Search

The cloning of the dopamine (DA) D2 receptor now permits the characterization and regulation of D2 messenger RNA (mRNA) in the brain. In this article, the authors describe their studies delineating the distribution of D2 receptor mRNA in the rodent and primate brain, and compare the distribution of message to D2 receptor binding sites. The effects of chronic DA agonist and antagonist treatment on D2 receptor mRNA are also presented, and provide insights into receptor regulation. Finally, the autoreceptor role of D2 receptors located in the midbrain is examined with a combination of 6-hydroxydopamine lesions and anatomic colocalization studies with tyrosine hydroxylase. These preclinical results provide a framework for subsequent investigation into the nature of D2 receptor gene expression in postmortem brains from patients with disorders putatively associated with dopaminergic dysfunction, especially schizophrenia. They also lay the groundwork for a more profound understanding of DA neurocircuitry by combining molecular biological and traditional anatomical techniques.

Studies of neurotransmitter kinetics based on intraventricular injections of radio-labeled metabolites have been limited by several problems, including the inability of most investigators to recover more than 45% of the infected isotope from brain homogenates within several minutes after the injection...

This article has been retracted at the request of John H. Krystal, MD, Editor of Biological Psychiatry, with agreement from all authors. See Elsevier Policy on Article Withdrawal ( https://www.elsevier.com/about/policies/article-withdrawal ). The authors discovered an error in the scoring of the ERP data in this article. Specifically, the ERP in the authors' acquisition and processing stream is live referenced to CZ, and then should be re-referenced in post-processing to TP9 and TP10, as described in the paper. However, the authors discovered that they had accidentally continued to include Cz along with TP9 and TP10 in the template to re-reference the ERP data in post-processing. The authors reprocessed all of the data with only TP9 and TP10 in the referencing, as originally described in the manuscript, and then re-ran all of the analyses. The majority of the key results remained the same in terms of significance and interpretation. The results continue to show that children in PCIT_ED show a greater increase in RewP as a function of treatment than the waitlist group; however, the correlation with the corrected data is in the same direction, but reduced in magnitude and no longer significant. Thus, a greater change in RewP is no longer significantly associated with a greater reduction in MDD symptoms. This error affects the abstract, the results, Table 2, Figures 1-3, discussion, and supplement. The authors voluntarily informed the Journal of this honest error upon its discovery. Because of the extent and nature of the changes to the paper, the editors and authors concluded that, to ensure maximum clarity and transparency, the only course of action was to retract this version of the paper. The authors revised the paper, which the Journal had re-reviewed. The new version was accepted and has been published: 10.1016/j.biopsych.2020.06.032.

BACKGROUND: Research documents bidirectional pathways linking peripheral inflammation and neural circuitries subserving emotion processing and regulation. To extend this work, this paper presents results from two independent studies examining the relationship between inflammation and resting state functional connectivity (rsFC), as measured by fMRI. METHODS: Study 1 involved 90 rural African-American young adults, age 25 years (52% female), and Study 2 involved 82 urban African-American youth, ages 13–14 (66% female). Both studies measured circulating inflammatory biomarkers (CRP, IL6, IL10, TNFα), which were averaged to form a composite. Study 2 also enumerated classical monocytes, a key leukocyte sub-population involved in immune-to-brain signaling. All participants completed a resting state fMRI scan. RESULTS: Consistent with prediction, higher scores on the inflammatory composite were associated with lower rsFC within an emotion regulation network in Study 1, controlling for sex. Study 2 replicated Study 1, showing that higher scores on the inflammatory composite were associated with lower rsFC within the emotion regulation network, controlling for sex, age and pubertal status, and found a similar pattern for rsFC within a central executive network. Study 2 also found that higher numbers of classical monocytes were associated with lower rsFC within both the emotion regulation and central executive networks. There was no relationship between rsFC in the anterior salience or default mode networks with inflammation in either study. CONCLUSIONS: These findings document relationships between peripheral inflammation and rsFC within an emotion regulation and central executive network, and replicate these associations with the emotion regulation network across two independent samples.

Over the last few years, the concept of food addiction has become a common feature in the scientific literature, as well as the popular press. Nevertheless, the use of the term “addiction” to describe pathological aspects of food intake in humans remains controversial, and even among those who affirm the validity of the concept, there is considerable disagreement about its utility for explaining the increasing prevalence of obesity throughout much of the world. An examination of the literature on food addiction indicates that mesolimbic and nigrostriatal dopamine systems often are cited as mechanisms that contribute to the establishment of food addiction. However, in reviewing this literature, it is important to have a detailed consideration of the complex nature of dopaminergic involvement in motivational processes. For example, although it is often stated that mesolimbic dopamine mediates “reward”, there is no standard or consistent technical meaning of this term. Moreover, there is a persistent tendency to link dopamine transmission with pleasure or hedonia, as opposed to other aspects of motivation or learning. The present paper provides a critical discussion of some aspects of the food addiction literature, viewed through the lens of recent findings and current theoretical views of dopaminergic involvement in food motivation. Furthermore, compulsive food intake and binge eating will be considered from an evolutionary perspective, in terms of the motivational subsystems that are involved in adaptive patterns of food consumption and seeking behaviors, and a consideration of how these could be altered in pathological conditions.

C OMMENTARY Cognitive Training in Schizophrenia: Golden Age or Wild West? Sophia Vinogradov, Melissa Fisher, and Srikantan Nagarajan ix years ago, at the first Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) meeting, a neuroscientist questioned whether attention dysfunction was malleable in schizophrenia, despite a recent report that patients were 5 times more likely to work when cognitive remediation was combined with supported employ- ment (1). The idea that impaired neural systems could demon- strate learning-induced plasticity was not part of the biological research lexicon at that point in time. Experimental neuroscien- tists were rightfully skeptical of a broad array of cognitive remediation interventions that were often studied under non- blinded and variously controlled conditions. Perplexing, also, was the homogeneity of effect sizes, despite widely varying treatment approaches, outcome measures, and length of intervention. S trained coach for 40 sessions of pencil-and-paper exercises in cognitive flexibility, working memory, and planning. After CRT, they demonstrated a reduction in overactivation of the central executive neural network independent component (CEN) as well as increased white matter integrity in the genu of the corpus callosum, compared with patients who met with a therapist for 40 sessions to discuss how to cope with symptoms and identify warning signs of relapse. Penade´s et al. (3) have driven the final nail into the coffin on the idea that the brain in schizophrenia is not malleable! The question is malleable in response to what? Which neurobehavioral mechanisms are driving that malleability? And what exactly does it represent in terms of both short-term and long-term significance? Golden Age or Wild West? Malleable in Response to What? Six years later, the field is at a tipping point. The systems neuroscience of learning-induced plasticity is a mature and sophisticated area of inquiry. Concomitantly, trials of cognitive enhancing medications in schizophrenia have been disappoint- ing, and investigators increasingly recognize that medications will need to be combined with cognitive enrichment strategies to drive meaningful clinical improvement. Studies of computerized cognitive training in schizophrenia show consistent patterns of increased prefrontal cortical activation as compared with various control conditions; the increased activation correlates with improvements in the trained cognitive domain, and in one instance, with transfer to an untrained meta-cognitive task and with better functioning at 6-month follow-up (2). Why, then, is the story not over? Why, when it comes to understanding how to optimize functionally meaningful and enduring cognitive improvement in schizophrenia, does it seem as if we have entered the Wild West rather than the Golden Age? How does one make sense of the plethora of computerized and noncomputerized behavioral training approaches described in the literature? Do we have any evidence whatsoever on the critical neural mechanisms that drive functionally meaningful change? Not surprisingly, the answers to these questions are complex, as highlighted by the report of Penade´s et al. (3) in this issue. Put simply, the field is poised between two opposing perspectives: one that more broadly focuses on treatment development versus a targeted focus on plasticity in defined neural systems (Table). In the study by Penade´s et al. (3), which belongs to the broad cognitive remediation legacy, 15 individuals with schizophrenia engaged in cognitive remediation therapy (CRT), meeting with a We do not know from the report by Penade´s et al. (3) whether the participants were blind to group allocation. We do not know whether the therapists in the control condition had the same training/enthusiasm/expectations for a positive outcome as did the CRT coaches, and we do not know whether the assessment personnel were blind to group assignment. Not only are all three factors a potential source of bias in the outcome data, they may actually represent critical mechanisms of neurobehavioral change. Almost half a century ago, Wagner (4) investigated brief attention and abstraction training in schizophrenia and found that the experimenter was a positive social reinforcer who clearly “enhanced the motivational condition of the subjects” and contributed to their improved cognitive performance. More recent research has established unequivocally that motivational factors and beliefs substantially affect people’s ability to recruit cognitive and neural resources to sustain learning over time (5). Thus, in the study by Penade´s et al. (3), as in many previous published reports, we cannot separate out the effects of nonspecific cognitive enhancing factors, such as therapist enthu- siasm, participant motivation and expectations, and general cognitive and socioaffective stimulation, from the effects of a specific neurobehavioral training strategy in a defined neural system (in this case, strategy coaching for executive functions and working memory). Such nonspecific cognitive enhancement is by no means a bad thing, and in clinical settings one would want to harness it as intentionally as possible, but in an experimental design, it confounds our ability to isolate and identify the precise mechanisms that drive critical responses in neural systems of interest. In this light, it is sobering to consider the highly rigorous double-blind study by Dickinson et al. (6) comparing a cognitive remediation program for schizophrenia based on problem-solving educational software plus therapist coaching versus game-based software plus coaching. This study tightly controlled for the effects of nonspecific cognitive enhan- cing factors such as participant expectation and therapist motivation and contact and found no significant group differences on neurocognitive or functional outcome measures, From the Departments of Psychiatry, (SV, MF) and Radiology and Biomedical Imaging (SN), University of California, San Francisco, San Francisco, California, and San Francisco Department of Veterans Affairs Medical Center (SV, MF), San Francisco, California. Address correspondence to Sophia Vinogradov, M.D., 116A–SFDVAMC, 4150 Clement Street, San Francisco, CA 94121; E-mail: sophia. vinogradov@ucsf.edu. Received Mar 20, 2013; accepted Mar 21, 2013. http://dx.doi.org/10.1016/j.biopsych.2013.03.015 BIOL PSYCHIATRY 2013;73:935–937 Published by Elsevier Inc on behalf of Society of Biological Psychiatry

Rapid advances in brain imaging have stimulated studies worldwide on the network architecture of the living brain, revealing general organizational principles in functional systems and the fiber connections that support them. Connectomics, a relatively new field stimulated by revolutionary developments in neuroimaging, has opened up a new landscape of discovery in neuroscience and has led to major international initiatives, such as the Human Connectome Project (1) (http://www.humanconnectomeproject.org). Maps of brain connectivity are shedding light on some of the most tantalizing questions in neuroscience: how the brain is organized, how it develops, and how it changes in disease. Statistical data on connection patterns are also being assembled into large databases, making it feasible to search for factors that affect connectivity, from neurogenetic disorders to bipolar disorder and schizophrenia, from therapeutic interventions to single letter differences in the human genome. As new methods emerge to assess brain connectivity, some research groups have begun to collect resting-state functional magnetic resonance imaging (rs-fMRI), diffusion-weighted imaging, and electroencephalography/magnetoencephalography to study the global breakdown of network integration in degenerative disease. Neuropsychologic deficits are often attributed to a disconnection between brain regions, sometimes producing a disconnection syndrome. The field of brain mapping has also evolved from reductionistic studies attempting to localize a brain dysfunction to a particular locus or structure in the brain to studies that examine the much more complex effects of disease, or experimental manipulations, on the connections or synchronization of activity throughout the brain. Wang et al. (2) reported a highly innovative study revealing how brain networks break down in Alzheimer's disease (AD). They use rs-fMRI and graph theory, a branch of mathematics used to study networks, to understand how functional connectivity degrades in people with amnestic mild cognitive impairment (MCI). MCI is a syndrome that carries a vastly increased risk of AD; approximately 15% of people with amnestic MCI per year develop symptoms sufficient for a diagnosis of AD. In their report, Wang et al. (2) used functional MRI to measure spontaneous, or so-called resting state, functional connectivity in the brain. To define a set of network nodes, they divide the cortical surface into 1024 regions and determine whether the time courses of activity are correlated between all pairs of such regions. In this kind of resting-state analysis, the activity of diverse brain regions is mapped, to infer functional connections between systems. The overall pattern of correlations may be broken down into statistical modes, including the default mode network (3), and other interacting systems whose properties can be manipulated experimentally. Wang et al. (2) took this approach further and studied correlations in functional signals within different frequency bands, using a wavelet transform method, to identify early signs of network failure in amnestic MCI. The brain can be described as a graph, or network, in which predefined cortical regions are connected by links, or edges, that describe the strength of correlations in their functional activity. In the study by Wang et al. (2), the amnestic MCI group showed decreased functional connectivity overall; a variety of network descriptors were correlated with the severity of cognitive impairment, suggesting that the deterioration of functional coherence contributes to impairment in recall ability. These same network metrics also distinguished MCI subjects from normal controls with high specificity and sensitivity, suggesting that they may be advantageous for diagnosis and tracking of AD, even in a prodromal phase when symptoms are subtle. As the authors noted, network measures could be used, in the future, to supplement other biomarkers from imaging, cerebrospinal fluid, genomics, and proteomics to better understand how AD pathology evolves and perhaps even to assist with differential diagnosis. The neural networks implicated by Wang et al. (2) are highly consistent with information gleaned from other imaging methods regarding the neuropathology of AD. The classical evolution of amyloid plaques and neurofibrillary tangles, hallmarks of AD that are documented in the highly cited work of (4), follows a relentless, spreading trajectory in the brain that is mirrored by a loss of neurons and their connections (Figure 1). The speed and trajectory of the spread differs in different patients, but the medial temporal circuitry of the hippocampus and entorhinal cortex are typically among the first to be involved, followed by parietal and limbic areas, and eventually frontal regions of the brain. Notably, the primary sensorimotor cortices are comparatively resistant to the effects of AD pathology, perhaps because of their high myelination levels, which may be protective. This progressive unraveling of brain integrity has been documented as a progressive wave of cortical thinning (5) and the dynamic spread of cerebral amyloid using positron emission tomography (PET) (6). One study showed that small-world measures of anatomical networks, computed from DTI, predicted future decline in people with mild cognitive impairment (7). Recent studies of familial AD also suggest an emerging wave of amyloid engulfing the brain decades before symptom onset. What makes these prodromal changes highly valuable is the fact that many of them occur well before overt cognitive symptoms become apparent. Figure 1 A comparison of several imaging modalities, illustrating typical differences among normal, MCI, and Alzheimer's disease subjects. This is a summary figure only, based on data from different studies and adapted to illustrate regional similarities. Tau ... Functional connectivity studies such as that of Wang et al. (2) lend insight and power to prior methods that have attempted to chart the spread of pathology. The current report also uses advanced mathematics to define new features for tracking and classification of brain disease. Wavelet methods and graph theory were once within the sole purview of pure mathematicians, but they now offer a remarkable way to sift through large and complex networks and home in on features that predict cognitive performance or clinical decline. Inevitably, the accumulation of pathology induces innumerable downstream changes in other brain systems not yet engulfed by pathology but reliant on functional connections with the impaired regions. If functional connectivity analyses can detect these system-wide changes, they will offer a powerful biomarker for earlier detection of AD and perhaps also for monitoring therapeutic effects. Evidence supporting a gradual disconnection process in AD has emerged from various techniques, including standard anatomical magnetic resonance imaging, electroencephalography, and PET. On diffusion-weighted magnetic resonance imaging, AD patients show a lower density of white matter association fibers in the cingulum, the splenium of the corpus callosum, and the superior longitudinal fasciculus. At the same time, interhemispheric functional synchronization also breaks down. Coherence studies by Wada et al. (8) found disturbed interhemispheric functional connectivity in AD, which has been linked to the disconnection syndrome observed clinically. PET studies also show reduced metabolism in a network of regions, with greater amyloid deposition in the posterior cingulate, retrosplenial, and lateral parietal cortex (9). Functional magnetic resonance imaging also shows deactivated regions that overlap with medial parietal/posterior cingulate regions that show reduced resting metabolic activity in AD subjects, compared with normal elderly and young adults (10). The use of connectomics to study brain disease is still in its infancy. Even the normal ranges of values for many network metrics, such as efficiency, clustering, and small-world properties, are not yet known. Work in large cohorts of developing and aging populations in our laboratories is attempting to define how such network measures change, and which markers are most reliable for defining changes, in terms robustness and ease of implementation across sites. As the field evolves from this stage of exuberant discovery to become a routine and integral component of clinical neuroimaging studies, we are likely to see efforts to harmonize analysis and acquisition methods across the world. This harmonization is currently being performed by large consortium efforts in neuroimaging genetics (e.g., the ENIGMA project, http://enigma.loni.ucla.edu; and ADNI, http://adni.loni.ucla.edu/). Such efforts will help us detect subtle factors, such as individual genetic polymorphisms, that affect brain connectivity. In the paper by Wang et al. (2), the appendix contains ample evidence to show that the effects are robust and do not depend on arbitrary choices in the analysis stream, such as the cortical regions used to define the network's nodes. This is in line with other technical efforts worldwide to determine how affected connectivity networks are by the protocols used to assess them. Data resolution, analysis methods, and scanner field strength all affect which kinds of connections are resolved. Recent studies show high-field imaging, at 7-Tesla, can pick up connectivity patterns generally consistent with lower-field scanners, but they also resolve additional connections and networks (11). As the field of connectomics evolves, we are likely to see a new landscape of collaboration among scientists aiming to understand networks of diverse kinds, from brain networks to genetic networks, to dissect and infer patterns and principles guiding information processing in the human brain.

This paper reviews recent developments in the phenomenology, neurobiology, and genetics of maternal behavior in animal model systems from an evolutionary perspective on psychopathology. Following a review of the phenomenology and neurobiology of maternal behavior, recent studies addressing the role of genetic factors in the maternal behavior of rodents were identified in a search of literature in peer-reviewed journals. Gene knockout studies were evaluated with regard to mouse strain background, method of behavioral phenotyping, and quantification of the behavioral deficits. Gene knockout data were then analyzed using a cluster analysis technique. At least nine genes have been identified that are necessary for the expression of one or more aspects of maternal behavior. These genes encode for three transcription factors: three enzymes, including dopamine beta hydroxylase and neuronal nitric oxide synthase; two receptors, including the prolactin and the estrogen alpha receptor; and one neuropeptide, oxytocin. Cluster analysis suggested possible relationships between specific genes. Gene knockout technology has provided new insights into the molecular basis of maternal behavior that are congruent with the existing neurobiological literature. Future studies of genetic and environmental influences on maternal behavior have the potential to inform models of disease pathogenesis.

Advances in brain imaging techniques have allowed neurobiological research to temporally analyze signals coding for the anticipation of rewards. In addicted populations, both hypo- and hyper-responsiveness of brain regions (e.g., ventral striatum) implicated in drug effects and reward system processing have been reported during anticipation of generalized reward. Here, we discuss the current state of knowledge of reward processing in addictive disorders from a widely used and validated task: the Monetary Incentive Delay Task (MIDT). The current paper constrains review to those studies applying the MIDT in addicted and at-risk adult populations, with a focus on anticipatory processing and striatal regions activated during task performance, as well as the relationship of these regions with individual difference (e.g., impulsivity) and treatment outcome variables. We further review drug influences in challenge studies as a means to examine acute influences on reward processing in abstinent, recreationally using and addicted populations. Here, we discuss that generalized reward processing in addicted and at-risk populations is often characterized by divergent anticipatory signaling in the ventral striatum. Although methodological/task variations may underlie some discrepant findings, anticipatory signaling in the ventral striatum may also be influenced by smoking status, drug metabolites and treatment status in addicted populations. Divergent results across abstinent, recreationally using and addicted populations demonstrate complexities in interpreting findings. Future studies will benefit from focusing on characterizing how impulsivity and other addiction-related features relate to anticipatory striatal signaling over time. Additionally, identifying how anticipatory signals recover/adjust following protracted abstinence will be important in understanding recovery processes.

This paper reviews prior research studies examining neurobiological correlates and treatment response of depression in children, adolescents, and adults. Although there are some similarities in research findings observed across the life cycle, both children and adolescents have been found to differ from depressed adults on measures of basal cortisol secretion, corticotropin stimulation post-corticotropin releasing hormone (CRH) infusion, response to several serotonergic probes, immunity indices, and efficacy of tricyclic medications. These differences are proposed to be due to 1) developmental factors, 2) stage of illness factors (e.g., number of episodes, total duration of illness), or 3) heterogeneity in clinical outcome (e.g., recurrent unipolar course vs. new-onset bipolar disorder). Relevant clinical and preclinical studies that provide support for these alternate explanations of the discrepant findings are reviewed, and directions for future research are discussed. To determine whether child-, adolescent-, and adult-onset depression represent the same condition, it is recommended that researchers 1) use the same neuroimaging paradigms in child, adolescent, and adult depressed cohorts; 2) carefully characterize subjects' stage of illness; and 3) conduct longitudinal clinical and repeat neurobiological assessments of patients of different ages at various stages of illness. In addition, careful attention to familial subtypes (e.g., depressive spectrum disorders vs. familial pure depressive disorders) and environmental factors (e.g., trauma history) are suggested for future investigations.

The variation in functional outcome in schizophrenia appears to be exaggerated in late life. The cognitive and functional deficits commonly seen in younger schizophrenic patients appear to worsen in some cases in late life, while others patients appear to have a stable course of illness without functional decline, and still other patients have been reported to have essentially no residual symptoms in their later years. Cognitive and functional deficits appear to worsen more significantly in patients with a lifetime course of severe functional deficit. Despite the profound functional and cognitive deficits in these patients, neuropathologic studies have found no evidence of typical causes of severe cognitive impairments. This paper reviews the current findings on cognitive and functional changes in aging in schizophrenia, with a specific focus on patients with a poor lifetime functional outcome.

Social phobia (or "social anxiety disorder") is a prevalent condition that has been the subject of increased scrutiny in recent years. The purpose of this paper is to review the neurobiology of social phobia. It is apparent from the extant literature that this disorder is poorly understood from a neurobiological perspective. There are nonetheless a number of clinical and preclinical observations which, at times, converge to illuminate areas worthy of further study. Included in this category are suggestive findings of central serotonergic dysregulation in social phobia, response to serotonin reuptake inhibitors in social phobia, and the role of serotonergic function in septohippocampal models of anxiety. Abnormalities in central dopaminergic function are also posited, supported to some extent by recent neuroimaging findings. There are in addition a number of animal and human behavioral models in existence that may be relevant to the study of social phobia. Included in this category are models of social dominance in wild baboons, social affiliation in the prairie vole, and behavioral inhibition to the unfamiliar in childhood. Newer technologies that are likely to play a major role in the delineation of the neural circuitry (e.g., functional magnetic resonance imaging) and heritability (e.g., molecular genetics) of social phobia are discussed. Finally, an interactive role for biology and experience in the expression of social phobia is considered.

This paper reviews the pathophysiology of panic disorder (PD), within the context of newly described "fear circuitries," which have been well characterized in preclinical models. Substantial advances in the neurosciences have made it possible for clinical neuroscientists to refine our understanding of the pathophysiology of PD and the mechanisms of currently effective treatment. These advances have in turn helped generate testable hypotheses for future neurobiological and psychopharmacologic research. Perturbation of mutual modulation ("cross talk") between key brain transmitter systems (serotonin, norepinephrine, gamma-aminobutyric acid, corticotropin-releasing factor, and others) may underlie the pathogenesis of panic-anxiety. Restoration of normal homeostasis may be an important therapeutic component of antipanic therapy and may provide information about underlying neurocircuits. Neuroimaging, an important new tool, has already begun to bridge the gap between the preclinical and clinical neurosciences through confirmation of hypothesized dysfunction of the complex human prefrontal cortex and its subcortical components. In higher species, such as humans, dysfunction of cortical inhibition or excessive cortical activation of caudal limbic structures is postulated to lead to activation of the phylogenetically conserved amygdalofugal pathways. Consistent with probable subtypes of PD, overlapping theoretical models of panic neurocircuitries are proposed, including ventilatory dysregulation, which is coupled with neurovascular instability in a critical area of the panic neurocircuitry--the amygdalohippocampus. Neuroimaging appears a critical tool in guiding further elaboration of the interaction of cortical and subcortical components of the panic neurocircuitry, whereas challenge studies appear crucial in gathering further information regarding brain stem dysfunction.

Background: A neural network computer model described in a companion paper predicted the effects of increased dopamine transmission on selective attention under two different hypotheses. Methods: To evaluate these predictions we conducted an empirical study in human subjects of D-amphetamine effects on performance of the Eriksen response competition task. Ten healthy volunteers were tested before and after placebo or D-amphetamine in a double-blind crossover design. Results: D-amphetamine induced a speeding of reaction time overall and an improvement of accuracy at fast reaction times but only in the task condition requiring selective attention. Conclusions: This pattern of results conforms to the prediction of the model under the hypothesis that D-amphetcmine primarily affects dopamine transmission in cognitive rather than motor networks. This suggests that the principles embodied in parallel distributed processing models of task performance may be sufficient to predict and explain specific behavioral effects of some drug actions in the central nervous system.

To study the relationships between clinical and biological data that are necessary for physiopathological analysis in the field of developmental disorders, we developed a quantified grouping system, based on four developmental assessment parameters. Parallel with this clinical research, we developed electrophysiological procedures adapted to the pathology of autism. In this paper, we report the utilization of an original multivariate descriptive statistical approach (correspondence analysis followed by cluster analysis) that allowed us to identify different bioclinical profiles using these clinical and electrophysiological data conjointly. These profiles are believed to be evidence for different underlying cerebral dysfunctions. This procedure proved effective in identifying two main bioclinical dimensions in a population of 145 developmentally disordered children. These dimensions reflect the association of intellectual impairment and centroparietal electrophysiological reactivity on the one hand, and autistic behavior and temporal electrophysiological reactivity on the other. This study, performed on a large population of children using objective methods of data analysis, provides validation of numerous multidisciplinary studies of autism and other developmental disorders carried out on small samples of children.

To the Editor: We read with great interest the papers relating food and addiction in Biological Psychiatry, Volume 73, Number 9. We agree with the Commentary written by Gearhardt & Brownell (pp. 802-3) that the food addiction model can be a game changer and have summarized this evidence previously(1, 2). Reviews of the neurobiology by Smith and Robbins emphasizing opioid systems in drug and food addiction (pp. 804-10) and Newman et al. suggesting the importance of Gamma Aminobutyric Acid (pp 843-50), along with Volkow & colleagues suggesting that neurobiological advances can help us develop new prevention and treatment for overeating based on addiction models (pp. 811-18) resonate with us. One of us had reported naltrexone effects in binge eating in humans in the 1980s (3). Binge eating affects reward-related brain regions, and pharmaceutical treatments for drug addiction can also be effective in treating overeating(4). The GABA-B agonist baclofen can reduce intake of dietary fat, and the opioid antagonist naltrexone can suppress intake of some foods. The study we reported at ACNP (5) tested the effects of naltrexone-baclofen combinations on binge intake of diets consisting of palatable nutrients. Male Sprague-Dawley rats were given binge access to standard chow and a sugar solution, fat emulsion, or sugar-fat emulsion for 21 days. Rats were then administered (i.p.) naltrexone (0.1 or 1.0 mg/kg), baclofen (1.0 or 1.8 mg/kg) and naltrexone-baclofen (0.1 mg/kg naltrexone and 1.0 mg/kg baclofen, or 1.0 mg/kg naltrexone and 1.8 mg/kg baclofen) and food intake was monitored. Naltrexone-baclofen (1.0 and 1.8 mg/kg, respectively) significantly suppressed binge eating of sugar-fat emulsion. This combination was also superior to either drug alone at reducing binge consumption of the fat emulsion or sugar solution. Baclofen (1.8 mg/kg) significantly reduced binge eating of the fat and sugar-fat emulsions, but naltrexone (1.0 mg/kg) did not show a significant effect on binge consumption in either of these groups. These findings suggest that the combination of baclofen and naltrexone is superior to either drug alone in suppressing binge intake of palatable foods rich in fat and/or sugar. This drug combination may be useful as a therapeutic tool for patients who binge eat, and it also provides a novel pharmacological support for the food addiction hypothesis as both of these medications are used in alcohol dependence and other addictions. Research led by Bart Hoebel, which has been continued by his junior colleague Nicole Avena since his death, has used animal models to show that rats will readily self-administer sugar in ways that resemble drugs of abuse, with loss of control, cross tolerance, failed attempts to quit, and withdrawal signs and symptoms produced spontaneously by opiate antagonist administration(6). This laboratory model might yield new treatments as Volkow has suggested, and it provides a unique way to assess the effects of the act of overeating of palatable foods, like sugars, independent of obesity. Successful treatments for hedonic overeating would not only provide support for the food addiction hypothesis, but also suggest a common mechanism through which addictive behaviors may occur.

Many studies in biological psychiatry compare the abundance of individual messenger RNAs between cases and control subjects or, more recently, between genotype groups. Most utilize some form of normalization procedure, usually expressing the transcript(s) of interest relative to that of a housekeeping gene or genes (also called reference genes), to overcome various sources of experimental error. Indeed, normalization is such a standard procedure that its purpose, principles, and limitations are sometimes overlooked, and some papers lack sufficient information as to its implementation. Here, we review the rationales for normalization and argue that in well-conducted psychiatric gene expression studies using human brain tissue, it is reducing intersubject variability rather than experimental error that is the major benefit of normalization. We also review the conceptual and empirical basis for the category of housekeeping genes—i.e., genes with a ubiquitous and invariant expression. We conclude that the evidence is against any such simple categorization and that a more pragmatic, less dogmatic, approach to the selection and implementation of reference genes is required, which takes into account the particular issues that pertain to human brain tissue studies. This pragmatism extends to the issue of whether normalization should be to one or multiple reference genes. We end by making several recommendations toward a more flexible, transparent, and comprehensive approach to data presentation and analysis. We illustrate the review with examples from studies of schizophrenia and mood disorder.

It has long been suspected that brain norepinephrine (NE) plays important roles in addiction, but this view has been largely overshadowed in recent years by prominent attention to other brain systems involved in addiction such as dopamine and glutamate, and even more recently, orexin (1, 2). However, new studies have begun to reverse this trend by providing compelling evidence for the importance of NE in addiction, as exemplified by 2 articles in the current issue (Schank et al., Zachariou et al.). Early studies of NE and addiction focused on opiates and opiate withdrawal. Opiates strongly inhibit impulse activity of NE locus coeruleus (LC) neurons, and opiate withdrawal strongly activates these cells, leading to the view that LC plays an important role in opiate abuse. However, lesions of LC or its projections have no effect on physical or aversive signs of acute opiate withdrawal (3, 4). Certainly, the highly elevated activity of LC neurons during withdrawal has consequences for behavior, but those consequences remain unclear. Recent studies have shown that NE neurons other than LC are important in opiate abuse. Thus, beta adrenoceptor stimulation in bed nucleus of the stria terminalis (BNST) is critical for the aversiveness of opiate withdrawal; this NE primarily originates from medullary A1 and A2 NE cells, not LC (4). This same NE input and receptor in BNST was found to be critical for stress-induced anxiety (5), suggesting that the aversiveness of opiate withdrawal may be related to withdrawal-induced anxiety (see figure 1 illustrating NE input to the BNST). Figure 1 Schematic illustrating NE projections to the BNST in rat brain, and subsequent outputs from the BNST to other regions of the limbic system. In the case of opioid withdrawal, activation of NE neurons in the NTS and A1 cell groups enhance NE release in ... Fewer studies have examined brain NE involvement in stimulant abuse. One article in the present issue extends analysis of NE and addiction in psychostimulant abuse, and some of the same themes appear as for opiate abuse. Aside from its well-known rewarding/reinforcing effects, acute cocaine also acts as a potent anxiogenic agent (6). Schank et al. (pg * of this issue) uses the elegant, recently developed dopamine-beta-hydroxylase (DBH) knock-out mouse to show that central NE is necessary for such cocaine-induced anxiety. This animal model lacks the DBH enzyme, which is essential for making NE from dopamine. Using a standard anxiety test (elevated plus maze), the investigators found that DBH knockouts do not exhibit an anxiety response to an acute cocaine injection, whereas wild-type mice do. Importantly, anxiety in these DBH knockouts could be rescued by administration of DOPS, a compound that can be converted into NE without need for DBH and without altering dopamine levels. In an unusual but strong step in a knockout study, the investigators then confirmed the above results with pharmacological manipulations in wild type mice, showing that the DBH inhibitor disulfiram, or the beta adrenoceptor antagonist propranolol, but not alpha1 or alpha2 adrenoceptor antagonists, produced a similar behavioral result. Thus, these studies indicate that anxiogenic effects of cocaine are due, at least in part, to NE acting at beta adrenoceptors. These results are consistent with many previous findings that link elevated brain NE with anxiety. Importantly, these results also resemble findings that elevated anxiety during withdrawal from opiate or cocaine is dependent upon beta receptor stimulation (7). As the authors point out, this withdrawal-induced anxiety may be a point where their findings are most relevant to clinical treatment. Because avoidance of withdrawal responses is a driving factor in relapse during abstinence, treatments that limit NE-linked anxiety may prolong abstinence and reduce relapse. This conclusion is consistent with previous findings that stress-induced reinstatement of cocaine-seeking is also blocked by beta adrenoceptor antagonist treatments (8). This relationship between the anxiety of acute cocaine and that of cocaine withdrawal is somewhat paradoxical at first — why would acute cocaine produce a response that resembles a response to cocaine withdrawal? Determining the cellular substrates of these noradrenergically-mediated anxiety responses will be important work for the future. Whatever the cellular mechanism underlying these anxiety responses, they are significant because they illustrate another paradoxical issue that may provide insights into important aspects of cocaine abuse. That is, in addition to its hedonic and reinforcing actions, acute cocaine produces anxiety, i.e., a withdrawal-like response. The desire to avoid withdrawal-associated anxiety may lead then lead to cocaine craving and intake, generating additional anxiety and again associated craving. Thus, similar anxieties produced by acute cocaine and cocaine withdrawal can produce a positive feedback cycle that may underlie some of the more insidious and clinically important aspects of cocaine abuse. This suggests that treating NE-driven anxiety associated with acute cocaine and cocaine withdrawal may be clinically beneficial. One outstanding question in this study is where NE is acting to drive anxiety- or stress-related responses to cocaine. Previous work indicates that the extended amygdala is a good possibility, particularly BNST. Delfs et al (4) showed that beta adrenocceptor stimulation in BNST is critical for the aversiveness of acute opiate withdrawal, and the associated source of NE is medullary A1 and A2 neurons. Subsequent studies showed that this same pathway is necessary for stress-induced reinstatement of cocaine- or opiate-seeking (9). As noted above, this same pathway is also strongly associated with stress-induced anxiety responses (5). Thus, medullary NE projections into the extended amygdala are importantly involved in these anxiety/stress responses linked to drug relapse. One important extension of the Schank et al study would be to determine if this pathway is also involved in the anxiogenic effects of acute cocaine; such a finding would further establish links between anxiety associated with acute cocaine and withdrawal, and focus research on further elucidation of mechanisms and treatments for these anxiety responses. As noted above, one important outstanding issue is how cocaine and opioids produce changes in NE neurons to alter associated behavioral responses to stress and anxiety. Stress and anxiety have a well-defined and broad association with drug addiction, ranging from precipitating relapse to being a vulnerability factor in developing addiction. Therefore, understanding the molecular adaptations produced by addictive drugs in NE neurons has the potential to reveal molecular targets for developing therapies to control addiction. In this volume, the paper by Zachariou et al (*) takes an important step in this direction. Based upon the well established relationship between changes in adenylyl cyclase (AC) activity, NE neuronal activity and the chronic morphine-induced withdrawal syndrome, these authors employed mice with genetic deletions in two of the three AC isoforms that are activated by calcium/calmodulin, AC1 and AC8. In addition, a mouse sustaining a double deletion of AC1 and AC8 was examined. Although findings with the AC1+AC8 knock out mice (KO) appeared partly confounded by compensatory changes, single deletion of each isozyme produced a consistent phenotype that was relatively resistant to the effects of chronic morphine, including reduced naloxone-precipitated behavioral withdrawal and decreased potentiation of basal firing rates and forskolin-induced firing of LC NE neurons. Furthermore, the development of tolerance in LC neurons to inhibition by mu opioids was attenuated in the AC1 and AC8 KO mice. Importantly, the acute analgesic effect of morphine and the development of tolerance to morphine-induced analgesia were intact in all three KO genotypes. These data nicely confirm the role of AC in regulating morphine-induced withdrawal syndrome, and the association between AC activity and morphine withdrawal. Perhaps the most important aspect of the Zachariou et al. is in making the first attempt to screen gene expression patterns in the LC for potential correlates of morphine withdrawal. This is a daunting task for many reasons, including tissue and individual behavioral heterogeneity. However, comparing the profile of morphine induced changes in gene expression between genotypes that present distinct phenotypic behavioral and electrophysiological responses to chronic morphine might permit the identification of the morphine-induced changes associated with withdrawal. Unfortunately, while this first valiant attempt at such broad genetic profiling of LC neurons did identify interesting distinctions between the genotypes, many of which were in line with expectations based upon earlier studies, it did not reveal a small number of clear candidates to target in future studies. In retrospect, it is perhaps overly optimistic to expect even the impressive database generated in this report to contain sufficient information to identify critical common factors regulating a complex behavior such as opiate withdrawal; especially given that the genetic model used was a constitutive deletion of the gene encoding an AC isozyme and that the deletion was throughout the brain and not specific to the LC. The solution of course is that this report be an important first step in future studies using additional genetic approaches to further isolate and evaluate components of the genome that may strongly regulate the withdrawal phenotype induced by chronic opioids.

This paper reviews the evidence that antipsychotic drugs induce neuroplasticity. We outline how the synaptic changes induced by the antipsychotic drug haloperidol may help our understanding of the mechanism of action of antipsychotic drugs in general, and how they may help to elucidate the neurobiology of schizophrenia. Studies have provided compelling evidence that haloperidol induces anatomical and molecular changes in the striatum. Anatomical changes have been documented at the level of regional brain volume, synapse morphology, and synapse number. At the molecular level, haloperidol has been shown to cause phosphorylation of proteins and to induce gene expression. The molecular responses to conventional antipsychotic drugs are predominantly observed in the striatum and nucleus accumbens, whereas atypical anti-psychotic drugs have a subtler and more widespread impact. We conclude that the ability of antipsychotic drugs to induce anatomical and molecular changes in the brain may be relevant for their antipsychotic properties. The delayed therapeutic action of antipsychotic drugs, together with their promotion of neuroplasticity suggests that modification of synaptic connections by antipsychotic drugs is important for their mode of action. The concept of schizophrenia as a disorder of synaptic organization will benefit from a better understanding of the synaptic changes induced by antipsychotic drugs.

Background: Abnormalities of dopamine function in schizophrenia are suggested by the common antidopaminergic properties of antipsychotic medications. However, direct evidence of a hyperdopaminergic state in schizophrenia has been difficult to demonstrate, given the difficulty to measure dopamine transmission in the living human brain. Such evidence has recently emerged. Three studies reported an increase in dopamine transmission following acute amphetamine challenge in patients with schizophrenia compared to matched healthy control subjects, thus demonstrating a dysregulation of dopamine in schizophrenia. In all studies, a large variance was observed within the schizophrenic group in the magnitude of this finding, and clinical predictors of this effect could not be identified. Methods: In this paper, we combined previously published and newly acquired data to obtain sufficient power to address this question. Results: The most important findings derived from this extended data set are: 1) dysregulation of dopamine function revealed by the amphetamine challenge is present at onset of illness and in patients never previously exposed to neuroleptic medications; 2) this dysregulation was observed in patients experiencing an episode of illness exacerbation, but not in patients studied during a remission phase. Conclusions: A hyperdopaminergic state is present in schizophrenia during the initial episode and subsequent relapses, but not in periods of remission. This finding has important consequences for the development of new treatment strategies for the remission phase.

Recent attention has been focused on the involvement of serotonin (5-HT) in the pathophysiology of schizophrenia and its role in mediating antipsychotic drug effects. There are two reasons for the new emphasis: the tremendous success of the so-called "atypical" antipsychotic drugs (a common feature of which is their high affinity for specific 5-HT receptor subtypes); and the elucidation of a complex family of 5-HT receptors whose function and pharmacology is only beginning to be understood. This paper will review the evidence that pertains to the role of 5-HT in mediating antipsychotic drug effects. The interaction of dopamine and 5-HT systems will be reviewed, and the mechanisms of action of atypical antipsychotic drugs will be evaluated in this context. The impact of serotonin on neurodevelopment, and the involvement of serotonin in the psychotomimetic and psychotogenic properties of hallucinogens, will be discussed. Together, these facts will be placed into the context of changes in serotonergic function in schizophrenia.

Depersonalization remains a fascinating and obscure clinical phenomenon. In addition to earlier Jacksonian neurobiological adumbrations, and conventional psychodynamic accounts, views started to be expressed in the 1930s that depersonalization might be a vestigial form of behavior, and since the 1960s that it might be a phenomenon related to the temporal lobe. Recent advances in the neurobiology of the limbic system, and the application of Geschwind's concept of disconnection in the corticolimbic system, have opened the possibility of developing testable models. This paper includes a review of these ideas and of the clinical features of depersonalization, particularly of its emotional changes, suggesting that they are important for the neurobiological understanding of depersonalization. It also draws attention to clinical similarities between the experiential narratives produced by patients suffering from depersonalization and those with corticolimbic disconnections. On the basis of this, a new model is proposed according to which the state of increased alertness observed in depersonalization results from an activation of prefrontal attentional systems (right dorsolateral prefrontal cortex) and reciprocal inhibition of the anterior cingulate, leading to experiences of "mind emptiness" and "indifference to pain" often seen in depersonalization. On the other hand, a left-sided prefrontal mechanism would inhibit the amygdala resulting in dampened autonomic output, hypoemotionality, and lack of emotional coloring that would, in turn, be reported as feelings of "unreality or detachment."

Background: Dopamine affects neural information processing, cognition, and behavior; however, the mechanisms through which these three levels of function are affected have remained unspecified. We present a parallel-distributed processing model of dopamine effects on neural ensembles that accounts for effects on human performance in a selective attention task. Methods: Task performance is stimulated using principles and mechanisms that capture salient aspects of information processing in neural ensembles. Dopamine effects are simulated as a change in gain of neural assemblies in the area of release. Results: The model leads to different predictions as a function of the hypothesized location of dopamine effects. Motor system effects are simulated as a change in gain over the response layer of the model. This induces speeding of reaction times but an impairment of accuracy. Cognitive attentional effects are simulated as a change in gain over the attention layer. This induces a speeding of reaction times and an improvement of accuracy, especially at very fast reaction times and when processing of the stimulus requires selective attention. Conclusions: A computer simulation using widely accepted principles of processing in neural ensembles can account for reaction time distributions and time-accuracy curves in a selective attention task. The simulation can be used to generate predictions about the effects of dopamine agonists on performance. An empirical study evaluating these predictions is described in a companion paper.

A large body of literature has emerged concerning the role of the neurotransmitter serotonin (5-hydroxytryptamine, or 5-HT) in the regulation of alcohol intake and the development of alcoholism. Despite the wealth of information, the functional significance of this neurotransmitter remains to be fully elucidated. This paper, part one of a two-part review, summarizes the available clinical research along two lines: the effects of alcohol on serotonergic functioning and the effects of pharmacological manipulation of serotonergic functioning on alcohol intake in normal (nonalcohol dependent) and alcohol-dependent individuals. It is concluded that considerable evidence exists to support the notion that some alcoholic individuals may have lowered central serotonin neurotransmission.

This paper concerns assessment of the full range of risks associated with prolonged use of antipsychotic medication. It is generally accepted that the most common side effects of drug therapy involve motor problems. Movement disorders arise because antipsychotics, in a substantial proportion of patients, disrupt the basal ganglia. The basal ganglia, however, are involved in much more than simply motor control. Specifically, this neural system has been implicated in sensory reactivity, attention, memory, and cognition. It follows from this that antipsychotic drugs, in addition to causing motor problems, might also disrupt complex psychological processes.

We and others have shown that in vitro tryptoline (tetrahydro-beta-carboline) formation accounts for the apparent-N-methylating activity of a brain enzymatic preparation using 5-methyltetrahydrofolic acid (5-MTHF) as a cofactor and tryptamines or catecholamines as substrates. This paper demonstrates that N5,10-methylenetetrahydrofolate reductase (methylene reductase) is responsible for this in vitro tryptoline formation with human brain enzymatic preparations. Others have described a folate-responsive psychosis which was associated with markedly reduced methylene reductase activity. Therefore, we also have examined this enzymatic activity in autopsied brains from chronic schizophrenics and controls. There were no statistically significant differences between activities for schizophrenics and controls in the six brain regions studied. Thus, although it is possible that some subgroup of schizophrenics may be characterized by abnormal methylene reductase activity, there does not appear to be a general association between the two.

Several writers, notably Montague Ullman and Frederick Snyder, conceive of REM sleep and the associated state of vivid dreaming as periods of vigilance. In Ullman's conceptualization, the emphasis is on dreaming in humans, whereas Snyder is concerned with REM sleep (activated sleep) in subhuman organisms. In this paper several objections to the sentinel and vigilance theories are raised, and a modified concept of vigilance, linking it with learning and memory, is put forward.

Background Prolonged high-dose anabolic-androgenic steroid (AAS) use has been associated with psychiatric symptoms and cognitive deficits, yet we have almost no knowledge of the long-term consequences of AAS use on the brain. The purpose of this study is to investigate the association between long-term AAS exposure and brain morphometry, including subcortical neuroanatomical volumes and regional cortical thickness. Methods Male AAS users and weightlifters with no experience with AASs or any other equivalent doping substances underwent structural magnetic resonance imaging scans of the brain. The current paper is based upon high-resolution structural T1-weighted images from 82 current or past AAS users exceeding 1 year of cumulative AAS use and 68 non–AAS-using weightlifters. Images were processed with the FreeSurfer software to compare neuroanatomical volumes and cerebral cortical thickness between the groups. Results Compared to non–AAS-using weightlifters, the AAS group had thinner cortex in widespread regions and significantly smaller neuroanatomical volumes, including total gray matter, cerebral cortex, and putamen. Both volumetric and thickness effects remained relatively stable across different AAS subsamples comprising various degrees of exposure to AASs and also when excluding participants with previous and current non-AAS drug abuse. The effects could not be explained by differences in verbal IQ, intracranial volume, anxiety/depression, or attention or behavioral problems. Conclusions This large-scale systematic investigation of AAS use on brain structure shows negative correlations between AAS use and brain volume and cortical thickness. Although the findings are correlational, they may serve to raise concern about the long-term consequences of AAS use on structural features of the brain.