Shifted Coupling of EEG Driving Frequencies and fMRI Resting State Networks in Schizophrenia Spectrum Disorders

INTRODUCTION: The cerebral resting state in schizophrenia is altered, as has been demonstrated separately by electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) resting state networks (RSNs). Previous simultaneous EEG/fMRI findings in healthy controls suggest that a consistent spatiotemporal coupling between neural oscillations (EEG frequency correlates) and RSN activity is necessary to organize cognitive processes optimally. We hypothesized that this coupling is disorganized in schizophrenia and related psychotic disorders, in particular regarding higher cognitive RSNs such as the default-mode (DMN) and left-working-memory network (LWMN). METHODS: Resting state was investigated in eleven patients with a schizophrenia spectrum disorder (n = 11) and matched healthy controls (n = 11) using simultaneous EEG/fMRI. The temporal association of each RSN to topographic spectral changes in the EEG was assessed by creating Covariance Maps. Group differences within, and group similarities across frequencies were estimated for the Covariance Maps. RESULTS: The coupling of EEG frequency bands to the DMN and the LWMN respectively, displayed significant similarities that were shifted towards lower EEG frequencies in patients compared to healthy controls. CONCLUSIONS: By combining EEG and fMRI, each measuring different properties of the same pathophysiology, an aberrant relationship between EEG frequencies and altered RSNs was observed in patients. RSNs of patients were related to lower EEG frequencies, indicating functional alterations of the spatiotemporal coupling. SIGNIFICANCE: The finding of a deviant and shifted coupling between RSNs and related EEG frequencies in patients with a schizophrenia spectrum disorder is significant, as it might indicate how failures in the processing of internal and external stimuli, as commonly seen during this symptomatology (i.e. thought disorders, hallucinations), arise.

'Alternate-goal bias' in antisaccades and the influence of expectation

Saccadic performance depends on the requirements of the current trial, but also may be influenced by other trials in the same experiment. This effect of trial context has been investigated most for saccadic error rate and reaction time but seldom for the positional accuracy of saccadic landing points. We investigated whether the direction of saccades towards one goal is affected by the location of a second goal used in other trials in the same experimental block. In our first experiment, landing points ('endpoints') of antisaccades but not prosaccades were shifted towards the location of the alternate goal. This spatial bias decreased with increasing angular separation between the current and alternative goals. In a second experiment, we explored whether expectancy about the goal location was responsible for the biasing of the saccadic endpoint. For this, we used a condition where the saccadic goal randomly changed from one trial to the next between locations on, above or below the horizontal meridian. We modulated the prior probability of the alternate-goal location by showing cues prior to stimulus onset. The results showed that expectation about the possible positions of the saccadic goal is sufficient to bias saccadic endpoints and can account for at least part of this phenomenon of 'alternate-goal bias'.

Pharmacogenetics in palliative care

Response to analgesics, anticancer pharmacotherapy and pharmacotherapy of other cancer related symptoms vary broadly between individuals. Age, disease, comorbidities, concomitant medication, organ function and patients' compliance may partly explain the differences. However, the focus of ongoing research has shifted towards genomic variants of phase I and II drug metabolizing enzymes with one important goal being an individual dose adjustment according to a patient's genotype. Polymorphisms of the cytochrome P 450 2D6 influence the metabolism of many drugs including the analgesics codeine, tramadol, hydrocodone and oxycodone, as well as the metabolism of tricyclic antidepressants and the anticancer drug tamoxifen. Other candidate genes such as (opioid)-receptors, transporters and other molecules important for pharmacotherapy in pain management are discussed. Although pharmacogenetics as a diagnostic tool has the potential to improve patient therapy, study results are often equivocal and limited by small sample sizes and often by their retrospective design. Well designed studies are needed to demonstrate superiority of pharmoacogenetics to conventional dosing regimes.

Anomalous global effects induced by 'blind' distractors in visual hemifield defects

Previous research has revealed that a stimulus presented in the blind visual field of participants with visual hemifield defects can evoke oculomotor competition, in the absence of awareness. Here we studied three cases to determine whether a distractor in a blind hemifield would be capable of inducing a global effect, a shift of saccade endpoint when target and distractor are close to each other, in participants with lesions of the optic radiations or striate cortex. We found that blind field distractors significantly shifted saccadic endpoints in two of three participants with lesions of either the striate cortex or distal optic radiations. The direction of the effect was paradoxical, however, in that saccadic endpoints shifted away from blind field distractors, whereas endpoints shifted towards distractors in the visible hemifields, which is the normal global effect. These results provide further evidence that elements presented in the blind visual field can generate modulatory interactions in the oculomotor system, which may differ from interactions in normal vision.

Counterbalancing effects of competition for resources and facilitation against grazing in alpine snowbed communities

Alpine snowbeds are habitats where the major limiting factors for plant growth are herbivory and a small time window for growth due to late snowmelt. Despite these limitations, snowbed vegetation usually forms a dense carpet of palatable plants due to favourable abiotic conditions for plant growth within the short growing season. These environmental characteristics make snowbeds particularly interesting to study the interplay of facilitation and competition. We hypothesised an interplay between resource competition and facilitation against herbivory. Further, we investigated whether these predicted neighbour effects were species-specific and/or dependent on ontogeny, and whether the balance of positive and negative plant–plant interactions shifted along a snowmelt gradient. We determined the neighbour effects by means of neighbour removal experiments along the snowmelt gradient, and linear mixed model analyses. The results showed that the effects of neighbour removal were weak but generally consistent among species and snowmelt dates, and depended on whether biomass production or survival was considered. Higher total biomass and increased fruiting in removal plots indicated that plants competed for nutrients, water, and light, thereby supporting the hypothesis of prevailing competition for resources in snowbeds. However, the presence of neighbours reduced herbivory and thereby also facilitated survival. For plant growth the facilitative effects against herbivores in snowbeds counterbalanced competition for resources, leading to a weak negative net effect. Overall the neighbour effects were not species-specific and did not change with snowmelt date. Our finding of counterbalancing effects of competition and facilitation within a plant community is of special theoretical value for species distribution models and can explain the success of models that give primary importance to abiotic factors and tend to overlook interrelations between biotic and abiotic effects on plants.

Chapter I: Definitions, epidemiology, clinical presentation and prognosis

The concept of chronic critical limb ischaemia (CLI) emerged late in the history of peripheral arterial occlusive disease (PAOD). The historical background and changing definitions of CLI over the last decades are important to know in order to understand why epidemiologic data are so difficult to compare between articles and over time. The prevalence of CLI is probably very high and largely underestimated, and significant differences exist between population studies and clinical series. The extremely high costs associated with management of these patients make CLI a real public health issue for the future. In the era of emerging vascular surgery in the 1950s, the initial classification of PAOD by Fontaine, with stages III and IV corresponding to CLI, was based only on clinical symptoms. Later, with increasing access to non-invasive haemodynamic measurements (ankle pressure, toe pressure), the need to prove a causal relationship between PAOD and clinical findings suggestive of CLI became a real concern, and the Rutherford classification published in 1986 included objective haemodynamic criteria. The first consensus document on CLI was published in 1991 and included clinical criteria associated with ankle and toe pressure and transcutaneous oxygen pressure (TcPO(2)) cut-off levels <50 mmHg, <30 mmHg and <10 mmHg respectively). This rigorous definition reflects an arterial insufficiency that is so severe as to cause microcirculatory changes and compromise tissue integrity, with a high rate of major amputation and mortality. The TASC I consensus document published in 2000 used less severe pressure cut-offs (≤ 50-70 mmHg, ≤ 30-50 mmHg and ≤ 30-50 mmHg respectively). The thresholds for toe pressure and especially TcPO(2) (which will be also included in TASC II consensus document) are however just below the lower limit of normality. It is therefore easy to infer that patients qualifying as CLI based on TASC criteria can suffer from far less severe disease than those qualifying as CLI in the initial 1991 consensus document. Furthermore, inclusion criteria of many recent interventional studies have even shifted further from the efforts of definition standardisation with objective criteria, by including patients as CLI based merely on Fontaine classification (stage III and IV) without haemodynamic criteria. The differences in the natural history of patients with CLI, including prognosis of the limb and the patient, are thus difficult to compare between studies in this context. Overall, CLI as defined by clinical and haemodynamic criteria remains a severe condition with poor prognosis, high medical costs and a major impact in terms of public health and patients' loss of functional capacity. The major progresses in best medical therapy of arterial disease and revascularisation procedures will certainly improve the outcome of CLI patients. In the future, an effort to apply a standardised definition with clinical and objective haemodynamic criteria will be needed to better demonstrate and compare the advances in management of these patients.

RecNcMIC3-1-R is a microneme- and rhoptry-based chimeric antigen that protects against acute neosporosis and limits cerebral parasite load in the mouse model for Neospora caninum infection

In order to achieve host cell entry, the apicomplexan parasite Neospora caninum relies on the contents of distinct organelles, named micronemes, rhoptries and dense granules, which are secreted at defined timepoints during and after host cell entry. It was shown previously that a vaccine composed of a mixture of three recombinant antigens, corresponding to the two microneme antigens NcMIC1 and NcMIC3 and the rhoptry protein NcROP2, prevented disease and limited cerebral infection and transplacental transmission in mice. In this study, we selected predicted immunogenic domains of each of these proteins and created four different chimeric antigens, with the respective domains incorporated into these chimers in different orders. Following vaccination, mice were challenged intraperitoneally with 2 × 10(6)N. caninum tachzyoites and were then carefully monitored for clinical symptoms during 4 weeks post-infection. Of the four chimeric antigens, only recNcMIC3-1-R provided complete protection against disease with 100% survivors, compared to 40-80% of survivors in the other groups. Serology did not show any clear differences in total IgG, IgG1 and IgG2a levels between the different treatment groups. Vaccination with all four chimeric variants generated an IL-4 biased cytokine expression, which then shifted to an IFN-γ-dominated response following experimental infection. Sera of recNcMIC3-1-R vaccinated mice reacted with each individual recombinant antigen, as well as with three distinct bands in Neospora extracts with similar Mr as NcMIC1, NcMIC3 and NcROP2, and exhibited distinct apical labeling in tachyzoites. These results suggest that recNcMIC3-1-R is an interesting chimeric vaccine candidate and should be followed up in subsequent studies in a fetal infection model.

Early last glacial maximum in the southern Central Andes reveals northward shift of the westerlies at similar to 39 ka

The latitudinal position of the southern westerlies has been suggested to be a key parameter for the climate on Earth. According to the general notion, the southern westerlies were shifted equatorward during the global Last Glacial Maximum (LGM: ~24–18 ka), resulting in reduced deep ocean ventilation, accumulation of old dissolved carbon, and low atmospheric CO2 concentrations. In order to test this notion, we applied surface exposure dating on moraines in the southern Central Andes, where glacial mass balances are particularly sensitive to changes in precipitation, i.e. to the latitudinal position of the westerlies. Our results provide robust evidence that the maximum glaciation occurred already at ~39 ka, significantly predating the global LGM. This questions the role of the westerlies for atmospheric CO2, and it highlights our limited understanding of the forcings of atmospheric circulation.

Conformationally Controlled Electron Delocalization in n-Type Rods: Synthesis, Structure, and Optical, Electrochemical, and Spectroelectrochemical Properties of Dicyanocyclophanes

A series of dicyanobiphenyl-cyclophanes 1-6 with various pi-backbone conformations and characteristic n-type semiconductor properties is presented. Their synthesis, optical, structural, electrochemical, spectroelectrochemical, and packing properties are investigated. The X-ray crystal structures of all n-type rods allow the systematic correlation of structural features with physical properties. In addition, the results are supported by quantum mechanical calculations based on density functional theory. A two-step reduction process is observed for all n-type rods, in which the first step is reversible. The potential gap between the reduction processes depends linearly on the cos(2) value of the torsion angle phi between the pi-systems. Similarly, optical absorption spectroscopy shows that the vertical excitation energy of the conjugation band correlates with the cos(2) value of the torsion angle phi. These correlations demonstrate that the fixed intramolecular torsion angle phi is the dominant factor determining the extent of electron delocalization in these model compounds, and that the angle phi measured in the solid-state structure is a good proxy for the molecular conformation in solution. Spectroelectrochemical investigations demonstrate that conformational rigidity is maintained even in the radical anion form. In particular, the absorption bands corresponding to the SOMO-LUMO+i transitions are shifted bathochromically, whereas the absorption bands corresponding to the HOMO-SOMO transition are shifted hypsochromically with increasing torsion angle phi.

N-H center dot center dot center dot pi hydrogen-bonding and large-amplitude tipping vibrations in jet-cooled pyrrole-benzene

The N-H center dot center dot center dot pi hydrogen bond is an important intermolecular interaction in many biological systems. We have investigated the infrared (IR) and ultraviolet (UV) spectra of the supersonic-jet cooled complex of pyrrole with benzene and benzene-d(6) (Pyr center dot Bz, Pyr center dot Bz-d(6)). DFT-D density functional, SCS-MP2 and SCS-CC2 calculations predict a T-shaped and (almost) C(s) symmetric structure with an N-H center dot center dot center dot pi hydrogen bond to the benzene ring. The pyrrole is tipped by omega(S(0)) = +/- 13 degrees relative to the surface normal of Bz. The N center dot center dot center dot ring distance is 3.13 angstrom. In the S(1) excited state, SCS-CC2 calculations predict an increased tipping angle omega(S(1)) = +/- 21 degrees. The IR depletion spectra support the T-shaped geometry: The NH stretch is redshifted by -59 cm(-1), relative to the "free" NH stretch of pyrrole at 3531 cm(-1), indicating a moderately strong N-H center dot center dot center dot pi interaction. The interaction is weaker than in the (Pyr)(2) dimer, where the NH donor shift is -87 cm(-1) [Dauster et al., Phys. Chem. Chem. Phys., 2008, 10, 2827]. The IR C-H stretch frequencies and intensities of the Bz subunit are very similar to those of the acceptor in the (Bz)(2) dimer, confirming that Bz acts as the acceptor. While the S(1) <- S(0) electronic origin of Bz is forbidden and is not observable in the gas-phase, the UV spectrum of Pyr center dot Bz in the same region exhibits a weak 0(0)(0) band that is red-shifted by 58 cm(-1) relative to that of Bz (38 086 cm(-1)). The origin appears due to symmetry-breaking of the p-electron system of Bz by the asymmetric pyrrole NH center dot center dot center dot pi hydrogen bond. This contrasts with (Bz)(2), which does not exhibit a 0(0)(0) band. The Bz moiety in Pyr center dot Bz exhibits a 6a(0)(1) band at 0(0)(0) + 518 cm(-1) that is about 20x more intense than the origin band. The symmetry breaking by the NH center dot center dot center dot pi hydrogen bond splits the degeneracy of the v(6)(e(2g)) vibration, giving rise to 6a' and 6b' sub-bands that are spaced by similar to 6 cm(-1). Both the 0(0)(0) and 6(0)(1) bands of Pyr center dot Bz carry a progression in the low-frequency (10 cm(-1)) excited-state tipping vibration omega', in agreement with the change of the omega tipping angle predicted by SCS-MP2 and SCS-CC2 calculations.

Exploratory studies on coordination chemistry of a redox-active bridging ligand: synthesis, properties and solid state structures of the complexes

The explorative coordination chemistry of the bridging ligand TTF-PPB is presented. Its strong binding ability to Co(II) and then to Ni(II) or Cu(II) in the presence of hexafluoroacetylacetonate (hfac(-)), forming new mono-and dinuclear complexes 1-3, is described. X-ray crystallographic studies have been conducted in the case of the free ligand TTF-PPB as well as its complexes [Co(TTF-PPB)(hfac)(2)] (1) and [Co(hfac)(2)(mu-TTF-PPB)Ni(hfac)(2)] (2). Each metal ion is bonded to two bidentate hfac-anions through their oxygen atoms and two nitrogen atoms of the PPB moiety with a distorted octahedral coordination geometry. Specifically, nitrogen donor atoms of TTF-PPB adopt a cis-coordination but not in the equatorial plane, which is quite rare. Electronic absorption, photoinduced intraligand charge transfer ((1)ILCT), and electrochemical behaviour of 1-3 have been investigated. UV-Vis spectroscopy shows very strong bands in the UV region consistent with ligand centred pi-pi* transitions and an intense broad band in the visible region corresponding to a spin-allowed pi-pi* (1)ILCT transition. Upon coordination, the (1)ILCT band is bathochromically shifted by 3100, 6100 and 5900 cm(-1) on going from 1 to 3. The electrochemical studies reveal that all of them undergo two reversible oxidation and one reversible reduction processes, ascribed to the successive oxidations of the TTF moiety and the reduction of the PPB unit, respectively.

Observations of middle atmospheric H2O and O3 during the 2010 major sudden stratospheric warming by a network of microwave radiometers

In this study, we present middle atmospheric water vapor (H2O) and ozone (O3) measurements obtained by ground-based microwave radiometers at three European locations in Bern (47° N), Onsala (57° N) and Sodankylä (67° N) during Northern winter 2009/2010. In January 2010, a major sudden stratospheric warming (SSW) occurred in the Northern Hemisphere whose signatures are evident in the ground-based observations of H2O and O3. The observed anomalies in H2O and O3 are mostly explained by the relative location of the polar vortex with respect to the measurement locations. The SSW started on 26 January 2010 and was most pronounced by the end of January. The zonal mean temperature in the middle stratosphere (10 hPa) increased by approximately 25 Kelvin within a few days. The stratospheric vortex weakened during the SSW and shifted towards Europe. In the mesosphere, the vortex broke down, which lead to large scale mixing of polar and midlatitudinal air. After the warming, the polar vortex in the stratosphere split into two weaker vortices and in the mesosphere, a new, pole-centered vortex formed with maximum wind speed of 70 m s−1 at approximately 40° N. The shift of the stratospheric vortex towards Europe was observed in Bern as an increase in stratospheric H2O and a decrease in O3. The breakdown of the mesospheric vortex during the SSW was observed at Onsala and Sodankylä as a sudden increase in mesospheric H2O. The following large-scale descent inside the newly formed mesospheric vortex was well captured by the H2O observations in Sodankylä. In order to combine the H2O observations from the three different locations, we applied the trajectory mapping technique on our H2O observations to derive synoptic scale maps of the H2O distribution. Based on our observations and the 3-D wind field, this method allows determining the approximate development of the stratospheric and mesospheric polar vortex and demonstrates the potential of a network of ground-based instruments.

Incidence of spinal compressive lesions in chondrodystrophic dogs with abnormal recovery after hemilaminectomy for treatment of thoracolumbar disc disease: a prospective magnetic resonance imaging study

OBJECTIVE: To investigate causes of the lack of clinical improvement after thoracolumbar disc surgery. STUDY DESIGN: Case-control magnetic resonance imaging (MRI) study. ANIMALS: Chondrodystrophic dogs with acute thoracolumbar disc disease treated by hemilaminectomy: 10 that had no short-term clinical improvement and 12 with "normal" clinical improvement. METHODS: Dogs that had surgery for treatment of intervertebral disc extrusion (2003-2008) where thoracolumbar disc disease was confirmed by MRI were evaluated to identify dogs that had lack of clinical improvement after surgery. Ten dogs with delayed recovery or clinical deterioration were reexamined with MRI and compared with 12 dogs with normal recovery and MRI reexamination after 6 weeks (control group). RESULTS: Of 173 dogs, 10 (5.8%) had clinical deterioration within 1-10 days after surgery. In 8 dogs, residual spinal cord compression was identified on MRI. Bleeding was present in 1 dog. In 3 dogs, the cause was an incorrect approach and insufficient disc material removal. In 3 dogs, recurrence occurred at the surgical site. In 1 dog, the centrally located extruded material was shifted to the contralateral side during surgery. These 8 dogs had repeat surgery and recovery was uneventful. In 2 dogs, deterioration could not be associated with a compressive disc lesion. Hemorrhagic myelomalacia was confirmed by pathologic examination in 1 dog. The other dog recovered after 6 months of conservative management. CONCLUSION: Delayed postsurgical recovery or deterioration is commonly associated with newly developed and/or remaining compressive disc lesion. CLINICAL RELEVANCE: We recommend early MRI reexamination to assess the postsurgical spinal canal and cord, and to plan further therapeutic measures in chondrodystrophic dogs with delayed recovery after decompressive hemilaminectomy for thoracolumbar disc disease.

The time window for generation of dendritic spikes by coincidence of action potentials and EPSPs is layer specific in somatosensory cortex

The precise timing of events in the brain has consequences for intracellular processes, synaptic plasticity, integration and network behaviour. Pyramidal neurons, the most widespread excitatory neuron of the neocortex have multiple spike initiation zones, which interact via dendritic and somatic spikes actively propagating in all directions within the dendritic tree. For these neurons, therefore, both the location and timing of synaptic inputs are critical. The time window for which the backpropagating action potential can influence dendritic spike generation has been extensively studied in layer 5 neocortical pyramidal neurons of rat somatosensory cortex. Here, we re-examine this coincidence detection window for pyramidal cell types across the rat somatosensory cortex in layers 2/3, 5 and 6. We find that the time-window for optimal interaction is widest and shifted in layer 5 pyramidal neurons relative to cells in layers 6 and 2/3. Inputs arriving at the same time and locations will therefore differentially affect spike-timing dependent processes in the different classes of pyramidal neurons.

Xenomelia: a social neuroscience view of altered bodily self-consciousness

Xenomelia, the "foreign limb syndrome," is characterized by the non-acceptance of one or more of one's own extremities and the resulting desire for elective limb amputation or paralysis. Formerly labeled "body integrity identity disorder" (BIID), the condition was originally considered a psychological or psychiatric disorder, but a brain-centered Zeitgeist and a rapidly growing interest in the neural underpinnings of bodily self-consciousness has shifted the focus toward dysfunctional central nervous system circuits. The present article outlays both mind-based and brain-based views highlighting their shortcomings. We propose that full insight into what should be conceived a "xenomelia spectrum disorder" will require interpretation of individual symptomatology in a social context. A proper social neuroscience of xenomelia respects the functional neuroanatomy of corporeal awareness, but also acknowledges the brain's plasticity in response to an individual's history, which is lived against a cultural background. This integrated view of xenomelia will promote the subfield of consciousness research concerned with the unity of body and self.