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Background Infections during fetal life or neonatal period, including infections with Toxoplasma gondii, may be associated with a risk for schizophrenia and other mental disorders. The objectives of this study were to study the association between serological markers for maternal and neonatal infection and the risk for schizophrenia, related psychoses, and affective disorders in a national cohort of newborns. Methods This study was a cohort-based, case-control study combining data from national population registers and patient registers and a national neonatal screening biobank in Denmark. Patients included persons born in Denmark in 1981 or later followed up through 1999 with respect to inpatient or outpatient treatment for schizophrenia or related disorders (ICD-10 F2) or affective disorders (ICD-10 F3). Results Toxoplasma gondii immunoglobulin G (IgG) levels corresponding to the upper quartile among control subjects were significantly associated with schizophrenia risk (odds ratio [OR] = 1.79, p = .045) after adjustment for urbanicity of place of birth, year of birth, gender, and psychiatric diagnoses among first-degree relatives. There was no significant association between any marker of infection and other schizophrenia-like disorders or affective disorders. Conclusions Our study supports an association between Toxoplasma gondii and early-onset schizophrenia. Further studies are needed to establish if the association is causal and if it generalizes to cases with onset after age 18.

This article has been retracted at the request of John H. Krystal, MD, Editor of Biological Psychiatry, with agreement from all authors.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

Background: \ud Numerous behavioral studies have highlighted the contribution of visual perceptual deficits to the nonverbal cognitive profile of individuals with 22q11.2 deletion syndrome. However, the neurobiological processes underlying these widespread behavioral alterations are yet to be fully understood. Thus, in this paper, we investigated the role of neural oscillations toward visuoperceptual deficits to elucidate the neurobiology of sensory impairments in deletion carriers.\ud \ud Methods: \ud We acquired 125 high-density electroencephalography recordings during a visual grating task in a group of 62 deletion carriers and 63 control subjects. Stimulus-elicited oscillatory responses were analyzed with 1) time-frequency analysis using wavelets decomposition at sensor and source level, 2) intertrial phase coherence, and 3) Granger causality connectivity in source space. Additional analyses examined the development of neural oscillations across age bins.\ud \ud Results: \ud Deletion carriers had decreased theta-band (4–8 Hz) and gamma-band (58–68 Hz) spectral power compared with control subjects in response to the visual stimuli, with an absence of age-related increase of theta- and gamma-band responses. Moreover, adult deletion carriers had decreased gamma- and theta-band responses but increased alpha/beta desynchronization (10–25 Hz) that correlated with behavioral performance. Granger causality estimates reflected an increased frontal-occipital connectivity in the beta range (22–40 Hz).\ud \ud Conclusions: \ud Deletion carriers exhibited decreased theta- and gamma-band responses to visual stimuli, while alpha/beta desynchronization was preserved. Overall, the lack of age-related changes in deletion carriers implicates developmental impairments in circuit mechanisms underlying neural oscillations. The dissociation between the maturation of theta/gamma- and alpha/beta-band responses may indicate a selective impairment in supragranular cortical layers, leading to compensatory top-down connectivity.

This article has been retracted at the request of the Editor. Reason: The original second author of this paper, Roxana M. Gonzalez, has acknowledged that she misreported data supporting an exploratory mediation analysis reported at the end of the original paper. None of the co-authors participated in or had knowledge of the second author's actions. The second author cooperated fully in determining the scope and impact of her actions and in rectifying the research record.

In the first section of this paper several aspects of tardive dyskinesia (TD) (clinical, epidemiological, pharmacological) are reviewed. We propose that this syndrome is not the consequence of dopamine receptor proliferation, but results from damage or degeneration of striatal cholinergic interneurons. We suggest that this cellular damage is caused by prolonged overactivation of these neurons, which occurs when they are released from dopaminergic inhibition following neuroleptic administration. Overactivity of central cholinergic systems during akinetic and motor retarded depression could be a contributory cause. The predisposition to L-DOPA-induced peak-dose dyskinesia in Parkinson's disease may depend on the same type of striatal neuronal loss. In the second part of the paper, the subject of supersensitivity psychosis and drug-resistant schizophrenia is reviewed. These two syndromes, are commonly associated with TD, have similar predisposing factors and pharmacology to TD, and are potentially persistent. We suggest that these conditions also result from degeneration of cholinergic striatal interneurons following chronic neuroleptic administration. The efficacy of clozapine for such treatment-refractory psychoses is explained in terms of its blockade of D-1 dopamine receptors. Other drugs effective against refractory psychoses (e.g. risperidone) are predicted to reduce activation at D-1 receptors.

Child abuse is a non-specific risk factor associated with increased risk for a range of psychiatric and substance use disorders. The paper in this issue by Dannlowski and colleagues [1] adds to a growing body of literature on the mechanisms by which adverse early experiences confer vulnerability to psychiatric illness. The paper by Nikulina and colleagues [2] delineate further genetic and other factors that account for individual differences in the outcomes of adults who were abused as children. Dannlowski and colleagues [1] completed structural and functional magnetic resonance imaging (MRI) assessments in a large cohort of carefully screened healthy controls, with a proportion of subjects having histories of child abuse and neglect. While other studies have detected brain changes in trauma controls – individuals with a history of trauma who did not meet current criteria for Posttraumatic Stress Disorder (PTSD), the trauma controls in all prior studies included individuals with current and/or past psychiatric diagnoses other than PTSD [3]. The study by Dannlowski and colleagues is the first to examine the relationship between neuroimaging assessments and dimensional measures of child maltreatment in a healthy, never psychiatrically ill cohort. Given the association between child maltreatment and PTSD and major depression (MDD), they hypothesized a priori brain changes in areas implicated in these disorders. Consistent with this hypothesis, more severe childhood maltreatment was associated with increased amygdala activation during an emotion-processing task, and decreased volume in the hippocampus, anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), medial prefrontal cortex (mPFC), and several other brain regions. Nikulina and colleagues [2] examined the interaction between monoamine oxidase-A (MAOA) genotype and child maltreatment in predicting MDD, dysthymia, and alcohol use disorder symptoms in adults. They identified sex and race effects that moderated the impact of MAOA genotype on adult outcomes. In the original paper by Caspi and colleagues [4], MAOA genotype was found to moderate the relationship between child maltreatment and antisocial behavior in males, with the high-activity MAOA allele protecting against psychopathology. Nikulina and colleagues reported significant three-way interactions that suggested the low-activity MAOA allele was protective in women and white participants when predicting depressive symptoms, and the high activity allele was protective against depressive symptoms in non-white maltreated females. The authors proposed that 1) the effects of MAOA genotype on antisocial behavior and mood are different; and 2) the direction of the effects of MAOA genotype is different for males and females, and whites and non-whites. Alternatively, they also suggested that their results might be “chance findings.” So, where do we go from here? Within the field there is a consensus that genes and environment interact to promote the development of depression and other stress-related psychiatric disorders, and agreement that the effects of severe stress are mediated by changes in brain structure and function. However, the nature of gene and environment interactions continues to be elusive, and the clinical significance of identified brain changes are not fully understood. What do we know, and what do we still need to learn to better understand the link between child maltreatment and psychiatric illness? What we know, Point 1: Many of the brain regions and circuits implicated in the pathophysiology of stress-related psychiatric problems are involved in the stress response As reviewed elsewhere and depicted in the simplified schematic in Figure 1, the brain responds to stress in an orchestrated manner [5, 6]. The stress response is initiated with the release of corticotropin releasing hormone (CRH) from the hypothalamus. CRH stimulates the release of adrenocorticotropin from the pituitary, which causes release of glucocorticoids (e.g., cortisol) from the adrenals. Glucocorticoids then stimulate CRH release from the amygdala, which in turn initiates norepinephrine release from the locus coeruleus and starts the sympathetic response to stress. The ACC, OFC, and mPFC play an important role in relaying information from primary sensory and association cortices to the amygdala and other subcortical structures, and inputs from these areas and the hippocampus help to attenuate the brain’s response to stress. The stress response also innervates the mesocortical and mesolimbic systems, which includes neurons of the ventral tegmentum area (VTA) that exert a suppressive effect on the stress system, and the nucleus accumbens (NAc), which receives inputs from VTA, amygdala, and mPFC. Figure 1 Brain Regions Involved In the Stress Response As depicted in Figure 1, many of the brain regions involved in the stress response are key structures in the emotion processing, reward, and executive function circuits --with dysregulation in these brain systems implicated in multiple stress-related psychiatric and substance use disorders [5]. For example, the amygdala, hippocampus, OFC, and mPFC, are key structures implicated in mood and anxiety disorders that are involved in the emotion processing circuit. The NAc and VTA, which receive inputs from multiple PFC areas, hippocampus, amygdala and hypothalamus, are key structures in the reward circuit and are involved in the pathophysiology of alcohol, substance use, and mood disorders. Given the overlap in the stress system and these other brain circuits, it is not surprising that severe stress in the form of child maltreatment is associated with increased risk for a range of psychiatric and substance use disorders. What we know, Point 2: The brain is not organized according to the psychiatric Diagnostic and Statistical Manual (DSM) There has been growing frustration with the limitations of the extant psychiatric nomenclature to delineate resilience and disease mechanisms. Consequently, the leadership of the National Institute of Mental Health (NIMH) established the Research Domain Criteria (RDoC) project, which has as its goal devising a new classification system for mental disorders that is informed by genetics, neuroscience, and psychology, and also takes into consideration the impact of trauma on the development of these conditions [7]. The three-way interactions between maltreatment history, MAOA genotype, and the demographic factors examined by Nikulina and colleagues accounted for 3%–5% of the variance in dysthymia symptoms [2]. Effect sizes have been greater in studies when genetic polymorphisms have been examined to account for individual differences in amygdala activation during emotion processing MRI tasks, accounting for approximately 10% of variance [8]. Clearly, however, something is still missing from the equation given the large proportion of unaccounted variance. With increasing appreciation of the role of epigenetics in disease processes [9], the incorporation of new molecular genetic approaches, together a RDoC perspective, will likely enhance risk and resilience research (See NIMH website for the RDoC project, http://www.nimh.nih.gov/research-funding/rdoc/index.shtml). What we know, Point 3: Genetic and detrimental early environment effects are not fixed Epigenetic mechanisms play a key role in the acute regulation of genes in response to changes in the environment [10]. Epigenetics refers to functionally relevant modifications to the genome that do not involve a change in DNA nucleotide sequence, but rather alter chromatin packing and affect the likelihood of a given gene product being transcribed. As reviewed elsewhere [10], animal models of neglect suggest early adverse rearing experiences are associated with epigenetic modification of the glucocorticoid receptor gene in the hippocampus. This results in fewer glucocorticoid receptors being made. As these receptors are key in initiating the cascade of events that put the breaks on the stress response, offspring of ‘neglectful’ dams have been found to have increased stress reactivity and exhibit anxious and depression-like behaviors. Epigenetic mechanisms have also been found to mediate brain changes in ocular dominance and visual deficits associated with early monocular deprivation experiments in cats. While these vision and brain changes were originally thought to be permanent, as reviewed elsewhere [10], emerging findings suggest they can be altered by pharmacological and environmental manipulations. Neither the effects of genes, nor early adversity, are fixed. What we still need to learn The two papers in this issue have helped to close the gap in our understanding of risk and resilience in individuals maltreated as children, but there is still more to learn. The paper by Dannlowski and colleagues [1] documented associations among structural and functional brain imaging parameters and dimensional measures of child maltreatment in individuals with no lifetime history of psychiatric illness. As the authors noted, these brain changes may serve as vulnerability markers for illness. Normative data on neuroimaging measures are still lacking, however, and we do not yet have brain measures that are diagnostic and predictive of impairment and distress. Nikulina and colleagues [2] identified genetic and demographic factors that accounted for individual differences in depression and alcohol misuse symptoms, although the amount of variance accounted for was relatively small. Longitudinal follow-up studies that utilize a RDoC perspective and integrate molecular genetics and imaging approaches, together with emerging technologies to examine whole genome epigenetic markers, will likely help to further elucidate the mechanisms by which early experiences of child maltreatment confer risk for psychiatric and substance use disorders later in life.

To the Editor: We appreciate the opportunity to comment on the criticism levied by Abramowitz and colleagues about our recent paper that describes an animal model of obsessive compulsive disorder (OCD). The purpose of animal research is to recapitulate conditions in mammalian systems that are more amenable to study than the human primate, while always striving to achieve both face and construct validity (1, 2). Such validity is demonstrated by homologous (not necessarily identical) behaviors in other species that are produced by neurobiological manipulations, based on etiological theories, and possess pharmacological isomorphism to the targeted disorder. Successful demonstration of these features provides the strongest platform to investigate causal mechanisms and novel treatments. While we agree with Abramowitz et al. that it is “difficult to imagine a true animal model of this condition [OCD] (especially one involving rodents),” the reported behaviors bear striking similarities with aspects of the clinical disorder. Although the true psychological state of the animal could not be directly assessed, the observed behaviors were both evolutionarily adaptive and affected by state-evoking stimuli – much like the relationship between stress and OCD behaviors in humans (3). In our original paper, developmental exposure to the tricyclic antidepressant, clomipramine, paradoxically produced adult rats that were more anxious (determined by both elevated plus maze and marble burying), hoarded, showed more perseveration, and demonstrated problems with reversal learning and working memory. The latter two behaviors were mediated by some degree of learning impairment that delays task acquisition, which is also observed in OCD patients (4). The main argument presented by Abramowitz et al., however, is whether animals can demonstrate true compulsions “…as opposed to some other form of repetitive behavior…”. Certainly, psychiatric disorders are complex and therefore difficult to model in animals. Repetitive behavior demonstrated by OCD patients may relieve uncertainty regarding a feared consequence (5), and thus such behavior is typically related to a specific obsession that is associated with an object or a place (6). On a neurobiological level, repetitive behaviors are believed to reflect supersensitive dopamine D2 receptors in striatal brain regions, amongst other brain changes (7). Early life exposure to clomipramine increases striatal D2 receptors (8), and the present findings clearly demonstrate that these animals repeatedly check novel objects and spend more time in their presence than control subjects (Figure 1). Much like a good clinician, ruling out other causes of behavioral symptoms is important for correct diagnosis, and thus converging evidence from multiple behaviors further strengthens the possible relevance of this model. First, stereotypies, such as repeated grooming and rearing in the rats, and a behavior that is non-specific for OCD, are not present in the clomipramine rats even when provoked with a D2 agonist (unpublished observation). Second, a ‘compulsive’ behavior could result from impaired working memory, where the individual simply does not remember whether a task was completed. The repetitive behaviors observed in OCD do not reflect impaired memory recall (9), and similarly, clomipramine animals are able to choose the correct arm to enter in the delayed working memory task, but have longer response latencies than control animals. Despite these observations that clomipramine-exposed animals show state-dependent checking behaviors, delay in working memory-related tasks, and heightened anxiety in anxiety-eliciting situations, direct assessment of whether checking and delayed responding are due to an obsession in the animals is impossible. However, contrary to the assertion that “It would be nearly impossible to demonstrate whether a rat is experiencing a true obsession versus general anxiety”, these data show that clomipramine-exposed rats demonstrate behaviors that are consistent with the clinical picture. Figure 1 Compulsive checking following a single dose of the D2 agonist quinpirole. Based on the modified methods of (13), a single, acute dose of quinpirole (0.5 mg/kg) was administered. Rats were placed in an open field containing four novel objects (shaded bars), ... In response to the charge that the clomipramine model is non-specific, anxiety and OCD are often not experienced in isolation, but rather are highly comorbid with depression. Thus, the current data might further underscore their shared common neurobiology and treatment response (10). In addition, the behavioral homologies in clomipramine-exposed rats are further substantiated by selective neurochemical changes in the orbital frontal cortex (5-HT2c receptors) and the striatum (D2 receptors) – two regions and receptors that are consistently implicated in OCD (11). Rather than working to discredit models based on the impossibility of animal researchers to assess cognition through verbal report, clinicians should be working with preclinical investigators to better translate symptoms into measurable behaviors. The neurobiological underpinnings of complex disorders, including OCD, necessitate that animal models themselves need also be more complex. In our opinion, focusing on a single gene or a single behavior is overly simplistic but is necessary to understand basic mechanisms. In parallel with this endophenotype/genomic approach, animal models also need to be based on externalized, observable behaviors – much like clinicians base diagnoses on multiple symptoms that they observe – and these models ideally should also demonstrate more than one target behavior. By manipulating developmental monoamine systems that are associated with OCD and its treatment, behavioral impairment in numerous domains increases in adulthood. It is by no accident that the very treatment that reduces the aforementioned behaviors can also produce them if provided during sensitive periods of development (12). Animal research provides an important platform for understanding disorder states, their causes, and a means to test novel treatments. At this stage, current treatments for OCD have significant limitations and none of them are preventive. The greatest promise of the clomipramine model may lie in exploiting the sensitive periods for these (OCD-like) behaviors and their associated biochemistry to develop an intervention that can neurochemically re-transform aberrant circuits to a more normal trajectory. Only future testing will tell. Susan L. Andersen Britta Thompson

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

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.

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.

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.

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.

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

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.