Reward learning as a potential target for pharmacological augmentation of cognitive remediation for schizophrenia: a roadmap for preclinical development.

RationaleImpaired cognitive abilities are a key characteristic of schizophrenia. Although currently approved pharmacological treatments have demonstrated efficacy for positive symptoms, to date no pharmacological treatments successfully reverse cognitive dysfunction in these patients. Cognitively-based interventions such as cognitive remediation (CR) and other psychosocial interventions however, may improve some of the cognitive and functional deficits of schizophrenia. Given that these treatments are time-consuming and labor-intensive, maximizing their effectiveness is a priority. Augmenting psychosocial interventions with pharmacological treatments may be a viable strategy for reducing the impact of cognitive deficits in patients with schizophrenia.ObjectiveWe propose a strategy to develop pharmacological treatments that can enhance the reward-related learning processes underlying successful skill-learning in psychosocial interventions. Specifically, we review clinical and preclinical evidence and paradigms that can be utilized to develop these pharmacological augmentation strategies. Prototypes for this approach include dopamine D1 receptor and α7 nicotinic acetylcholine receptor agonists as attractive targets to specifically enhance reward-related learning during CR.ConclusionThe approach outlined here could be used broadly to develop pharmacological augmentation strategies across a number of cognitive domains underlying successful psychosocial treatment

MR. JUSTICE CARDOZO AND PROBLEMS OF GOVERNMENT

The sorrow with which the entire nation learned of the death of Mr. Justice Cardozo bears witness to the sense of loss felt by the great body of his fellow citizens. Few of the people who mourn him had personal opportunity to know the high qualities of his mind or his saintly character. Yet they truly feel that between him and the thought and spirit of his time there was fundamental sympathy and understanding. In a real sense the cast of his thinking was the product of his age. This awareness of his time was coupled in him with sensitiveness to the aspirations of his fellow men and with restraint born of an inherent humility. Such qualities could not fail to find expression in his judicial acts. Wholly apart from the expressed judgments supporting them, these acts had their impact upon the daily life of his fellows and registered their meaning clearly. So clearly, that thousands of men and women who never knew him and who never read his opinions, feel rightly that the nation has lost a great judge

Sleep disturbance at pre-deployment is a significant predictor of post-deployment re-experiencing symptoms.

Background: Insomnia is common in service members and associated with many mental and physical health problems. Recently, longitudinal data have been used to assess the impact of disturbed sleep on mental health outcomes. These studies have consistently shown relationships between sleep disturbance and development of mental illness. Objective: The present study examined the longitudinal relationship between sleep disturbance and PTSD symptomatology in a cohort of Marines and Navy Corpsmen deployed to Iraq and Afghanistan (n = 2,404) assessed prior to deployment, as well as at -3 and 6 months post-deployment. Additionally, we aimed to investigate the extent to which these relationships are moderated by combat-stress severity, and to what extent these findings are replicated in a second, separate cohort of Marines and Navy corpsmen (n = 938) assessed with identical measures prior to deployment and within 3 months of return. Method: The present study employed latent variable path models to examine the relationships between pre-deployment sleep disturbance and post-deployment re-experiencing symptoms. Initial cross-lagged path models were conducted on discovery and replication samples to validate the hypothesized predictive relationships. Follow up moderation path models were then conducted to include the effect of combat-stress severity on these relationships. Results: Initial cross-lagged models supported a significant relationship between pre-deployment sleep disturbance and future re-experiencing PTSD symptoms at all time points. Initial moderation models showed a small moderator effect of combat-stress severity, though the main predictive relationship between pre-deployment sleep disturbance and PTSD symptoms remained significant. The moderator effect was not significant in the replication sample. Conclusions: The results of this study support pre-deployment sleep disturbance as a risk factor for development of post-deployment PTSD symptoms. Interventions aimed at normalizing sleep may be important in preventive measures for PTSD

Interoceptive fear conditioning and Panic Disorder II : clarifying the role of CS-US discrimination

Despite the role afforded interoceptive fear conditioning in learning theory accounts of panic disorder, there exists little research demonstrating such learning in humans. A recent study by Acheson and colleagues (2007) was the first to successfully demonstrate interoceptive fear conditioning in humans. The authors employed a single-cue fear learning paradigm with 20% carbon dioxide-enriched air as interoceptive conditioned (CS) and unconditioned (US) stimuli. The current study had two aims: 1) to replicate the results of Acheson et al. (2007) while improving upon the methodology, and 2) to clarify the role of CS - US discrimination in fear learning and extinction. 104 subjects recruited from the University at Albany, SUNY subject pool met inclusion criteria and were semi-randomly assigned to four conditions: 1) CS-only, 2) CS-US Paired, 3) CS-US Unpaired, and 4) Discrimination. The discrimination condition was identical to the unpaired condition, with the exception of a light presented concurrently with the CS as a discrimination stimulus . The study was successful in replicating Acheson et al. (2007) in that the paired condition displayed greater magnitude electrodermal and evaluative responding relative to the CS-only condition. The unpaired condition displayed greater magnitude of evaluative responding, but not electrodermal response, during acquisition. These results did not show the same resistance to extinction seen by Acheson et al. (2007). The addition of a discrimination cue successfully attenuated fearful responding to the unpaired contingency. Results are consistent with contemporary learning theory accounts of panic, and are discussed in regards to the role of unpredictability and interoceptive conditioning in the etiology of panic disorder

The ANZUS Treaty during the Cold War: a reinterpretation of U.S. diplomacy in the Southwest Pacific

This article explains the origins of the Australia–New Zealand–United States (ANZUS) Treaty by highlighting U.S. ambitions in the Pacific region after World War II. Three clarifications to the historiography merit attention. First, an alliance with Australia and New Zealand reflected the pursuit of U.S. interests rather than the skill of antipodean diplomacy. Despite initial reservations in Washington, geostrategic anxiety and economic ambition ultimately spurred cooperation. The U.S. government's eventual recourse to coercive diplomacy against the other ANZUS members, and the exclusion of Britain from the alliance, substantiate claims of self-interest. Second, the historiography neglects the economic rationale underlying the U.S. commitment to Pacific security. Regional cooperation ensured the revival of Japan, the avoidance of discriminatory trade policies, and the stability of the Bretton Woods monetary system. Third, scholars have unduly played down and misunderstood the concept of race. U.S. foreign policy elites invoked ideas about a “White Man's Club” in Asia to obscure the pursuit of U.S. interests in the region and to ensure British exclusion from the treaty

Effects of total sleep deprivation on sensorimotor gating in humans

Sensorimotor gating is a measure of pre-attentional information processing and can be measured by prepulse inhibition (PPI) of the startle reflex. Sleep deprivation has been shown to disrupt PPI in animals and humans, and has been proposed as an early phase 2 model to probe antipsychotic efficacy in heathy humans. To further investigate the reliability and efficacy of sleep deprivation to produce PPI deficits we tested the effects of total sleep deprivation (TSD) on PPI in healthy controls in a highly controlled sleep laboratory environment. Participants spent 4 days and nights in a controlled laboratory environment with their sleep monitored with polysomnography. Participants were randomly assigned to either normal sleep on all 4 nights (N = 17) or 36 h of TSD on the 3rd or 4th night (N = 40). Participants were assessed for sleepiness using the Karolinska Sleepiness Scale (KSS) and underwent a daily PPI task (interstimlulus intervals 30-2000 ms) in the evening. Both within-subject effects (TSD vs. normal sleep in TSD group alone) and between-subject effects (TSD vs. no TSD group) of TSD on PPI were assessed. TSD increased subjective sleepiness measured with the KSS, but did not significantly alter overall startle, habituation or PPI. Sleep measures including duration, rapid eye movement and slow wave sleep duration were also not associated with PPI performance. The current results show that human sensorimotor gating may not be reliably sensitive to sleep deprivation. Further research is required for TSD to be considered a dependable model of PPI disruption for drug discovery in humans

High executive functioning is associated with reduced posttraumatic stress after trauma exposure among male U.S. military personnel

IntroductionEvidence suggests that executive function (EF) may play a key role in development of PTSD, possibly influenced by factors such as trauma type and timing. Since EF can be improved through intervention, it may be an important target for promoting resilience to trauma exposure. However, more research is needed to understand the relation between trauma exposure, EF, and PTSD. The goal of this study was to improve understanding of EF as a potential antecedent or protective factor for the development of PTSD among military personnel.MethodIn a cohort of U.S. Marines and Navy personnel (N = 1,373), the current study tested the association between exposure to traumatic events (pre-deployment and during deployment) and PTSD severity, and whether EF moderated these associations. Three types of pre-deployment trauma exposure were examined: cumulative exposure, which included total number of events participants endorsed as having happened to them, witnessed, or learned about; direct exposure, which included total number of events participants endorsed as having happened to them; and interpersonal exposure, which included total number of interpersonally traumatic events participants’ endorsed. EF was measured using the Penn Computerized Neurocognitive Battery.ResultsEF was associated with less PTSD symptom severity at pre-deployment, even when adjusting for trauma exposure, alcohol use, traumatic brain injury, and number of years in the military. EF also moderated the relation between cumulative trauma exposure and interpersonal trauma exposure and PTSD, with higher EF linked to a 20 and 33% reduction in expected point increase in PTSD symptoms with cumulative and interpersonal trauma exposure, respectively. Finally, higher pre-deployment EF was associated with reduced PTSD symptom severity at post-deployment, independent of deployment-related trauma exposure and adjusting for pre-deployment PTSD.ConclusionOur results suggest that EF plays a significant, if small role in the development of PTSD symptoms after trauma exposure among military personnel. These findings provide important considerations for future research and intervention and prevention, specifically, incorporating a focus on improving EF in PTSD treatment

Pharmacological profiling of small molecule modulators of the TMEM16A channel and their implications for the control of artery and capillary function

Background and purpose: TMEM16A chloride channels constitute a depolarising mechanism in arterial smooth muscle cells (SMCs) and contractile cerebral pericytes. TMEM16A pharmacology is incompletely defined. We elucidated the mode of action and selectivity of a recently identified positive allosteric modulator of TMEM16A (PAM_16A) and of a range of TMEM16A inhibitors. We also explore the consequences of selective modulation of TMEM16A activity on arterial and capillary function. Experimental approach: Patch‐clamp electrophysiology, isometric tension recordings, live imaging of cerebral cortical capillaries and assessment of cell death were employed to explore the effect of selective pharmacological control of TMEM16A on vascular function. Key Results: In low intracellular free Ca2+ concentrations ([Ca2+]i), nanomolar concentrations of PAM_16A activated heterologous TMEM16A channels, while being almost ineffective on the closely related TMEM16B channel. In either the absence of Ca2+ or in saturating [Ca2+]i, PAM_16A had no effect on TMEM16A currents at physiological potentials. PAM_16A selectively activated TMEM16A currents in SMCs and enhanced aortic contraction caused by phenylephrine or angiotensin‐II and capillary (pericyte) constriction evoked by endothelin‐1 or oxygen–glucose deprivation (OGD) to simulate cerebral ischaemia. Conversely, selective TMEM16A inhibition with Ani9 facilitated aortic, mesenteric and pericyte relaxation, and protected against OGD‐mediated pericyte cell death. Unlike PAM_16A and Ani9, a range of other available modulators were found to interfere with endogenous cationic currents in SMCs. Conclusions and implications: Arterial tone and capillary diameter can be controlled with TMEM16A modulators, highlighting TMEM16A as a target for disorders with a vascular component, including hypertension, stroke, Alzheimer's disease and vascular dementia