An interfering Go/No-go task does not affect accuracy in a Concealed Information Test

Following the idea that response inhibition processes play a central role in concealing information, the present study investigated the influence of a Go/No-go task as an interfering mental activity, performed parallel to the Concealed Information Test (CIT), on the detectability of concealed information. 40 undergraduate students participated in a mock-crime experiment and simultaneously performed a CIT and a Go/No-go task. Electrodermal activity (EDA), respiration line length (RLL), heart rate (HR) and finger pulse waveform length (FPWL) were registered. Reaction times were recorded as behavioral measures in the Go/No-go task as well as in the CIT. As a within-subject control condition, the CIT was also applied without an additional task. The parallel task did not influence the mean differences of the physiological measures of the mock-crime-related probe and the irrelevant items. This finding might possibly be due to the fact that the applied parallel task induced a tonic rather than a phasic mental activity, which did not influence differential responding to CIT items. No physiological evidence for an interaction between the parallel task and sub-processes of deception (e.g. inhibition) was found. Subjects' performance in the Go/No-go parallel task did not contribute to the detection of concealed information. Generalizability needs further investigations of different variations of the parallel task.

Long-term follow-up in patients with Lennox-Gastaut syndrome. Epileptological aspects, psychomotor development and social adaptation

In 1989/90 a follow-up was made possible on 72 of 78 patients who have been treated for the supposed or confirmed diagnosis of a Lennox-Gastaut-Syndrome at the university children hospital of Berne between 1964 and 1978. Nine patients were excluded of this study because the diagnosis was proved wrong retrospectively, leaving 63 cases. Of these, eleven patients (17.5%) have died. The remaining 52 (82.5%) were evaluated regarding their epilepsy, psychomotor development and social adaptation. The follow-up was good for 14.3%, intermediate for 23.8% and poor for 44.4%. Bad prognostic factors were found to be: first manifestation of epilepsy during the first year of life, occurrence of infantile spasms or hypsarrhythmia in the EEG and pathological neurological signs at the beginning of the disease. In the course of illness a change of seizure phenomenology was observed. The infantile spasms were seen only during the first three years of epilepsy. After the second year of disease psychomotor seizures became more and more frequent. Atypical absences, already seen at the beginning, were the most frequent form of seizure from the third year of epilepsy until the end of our observations. During the course of disease the frequency of generalized tonic and tonic-clonic seizures decreased little.

Structure of alpha6 beta3 delta GABA(A) receptors and their lack of ethanol sensitivity

Delta (delta) subunit containing GABA(A) receptors are expressed extra-synaptically and mediate tonic inhibition. In cerebellar granule cells, they often form a receptor together with alpha(6) subunits. We were interested to determine the architecture of these receptors. We predefined the subunit arrangement of 24 different GABA(A) receptor pentamers by subunit concatenation. These receptors (composed of alpha(6), beta(3) and delta subunits) were expressed in Xenopus oocytes and their electrophysiological properties analyzed. Currents elicited in response to GABA were determined in presence and absence of 3alpha, 21-dihydroxy-5alpha-pregnan-20-one and to 4,5,6,7-tetrahydroisoxazolo[5,4-c]-pyridin-3-ol. alpha(6)-beta(3)-alpha(6)/delta receptors showed a substantial response to GABA alone. Three receptors, beta(3)-alpha(6)-delta/alpha(6)-beta(3), alpha(6)-beta(3)-alpha(6)/beta(3)-delta and beta(3)-delta-beta(3)/alpha(6)-beta(3), were only uncovered in the combined presence of the neurosteroid 3alpha, 21-dihydroxy-5alpha-pregnan-20-one with GABA. All four receptors were activated by 4,5,6,7-tetrahydroisoxazolo[5,4-c]-pyridin-3-ol. None of the functional receptors was modulated by physiological concentrations (up to 30 mM) of ethanol. GABA concentration response curves indicated that the delta subunit can contribute to the formation of an agonist site. We conclude from the investigated receptors that the delta subunit can assume multiple positions in a receptor pentamer composed of alpha(6), beta(3) and delta subunits.

Unanticipated structural and functional properties of delta-subunit-containing GABAA receptors

GABA(A) receptors mediate inhibitory neurotransmission in the mammalian brain via synaptic and extrasynaptic receptors. The delta (delta)-subunit-containing receptors are expressed exclusively extra-synaptically and mediate tonic inhibition. In the present study, we were interested in determining the architecture of receptors containing the delta-subunit. To investigate this, we predefined the subunit arrangement by concatenation. We prepared five dual and three triple concatenated subunit constructs. These concatenated dual and triple constructs were used to predefine nine different GABA(A) receptor pentamers. These pentamers composed of alpha(1)-, beta(3)-, and delta-subunits were expressed in Xenopus oocytes and maximal currents elicited in response to 1 mm GABA were determined in the presence and absence of THDOC (3alpha, 21-dihydroxy-5alpha-pregnane-20-one). beta(3)-alpha(1)-delta/alpha(1)-beta(3) and beta(3)-alpha(1)-delta/beta(3)-alpha(1) resulted in the expression of large currents in response to GABA. Interestingly, the presence of the neurosteroid THDOC uncovered alpha(1)-beta(3)-alpha(1)/beta(3)-delta receptors, additionally. The functional receptors were characterized in detail using the agonist GABA, THDOC, Zn(2+), and ethanol and their properties were compared with those of non-concatenated alpha(1)beta(3) and alpha(1)beta(3)delta receptors. Each concatenated receptor isoform displayed a specific set of properties, but none of them responded to 30 mm ethanol. We conclude from the investigated receptors that delta can assume multiple positions in the receptor pentamer. The GABA dose-response properties of alpha(1)-beta(3)-alpha(1)/beta(3)-delta and beta(3)-alpha(1)-delta/alpha(1)-beta(3) match most closely the properties of non-concatenated alpha(1)beta(3)delta receptors. Furthermore, we show that the delta-subunit can contribute to the formation of an agonist site in alpha(1)-beta(3)-alpha(1)/beta(3)-delta receptors.

Determination of the minimum alveolar concentration of isoflurane in Shetland ponies using constant current or constant voltage electrical stimulation

OBJECTIVE: To determine the minimum alveolar concentration (MAC) of isoflurane in Shetland ponies using a sequence of three different supramaximal noxious stimulations at each tested concentration of isoflurane rather than a single stimulation. STUDY DESIGN: Prospective, experimental trial. ANIMALS: Seven 4-year-old, gelding Shetland ponies. METHODS: The MAC of isoflurane was determined for each pony. Three different modes of electrical stimulation were applied consecutively (2 minute intervals): two using constant voltage (90 V) on the gingiva via needle- (CVneedle) or surface-electrodes (CVsurface) and one using constant current (CC; 40 mA) via surface electrodes applied to the skin over the digital nerve. The ability to clearly interpret the responses as positive, the latency of the evoked responses and the inter-electrode resistance were recorded for each stimulus. RESULTS: Individual isoflurane MAC (%) values ranged from 0.60 to 1.17 with a mean (+/-SD) of 0.97 (+/-0.17). The responses were more clearly interpreted with CC, but did not reach statistical significance. The CVsurface mode produced responses with a longer delay. The CVneedle mode was accompanied by variable inter-electrode resistances resulting in uncontrolled stimulus intensity. At 0.9 MAC, the third stimulation induced more positive responses than the first stimulation, independent of the mode of stimulation used. CONCLUSIONS: The MAC of isoflurane in the Shetland ponies was lower than expected with considerable variability among individuals. Constant current surface electrode stimulations were the most repeatable. A summation over the sequence of three supramaximal stimulations was observed around 0.9 MAC. CLINICAL RELEVANCE: The possibility that Shetland ponies require less isoflurane than horses needs further investigation. Constant current surface-electrode stimulations were the most repeatable. Repetitive supramaximal stimuli may have evoked movements at isoflurane concentrations that provide immobility when single supramaximal stimulation was applied.

A phosphoinositide 3-kinase (PI3K)-serum- and glucocorticoid-inducible kinase 1 (SGK1) pathway promotes Kv7.1 channel surface expression by inhibiting Nedd4-2 protein

Epithelial cell polarization involves several kinase signaling cascades that eventually divide the surface membrane into an apical and a basolateral part. One kinase, which is activated during the polarization process, is phosphoinositide 3-kinase (PI3K). In MDCK cells, the basolateral potassium channel Kv7.1 requires PI3K activity for surface-expression during the polarization process. Here, we demonstrate that Kv7.1 surface expression requires tonic PI3K activity as PI3K inhibition triggers endocytosis of these channels in polarized MDCK. Pharmacological inhibition of SGK1 gave similar results as PI3K inhibition, whereas overexpression of constitutively active SGK1 overruled it, suggesting that SGK1 is the primary downstream target of PI3K in this process. Furthermore, knockdown of the ubiquitin ligase Nedd4-2 overruled PI3K inhibition, whereas a Nedd4-2 interaction-deficient Kv7.1 mutant was resistant to both PI3K and SGK1 inhibition. Altogether, these data suggest that a PI3K-SGK1 pathway stabilizes Kv7.1 surface expression by inhibiting Nedd4-2-dependent endocytosis and thereby demonstrates that Nedd4-2 is a key regulator of Kv7.1 localization and turnover in epithelial cells.

Seizure activity occurring in two dogs after S-ketamine-induction.

Two healthy dogs were anaesthetized to undergo elective orthopaedic procedures. After premedication with methadone and acepromazine, general anaesthesia was induced with midazolam and S-ketamine. Immediately after anaesthetic induction, seizures occurred in both dogs. In the first dog the syndrome was characterized by tonic and clonic motor activity, muscular hypertone, hypersalivation, urination, defecation and hyperthermia. In the second dog muscular twitches of the temporal and masseter regions were observed, followed by increased skeletal muscles tone, hypersalivation, spontaneous urination and increase in body temperature. Recoveries from anaesthesia were uneventful and no seizures were observed. Considering the temporal association between anaesthetic induction and occurrence of seizures, and the fact that other causative factors could not be identified, it is hypothesized that S-ketamine played a role in determining the convulsive phenomena observed in these patients. S-ketamine might carry the potential for inducing seizures in otherwise healthy dogs, despite the concomitant use of GABA-ergic drugs.

Non-Hebbian Long-Term Potentiation of Inhibitory Synapses in the Thalamus

The thalamus integrates and transmits sensory information to the neocortex. The activity of thalamocortical relay (TC) cells is modulated by specific inhibitory circuits. Although this inhibition plays a crucial role in regulating thalamic activity, little is known about long-term changes in synaptic strength at these inhibitory synapses. Therefore, we studied long-term plasticity of inhibitory inputs to TC cells in the posterior medial nucleus of the thalamus by combining patch-clamp recordings with two-photon fluorescence microscopy in rat brain slices. We found that specific activity patterns in the postsynaptic TC cell induced inhibitory long-term potentiation (iLTP). This iLTP was non-Hebbian because it did not depend on the timing between presynaptic and postsynaptic activity, but it could be induced by postsynaptic burst activity alone. iLTP required postsynaptic dendritic Ca2+ influx evoked by low-threshold Ca2+ spikes. In contrast, tonic postsynaptic spiking from a depolarized membrane potential (−50 mV), which suppressed these low-threshold Ca2+ spikes, induced no plasticity. The postsynaptic dendritic Ca2+ increase triggered the synthesis of nitric oxide that retrogradely activated presynaptic guanylyl cyclase, resulting in the presynaptic expression of iLTP. The dependence of iLTP on the membrane potential and therefore on the postsynaptic discharge mode suggests that this form of iLTP might occur during sleep, when TC cells discharge in bursts. Therefore, iLTP might be involved in sleep state-dependent modulation of thalamic information processing and thalamic oscillations.

Paleozoic-aged brine and authigenic helium preserved in an Ordovician shale aquiclude

Consideration of the geosphere for isolation of nuclear waste has generated substantial interest in the origin, age, and movement of fl uids and gases in low-permeability rock formations. Here, we present profi les of isotopes, solutes, and helium in porewaters recovered from 860 m of Cambrian to Devonian strata on the eastern fl ank of the Michigan Basin. Of particular interest is a 240-m-thick, halite-mineralized, Ordovician shale and carbonate aquiclude, which hosts Br–-enriched, post-dolomitic brine (5.8 molal Cl) originating as evaporated Silurian seawater. Authigenic helium that has been accumulating in the aquiclude for more than 260 m.y. is found to be isolated from underlying allochthonous, 3He-enriched helium that originated from the rifted base of the Michigan Basin and the Canadian Shield. The Paleozoic age and immobility of the pore fl uids in this Ordovician aquiclude considerably strengthen the safety case for deep geological repositories, but also provide new insights into the origin of deep crustal brines and opportunities for research on other components of a preserved Paleozoic porewater system.

Transport of 234U in the Opalinus Clay on centimetre to decimetre scales

The Opalinus Clay formation in North Switzerland is a potential host rock for a deep underground radioactive waste repository. The distribution of U-238, U-234 and Th-230 was studied in rock samples of the Opalinus Clay from an exploratory borehole at Benken (Canton of Zurich) using MC-ICP-MS. The aim of U-234 was to assess the in situ, long-term migration behaviour in this rock. Very low hydraulic conductivities of the Opalinus Clay, reducing potential of the pore water and its chemical equilibrium with the host rock are expected to render both U-238 and Th-230 immobile. If U is heterogeneously distributed in the Opalinus Clay, gradients in the supply of U-234 from the rock matrix to the pore water by the decay of U-238 will be established. Diffusive redistribution separates U-234 from its immobile parent U-238 resulting in bulk rock U-234/U-238 activity disequilibria. These may provide a means of estimating the mobility of U-234 in the rock if the diffusion rate of U-234 is significant compared to its decay rate. Sampling was carried out on two scales. Drilling of cm-spaced samples from the drill-core was done to study mobility over short distances and elucidate possible small-scale lithological control. Homogenized 25-cm-long portions of a 2-m-long drill-core section were prepared to provide information on transport over a longer distance. Variations in U and/or Th content on the cm-scale between clays and carbonate-sandy layers are revealed by beta-scanning, which shows that the (dominant) clay is richer in both elements. Samples were digested using aqua regia followed by total HF dissolution, yielding two fractions. in all studied samples U was found to be concentrated in the HF digestion fraction. It has a high U/Th ratio and a study by SEM-EDS points to sub-mu m up to several mu m in size zircon grains as the main U-rich phase. This fraction consistently has U-234/U-238 activity ratios below unity. The minute zircon grains constitute the major reservoir of U in the rock and act as constant rate suppliers of U-234 into the rock matrix and the pore water. The aqua regia leach fraction was found to be enriched in Th, and complementary to the HF fraction, having U-234/U-238 activity ratios above unity. It is believed that these U activity ratios reflect the surplus of having U-234 delivered from the zircon grains. Some cm-spaced samples show bulk rock U-234/U-238 activity ratios that are markedly out of equilibrium. In most of them a striking negative correlation between the total U content and the bulk rock U-234/U-238 activity ratios is observed. This is interpreted to indicate net U-234 transfer from regions of higher supply of U-234 towards those of lower supply which is, in most cases, equivalent to transfer from clayey towards carbonate/sandy portions of the rock. In contrast, the 25 cm averaged samples all have uniform bulk rock U-234/U-238 activity ratios in equilibrium, indicating U immobility in the last 1-1.5 Ma on this spatial scale. It is concluded that the small-scale lithological variations which govern U spatial distribution in the Opalinus Clay are the major factor determining U-234 in situ supply rates, regulating its diffusive fluxes and controlling the observed bulk rock U-234/U-238 activity ratios. A simple box-model is presented to simulate the measured bulk rock U-234/U-238 activity ratios and to give an additional insight into the studied system. (C) 2008 Elsevier Ltd. All rights reserved.

Spontaneous peristaltic airway contractions propel lung liquid through the bronchial tree of intact and fetal lung explants

Spontaneous contractions of the fetal airways are a well recognized but poorly characterized phenomenon. In the present study spontaneous narrowing of the airways was analyzed in freshly isolated lungs from early to late gestation in fetal pigs and rabbits and in cultured fetal mouse lungs. Propagating waves of contraction traveling proximal to distal were observed in fresh lungs throughout gestation which displaced the lung liquid along the lumen. In the pseudoglandular and canalicular stages (fetal pigs) the frequency ranged from 2.3 to 3.3 contractions/min with a 39 to 46% maximum reduction of lumen diameter. In the saccular stage (rabbit) the frequency was 10 to 12/min with a narrowing of approximately 30%. In the organ cultures the waves of narrowing started at the trachea in whole lungs, or at the main bronchus in lobes (5.2 +/- 1.5 contractions/min, 22 +/- 8% reduction of lumen diameter), and as they proceeded distally along the epithelial tubes the luminal liquid was shifted toward the terminal tubules, which expanded the endbuds. As the tubules relaxed the flow of liquid was reversed. Thus the behavior of airway smooth muscle in the fetal lung is phasic in type (like gastrointestinal muscle) in contrast to that in postnatal lung, where it is tonic. An intraluminal positive pressure of 2.33 +/- 0.77 cm H(2)O was recorded in rabbit fetal trachea. It is proposed that the active tone of the smooth muscle maintains the positive intraluminal pressure and acts as a stimulus to lung growth via the force exerted across the airway wall and adjacent parenchyma. The expansion of the compliant endbuds by the fluid shifts at the airway tip may promote their growth into the surrounding mesenchyme.

Control of ventricular ciliary beating by the melanin concentrating hormone-expressing neurons of the lateral hypothalamus: a functional imaging survey

The cyclic peptide Melanin Concentrating Hormone (MCH) is known to control a large number of brain functions in mammals such as food intake and metabolism, stress response, anxiety, sleep/wake cycle, memory, and reward. Based on neuro-anatomical and electrophysiological studies these functions were attributed to neuronal circuits expressing MCHR1, the single MCH receptor in rodents. In complement to our recently published work (1) we provided here new data regarding the action of MCH on ependymocytes in the mouse brain. First, we establish that MCHR1 mRNA is expressed in the ependymal cells of the third ventricle epithelium. Second, we demonstrated a tonic control of MCH-expressing neurons on ependymal cilia beat frequency using in vitro optogenics. Finally, we performed in vivo measurements of CSF flow using fluorescent micro-beads in wild-type and MCHR1-knockout mice. Collectively, our results demonstrated that MCH-expressing neurons modulate ciliary beating of ependymal cells at the third ventricle and could contribute to maintain cerebro-spinal fluid homeostasis.

Professional musicians listen differently to music

INTRODUCTION: Experience-based adaptation of emotional responses is an important faculty for cognitive and emotional functioning. Professional musicians represent an ideal model in which to elicit experience-driven changes in the emotional processing domain. The changes of the central representation of emotional arousal due to musical expertise are still largely unknown. The aim of the present study was to investigate the electroencephalogram (EEG) correlates of experience-driven changes in the domain of emotional arousal. Therefore, the differences in perceived (subjective arousal via ratings) and physiologically measured (EEG) arousal between amateur and professional musicians were examined. PROCEDURE: A total of 15 professional and 19 amateur musicians listened to the first movement of Ludwig van Beethoven's 5th symphony (duration=∼7.4min), during which a continuous 76-channel EEG was recorded. In a second session, the participants evaluated their emotional arousal during listening. In a tonic analysis, we examined the average EEG data over the time course of the music piece. For a phasic analysis, a fast Fourier transform was performed and covariance maps of spectral power were computed in association with the subjective arousal ratings. RESULTS: The subjective arousal ratings of the professional musicians were more consistent than those of the amateur musicians. In the tonic EEG analysis, a mid-frontal theta activity was observed in the professionals. In the phasic EEG, the professionals exhibited an increase of posterior alpha, central delta, and beta rhythm during high arousal. DISCUSSION: Professionals exhibited different and/or more intense patterns of emotional activation when they listened to the music. The results of the present study underscore the impact of music experience on emotional reactions.

A novel open channel blocker of GABA-A receptors

GABA-A receptors are chloride ion channels composed of five subunits, mediating fast synaptic and tonic inhibition in the mammalian brain. 19 different subunit isoforms have been identified, with the major receptor type in mammalian adult brain consisting of α1, β2, and γ2 subunits. GABA-A receptors are the target of numerous sedating and anxiolytic drugs such as benzodiazepines. The currently known endogenous ligands are GABA, neurosteroids and the endocannabinoid 2- arachidonoyl glycerol (2-AG). The pharmacological properties of this chloride ion channel strictly depend on receptor subunit composition and arrangement. GABA-A receptors bind and are inhibited by epileptogenic agents such as picrotoxin, and cyclodiene insecticides such as dieldrin. We screened aromatic monovalent anions with five-fold symmetry for inhibition of GABA-A receptors. One of the anions, PCCPinhibited currents elicited by GABA with comparable potency as picrotoxin. This inhibition showed all characteristics of an open channel block. The GABA-A receptor ion channel is lined by residues from the M2 membrane-spanning segment. To identify important residues of the pore involved in the interaction with the blocking molecules PCCP-, a mutation scan was performed in combination with subsequent analysis of the expressed mutant proteins using electrophysiological techniques. In a second project we characterised a light-switchable modulator of GABA-A receptors based on propofol. It was my responsibility to investigate the switching kinetics in patch clamp experiments. After its discovery in 1980, propofol has become the most widely used intravenous general anaesthetic. It is commonly accepted that the anaesthesia induced by this unusually lipophilic drug mostly results from potentiation of GABA induced currents. While GABA-A receptors respond to a variety of ligands, they are normally not sensitive towards light. This light sensitivity could be indirectly achieved by using modulators that can be optically switched between an active and an inactive form. We tested an azobenzene derivative of propofol where an aryldiazene unit is directly coupled to the pharmacophore. This molecule was termed azopropofol (AP2). The effect of AP2 on Cl- currents was investigated with electrophysiological techniques using α1β2γ2 GABA-A receptors expressed in Xenopus oocytes and HEK-cells. In the third project we wanted to investigate the functional role of GABA-A receptors in the liver, and their possible involvement in cell proliferation. GABA-A receptors are also found in a wide range of peripheral tissues, including parts of the peripheral nervous system and non-neural tissues such as smooth muscle, the female reproductive system, liver and several cancer tissues. However their precise function in non neuronal or cancerous cells is still unknown. For this purpose we investigated expression, localization and function of the hepatocytes GABA-A receptors in model cell lines and healthy and cancerous hepatocytes.

The Road Not Taken: Enabling and Limiting Mobility in the Eastern Pamirs

Based on fieldwork conducted between 2008 and 2011, this article explores the role of roads in enabling and limiting the movement of people and goods in Tajikistan’s Eastern Pamirs. The article focuses on the Pamir Highway and a newly established trade route linking Tajikistan with China. Besides materially facilitating mobility, both roads serve as trajectories for opportunities, but often also signify the lack of such to those who live along them. This article thus seeks to analyse the shifting roles of roads against the backdrop of past and present state dispensations, shifting ideologies and newly emerging economic practices. By emphasising roads as both enabling and limiting spatial entities shaped by materiality, politics and economics, this article argues, on the one hand, that roads are important factors in directing and accelerating the mobility of people and goods and, on the other, that roads are also symbols of immobility inasmuch as they set limitations on the movement of people.