Pharmacology of cognitive enhancers for exposure-based therapy of fear, anxiety and trauma-related disorders

AbstractPathological fear and anxiety are highly debilitating and, despite considerable advances in psychotherapy and pharmacotherapy they remain insufficiently treated in many patients with PTSD, phobias, panic and other anxiety disorders. Increasing preclinical and clinical evidence indicates that pharmacological treatments including cognitive enhancers, when given as adjuncts to psychotherapeutic approaches [cognitive behavioral therapy including extinction-based exposure therapy] enhance treatment efficacy, while using anxiolytics such as benzodiazepines as adjuncts can undermine long-term treatment success. The purpose of this review is to outline the literature showing how pharmacological interventions targeting neurotransmitter systems including serotonin, dopamine, noradrenaline, histamine, glutamate, GABA, cannabinoids, neuropeptides (oxytocin, neuropeptides Y and S, opioids) and other targets (neurotrophins BDNF and FGF2, glucocorticoids, L-type-calcium channels, epigenetic modifications) as well as their downstream signaling pathways, can augment fear extinction and strengthen extinction memory persistently in preclinical models. Particularly promising approaches are discussed in regard to their effects on specific aspects of fear extinction namely, acquisition, consolidation and retrieval, including long-term protection from return of fear (relapse) phenomena like spontaneous recovery, reinstatement and renewal of fear. We also highlight the promising translational value of the preclinial research and the clinical potential of targeting certain neurochemical systems with, for example d-cycloserine, yohimbine, cortisol, and L-DOPA. The current body of research reveals important new insights into the neurobiology and neurochemistry of fear extinction and holds significant promise for pharmacologically-augmented psychotherapy as an improved approach to treat trauma and anxiety-related disorders in a more efficient and persistent way promoting enhanced symptom remission and recovery

High Resolution Infrared Imaging of the Compact Nuclear Source in NGC4258

We present high resolution imaging of the nucleus of NGC4258 from 1 micron to 18 microns. Our observations reveal that the previously discovered compact source of emission is unresolved even at the near-infrared resolution of about 0.2 arcsec FWHM which corresponds to about 7 pc at the distance of the galaxy. This is consistent with the source of emission being the region in the neighborhood of the purported 3.5*10^7 M_sun black hole. After correcting for about 18 mags of visual extinction, the infrared data are consistent with a F_nu \propto nu^(-1.4+/-0.1) spectrum from 1.1 micron to 18 micron, implying a non-thermal origin. Based on this spectrum, the total extinction corrected infrared luminosity (1-20 micron) of the central source is 2*10^8 L_sun. We argue that the infrared spectrum and luminosity of the central source obviates the need for a substantial contribution from a standard, thin accretion disk at these wavelengths and calculate the accretion rate through an advection dominated accretion flow to be Mdot \sim 10^(-3) M_sun/yr. The agreement between these observations and the theoretical spectral energy distribution for advection dominated flows provides evidence for the existence of an advection dominated flow in this low luminosity AGN.Comment: 21 pages, 5 figures, Appearing in Mar 2000 ApJ vol. 53

Local tetragonal distortion in La_{0.7}Sr_{0.3}MnO_3 strained thin films probed by x-ray absorption spectroscopy

We report on an angular resolved X-ray Absorption Spectroscopy study of $La_{0.7}Sr_{0.3}MnO_{3}$ thin films epitaxially grown by pulsed laser deposition on slightly mismatched substrates which induce tensile or compressive strains. XANES spectra give evidence of tetragonal distortion within the $MnO_{6}$ octahedra, with opposite directions for tensile and compressive strains. Quantitative analysis has been done and a model of tetragonal distortion reflecting the strain has been established. EXAFS data collected in plane for tensile substrate confirm the change in the $Mn-O$ average bond distance and the increase of $Mn-Mn$ length matching with the enlargement of the cell parameter. From these results we conclude that there is no significant change in the $Mn-O-Mn$ angle. Our observations conflict with the scenarios which this angle is the main driving parameter in the sensitivity of manganite films properties to external strains and suggest that the distortion within the octahedra plays a key role in the modification of the transport and magnetic properties.Comment: 8 pages, 6 figure

A Mid-Infrared Imaging Survey of Embedded Young Stellar Objects in the Rho Ophiuchi Cloud Core

Results of a comprehensive, new, ground-based mid-infrared imaging survey of the young stellar population of the Rho Ophiuchi cloud are presented. Data were acquired at the Palomar 5-m and at the Keck 10-m telescopes with the MIRLIN and LWS instruments, at 0.25 arcsec and 0.25 arcsec resolutions, respectively. Of 172 survey objects, 85 were detected. Among the 22 multiple systems observed, 15 were resolved and their individual component fluxes determined. A plot of the frequency distribution of the detected objects with SED spectral slope shows that YSOs spend ~400,000 yr in the Flat Spectrum phase, clearing out their remnant infall envelopes. Mid-infrared variability is found among a significant fraction of the surveyed objects, and is found to occur for all SED classes with optically thick disks. Large-amplitude near-infrared variability, also found for all SED classes with optically thick disks, seems to occur with somewhat higher frequency at the earlier evolutionary stages. Although a general trend of mid-infrared excess and NIR veiling exists proceeding through SED classes, with Class I objects generally exhibiting K-veilings > 1, Flat Spectrum objects with K-veilings > 0.58, and Class III objects with K-veilings =0, Class II objects exhibit the widest range of K-band veiling values, 0-4.5. However, the highly variable value of veiling that a single source can exhibit in any of the SED classes in which active disk accretion can take place is striking, and is direct observational evidence for highly time-variable accretion activity in disks. Finally, by comparing mid-infrared vs. near-infrared excesses in a subsample with well-determined effective temperatures and extinction values, disk clearing mechanisms are explored. The results are consistent with disk clearing proceeding from the inside-out.Comment: 18 pages + 5 tables + 7 figure

The Compact Nucleus of the Deep Silicate Absorption Galaxy NGC 4418

High resolution, Hubble Space Telescope (HST) near-infrared and Keck mid-infrared images of the heavily extinguished, infrared luminous galaxy NGC 4418 are presented. These data make it possible to observe the imbedded near-infrared structure on scales of 10-20 pc, and to constrain the size of the mid-infrared emitting region. The 1.1-2.2 um data of NGC 4418 show no clear evidence of nuclear star clusters or of a reddened active galactic nucleus. Instead, the nucleus of the galaxy consists of a ~100-200 pc linear structure with fainter structures extending radially outward. The near-infrared colors of the linear feature are consistent with a 10-300 Myr starburst suffering moderate levels (few magnitudes) of visual extinction. At 7.9-24.5 um, NGC 4418 has estimated size upper limits in the range of 30-80 pc. These dimensions are consistent with the highest resolution radio observations obtained to date of NGC 4418, as well as the size of 50-70 pc expected for a blackbody with a temperature derived from the 25 um, 60 um, and 100 um flux densities of the galaxy. Further, a spectral energy distribution constructed from the multi-wavelength mid-infrared observations show the strong silicate absorption feature at 10 um, consistent with previous mid-infrared observations of NGC 4418. An infrared surface brightness of 2.1x10^13 L_sun kpc^-2 is derived for NGC 4418. Such a value, though consistent with the surface brightness of warm ultraluminous infrared galaxies (ULIGs: L_IR [8-1000 um] >~ 10^12 L_sun) such as IRAS 05189-2524 and IRAS 08572+3915, is not large enough to distinguish NGC 4418 as a galaxy powered by an Active Galactic Nucleus (AGN), as opposed to a lower surface brightness starburst.Comment: LaTex, 7 pages, including 2 jpg figures and 3 postscript figures, AJ, in press (May, 2003

Spatio-temporal distribution of euphausiids: an important component to understanding ecosystem processes in the Gulf of Alaska and eastern Bering Sea

Abstract Euphausiids (principally Thysanoessa spp.) are found in high abundance in both the eastern Bering Sea (EBS) and the Gulf of Alaska (GOA). They are an important part of these cold-water coastal and pelagic ecosystems as a key prey item for many species, including marine mammals, seabirds, and fish, forming an ecological link between primary production and higher trophic levels. Acoustic-trawl (AT) survey methods provide a means of monitoring euphausiid abundance and distribution over a large spatial scale. Four years of AT and bottom-trawl survey data (2003, 2005, 2011, and 2013) were available from consistently sampled areas around Kodiak Island, including Shelikof Strait, Barnabas Trough, and Chiniak Trough. We identified euphausiid backscatter using relative frequency response and targeted trawling, and created an annual index of abundance for euphausiids. This index has broad application, including use in the stock assessments for GOA walleye pollock (Gadus chalcogrammus) and other species, as an ecosystem indicator, and to inform ecological research. We then used generalized additive models (GAMs) to examine the relationship between relative euphausiid abundance and potential predictors, including pollock abundance, temperature, bottom depth, and primary production. Model results were compared with an updated GAM of euphausiid abundance from the EBS to determine if the factors driving abundance and distribution were consistent between both systems. Temperature was not a strong predictor of euphausiid abundance in the GOA as in the EBS; warmer temperatures and lack of seasonal ice cover in the GOA may be a key difference between these ecosystems. Pollock abundance was significant in both the GOA and the EBS models, but was not a strongly negative predictor of euphausiid abundance in either system, a result not consistent with top-down control of euphausiid abundance

Mid-Infrared Observations of Class I/Flat-Spectrum Systems in Six Nearby Molecular Clouds

We have obtained new mid-infrared observations of 65 Class I/Flat-Spectrum (F.S.) objects in the Perseus, Taurus, Chamaeleon I/II, Rho Ophiuchi, and Serpens dark clouds. We detected 45/48 (94%) of the single sources, 16/16 (100%) of the primary components, and 12/16 (75%) of the secondary/triple components of the binary/multiple objects surveyed. The composite spectral energy distributions (SEDs) for all of our sample sources are either Class I or F.S., and, in 15/16 multiple systems, at least one of the individual components displays a Class I or F.S. spectral index. However, the occurrence of mixed pairings, such as F.S. with Class I, F.S. with Class II, and, in one case, F.S. with Class III, is surprisingly frequent. Such behaviour is not consistent with that of multiple systems among T Tauri stars (TTS), where the companion of a classical TTS also tends to be a classical TTS, although other mixed pairings have been previously observed among Class II objects. Based on an analysis of the spectral indices of the individual binary components, there appears to be a higher proportion of mixed Class I/F.S. systems (65-80%) than that of mixed Classical/Weak-Lined TTS (25-40%), demonstrating that the envelopes of Class I/ F.S. systems are rapidly evolving during this evolutionary phase. We report the discovery of a steep spectral index secondary companion to ISO-ChaI 97, detected for the first time via our mid-infrared observations. In our previous near- infrared imaging survey of binary/multiple Class I/F.S. sources, ISO-ChaI 97 appeared to be single. With a spectral index of Alpha >= 3.9, the secondary component of this system is a member of a rare class of very steep spectral index objects, those with Alpha > 3. Only three such objects have previously been reported, all of which are either Class 0 or Class I.Comment: 31 pages, 4 figures, 6 table