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This paper proposes a heuristic framework for an Addictions Neuroclinical Assessment (ANA) that incorporates key functional domains derived from the neurocircuitry of addiction. We review how addictive disorders (AD) are presently diagnosed, and the need for new neuroclinical measures to differentiate patients who meet clinical criteria for addiction to the same agent while differing in etiology, prognosis and treatment response. The need for a better understanding of the mechanisms provoking and maintaining addiction, as evidenced by the limitations of current treatments and within-diagnosis clinical heterogeneity, is articulated. In addition, recent changes in the nosology of AD, challenges to current classification systems, and prior attempts to subtype individuals with AD are described. Complementary initiatives, including the Research Domain Criteria (RDoC) project, which have established frameworks for the neuroscience of psychiatric disorders, are discussed. Three domains, executive function, incentive salience, and negative emotionality, tied to different phases in the cycle of addiction, form the core functional elements of AD. Measurement of these domains in epidemiologic, genetic, clinical, and treatment studies will provide the underpinnings for an understanding of cross-population and temporal variation in addictions, shared mechanisms in addictive disorders, impact of changing environmental influences, and gene identification. Finally, we show that it is practical to implement such a deep neuroclinical assessment using a combination of neuroimaging and performance measures. Neuroclinical assessment is key to reconceptualizing the nosology of AD on the basis of process and etiology, an advance that can lead to improved prevention and treatment.

This work is based on histological examination with the light microscope of Nissl-stained frogs’ retinae following melatonin and lysergic acid die~ylamide (LSD) administ~tion. In a previous paper (Kemali et al. 1983) we have demonstrated with the light microscope that administration of LSD induced in the frog retina a modification of the pigment screening (PS) pattern through some unknown mechanism. PS is a phenomenon encountered in the retina of low vertebrates and involves the migration of melanin granules from the retinal pigment epithelium in response to illumination changes. In the light, melanin granules disperse along the pigment epithelium processes, which protrude among the outer segments of the photoreceptors. In the dark, on the other hand, melanin granules aggregate within the cell body of the pigment epithelium (for review see Nguyen-Legros 1978). In another earlier paper (Kemali et al. 1984) we have demons~ated that the adminis~ation of dopaminergic agents to the frog did not induce any substantial modifications of this PS pattern, suggesting that dopamine is probably not directly involved in this retinomotor phenomenon, The aim of the present investigation was to

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.

Recognition memory judgments can be based on recollection of qualitative information about an earlier study event or on assessments of stimulus familiarity. Schizophrenia is associated with pronounced deficits in overall recognition memory and these deficits are highly predictive of global functioning. However, the extent to which these deficits reflect impairments in recollection or familiarity is less well understood. In the current paper, we reviewed studies that utilized remember-know-new (RKN), process dissociation (PD), and receiver operating characteristic (ROC) procedures to investigate recollection and familiarity in schizophrenia. We also performed a quantitative reanalysis of these study results to obtain recollection and familiarity estimates that account for methodological differences between studies. Contrary to previous conclusions that recollection is selectively impaired in schizophrenia, we found evidence for both familiarity and recollection deficits across studies, suggesting multi-focal medial temporal lobe and/or prefrontal cortex dysfunction. The familiarity deficits were more variable with frequent small to medium rather than medium to large effect sizes, suggesting that familiarity could be potentially utilized as a compensatory ability while recollection is conceptualized as a therapeutic target for new treatment development.

In their recent paper, “Poststress block of kappa opioid receptors rescues long-term potentiation of inhibitory synapses and prevents reinstatement of cocaine seeking,” Polter and colleagues showed that cold-water swim stress exposure blocks LTP of GABAergic synaptic input recorded in ventral tegmental area (VTA) dopamine neurons of male Sprague-Dawley rats (1). The effects of stress exposure on LTPGABA were blocked by pretreatment with the glucocorticoid antagonist RU-486 or the kappa opioid receptor (KOR) antagonist norbinaltorphimine (norBNI). Importantly, norBNI given 4 days after stress exposure could reverse the effects of swim-stress on LTPGABA and block stress-induced reinstatement of cocaine self-administration. Because stress-exposure is such a well-recognized risk factor for the development of compulsive drug abuse and relapse during intervals of abstinence, the demonstration that norBNI given after stress exposure could promote stress-resilience and reverse the adverse effects of prior stress exposure are important preclinical advances in the development of addiction therapeutics. The Polter study also increases our understanding of the complex effects of stress on the reward circuitry controlling addictive drug effects. Multiple synaptic inputs converge on the VTA dopaminergic neurons to regulate their excitability, and these neurons, in turn, project broadly to critical targets in the brain to coordinate the drug seeking behaviors initiated by addictive drugs (2) (Figure 1). Understanding this circuit and defining the effects of stress-mediators on the functioning of these neurons seems vital in the development of novel treatments for addiction, which has appropriately been described as a ‘stress-surfeit’ disorder by Koob and colleagues (3). The intimate relationship between stress vulnerability and addiction risk was summarized there and in other reviews on this topic, and the reciprocal concepts that stress exposure increases addiction risk and that addictive drug exposure increases stress vulnerability have now been supported by an extensive literature. Breaking this cycle by blocking the actions of the stress-mediators holds great promise, but understanding how these antagonists act on the reward circuit requires the kind of high-resolution circuit analysis described by Polter and colleagues (1). Figure 1 The ventral tegmental area (VTA) is a key player in the brain’s reward system, and the stress-mediators CRF, corticosterone, and dynorphin have dramatic effects on the neurophysiology of this brain region. Some of the principal actions of dynorphin ... Stress exposure produces adaptive physiological responses vital for the individual’s survival. As such, some mildly stressful experiences can be perceived as ‘exciting’ and positive when controlled by the individual, but persistent uncontrolled stressful experiences are aversive and can cause lasting changes in the reward circuitry (4). Corticotrophin releasing factor (CRF) orchestrates the classically recognized stress response by activating the hypothalamic-pituitary-adrenal glucocorticoid response, but CRF also acts intracerebrally to produce some of the cognitive and emotional responses to stress. These can be adaptive by promoting escape behaviors, but can be maladaptive when promoting mood and cognitive disorders. The mechanisms of these maladaptive responses are being actively studied by many research groups, but a key role of CRF-induced activation of the endogenous dynorphin opioid peptides and their cognate kappa opioid receptors has been implicated as essential mediators of these adverse responses (5). Dynorphins have been shown to encode the dysphoric effects of stress (6); stress-induced release of dynorphins potentiates the rewarding effects of drugs of abuse including cocaine, ethanol, and nicotine (7); and the dynorphins mediate stress-induced reinstatement of drug seeking behaviors (5). Mice lacking the prodynorphin or KOR genes or pretreated with the KOR antagonists norBNI or JDtic demonstrate stress-resilience in assays of anxiety-like, aversion, and reinstatement behaviors (5). This preclinical research suggests that KOR antagonists may have therapeutic potential, and results from early clinical studies support this conception (8). Nevertheless, understanding of how dynorphin acts in brain to increase addiction and mood disorder risk is still incomplete. Kappa opioid regulation of serotonergic inputs from dorsal raphe to nucleus accumbens (NAc) has been described (9). Dynorphin released during stress exposure within the NAc (presumably by prodynorphin-expressing medium spiny neurons) activates KOR expressed on serotonergic nerve terminals; KOR stimulation activates p38 MAPK to increase cell surface expression of the serotonin transporter SERT; and the resulting transient hyposerotonergic state in the NAc is necessary for stress-induced aversion, social avoidance and reinstatement of extinguished cocaine place preference (9). The Kauer lab has previously demonstrated that stress can block long-term potentiation of GABAergic inputs onto dopamine neurons (10). They further demonstrated that this effect of stress requires KOR activation, as it is blocked by pretreatment with either the mixed opiate antagonist naloxone or the selective KOR antagonist norBNI. Intriguingly, they also showed that selective injection of norBNI into the VTA attenuates stress-induced reinstatement to cocaine self-administration. This suggests that the potentiation of GABAergic signaling onto dopaminergic neurons may play a key role in reinstatement of cocaine-seeking behavior. In this issue, Polter et al follow-up on that observation by probing the duration of stress-induced blockade of LTPGABA (1). They find that stress blocks LTPGABA at 1 and 5, but not 10 days after exposure to a single cold water forced swim. They further find that norBNI administered after stress still blocks its effects on GABAergic signaling, whether administered at 2 hr, 24 hr, or 4 days after stress exposure. This is independent of any effect on glucocorticoid signaling, as the authors confirmed results reported previously showing that norBNI pretreatment fails to alter serum corticosterone after stress exposure. Further, although the glucocorticoid receptor antagonist RU-486 can also block the effects of stress on LTPGABA induction, it only does so if administered within one hour of stress exposure. But most dramatically, they demonstrate that after extinction of cocaine self-administration, norBNI can block stress-induced reinstatement of cocaine-seeking even if administered subsequent to stress. These two results combined strongly suggest that in cocaine-experienced animals, a single stress exposure can induce a long-lasting state of dynorphin release and/or KOR activation that can mediate substantial alterations to behavior. Future studies are needed to further define the key elements of this neural circuit and the sites of stress-induced regulation. The Polter et al study used systemic norBNI administration, and subsequent studies using cell-specific activation and inactivation methods will be revealing. For instance, it has also been demonstrated that KOR activation in the dorsal raphe nucleus is required for stress-induced reinstatement of place preference for cocaine (6). KOR-induced activation of p38 MAPK is also required for CPP reinstatement, an effect that may be mediated specifically by KORs located on serotonergic terminals within the nucleus accumbens (9). If stress acts by inducing a long-lasting state of ongoing dynorphin release, it is also possible that the effect may be mediated by inhibition of dopamine release via action at terminals in the nucleus accumbens, medial prefrontal cortex or even via direct inhibition of dopamine neurons in the VTA. The development of better treatments for drug use relapse and its exacerbation by stress after prolonged abstinence from drug abuse in vulnerable individuals is urgently needed. Addictive disorders may have well documented pathologies, but the specific role of dynorphin in the human syndromes remains poorly defined. Kappa antagonists developed for human use will hopefully have beneficial effects in stress-vulnerable individuals, but a better understanding of dynorphin’s functions seems essential if we are to properly anticipate the range of beneficial and possibly adverse consequences that a KOR antagonist might clinically produce.

Schizophrenia and certain idiopathic neuroses and retardations may be caused by polygenic sensitization to exogeneous peptide antigens or viruses causing a covert immune complex basal lamina disease of the choroid plexus. This organ has the general structure and disease susceptibility of many other transport organs but acts as a second blood--brain barrier putting at risk to contamination and dysfunction the periventricular primary personality (limbic) brain now thought to be centrally involved in schizophrenia. Genetic variability selects different antigens and different target organs so that a complex statistical structure of disease expression can result over the transport organ group as well as between this group and the endocrines and exocrines. This leads to the concept of intra- and intercombined system diseases all of which may have a covert biphasic (hyper-hypo) time course. To this extrinsic combinatorial complexity may be added an intrinsic or neural combinatorial complexity resulting from the fact that the choroid plexus is threaded throughout the limbic system and subject to spotty disease characteristic of many immunopathies. In this way a wide range of behavioral disorders may arise as well as mental retardations if the process occurs during development. In this paper we discuss basic mechanisms. In the next paper of the series we examine systemic lupus erythematosus, the prototypical "combined transport dysfunction," as a model for schizophrenia. In the last paper we search for specific exogeneous peptide triggers for schizophrenia viewed as one expression of combined transport organ dysfunction. We conclude that immunofluorescent and virological surveys should be conducted in all mental illnesses as well as clinical trials of interferon therapy and elemental diets.

Prolactin (PRL) levels after thyrotropin-releasing hormone (TRH) (delta PRL) were determined 4 times and basal prolactin levels 6 times in 10 healthy medical students before, during, and after a major examination in medicine. No significant differences in basal or delta PRL levels occurred during the examination period. Basal PRL was also measured in 14 doctors of medicine after delivering a paper at a clinical conference and a further 9 doctors both before and after delivering a paper. PRL was measured serially at 20-min intervals in 4 doctors on the day on which they presented the paper. No significant differences in PRL levels were found in any of the tests conducted during this kind of stress as compared with the corresponding values obtained under nonstressful conditions. Increases in PRL before delivering the paper were seen in 3 subjects, but such increases also occurred completely independently of stress. An 18-hr fast did not influence PRL secretion in 11 healthy volunteers. Both the information obtained from a review of the literature on the influence of stress on PRL secretion and our own results strongly suggest that contrary to common opinion, there is no evidence at all that psychological stress affects PRL secretion in man.

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.

s e b n u v m s d A ddictions have been suggested psychologically to result from loss of executive control over maladaptive habits (1). Indeed, over the course of the development of addiction, rug seeking becomes progressively controlled by drug-associated timuli, acting as both conditioned reinforcers and as pavlovian eliciors of relapse and/or craving. This may reflect the subversion by drugs f natural instrumental learning processes, such as response-outcome nd stimulus-response instrumental learning mechanisms as well s pavlovian-instrumental interactions, thereby facilitating the deelopment of habitual control over drug seeking and taking (1,2). he paper by Corbit et al. (3) directly addresses this issue by showng that alcohol seeking becomes habitual over an extended period f access, being resistant to reinforcer devaluation and that this hift from goal-directed to habitual control is underpinned by a hift from dorsomedial to dorsolateral striatal control over behavor. Early theoretical arguments for a role of habits in the developent of drug addiction were based on the observation that “drugse behaviors tend to be relatively fast and efficient, readily enbled by particular stimulus configurations (i.e., stimulus bound), nitiated and completed without intention, difficult to impede in he presence of triggering stimuli, effortless, and enacted in the bsence of awareness” (4). These behavioral features resonate with he main characteristics of behavioral automaticity, often assumed o reflect habits, that Tiffany (4) emphasized: speed, autonomy, lack f control, effortlessness, and absence of conscious awareness. hus, in humans, habitual responses do not depend on awareness ut are directly triggered by conditioned stimuli without any reruitment of higher cognitive processes, such as intention or deciion making, and are therefore difficult to inhibit in the presence of he eliciting stimuli. Additionally, habitual responses are relatively nsensitive to variations in their consequences and impervious to hanges in the value of the goal (for review see [2]). Thus, drug use hat is initially goal directed, controlled by the reinforcing value of he drug, progressively becomes divorced from reward value to be ore controlled by response-eliciting, drug-associated stimuli in he environment. Perhaps the first evidence that animal models can provide inights into the psychobiologic processes that govern the transition rom controlled to uncontrolled alcohol drinking was the demon

t n i r P osttraumatic stress disorder (PTSD) is a common, distressing, and debilitating consequence of the experience of extremely stressful life events, exemplified by combat, sexual assault, torture, or natural disasters. Although the majority of people exposed to these extreme events recover within days to months, long-term follow-up of Vietnam Veterans and survivors of the Nazi Death Camps indicate that for many traumatized people, symptoms persist for decades, perhaps for the rest of their lives (1,2). The very persistence of the impact of what can be a single life experience suggests that traumatization profoundly engages neuroplasticity mechanisms. In addition, compromised neuroplasticity may be a factor preventing individuals with PTSD from benefiting from available social supports and from psychotherapies and pharmacotherapies for PTSD. In this issue of Biological Psychiatry, de Kleine et al. (3) present the first test of the hypothesis that enhancing N-methyl-D-aspartate (NMDA) glutamate receptor function could increase the efficacy of prolonged exposure (PE) therapy, an evidence-based behavioral therapy for PTSD. In this case, NMDA receptor function was enhanced by administration of the partial agonist of the glycineB site of the NMDA receptor, D-cycloserine, a drug that did not show direct effects on PTSD symptoms outside the context of behavioral therapy (4). In the study by de Kleine et al. (3), 75 patients with PTSD were randomized to receive D-cycloserine 50 mg or placebo 1 hour prior to PE sessions. Eight patients dropped out before taking a dose of research medication. The study was designed to deliver 10 PE sessions, but 19 of the 67 patients (28.5%) who took at least one dose of randomized medication and who met remission criteria on a self-rated PTSD scale were permitted to terminate treatment early. In the intent-to-treat analysis, there were no significant treatment effects on the clinician-rated (Clinician Administered PTSD Scale) and self-rated PTSD symptom measures. However, in the intent-to-treat analysis, D-cycloserine was associated with a 3-fold increase in the likelihood of showing a clinically meaningful improvement of PTSD symptoms (10 point or greater reduction of the total score on the Clinician Administered PTSD Scale). In the group of treatment completers, patients treated with D-cycloserine were more than 4 times as likely to show a clinical response by the end of treatment and more than 9 times as likely to maintain this response at a 3-month posttreatment follow-up evaluation. This paper extends the impact of the work initiated by the group at Emory University (Atlanta, Georgia) that provided evidence in

Background: This paper addresses bulimia symptoms in a large community sample of twins aged 8 to 17 years. We aim to identify environmental correlates of bulimia symptoms and relationships with other psychiatric disorder symptoms. The twin design allows examination of the structure of genetic and environmental effects. Methods: DSM-IIIR bulimia symptoms and consequential impairment were measured by interview in the first wave of the Virginia Twin Study of Adolescent Behavioral Development. Comorbidity with other psychiatric symptoms and environmental correlates were examined and the relative contributions of genes and environment were assessed using structural equation modeling. Results: An item-response theory model indicated that the range of bulimic symptoms represented a single underlying trait. Bulimia symptoms were more common in postmenarche girls and positively associated with body-mass index. Subdiagnostic symptomatology was associated with impairment in psychosocial functioning. Bulimia symptoms were strongly associated with other psychiatric disorders symptoms including anxiety and depression. Genetic model fitting identified strong additive genetic effects on the symptom score. Accounting for a potential violation of the equal environment assumption for identical and fraternal twins slightly reduced estimated genetic variance. Conclusions: The pattern of comorbidity suggests overlap between bulimia symptoms and those of internalizing disorders. Substantial genetic variance (44%) was evident in the most conservative model.

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.

This paper considers the influence of temperamental factors on the development of anxious symptoms in children and adolescents. About 20 percent of healthy children are born with a temperamental bias that predisposes them to be highly reactive to unfamiliar stimulation as infants and to be fearful of or avoidant to unfamiliar events and people as young children. Experiences act on this initial temperamental bias and, by adolescence, about one-third of this group is likely to show signs of serious social anxiety. These children are also likely to have one or more biological features, including a sympathetically more reactive cardiovascular system, asymmetry of cortical activation in EEG favoring a more active right frontal area, more power in the EEG in the higher frequency range, and a narrower facial skeleton. The data imply that this temperamental bias should be conceptualized as constraining the probability of developing a consistently fearless and spontaneous profile rather than as determining an anxious or introverted phenotype.

Schizophrenia is likely to be caused by several susceptibility genes and may have environmental factors that interact with susceptibility genes and/or nongenetic causes. Recent evidence supports the likelihood that 22q11 Deletion Syndrome (22qDS) represents an identifiable genetic subtype of schizophrenia. 22qDS is an under-recognized genetic syndrome associated with microdeletions on chromosome 22 and a variable expression that often includes mild congenital dysmorphic features, hypernasal speech, and learning difficulties. Initial evidence indicates that a minority of patients with schizophrenia (∼2%) may have 22qDS and that prevalence may be somewhat higher in subpopulations with developmental delay. This paper proposes clinical criteria (including facial features, learning disabilities, hypernasal speech, congenital heart defects and other congenital anomalies) to aid in identifying patients with schizophrenia who may have this subtype and outlines features that may increase the index of suspicion for this syndrome. Although no specific causal gene or genes have yet been identified in the deletion region, 22qDS may represent a more homogeneous subtype of schizophrenia. This subtype may serve as a model for neurodevelopmental origins of schizophrenia that could aid in delineating etiologic and pathogenetic mechanisms.

The present review explores the descriptive epidemiology of schizophrenia. Risk factors and correlates are divided into three groups based on whether the available evidence is consistent and strong, consistent and potentially strong, or inconsistent. The paper then considers epidemiologic studies of the course of illness, including a description of findings from the Suffolk County Mental Health Project. Given renewed attention to the need for preventive interventions for individuals at high risk for developing a psychotic illness, epidemiologic values have become more and more central to the conduct of clinical research.

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.

The genetic association strategy is currently being applied to a number of psychiatric phenotypes including disease vulnerability, personality variation and clinical response to psychotropic drugs. Association studies offer the prospect of identification of the specific alleles that confer significant effects on clinical phenotype. However, it should be noted that this strategy has additional advantages as well as unique drawbacks. In this paper, we review the basic methodology utilized in each step of a typical psychiatric genetic association study and discuss their potential benefits and pitfalls with particular emphasis on the selection of clinical phenotype, the identification of a candidate gene, the selection of a candidate variant, clinical data set design, and the statistical analysis of association data. With appropriate design and execution, it is hoped that the association strategy will prove to be as successful in psychiatry as it has proven to be in other branches of medicine.

Since bipolar disorder is inherently a longitudinal illness characterized by recurrence and cycling of mood episodes, neurobiological theories involving kindlinglike phenomena appear to possess a certain explanatory power. An approach to understanding kindlinglike phenomena at the molecular level has been made possible by advances in research on second-messenger systems in the brain. The time frame of interest has shifted from the microseconds of presynaptic events to hours, days, months, and even years in the longer duration of events beyond the synapse--through second messengers, gene regulation, and synthesis of long-acting trophic factors. These complex interlocking systems may explain how environmental stress could interact over time with genetic vulnerability to produce illness. In its two sections, this paper will review an approach to understanding two major aspects of the neurobiology of bipolar disorder: kindling phenomena and second-messenger mechanisms. We will suggest that these two fields of research together help explain the biology of recurrence.

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.

In recent years, there has been considerable excitement about the possibility that the “molecular medicine revolution” would lead to identification of numerous putative targets designed to slow the atrophic/degenerative process in various neuropsychiatric disorders. Indeed, tremendous progress was made in the identification of cellular processes and pathways involved in numerous degenerative diseases; however, to date, proliferation of candidate drugs has not resulted in viable novel clinical treatments for these devastating disorders (Heemskerk et al., 2002). Ironically, the paper by Bearden and associates in this issue of the journal suggests that an old medication present in our therapeutic armamentarium for half a century, exerts neurotrophic effects not only in animal models, but also in humans. Bearden et al. used high-resolution magnetic resonance imaging and cortical pattern matching methods to map gray matter differences in 28 bipolar patients; 20 lithium-treated, and 28 healthy controls. Their results showed gray matter density was significantly greater in bipolar patients, compared with healthy subjects, in diffuse cortical regions, notably bilateral cingulated and paralimbic cortices, areas utilized in attention, motivation and emotion. Additionally, their data revealed greater gray matter density in the right anterior cingulate in lithium-treated patients relative to the bipolar subjects not taking lithium. Their lithium-treated sample included subjects who were on lithium for varying time durations, at different individual doses. The lack of difference in gray mater density between the untreated patients and healthy controls, as well as growing evidence that lithium exerts major effects on a number of cellular proteins and pathways (vide infra) known to regulate cell atrophy/death lends support to the view that gray matter enlargement is mediated through the trophic actions of lithium in the brain.

Suicide is a major public health problem as about 40,000 people die by suicide in the U.S. annually. Prevention and treatment of suicidal behavior is therefore very important. The major problem in the prevention of suicide is early identification and treatment of suicide-prone patients. Suicide is a multifactorial problem involving clinical, genetic and neurobiological risk factors. The identification of risk factors that could accurately predict completed suicide has been therefore investigated by many researchers. An important risk factor for completed suicide is a history of previous suicide attempts and presence of suicidal ideation, and these have been suggested as major predictors of subsequent suicide attempt or suicide. Since clinical risk factors by themselves are not strong predictors of suicide, a combination of clinical and neurobiological risk factors may improve the ability to predict suicide. In that context, several biological markers have been studied in suicidal behavior. These include 5-hydroxytryptamine (5HT)2A receptors, 5-hydroxyindoleacetic acid (5HIAA), serotonin transporter (5HTT) and the dexamethasone suppression test (DST; an index of hypothalamic pituitary adrenal [HPA] axis function), for prediction of suicidal behavior or completed suicide (1). Several studies suggest dysregulation of the immune system and cytokines in suicidal behavior. Steiner et al. (2) found increased microgliosis in the postmortem brain of suicide victims with affective disorders and schizophrenia compared with normal control subjects. Some investigators observed that the administration of proinflammatory cytokines like interferon (IFN)-α to cancer patients causes symptoms known as sickness behavior. These symptoms appear to be similar to depression, psychosis, mania and sometimes suicidal behavior. A review of IFN-α treatment of chronic hepatitis-C patients (3) showed the emergence of suicidal ideation and attempts during IFN-α treatment also suggesting that cytokines may be involved in suicide. In order to examine if cytokine dysregulation is associated with suicide, several investigators determined cytokines and chemokines levels in plasma, cerebrospinal fluid (CSF), and postmortem brain of suicidal patients. In general, these studies indicate abnormalities of several cytokines in suicide. However, single studies do not provide adequate evidence either about their role in suicide or as potential risk factors for suicide, as they are generally of low power. Meta-analysis is an important tool to clarify these findings and improve the strength of evidence, taking into account the sources of heterogeneity among various studies. The accompanying paper by Black and Miller (4), who performed a meta-analysis of these studies to examine if any of the cytokines or chemokines were abnormally expressed in suicidal patients compared to non-suicidal patients or normal controls, is therefore important in identifying the role of cytokines in suicide and their potential as biomarkers. The cytokines have been widely studied in mood disorders, schizophrenia and alcohol abuse, but there are not many studies of cytokines in suicidal patients. The cytokines in suicide have been studied in plasma, CSF and postmortem brain. In addition, in vivo studies of cytokines have also been conducted. In order to examine if alterations in cytokine levels are specific and/or are risk factors for suicide the comparisons of cytokine levels between suicidal patients, non-suicidal patients and normal controls were performed. Using these criteria in the meta-analysis performed by Black and Miller (4) some important findings emerged. The most significant observation of cytokine abnormalities was that interleukin (IL)-1β was higher in suicidal patients compared with non-suicidal patients. IL-6, but not tumor necrosis factor (TNF)-α, was higher only after the removal of one study. A different pattern emerged when they (4) compared the suicidal patients against normal controls. In this case, they found that the blood levels of IL-6, IL-10, and C-reactive protein (CRP) were significantly increased in suicidal patients compared with normal controls. No differences were observed in the levels of IL-1β and TNF-α between suicidal patients and normal controls. The results of the comparison between suicidal patients and normal controls are thus intriguing as they are not consistent with the results obtained by comparing suicidal and non-suicidal patients and raise the possibility that observed differences between suicidal patients and normal controls may be related to diagnosis, rather than to suicide. Since different diagnoses may have different risks of suicidal ideation and attempt (5), it will be important to examine the effect of diagnosis in these cases, as they rightly pointed that out (4). IL-2 may be another cytokine with a potential of distinguishing suicidal patients vs. non-suicidal patients as in this meta-analysis a decrease in IL-2 (in vitro) was observed in suicidal patients compared to both non-suicidal patients and controls. Also, an interesting observation by Black and Miller (4) was that the in vivo blood levels of these cytokines distinguished psychiatric suicidal patients from both psychiatric patients without suicidality and also from normal controls. Another reason for this robust finding was that relatively more studies were available for the meta-analysis as opposed to single or fewer studies for other cytokines. The role of chemokines in suicide is less clear as there were only a few studies of chemokines in suicidal patients. An issue is the suitability of peripheral cytokine measures as a function of CNS cytokines. To address this issue levels of cytokines have been studied in the CSF and postmortem brain of suicides. Although these are only single studies available for this meta-analysis, they suggest similar changes in postmortem brain of suicide subjects at least for IL-6. Most of the studies in CSF, postmortem brain or in vitro were either single studies or few studies for a meaningful analysis. Nonetheless, several of these studies in CSF and postmortem brain show differences between suicidal subjects compared to non-suicidal patients or normal controls for IL-1β, IL-6, TNF-α and IL-8. The studies in postmortem brain and CSF suggest that peripheral cytokines may be a good measure of cytokine levels in the brain. Although cytokines are also synthesized in the brain, bidirectional movements of cytokines between periphery and the CNS through several mechanisms have been suggested. Thus, peripheral cytokines could not only be suitable biomarkers for suicide, but may also mirror similar changes in the brain.

Cotard syndrome is a fascinating entity, in which the patient lingers under extreme nihilistic delusions. While its etiology is still unclear, modern imaging techniques have revealed interesting possibilities regarding the role of insular cortex in mediating interoception and selfperception. Our paper reports development of Cotard syndrome in a 65-years old female suffering from symptoms of dementia and depression, who’s subsequent MRI revealed atrophy of bilateral insular cortices. We propose that etiology of Cotard syndrome in this case may be a reduction in her ability to validate internal perception against external information and subsequent coloring of anomalous perceptions by depressive cognitions.

Background: Sleep disturbances are common in major depressive disorder. In previous open-label trials, nefazodone improved sleep continuity and increased rapid eye movement (REM) sleep, while not affecting stage 3/4 sleep or REM latency; in contrast, fluoxetine suppressed REM sleep. This study compared the objective and subjective effects of nefazodone and fluoxetine on sleep. Methods: This paper reports combined results of three identical, multisite, randomized, double-blind, 8-week, acute-phase trials comparing nefazodone ( n = 64) with fluoxetine ( n = 61) in outpatients with nonpsychotic major depressive disorder and insomnia. Sleep electroencephalographic (EEG) recordings were gathered at baseline and weeks 2, 4, and 8. Clinical ratings were obtained at weeks 1–4, 6, and 8. Results: Nefazodone and fluoxetine were equally effective in reducing depressive symptoms; however, nefazodone differentially and progressively increased (while fluoxetine reduced) sleep efficiency and reduced (while fluoxetine increased) the number of awakenings in a linear fashion over the 8-week trial. Fluoxetine, but not nefazodone, prolonged REM latency and suppressed REM sleep. Nefazodone significantly increased total REM sleep time. Clinical evaluations of sleep quality were significantly improved with nefazodone compared with fluoxetine. Conclusions: Nefazodone and fluoxetine were equally effective antidepressants. Nefazodone was associated with normal objective, and clinician- and patient-rated assessments of sleep when compared with fluoxetine. These differential sleep EEG effects are consstent with the notion that nefazodone and fluoxetine may have somewhat different modes and spectra of action.

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.

The amplitude and suppression of the auditory P50 event-related potential may be useful for studying schizophrenia and drug abuse; however, the low reliability of the P50 suppression measure limits its value for correlation with clinical measures. Reliability can be increased either by improving measurement methods or by reducing or eliminating sources of variance in the recordings. In this paper, the effect on P50 amplitude and suppression of variation in wakeful alertness within an experimental session was examined in 20 normal subjects. The percentage of beta power in the interval immediately prior to the P50 stimuli was used as an index of alertness. P50 amplitudes or C-T ratios were estimated using peak-picking and using the singular value decomposition (SVD) method. No effects of variation of wakeful alertness were observed on any P50 amplitude or suppression measure. Comparing the peak-picking vs SVD estimates replicated our prior results showing markedly higher reliabilities with SVD. We conclude: 1) that variation within an experimental session in wakeful alertness level as indexed by the percentage of beta power does not affect P50 amplitude or suppression, and 2) the SVD method brings the reliability of the C-T ratio up to levels where its usefulness in clinical studies can be examined.

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.

The aim of the present paper was to perform a single trial analysis of event-related potentials in order to elucidate the mechanisms behind a reduced P300 amplitude occurring in unmedicated depressives (n = 11) and schizophrenics (n = 18). For this purpose, tools from linear system theory were applied to single trials in an oddball paradigm. This analysis provides estimates of the magnitude of the positive deflection occurring around the latency of P300 following target and nontarget simuli. According to the density functions of these amplitude distributions, we operationally defined "false-negative" (P300 amplitude lower than an individual threshold under target conditions) as well as "false-positive" responses (P300 amplitude higher than the threshold following nontarget stimuli). Our investigations revealed a reduction of the single-trial P300 amplitude in depression and a combination of amplitude reduction along with fewer elicited single-trial P300 waves in schizophrenics.

Cellular Ca(2+)-dysregulation has been proposed as an important mechanism in certain diseases such as bipolar affective disorder (BPAD) and malignant hyperthermia. Recently it has been found that in BPAD, the plasma membrane Ca(2+)-channel blockers verapamil and nimodipine are useful substitutes in Li(+)-treatable patients. We have investigated the effects of these drugs and the antipsychotic drugs (clozapine, fluspirilene, and haloperidol) on IP3-induced Ca(2+)-release from Ca(2+)-loaded rat brain microsomes. In the presence of either the Ca(2+)-channel blockers or the neuroleptic drugs, Ca(2+)-release was blocked in a dose-dependent fashion. For the neuroleptics, the EC50 ranged from 22 microM for fluspirilene to 145 microM for haloperidol. The EC50 for nimodipine was 160 microM and 450 microM for verapamil. Carbamazapine and valproic acid, anticonvulsants recently used for treating BPAD, were relatively ineffective, as were various haloperidol metabolites. The research described in this paper establishes for the first time that antipsychotic drugs, as well as certain Ca(2+)-channel blockers, directly block the IP3-induced Ca(2+)-release in a rat brain microsome assay.

This paper presents the results of a study comparing the effectiveness of a beta-adrenergic blocking agent, atenolol, a monoamine oxidase inhibitor (MAO-I), phenelzine, and the combination in treatment of 61 adults with migraine headache. The goals of the study are (1) to investigate the safety of concomitant treatment of migraine with beta-blockers and phenelzine, (2) to assess whether orthostatic hypertension and other side effects would be relieved, and (3) to compare the results of this open trial of phenelzine to those of a previous study using similar methods. Phenelzine was associated with a large decrease in the frequency and severity of migraine attacks. Anxiety and depression were also reduced by phenelzine both alone, and in combination with a beta-blocker. The results show that the combination of MAO-I's and beta-blockers can be administered safely, and can lead to the reduction in the side effects with either drug alone.

This paper reports the behavioral responses to m-chlorophenylpiperazine (m-CPP), a serotonin agonist, in patients with seasonal affective disorder (SAD) and controls during the summer. Results are compared with the responses of SAD patients and controls given m-CPP in the winter. Results of the winter study were reported earlier by our group. Baseline Hamilton depression ratings in SAD patients were significantly lower in the summer than in winter (p

Bedi et al., (1) conducted an acute, double-blind challenge study with two doses of MDMA (1.5 mg/kg and 0.75 mg/kg), methamphetamine and placebo in 21 adults using a crossover design. All subjects had reported a prior history of taking MDMA as a recreational drug. The study adds to the longstanding effort to evaluate the potential “empathogenic” effects of MDMA. Outcomes included subjective reports on visual analog scales on feeling sociable, playful, loving and lonely. Change in self-reported friendliness on the Profile of Mood States (POMS) was also measured. In addition, subjects were asked to evaluate complex emotions such as fear, anger, happiness, sadness in response to video presentations of changing facial expressions – either full face or just the eye region. Finally, the study included presentation of brief vocal clips; subjects were asked to judge whether the voice communicated emotional tones such as happiness, sadness, anger or fearfulness. Although no specific outcome was nominated as primary, the authors were careful to correct for multiple comparisons. Compared to placebo, the 1.5 mg/kg dose of MDMA showed a significantly higher score on the friendliness scale of the POMS and on the playful and loving visual analog scales. The 1.5 mg/kg MDMA condition also showed decreased accuracy on the identification of fearful facial expressions. Contrary to the authors’ expectation, methamphetamine produced significantly higher scores on the sociable and playful visual analog scales. We note that these observations are not inconsistent with the stimulant and euphoriant properties of methamphetamine. The neuropharmacology of MDMA should be considered in the context of other serotonergic enhancers including the precursor tryptophan, selective serotonin reuptake inhibitors (SSRIs), and the serotonin releasing agent, fenfluramine. Although these agents act through a variety of mechanisms, all increase extracellular serotonin, resulting in increased stimulation across a broad range of serotonin receptor subtypes. At typical doses for each of these compounds, neurochemical studies suggest a continuum of serotonergic enhancement from tryptophan through the SSRIs, fenfluramine and MDMA having the largest effect. Pharmacodynamically, the picture is more complex as the relative importance of the stimulatory effects on any specific receptor subtype in a particular neuroanatomic region changes as serotonin levels rise throughout the brain. Effects at 5-HT2A and 5-HT1A receptors appear to be of particular importance in the pharmacology of MDMA. Moreover, compared to methamphetamine, MDMA produces far less dopaminergic receptor stimulation (2). Human and animal studies show that serotonin enhancers can have pro-social effects. In humans, for example, tryptophan is reported to decrease quarrelsome behaviors, increase agreeable behaviors and perceived affability in roommates (3). Acute and chronic exposure to SRRIs have been reported to improve processing of social cues, increase cooperation and affiliation, and decrease hostility (4). As noted by Bedi and colleagues (1), several studies have consistently observed self-reported prosocial effects of MDMA on the related qualities of friendliness, extroversion, closeness and amicability. By studying the effects of MDMA on self-reported sociability, and friendliness as well as performance on emotion recognition tasks, the investigators hoped to characterize the potential benefits of MDMA on social cognition and empathy. As suggested in the title of the paper, MDMA has been labeled an “empathogen.” To be sure, empathy is a critical concept when considering the action of MDMA and when interpreting the findings of Bedi et al. (1). The simplest definition of empathy is the ability to share emotions with another person. However, the current discourse on empathy suggests that it incorporates two interacting elements: the recognition of emotions in others (cognitive component) as well as the actual experience of sharing emotion (5; 6). Bedi et al (1) cite recent studies reporting benefit of MDMA-assisted psychotherapy in PTSD as evidence of the “empathogenic” effects of MDMA. On balance, the findings presented in the Bedi et al. (1) study indicate that although MDMA might enhance the emotional component of empathy, it appears to cause impairment in cognitve component. The potential relevance of these findings to autism, a disorder characterized by profound delay in social relatedness is intriguing – but unlikely. First, even if additional study shows that MDMA has positive effects on the emotional component of empathy, accumulating evidence suggests that it is the cognitive aspects of empathy that are deficient in autism. By contrast, the emotional component appears less impaired (7; 8). This insight concerning the ability of individuals with autism to feel the emotions of others is relatively recent. It parallels the emerging evidence that individuals with autism do not display a reduced sensitivity to painful stimulation, but rather have an altered expression of the sensation of pain (9) – suggesting that the obvious may not be true. Second, serotonin enhancing drugs such as fenfluramine and citalopram do not appear effective in autism (10). Third, although concern about the neurotoxicity of MDMA has declined based on accumulated evidence over the past decade, the potential for adverse effects should not be dismissed (11). This concern may be heightened in vulnerable populations such as individuals with autism. Finally, given that autism is characterized by decreased sensitivity to reading social cues, the finding that MDMA reduced the ability to detect fearful facial expression seems potentially counterproductive in this population. Thus, even setting aside possible safety concerns, MDMA (and perhaps other serotonin enhancing drugs) appear unlikely to be useful in autism. Nonetheless, the challenge paradigm used in the study could be adapted and applied to subjects with high functioning autism to investigate effects of other promising compounds. The study model could be enhanced through the application of computer technology to present facial expression and eye tracking technology to evaluate facial scanning techniques. Future studies could combine promising compounds with cognitive training focused on improving reading faces and emotion recognition.

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.

About 10 years ago, Cloninger defined the behavioral trait “novelty seeking” (NS) (Cloninger 1986, 1987). Two twin studies estimated the heritability of NS to be about 50% (Heath et al 1994; Stallings et al 1996). In early 1996, two papers reported significant associations between NS and a polymorphism of the type 4 dopamine receptor gene (DRD4) (Benjamin et al 1996; Ebstein et al 1996). A subsequent Finnish study did not replicate these findings (Malhotra et al 1996), and we were also unable to reproduce these findings (Sullivan et al in press). Consequently, the importance of individual variation at DRD4 to the behavioral trait of NS is uncertain. In planning the above study, it seemed that the dopamine transporter (DAT) might be an additional candidate gene for the behavioral trait of NS: 1) DAT plays a pivotal role in terminating dopaminergic neurotransmission (Giros and Caron 1993; Giros et al 1996); 2) DAT “knockout” mice are markedly hyperlocomotory (Giros et al 1996), perhaps analogous to high NS humans (Cloninger et al 1994); and 3) the DAT polymorphism DAT1 has been associated with attention-deficit hyperactivity disorder (ADHD), a disorder reminescent of high NS. The purpose of the present study was to investigate whether DAT1 was associated with NS in two groups of New Zealand subjects. Based on prior data (Cook et al 1995), we hypothesized that the DAT1 10-repeat allele would be associated with higher NS scores.

Apolipoprotein E (Apo E) is a protein with 299 amino acids coded by a gene on chromosome 19. The three major isoforms of Apo E (Apo E2, Apo E3, and Apo E4) are products of three alleles (Apo E-e2, Apo E-e3, and Apo E-e4). Inheriting the e4 allele of the Apo E is associated with increased risk of developing Alzheimer's disease (AD). Many papers show linkage of the presence of Apo E-e4 and late-onset AD (Corder et al 1993; Nalbantoglu et al 1994; Noguchi et al 1993; Saunders et al 1993; Strittmatter et al 1993; Yoshizawa et al 1994); however, the frequency of the Apo E-e4 was low in "schizophrenics with progressive dementia" and late paraphrenia (Martiuoli et al 1995; Howard et al 1995). In contrast, Harrington et al reported that Apo E-e4 allele frequency was increased in patients with schizophrenia (Harrington et al 1995). Thus, we determined the Apo E genotype in patients with schizophrenia whose status had been strictly diagnosed and investigated the association of the Apo E-e4 allele and schizophrenia.

C onvergent genetic, neuroimaging, and clinical evidence indicate both overlap and discontinuity between schizophrenia and bipolar disorder. Varieties of thought disorder and various impairments of language can be features of either or both, although the classically described disruptions of speech differ in each syndrome. The extent to which common and distinct neural mechanisms underlie these symptoms and syndromes remains unclear. This current issue of Biological Psychiatry includes two papers that suggest how brain imaging could offer a greater understanding of the biologic basis of symptoms in these disorders. Jamadar et al. (1) investigated the relationship between semantic retrieval impairment, functional brain activity, and psychotic symptoms in schizophrenia and bipolar disorder. Anticevic et al. (2) used functional magnetic resonance imaging (fMRI) to explore a potential link between global prefrontal and frontoamygdala dysconnectivity in bipolar disorder with a history of psychotic symptoms.

Alpha-one-acid-glycoprotein (orosomucoid, AAG), a serum component elevated during inflammation, and related to various immunological functions (Singh 1989), has only recently begun to receive attention in clinical psychiatric research. Its plasma and cerebrospinal fluid (CSF) concentration, which have been the subject of research in the past, have been shown to vary significantly depending on physiological (Parish and Spivey 1991; Routledge 1989) and pathological conditions (Routledge 1989; Kremer et al 1988; Piafsky 1980). AAG's plasma level has also been shown to be increased in patients with psychiatric illnesses such as depression (Nemeroff et al 1990; Healy and Calvin 1991) and schizophrenia (Goodman et al 1961; Bock et al 1971; Seal and Eist 1966). AAG is the major binding protein of basic (cationic) medications such as chlorpromazine, methadone, haloperidol, tricyclic antidepressants, propranolol, and primaquine (Kremer et al 1988; Piafsky 1980; Essassi et al 1989; Eap et al 1990; Amitai et al 1993; Kennedy and Frischer 1990). There have been various papers discussing AAG as an important pharmakokinetic parameter of these medications. However, there are no clinical studies correlating AAG blood level with response to these medications. In this study we investigated how schizophrenic patients

i a c s t r l o s d n K etamine and related drugs are arguably one of the most exciting developments in antidepressant pharmacology in more than half a century and are a potentially new mechaism capable of mediating antidepressant action. That mechanism s the antagonism of the N-methyl-D-aspartate (NMDA) receptor NR) and possibly one or more subtypes of that receptor. By blockng NMDA receptors, ketamine and related drugs target glutamate, hich is the major excitatory neurotransmitter in the brain and a ransmitter not directly affected by any currently marketed antideressant. In their thought-provoking paper, aan het Rot and colleagues (1) eview many of the studies that have been done with ketamine to ate and suggest some necessary steps forward in its development.

i N ( t T he history of the field of biological psychiatry can be cynically encapsulated by the quest to reverse engineer serendipitous clinical findings. The role of monoamines in depression, doamine in schizophrenia, and second messengers in bipolar disorer have all been reversed engineered from understanding the ffects of tricyclics, antipsychotics, and lithium, respectively. In this ontext, the emergence of N-acetylcysteine (NAC) as a potential therapeutic modality provides a dual opportunity: a novel therapy and a key to unlocking the pathophysiology of the targeted disorders. One of the perplexing and curious things about NAC is that it appears to be of potential value for a multitude of phenomena in a diversity of seemingly disparate disorders. Mirroring what we have seen with atypical antipsychotics and even antidepressants, efficacy patterns of NAC show little respect for the chapter structure of the DSM-IV system. Positive trials are reported for negative and extrapyramidal symptoms in schizophrenia, depression in bipolar disorder, cocaine craving, smoking cessation, trichotillomania, and gambling (1). Given the frequency of negative studies for established agents, the paucity of negative published studies is noteworthy. In this issue of the Biological Psychiatry, Hardan et al. (2) present antalizing data on the efficacy of NAC in autism. In a pilot study of 3 subjects aged 3.2–10.7 years, a significant reduction in irritability as seen, together with a benign tolerability profile. In context, utism is a complex disorder with a history littered with failures of iological therapies. Indeed, there are no established biological herapies that have demonstrated a consistent and favorable risk/ enefit profile, with only the nonspecific effect of risperidone and ripiprazole on aggressive and disruptive behavior in severely afected children suggested and at a substantial tolerability cost (3). Research into the underlying pathophysiology of autism sugests many putative therapeutic targets, including redox and gluamate dysregulation, apoptosis and neuronal pruning, neurogensis, mitochondrial dysfunction, inflammation, and even mercury oxicity. Part of the appeal of NAC is that it has efficacy at many of hese targets. However, part of the fog of the field is that various ther, seemingly diverse, disorders share many of these pathophysologic findings. Why the agent works (pending confirmation of fficacy confirmed by some of the trials of NAC in autism that are egistered [ACTRN12610000635066] and ongoing) will be critical to nlock the Rosetta stone of pathophysiology. In this light, the paper of Gunduz-Bruce et al. (4), also in this issue f the Biological Psychiatry, is a critical step forward. Whereas animal tudies have suggested that NAC is able to reverse the neurobehavoral effects of ketamine, this study in human volunteers did not emonstrate a comparable pattern. NAC nevertheless reduced misatch negativity (MMN) for the frequency deviant and increased 300 amplitude for both target and novel stimuli. These data are artly supported by the study of Lavoie et al. (5), who found that

o w b e i I t has been said that scientific progress depends more on new technologies than new concepts. In truth, it is often new technologies that generate new concepts. For systems neuroscince, optogenetics has been unquestionably the hottest technolgy developed in the past 7 years. A PubMed search yields more han 250 citations for “optogenetic” as of April 2012. Judging from he number of posters using optogenetics at the 2011 meeting of he Society for Neuroscience, this number will surely double in the ext year. Some of the great early successes of this approach are summaized in this special issue of Biological Psychiatry. As the reader will ee, optogenetics has allowed systems neuroscience to move from he correlational descriptions of neurophysiology and neuroanatmy to mechanistic studies with precise temporal and cellular conrol. Simply stated, optogenetics lets us tune circuits in unrestrained ehaving animals, demonstrating that activity of a particular cell opulation is necessary or sufficient for a particular function. From its first description of use in mammals in 2005 (1), the ight-activated, circuit-breaking technology has progressed rapidly. ew opsins allowed studies of inhibition as well as excitation. Linkng the opsin to cre-dependent expression conferred high specificty of cellular expression. The application of this method to rats and onhuman primates has brought circuit breaking to a broad range f interesting behavioral questions. Subsequent articles in this issue escribe how this tool can shed light (excuse the inevitable pun) on he circuits for aggression, anxiety, arousal, reward, depression, ocial behavior, and even cortical oscillations. But if new technologies generate new concepts, what are the ew concepts resulting from optogenetics? Has optogenetics simly allowed us to prove what we already suspected (parvalbuminositive inhibitory neurons generate gamma synchrony; hypocrein-positive cells regulate arousal) (2,3), or is there a new insight rom this tool that was unpredicted? One could well argue that imilar to better telescopes that have given us the details of galaxies hat heretofore were murky clusters, optogenetics has shown us he precise cellular architecture underlying complex behaviors. Alhough this is perhaps not an entirely new concept, because of ptogenetics, it is now undeniable that there is a precise cellular rchitecture underlying complex behavior. One need read no further than the paper by Anderson (4) in this ssue to appreciate the conceptual power of understanding this rchitecture. Anderson tested Tinbergen’s hypothesis of behavioral ierarchies by finding specific neurons in the mouse ventromedial ypothalamic nucleus that mediate attack behavior intermingled ith and potentially inhibited by neurons involved in mating. Score ne for technology-clarifying concepts. But it is important to remember, as Deisseroth noted (in this ssue), that optogenetics is best viewed as one tool in a toolbox for

e w b I t used to be called cold versus hot cognition, two terms that referred to tasks that either intentionally used stimuli devoid of social or emotional content to reduce unexpected confounds cold) versus tasks that intentionally addressed social and emoional processing (hot). Now following impressive advances in basic ehavioral neuroscience, this latter area is sometimes called social ognitive and affective neuroscience (SCAN), or simply social cogition. There is clearly an increased focus in the social cognition of chizophrenia as evidenced by published papers and conference resentations. The emergent research focus over the past decade as been driven by several factors, including the following: 1) inreased support for social cognition’s role in functional outcome in chizophrenia; 2) a greater understanding about the factors that ead to development of particular clinical symptoms, such as paraoia; 3) new evidence on the stability of social cognitive impairent across phases of illness; 4) increasing support for psychopharacologic and psychosocial interventions for social cognitive mpairment; and 5) a growing application of neuroimaging methds from SCAN to identify aberrant neural substrates in schizophreia (1,2). It is this last area involving SCAN methods that is the focus f the meta-analysis by Taylor et al. (3). As an indication of rapid growth in this area, the functional magnetic resonance imaging (fMRI) meta-analysis by Taylor et al. (3) is the third one involving social cognitive paradigms in schizophrenia to appear in a 1-year period (4,5). It differs from the previous meta-analyses that focused on emotion perception because it also considers emotional experience. These domains are rarely studied together. Emotion perception is the most studied aspect of social cognition in schizophrenia and usually involves the identification of emotions displayed in static faces (6). Patients consistently show trouble with identification, matching, and discrimination of emotional faces relative to controls. Electrophysiology (EEG) and fMRI approaches are able to examine neural underpinnings for explicit tasks, as well as implicit paradigms (e.g., the physiologic response to fearful versus neutral faces while subjects are asked to identify the gender of faces). Emotional experience, in contrast to emotion perception, asks the subjects to look inward and evaluate their own responses to evocative stimuli. Although somewhat counterintuitive, the findings from rating scales, interviews, and EEG show lack of differences between groups. Patients appear to experience emotional stimuli to the same extent as healthy persons, even though they rate higher on anhedonia scales. Although the results from Taylor et al. (3) are not specifically framed as such, they can be interpreted in terms of two broad social cognitive processes: lower-level bottom-up versus higher-level topdown (7,8). Lower-level social cognitive processes involve recognizing

The paper by Maher, Vanyukov and colleagues is an extensive study of two cohorts phenotyped with a common liability of substance abuse disorders that reports an association of an arginine vasopressin (AVP) 1A receptor gene variant with these disorders (1). The AVP1A receptors are located throughout the brain and function in many roles, especially in stress responsivity. In contrast, the AVP1B receptors are located on corticotropes in the anterior pituitary and work primarily as part of the activating system of the stress-responsive hypothalamic-pituitary-adrenal (HPA) axis by driving the processing and release of the constitutive peptides, ACTH and beta-endorphin, of proopiomelanocortin (POMC), of particular interest for the field of addictive diseases. The AVP1B receptor acts in parallel to the CRF-R1 receptor, where corticotropin releasing factor (CRF) acts to similarly drive the processing and release of POMC peptides of the HPA axis.

Alcohol abuse and alcoholism represent major health problems in Western countries and are emerging as major concerns in many developing countries. Despite the large social and economic impact of excessive alcohol consumption, treatment options, particularly pharmacotherapies, are limited. This is, in part, due to a lack of a detailed understanding of the targets of alcohol action in brain that might be responsible for promoting excessive alcohol consumption. Accumulating evidence in recent years indicates important roles for calcium (Ca2+)-activated potassium (K+) channels in behavioral responses to alcohol and the development of alcoholism (1). In this issue of Biological Psychiatry, two articles propose that small-conductance Ca2+-activated K+ (SK) channels may be novel therapeutic targets for alcohol dependence and excessive drinking associated with alcoholism (refs to the two papers here). Among ion channels expressed in the plasma membrane, SK channels are unique in that they are solely activated, or gated, by cytosolic Ca2+ and not directly by membrane potential (2). Thus, Ca2+ influx through Ca2+-permeable ion channels, such as NMDA-type glutamate receptors or voltage-gated Ca2+ channels, elicits SK channel opening, resulting in negative feedback regulation of excitatory glutamatergic transmission and action potential firing (Figure 1). Figure 1 Schematic diagram illustrating how SK channels are activated during excitatory glutamatergic transmission or action potential firing. NMDA-type glutamate receptors are activated by synaptically released glutamate, while voltage-gated Ca2+ channels are ... In the first study, Mulholland et al. examined changes in SK channel function and expression following chronic ethanol exposure in the cornu ammonis 1 (CA1) region of the hippocampus, a brain area that is thought to be involved in withdrawal-induced seizures and in cognitive impairments observed in alcoholics. In CA1 pyramidal neurons, SK2 subtype SK channels are localized to dendritic spines, where they are tightly coupled to synaptically driven Ca2+ influx via NMDA receptors or voltage-gated Ca2+ channels (3). This synaptic activation of SK2 channels constitutes a Ca2+-mediated negative feedback loop to dampen excitatory postsynaptic potentials (EPSPs) and spine Ca2+ signals that are critical for the induction of synaptic plasticity and glutamate-induced neurotoxicity. Indeed, blocking SK channels with the specific antagonist apamin facilitates hippocampal synaptic plasticity in brain slices and hippocampus-dependent memory encoding in behaving animals (2). Using organotypic slice preparations from Sprague Dawley rat pups, Mulholland et al. first show that chronic ethanol treatment (75 mmol/L for 7–9 days) results in 1) reduced SK channel function, assessed by measuring the apamin-sensitive component of depolarization-induced outward currents or that of glutamatergic EPSPs, in CA1 pyramidal neurons, and 2) downregulation of membrane expression of SK2 channels in the hippocampus. They further find that SK2 expression is selectively decreased at synaptic sites in the hippocampus of adult C3H/He mice following continuous ethanol vapor inhalation for 64 hours, confirming that SK2 downregulation occurs after in vivo ethanol exposure. Importantly, enhancing SK channel function using the selective activator 1-ethyl-2-benzimidazolinone (1-EBIO) prevents neuronal hyperexcitability and neurotoxicity observed during ethanol withdrawal in rat organotypic slices and also reduces the severity of seizures in adult mice withdrawn from ethanol vapor inhalation. In the second study, Hopf et al. tested the effect of chlorzoxazone (CZX), an SK channel activator that is FDA-approved as a centrally acting muscle relaxant, on alcohol intake after a history of chronic consumption using adult Wistar rats. In another report, this group has shown that long-term voluntary self-administration of alcohol, but not sucrose self-administration, causes reduced SK channel function and expression, leading to increased excitability, in neurons of the nucleus accumbens (NAcb) core, a brain area that is critical for motivated behaviors driven by cue-reward associations (4). This change is selective for the NAcb core and is not observed in the NAcb shell or the dorsal striatum. Accordingly, local infusion of 1-EBIO into the NAcb core, but not into the shell, reduces alcohol- but not sucrose-seeking behaviors. In the current study, Hopf et al. extend these findings by showing that systemic injection of CZX reduces alcohol intake after a prolonged history of intermittent access to alcohol (IAA; 24 hours/day, 3 days/week for 5–6 weeks followed by 3 hours/day, 3 days/week for 5–6 weeks) but not in rats that had continuous access to alcohol (CAA; 24 hour/day, 7 days/week for ~12 weeks). In support of this result, NAcb core neurons exhibit enhanced excitability and increased CZX inhibition of firing in brain slices prepared from IAA rats but not those from CAA rats. Collectively, these studies raise an exciting possibility that CZX and other SK channel activators may be used to alleviate alcohol withdrawal symptoms and reduce alcohol drinking in alcoholics. However, several concerns/questions need to be considered before enthusiastically embracing the therapeutic potential of SK activators. First, SK channels are expressed in wide range of neurons in diverse brain areas subserving different behavioral and cognitive functions (2). Therefore, global enhancement of SK channel function may cause unwanted side effects. For example, SK channels critically regulate the firing of neurons in the basal ganglia structures important for controlling locomotor activity. The locomotor depressing effect of CZX observed in the study by Hopf et al., although statistically non-significant at a low dosage (10 mg/kg), might turn out to be disturbing in human patients. Furthermore, enhancement of SK function in the hippocampus may actually aggravate cognitive impairments associated with alcoholism. Indeed, transgenic SK channel overexpression or SK channel upregulation during aging have been associated with deficits in hippocampal synaptic plasticity and hippocampus-dependent learning tasks (2). On the other hand, enhancement of SK function in other brain areas might improve alcohol-related symptoms not addressed in the two studies. For example, it has been shown that CZX improves motor performance in a mouse model of cerebellar ataxia (5), suggesting that it may ameliorate motor incoordination during acute alcohol intoxication. Furthermore, enhancement of SK function in the amygdala may act to reduce anxiety symptoms that drive compulsive alcohol intake. Second, it would be important to determine the extent of SK channel changes in different brain areas and the SK subtype (SK1–3) selectivity of these changes. In this regard, it is of note that SK3, but not SK2, channels are downregulated in NAcb core neurons after long-term alcohol intake (4). Although neither 1-EBIO nor CZX are specific for different SK subtypes, development of subtype selective activators might enable targeting of SK channels in specific brain areas/neurons. Third, is the intermittent drinking model, where CZX decreased drinking, a good model of alcohol dependence or even excessive drinking in humans? CZX did not reduce alcohol consumption in the continuous access model and it will be important to determine effects of CZX on other animals models that emulate human alcohol consumption (6). Fourth, what are the cellular and molecular mechanisms causing downregulation of SK channels during long-term alcohol exposure? Does protein kinase A-mediated internalization of SK channels play a role in removal of these channels from the plasma membrane (2)? It is surprising that such a diversity of treatments and alcohol concentrations all change the expression and/or function of SK channels. For example, Mulholland et al. used continuous exposure to a relatively high (75 mM) concentration of ethanol for the in vitro experiments, whereas the rat operant self-administration paradigm would result in much lower ethanol concentrations in brain for a short period of time each day (4). This raises the question of whether different mechanisms are responsible for the actions of these different alcohol treatments. Elucidating these mechanisms might enable actual reversal, or even prevention, of SK channel downregulation, thus “curing” this form of alcohol-induced neuroadaptation. Finally, another key mechanistic question is whether there are changes in expression of genes coding for SK channels (Kcnn genes) in animals treated with alcohol or human alcoholics. There are extensive brain gene expression databases in the alcohol field and a site such as the Ethanol-Related Gene Resource (ERGR, http://bioinfo.mc.vanderbilt.edu/ERGR/index.php) can be queried. A search of ERGR finds that operant self-administration of alcohol in rats increases the expression of Kcnn2 (SK2) (7). Examination of databases comparing gene expression in alcoholic and nonalcoholic human brain shows that Kcnn mRNAs were not reliably detected in those studies (8). An important goal for the future is to determine if there are changes in Kcnn gene expression or SK function in human alcoholics. Despite these potential concerns and remaining questions, the two studies clearly open a new line of investigation that may provide novel treatment option for alcohol dependence. In light of the fact that CZX is an FDA-approved drug, small K channels may offer big hope to researchers, physicians, and patients battling alcoholism.

f one accepts that psychiatric disorders are brain disorders, then direct examination of the brain is as integral to their biological study as is the study of bone marrow for a hematologist. Howver, such studies are rare in this journal: in 1998, only approxiately 3% of data articles were based on postmortem brain tissue, nd in 2008, the figure was 2%— compared with more than 20% sing brain imaging of one modality or another. It is not that postortem studies are not of interest; the mean number of times they ave been cited equals or exceeds the journal average for that year. This special issue was stimulated by discussion among the ediors as to why there are so few postmortem brain papers, and what, f anything, should be done about it. One good reason for their arity is, of course, that biological psychiatry is a broad church— ncreasingly so—and a wide range of approaches and methods are sed. There are also insurmountable limits as to what postmortem tudies can achieve, of which two in particular stand out. First, they re subject to many confounders and differential confounders (e.g., hronicity of illness, medication, smoking, perimortem factors), hich make primary changes intrinsic to the illness hard to distinuish from myriad secondary, compensatory, and epiphenomenal ffects. Second, by their nature, results are ultimately descriptive nd correlational; it is not possible to manipulate or perturb the rain and measure a response to test hypotheses or probe mechaisms critically. These two factors make it appropriate that only a mall proportion of articles in a leading biological psychiatry journal re based on the use of postmortem tissue. However, as in any other eld, there are good and bad studies, strengths and weaknesses of he approach, and a mixture of established and controversial findngs. The articles in this issue discuss one or more of these topics. he focus is on postmortem studies of psychosis, although the key onsiderations generalize to other psychiatric disorders. The first prerequisite is to have brain tissue of suitable quality nd quantity. Norms for both parameters have increased substanially over recent years. For example, exclusion of brains with a low H (because this predicts poor mRNA integrity) has become comon and reduces the number of brains available. Over the same eriod, the average sample size has risen dramatically: in 1991, an arly molecular study of schizophrenia in a leading journal had 14 ubjects (1), whereas now 150 or more are becoming commonplace 2,3), and a recent study included 400 (4). The trend toward large amples reflects a) a desire to make results more robust, b) studies n which findings are related to genotype (see Kleinman et al., [5]), nd c) the inclusion of additional diagnostic categories, for examle, addition of a mood disorder group to a “schizophrenia versus ontrol” study, a strategy championed by the Stanley Medical Reearch Institute (6). Fortunately, the ability to rate and control for rain quality in a molecular sense has improved (see Mccullummith and Meador-Woodruff; Tunbridge et al. [7,8]), as have the size

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.