Synchronized dynamics of cortical neurons with time-delay feedback

The dynamics of three mutually coupled cortical neurons with time delays in the coupling are explored numerically and analytically. The neurons are coupled in a line, with the middle neuron sending a somewhat stronger projection to the outer neurons than the feedback it receives, to model for instance the relay of a signal from primary to higher cortical areas. For a given coupling architecture, the delays introduce correlations in the time series at the time-scale of the delay. It was found that the middle neuron leads the outer ones by the delay time, while the outer neurons are synchronized with zero lag times. Synchronization is found to be highly dependent on the synaptic time constant, with faster synapses increasing both the degree of synchronization and the firing rate. Analysis shows that presynaptic input during the interspike interval stabilizes the synchronous state, even for arbitrarily weak coupling, and independent of the initial phase. The finding may be of significance to synchronization of large groups of cells in the cortex that are spatially distanced from each other.Comment: 21 pages, 11 figure

Self-organization in the olfactory system: one shot odor recognition in insects

We show in a model of spiking neurons that synaptic plasticity in the mushroom bodies in combination with the general fan-in, fan-out properties of the early processing layers of the olfactory system might be sufficient to account for its efficient recognition of odors. For a large variety of initial conditions the model system consistently finds a working solution without any fine-tuning, and is, therefore, inherently robust. We demonstrate that gain control through the known feedforward inhibition of lateral horn interneurons increases the capacity of the system but is not essential for its general function. We also predict an upper limit for the number of odor classes Drosophila can discriminate based on the number and connectivity of its olfactory neurons

Information transmission in oscillatory neural activity

Periodic neural activity not locked to the stimulus or to motor responses is usually ignored. Here, we present new tools for modeling and quantifying the information transmission based on periodic neural activity that occurs with quasi-random phase relative to the stimulus. We propose a model to reproduce characteristic features of oscillatory spike trains, such as histograms of inter-spike intervals and phase locking of spikes to an oscillatory influence. The proposed model is based on an inhomogeneous Gamma process governed by a density function that is a product of the usual stimulus-dependent rate and a quasi-periodic function. Further, we present an analysis method generalizing the direct method (Rieke et al, 1999; Brenner et al, 2000) to assess the information content in such data. We demonstrate these tools on recordings from relay cells in the lateral geniculate nucleus of the cat.Comment: 18 pages, 8 figures, to appear in Biological Cybernetic

A phase I dose escalation study of BIBW 2992, an irreversible dual inhibitor of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) tyrosine kinase in a 2-week on, 2-week off schedule in patients with advanced solid tumours

To assess tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and clinical activity of the dual epidermal growth factor receptor (EGFR) 1 and 2 (HER2) tyrosine kinase inhibitor BIBW 2992. An escalating schedule of once-daily (OD) BIBW 2992 for 14 days followed by 14 days off medication was explored. Thirty-eight patients were enrolled. Dose levels were 10, 20, 30, 45, 70, 85, and 100 mg. At 100 mg dose-limiting toxicity (DLT) (common toxicity criteria grade 3 skin rash and grade 3 diarrhoea despite treatment with loperamide) occurred in two patients. In the next-lower dose of 70 mg, DLT (grade 3 fatigue and ALAT elevation) occurred in one of six patients. An intermediate dose level of 85 mg was studied. Here DLT occurred in two patients (grade 3 diarrhoea despite treatment and grade 2 diarrhoea lasting more than 7 days despite treatment). An additional 12 patients were treated at 70 mg. BIBW 2992 PK after single and multiple doses revealed moderately fast absorption, and no deviation from dose proportionality. Pharmacodynamics analysis in skin biopsies did not show significant changes in EGFR-associated biomarkers. However, a significant inhibitory effect on the proliferation index of epidermal keratinocytes was observed. No partial or complete responses were observed, stable disease lasting more than four cycles was seen in seven patients. The recommended dose for studies with BIBW 2992 for 14 days followed by 14 days off medication is 70 mg OD

Gain control network conditions in early sensory coding

Gain control is essential for the proper function of any sensory system. However, the precise mechanisms for achieving effective gain control in the brain are unknown. Based on our understanding of the existence and strength of connections in the insect olfactory system, we analyze the conditions that lead to controlled gain in a randomly connected network of excitatory and inhibitory neurons. We consider two scenarios for the variation of input into the system. In the first case, the intensity of the sensory input controls the input currents to a fixed proportion of neurons of the excitatory and inhibitory populations. In the second case, increasing intensity of the sensory stimulus will both, recruit an increasing number of neurons that receive input and change the input current that they receive. Using a mean field approximation for the network activity we derive relationships between the parameters of the network that ensure that the overall level of activity of the excitatory population remains unchanged for increasing intensity of the external stimulation. We find that, first, the main parameters that regulate network gain are the probabilities of connections from the inhibitory population to the excitatory population and of the connections within the inhibitory population. Second, we show that strict gain control is not achievable in a random network in the second case, when the input recruits an increasing number of neurons. Finally, we confirm that the gain control conditions derived from the mean field approximation are valid in simulations of firing rate models and Hodgkin-Huxley conductance based models

Stimulus-dependent maximum entropy models of neural population codes

Neural populations encode information about their stimulus in a collective fashion, by joint activity patterns of spiking and silence. A full account of this mapping from stimulus to neural activity is given by the conditional probability distribution over neural codewords given the sensory input. To be able to infer a model for this distribution from large-scale neural recordings, we introduce a stimulus-dependent maximum entropy (SDME) model---a minimal extension of the canonical linear-nonlinear model of a single neuron, to a pairwise-coupled neural population. The model is able to capture the single-cell response properties as well as the correlations in neural spiking due to shared stimulus and due to effective neuron-to-neuron connections. Here we show that in a population of 100 retinal ganglion cells in the salamander retina responding to temporal white-noise stimuli, dependencies between cells play an important encoding role. As a result, the SDME model gives a more accurate account of single cell responses and in particular outperforms uncoupled models in reproducing the distributions of codewords emitted in response to a stimulus. We show how the SDME model, in conjunction with static maximum entropy models of population vocabulary, can be used to estimate information-theoretic quantities like surprise and information transmission in a neural population.Comment: 11 pages, 7 figure

Communication and information-giving in high-risk breast cancer consultations: influence on patient outcomes

This longitudinal study aimed to document (i) the information-giving and patient-communication styles of clinical geneticists and genetic counsellors (consultants) in familial breast cancer clinics and (ii) assess the effect of these styles on women`s knowledge, whether their expectations were met, satisfaction, risk perception and psychological status. A total of 158 women from high-risk breast cancer families completed self-report questionnaires at 2 weeks preconsultation and 4 weeks postconsultation. The consultations were audiotaped, transcribed and coded. Multivariate logistic regressions showed that discussing prophylactic mastectomy (P = 0.00) and oophorectomy (P = 0.01) led to women having significantly more expectations met; discussing genetic testing significantly decreased anxiety (P = 0.03) and facilitating understanding significantly decreased depression (P = 0,05). Receiving a summary letter of the consultation significantly lowered anxiety (P = 0.01) and significantly increased the accuracy of perceived risk (P = 0.02). Women whose consultant used more supportive communications experienced significantly more anxiety about breast cancer at the 4 weeks follow-up (P=0.00), These women were not significantly more anxious before genetic counselling. In conclusion, this study found that consultants vary in the amount of information they give and the way they communicate; and this variation can result in better or worse psychosocial outcomes. Greater use of supportive and counselling communications appeared to increase anxiety about breast cancer. Identifying methods to assist consultants to address emotional issues effectively may be helpful

A Common Polymorphism in the Promoter Region of the TNFSF4 Gene Is Associated with Lower Allele-Specific Expression and Risk of Myocardial Infarction

BACKGROUND: The TNFSF4/TNFRSF4 system, along with several other receptor-ligand pairs, is involved in the recruitment and activation of T-cells and is therefore tentatively implicated in atherosclerosis and acute coronary syndromes. We have previously shown that genetic variants in TNFSF4 are associated with myocardial infarction (MI) in women. This prompted functional studies of TNFSF4 expression. METHODS AND RESULTS: Based on a screening of the TNFSF4 genomic region, a promoter polymorphism (rs45454293) and a haplotype were identified, conceivably involved in gene regulation. The rs45454293T-allele, in agreement with the linked rs3850641G-allele, proved to be associated with increased risk of MI in women. Haplotype-specific chromatin immunoprecipitation of activated polymerase II, as a measure of transcriptional activity in vivo, suggested that the haplotype including the rs45454293 and rs3850641 polymorphisms is functionally important, the rs45454293T- and rs3850641G-alleles being associated with lower transcriptional activity in cells heterozygous for both polymorphisms. The functional role of rs45454293 on transcriptional levels of TNFSF4 was clarified by luciferase reporter assays, where the rs45454293T-allele decreased gene expression when compared with the rs45454293C-allele, while the rs3850641 SNP did not have any effect on TNFSF4 promoter activity. Electromobility shift assay showed that the rs45454293 polymorphism, but not rs3850641, affects the binding of nuclear factors, thus suggesting that the lower transcriptional activity is attributed to binding of one or more transcriptional repressor(s) to the T-allele. CONCLUSIONS: Our data indicate that the TNFSF4 rs45454293T-allele is associated with lower TNFSF4 expression and increased risk of MI