Adjunctive cognitive training with exposure enhances fear and neural outcomes in social anxiety.

Exposure-based cognitive behavioral therapy (CBT) is the gold standard for treating social anxiety disorder (SAD), yet response is not universal. CBT is thought to operate via extinction-related learning during exposure, which in turn relies on cognitive processes such as working memory. The present proof-of-concept study investigates the potential for training working memory to improve anxiety related outcomes following exposure. Thirty-three adults with elevated social anxiety were randomized to complete a working memory training or sham training condition. Post-training, participants completed a working memory assessment, speech exposure session, and two fMRI tasks. Participants who received working memory training demonstrated lower distress ratings by the end of the speech exposures and better performance on the fMRI working memory task than those in sham. Working memory training completers had greater neural activation in frontoparietal regions during an in-scanner working memory task and exhibited less neural activation in the fusiform gyrus in response to an emotional face processing task than those in sham. Adding working memory training to exposure procedures could strengthen functioning of frontoparietal regions and alter emotional processing - key mechanisms implicated in extinction learning. Findings provide preliminary evidence that training working memory in conjunction with exposure may enhance exposure success.

Attenuated prefrontal and temporal neural activity during working memory as a potential biomarker of suicidal ideation in veterans with PTSD.

BACKGROUND: Suicide is a significant health concern among veterans, and suicidal ideation is a common and functionally debilitating condition that frequently precedes suicidal behavior. Characterizing neurobiological substrates associated with suicidal ideation in veterans may inform evaluation of risk for this population. Associations between suicidal ideation and functional abnormalities in prefrontal, temporal, and striatal regions supporting cognitive task performance have been documented in individuals with mood and psychotic disorders, suggesting a potential role for neurocognitive vulnerabilities in this condition. To date, however, relatively little research has explored neural correlates of suicidal ideation, particularly among individuals with posttraumatic stress disorder (PTSD). METHODS: Twenty three combat veterans diagnosed with PTSD completed an adapted Reading Span (Rspan) working memory task during functional magnetic resonance imaging (fMRI). Participants were classified based on presence of current SI. We evaluated differences between these groups on neural activation in response to interference-based working memory demands within the task. Primary analyses were conducted using a voxel-wise between-group t-test. RESULTS: Task-based activations were observed in regions including the cingulate, middle frontal, parietal, and occipital cortex, striatum, and cerebellum. Relative to individuals without SI, individuals with SI demonstrated less activation in a large region spanning the lateral prefrontal cortex and cingulate cortex, as well as the inferior temporal cortex, in response to interference demands. CONCLUSIONS: Results are consistent with models proposing that prefrontal neural substrates involved in cognitive regulation are implicated in suicidal ideation. Involvement of temporal functioning may also exist based on current findings. Future research is needed to understand whether disturbances in prefrontal regulatory control reflect a specific profile subtype with distinct neural correlates, and how such neural patterns may be used to improve detection and treatment personalization.

A test house study of pesticides and pesticide degradation products following an indoor application.

UNLABELLED: Preexisting pesticide degradates are a concern for pesticide biomonitoring studies as exposure to them may result in overestimation of pesticide exposure. The purpose of this research was to determine whether there was significant formation and movement, of pesticide degradates over a 5-week period in a controlled indoor setting after insecticide application. Movement of the pesticides during the study was also evaluated. In a simulated crack and crevice application, commercially available formulations of fipronil, propoxur, cis/trans-permethrin, and cypermethrin were applied to a series of wooden slats affixed to the wall in one room of an unoccupied test house. Floor surface samples were collected through 35 days post-application. Concentrations of the pesticides and the following degradates were determined: 2-iso-propoxyphenol, cis/trans 3-(2,2-dichlorovinyl)-3-3-dimethyl-(1-cyclopropane) carboxylic acid, 3-phenoxybenzoic acid, fipronil sulfone, fipronil sulfide, and fipronil desulfinyl. Deltamethrin, which had never been applied, and chlorpyrifos, which had been applied several years earlier, and their degradation products, cis-3-(2,2-dibromovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid, and, 3,5,6-trichloro-2-pyridinol, respectively, were also measured. Propoxur was the only insecticide with mass movement away from the application site. There was no measurable formation or movement of the degradates. However, all degradates were present at low levels in the formulated product. These results indicate longitudinal repetitive sampling of indoor degradate levels during short-term studies, is unnecessary. PRACTICAL IMPLICATIONS: Exposure to preexisting pesticide degradates may inflate estimates of exposure in biomonitoring studies where these compounds are used as biomarkers. To date, there is no published information on formation of pesticide degradates following an indoor application. We found that the study pesticides have low rates of degradation and are unlikely to be a significant factor affecting results of short-term (weeks) biomonitoring studies. Therefore, relatively few indoor samples are needed to estimate background levels of degradation products resulting from a recent pesticide application.

A preliminary examination of the translocation of microencapsulated cyfluthrin following applications to the perimeter of residential dwellings.

Methods have been developed to monitor the translocation of microencapsulated cyfluthrin following perimeter applications to residential dwellings. A pilot study was implemented to determine both the potential for application spray to drift away from dwellings and the intrusion of residues into homes following perimeter treatments. Residential monitoring included measuring spray drift using cellulose filter paper and the collection of soil samples from within the spray zone. In addition, interior air was monitored using fiberglass filter paper as a sorbent medium and cotton ball swabs were used to collect surface wipes. Fortification of matrixes resulted in recoveries of > 90%. Spray drift was highest at the point of application and declined to low but measurable levels 9.1 m from the foundations of dwellings. Soil residues declined to low, but measurable levels by 45 days post-application. No cyfluthrin was measured from indoor air; however, some interior surfaces had detectable levels of cyfluthrin until three days post-application. Findings indicate that spray drift resulting from perimeter applications might contaminate non-target surfaces outside the spray zone. Soil borne residues may serve as persistent sources for human exposure and potentially intrude into dwellings through the activities of occupants and pets. Residues do not appreciably translocate through air and consequently inhalation is not a likely route for human exposure. Surface residues detected indoors suggest that the physical movement of residues from the exterior to the interior might be a viable route of movement of residues following this type of application.

Structure-activity studies for a novel series of N-(arylethyl)-N-(1,2,3,4-tetrahydronaphthalen-1-ylmethyl)-N-methylamine s possessing dual 5-HT uptake inhibiting and alpha2-antagonistic activities.

In search of an alpha2-antagonist/5-HT uptake inhibitor as a potential new class of antidepressant with a more rapid onset of action, compound 3 was prepared and observed to possess high affinity for the alpha2-receptor (K(i) = 6.71 nM) and the 5-HT uptake site (20.6 nM). A series of tertiary amine analogs of 3 were synthesized and assayed for their affinity at both the alpha2-receptor and the 5-HT uptake site. The structure-activity relationship reveals that a variety of structural modifications to the arylethyl fragment are possible with retention of this dual activity. On the tetralin portion, 5-OMe substitution and the (R) stereochemistry at C-1 are optimal with alternate substitutions producing compounds retaining high affinity for the alpha2-receptor but lacking affinity for the 5-HT uptake site. Data for several rigidified 5-O-alkyl analogs suggests that the favored orientation of the oxygen lone pairs may be away from the 6-position of the tetralin.

Mono- and bis(aminomethyl)phenylacetic acid esters as short-acting antiarrhythmic agents. 2.

The synthesis, antiarrhythmic activity, and blood hydrolysis properties of a series of mono- and bis(aminomethyl)phenylacetic acid esters related to a previously reported class Ic antiarrhythmic agent (ACC-9358) are described. Of the various oxa-, aza-, thia-, and carbacyclic esters initially prepared in the bis(pyrrolidinomethyl)-4-hydroxyphenylacetic acid series, the 1,4-benzodioxanyl-2-methyl(3q) and the thienyl-2-methyl(31) esters were evaluated in vivo for antiarrhythmic efficacy. In addition, a number of monoappended phenylacetic esters of 3q with or without the 4-hydroxy group were also prepared for evaluation of antiarrhythmic, lipophilic, and metabolic properties. Of these compounds, 3q possessed the most desirable pharmacological and pharmacokinetic profile.

Ester derivatives of 2,6-bis(1-pyrrolidinylmethyl)-4-benzamidophenol as short-acting antiarrhythmic agents. 1.

In an effort to find a replacement for the iv antiarrhythmic drug lidocaine having reduced systemic and central nervous system effects, activity against supraventricular as well as ventricular arrhythmias, and a biological half-life of less than 15 min, derivatives of the orally active class Ic clinical agent 2,6-bis(1-pyrrolidinylmethyl)-4-benzamidophenol, 1 (ACC-9358), were synthesized and tested. Compounds with ester groups attached to the phenyl ring were either weakly active or toxic. Replacement of the formanilide function with alkyl esters afforded compounds with antiarrhythmic activity in the range of 1. When the ester carboxyl was separated from the bis(aminomethyl)phenol by methylene units, very short half-lives were observed in human blood. In general, these compounds also had low lipophilic character.

Synthesis and antiarrhythmic and parasympatholytic properties of substituted phenols. 3. Modifications to the linkage region (region 3).

As part of a continuing program of systematically modifying the structure of the class I antiarrhythmic drug changrolin, we synthesized 15 analogues in which the linkage between the two aromatic regions was altered. High antiarrhythmic activity and low parasympatholytic activity was found when the linkage region, designated region 3, contained a carbonyl moiety, including ketones, amides, and ureas. Secondary amides were superior to tertiary amides, while amide reversal resulted in no change in activities. One compound in this series, 7, 2,6-bis(1-pyrrolidinyl-methyl)-4-benzamidophenol (ACC-9358), is undergoing preclinical evaluations.

Synthesis and antiarrhythmic and parasympatholytic properties of substituted phenols. 2. Amides.

Thirty amides patterned after the antiarrhythmic drug changrolin were synthesized and their antiarrhythmic and parasympatholytic activities were assessed. There was no correlation between antiarrhythmic and parasympatholytic activities. Several of the amides were found to be potent antiarrhythmic agents that possessed low parasympatholytic activity. All of the compounds appear to act by a class I mechanism.

Synthesis and antiarrhythmic and parasympatholytic properties of substituted phenols. 1. Heteroarylamine derivatives.

Twenty-four structural derivatives of the antiarrhythmic drug changrolin were synthesized and tested for antiarrhythmic and parasympatholytic activities. It was found that while the bis(pyrrolidinylmethyl)phenol pattern of changrolin appeared to be optimal in this series, a wide latitude existed for the heteroaryl substituent for maintaining good antiarrhythmic activity. Further, the antiarrhythmic and parasympatholytic activities tended to exhibit parallel changes.

N-Aralkyl substitution of 2-amino-5,6- and -6,7-dihydroxy-1,2,3,4-tetrahydronaphthalenes. 2. Derivatives of a hypotensive-positive inotropic agent.

Seven derivatives of 2-[[2-(3,4-dihydroxyphenyl)-1-methylethyl]amino]-6,7-dihydroxy-1,2,3,4- tetrahydronaphthalene, an inotropic agent which also causes a decrease in blood pressure, were synthesized and tested for inotropic potency, cardioselectivity, and inotropic selectivity. The derivatives were designed to explore whether catechol moieties and rigid rotamers of dopamine are necessary for the activity which was found in the parent compound. The derivatives had phenolic functions in place of catechols, and they had phenethylamine in place of the tetrahydronaphthalene moiety. In no case was the profile of activity of the parent compound duplicated in the derivatives.

N-Aralkyl substitution of 2-amino-5,6- and -6,7-dihydroxy-1,2,3,4-tetrahydronaphthalenes. 1. Cardiac and pressor/depressor activities.

Amino substitution o rigid forms of dopamine [2-amino-5,6-dihydroxy-1,2,3,4-tetrahydronaphthalene (A-5,6-DTN) and 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (A-6,7-DTN)] with aralkyl functionalities was carried out to investigate the role of such structural modifications upon cardiac inotropic/chronotropic and blood pressure activity. Derivatives of A-5,6-DTN were strong vasodepressor agents devoid action was associated with the dihydroxyphenyl-1-methylethyl derivative, which was also an inotropic selective compound. The amino substituent of dobutamine was ineffective in reducing peripheral vascular action when combined with the rigid forms of dopamine. It was also ineffective in imparting inotropic selectivity when combined with A-5,6-DTN. An analysis of these observations in light of existing structure-activity relationships of aminoaralkyl substitution of other catecholamine structure is presented.