Hippocampus is place of interaction between unconscious and conscious memories retrieval

Recent experiments suggest that humans can form and later retrieve new semantic relations unconsciously by way of hippocampus - the key structure thought to support conscious relational (episodic) memory. Given that the hippocampus subserves both conscious and unconscious relational encoding/retrieval, we expected the hippocampus to be place of unconscious-conscious interactions. This hypothesis was tested in an fMRI experiment on the interaction between the unconscious retrieval of face-associated occupations and the subsequent conscious retrieval of celebrities’ occupations. For subliminal encoding, masked combinations of an unfamiliar face and a written occupation (“actor” or “politician”) were subliminally presented. At test, we presented the former subliminal faces again, without occupations and masks, as conscious retrieval cues. We hypothesized that faces would trigger the unconscious reactivation of the associated occupation - actor or politician -, which in turn would facilitate or inhibit the subsequent conscious recollection of a celebrity’s occupation. Following the presentation of a former subliminal face, we presented the portrait of a celebrity that participants were required to sort according to “actor” or “politician”. Depending on whether the triggered unconscious occupation was congruent or incongruent with the celebrity’s occupation, we expected an expedited or retarded conscious retrieval process as reflected in reaction times. Conscious retrieval was expedited in the congruent condition, but there was no effect in the incongruent condition. fMRI data collected during subliminal relational encoding confirmed that the hippocampus was interacting with neocortical semantic storage sites. fMRI data collected at test indicated that the facilitated conscious retrieval of celebrity-associated occupations was related to deactivations in this same network spanning hippocampus and neocortical semantic storage sites. Hence, unconscious retrieval likely preactivated this network, which allowed for a sparing recruitment of additional neural resources to assist conscious retrieval. This finding supports the notion that consciously and unconsciously acquired relational memories are stored in a single, cohesive hippocampal-neocortical memory space.

Hippocampus Is Place of Interaction between Unconscious and Conscious Memories.

Recent evidence suggests that humans can form and later retrieve new semantic relations unconsciously by way of hippocampus-the key structure also recruited for conscious relational (episodic) memory. If the hippocampus subserves both conscious and unconscious relational encoding/retrieval, one would expect the hippocampus to be place of unconscious-conscious interactions during memory retrieval. We tested this hypothesis in an fMRI experiment probing the interaction between the unconscious and conscious retrieval of face-associated information. For the establishment of unconscious relational memories, we presented subliminal (masked) combinations of unfamiliar faces and written occupations ("actor" or "politician"). At test, we presented the former subliminal faces, but now supraliminally, as cues for the reactivation of the unconsciously associated occupations. We hypothesized that unconscious reactivation of the associated occupation-actor or politician-would facilitate or inhibit the subsequent conscious retrieval of a celebrity's occupation, which was also actor or politician. Depending on whether the reactivated unconscious occupation was congruent or incongruent to the celebrity's occupation, we expected either quicker or delayed conscious retrieval process. Conscious retrieval was quicker in the congruent relative to a neutral baseline condition but not delayed in the incongruent condition. fMRI data collected during subliminal face-occupation encoding confirmed previous evidence that the hippocampus was interacting with neocortical storage sites of semantic knowledge to support relational encoding. fMRI data collected at test revealed that the facilitated conscious retrieval was paralleled by deactivations in the hippocampus and neocortical storage sites of semantic knowledge. We assume that the unconscious reactivation has pre-activated overlapping relational representations in the hippocampus reducing the neural effort for conscious retrieval. This finding supports the notion of synergistic interactions between conscious and unconscious relational memories in a common, cohesive hippocampal-neocortical memory space.

Why do humans make antisaccade errors?

Antisaccade errors are attributed to failure to inhibit the habitual prosaccade. We investigated whether the amount of information about the required response the patient has before the trial begins also contributes to error rate. Participants performed antisaccades in five conditions. The traditional design had two goals on the left and right horizontal meridians. In the second condition, stimulus-goal confusability between trials was eliminated by displacing one goal upward. In the third, hemifield uncertainty was eliminated by placing both goals in the same hemifield. In the fourth, goal uncertainty was eliminated by having only one goal, but interspersed with no-go trials. The fifth condition eliminated all uncertainty by having the same goal on every trial. Antisaccade error rate increased by 2% with each additional source of uncertainty, with the main effect being hemifield information, and a trend for stimulus-goal confusability. A control experiment for the effects of increasing angular separation between targets without changing these types of prior response information showed no effects on latency or error rate. We conclude that other factors besides prosaccade inhibition contribute to antisaccade error rates in traditional designs, possibly by modulating the strength of goal activation.

Aortic arch morphometry in living humans

Anatomical features of the aortic arch such as its steepness, the take-off angles and the distances between its supra-aortic branches can influence the feasibility and difficulty of interventional and/or surgical maneuvers. These anatomical characteristics were assessed by means of 3D multiplanar reconstruction of thoracic angio-computed tomography scans of 92 living patients (79 males, 13 females, mean age 69.4 ± 9.9 years) carried out for various indications (gross pathology of the thoracic aorta excluded). There was a significant variation of all measured parameters between the subjects - a standard aortic arch (i.e. with all measured parameters within 2 SD) does not seem to exist. There were no significant differences between genders but some of the parameters correlated significantly to age.

Garlic extract induces intestinal P-glycoprotein, but exhibits no effect on intestinal and hepatic CYP3A4 in humans

Garlic extracts have been shown to decrease drug exposure for saquinavir, a P-glycoprotein and cytochrome P450 3A4 substrate. In order to explore the underlying mechanisms and to study the effects of garlic on pre-systemic drug elimination, healthy volunteers were administered garlic extract for 21 days. Prior to and at the end of this period, expression of duodenal P-glycoprotein and cytochrome P450 3A4 protein were assayed and normalized to villin, while hepatic cytochrome P450 3A4 function and simvastatin, pravastatin and saquinavir pharmacokinetics were also evaluated. Ingestion of garlic extract increased expression of duodenal P-glycoprotein to 131% (95% CI, 105-163%), without increasing the expression of cytochrome P450 3A4 which amounted to 87% (95% CI, 67-112%), relative to baseline in both cases. For the erythromycin breath test performed, the average result was 96% (95% CI, 83-112%). Ingestion of garlic extract had no effect on drug and metabolite AUCs following a single dose of simvastatin or pravastatin, although the average area under the plasma concentration curve (AUC) of saquinavir decreased to 85% (95% CI, 66-109%), and changes in intestinal P-glycoprotein expression negatively correlated with this change. In conclusion, garlic extract induces intestinal expression of P-glycoprotein independent of cytochrome P450 3A4 in human intestine and liver.

Preventing vasospasm improves outcome after aneurysmal subarachnoid hemorrhage: rationale and design of CONSCIOUS-2 and CONSCIOUS-3 trials

Cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH) is a frequent but unpredictable complication associated with poor outcome. Current vasospasm therapies are suboptimal; new therapies are needed. Clazosentan, an endothelin receptor antagonist, has shown promise in phase 2 studies, and two randomized, double-blind, placebo-controlled phase 3 trials (CONSCIOUS-2 and CONSCIOUS-3) are underway to further investigate its impact on vasospasm-related outcome after aSAH. Here, we describe the design of these studies, which was challenging with respect to defining endpoints and standardizing endpoint interpretation and patient care. Main inclusion criteria are: age 18-75 years; SAH due to ruptured saccular aneurysm secured by surgical clipping (CONSCIOUS-2) or endovascular coiling (CONSCIOUS-3); substantial subarachnoid clot; and World Federation of Neurosurgical Societies grades I-IV prior to aneurysm-securing procedure. In CONSCIOUS-2, patients are randomized 2:1 to clazosentan (5 mg/h) or placebo. In CONSCIOUS-3, patients are randomized 1:1:1 to clazosentan 5, 15 mg/h, or placebo. Treatment is initiated within 56 h of aSAH and continued until 14 days after aSAH. Primary endpoint is a composite of mortality and vasospasm-related morbidity within 6 weeks of aSAH (all-cause mortality, vasospasm-related new cerebral infarction, vasospasm-related delayed ischemic neurological deficit, neurological signs or symptoms in the presence of angiographic vasospasm leading to rescue therapy initiation). Main secondary endpoint is extended Glasgow Outcome Scale at week 12. A critical events committee assesses all data centrally to ensure consistency in interpretation, and patient management guidelines are used to standardize care. Results are expected at the end of 2010 and 2011 for CONSCIOUS-2 and CONSCIOUS-3, respectively.

Transcriptional profiling of osseointegration in humans

To determine the temporal gene expression profile associated with the early healing events during osseointegration in a human model.

Early osseointegration to hydrophilic and hydrophobic implant surfaces in humans

To evaluate the rate and degree of osseointegration at chemically modified moderately rough, hydrophilic (SLActive) and moderately rough, hydrophobic (SLA) implant surfaces during early phases of healing in a human model.

Incretin receptors in non-neoplastic and neoplastic thyroid C cells in rodents and humans: relevance for incretin-based diabetes therapy

While incretins are of great interest for the therapy of diabetes 2, the focus has recently been brought to the thyroid, since rodents treated with glucagon-like peptide-1 (GLP-1) analogs were found to occasionally develop medullary thyroid carcinomas. Incretin receptors for GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) were therefore measured in various rodent and human thyroid conditions. In vitro GLP-1 and GIP receptor autoradiography were performed in normal thyroids, C-cell hyperplasia and medullary thyroid carcinomas in rodents. Receptor incidence and density were assessed and compared with the receptor expression in human thyroids, medullary thyroid carcinomas, and TT cells. GLP-1 receptors are expressed in C cells of normal rat and mice thyroids. Their density is markedly increased in rat C-cell hyperplasia and medullary thyroid carcinomas, where their incidence amounts to 100%. GIP receptors are neither detected in normal rodent thyroids nor in C-cell hyperplasia, but are present in all rat medullary thyroid carcinomas. No GLP-1 or GIP receptors are detected in normal human thyroids. Whereas only 27% of all human medullary thyroid carcinomas express GLP-1 receptors, up to 89% express GIP receptors in a high density. TT cells lack GLP-1 receptors but express GIP receptors. GLP-1 receptors are frequently expressed in non-neoplastic and neoplastic C cells in rodents while they are rarely detected in human C-cell neoplasia, suggesting species differences. Conversely, GIP receptors appear to be massively overexpressed in neoplastic C cells in both species. The presence of incretin receptors in thyroid C cell lesions suggests that this organ should be monitored before and during incretin-based therapy of diabetes.

Value of the radiolabelled GLP-1 receptor antagonist exendin(9-39) for targeting of GLP-1 receptor-expressing pancreatic tissues in mice and humans

Radiolabelled glucagon-like peptide 1 (GLP-1) receptor agonists have recently been shown to successfully image benign insulinomas in patients. Moreover, it was recently reported that antagonist tracers were superior to agonist tracers for somatostatin and gastrin-releasing peptide receptor targeting of tumours. The present preclinical study determines therefore the value of an established GLP-1 receptor antagonist for the in vitro visualization of GLP-1 receptor-expressing tissues in mice and humans.

The norepinephrine transporter inhibitor reboxetine reduces stimulant effects of MDMA ("ecstasy") in humans

This study assessed the pharmacodynamic and pharmacokinetic effects of the interaction between the selective norepinephrine (NE) transporter inhibitor reboxetine and 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") in 16 healthy subjects. The study used a double-blind, placebo-controlled crossover design. Reboxetine reduced the effects of MDMA including elevations in plasma levels of NE, increases in blood pressure and heart rate, subjective drug high, stimulation, and emotional excitation. These effects were evident despite an increase in the concentrations of MDMA and its active metabolite 3,4-methylenedioxyamphetamine (MDA) in plasma. The results demonstrate that transporter-mediated NE release has a critical role in the cardiovascular and stimulant-like effects of MDMA in humans.

Interhemispheric connections shape subjective experience of bistable motion

The right and left visual hemifields are represented in different cerebral hemispheres and are bound together by connections through the corpus callosum. Much has been learned on the functions of these connections from split-brain patients [1-4], but little is known about their contribution to conscious visual perception in healthy humans. We used diffusion tensor imaging and functional magnetic resonance imaging to investigate which callosal connections contribute to the subjective experience of a visual motion stimulus that requires interhemispheric integration. The "motion quartet" is an ambiguous version of apparent motion that leads to perceptions of either horizontal or vertical motion [5]. Interestingly, observers are more likely to perceive vertical than horizontal motion when the stimulus is presented centrally in the visual field [6]. This asymmetry has been attributed to the fact that, with central fixation, perception of horizontal motion requires integration across hemispheres whereas perception of vertical motion requires only intrahemispheric processing [7]. We are able to show that the microstructure of individually tracked callosal segments connecting motion-sensitive areas of the human MT/V5 complex (hMT/V5+; [8]) can predict the conscious perception of observers. Neither connections between primary visual cortex (V1) nor other surrounding callosal regions exhibit a similar relationship.