword for PFC function. Because of its slow kinetics, NR2B endows the PFC with not only “neural psychic” properties, but also susceptibilities for neuroexcitotoxicity and psychiatric disorders. This review aims to clarify the interplay among working memory, the PFC, and NMDA receptors; demonstrate the importance of the NR2B subunit in the maintenance of persistent activity; understand the risks and vulnerabilities of how NR2B is related to the development of neuropsychiatric disorders; identify gaps that currently exist in our understanding of these processes; and provide insights regarding future directions that may clarify these issues. We conclude that the PFC is a specialized brain region with distinct delayed maturation, unique neuronal circuitry, and characteristic NMDA receptor function. The unique properties and development of NMDA receptors, especially enrichment of NR2B subunits, endows the PFC with not only the capability to generate sustained activity for working memory, but also serves as a major vulnerability to environmental insults and risk factors for psychiatric disorders.
doi:10.1016/j.neubiorev.2015.06.022
PMCID: PMC4567400  PMID: 26143512
Prefrontal cortex; working memory; NMDA receptors; neuron development; schizophrenia; psychiatric disorders
15.  Blood biomarkers for brain injury: What are we measuring? 
Accurate diagnosis for mild traumatic brain injury (mTBI) remains challenging, as prognosis and return-to-play/work decisions are based largely on patient reports. Numerous investigations have identified and characterized cellular factors in the blood as potential biomarkers for TBI, in the hope that these factors may be used to gauge the severity of brain injury. None of these potential biomarkers have advanced to use in the clinical setting. Some of the most extensively studied blood biomarkers for TBI include S100β, neuron-specific enolase, glial fibrillary acidic protein, and Tau. Understanding the biological function of each of these factors may be imperative to achieve progress in the field. We address the basic question: what are we measuring? This review will discuss blood biomarkers in terms of cellular origin, normal and pathological function, and possible reasons for increased blood levels. Considerations in the selection, evaluation, and validation of potential biomarkers will also be addressed, along with mechanisms that allow brain-derived proteins to enter the bloodstream after TBI. Lastly, we will highlight perspectives and implications for repetitive neurotrauma in the field of blood biomarkers for brain injury.
doi:10.1016/j.neubiorev.2016.05.009
PMCID: PMC5003664  PMID: 27181909
Blood biomarker; Concussion; Mild TBI; Blood-brain barrier
16.  LIMBIC CIRCUITRY OF THE MIDLINE THALAMUS 
The thalamus was subdivided into three major groups: sensorimotor nuclei (or principal/relay nuclei), limbic nuclei and nuclei bridging these two domains. Limbic nuclei of thalamus (or ‘limbic thalamus’) consist of the anterior nuclei, midline nuclei, medial division of the mediodorsal nucleus (MDm) and central medial nucleus (CM) of the intralaminar complex. The midline nuclei include the paraventricular (PV) and paratenial (PT) nuclei, dorsally, and the reuniens (RE) and rhomboid (RH) nuclei, ventrally. The ‘limbic’ thalamic nuclei predominantly connect with limbic-related structures and serve a direct role in limbic–associated functions. Regarding the midline nuclei, RE/RH mainly target limbic cortical structures, particularly the hippocampus and the medial prefrontal cortex. Accordingly, RE/RH participate in functions involving interactions of the HF and mPFC. By contrast, PV/PT mainly project to limbic subcortical structures, particularly the amygdala and nucleus accumbens, and hence are critically involved in affective behaviors such as stress/anxiety, feeding behavior, and drug seeking activities. The anatomical/functional characteristics of MDm and CM are very similar to those of the midline nuclei and hence the collection of nuclei extending dorsoventrally along the midline/paramidline of the thalamus constitute the core of the ‘limbic thalamus’.
doi:10.1016/j.neubiorev.2015.01.014
PMCID: PMC4976455  PMID: 25616182
nucleus reuniens; rhomboid nucleus; paratenial nucleus; paraventricular nucleus; mediodorsal nucleus; central medial nucleus; learning and memory; cognition; affect; stress/anxiety; feeding behavior; drug seeking activity
17.  Actions and interactions of estradiol and glucocorticoids in cognition and the brain: Implications for aging women. 
Menopause involves dramatic declines in estradiol production and levels. Importantly, estradiol and the class of stress hormones known as glucocorticoids exert countervailing effects throughout the body, with estradiol exerting positive effects on the brain and cognition, glucocorticoids exerting negative effects on the brain and cognition, and estradiol able to mitigate negative effects of glucocorticoids. Although the effects of these hormones in isolation have been extensively studied, the effects of estradiol on the stress response and the neuroprotection offered against glucocorticoid exposure in humans are less well known. Here we review evidence suggesting that estradiol-related protection against glucocorticoids mitigates stress-induced interference with cognitive processes. Animal and human research indicates that estradiol-related mitigation of glucocorticoid damage and interference is one benefit of estradiol supplementation during peri-menopause or soon after menopause. The evidence for estradiol-related protection against glucocorticoids suggests that maintaining estradiol levels in post-menopausal women could protect them from stress-induced declines in neural and cognitive integrity.
doi:10.1016/j.neubiorev.2015.04.005
PMCID: PMC4501869  PMID: 25929443
Menopause; Glucocorticoids; Estradiol; Stress; Working Memory; Neurodegeneration; Neuroprotection; Hippocampus; Executive Function
18.  PSYCHIATRIC DISORDERS AND LEUKOCYTE TELOMERE LENGTH: UNDERLYING MECHANISMS LINKING MENTAL ILLNESS WITH CELLULAR AGING 
Many psychiatric illnesses are associated with early mortality and with an increased risk of developing physical diseases that are more typically seen in the elderly. Moreover, certain psychiatric illnesses may be associated with accelerated cellular aging, evidenced by shortened leukocyte telomere length (LTL), which could underlie this association. Shortened LTL reflects a cell’s mitotic history and cumulative exposure to inflammation and oxidation as well as the availability of telomerase, a telomere-lengthening enzyme. Critically short telomeres can cause cells to undergo senescence, apoptosis or genomic instability, and shorter LTL correlates with poorer health and predicts mortality. Emerging data suggest that LTL may be reduced in certain psychiatric illnesses, perhaps in proportion to exposure to the psychiatric illnesses, although conflicting data exist. Telomerase has been less well characterized in psychiatric illnesses, but a role in depression and in antidepressant and neurotrophic effects has been suggested by preclinical and clinical studies. In this article, studies on LTL and telomerase activity in psychiatric illnesses are critically reviewed, potential mediators are discussed, and future directions are suggested. A deeper understanding of cellular aging in psychiatric illnesses could lead to re-conceptualizing them as systemic illnesses with manifestations inside and outside the brain and could identify new treatment targets.
doi:10.1016/j.neubiorev.2015.05.007
PMCID: PMC4501875  PMID: 25999120
aging; telomeres; telomerase; inflammation; oxidative stress; stress; early life adversity; depression; major depressive disorder; bipolar affective disorder; manic-depression; post-traumatic stress disorder; anxiety; schizophrenia; psychosis; disease; mortality; antidepressant; neurotrophic; leukocytes
19.  There are things that we know that we know, and there are things that we do not know we do not know: Confidence in Decision-Making 
Metacognition, the ability to think about our own thoughts, is a fundamental component of our mental life and is involved in memory, learning, planning and decision-making. Here we focus on one aspect of metacognition, namely confidence in perceptual decisions. We review the literature in psychophysics, neuropsychology and neuroscience. Although still a very new field, several recent studies suggest there are specific brain circuits devoted to monitoring and reporting confidence, whereas others suggest that confidence information is encoded within decision-making circuits. We provide suggestions, based on interdisciplinary research, to disentangle these disparate results.
doi:10.1016/j.neubiorev.2015.04.006
PMCID: PMC4501881  PMID: 25929444
metacognition; confidence; consciousness; awareness; monitoring
20.  An integrative neural model of social perception, action observation, and theory of mind 
In the field of social neuroscience, major branches of research have been instrumental in describing independent components of typical and aberrant social information processing, but the field as a whole lacks a comprehensive model that integrates different branches. We review existing research related to the neural basis of three key neural systems underlying social information processing: social perception, action observation, and theory of mind. We propose an integrative model that unites these three processes and highlights the posterior superior temporal sulcus (pSTS), which plays a central role in all three systems. Furthermore, we integrate these neural systems with the dual system account of implicit and explicit social information processing. Large-scale meta-analyses based on Neurosynth confirmed that the pSTS is at the intersection of the three neural systems. Resting-state functional connectivity analysis with 1000 subjects confirmed that the pSTS is connected to all other regions in these systems. The findings presented in this review are specifically relevant for psychiatric research especially disorders characterized by social deficits such as autism spectrum disorder.
doi:10.1016/j.neubiorev.2015.01.020
PMCID: PMC4940188  PMID: 25660957
Social neuroscience; Neural systems; Social information processing; Social perception; Action observation; Mirror system; Imitation; Theory of mind; Mentalizing; Posterior superior temporal sulcus; Functional connectivity; Autism spectrum disorder; Psychiatric disorders
21.  Developmental studies of the hippocampus and hippocampal-dependent behaviors: Insights from interdisciplinary studies and tips for new investigators 
The hippocampus is not fully developed at birth and, with respect to spatial cognition, only begins to show signs of adult-like function at three postnatal weeks in rodents. Studying the developmental period spanning roughly two to four weeks of age permits an understanding of the neural framework necessary for the emergence of spatial navigation and, quite possibly, human episodic memory. However, due to developmental factors, behavior data collection and interpretation can be severely compromised if inappropriate designs are applied. As such, we propose methodological considerations for the behavioral assessment of hippocampal function in developing rats that take into account animal size, growth rate, and sensory and motor ability. We further summarize recent key interdisciplinary studies that are beginning to unravel the molecular machinery and physiological alterations responsible for hippocampal maturation. In general, hippocampal development is a protracted process during which unique contributions to spatial cognition and complex recognition memory come “on line” at different postnatal ages creating a unique situation for elucidating the neural bases of specific components of higher cognitive abilities.
doi:10.1016/j.neubiorev.2014.04.009
PMCID: PMC4939092  PMID: 24769291
Spatial navigation; Learning and memory; Postnatal development; Hippocampus; Y-maze; AMPAR; NMDAR; Behavioral testing; Novelty; Environment; Place field; Juvenile
22.  Thalamic structures and associated cognitive functions: Relations with age and aging 
The thalamus, with its cortical, subcortical, and cerebellar connections, is a critical node in networks supporting cognitive functions known to decline in normal aging, including component processes of memory and executive functions of attention and information processing. The macrostructure, microstructure, and neural connectivity of the thalamus changes across the adult lifespan. Structural and functional magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) have demonstrated, regional thalamic volume shrinkage and microstructural degradation, with anterior regions generally more compromised than posterior regions. The integrity of selective thalamic nuclei and projections decline with advancing age, particularly those in thalamofrontal, thalamoparietal, and thalamolimbic networks. This review presents studies that assess the relations between age and aging and the structure, function, and connectivity of the thalamus and associated neural networks and focuses on their relations with processes of attention, speed of information processing, and working and episodic memory.
doi:10.1016/j.neubiorev.2015.03.008
PMCID: PMC4457546  PMID: 25862940
thalamus; aging; MRI; DTI; connectivity; thalamocortical; memory; executive functions; attention
23.  Noradrenaline effects on social behaviour, intergroup relations, and moral decisions 
Highlights
•The involvement of noradrenaline in moral and social judgments is reviewed.•Noradrenergic transmission is causally involved in implicit racial biases, racial face perception, as well as increasing social harm aversion.•Fear and anger – mediated by limbic circuit brain activation – might mediate moral and social decisions and acts.
Recent research has begun to elucidate the neural basis of higher order social concepts, such as the mechanisms involved in intergroup relations, and moral judgments. Most theories have concentrated on higher order emotions, such as guilt, shame, or empathy, as core mechanisms. Accordingly, psychopharmacological and neurobiological studies have investigated the effects of manipulating serotonin or oxytocin activity on moral and social decisions and attitudes. However, recently it has been determined that changes in more basic emotions, such as fear and anger, might also have a significant role in social and moral cognition. This article summarizes psychopharmacological and fMRI research on the role of noradrenaline in higher order social cognition suggesting that indeed noradrenergic mediated affective changes might play key – and probably causal – role in certain social attitudes and moral judgments. Social judgments may also be directly influenced by numerous neurotransmitter manipulations but these effects could be mediated by modulation of basic emotions which appear to play an essential role in the formation of social concepts and moral behaviour.
doi:10.1016/j.neubiorev.2016.03.031
PMCID: PMC4899514  PMID: 27126289
24.  A review of vulnerability and risks for schizophrenia: Beyond the two hit hypothesis 
Schizophrenia risk has often been conceptualized using a model which requires two hits in order to generate the clinical phenotype—the first as an early priming in a genetically predisposed individual and the second a likely environmental insult. The aim of this paper was to review the literature and reformulate this binary risk-vulnerability model. We sourced the data for this narrative review from the electronic database PUBMED. Our search terms were not limited by language or date of publication. The development of schizophrenia may be driven by genetic vulnerability interacting with multiple vulnerability factors including lowered prenatal vitamin D exposure, viral infections, smoking intelligence quotient, social cognition cannabis use, social defeat, nutrition and childhood trauma. It is likely that these genetic risks, environmental risks and vulnerability factors are cumulative and interactive with each other and with critical periods of neurodevelopmental vulnerability. The development of schizophrenia is likely to be more complex and nuanced than the binary two hit model originally proposed nearly thirty years ago. Risk appears influenced by a more complex process involving genetic risk interfacing with multiple potentially interacting hits and vulnerability factors occurring at key periods of neurodevelopmental activity, which culminate in the expression of disease state. These risks are common across a number of neuropsychiatric and medical disorders, which might inform common preventive and intervention strategies across non-communicable disorders.
doi:10.1016/j.neubiorev.2016.03.017
PMCID: PMC4876729  PMID: 27073049
25.  Neurocognitive Outcomes in Long-term Survivors of Childhood Acute Lymphoblastic Leukemia Treated on Contemporary Treatment Protocols: A Systematic Review 
The intensified administration of chemotherapeutic drugs has gradually replaced cranial radiation therapy (CRT) for the treatment of childhood acute lymphoblastic leukemia (ALL). While CRT is often implicated in neurocognitive impairment in ALL survivors, there is a paucity of literature that evaluates the persistence of neurocognitive deficits in long-term survivors of pediatric ALL who were treated with contemporary chemotherapy-only protocols. Results from this systematic review concurred to the probable cognitive-sparing effect of chemotherapy-based protocols over CRT in long-term survivors. However, coupled with multiple intrinsic and extrinsic factors, survivors who received chemotherapy treatment still suffered from apparent cognitive impairment, particularly in the attention and executive function domains. Notably, there is evidence to suggest that the late neurotoxic effect of methotrexate on survivors’ neurocognitive performance may be dose-related. This review also recommends future pharmacokinetic, neuroimaging and genetic studies to illuminate the multifactorial nature of this subject matter and discusses the potential value of neurochemical, physiological, inflammatory and genetic markers for the prediction of susceptibility to neurocognitive impairment in long-term survivors of childhood ALL.
doi:10.1016/j.neubiorev.2015.03.016
PMCID: PMC4425605  PMID: 25857254
Acute lymphoblastic leukemia; cancer survivorship; chemotherapy; neurocognitive; pediatric cancer

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