Showing papers in "Frontiers in Psychiatry in 2013"

The Computational Anatomy of Psychosis

Abstract: This paper considers psychotic symptoms in terms of false inferences or beliefs. It is based on the notion that the brain is an inference machine that actively constructs hypotheses to explain or predict its sensations. This perspective provides a normative (Bayes optimal) account of action and perception that emphasises probabilistic representations; in particular, the confidence or precision of beliefs about the world. We will consider hallucinosis, abnormal eye movements, sensory attenuation deficits, catatonia and delusions as various expressions of the same core pathology: namely, an aberrant encoding of precision. From a cognitive perspective, this represents a pernicious failure of metacognition (beliefs about beliefs) that can confound perceptual inference. In the embodied setting of active (Bayesian) inference, it can lead to behaviours that are paradoxically more accurate than Bayes optimal behaviour. Crucially, this normative account is accompanied by a neuronally plausible process theory based upon hierarchical predictive coding. In predictive coding, precision is thought to be encoded by the postsynaptic gain of neurons reporting prediction error. This suggests that both pervasive trait abnormalities and florid failures of inference in the psychotic state can be linked to factors controlling postsynaptic gain – such as NMDA receptor function and (dopaminergic) neuromodulation. We illustrate these points using biologically plausible simulations of perceptual synthesis, smooth pursuit eye movements and attribution of agency – that all use the same predictive coding scheme and pathology: namely, a reduction in the precision of prior beliefs, relative to sensory evidence.

Proof of concept trial of dronabinol in obstructive sleep apnea

Abstract: D THC), an exogenous Cannabinoid type 1 and type 2 (CB1 and CB2) receptor agonist in patients with Obstructive Sleep Apnea (OSA). Design and Setting: Proof of concept; single-center dose-escalation study of dron- abinol. Participants: Seventeen adults with a baseline Apnea Hypopnea Index (AHI)15/h. Baseline polysomnography (PSG) was performed after a 7-day washout of Continuous Pos- itive Airway Pressure treatment. Intervention: Dronabinol was administered after baseline PSG, starting at 2.5 mg once daily. The dose was increased weekly, as tolerated, to 5 mg and finally to 10 mg once daily. Measurements and Results: Repeat PSG assessments were performed on nights 7, 14, and 21 of dronabinol treatment. Change in AHI (DAHI, mean ± SD) was significant from baseline to night 21 (14.1 17.5; p = 0.007). No degra- dation of sleep architecture or serious adverse events was noted. Conclusion: Dronabinol treatment is safe and well-tolerated in OSA patients at doses of 2.5-10 mg daily and sig- nificantly reduces AHI in the short-term. These findings should be confirmed in a larger study in order to identify sub-populations with OSA that may benefit from cannabimimetic pharmacologic therapy.

Effects of Exercise and Physical Activity on Anxiety

Abstract: The beneficial effects of regular physical activity on health are indisputable in the field of modern medicine. Exercise is often the first step in lifestyle modifications for the prevention and management of chronic diseases. According to a US Department of Health and Human Services report on physical activity, regular exercise significantly reduced causes of mortality by up to 30% for men and women (DHHS, 2002). These health benefits are seen consistently across all age groups and racial/ethnic categories. The Centers for Disease Control and Prevention currently recommends 30 min of moderate- to high-intensity exercise for at least 5 days a week for all healthy individuals (DHHS, 2002). In addition to significantly lowering causes of mortality, regular exercise and physical activity lowers prevalence of chronic disease(s). There is a strong evidence to support that 2–2.5 h of moderate- to high-intensity exercise per week is sufficient to reduce one’s risk for the occurrence of a chronic disease(s). Numerous epidemiological studies have shown that exercise improves one’s self-esteem, and a sense of wellbeing. Individuals who exercise regularly exhibit slower rates of age-related memory and cognitive decline in comparison to those who are more sedentary. Such observations have provided the basis for using exercise to improve memory and cognition in cognitive disorders such as Alzheimer’s Dementia. Adults who engage in regular physical activity experience fewer depressive and anxiety symptoms, thus supporting the notion that exercise offers a protective effect against the development of mental disorders (van Minnen et al., 2010). Anxiety disorders are common psychiatric conditions with a lifetime prevalence of nearly 29% in the United States (Kessler et al., 2005). These disorders are chronic, debilitating, and impact multiple aspects of one’s life. The economic burden of anxiety disorders in the US was estimated to be $42.3 billion in the 1990s (Greenberg et al., 1999). The prominent anxiety disorders defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) are General Anxiety Disorder (GAD), Panic Disorder (PD), Posttraumatic Stress Disorder (PTSD), Obsessive Compulsive Disorder (OCD), Social Anxiety Disorder, and Specific Phobia (APA, 2000). The exact etiology and pathophysiology of these conditions is not fully understood. Comprehending the effects of exercise and physical activity on the mechanisms of anxiety disorders might further our knowledge of these psychiatric disorders. The purpose of this article is to highlight the known and emerging mechanisms that may result in the anxiolytic effects of exercise.

Addiction is a reward deficit and stress surfeit disorder.

Abstract: Drug addiction can be defined by a three-stage cycle—binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation—that involves allostatic changes in the brain reward and stress systems. Two primary sources of reinforcement, positive and negative reinforcement, have been hypothesized to play a role in this allostatic process. The negative emotional state that drives negative reinforcement is hypothesized to derive from dysregulation of key neurochemical elements involved in the brain reward and stress systems. Specific neurochemical elements in these structures include not only decreases in reward system function (within-system opponent processes) but also recruitment of the brain stress systems mediated by corticotropin-releasing factor (CRF) and dynorphin-κ opioid systems in the ventral striatum, extended amygdala, and frontal cortex (both between-system opponent processes). CRF antagonists block anxiety-like responses associated with withdrawal, block increases in reward thresholds produced by withdrawal from drugs of abuse, and block compulsive-like drug taking during extended access. Excessive drug taking also engages the activation of CRF in the medial prefrontal cortex, paralleled by deficits in executive function that may facilitate the transition to compulsive-like responding. Neuropeptide Y, a powerful anti-stress neurotransmitter, has a profile of action on compulsive-like responding for ethanol similar to a CRF1 antagonist. Blockade of the κ opioid system can also block dysphoric-like effects associated with withdrawal from drugs of abuse and block the development of compulsive-like responding during extended access to drugs of abuse, suggesting another powerful brain stress system that contributes to compulsive drug seeking. The loss of reward function and recruitment of brain systems provide a powerful neurochemical basis that drives the compulsivity of addiction.

Yoga on our minds: a systematic review of yoga for neuropsychiatric disorders

Abstract: Background: The demand for clinically efficacious, safe, patient acceptable and cost-effective forms of treatment for mental illness is growing. Several studies have demonstrated benefit from yoga in specific psychiatric symptoms and a general sense of well-being. Objective: To systematically examine the evidence for efficacy of yoga in the treatment of selected major psychiatric disorders. Methods: Electronic searches of The Cochrane Central Register of Controlled Trials (CENTRAL) and the standard bibliographic databases, MEDLINE, EMBASE and PsycINFO, were performed through April 2011 and an updated in June 2011 using the keywords yoga AND psychiatry OR depression OR anxiety OR schizophrenia OR cognition OR memory OR attention AND randomized controlled trial. Studies with yoga as the independent variable and one of the above mentioned terms as the dependent variable were included and exclusion criteria were applied. Results: The search yielded a total of 124 trials, of which 16 met rigorous criteria for the final review. Grade B evidence supporting a potential acute benefit for yoga exists in depression (4 RCTs), as an adjunct to pharmacotherapy in schizophrenia (3 RCTs), in children with ADHD (2 RCTs) and Grade C evidence in sleep complaints (3 RCTs). RCTs in cognitive disorders and eating disorders yielded conflicting results. No studies looked at primary prevention, relapse prevention or comparative effectiveness versus pharmacotherapy. Conclusions: There is emerging evidence from randomized trials to support popular beliefs about yoga for depression, sleep disorders, and as an augmentation therapy. Limitations of literature include inability to do double-blind studies, multiplicity of comparisons within small studies and lack of replication. Biomarker and neuroimaging studies, those comparing yoga with standard pharmaco- and psychotherapies, and studies of long-term efficacy are needed to fully translate the promise of yoga for enhancing mental health.

Epigenetic Biomarkers as Predictors and Correlates of Symptom Improvement Following Psychotherapy in Combat Veterans with PTSD.

Abstract: Epigenetic alterations offer promise as prognostic or diagnostic markers, but it is not known whether these measures associate with, or predict, clinical state. These questions were addressed in a pilot study with combat veterans with PTSD to determine whether cytosine methylation in promoter regions of the glucocorticoid related NR3C1 and FKBP51 genes would predict or associate with treatment outcome. Veterans with PTSD received prolonged exposure (PE) psychotherapy, yielding responders (n=8), defined by no longer meeting diagnostic criteria for PTSD, and non-responders (n=8). Blood samples were obtained at pre-treatment, after 12 weeks of psychotherapy (post-treatment), and after a 3 month follow-up. Methylation was examined in DNA extracted from lymphocytes. Measures reflecting glucocorticoid receptor (GR) activity were also obtained from lymphocytes (i.e., plasma and 24h-urinary cortisol, plasma ACTH, lysozyme IC50-DEX, and plasma neuropetide-Y). Methylation of the GR gene (NR3C1) exon 1F promoter assessed at pre-treatment predicted treatment outcome, but was not significantly altered in responders or non-responders at post-treatment or follow-up. In contrast, methylation of the FKBP5 gene (FKBP51) exon 1 promoter region did not predict treatment response, but decreased in association with recovery. In a subset, a corresponding group difference in FKBP5 gene expression was observed, with responders showing higher gene expression at post-treatment than non-responders. Endocrine markers also changed in association with symptom change. These preliminary observations require replication and validation. However, the results support research indicating that some glucocorticoid related genes are subject to environmental regulation throughout life. Moreover, psychotherapy constitutes a form of ‘environmental regulation’ that may alter epigenetic state. Finally, the results further suggest that different genes may be associated with prognosis and symptom state, respec

Dare to Delay? The Impacts of Adolescent Alcohol and Marijuana Use Onset on Cognition, Brain Structure, and Function

Abstract: Throughout the world, drug and alcohol use has a clear adolescent onset (Degenhardt et al., 2008). Alcohol continues to be the most popular drug among teens and emerging adults, with almost a third of 12th graders and 40% of college students reporting recent binge drinking (Johnston et al., 2009, 2010), and marijuana (MJ) is the second most popular drug in teens (Johnston et al., 2010). The initiation of drug use is consistent with an overall increase in risk-taking behaviors during adolescence that coincides with significant neurodevelopmental changes in both gray and white matter (Giedd et al., 1996a; Paus et al., 1999; Sowell et al., 1999, 2002, 2004; Gogtay et al., 2004; Barnea-Goraly et al., 2005; Lenroot and Giedd, 2006). Animal studies have suggested that compared to adults, adolescents may be particularly vulnerable to the neurotoxic effects of drugs, especially alcohol and MJ (see Schneider and Koch, 2003; Barron et al., 2005; Monti et al., 2005; Cha et al., 2006; Rubino et al., 2009; Spear, 2010). In this review, we will provide a detailed overview of studies that examined the impact of early adolescent onset of alcohol and MJ use on neurocognition (e.g., Ehrenreich et al., 1999; Wilson et al., 2000; Tapert et al., 2002a; Hartley et al., 2004; Fried et al., 2005; Townshend and Duka, 2005; Medina et al., 2007a; McQueeny et al., 2009; Gruber et al., 2011, 2012; Hanson et al., 2011; Lisdahl and Price, 2012), with a special emphasis on recent prospective longitudinal studies (e.g., White et al., 2011; Hicks et al., 2012; Meier et al., 2012). Finally, we will explore potential clinical and public health implications of these findings.

Executive functioning in schizophrenia.

Abstract: The executive function (EF) is a set of abilities, which allows us to invoke voluntary control of our behavioral responses. These functions enable human beings to develop and carry out plans, make up analogies, obey social rules, solve problems, adapt to unexpected circumstances, do many tasks simultaneously, and locate episodes in time and place. EF includes divided attention and sustained attention, working memory (WM), set-shifting, flexibility, planning, and the regulation of goal directed behavior and can be defined as a brain function underlying the human faculty to act or think not only in reaction to external events but also in relation with internal goals and states. EF is mostly associated with dorsolateral prefrontal cortex (PFC). Besides EF, PFC is involved in self-regulation of behavior, i.e., the ability to regulate behavior according to internal goals and constraints, particularly in less structured situations. Self-regulation of behavior is subtended by ventral medial/orbital PFC. Impairment of EF is one of the most commonly observed deficits in schizophrenia through the various disease stages. Impairment in tasks measuring conceptualization, planning, cognitive flexibility, verbal fluency, ability to solve complex problems, and WM occur in schizophrenia. Disorders detected by executive tests are consistent with evidence from functional neuroimaging, which have shown PFC dysfunction in patients while performing these kinds of tasks. Schizophrenics also exhibit deficit in odor identifying, decision-making, and self-regulation of behavior suggesting dysfunction of the orbital PFC. However, impairment in executive tests is explained by dysfunction of prefronto-striato-thalamic, prefronto-parietal, and prefronto-temporal neural networks mainly. Disorders in EFs may be considered central facts with respect to schizophrenia and it has been suggested that negative symptoms may be explained by that executive dysfunction.

Does Cannabidiol Protect Against Adverse Psychological Effects of THC

Abstract: The recreational use of cannabis can have persistent adverse effects on mental health. Delta-9-tetrahydrocannabinol (THC) is the main psychoactive constituent of cannabis, and most, if not all, of the effects associated with the use of cannabis are caused by THC. Recent studies have suggested a possible protective effect of another cannabinoid, cannabidiol (CBD). A literature search was performed in the bibliographic databases PubMed, PsycINFO and Web of Science using the keyword ‘cannabidiol.’ After removing duplicate entries, 1295 unique titles remained. Based on the titles and abstracts, an initial selection was made. The reference lists of the publications identified in this manner were examined for additional references. Cannabis is not a safe drug. Depending on how often someone uses, the age of onset, the potency of the cannabis that is used and someone's individual sensitivity, the recreational use of cannabis may cause permanent psychological disorders. Most recreational users will never be faced with such persistent mental illness, but in some individuals cannabis use leads to undesirable effects: cognitive impairment, anxiety, paranoia and increased risks of developing chronic psychosis or drug addiction. Studies examining the protective effects of CBD have shown that CBD can counteract the negative effects of THC. However, the question remains of how the laboratory results translate to the types of cannabis that are encountered by real-world recreational users.

Environmental factors in autism.

Abstract: Autism is a neurodevelopmental disorders characterized by impairments in communication and social behavior, and by repetitive behaviors. Although genetic factors might be largely responsible for the occurrence of autism they cannot fully account for all cases and it is likely that in addition to a certain combination of autism-related genes, specific environmental factors might act as risk factors triggering the development of autism. Thus, the role of environmental factors in autism is an important area of research and recent data will be discussed in this review. Interestingly, the results show that many environmental risk factors are interrelated and their identification and comparison might unveil a common scheme of alterations on a contextual as well as molecular level. For example, both, disruption in the immune system and in zinc homeostasis may affect synaptic transmission in autism. Thus, here, a model is proposed that interconnects the most important and scientifically recognized environmental factors. Moreover, similarities in how these risk factors impact synapse function are discussed and a possible influence on an already well described genetic pathway leading to the development of autism via zinc homeostasis is proposed.

Cannabis Use during Adolescent Development: Susceptibility to Psychiatric Illness.

Abstract: Cannabis use is increasingly pervasive among adolescents today, even more common than cigarette smoking.The evolving policy surrounding the legalization of cannabis reaffirms the need to understand the relationship between cannabis exposure early in life and psychiatric illnesses. cannabis contains psychoactive components, notably 9 D -tetrahydrocannabinol (THC), that interfere with the brain's endogenous endocannabinoid system, which is crit- ically involved in both pre- and post-natal neurodevelopment. Consequently, THC and related compounds could potentially usurp normal adolescent neurodevelopment, shift- ing the brain's developmental trajectory toward a disease-vulnerable state, predisposing early cannabis users to motivational, affective, and psychotic disorders. Numerous human studies, including prospective longitudinal studies, demonstrate that early cannabis use is associated with major depressive disorder and drug addiction. A strong association between schizophrenia and cannabis use is also apparent, especially when considering genetic factors that interact with this environmental exposure. These human studies set a foundation for carefully controlled animal studies which demonstrate similar pat- terns following early cannabinoid exposure. Given the vulnerable nature of adolescent neurodevelopment and the persistent changes that follow early cannabis exposure, the experimental findings outlined should be carefully considered by policymakers. In order to fully address the growing issues of psychiatric illnesses and to ensure a healthy future, measures should be taken to reduce cannabis use among teens.

BDNF and schizophrenia: from neurodevelopment to neuronal plasticity, learning, and memory.

Abstract: Brain-Derived Neurotrophic Factor (BDNF) is a neurotrophin that has been related not only to neurodevelopment and neuroprotection, but also to synapse regulation, learning, and memory. Research focused on the neurobiology of schizophrenia has emphasized the relevance of neurodevelopmental and neurotoxicity-related elements in the pathogenesis of this disease. Research focused on the clinical features of schizophrenia in the past decades has emphasized the relevance of cognitive deficits of this illness, considered a core manifestation and an important predictor for functional outcome. Variations in neurotrophins such as BDNF may have a role as part of the molecular mechanisms underlying these processes, from the neurodevelopmental alterations to the molecular mechanisms of cognitive dysfunction in schizophrenia patients.

Sex-Specific and Strain-Dependent Effects of Early Life Adversity on Behavioral and Epigenetic Outcomes

Abstract: Early life adversity can have a significant long-term impact with implications for the emergence of psychopathology. Disruption to mother-infant interactions is a form of early life adversity that may, in particular, have profound programing effects on the developing brain. However, despite converging evidence from human and animal studies, the precise mechanistic pathways underlying adversity-associated neurobehavioral changes have yet to be elucidated. One approach to the study of mechanism is exploration of epigenetic changes associated with early life experience. In the current study, we examined the effects of postnatal maternal separation (MS) in mice and assessed the behavioral, brain gene expression, and epigenetic effects of this manipulation in offspring. Importantly, we included two different mouse strains (C57BL/6J and Balb/cJ) and both male and female offspring to determine strain- and/or sex-associated differential response to MS. We found both strain-specific and sex-dependent effects of MS in early adolescent offspring on measures of open-field exploration, sucrose preference, and social behavior. Analyses of cortical and hippocampal mRNA levels of the glucocorticoid receptor (Nr3c1) and brain-derived neurotrophic factor (Bdnf) genes revealed decreased hippocampal Bdnf expression in maternally separated C57BL/6J females and increased cortical Bdnf expression in maternally separated male and female Balb/cJ offspring. Analyses of Nr3c1and Bdnf (IV and IX) CpG methylation indicated increased hippocampal Nr3c1 methylation in maternally separated C57BL/6J males and increased hippocampal Bdnf IX methylation in male and female maternally separated Balb/c mice. Overall, though effect sizes were modest, these findings suggest a complex interaction between early life adversity, genetic background, and sex in the determination of neurobehavioral and epigenetic outcomes that may account for differential vulnerability to later-life disorder.

A Triadic Neurocognitive Approach to Addiction for Clinical Interventions

Abstract: According to the triadic neurocognitive model of addiction to drugs (e.g., cocaine) and non-drugs (e.g., gambling), weakened "willpower" associated with these behaviors is the product of an abnormal functioning in one or more of three key neural and cognitive systems: (1) an amygdala-striatum dependent system mediating automatic, habitual, and salient behaviors; (2) a prefrontal cortex dependent system important for self-regulation and forecasting the future consequences of a behavior; and (3) an insula dependent system for the reception of interoceptive signals and their translation into feeling states (such as urge and craving), which in turn plays a strong influential role in decision-making and impulse control processes related to uncertainty, risk, and reward. The described three-systems account for poor decision-making (i.e., prioritizing short-term consequences of a decisional option) and stimulus-driven actions, thus leading to a more elevated risk for relapse. Finally, this article elaborates on the need for "personalized" clinical model-based interventions targeting interactions between implicit processes, interoceptive signaling, and supervisory function aimed at helping individuals become less governed by immediate situations and automatic pre-potent responses, and more influenced by systems involved in the pursuit of future valued goals.

Cognitive impairment in bipolar disorder and schizophrenia: a systematic review.

Abstract: AIMS: Previous comparisons of cognitive decline among patients with bipolar disorder and schizophrenia have found somehow quite similar profiles of deficits, but results have varied between studies. Therefore an extensive and thoughtful systematic review of the matter is warranted. METHODS: Studies were found through systematic search (PubMed) following PRISMA guidelines. To be included, studies must have assessed the following cognitive functions: executive functions, memory, IQ, attention-concentration and perceptuomotor function. In order to make comparison between the two entities, studies should include bipolar disorder patients with operationally defined euthymia, schizophrenic patients in remission, and third group of healthy control patients. Comparisons were made after controlling for years of schooling and residual affective symptoms. RESULTS: We found that overall both SZ and BD patients present deficits on all neurocognitive measures compared to healthy controls (HC). In particular, SZ patients show more severe and pervasive cognitive deficits while BD patients present a milder and more confined impairment. In addition, evidence from the literature suggests that SZ and BD patients share a similar cognitive impairment profile with different degrees of deficits. Therefore, the difference between the two groups seems to be more quantitative (degree of deficit) rather than qualitative (profile), supporting a dimensional approach to the two clinical entities. Limitations of the present review includes the impossibility to control for effects of medication, varying time required for assessment across studies, illness diagnosis reliability and course severity CONCLUSIONS: Patients with bipolar disorder might exhibit a cognitive impairment that could be similar to schizophrenia in terms of their profile, although patients with schizophrenia may have more severe and widespread impairments.

Electroconvulsive Therapy Response in Major Depressive Disorder: A Pilot Functional Network Connectivity Resting State fMRI Investigation

Abstract: Major depressive disorder (MDD) is associated with increased functional connectivity in specific neural networks. Electroconvulsive therapy (ECT), the gold-standard treatment for acute, treatment resistant MDD, but temporal dependencies between networks associated with ECT response have yet to be investigated. In the present longitudinal, case-control investigation, we used independent component analysis (ICA) to identify distinct networks of brain regions with temporally coherent hemodynamic signal change and functional network connectivity (FNC) to assess component time course correlations across these networks. MDD subjects completed imaging and clinical assessments immediately prior to the ECT series and a minimum of five days after the last ECT treatment. We focused our analysis on four networks affected in MDD: the subcallosal cingulate gyrus, default mode, dorsal lateral prefrontal cortex, and dorsal medial prefrontal cortex. In a sample of ECT subjects (n = 12) with MDD, remission associated with the ECT series reverses the relationship from negative to positive between the posterior default mode and two other networks: the dorsal medial prefrontal cortex and left dorsal lateral prefrontal cortex. Relative to demographically healthy subjects (n = 12), the FNC between the posterior default mode areas and the dorsal medial prefrontal cortex normalizes with ECT response. The FNC changes following treatment did not correlate with symptom improvement; however, a direct comparison between ECT remitters and non-remitters showed the pattern of increased FNC between the posterior default mode and left dorsal lateral prefrontal cortex networks following ECT to be specific to those who responded to the treatment. The differences between ECT remitters and non-remitters suggest that this increased FNC between posterior default mode areas and the left dorsolateral prefrontal cortex is a neural correlate and potential biomarker of recovery from a depressed episode.

NMDA Receptor Activity in Neuropsychiatric Disorders.

Abstract: N-Methyl-D-aspartate (NMDA) receptors play a variety of physiologic roles and their proper signaling is essential for cellular homeostasis. Any disruption in this pathway, leading to either enhanced or decreased activity, may result in the manifestation of neuropsychiatric pathologies such as schizophrenia, mood disorders, substance induced psychosis, Huntington's disease, Alzheimer's disease, and neuropsychiatric systemic lupus erythematosus. Here, we explore the notion that the overlap in activity of at least one biochemical pathway, the NMDA receptor pathway, may be the link to understanding the overlap in psychotic symptoms between diseases. This review intends to present a broad overview of those neuropsychiatric disorders for which alternations in NMDA receptor activity is prominent thus suggesting that continued direction of pharmaceutical intervention to this pathway may present a viable option for managing symptoms.

Addiction and Choice: Theory and New Data

Abstract: Addiction’s biological basis has been the focus of much research. The findings have persuaded experts and the public that drug use in addicts is compulsive. But the word “compulsive” identifies patterns of behavior. Thus, the question is not whether addiction has a biology, but whether it is sensible to say that addicts use drugs compulsively. Research shows most of those who meet the American Psychiatric Association’s criteria for addiction quit using illegal drugs by age thirty, that they usually quit without professional help, and that the correlates of quitting include legal concerns, economic pressures, and the desire for respect, particularly from family members. That is, the correlates of quitting are the correlates of choice. However, addiction is, by definition, a disorder, and thereby not beneficial in the long run. This is precisely the pattern of choices predicted by quantitative choice principles, such as the matching law, melioration, and hyperbolic discounting. Although the brain disease model of addiction is perceived by many as received knowledge it is not supported by research or logic. In contrast, well established, quantitative choice principles predict both the possibility and the details of addiction.

Neuronal nicotinic acetylcholine receptors: common molecular substrates of nicotine and alcohol dependence.

Abstract: Alcohol and nicotine are often co-abused. As many as 80-95% of alcoholics are also smokers, suggesting that ethanol and nicotine, the primary addictive component of tobacco smoke, may functionally interact in the central nervous system and/or share a common mechanism of action. While nicotine initiates dependence by binding to and activating neuronal nicotinic acetylcholine receptors (nAChRs), ligand-gated cation channels normally activated by endogenous acetylcholine (ACh), ethanol is much less specific with the ability to modulate multiple gene products including those encoding voltage-gated ion channels, and excitatory/inhibitory neurotransmitter receptors. However, emerging data indicate that ethanol interacts with nAChRs, both directly and indirectly, in the mesocorticolimbic dopaminergic (DAergic) reward circuitry to affect brain reward systems. Like nicotine, ethanol activates DAergic neurons of the ventral tegmental area (VTA) which project to the nucleus accumbens (NAc). Blockade of VTA nAChRs reduces ethanol-mediated activation of DAergic neurons, NAc DA release, consumption, and operant responding for ethanol in rodents. Thus, ethanol may increase ACh release into the VTA driving activation of DAergic neurons through nAChRs. In addition, ethanol potentiates distinct nAChR subtype responses to ACh and nicotine in vitro and in DAergic neurons. The smoking cessation therapeutic and nAChR partial agonist, varenicline, reduces alcohol consumption in heavy drinking smokers and rodent models of alcohol consumption. Finally, single nucleotide polymorphisms in nAChR subunit genes are associated with alcohol dependence phenotypes and smoking behaviors in human populations. Together, results from preclinical, clinical, and genetic studies indicate that nAChRs may have an inherent role in the abusive properties of ethanol, as well as in nicotine and alcohol co-dependence.

Mismatch Negativity: Translating the Potential

Abstract: The mismatch negativity (MMN) component of the auditory event-related potential has become a valuable tool in cognitive neuroscience. Its reduced size in persons with schizophrenia is of unknown origin but theories proposed include links to problems in experience-dependent plasticity reliant on N-methyl-d-aspartate glutamate receptors. In this review we address the utility of this tool in revealing the nature and time course of problems in perceptual inference in this illness together with its potential for use in translational research testing animal models of schizophrenia-related phenotypes. Specifically, we review the reasons for interest in MMN in schizophrenia, issues pertaining to the measurement of MMN, its use as a vulnerability index for the development of schizophrenia, the pharmacological sensitivity of MMN and the progress in developing animal models of MMN. Within this process we highlight the challenges posed by knowledge gaps pertaining to the tool and the pharmacology of the underlying system.

Treating Depression and Depression-Like Behavior with Physical Activity: An Immune Perspective

Abstract: The increasing burden of major depressive disorder makes the search for an extended understanding of etiology, and for the development of additional treatments highly significant. Biological factors may be useful biomarkers for treatment with physical activity (PA), and neurobiological effects of PA may herald new therapeutic development in the future. This paper provides a thorough and up-to-date review of studies examining the neuroimmunomodulatory effects of PA on the brain in depression and depression-like behaviors. From a neuroimmune perspective, evidence suggests PA does enhance the beneficial and reduce the detrimental effects of the neuroimmune system. PA appears to increase the following factors: interleukin (IL)-10, IL-6 (acutely), macrophage migration inhibitory factor, central nervous system-specific autoreactive CD4+ T cells, M2 microglia, quiescent astrocytes, CX3CL1, and insulin-like growth factor-1. On the other hand, PA appears to reduce detrimental neuroimmune factors such as: Th1/Th2 balance, pro-inflammatory cytokines, C-reactive protein, M1 microglia, and reactive astrocytes. The effect of other mechanisms is unknown, such as: CD4+CD25+ T regulatory cells (T regs), CD200, chemokines, miRNA, M2-type blood-derived macrophages, and tumor necrosis factor (TNF)-α [via receptor 2 (R2)]. The beneficial effects of PA are likely to occur centrally and peripherally (e.g., in visceral fat reduction). The investigation of the neuroimmune effects of PA on depression and depression-like behavior is a rapidly developing and important field.

Resting-State Functional Connectivity in Late-Life Depression: Higher Global Connectivity and More Long Distance Connections

Abstract: Functional magnetic resonance imaging recordings in the resting-state (RS) from the human brain are characterized by spontaneous low-frequency fluctuations in the blood oxygenation level dependent signal that reveal functional connectivity (FC) via their spatial synchronicity. This RS study applied network analysis to compare FC between late-life depression (LLD) patients and control subjects. Raw cross-correlation matrices (CM) for LLD were characterized by higher FC. We analyzed the small-world (SW) and modular organization of these networks consisting of 110 nodes each as well as the connectivity patterns of individual nodes of the basal ganglia. Topological network measures showed no significant differences between groups. The composition of top hubs was similar between LLD and control subjects, however in the LLD group posterior medial-parietal regions were more highly connected compared to controls. In LLD, a number of brain regions showed connections with more distant neighbors leading to an increase of the average Euclidean distance between connected regions compared to controls. In addition, right caudate nucleus connectivity was more diffuse in LLD. In summary, LLD was associated with overall increased FC strength and changes in the average distance between connected nodes, but did not lead to global changes in SW or modular organization.

The plasticity of extinction: contribution of the prefrontal cortex in treating addiction through inhibitory learning

Abstract: Theories of drug addiction that incorporate various concepts from the fields of learning and memory have led to the idea that classical and operant conditioning principles underlie the compulsiveness of addictive behaviors. Relapse often results from exposure to drug-associated cues, and the ability to extinguish these conditioned behaviors through inhibitory learning could serve as a potential therapeutic mechanism for those who suffer from addiction. This review will examine the evidence that extinction learning alters neuronal plasticity in specific brain regions and pathways. In particular, subregions of the prefrontal cortex and their projections to other brain regions have been shown to differentially modulate drug-seeking and extinction behavior. Additionally, there is a growing body of research demonstrating that manipulation of neuronal plasticity can alter extinction learning. Therefore, the ability to alter plasticity within areas of the prefrontal cortex through pharmacological manipulation could facilitate the acquisition of extinction and provide a novel intervention to aid in the extinction of drug-related memories.

Mismatch Negativity as a “Translatable” Brain Marker Toward Early Intervention for Psychosis: A Review

Abstract: Recent reviews and meta-analyses suggest that reducing the duration of untreated psychosis leads to better symptomatic and functional outcome in patients with psychotic disorder Early intervention attenuates the symptoms of individuals at clinical high-risk (HR) for psychosis and may delay or prevent their transition to psychosis Identifying biological markers in the early stages of psychotic disorder is an important step toward elucidating the pathophysiology, improving prediction of the transition to psychosis, and introducing targeted early intervention for help-seeking individuals aiming for better outcome Mismatch negativity (MMN) is a component of event-related potentials that reflects preattentive auditory sensory memory and is a promising biomarker candidate for schizophrenia Reduced MMN amplitude is a robust finding in patients with chronic schizophrenia Recent reports have shown that people in the early stages of psychotic disorder exhibit attenuation of MMN amplitude MMN in response to duration deviants and in response to frequency deviants reveals different patterns of deficits These findings suggest that MMN may be useful for identifying clinical stages of psychosis and for predicting the risk of development MMN may also be a “translatable” biomarker since it reflects N-methyl-d-aspartte receptor function, which plays a fundamental role in schizophrenia pathophysiology Furthermore, MMN-like responses can be recorded in animals such as mice and rats This article reviews MMN studies conducted on individuals with HR for psychosis, first-episode psychosis, recent-onset psychosis, and on animals Based on the findings, the authors discuss the potential of MMN as a clinical biomarker for early intervention for help-seeking individuals in the early stages of psychotic disorder, and as a translatable neurophysiological marker for the preclinical assessment of pharmacological agents used in animal models that mimic early stages of the disorder

Social Cognition in Schizophrenia: From Social Stimuli Processing to Social Engagement

Abstract: Social cognition consists of several skills which allow us to interact with other humans. These skills include social stimuli processing, drawing inferences about others' mental states, and engaging in social interactions. In recent years, there has been growing evidence of social cognitive impairments in patients with schizophrenia. Apparently, these impairments are separable from general neurocognitive impairments, such as attention, memory and executive functioning. Moreover, social cognition seems to be a main determinant of functional outcome and could be used as a guide to elaborate new pharmacological and psychological treatments. However, most of these studies focus on individual mechanisms and observational perspectives; only few of them study schizophrenic patients during interactive situations. We first review evidences of social cognitive impairments both in social stimuli processing and in mental state attribution. We focus on the relationship between these functions and both general cognitive impairments and functional outcome. We next review recent game theory approaches to the study of how social engagement occurs in schizophrenic patients. The advantage of using game theory is that game-oriented tasks can assess social decision-making in an interactive everyday situation model. Finally, we review proposed theoretical models used to explain social alterations and their underlying biological mechanisms. Based on interactive studies, we propose a framework which takes into account the dynamic nature of social processes. Thus, understanding social skills as a result of dynamical systems could facilitate the development of both basic research and clinical applications oriented to psychiatric populations.

Head-to-Head Comparison of Transcranial Random Noise Stimulation, Transcranial AC Stimulation, and Transcranial DC Stimulation for Tinnitus

Abstract: Tinnitus is the perception of a sound in the absence of an external sound stimulus. This phantom sound has been related to plastic changes and hyperactivity in the auditory cortex. Different neuromodulation techniques such as TMS and tDCS have been used in an attempt to modify local and distant neuroplasticity as to reduce tinnitus symptoms. Recently, two techniques of pulsed electrical stimulation using weak electrical currents - transcranial alternating current stimulation (tACS) and transcranial random noise stimulation (tRNS) - have also shown significant neuromodulatory effects. In the present study we conducted the first head-to-head comparison of three different transcranial electrical stimulation (tES) techniques, namely tDCS, tACS and tRNS in 111 tinnitus patients by placing the electrodes overlying the auditory cortex bilaterally. The results demonstrated that tRNS induced the larger transient suppresive effect on the tinnitus loudness and the tinnitus related distress as compared to tDCS and tACS. Both tDCS and tACS induced small and non-significant effects on tinnitus symptoms, supporting the superior effects of tRNS as a method for tinnitus suppression.

Meditative Movement for Depression and Anxiety

Abstract: This review focuses on Meditative Movement (MM) and its effects on anxiety, depression and other affective states. MM is a term identifying forms of exercise that use movement in conjunction with meditative attention to body sensations, including proprioception, interoception and kinesthesis. MM includes the traditional Chinese methods of Qigong (Chi Kung) and Taijiquan (Tai Chi), some forms of Yoga and other Asian practices, as well as Western Somatic practices; however this review focuses primarily on Qigong and Taijiquan. We clarify the differences between MM and conventional exercise, present descriptions of several of the key methodologies of MM, and suggest how research into these practices may be approached in a systematic way. We also present evidence for possible mechanisms of the effects of MM on affective states, including the roles of posture, rhythm, coherent breathing, and the involvement of specific cortical and subcortical structures. We survey research outcomes summarized in reviews published since 2007. Results suggest that MM may be at least as effective as conventional exercise or other interventions in ameliorating anxiety and depression; however, study quality is generally poor and there are many confounding factors. This makes it difficult to draw definitive conclusions at this time. We suggest, however, that more research is warranted, and we offer specific suggestions for ensuring high-quality and productive future studies.

Addiction is Not a Brain Disease (and it Matters)

Abstract: The claim that addiction is a brain disease is almost universally accepted among scientists who work on addiction. The claim’s attraction rests on two grounds: the fact that addiction seems to be characterized by dysfunction in specific neural pathways and the fact that the claim seems to the compassionate response to people who are suffering. I argue that neural dysfunction is not sufficient for disease: something is a brain disease only when neural dysfunction is sufficient for impairment. I claim that the neural dysfunction that is characteristic of addiction is not sufficient for impairment, because people who suffer from that dysfunction are impaired, sufficiently to count as diseased, only given certain features of their context. Hence addiction is not a brain disease (though it is often a disease, and it may always involve brain dysfunction). I argue that accepting that addiction is not a brain disease does not entail a moralizing attitude toward people who suffer as a result of addiction; if anything, it allows for a more compassionate, and more effective, response to addiction.

PTSD and DNA methylation in select immune function gene promoter regions: a repeated measures case-control study of U.S. military service members

Abstract: Background: The underlying molecular mechanisms of PTSD are largely unknown. Distinct expression signatures for PTSD have been found, in particular for immune activation transcripts. DNA methylation may be significant in the pathophysiology of PTSD, since the process is intrinsically linked to gene expression. We evaluated temporal changes in DNA methylation in select promoter regions of immune system-related genes in U.S. military service members with a PTSD diagnosis, pre- and post-diagnosis, and in controls. Methods: Cases (nD 75) had a post-deployment diagnosis of PTSD in their medical record. Controls (nD 75) were randomly selected service members with no PTSD diagnosis. DNA was extracted from pre- and post-deployment sera. DNA methylation (%5-mC) was quantified at specific CpG sites in promoter regions of insulin-like growth factor 2 (IGF2), long non-coding RNA transcript H19, interleukin-8 (IL8), IL16, and IL18 via pyrosequencing. We used multivariate analysis of variance and generalized linear models to calculate adjusted means (adjusted for age, gender, and race) to make temporal comparisons of %5-mC for cases (pre- to post-deployment) versus controls (pre- to post-deployment). Results: There were significant differences in the change of %5-mC pre- to postdeployment between cases and controls for H19 (cases: C0.57%, controls: 1.97%; pD 0.04) and IL18 (cases:C1.39%, controls:3.83%; pD 0.01). For H19 the difference was driven by a significant reduction in %5-mC among controls; for IL18 the difference was driven by both a reduction in %5-mC among controls and an increase in %5-mC among cases. Stratified analyses revealed more pronounced differences in the adjusted means of pre-post H19 and IL18 methylation differences for cases versus controls among older service members, males, service members of white race, and those with shorter deployments (6‐12 months). Conclusion: In the study of deployed personnel, those who did not develop PTSD had reduced %5-mC levels of H19 and IL18 after deployment, while those who did develop PTSD had increased levels of IL18. Additionally, pre-deployment the people who later became cases had lower levels of IL18 %5-mC compared with controls. These findings are preliminary and should be investigated in larger studies.

Emerging role for corticotropin releasing factor signaling in the bed nucleus of the stria terminalis at the intersection of stress and reward.

Abstract: Stress and anxiety play an important role in the development and maintenance of drug and alcohol addiction. The bed nucleus of the stria terminalis (BNST), a brain region involved in the production of long-term stress-related behaviors, plays an important role in animal models of relapse, such as reinstatement to previously extinguished drug-seeking behaviors. While a number of neurotransmitter systems have been suggested to play a role in these behaviors, recent evidence points to the neuropeptide corticotropin releasing factor (CRF) as being critically important in BNST-mediated reinstatement behaviors. Although numerous studies indicate that the BNST is a complex brain region with multiple afferent and efferent systems and a variety of cell types, there has only been limited work to determine how CRF modulates this complex neuronal system at the circuit level. Recent work from our lab and others have begun to unravel these BNST neurocircuits and explore their roles in CRF-related reinstatement behaviors. This review will examine the role of CRF signaling in drug addiction and reinstatement with an emphasis on critical neurocircuitry within the BNST that may offer new insights into treatments for addiction.