PURPOSE: The high prevalence of alcohol use disorder among individuals with a history of trauma and posttraumatic stress disorder is well documented. The current study applied network analysis to map the structure of symptom associations between these disorders. METHODS: Data come from a community sample of 449 Australian adults with a history of trauma and alcohol consumption during the last 12 months. Data analysis consisted of the construction of the comorbidity network of PTSD/AUD symptoms, identification of the bridging symptoms, computation of the centrality measures, and evaluation of the robustness of the results. RESULTS: Results highlighted two main symptom clusters, corresponding to two disorders, and that only nine edges connected the two clusters. Bridging symptoms connecting the two clusters were: alcohol use in dangerous situations, physical or mental health problems as a result of alcohol use, loss of interest or reduced social activities, and reckless/self-destructive behaviour. CONCLUSIONS: Identification of both central symptoms, because of their key role in the constellation and strong associations with majority of symptoms, and bridge symptoms, because of their mediating role between two disorders, has some implications in terms of self-medication and risk-taking/self-regulation theories of comorbidity and provides a number of clinical implications, which warrants further exploration within clinical samples.

There is a pressing need in the substance abuse field for more comprehensive models of etiology and treatment that address the complex issues of addiction, including the biological, social, cultural, spiritual and developmental needs of individuals and groups. This article presents a theoretical framework for an integral approach to substance abuse that expands on the existing biopsychosocial model. One contribution of the model is an integrated approach to spirituality from a cross-cultural perspective. This integral approach examines substance abuse etiology and treatment from a four-quadrant perspective adapted from the work of Ken Wilber, and incorporates concepts from integrative medicine and transpersonal psychology/psychiatry. Implications of the model are explored.

Research has consistently demonstrated a relationship between peer victimization, a major issue in early adolescence, and depression. However, longitudinal studies examining the relationship between peer victimization and depressive symptoms have yielded mixed results. Thus, the current study examined how specific aspects of peer victimization and subtypes of depressive symptoms are related over a two-year period. Adolescent females (N = 265) completed a questionnaire battery at baseline and two-year follow-up. Results indicated that baseline depressive symptoms prospectively predict peer overt victimization, relational victimization, and decreased prosocial behaviors at follow-up; baseline peer victimization did not predict depressive symptoms at follow-up. Further, results demonstrate the differential predictive value of specific depressive symptoms for overt vs. relational aggression and decreased prosocial behavior. Taken together, this study provides insight into the impact of depressive symptoms on peer victimization and the importance of addressing peer relations in the context of treatment for adolescent depression.

Reductionism, as a paradigm, is expired, and complexity, as a field, is tired. Data-based mathematical models of complex systems are offering a fresh perspective, rapidly developing into a new discipline: network science.

This study was designed to assess differences in sex-related risk behaviors between drug injectors who did not smoke crack cocaine, crack smokers who did not inject drugs, and drug users who both injected drugs and smoked crack. Current drug users (i.e. used within the past 30 days) from 22 cities were recruited and assessed. The sample (n = 26,982) included 28% who injected only, 42% who smoked crack only, and 30% who both injected and smoked crack. Results showed that active drug users were at risk of HIV infection through sexual transmission: in the 30 day period prior to their interview, 28% reported sex with two or more individuals, 23% had an IDU sex partner, and 24% had exchanged sex for drugs or money. In addition, more than 80% did not use a condom during sex. Crack only smokers and crack smoking injectors were more likely than injectors only to report multiple sex partners and exchanging sex. Because of these high risk behaviors, condom use was of particular importance. The number of days of alcohol use and having an IDU sex partner were independently associated with not using a condom. Crack smoking injectors reported the highest average number of days of alcohol consumption and were the most likely to have had an IDU sex partner.

In network approaches to psychopathology, disorders result from the causal interplay between symptoms (e.g., worry --> insomnia --> fatigue), possibly involving feedback loops (e.g., a person may engage in substance abuse to forget the problems that arose due to substance abuse). The present review examines methodologies suited to identify such symptom networks and discusses network analysis techniques that may be used to extract clinically and scientifically useful information from such networks (e.g., which symptom is most central in a person's network). The authors also show how network analysis techniques may be used to construct simulation models that mimic symptom dynamics. Network approaches naturally explain the limited success of traditional research strategies, which are typically based on the idea that symptoms are manifestations of some common underlying factor, while offering promising methodological alternatives. In addition, these techniques may offer possibilities to guide and evaluate therapeutic interventions.

The serotonergic (5-HT) system has been implicated in various physiological processes and neuropsychiatric disorders, but in many aspects its role in normal and pathologic brain function is still unclear. One reason for this might be the lack of appropriate animal models which can address the complexity of physiological and pathophysiological 5-HT functioning. In this respect, rats offer many advantages over mice as they have been the animal of choice for sophisticated neurophysiological and behavioral studies. However, only recently technologies for the targeted and tissue specific modification of rat genes - a prerequisite for a detailed study of the 5-HT system - have been successfully developed. Here, we describe a rat transgenic system for inducible gene manipulations in 5-HT neurons. We generated a Cre driver line consisting of a tamoxifen-inducible CreERT2 recombinase under the control of mouse Tph2 regulatory sequences. Tissue-specific serotonergic Cre recombinase expression was detected in four transgenic TPH2-CreERT2 rat founder lines. For functional analysis of Cre-mediated recombination, we used a rat Cre reporter line (CAG-loxP.EGFP), in which EGFP is expressed after Cre-mediated removal of a loxP-flanked lacZ STOP cassette. We show an in-depth characterisation of this rat Cre reporter line and demonstrate its applicability for monitoring Cre-mediated recombination in all major neuronal subpopulations of the rat brain. Upon tamoxifen induction, double transgenic TPH2-CreERT2/CAG-loxP.EGFP rats show selective and efficient EGFP expression in 5-HT neurons. Without tamoxifen administration, EGFP is only expressed in few 5-HT neurons which confirms minimal background recombination. This 5-HT neuron specific CreERT2 line allows Cre-mediated, inducible gene deletion or gene overexpression in transgenic rats which provides new opportunities to decipher the complex functions of the mammalian serotonergic system.

Centrality indices are a popular tool to analyze structural aspects of psychological networks. As centrality indices were originally developed in the context of social networks, it is unclear to what extent these indices are suitable in a psychological network context. In this article we critically examine several issues with the use of the most popular centrality indices in psychological networks: degree, betweenness, and closeness centrality. We show that problems with centrality indices discussed in the social network literature also apply to the psychological networks. Assumptions underlying centrality indices, such as presence of a flow and shortest paths, may not correspond with a general theory of how psychological variables relate to one another. Furthermore, the assumptions of node distinctiveness and node exchangeability may not hold in psychological networks. We conclude that, for psychological networks, betweenness and closeness centrality seem especially unsuitable as measures of node importance. We therefore suggest three ways forward: (a) using centrality measures that are tailored to the psychological network context, (b) reconsidering existing measures of importance used in statistical models underlying psychological networks, and (c) discarding the concept of node centrality entirely. Foremost, we argue that one has to make explicit what one means when one states that a node is central, and what assumptions the centrality measure of choice entails, to make sure that there is a match between the process under study and the centrality measure that is used. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Scale-free organizations, characterized by uneven distributions of linkages between nodal elements, describe the structure and function of many life-based complex systems developing under evolutionary pressures. We explore motivated behavior as a scale-free map toward a comprehensive translational theory of addiction. Motivational and behavioral repertoires are reframed as link and nodal element sets, respectively, comprising a scale-free structure. These sets are generated by semi-independent information-processing streams within cortical-striatal circuits that cooperatively provide decision-making and sequential processing functions necessary for traversing maps of motivational links connecting behavioral nodes. Dopamine modulation of cortical-striatal plasticity serves a central-hierarchical mechanism for survival-adaptive sculpting and development of motivational-behavioral repertoires by guiding a scale-free design. Drug-induced dopamine activity promotes drug taking as a highly connected behavioral hub at the expense of natural-adaptive motivational links and behavioral nodes. Conceptualizing addiction as pathological alteration of scale-free motivational-behavioral repertoires unifies neurobiological, neurocomputational and behavioral research while addressing addiction vulnerability in adolescence and psychiatric illness. This model may inform integrative research in defining more effective prevention and treatment strategies for addiction.

BACKGROUND: Pancreatic neuritis is a histopathological hallmark of pancreatic neuropathy and correlates to abdominal neuropathic pain sensation in pancreatic adenocarcinoma (PCa) and chronic pancreatitis (CP). However, inflammatory cell subtypes that compose pancreatic neuritis and their correlation to the neuropathic pain syndrome in PCa and CP are yet unknown. METHODS: Inflammatory cells within pancreatic neuritis lesions of patients with PCa (n = 20) and CP (n = 20) were immunolabeled and colorimetrically quantified with the pan-leukocyte marker CD45, with CD68 (macrophages), CD8 (cytotoxic T-lymphocytes), CD4 (T-helper cells), CD20 (B-lymphocytes), NCL-PC (plasma cells), neutrophil elastase, PRG2 (eosinophils), anti-mast cell (MC) tryptase and correlated to pain sensation. Perineural mast cell subtypes were analyzed by double immunolabeling with MC chymase. Expression and neural immunoreactivity of protease-activated receptor type 1 (PAR-1) and type 2 (PAR-2) were analyzed in PCa and CP and correlated to pain status of the patients. RESULTS: In PCa and CP, nerves were predominantly infiltrated by cytotoxic T-lymphocytes (PCa: 35% of all perineural inflammatory cells, CP: 33%), macrophages (PCa: 39%, CP: 33%) and MC (PCa: 21%, CP: 27%). In both entities, neuropathic pain sensation was associated with a specific increase of perineural MC (PCa without pain: 14% vs. PCa with pain: 31%; CP without pain: 19% vs. CP with pain: 34%), not affecting the frequency of other inflammatory cell subtypes. The vast majority of these MC contained MC chymase. PAR-1 and PAR-2 expression did not correlate to the pain sensation of PCa and CP patients. CONCLUSION: Pancreatic neuritis in PC and CP is composed of cytotoxic T-lymphocytes, macrophages and MC. The specific enrichment of MC around intrapancreatic nerves in neuropathic pain due to PCa and CP suggests the presence of MC-induced visceral hypersensitivity in the pancreas. Therefore, pancreatic and enteric neuropathies seem to share a similar type of neuro-immune interaction in the generation of visceral pain.

BACKGROUND: Network analysis (NA) is an analytical tool that allows one to explore the map of connections and eventual dynamic influences among symptoms and other elements of mental disorders. In recent years, the use of NA in psychopathology has rapidly grown, which calls for a systematic and critical analysis of its clinical utility. METHODS: Following PRISMA guidelines, a systematic review of published empirical studies applying NA in psychopathology, between 2010 and 2017, was conducted. We included the literature published in PubMed and PsycINFO using as keywords any combination of

Many studies have shown that the mycoplasmal membrane protein p37 enhances cancer cell migration, invasion, and metastasis. Previously, we generated 6 monoclonal antibodies (MAbs) against the mycoplasmal protein p37 and showed the presence of mycoplasma-infected circulating tumor cells in the blood of hepatocellular carcinoma patients by using CA27, one of the six MAbs. When mycoplasmas were incubated with cancer cells in the presence of CA27, mycoplasma infection was completely inhibited, suggesting that CA27 is a neutralizing antibody inhibiting mycoplasma infection. To examine the neutralizing epitope of CA27, we generated a series of glutathione S-transferase (GST)-fused p37 deletion mutant proteins in which p37 was partly deleted. To express p37-coding sequences in E.coli, mycoplasmal TGA codons were substituted with TGG in the p37 deletion mutant genes. GST-fused p37 deletion mutant proteins were then screened to identify the epitope targeted by CA27. Western blots showed that CA27 bound to the residues 216-246 on the middle part of the p37 protein while it did not bind to the residues 183-219 and 216-240. Fine mapping showed that CA27 was able to bind to the residues 226-246, but its binding activity was relatively weakened as compared to that to the residues 216-246, suggesting that the residues 226-246 is essential for optimal binding activity of CA27. Interestingly, the treatment of the purified GST-tagged epitopes with urea showed that CA27 binding to the epitope was sodium dodecyl sulfate-resistant but urea-sensitive. The same 226-246 residues were also recognized by two other anti-p37 MAbs, suggesting that the epitope is immunodominant. The identification of the novel neutralizing epitope may provide new insight into the interaction between the p37 protein and host receptors.

The pivotal problem of comorbidity research lies in the psychometric foundation it rests on, that is, latent variable theory, in which a mental disorder is viewed as a latent variable that causes a constellation of symptoms. From this perspective, comorbidity is a (bi)directional relationship between multiple latent variables. We argue that such a latent variable perspective encounters serious problems in the study of comorbidity, and offer a radically different conceptualization in terms of a network approach, where comorbidity is hypothesized to arise from direct relations between symptoms of multiple disorders. We propose a method to visualize comorbidity networks and, based on an empirical network for major depression and generalized anxiety, we argue that this approach generates realistic hypotheses about pathways to comorbidity, overlapping symptoms, and diagnostic boundaries, that are not naturally accommodated by latent variable models: Some pathways to comorbidity through the symptom space are more likely than others; those pathways generally have the same direction (i.e., from symptoms of one disorder to symptoms of the other); overlapping symptoms play an important role in comorbidity; and boundaries between diagnostic categories are necessarily fuzzy.

RATIONALE: Studies in socially housed monkeys have demonstrated an influence of position in the social dominance hierarchy on brain dopamine D2 receptors and the reinforcing effects of cocaine that dissipates after long-term cocaine self-administration. OBJECTIVE: The aims of the study were to examine the effects of abstinence from cocaine on D2 receptors in socially housed monkeys and to extend behavioral characterizations to measures of reactivity to a novel object. MATERIALS AND METHODS: Twelve socially housed male cynomolgus monkeys with extensive cocaine self-administration experience were used (average lifetime intakes approximately 270 and 215 mg/kg for dominant and subordinate monkeys, respectively). Abstinence lasted for approximately 8 months, after which D2 receptor availability was assessed using positron emission tomography and the D2 ligand [18F]fluoroclebopride. Reaction to novelty was also assessed in these subjects as well as nine individually housed monkeys. RESULTS: During abstinence, D2 receptor availability in the caudate nucleus was significantly higher in dominant versus subordinate monkeys. Average latency to touch a novel object was also significantly higher in dominant monkeys compared to subordinates or individually housed monkeys. In socially experienced monkeys, a significant positive correlation was observed between caudate nucleus D2 receptor availability and latencies to touch the novel object. CONCLUSIONS: Although chronic cocaine self-administration blunts the ability of social dominance to alter D2 receptor availability and sensitivity to the reinforcing effects of cocaine, this influence reemerges during abstinence. In addition, the data suggest that prior experience with social dominance can lead to longer latencies in reaction to novelty--a personality trait associated with low vulnerability to cocaine abuse.

Romantic rejection causes a profound sense of loss and negative affect. It can induce clinical depression and in extreme cases lead to suicide and/or homicide. To begin to identify the neural systems associated with this natural loss state, we used functional magnetic resonance imaging to study 10 women and 5 men who had recently been rejected by a partner but reported they were still intensely

BACKGROUND: Traditional approaches for the classification of eating disorders (EDs) attribute symptoms to an underlying, latent disease entity. The network approach is an alternative model in which mental disorders are represented as networks of interacting, self-reinforcing symptoms. This project was the first to use network analysis to identify interconnected systems of ED symptoms. METHOD: Adult participants (n = 143; 77.6% women) with a Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) ED were recruited from the community to take part in a larger ongoing longitudinal study. The Structured Clinical Interview for DSM Disorders (SCID-I) was used to establish diagnoses. An undirected network of ED symptoms was created using items from the Eating Pathology Symptoms Inventory (EPSI) and the R package qgraph. RESULTS: Body checking emerged as the strongest and most important single symptom in the entire network by having the shortest average distance to other symptoms in the network, and by being the most frequent symptom on the path between any two other symptoms. Feeling the need to exercise every day and two symptoms assessing dietary restraint/restricting emerged as 'key players', such that their removal from the network resulted in maximal fracturing of the network into smaller components. CONCLUSIONS: Although cognitive-behavioral therapy for EDs focuses on reducing body checking to promote recovery, our data indicate that amplified efforts to address body checking may produce stronger (and more enduring) effects. Finally, results of the 'key players analysis' suggested that targeting interventions at these key nodes might prevent or slow the cascade of symptoms through the 'network' of ED psychopathology.

Since the introduction of mental disorders as networks of causally interacting symptoms, this novel framework has received considerable attention. The past years have resulted in over 40 scientific publications and numerous conference symposia and workshops. Now is an excellent moment to take stock of the network approach: What are its most fundamental challenges, and what are potential ways forward in addressing them? After a brief conceptual introduction, we first discuss challenges to network theory: (1) What is the validity of the network approach beyond some commonly investigated disorders such as major depression? (2) How do we best define psychopathological networks and their constituent elements? And (3) how can we gain a better understanding of the causal nature and real-life underpinnings of associations among symptoms? Next, after a short technical introduction to network modeling, we discuss challenges to network methodology: (4) heterogeneity of samples studied with network analytic models, and (5) a lurking replicability crisis in this strongly data-driven and exploratory field. Addressing these challenges may propel the network approach from its adolescence into adulthood and promises advances in understanding psychopathology both at the nomothetic and idiographic level.

In depression research, symptoms are routinely assessed via rating scales and added to construct sum-scores. These scores are used as a proxy for depression severity in cross-sectional research, and differences in sum-scores over time are taken to reflect changes in an underlying depression construct. To allow for such interpretations, rating scales must (a) measure a single construct, and (b) measure that construct in the same way across time. These requirements are referred to as unidimensionality and measurement invariance. We investigated these 2 requirements in 2 large prospective studies (combined n = 3,509) in which overall depression levels decrease, examining 4 common depression rating scales (1 self-report, 3 clinician-report) with different time intervals between assessments (between 6 weeks and 2 years). A consistent pattern of results emerged. For all instruments, neither unidimensionality nor measurement invariance appeared remotely tenable. At least 3 factors were required to describe each scale, and the factor structure changed over time. Typically, the structure became less multifactorial as depression severity decreased (without however reaching unidimensionality). The decrease in the sum-scores was accompanied by an increase in the variances of the sum-scores, and increases in internal consistency. These findings challenge the common interpretation of sum-scores and their changes as reflecting 1 underlying construct. The violations of common measurement requirements are sufficiently severe to suggest alternative interpretations of depression sum-scores as formative instead of reflective measures. We discuss the possible causes of these violations such as response shift bias, restriction of range, and regression to the mean. (PsycINFO Database Record

The loss of control over drug intake that occurs in addiction was initially believed to result from disruption of subcortical reward circuits. However, imaging studies in addictive behaviours have identified a key involvement of the prefrontal cortex (PFC) both through its regulation of limbic reward regions and its involvement in higher-order executive function (for example, self-control, salience attribution and awareness). This Review focuses on functional neuroimaging studies conducted in the past decade that have expanded our understanding of the involvement of the PFC in drug addiction. Disruption of the PFC in addiction underlies not only compulsive drug taking but also accounts for the disadvantageous behaviours that are associated with addiction and the erosion of free will.

The relationship between acquisitive crime and drug misuse problems was studied among 753 clients recruited to the National Treatment Outcome Research Study (NTORS). More than 17000 offences were reported during the 90-day period prior to treatment. Half of the clients committed no acquisitive crimes during this period whereas 10% committed 76% of the crimes. At 1-year follow-up, the number of crimes was reduced to one third of intake levels, and criminal involvement was reduced by about half. Reductions in regular heroin use were strongly associated with reductions in crime. The reduction in crime following treatment is of great importance and provides immediate benefit to society through the reduced economic costs of crime.

AIMS: This study investigates factors associated with abstinence, lapse or relapse to heroin use after residential treatment and, specifically, the extent to which changes in cognitive, avoidance and distraction coping responses were related to heroin use and other drug use outcomes. DESIGN, SETTING, PARTICIPANTS: The sample comprised 242 clients from 23 residential programmes in the NTORS project, who used heroin before treatment and who were followed-up after treatment during the first 12 months of the study. MEASUREMENTS: Data on client characteristics and problems, coping responses, drug use and other outcomes, were collected by structured face-to-face interviews. FINDINGS: Many clients (60%) used heroin after treatment, with the first occasion of heroin use usually occurring very soon after leaving treatment: 40% remained abstinent from heroin. Analyses were conducted for three groups based upon heroin outcome status (abstinent, lapsed, relapsed). Clients who avoided a full relapse to heroin use (abstinent and lapse groups) consistently made more use of cognitive, avoidance and distraction coping strategies at follow-up than at intake. Treatment completion was related to better outcome. The lapse and relapse groups reported higher rates of use of illicit drugs other than heroin after treatment than the abstinent group. CONCLUSIONS: Despite generally satisfactory drug use outcomes, the lapses and relapses to heroin use give rise to concern. Treatment services should develop further and strengthen relapse prevention and relapse coping skills among drug misusers.

To conduct a multilevel meta-analysis of multiple single-case experimental design (SCED) studies, the individual participant data (IPD) can be analyzed in one or two stages. In the one-stage approach, a multilevel model is estimated based on the raw data. In the two-stage approach, an effect size is calculated for each participant and these effect sizes and their sampling variances are subsequently combined to estimate a meta-analytic multilevel model. The multilevel model in the two-stage approach has fewer parameters to estimate, in exchange for the reduction of information of the raw data to effect sizes. In this paper we explore how the one-stage and two-stage IPD approaches can be applied in the context of meta-analysis of single-case designs. Both approaches are compared for several single-case designs of increasing complexity. Through a simulation study we show that the two-stage approach obtains better convergence rates for more complex models, but that model estimation does not necessarily converge at a faster speed. The point estimates of the fixed effects are unbiased for both approaches across all models, as such confirming results from methodological research on IPD meta-analysis of group-comparison designs. In light of these results, we discuss the implementation of both methods in R.

BACKGROUND: Psychosis spectrum disorder is a heterogeneous, multifactorial clinical phenotype, known to have a high heritability, only a minor portion of which can be explained by molecular measures of genetic variation. This study proposes that the identification of genetic variation underlying psychotic disorder may have suffered due to issues in the psychometric conceptualization of the phenotype. Here we aim to open a new line of research into the genetics of mental disorders by explicitly incorporating genes into symptom networks. Specifically, we investigate whether links between a polygenic risk score (PRS) for schizophrenia and measures of psychosis proneness can be identified in a network model. METHODS: We analyzed data from n = 2180 subjects (controls, patients diagnosed with a non-affective psychotic disorder, and the first-degree relatives of the patients). A network structure was computed to examine associations between the 42 symptoms of the Community Assessment of Psychic Experiences (CAPE) and the PRS for schizophrenia. RESULTS: The resulting network shows that the PRS is directly connected to the spectrum of positive and depressive symptoms, with the items conspiracy and no future being more often located on predictive pathways from PRS to other symptoms. CONCLUSIONS: To our knowledge, the current exploratory study provides a first application of the network framework to the field of behavior genetics research. This allows for a novel outlook on the investigation of the relations between genome-wide association study-based PRSs and symptoms of mental disorders, by focusing on the dependencies among variables.

Progress has been made over the last 10 years in determining the neural mechanisms of sensitization induced by amphetamine-like psychostimulants, opioids and stressors. Changes in dopamine transmission in axon terminal fields such as the nucleus accumbens appear to underlie the expression of sensitization, but the actions of drugs and stressors in the somatodendritic regions of the A10/A9 dopamine neurons seem critical for the initiation of sensitization. Manipulations that increase somatodendritic dopamine release and permit the stimulation of D1 dopamine receptors in this region induce changes in the dopamine system that lead to the development of long-term sensitization. However, it is not known exactly how the changes in the A10/A9 region are encoded to permit augmented dopamine transmission in the terminal field. One possibility is that the dopamine neurons of sensitized animals have become increasingly sensitive to excitatory pharmacological and environmental stimuli or desensitized to inhibitory regulation. Alternatively, changes in cellular activity or protein synthesis may result in a change in the presynaptic regulation of axon terminal dopamine release.

The soft medical model for psychiatric illness, which was operationalized in DSM-III, defines psychiatric disorders as syndromes with shared symptoms, signs, course of illness and response to treatment. Many in our field want to move to a hard medical model based on etiological mechanisms. This essay explores the feasibility of this move and asks whether psychiatric disorders have the needed single clear level of explanation for an etiologically based nosology. I propose seven criteria for a good explanation: (i) strength, (ii) causal confidence, (iii) generalizability, (iv) specificity, (v) manipulability, (vi) proximity and (vii) generativity. Applying them to cystic fibrosis, a gene-level approach to etiology performs well across the board. By contrast, a detailed review of alcohol dependence and a briefer review of major depression suggests that psychiatric disorders have multiple explanatory perspectives no one of which can be privileged over others using scientific data alone. Therefore, a move toward an etiologically based diagnostic system cannot assume that one level of explanation will stand out as the obvious candidate on which to base the nosology. This leaves two options. Either a hard medical model will be implemented that will require a consensus about a preferred level of explanation which must reflect value judgments as well as science. To take this approach, we need to agree on what we most want from our explanations. Alternatively, we will need to move away from the traditional hard medical model that requires that we ground our diagnoses in single biological essences, and focus instead on fuzzy, cross-level mechanisms, which may more realistically capture the true nature of psychiatric disorders.

This essay explores four answers to the question 'What kinds of things are psychiatric disorders?' Essentialist kinds are classes whose members share an essence from which their defining features arise. Although elegant and appropriate for some physical (e.g. atomic elements) and medical (e.g. Mendelian disorders) phenomena, this model is inappropriate for psychiatric disorders, which are multi-factorial and 'fuzzy'. Socially constructed kinds are classes whose members are defined by the cultural context in which they arise. This model excludes the importance of shared physiological mechanisms by which the same disorder could be identified across different cultures. Advocates of practical kinds put off metaphysical questions about 'reality' and focus on defining classes that are useful. Practical kinds models for psychiatric disorders, implicit in the DSM nosologies, do not require that diagnoses be grounded in shared causal processes. If psychiatry seeks to tie disorders to etiology and underlying mechanisms, a model first proposed for biological species, mechanistic property cluster (MPC) kinds, can provide a useful framework. MPC kinds are defined not in terms of essences but in terms of complex, mutually reinforcing networks of causal mechanisms. We argue that psychiatric disorders are objectively grounded features of the causal structure of the mind/brain. MPC kinds are fuzzy sets defined by mechanisms at multiple levels that act and interact to produce the key features of the kind. Like species, psychiatric disorders are populations with central paradigmatic and more marginal members. The MPC view is the best current answer to 'What kinds of things are psychiatric disorders?'

The primary goal of this study is to ascertain whether relapse to drug dependence, in terms of continuous abstinence assessment, exhibits a typical pattern that can be characterized by a common quantitative function. If the relapse curve is indeed ubiquitous, then some underlying mechanism must be operating to shape the curve that transcends variables such as drug class, population, or treatment type. Survival analyses are performed on 20 alcohol and tobacco treatment studies using the proportions of individuals remaining abstinent after a period of initial abstinence. Several parametric models of relapse are compared, and the results demonstrate that a log-logistic distribution is the most accurate reflection of the available data and the basic shape of the relapse curve is uniform. In most reports examined, the rate of relapse decelerates after initial abstinence has been achieved, and therefore, the amount of accumulated time abstinent may be the transcending variable that operates to shape the relapse curve.

Drugs of abuse are very powerful reinforcers, and even in conditions of limited access (where the organism is not dependent) these drugs will motivate high rates of operant responding. This presumed hedonic property and the drugs' neuropharmacological specificity provide a means of studying the neuropharmacology and neuroanatomy of brain reward. Three major brain systems appear to be involved in drug reward--dopamine, opioid and GABA. Evidence suggests a midbrain-forebrain-extrapyramidal circuit with its focus in the nucleus accumbens. Data implicating dopamine and opioid systems in indirect sympathomimetic and opiate reward include critical elements in both the nucleus accumbens and ventral tegmental areas. Ethanol reward appears to depend on an interaction with the GABAA receptor complex but may also involve common elements such as dopamine and opioid peptides in this midbrain-forebrain-extrapyramidal circuit. These results suggest that brain reward systems have a multidetermined neuropharmacological basis that may involve some common neuroanatomical elements.

The reliability and validity of traditional taxonomies are limited by arbitrary boundaries between psychopathology and normality, often unclear boundaries between disorders, frequent disorder co-occurrence, heterogeneity within disorders, and diagnostic instability. These taxonomies went beyond evidence available on the structure of psychopathology and were shaped by a variety of other considerations, which may explain the aforementioned shortcomings. The Hierarchical Taxonomy Of Psychopathology (HiTOP) model has emerged as a research effort to address these problems. It constructs psychopathological syndromes and their components/subtypes based on the observed covariation of symptoms, grouping related symptoms together and thus reducing heterogeneity. It also combines co-occurring syndromes into spectra, thereby mapping out comorbidity. Moreover, it characterizes these phenomena dimensionally, which addresses boundary problems and diagnostic instability. Here, we review the development of the HiTOP and the relevant evidence. The new classification already covers most forms of psychopathology. Dimensional measures have been developed to assess many of the identified components, syndromes, and spectra. Several domains of this model are ready for clinical and research applications. The HiTOP promises to improve research and clinical practice by addressing the aforementioned shortcomings of traditional nosologies. It also provides an effective way to summarize and convey information on risk factors, etiology, pathophysiology, phenomenology, illness course, and treatment response. This can greatly improve the utility of the diagnosis of mental disorders. The new classification remains a work in progress. However, it is developing rapidly and is poised to advance mental health research and care significantly as the relevant science matures. (PsycINFO Database Record

AbstractTo speak of cognitive regulation versus emotion regulation may be misleading. However, some forms of regulation are carried out by executive processes, subject to voluntary control, while others are carried out by “automatic” processes that are far more primitive. Both sets of processes are in constant interaction, and that interaction gives rise to a stream of activity that is both cognitive and emotional. Studying the brain helps us understand these reciprocal regulatory influences in some detail. Cortical activities regulate subcortical activities through executive modulation of prepotent appraisals and emotional responses. Subcortical systems regulate the cortex by tuning its activities to the demands or opportunities provided by the environment. Cortical controls buy us time, as needed for planning and intelligent action. Subcortical controls provide energy, focus, and direction, as needed for relevant emotion-guided behaviour. We review the neural processes at work in both directions of regulatory activity, looking at the anterior cingulate cortex (ACC) as a hub of cortical systems mediating downward control, and discussing limbic, hypothalamic, and brainstem systems that mediate upward control. A macrosystem that displays both directions of control includes the ACC and the amygdala within a feedback circuit whose features vary with clinical-personality differences. Developmental changes in ACC-mediated self-regulation support advances in directed attention, response inhibition, and self-monitoring. Developmental changes in amygdala-mediated self-regulation involve the compilation of meanings that direct thought and behaviour, thus consolidating individual differences over the lifespan. In this way, the capacity to exert voluntary control develops alongside the accumulation of associations that trigger the responses that demand control. The balance between these developmental progressions has implications for personality formation and mental health.]]>

Graduation from college is an important milestone for young adults, marked by mixed emotions and poignancy, and therefore is an especially salient context for studying meaning in life. The present research used experience-sampling methodology to examine the antecedents and consequences of students' experience of meaning in life over the course of graduation. Participants were 74 graduating students who provided a total of 538 reports over the span of three days, including commencement day. Increased levels of state meaning in life during the days around commencement were linked to spending time with people in general and with family in particular, as well as thinking about one's years in college. Thinking about one's years in college mediated the effects of present company on state meaning in life. Graduates who experienced higher levels of state meaning in life during the days around their commencement ceremony had higher trait levels of meaning in life one week following commencement. We discuss how making meaning of a poignant experience has implications for healthy psychological development.

Structural MRIs of the brains of humans with extensive navigation experience, licensed London taxi drivers, were analyzed and compared with those of control subjects who did not drive taxis. The posterior hippocampi of taxi drivers were significantly larger relative to those of control subjects. A more anterior hippocampal region was larger in control subjects than in taxi drivers. Hippocampal volume correlated with the amount of time spent as a taxi driver (positively in the posterior and negatively in the anterior hippocampus). These data are in accordance with the idea that the posterior hippocampus stores a spatial representation of the environment and can expand regionally to accommodate elaboration of this representation in people with a high dependence on navigational skills. It seems that there is a capacity for local plastic change in the structure of the healthy adult human brain in response to environmental demands.

A comparative analysis of recovery resources (abstinence social support, abstinence self-efficacy) was conducted among two groups exiting inpatient treatment for substance use disorders: persons with psychiatric comorbid substance use disorders and persons with substance use disorders. Both groups reported comparable levels of abstinence social support, but this resource was not significantly related to substance use among persons with psychiatric comorbid substance use disorders. Although abstinence self-efficacy was significantly related to substance use, persons with psychiatric comorbid substance use disorders reported significantly lower levels of abstinence self-efficacy than persons with substance use disorders. Findings suggest that persons with psychiatric comorbid substance use disorders exit alcohol/drug treatment with lower levels of abstinence self-efficacy compared to their substance use disorder peers.

As preparations for the fifth revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM) are under way, this paper focuses upon changes proposed for the substance use disorders section. It briefly outlines the history behind the current nomenclature, and the selection of the term 'dependence' over 'addiction' in earlier versions of the DSM. The term 'dependence', while used in past decades to refer to uncontrolled drug-seeking behavior, has an alternative meaning--the physiological adaptation that occurs when medications acting on the central nervous system are ingested with rebound when the medication is abruptly discontinued. These dual meanings have led to confusion and may have propagated current clinical practices related to under-treatment of pain, as physicians fear creating an 'addiction' by prescribing opioids. In part to address this problem, a change proposed for DSM-V is to alter the chapter name to 'Addiction and Related Disorders', which will include disordered gambling. The specific substance use disorders may be referred to as 'alcohol use' or 'opioid use' disorders. The criteria for the disorders are likely to remain similar, with the exception of removal of the 'committing illegal acts' criterion and addition of a 'craving' criterion. The other major change relates to the elimination of the abuse/dependence dichotomy, given the lack of data supporting an intermediate stage. These changes are anticipated to improve clarification and diagnosis and treatment of substance use and related disorders.

BACKGROUND: The DSM uses one set of abuse and dependence criteria to assess multiple substance use disorders (SUDs). Most SUD research aggregates across these symptoms to study the behavior of SUD as a static construct. We use an alternative approach that conceptualizes symptoms as directly interacting variables in psychopathological networks. We apply network models to symptom-level data to investigate the unique roles of individual symptoms and their interactions in SUD. METHODS: We analyzed 11 DSM III-R/IV abuse and dependence criteria in a sample of 2405 adult twins who reported use of at least one illicit substance six or more times from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders (VATSPSUD). We estimated a symptom network for each substance class as well as a global network collapsed across all substance classes. We examined similarities and differences across the 6 networks in terms of symptom-to-symptom connections and symptom centrality. RESULTS: The global network model revealed several interesting symptom connections, such as a strong predictive relation between tolerance and more-than-planned substance use. The most central symptom was using a drug more than planned. In addition, several interesting differences across substances emerged, both in the strength of symptom connections as well as the centrality of symptoms to each network. CONCLUSIONS: When analyzed as networks, abuse and dependence symptoms do not function equivalently across illicit substance classes. These findings suggest the value of analyzing individual symptoms and their associations to gain new insight into the mechanisms of SUD.

The network approach to psychopathology posits that mental disorders can be conceptualized and studied as causal systems of mutually reinforcing symptoms. This approach, first posited in 2008, has grown substantially over the past decade and is now a full-fledged area of psychiatric research. In this article, we provide an overview and critical analysis of 363 articles produced in the first decade of this research program, with a focus on key theoretical, methodological, and empirical contributions. In addition, we turn our attention to the next decade of the network approach and propose critical avenues for future research in each of these domains. We argue that this program of research will be best served by working toward two overarching aims: (a) the identification of robust empirical phenomena and (b) the development of formal theories that can explain those phenomena. We recommend specific steps forward within this broad framework and argue that these steps are necessary if the network approach is to develop into a progressive program of research capable of producing a cumulative body of knowledge about how specific mental disorders operate as causal systems.

Considerable experimental and clinical evidence links forebrain dopamine (DA) systems to the performance of motor activities and to motivational processes. Much of the support for this conclusion was obtained from studies utilizing lesions or drugs to manipulate aspects of central dopaminergic function. Although such experiments yield important information concerning the behavioral consequences of interference with DA systems in brain, they do not demonstrate any relation between the dynamic activity of DA neurons and the level or type of motor function exhibited by the organism. This review discusses the emerging field of behavioral neurochemistry, and provides an overview of recent studies investigating the relation between nucleus accumbens DA release and behavior. Particular emphasis is placed upon current research involving microdialysis, voltammetry and electrophysiology. These different methods are viewed as complementary techniques for investigating the activity of DA systems in behaving animals. Evidence indicates that DA activity is most reliably activated by stimuli that trigger instrumental behavior and during the preparatory or instrumental phase of motivated behavior. The effects of consummatory reactions to positive reinforcers are somewhat equivocal; with food consumption, dialysis studies have yielded inconsistent results, while some voltammetric and electrophysiological studies have shown that DA activity in accumbens or ventral tegmental area actually decreases during consumption of food reinforcement. Moreover, the responsiveness of accumbens DA activity during behavioral stimulation is not unique to appetitive conditions, as several studies have shown that aversive or stressful conditions also stimulate accumbens DA release or metabolism. It is reasonable to suggest at this time that accumbens DA neurons are activated by a variety of different motivational conditions, but that the consequence of that activation is to modulate the behavioral reactivity of the organism. This type of function is seen as representing an area of overlap between motor and motivational processes.

Complex dynamical systems, ranging from ecosystems to financial markets and the climate, can have tipping points at which a sudden shift to a contrasting dynamical regime may occur. Although predicting such critical points before they are reached is extremely difficult, work in different scientific fields is now suggesting the existence of generic early-warning signals that may indicate for a wide class of systems if a critical threshold is approaching.

Multiple neurochemical pathways are involved in mediating craving and relapse to alcohol. Opioidergic and glutamatergic systems have a key role in alcoholism, as demonstrated by the clinically effective compounds naltrexone and acamprosate acting through these systems. The dopaminergic system has long featured in alcoholism research; hitherto disappointing results from clinical studies could improve following the discovery that dopamine D3 receptor antagonism produces consistent and robust results in preclinical studies. Corticotropin-releasing factor signalling and the endocannabinoid system integrate stress-related events and thereby mediate relapse behaviour. Overall, these new targets have yielded several compounds that are undergoing clinical testing. However, the heterogeneity in treatment response makes it necessary to characterize genetic and protein markers and endophenotypes for individualized pharmacotherapy.

Quitting smoking is the single most effective strategy to reduce morbidity and premature mortality in smokers. Research has demonstrated the effectiveness of pharmacotherapy in smoking cessation, but few studies have directly compared varenicline and monotherapy nicotine replacement therapy (NRT) and none have examined varenicline and combinations of NRT products. The majority of smoking cessation trials involve carefully circumscribed populations, making their results less generalizable to those with severe medical conditions or psychiatric comorbidities. This paper reports on the rationale, methodology and participant characteristics of a randomized controlled trial designed to: (1) determine which pharmacotherapy - NRT, long term combinations of NRT, or varenicline - is most effective in achieving abstinence; (2) investigate the incidence of neuropsychiatric symptoms among participants over the course of their quit attempt; and (3) assess whether there is a significant difference in the incidence of neuropsychiatric symptoms in those receiving differing pharmacotherapies, and between those with and without psychiatric illnesses. The primary outcome was carbon monoxide confirmed abstinence from weeks 5-52 following a target quit date. Secondary outcomes included neuropsychiatric (i.e., depression, suicidal ideation, anxiety, anger) and withdrawal symptoms. Smokers (N=737) were randomly assigned to one of three treatment conditions, and were scheduled to attend 8 follow-up appointments over 12 months. All participants received 6-15 minute practical counseling sessions with nurse counselors experienced in treating tobacco dependence. We expect that the results will lead to an enhanced understanding of the efficacy of these pharmacotherapies, including those with a history of psychiatric illness.

Understanding the changes in the brain which occur in the transition from normal to addictive behavior has major implications in public health. Here we postulate that while reward circuits (nucleus accumbens, amygdala), which have been central to theories of drug addiction, may be crucial to initiate drug self-administration, the addictive state also involves disruption of circuits involved with compulsive behaviors and with drive. We postulate that intermittent dopaminergic activation of reward circuits secondary to drug self-administration leads to dysfunction of the orbitofrontal cortex via the striato-thalamo-orbitofrontal circuit. This is supported by imaging studies showing that in drug abusers studied during protracted withdrawal, the orbitofrontal cortex is hypoactive in proportion to the levels of dopamine D2 receptors in the striatum. In contrast, when drug abusers are tested shortly after last cocaine use or during drug-induced craving, the orbitofrontal cortex is hypermetabolic in proportion to the intensity of the craving. Because the orbitofrontal cortex is involved with drive and with compulsive repetitive behaviors, its abnormal activation in the addicted subject could explain why compulsive drug self-administration occurs even with tolerance to the pleasurable drug effects and in the presence of adverse reactions. This model implies that pleasure per se is not enough to maintain compulsive drug administration in the drugaddicted subject and that drugs that could interfere with the activation of the striato-thalamo-orbitofrontal circuit could be beneficial in the treatment of drug addiction.

Microdialysis is a sampling method that is used to determine the extracellular concentration of neurotransmitters in the brain. The method can be applied to conscious and unrestrained animals and is very suitable for the study of the chemistry of endogenous behaviour. This article reviews the contribution that microdialysis made to our understanding of the chemistry of behaviour. Methodological and practical considerations such as the implantation time and the use of guide cannulas are reviewed. The question whether neurotransmitters and related metabolites in dialysates reflect true synaptic release is critically discussed. There is much evidence that dopamine, noradrenaline, acetylcholine and serotonin in dialysates are related to neurotransmission, but there is serious doubt whether this is the case with amino acid transmitters such as GABA, glutamate and aspartate. Until now far over 100 papers appeared that used microdialysis in behavioural studies. Behavioural activation, the sleep-awake cycle and diurnal rhythms were subject of several of these studies. Various workers have described neurochemical changes in the brain that are related to feeding. Other studies were concerned with sexual behaviour and the sexual cycle in females. Parturition, maternal behaviour and offspring recognition have been studied in a series of microdialysis studies carried out in sheep. An overview is given of the microdialysis studies that were carried out to understand the biochemistry of stress. In this respect dopamine and noradrenaline have received much attention. A great number of microdialysis studies dealt with the role of dopamine in self-stimulation, reward and aversive emotions. It is concluded that microdialysis is at presently the most versatile and practical method to study the chemistry of behaviour and it is to be expected that it will soon be a routine methodology in behavioural research. Finally, perspectives and possible future developments of the methods are discussed.

BACKGROUND: It has been suggested that the structure of psychopathology is best described as a complex network of components that interact in dynamic ways. The goal of the present paper was to examine the concept of psychopathology from a network perspective, combining complementary top-down and bottom-up approaches using momentary assessment techniques. METHOD: A pooled Experience Sampling Method (ESM) dataset of three groups (individuals with a diagnosis of depression, psychotic disorder or no diagnosis) was used (pooled N = 599). The top-down approach explored the network structure of mental states across different diagnostic categories. For this purpose, networks of five momentary mental states ('cheerful', 'content', 'down', 'insecure' and 'suspicious') were compared between the three groups. The complementary bottom-up approach used principal component analysis to explore whether empirically derived network structures yield meaningful higher order clusters. RESULTS: Individuals with a clinical diagnosis had more strongly connected moment-to-moment network structures, especially the depressed group. This group also showed more interconnections specifically between positive and negative mental states than the psychotic group. In the bottom-up approach, all possible connections between mental states were clustered into seven main components that together captured the main characteristics of the network dynamics. CONCLUSIONS: Our combination of (i) comparing network structure of mental states across three diagnostically different groups and (ii) searching for trans-diagnostic network components across all pooled individuals showed that these two approaches yield different, complementary perspectives in the field of psychopathology. The network paradigm therefore may be useful to map transdiagnostic processes.

The author traces the history of the development of DSM-III within the larger context--intellectual, economic, scientific, and ideological--of the development of American psychiatry since World War II. Data were obtained through a literature review, investigation of archival material from the DSM-III task force and APA, and interviews with key participants. This research indicates that from the end of World War II until the mid-1970s, a broadly conceived biopsychosocial model, informed by psychoanalysis, sociological thinking, and biological knowledge, was the organizing model for American psychiatry. However, the biopsychosocial model did not clearly demarcate the mentally well from the mentally ill, and this failure led to a crisis in the legitimacy of psychiatry by the 1970s. The publication of DSM-III in 1980 represented an answer to this crisis, as the essential focus of psychiatric knowledge shifted from the clinically-based biopsychosocial model to a research-based medical model. The author concludes that while DSM-III, and the return to descriptive psychiatry which it inaugurated, has had positive consequences for the profession, at the same time it represents a significant narrowing of psychiatry's clinical gaze.