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1.  Moment-to-moment brain signal variability: A next frontier in human brain mapping? 
Neuroscientists have long observed that brain activity is naturally variable from moment-to-moment, but neuroimaging research has largely ignored the potential importance of this phenomenon. An emerging research focus on within-person brain signal variability is providing novel insights, and offering highly predictive, complementary, and even orthogonal views of brain function in relation to human life-span development, cognitive performance, and various clinical conditions. As a result, brain signal variability is evolving as a bona fide signal of interest, and should no longer be dismissed as meaningless noise when mapping the human brain.
PMCID: PMC3732213  PMID: 23458776 CAMSID: cams2986
brain signal variability; noise; complexity; dynamics; fMRI; EEG; MEG
2.  Progressive brain changes in schizophrenia related to antipsychotic treatment? A meta-analysis of longitudinal MRI studies 
Antipsychotic treatment is the first-line treatment option for schizophrenia. Individual studies suggested they can significantly affect brain structure and account for progressive brain changes observed during the illness.
To quantitatively examine the effect of antipsychotics as compared to illness related factors on progressive brain changes in schizophrenia.
Data sources
Electronic databases were searched until April 2012. All magnetic resonance imaging studies reporting progressive brain changes in schizophrenia subjects and antipsychotic exposure were retrieved.
Study selection
30 longitudinal MRI studies with antipsychotic administration in schizophrenia patients met the inclusion criteria.
Data extraction
Brain volumes before and after antipsychotic exposure, duration of illness, severity of psychotic symptoms as well as demographic, clinical, and methodological variables were extracted from each publication, or obtained directly from its authors.
Data synthesis
The overall sample was of 1046 schizophrenia patients and 780 controls for a median duration of follow-up of 72.4 weeks. At baseline, patients showed significant whole brain volume reductions and enlarged lateral ventricle (LV) volumes compared to controls. No baseline volumetric abnormalities were detected in the gray matter volumes (GMV), white matter volumes, cerebrospinal fluid and caudate nucleus. Longitudinally, there were progressive GMV decreases and LV enlargements in patients but not in controls. The GMV decreases were inversely correlated with cumulative exposure to antipsychotic treatments, while no effects were observed for duration of illness or illness severity.
Schizophrenia is characterized by progressive gray matter volume decreases and lateral ventricular volume increases. Some of these neuroanatomical alterations may be associated with antipsychotic treatment.
PMCID: PMC3964856  PMID: 23769814
Psychosis; Schizophrenia; Antipsychotic; Neuroimaging; MRI; Structural; Dopamine
3.  Harnessing cognitive neuroscience to develop new treatments for improving cognition in schizophrenia: CNTRICS selected cognitive paradigms for animal models 
Neuroscience and biobehavioral reviews  2013;37(9 0 0):2087-2091.
Over the past two decades, the awareness of the disabling and treatment-refractory effects of impaired cognition in schizophrenia has increased dramatically. In response to this still unmet need in the treatment of schizophrenia, the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) initiative was developed. The goal of CNTRICS is to harness cognitive neuroscience to develop a brain-based set of tools for measuring cognition in schizophrenia and to test new treatments. CNTRICS meetings focused on development of tasks with cognitive construct validity for use in both human and animal model studies. This special issue presents papers discussing the cognitive testing paradigms selected by CNTRICS for animal model systems. These paradigms are designed to measure cognitive constructs within the domains of perception, attention, executive function, working memory, object/relational long-term memory, and social/affective processes.
PMCID: PMC3965347  PMID: 24090823
Psychosis; Psychopharmacology; Behavior; Rat; Mouse; Non-human primate
4.  Are there Volumetric Brain Differences Associated with the Use of Cocaine and Amphetamine-Type Stimulants? 
While a large number of studies have examined brain volume differences associated with cocaine use, much less is known about structural differences related to amphetamine-type stimulant (ATS) use. What is known about cocaine may help to interpret emerging information on the interaction of brain volume with ATS consumption. To date, volumetric studies on the two types of stimulant have focused almost exclusively on brain differences associated with chronic use. There is considerable variability in the findings between studies which may be explained in part by the wide variety of methodologies employed. Despite this variability, seven recurrent themes are worth noting: 1) loci of lower cortical volume (approximately 10% on average) are consistently reported, 2) almost all studies indicate less volume in all or parts of the frontal cortex, 3) more specifically, a core group of studies implicate the ventromedial prefrontal cortex (including the medial portion of the orbital frontal cortex) and 4) the insula, 5) an enlarged striatal volume has been repeatedly observed, 6) reports on volume differences in the hippocampus and amygdala have been equivocal, 7) evidence supporting differential interaction of brain structure with cocaine vs. ATS is scant but the volume of all or parts of the temporal cortex appear lower in a majority of studies on cocaine but not ATS. Future research should include longitudinal designs on larger sample sizes and examine other stages of exposure to psychostimulants.
PMCID: PMC3604030  PMID: 23253945
MRI; Volumetric; Voxel-based morphometry; Grey matter volume; Stimulants; Cocaine; Amphetamine-type stimulants; Amphetamine; Methamphetamine; MDMA
5.  Melanopsin, Photosensitive Ganglion Cells, and Seasonal Affective Disorder 
ROECKLEIN, K.A., WONG, P.M., MILLER, M.A., DONOFRY, S.D., KAMARCK, M.L., BRAINARD, G.C. Melanopsin, Photosensitive Ganglion Cells, and Seasonal Affective Disorder…NEUROSCI BIOBEHAV REV x(x) XXX-XXX, 2012. In two recent reports, melanopsin gene variations were associated with seasonal affective disorder (SAD), and in changes in the timing of sleep and activity in healthy individuals. New studies have deepened our understanding of the retinohypothalamic tract, which translates environmental light received by the retina into neural signals sent to a set of nonvisual nuclei in the brain that are responsible for functions other than sight including circadian, neuroendocrine and neurobehavioral regulation. Because this pathway mediates seasonal changes in physiology, behavior, and mood, individual variations in the pathway may explain why approximately 1–2% of the North American population develops mood disorders with a seasonal pattern (i.e., Major Depressive and Bipolar Disorders with a seasonal pattern, also known as seasonal affective disorder/SAD). Components of depression including mood changes, sleep patterns, appetite, and cognitive performance can be affected by the biological and behavioral responses to light. Specifically, variations in the gene sequence for the retinal photopigment, melanopsin, may be responsible for significant increased risk for mood disorders with a seasonal pattern, and may do so by leading to changes in activity and sleep timing in winter. The retinal sensitivity of SAD is hypothesized to be decreased compared to controls, and that further decrements in winter light levels may combine to trigger depression in winter. Here we outline steps for new research to address the possible role of melanopsin in seasonal affective disorder including chromatic pupillometry designed to measure the sensitivity of melanopsin containing retinal ganglion cells.
PMCID: PMC3604141  PMID: 23286902
depression; retinohyopothalamic pathway; melanopsin; sleep; seasonal affective disorder; Photosensitive Retinal Ganglion Cells
6.  Neural bases of eye and gaze processing: The core of social cognition 
Eyes and gaze are very important stimuli for human social interactions. Recent studies suggest that impairments in recognizing face identity, facial emotions or in inferring attention and intentions of others could be linked to difficulties in extracting the relevant information from the eye region including gaze direction. In this review, we address the central role of eyes and gaze in social cognition. We start with behavioral data demonstrating the importance of the eye region and the impact of gaze on the most significant aspects of face processing. We review neuropsychological cases and data from various imaging techniques such as fMRI/PET and ERP/MEG, in an attempt to best describe the spatio-temporal networks underlying these processes. The existence of a neuronal eye detector mechanism is discussed as well as the links between eye gaze and social cognition impairments in autism. We suggest impairments in processing eyes and gaze may represent a core deficiency in several other brain pathologies and may be central to abnormal social cognition.
PMCID: PMC3925117  PMID: 19428496 CAMSID: cams3881
Eyes; Gaze; Face; Social cognition; Theory of mind; Neuroimaging; ERPs; MEG
7.  Social Neuroscience and Hyperscanning Techniques: Past, Present and Future 
Neuroscience and biobehavioral reviews  2012;10.1016/j.neubiorev.2012.07.006.
This paper reviews the published literature on the hyperscanning methodologies using hemodynamic or neuro-electric modalities. In particular, we describe how different brain recording devices have been employed in different experimental paradigms to gain information about the subtle nature of human interactions. This review also included papers based on single-subject recordings in which a correlation was found between the activities of different (non-simultaneously recorded) participants in the experiment. The descriptions begin with the methodological issues related to the simultaneous measurements and the descriptions of the results generated by such approaches will follow. Finally, a discussion of the possible future uses of such new approaches to explore human social interactions will be presented.
PMCID: PMC3522775  PMID: 22917915
8.  Principles of motivation revealed by the diverse functions of neuropharmacological and neuroanatomical substrates underlying feeding behavior 
Neuroscience and biobehavioral reviews  2013;37(9 0 0):1985-1998.
Circuits that participate in specific subcomponents of feeding (e.g., gustatory perception, peripheral feedback relevant to satiety and energy balance, reward coding, etc.) are found at all levels of the neural axis. Further complexity is conferred by the wide variety of feeding-modulatory neurotransmitters and neuropeptides that act within these circuits. An ongoing challenge has been to refine the understanding of the functional specificity of these neurotransmitters and circuits, and there have been exciting advances in recent years. We focus here on foundational work of Dr. Ann Kelley that identified distinguishable actions of striatal opioid peptide modulation and dopamine transmission in subcomponents of reward processing. We also discuss her work in overlaying these neuropharmacological effects upon anatomical pathways that link the telencephalon (cortex and basal ganglia) with feeding-control circuits in the hypothalamus. Using these seminal contributions as a starting point, we will discuss new findings that expand our understanding of (1) the specific, differentiable motivational processes that are governed by central dopamine and opioid transmission, (2) the manner in which other striatal neuromodulators, specifically acetylcholine, endocannabinoids and adenosine, modulate these motivational processes (including via interactions with opioid systems), and (3) the organization of the cortical-subcortical network that subserves opioid-driven feeding. The findings discussed here strengthen the view that incentive-motivational properties of food are coded by substrates and neural circuits that are distinguishable from those that mediate the acute hedonic experience of food reward. Striatal opioid transmission modulates reward processing by engaging frontotemporal circuits, possibly via a hypothalamic-thalamic axis, that ultimately impinges upon hypothalamic modules dedicated to autonomic function and motor pattern control. We will conclude by discussing implications for understanding disorders of “non-homeostatic” feeding.
PMCID: PMC3910434  PMID: 23466532
Feeding; Reward; Motivation; Dopamine; Opioid; Acetylcholine; Nucleus accumbens; Amygdala; Hypothalamus
9.  Atypical Attentional Networks and the Emergence of Autism 
The sociocommunicative impairments that define autism spectrum disorder (ASD) are not present at birth but emerge gradually over the first two years of life. In typical development, basic attentional processes may provide a critical foundation for sociocommunicative abilities. Therefore early attentional dysfunction in ASD may result in atypical development of social communication. Prior research has demonstrated that persons with ASD exhibit early and lifelong impairments in attention. The primary aim of this paper is to provide a review of the extant research on attention in ASD using a framework of functionally independent attentional networks as conceptualized by Posner and colleagues: the alerting, orienting and executive control networks (Posner and Petersen, 1990; Petersen & Posner, 2012). The neural substrates and typical development of each attentional network is briefly discussed, a review of the ASD attention literature is presented, and a hypothesis is proposed that links aberrant attentional mechanisms, specifically impaired disengagement of attention, with the emergence of core ASD symptoms.
PMCID: PMC3563720  PMID: 23206665
autism; attention; development; alerting; arousal; orienting; disengagement; executive control
10.  Brain interleukin-15 in neuroinflammation and behavior 
Interleukin (IL)-15 is a ubiquitously expressed cytokine existing in both intracellular and secretory forms. Here we review the expression, regulation, and functions of IL15 and its receptors in the brain. IL15 receptors show robust upregulation after neuroinflammation, suggesting a major role of IL15 signaling in cerebral function. Involvement of the IL15 system in neuropsychiatric behavior is reflected by the effects of IL15, IL15Rα, and IL2Rγ deletions on neurobehavior and neurotransmitters, the effects of IL15 treatment on neuronal activity, and the potential role of IL15 in neuroplasticity/neurogenesis. The results show that IL15 modulates GABA and serotonin transmission. This may underlie deficits in mood (depressive-like behavior and decreased normal anxiety) and memory, as well as activity level, sleep, and thermoregulation. Although IL15 has only a low level of permeation across the blood-brain barrier, peripheral IL15 is able to activate multiple signaling pathways in neurons widely distributed in CNS regions. The effects of IL15 in “preventing” neuropsychiatric symptoms in normal mice implicate a potential therapeutic role of this polypeptide cytokine.
PMCID: PMC3563733  PMID: 23201098
cytokine; peptide; interleukin-15; depression; anxiety; memory; neurobehavior; neurotransmitter; neurogenesis; metabolic activity
11.  A meta-analysis of sex differences in human brain structure☆ 
•This is the first meta-analysis of sex differences in the typical human brain.•Regional sex differences overlap with areas implicated in psychiatric conditions.•The amygdala, hippocampus, planum temporale and insula display sex differences.•On average, males have larger brain volumes than females.•Most articles providing sex differences in volume are in the ‘mature’ category.
The prevalence, age of onset, and symptomatology of many neuropsychiatric conditions differ between males and females. To understand the causes and consequences of sex differences it is important to establish where they occur in the human brain. We report the first meta-analysis of typical sex differences on global brain volume, a descriptive account of the breakdown of studies of each compartmental volume by six age categories, and whole-brain voxel-wise meta-analyses on brain volume and density. Gaussian-process regression coordinate-based meta-analysis was used to examine sex differences in voxel-based regional volume and density. On average, males have larger total brain volumes than females. Examination of the breakdown of studies providing total volumes by age categories indicated a bias towards the 18–59 year-old category. Regional sex differences in volume and tissue density include the amygdala, hippocampus and insula, areas known to be implicated in sex-biased neuropsychiatric conditions. Together, these results suggest candidate regions for investigating the asymmetric effect that sex has on the developing brain, and for understanding sex-biased neurological and psychiatric conditions.
PMCID: PMC3969295  PMID: 24374381
Brain; Sex differences; Meta-analysis; Gaussian-process regression (GPR); Voxel-based morphometry; Volume
12.  Developmental pathways to autism: A review of prospective studies of infants at risk☆ 
•Prospective studies of infants at familial risk are characterizing developmental pathways to ASD.•Children with ASD show social and communication difficulties in the second year of life.•Early neurocognitive markers include atypical neural response to gaze and slowed disengagement.•Mapping how ASD unfolds from birth is central to early identification and intervention.
Autism Spectrum Disorders (ASDs) are neurodevelopmental disorders characterized by impairments in social interaction and communication, and the presence of restrictive and repetitive behaviors. Symptoms of ASD likely emerge from a complex interaction between pre-existing neurodevelopmental vulnerabilities and the child's environment, modified by compensatory skills and protective factors. Prospective studies of infants at high familial risk for ASD (who have an older sibling with a diagnosis) are beginning to characterize these developmental pathways to the emergence of clinical symptoms. Here, we review the range of behavioral and neurocognitive markers for later ASD that have been identified in high-risk infants in the first years of life. We discuss theoretical implications of emerging patterns, and identify key directions for future work, including potential resolutions to several methodological challenges for the field. Mapping how ASD unfolds from birth is critical to our understanding of the developmental mechanisms underlying this disorder. A more nuanced understanding of developmental pathways to ASD will help us not only to identify children who need early intervention, but also to improve the range of interventions available to them.
PMCID: PMC3969297  PMID: 24361967
ASD; Autism; Infant sibling; High-risk; Causal path; Developmental mechanisms
13.  Neurosteroids, stress and depression: Potential therapeutic opportunities 
Neurosteroids are potent and effective neuromodulators that are synthesized from cholesterol in the brain. These agents and their synthetic derivatives influence the function of multiple signaling pathways including receptors for γ-aminobutyric acid (GABA) and glutamate, the major inhibitory and excitatory neurotransmitters in the central nervous system (CNS). Increasing evidence indicates that dysregulation of neurosteroid production plays a role in the pathophysiology of stress and stress-related psychiatric disorders, including mood and anxiety disorders. In this paper, we review the mechanisms of neurosteroid action in brain with an emphasis on those neurosteroids that potently modulate the function of GABAA receptors. We then discuss evidence indicating a role for GABA and neurosteroids in stress and depression, and focus on potential strategies that can be used to manipulate CNS neurosteroid synthesis and function for therapeutic purposes.
PMCID: PMC3591791  PMID: 23085210
Neurosteroids; Neuroactive steroids; Allopregnanolone; Stress; Depression; Anxiety; Hippocampus
14.  Auditory verbal hallucinations as atypical inner speech monitoring, and the potential of neurostimulation as a treatment option 
Neuroscience and biobehavioral reviews  2013;37(10 0 2):10.1016/j.neubiorev.2013.10.001.
Auditory verbal hallucinations (AVHs) are the experience of hearing voices in the absence of any speaker, often associated with a schizophrenia diagnosis. Prominent cognitive models of AVHs suggest they may be the result of inner speech being misattributed to an external or non-self source, due to atypical self- or reality monitoring. These arguments are supported by studies showing that people experiencing AVHs often show an externalising bias during monitoring tasks, and neuroimaging evidence which implicates superior temporal brain regions, both during AVHs and during tasks that measure verbal self-monitoring performance. Recently, efficacy of noninvasive neurostimulation techniques as a treatment option for AVHs has been tested. Meta-analyses show a moderate effect size in reduction of AVH frequency, but there has been little attempt to explain the therapeutic effect of neurostimulation in relation to existing cognitive models. This article reviews inner speech models of AVHs, and argues that a possible explanation for reduction in frequency following treatment may be modulation of activity in the brain regions involving the monitoring of inner speech.
PMCID: PMC3870271  PMID: 24125858
Auditory verbal hallucinations; Inner speech; Self-monitoring; Reality monitoring; Neurostimulation; TMS; tDCS
15.  Auditory verbal hallucinations as atypical inner speech monitoring, and the potential of neurostimulation as a treatment option☆ 
Neuroscience and Biobehavioral Reviews  2013;37(10):2794-2805.
•We discuss ‘inner speech’ theories of auditory verbal hallucinations.•Atypical self-monitoring may lead to the experience of inner speech as external.•We summarize research into the use of neurostimulation to treat hallucinations.•Effects of neurostimulation may be due to modulation of self-monitoring networks.
Auditory verbal hallucinations (AVHs) are the experience of hearing voices in the absence of any speaker, often associated with a schizophrenia diagnosis. Prominent cognitive models of AVHs suggest they may be the result of inner speech being misattributed to an external or non-self source, due to atypical self- or reality monitoring. These arguments are supported by studies showing that people experiencing AVHs often show an externalising bias during monitoring tasks, and neuroimaging evidence which implicates superior temporal brain regions, both during AVHs and during tasks that measure verbal self-monitoring performance. Recently, efficacy of noninvasive neurostimulation techniques as a treatment option for AVHs has been tested. Meta-analyses show a moderate effect size in reduction of AVH frequency, but there has been little attempt to explain the therapeutic effect of neurostimulation in relation to existing cognitive models. This article reviews inner speech models of AVHs, and argues that a possible explanation for reduction in frequency following treatment may be modulation of activity in the brain regions involving the monitoring of inner speech.
PMCID: PMC3870271  PMID: 24125858
Auditory verbal hallucinations; Inner speech; Self-monitoring; Reality monitoring; Neurostimulation; TMS; tDCS
16.  Altered likelihood of brain activation in attention and working memory networks in patients with multiple sclerosis: An ALE meta-analysis☆ 
Neuroscience and Biobehavioral Reviews  2013;37(10):2699-2708.
•We conducted an ALE meta-analysis of fMRI studies investigating MS patients.•We included nine fMRI studies performing working memory/attention tasks.•Healthy controls showed higher activation in the IPL and the DLPFC.•For MS patients higher activation was obtained in the VLPFC.
Multiple sclerosis (MS) is a chronic neurological disease, frequently affecting attention and working memory functions. Functional imaging studies investigating those functions in MS patients are hard to compare, as they include heterogeneous patient groups and use different paradigms for cognitive testing. The aim of this study was to investigate alterations in neuronal activation between MS patients and healthy controls performing attention and working memory tasks. Two meta-analyses of previously published fMRI studies investigating attention and working memory were conducted for MS patients and healthy controls, respectively. Resulting maps were contrasted to compare brain activation in patients and healthy controls. Significantly increased brain activation in the inferior parietal lobule and the dorsolateral prefrontal cortex was detected for healthy controls. In contrast, higher neuronal activation in MS patients was obtained in the left ventrolateral prefrontal cortex and the right premotor area. With this meta-analytic approach previous results of investigations examining cognitive function using fMRI are summarized and compared. Therefore a more general view on cognitive dysfunction in this heterogeneous disease is enabled.
PMCID: PMC3878376  PMID: 24056084
Multiple sclerosis; Brain imaging; Working memory; Attention; Activation likelihood estimation; VLPFC; DLPFC; n-Back; PASAT; PVSAT
17.  The contribution of brain sub-cortical loops in the expression and acquisition of action understanding abilities☆ 
Neuroscience and Biobehavioral Reviews  2013;37(10):2504-2515.
•Focusing on cortical areas is too restrictive to explain action understanding ability.•We propose that sub-cortical areas support action understanding ability.•Cortical and sub-cortical processes allow acquisition of action understanding ability.
Research on action understanding in cognitive neuroscience has led to the identification of a wide “action understanding network” mainly encompassing parietal and premotor cortical areas. Within this cortical network mirror neurons are critically involved implementing a neural mechanism according to which, during action understanding, observed actions are reflected in the motor patterns for the same actions of the observer. We suggest that focusing only on cortical areas and processes could be too restrictive to explain important facets of action understanding regarding, for example, the influence of the observer's motor experience, the multiple levels at which an observed action can be understood, and the acquisition of action understanding ability. In this respect, we propose that aside from the cortical action understanding network, sub-cortical processes pivoting on cerebellar and basal ganglia cortical loops could crucially support both the expression and the acquisition of action understanding abilities. Within the paper we will discuss how this extended view can overcome some limitations of the “pure” cortical perspective, supporting new theoretical predictions on the brain mechanisms underlying action understanding that could be tested by future empirical investigations.
PMCID: PMC3878436  PMID: 23911926
Psychology; Neuroscience; Mirror neurons; Action understanding; Sub-cortical processes; Cerebellar cortical loops; Basal ganglia cortical loops; Forward models; Inverse models
18.  Re-evaluating the role of TPJ in attentional control: Contextual updating?☆ 
Neuroscience and Biobehavioral Reviews  2013;37(10):2608-2620.
•We examine the function of the temporo-parietal junction (TJP) in the human brain.•The function of TPJ is critically evaluated using data from cognitive neuroscience.•We conclude TPJ function in many domains is well described by contextual updating.
The right temporo-parietal junction (TPJ) is widely considered as part of a network that reorients attention to task-relevant, but currently unattended stimuli (Corbetta and Shulman, 2002). Despite the prevalence of this theory in cognitive neuroscience, there is little direct evidence for the principal hypothesis that TPJ sends an early reorientation signal that “circuit breaks” attentional processing in regions of the dorsal attentional network (e.g., the frontal eye fields) or is completely right lateralized during attentional processing. In this review, we examine both functional neuroimaging work on TPJ in the attentional literature as well as anatomical findings. We first critically evaluate the idea that TPJ reorients attention and is right lateralized; we then suggest that TPJ signals might rather reflect post-perceptual processes involved in contextual updating and adjustments of top-down expectations; and then finally discuss how these ideas relate to the electrophysiological (P300) literature, and to TPJ findings in other cognitive and social domains. We conclude that while much work is needed to define the computational functions of regions encapsulated as TPJ, there is now substantial evidence that it is not specialized for stimulus-driven attentional reorienting.
PMCID: PMC3878596  PMID: 23999082
Temporo-parietal junction; Attention; Ventral attentional control network; Theory of mind; Inferior parietal cortex
19.  Innovative solutions to novel drug development in mental health 
Neuroscience and Biobehavioral Reviews  2013;37(10):2438-2444.
•New approaches to identifying and validating potential drug targets are essential.•A novel drug toolbox and innovative private-public partnerships are required.•Translational neuroscience research will enhance understanding of mental health.•The training of a new cadre of clinician scientists is a necessary foundation.•Neuropsychiatric disorders require holistic, early, effective treatment.
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.
PMCID: PMC3788850  PMID: 23563062
Translation; Back-translation; Pharmacological tool box; Cognitive and psychosocial treatments; Novel drug development; Biomarkers; Neurobiological mechanisms; Neuropsychiatric disorders
20.  α2 adrenergic receptor dysregulation in depressive disorders: implications for the neurobiology of depression and antidepressant therapy 
Neuroscience and biobehavioral reviews  2012;36(10):2214-2225.
Dysfunction in noradrenergic neurotransmission has long been theorized to occur in depressive disorders. The α2 adrenergic receptor (AR) family, as a group of key players in regulating the noradrenergic system, has been investigated for involvement in the neurobiology of depression and mechanisms of antidepressant therapies. However, a clear picture of the α2ARs in depressive disorders has not been established due to the existence of apparently conflicting findings in the literature. In this article, we report that a careful accounting of methodological differences within the literature can resolve the present lack of consensus on involvement of α2ARs in depression. In particular, the pharmacological properties of the radioligand (e.g. agonist versus antagonist) utilized for determining receptor density are crucial in determining study outcome. Upregulation of α2AR density detected by radiolabeled agonists but not by antagonists in patients with depressive disorders suggests a selective increase in the density of high-affinity conformational state α2ARs, which is indicative of enhanced G protein coupling to the receptor. Importantly, this high-affinity state α2AR upregulation can be normalized with antidepressant treatments. Thus, depressive disorders appear to be associated with increased α2AR sensitivity and responsiveness, which may represent a physiological basis for the putative noradrenergic dysfunction in depressive disorders. In addition, we review changes in some key α2AR accessory proteins in depressive disorders and discuss their potential contribution to α2AR dysfunction.
PMCID: PMC3508310  PMID: 22910678
α2 adrenergic receptor; antidepressant; depressive disorder; locus coeruleus
21.  Alcohol dependence as a chronic pain disorder 
Neuroscience and biobehavioral reviews  2012;36(10):2179-2192.
Dysregulation of pain neurocircuitry and neurochemistry has been increasingly recognized as playing a critical role in a diverse spectrum of diseases including migraine, fibromyalgia, depression, and PTSD. Evidence presented here supports the hypothesis that alcohol dependence is among the pathologies arising from aberrant neurobiological substrates of pain. In this review, we explore the possible influence of alcohol analgesia and hyperalgesia in promoting alcohol misuse and dependence. We examine evidence that neuroanatomical sites involved in the negative emotional states of alcohol dependence also play an important role in pain transmission and may be functionally altered under chronic pain conditions. We also consider possible genetic links between pain transmission and alcohol dependence. We propose an allostatic load model in which episodes of alcohol intoxication and withdrawal, traumatic stressors, and injury are each capable of dysregulating an overlapping set of neural substrates to engender sensory and affective pain states that are integral to alcohol dependence and comorbid conditions such as anxiety, depression, and chronic pain.
PMCID: PMC3612891  PMID: 22975446
Alcohol dependence; Chronic pain; Nociception; Negative affect; Stress; Anxiety; Allostasis
22.  Implicit and Explicit Categorization: A Tale of Four Species 
Neuroscience and biobehavioral reviews  2012;36(10):2355-2369.
Categorization is essential for survival, and it is a widely studied cognitive adaptation in humans and animals. An influential neuroscience perspective differentiates in humans an explicit, rule-based categorization system from an implicit system that slowly associates response outputs to different regions of perceptual space. This perspective is being extended to study categorization in other vertebrate species, using category tasks that have a one-dimensional, rule-based solution or a two-dimensional, information-integration solution. Humans, macaques, and capuchin monkeys strongly dimensionalize perceptual stimuli and learn rule-based tasks more quickly. In sharp contrast, pigeons learn these two tasks equally quickly. Pigeons represent a cognitive system in which the commitment to dimensional analysis and category rules was not strongly made. Their results may reveal the character of the ancestral vertebrate categorization system from which that of primates emerged. The primate results establish continuity with human cognition, suggesting that nonhuman primates share aspects of humans' capacity for explicit cognition. The emergence of dimensional analysis and rule learning could have been an important step in primates' cognitive evolution.
PMCID: PMC3777558  PMID: 22981878
category learning; cognitive neuroscience; implicit/explicit cognition; primate cognition; comparative cognition
23.  A Systematic Review of fMRI Reward Paradigms in Adolescents versus Adults: The Impact of Task Design and Implications for Understanding Neurodevelopment 
Neuroscience and biobehavioral reviews  2013;37(5):10.1016/j.neubiorev.2013.03.004.
The neural systems underlying reward-related behaviors across development have recently generated a great amount of interest. Yet, the neurodevelopmental literature on reward processing is marked by inconsistencies due to the heterogeneity of the reward paradigms used, the complexity of the behaviors being studied, and the developing brain itself as a moving target. The present review will examine task design as one source of variability across findings by compiling this literature along three dimensions: (1) task structures, (2) cognitive processes, and (3) neural systems. We start with the presentation of a heuristic neural systems model, the Triadic Model, as a way to provide a theoretical framework for the neuroscience research on motivated behaviors. We then discuss the principles guiding reward task development. Finally, we review the extant developmental neuroimaging literature on reward-related processing, organized by reward task type. We hope that this approach will help to clarify the literature on the functional neurodevelopment of reward-related neural systems, and to identify the role of the experimental parameters that significantly influence these findings.
PMCID: PMC3809756  PMID: 23518270
Reward; Triadic Model; Adolescence; Development; Neuroimaging; Task Design; Approach; Avoidance; Motivation; Emotion; Social; Pediatric; Incentive
24.  The dopaminergic basis of human behaviors: a review of molecular imaging studies 
This systematic review describes human molecular imaging studies which have investigated alterations in extracellular DA levels during performance of behavioral tasks. Whilst heterogeneity in experimental methods limits meta-analysis, we describe the advantages and limitations of different methodological approaches. Interpretation of experimental results may be limited by regional cerebral blood flow (rCBF) changes, head movement and choice of control conditions. We revisit our original study of striatal DA release during video-game playing (Koepp et al., 1998) to illustrate the potentially confounding influences of head movement and alterations in rCBF. Changes in [11C]raclopride binding may be detected in extrastriatal as well as striatal brain regions – however we review evidence which suggests that extrastriatal changes may not be clearly interpreted in terms of DA release. Whilst several investigations have detected increases in striatal extracellular DA concentrations during task components such as motor learning and execution, reward-related processes, stress and cognitive performance, the presence of potentially biasing factors should be carefully considered (and, where possible, accounted for) when designing and interpreting future studies.
PMCID: PMC3797507  PMID: 19481108
Dopamine; PET; SPET; striatum; D2/3 receptor; [11C]raclopride; cognition; reward; stress; motor
25.  Early Life Manipulations Alter Learning and Memory in Rats 
Much research shows early life manipulations have enduring behavioral, neural, and hormonal effects. However, findings of learning and memory performance vary widely across studies. We reviewed studies in which pre-weaning rat pups were exposed to stressors and tested on learning and memory tasks in adulthood. Tasks were classified as aversive conditioning, inhibitory learning, or spatial/relational memory. Variables of duration, type, and timing of neonatal manipulation and sex and strain of animals were examined to determine if any predict enhanced or impaired performance. Brief separations enhanced and prolonged separations impaired performance on spatial/relational tasks. Performance was impaired in aversive conditioning and enhanced in inhibitory learning tasks regardless of manipulation duration. Opposing effects on performance for spatial/relational memory also depended upon timing of manipulation. Enhanced performance was likely if the manipulation occurred during postnatal week 3 but performance was impaired if it was confined to the first two postnatal weeks. Thus, the relationship between early life experiences and adulthood learning and memory performance is multifaceted and decidedly task-dependent.
PMCID: PMC3463710  PMID: 22819985
early life stress; neonatal isolation; maternal separation; neonatal handling; aversive conditioning; spatial memory; hippocampus; development

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