New insights for predicting surgery outcome in patients with temporal lobe epilepsy. A systematic review.

Resective surgery is the treatment of choice for one-third of adult patients with focal, drug-resistant epilepsy. This procedure is associated with substantial clinical and cognitive risks. In clinical practice, there is no validated model for epilepsy surgery outcome prediction (ESOP). Meta-analyses on ESOP studies assessing prognostic factors report discrepancies in terms of study design. Our review aims to systematically investigate methodological and analytical aspects of studies predicting clinical and cognitive outcomes after temporal lobe epilepsy surgery. A systematic review of ESOP studies published between 2000 and 2022 from three databases (MEDLINE, Web of Science, and PsycINFO) was completed by following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. It yielded 4867 articles. Among them, 21 corresponded to our inclusion criteria and were therefore retained in the final review. The risk of bias was assessed using A Tool to Assess Risk of Bias and Applicability of Prediction Model Studies (PROBAST). Data extracted from the 21 studies were analyzed using narrative synthesis and descriptive statistics. Our findings show an increase in the use of multimodal datasets and machine learning analyses in recent ESOP studies, although regression remained the most frequently used approach. We also identified a more frequent use of network notions in recent ESOP studies. Nevertheless, several methodological issues were noted, such as small sample sizes, lack of information on the follow-up period, variability in seizure outcome, and the definition of neuropsychological postoperative change. Of 21 studies, only one provided a clinical tool to anticipate the cognitive outcome after epilepsy surgery. We conclude that methodological issues should be overcome before we move towards more complete models to better predict clinical and cognitive outcomes after epilepsy surgery. Recommendations for future studies to harness the possibilities of multimodal datasets and data fusion, are provided. A stronger bridge between fundamental and clinical research may result in developing accessible clinical tools.

Unraveling the functional attributes of the language connectome: crucial subnetworks, flexibility and variability.

Language processing is a highly integrative function, intertwining linguistic operations (processing the language code intentionally used for communication) and extra-linguistic processes (e.g., attention monitoring, predictive inference, long-term memory). This synergetic cognitive architecture requires a distributed and specialized neural substrate. Brain systems have mainly been examined at rest. However, task-related functional connectivity provides additional and valuable information about how information is processed when various cognitive states are involved. We gathered thirteen language fMRI tasks in a unique database of one hundred and fifty neurotypical adults (InLang [Interactive networks of Language] database), providing the opportunity to assess language features across a wide range of linguistic processes. Using this database, we applied network theory as a computational tool to model the task-related functional connectome of language (LANG atlas). The organization of this data-driven neurocognitive atlas of language was examined at multiple levels, uncovering its major components (or crucial subnetworks), and its anatomical and functional correlates. In addition, we estimated its reconfiguration as a function of linguistic demand (flexibility) or several factors such as age or gender (variability). We observed that several discrete networks could be specifically shaped to promote key functional features of language: coding-decoding (Net1), control-executive (Net2), abstract-knowledge (Net3), and sensorimotor (Net4) functions. The architecture of these systems and the functional connectivity of the pivotal brain regions varied according to the nature of the linguistic process, gender, or age. By accounting for the multifaceted nature of language and modulating factors, this study can contribute to enriching and refining existing neurocognitive models of language. The LANG atlas can also be considered a reference for comparative or clinical studies involving various patients and conditions.

Leveraging manifold learning techniques to explore white matter anomalies: An application of the TractLearn pipeline in epilepsy.

An accurate description of brain white matter anatomy in vivo remains a challenge. However, technical progress allows us to analyze structural variations in an increasingly sophisticated way. Current methods of processing diffusion MRI data now make it possible to correct some limiting biases. In addition, the development of statistical learning algorithms offers the opportunity to analyze the data from a new perspective. We applied newly developed tractography models to extract quantitative white matter parameters in a group of patients with chronic temporal lobe epilepsy. Furthermore, we implemented a statistical learning workflow optimized for the MRI diffusion data - the TractLearn pipeline - to model inter-individual variability and predict structural changes in patients. Finally, we interpreted white matter abnormalities in the context of several other parameters reflecting clinical status, as well as neuronal and cognitive functioning for these patients. Overall, we show the relevance of such a diffusion data processing pipeline for the evaluation of clinical populations. The "global to fine scale" funnel statistical approach proposed in this study also contributes to the understanding of neuroplasticity mechanisms involved in refractory epilepsy, thus enriching previous findings.

A machine learning approach to explore cognitive signatures in patients with temporo-mesial epilepsy.

We aimed to identify cognitive signatures (phenotypes) of patients suffering from mesial temporal lobe epilepsy (mTLE) with respect to their epilepsy lateralization (left or right), through the use of SVM (Support Vector Machine) and XGBoost (eXtreme Gradient Boosting) machine learning (ML) algorithms. Specifically, we explored the ability of the two algorithms to identify the most significant scores (features, in ML terms) that segregate the left from the right mTLE patients. We had two versions of our dataset which consisted of neuropsychological test scores: a "reduced and working" version (n = 46 patients) without any missing data, and another one "original" (n = 57) with missing data but useful for testing the robustness of results obtained with the working dataset. The emphasis was placed on a precautionary machine learning (ML) approach for classification, with reproducible and generalizable results. The effects of several clinical medical variables were also studied. We obtained excellent predictive classification performances (>75%) of left and right mTLE with both versions of the dataset. The most segregating features were four language and memory tests, with a remarkable stability close to 100%. Thus, these cognitive tests appear to be highly relevant for neuropsychological assessment of patients. Moreover, clinical variables such as structural asymmetry between hippocampal gyri, the age of patients and the number of anti-epileptic drugs, influenced the cognitive phenotype. This exploratory study represents an in-depth analysis of cognitive scores and allows observing interesting interactions between language and memory performance. We discuss implications of these findings in terms of clinical and theoretical applications and perspectives in the field of neuropsychology.

A real-time marker of object-based attention in the human brain. A possible component of a "gate-keeping mechanism" performing late attentional selection in the Ventro-Lateral Prefrontal Cortex.

The decision to process an incoming stimulus attentively - and to trigger a follow-up cascade of high-level processes - is strategic for the human brain as it becomes transiently unavailable to subsequent stimulus processing. In this study, we set to identify brain networks that carry out such evaluations. We therefore assessed the time-course of neural responses with intracerebral EEG in human patients during an attentional reading task, contrasting to-be-attended vs. to-be-ignored items. We measured High-Frequency Activity [50-150 â€‹Hz] as a proxy of population-level spiking activity and we identified a crucial component of a Gate-Keeping Mechanism bilateral in the mid-Ventro-Lateral Prefrontal Cortex (VLPFC), at the interplay of the Ventral and Dorsal Attention Networks, that selectively reacts before domain specialized cortical regions that engage in full stimulus analysis according to task demands.

Aging modulates fronto-temporal cortical interactions during lexical production. A dynamic causal modeling study.

In this dynamic causal modeling (DCM) study, we evaluated the effect of age on the effective connectivity of a cerebral network involved in lexical production. Younger and older adults performed an object naming task during fMRI. The DCM was used to explore the interactions between four regions of interest: the occipital cortex, OC; the lateral temporal cortex, LTC; the medial temporal cortex, MTC; and the inferior frontal cortex, IFC. We mainly focused on the modulation of the fronto-temporal interaction, according to the hypothesis that aging requires strategies that modulate the access to the semantic knowledge, either through a neural reserve mechanism (increased MTC-LTC connectivity) or through a neural compensation mechanism (supplementary IFC-MTC connectivity). For younger adults, our results indicated a bi-directional interaction between the left IFC and LTC suggesting a typical activation related to lexico-semantic representations. For older adults, our results reveal the existence of bi-directional interaction between the IFC and MTC, but not between the IFC and LTC - which in turn suggests that older adults adapt a new strategy, via supplemental access to conceptual access and semantic retrieval processes. This neural compensation strategy would be facilitated by a top-down mechanism from the IFC to the MTC. We discuss our results in the context of the possible additional strategies used by older compared to younger adults, to retrieve and produce words.

Neural correlates of the healthiness evaluation processes of food labels.

OBJECTIVES: This fMRI study evaluated the cognitive mechanisms and the cerebral substrates when evaluating the healthiness of food products from nutritional information displayed either with a traffic light (TL) system, a colored nutritional label, or with a guideline daily amount (GDA) system, a numeric label. We postulated that TL label would recruit emotional processes and activation of subjacent cerebral regions (e.g. insula and amygdala). On the contrary, the nutritional information presented in a GDA label, would recruit, due to its numeric format and higher complexity, supplementary cognitive processes and activation of related brain regions (e.g. middle and superior frontal as well as parietal cortices). METHODS: We examined 50 healthy participants during an evaluation task on the healthiness of real food products from nutritional information only. Per total, 60 food products nutritional labels have been presented, with either colored (TL) or numeric (GDA) nutritional information and three levels of complexity of nutritional information. RESULTS: In line with our predictions, evaluations based on GDA recruited prefrontal and parietal regions reported for analytic processes. Contrary to our predictions, the same network has been recruited when evaluations were based on TL. Finally, we found significant correlation between response time and the superior parietal lobule in the GDA condition. DISCUSSION: Our results suggested that TL did not have an effect on the used strategy compared to GDA, based on calculation and arithmetic processes. Correlations between response time and brain activations suggested a significant involvement of the arithmetic mechanisms in the evaluation of food healthiness.

Machine learning-XGBoost analysis of language networks to classify patients with epilepsy.

Our goal was to apply a statistical approach to allow the identification of atypical language patterns and to differentiate patients with epilepsy from healthy subjects, based on their cerebral activity, as assessed by functional MRI (fMRI). Patients with focal epilepsy show reorganization or plasticity of brain networks involved in cognitive functions, inducing 'atypical' (compared to 'typical' in healthy people) brain profiles. Moreover, some of these patients suffer from drug-resistant epilepsy, and they undergo surgery to stop seizures. The neurosurgeon should only remove the zone generating seizures and must preserve cognitive functions to avoid deficits. To preserve functions, one should know how they are represented in the patient's brain, which is in general different from that of healthy subjects. For this purpose, in the pre-surgical stage, robust and efficient methods are required to identify atypical from typical representations. Given the frequent location of regions generating seizures in the vicinity of language networks, one important function to be considered is language. The risk of language impairment after surgery is determined pre-surgically by mapping language networks. In clinical settings, cognitive mapping is classically performed with fMRI. The fMRI analyses allowing the identification of atypical patterns of language networks in patients are not sufficiently robust and require additional statistic approaches. In this study, we report the use of a statistical nonlinear machine learning classification, the Extreme Gradient Boosting (XGBoost) algorithm, to identify atypical patterns and classify 55 participants as healthy subjects or patients with epilepsy. XGBoost analyses were based on neurophysiological features in five language regions (three frontal and two temporal) in both hemispheres and activated with fMRI for a phonological (PHONO) and a semantic (SEM) language task. These features were combined into 135 cognitively plausible subsets and further submitted to selection and binary classification. Classification performance was scored with the Area Under the receiver operating characteristic curve (AUC). Our results showed that the subset SEM_LH BA_47-21 (left fronto-temporal activation induced by the SEM task) provided the best discrimination between the two groups (AUC of 91 ± 5%). The results are discussed in the framework of the current debates of language reorganization in focal epilepsy.

Modulation of the inter-hemispheric processing of semantic information during normal aging. A divided visual field experiment.

We evaluated the effect of normal aging on the inter-hemispheric processing of semantic information by using the divided visual field (DVF) method, with words and pictures. Two main theoretical models have been considered, (a) the HAROLD model which posits that aging is associated with supplementary recruitment of the right hemisphere (RH) and decreased hemispheric specialization, and (b) the RH decline theory, which assumes that the RH becomes less efficient with aging, associated with increased LH specialization. Two groups of subjects were examined, a Young Group (YG) and an Old Group (OG), while participants performed a semantic categorization task (living vs. non-living) in words and pictures. The DVF was realized in two steps: (a) unilateral DVF presentation with stimuli presented separately in each visual field, left or right, allowing for their initial processing by only one hemisphere, right or left, respectively; (b) bilateral DVF presentation (BVF) with stimuli presented simultaneously in both visual fields, followed by their processing by both hemispheres. These two types of presentation permitted the evaluation of two main characteristics of the inter-hemispheric processing of information, the hemispheric specialization (HS) and the inter-hemispheric cooperation (IHC). Moreover, the BVF allowed determining the driver-hemisphere for processing information presented in BVF. Results obtained in OG indicated that: (a) semantic categorization was performed as accurately as YG, even if more slowly, (b) a non-semantic RH decline was observed, and (c) the LH controls the semantic processing during the BVF, suggesting an increased role of the LH in aging. However, despite the stronger involvement of the LH in OG, the RH is not completely devoid of semantic abilities. As discussed in the paper, neither the HAROLD nor the RH decline does fully explain this pattern of results. We rather suggest that the effect of aging on the hemispheric specialization and inter-hemispheric cooperation during semantic processing is explained not by only one model, but by an interaction between several complementary mechanisms and models.

Functional MRI evidence for the decline of word retrieval and generation during normal aging.

This fMRI study aimed to explore the effect of normal aging on word retrieval and generation. The question addressed is whether lexical production decline is determined by a direct mechanism, which concerns the language operations or is rather indirectly induced by a decline of executive functions. Indeed, the main hypothesis was that normal aging does not induce loss of lexical knowledge, but there is only a general slowdown in retrieval mechanisms involved in lexical processing, due to possible decline of the executive functions. We used three tasks (verbal fluency, object naming, and semantic categorization). Two groups of participants were tested (Young, Y and Aged, A), without cognitive and psychiatric impairment and showing similar levels of vocabulary. Neuropsychological testing revealed that older participants had lower executive function scores, longer processing speeds, and tended to have lower verbal fluency scores. Additionally, older participants showed higher scores for verbal automatisms and overlearned information. In terms of behavioral data, older participants performed as accurate as younger adults, but they were significantly slower for the semantic categorization and were less fluent for verbal fluency task. Functional MRI analyses suggested that older adults did not simply activate fewer brain regions involved in word production, but they actually showed an atypical pattern of activation. Significant correlations between the BOLD (Blood Oxygen Level Dependent) signal of aging-related (A > Y) regions and cognitive scores suggested that this atypical pattern of the activation may reveal several compensatory mechanisms (a) to overcome the slowdown in retrieval, due to the decline of executive functions and processing speed and (b) to inhibit verbal automatic processes. The BOLD signal measured in some other aging-dependent regions did not correlate with the behavioral and neuropsychological scores, and the overactivation of these uncorrelated regions would simply reveal dedifferentiation that occurs with aging. Altogether, our results suggest that normal aging is associated with a more difficult access to lexico-semantic operations and representations by a slowdown in executive functions, without any conceptual loss.

What is that little voice inside my head? Inner speech phenomenology, its role in cognitive performance, and its relation to self-monitoring.

The little voice inside our head, or inner speech, is a common everyday experience. It plays a central role in human consciousness at the interplay of language and thought. An impressive host of research works has been carried out on inner speech these last fifty years. Here we first describe the phenomenology of inner speech by examining five issues: common behavioural and cerebral correlates with overt speech, different types of inner speech (wilful verbal thought generation and verbal mind wandering), presence of inner speech in reading and in writing, inner signing and voice-hallucinations in deaf people. Secondly, we review the role of inner speech in cognitive performance (i.e., enhancement vs. perturbation). Finally, we consider agency in inner speech and how our inner voice is known to be self-generated and not produced by someone else.

Rehabilitation of verbal memory by means of preserved nonverbal memory abilities after epilepsy surgery.

We present a patient with epilepsy who underwent left anterior temporal cortex resection, sparing the hippocampus, to stop drug-refractory seizures. Given that one year after surgery the patient showed verbal memory difficulties, we proposed a short (twelve weeks) and intensive (two times a week) training based on visual imagery strategies as the nonverbal memory abilities were preserved. Neuropsychological and fMRI assessments were performed before and after rehabilitation to evaluate the cognitive progress and cerebral modifications induced by this rehabilitation program. Our results showed that the rehabilitation program improved both scores for verbal memory and the everyday quality of life. Changes in cerebral activity highlighted by fMRI suggest that the program might have facilitated the development of compensatory strategies, as reflected by the shift of activation from the anterior to the posterior cerebral network during a verbal memory task. One year after the rehabilitation program, the patient reported using mental imagery in everyday life for routine and professional activities. Although supplementary evidence is necessary to increase the robustness of these findings, this case report suggests that an efficient rehabilitation program is feasible and (a) should be based on the individual cognitive profile and on the preserved cognitive abilities, (b) can be short but intensive, (c) can be applied even months after the lesion occurrence, and (d) can induce a positive effect which may be sustainable over time.

Behavioral assessment of emotional and motivational appraisal during visual processing of emotional scenes depending on spatial frequencies.

Previous studies performed on visual processing of emotional stimuli have revealed preference for a specific type of visual spatial frequencies (high spatial frequency, HSF; low spatial frequency, LSF) according to task demands. The majority of studies used a face and focused on the appraisal of the emotional state of others. The present behavioral study investigates the relative role of spatial frequencies on processing emotional natural scenes during two explicit cognitive appraisal tasks, one emotional, based on the self-emotional experience and one motivational, based on the tendency to action. Our results suggest that HSF information was the most relevant to rapidly identify the self-emotional experience (unpleasant, pleasant, and neutral) while LSF was required to rapidly identify the tendency to action (avoidance, approach, and no action). The tendency to action based on LSF analysis showed a priority for unpleasant stimuli whereas the identification of emotional experience based on HSF analysis showed a priority for pleasant stimuli. The present study confirms the interest of considering both emotional and motivational characteristics of visual stimuli.

Hemisphere specialisation and inter-hemispheric cooperation during a phonological task: effect of lexicality as assessed by the divided visual field approach.

In the presented experiment we explored the effect of lexicality on hemisphere specialisation and cooperation during a phonological task. The divided visual field (DVF) method with bilateral presentation (BVF) of redundant (identical) stimuli is considered an appropriate approach to assess inter-hemispheric cooperation (IHC). IHC is supposed to increase the efficiency of cognitive processes. Specifically, it has been shown that, compared to unilateral hemifield presentation, word processing is significantly more efficient if stimuli were presented under bilateral redundancy conditions. The performance enhancement during bilateral vs. unilateral presentation is called bilateral redundant gain (BRG). In the present experiment a DVF was used and participants were required to perform a rhyme detection task in two blocks, one in words and another one in pseudowords. Each item was presented in two different modes, one unilateral (right or left hemi-visual field) and another one bilateral (simultaneous redundant presentation). Unilateral trials allow one to study hemispheric specialisation, while bilateral redundant trials allow one to study inter-hemispheric cooperation. We obtained left hemisphere specialisation for both types of items (word, pseudoword). Moreover, words were more efficiently processed than pseudowords. Additionally, words were processed more efficiently in BVF than in unilateral presentation, inducing BRG. No similar effect was obtained for pseudowords. These results are discussed in respect to findings reported by other studies suggesting that hemispheric specialisation depends on lexicality. Moreover, compared to lexical decision tasks used in previous studies, the phonological task used in the present study seems to modulate the inter-hemispheric cooperation less.

Neural dissociation of phonological and visual attention span disorders in developmental dyslexia: FMRI evidence from two case reports.

A dissociation between phonological and visual attention (VA) span disorders has been reported in dyslexic children. This study investigates whether this cognitively-based dissociation has a neurobiological counterpart through the investigation of two cases of developmental dyslexia. LL showed a phonological disorder but preserved VA span whereas FG exhibited the reverse pattern. During a phonological rhyme judgement task, LL showed decreased activation of the left inferior frontal gyrus whereas this region was activated at the level of the controls in FG. Conversely, during a visual categorization task, FG demonstrated decreased activation of the parietal lobules whereas these regions were activated in LL as in the controls. These contrasted patterns of brain activation thus mirror the cognitive disorders' dissociation. These findings provide the first evidence for an association between distinct brain mechanisms and distinct cognitive deficits in developmental dyslexia, emphasizing the importance of taking into account the heterogeneity of the reading disorder.

Functional MRI and neuropsychological evidence for language plasticity before and after surgery in one patient with left temporal lobe epilepsy.

This study explores the language reorganization before and after surgery in a 55-year-old right-handed female patient presenting with left temporal refractory epilepsy. Two aspects of language were explored, phonological and semantic, by using neuropsychological assessments and fMRI protocols. To assess the possible reorganization of language, fMRI results for B.L. were compared with results obtained in a group of healthy control subjects (results not presented in detail). According to our results and compared with healthy subjects, B.L. shows reorganization of temporal regions only. The reorganization had various patterns according to the task. Before surgery, neuropsychological testing in B.L. revealed impairment in phonological abilities and fMRI suggested right temporal involvement (interhemisphere reorganization) during the phonological task; semantic abilities were unaltered and fMRI showed bilateral activation of temporal regions during the semantic task. After surgery, the phonological deficit disappeared and fMRI showed left perilesional location of temporal activation (intrahemispheric reorganization); semantic abilities remain preserved and temporal activation remained located bilaterally but predominantly to the right during the semantic task. Our results suggest that cerebral reorganization of language depends on the language operation tested. Moreover, the results underline the importance of differential assessment of language operations and show functional reorganization after beneficial surgery in an older patient.

An fMRI study of the social competition in healthy subjects.

Social interaction requires the ability to infer another person's mental state (Theory of Mind, ToM) and also executive functions. This fMRI study aimed to identify the cerebral correlates activated by ToM during a specific social interaction, the human-human competition. In this framework, we tested a conflict resolution task (Stroop) adapted to a virtual situation of competition. The participants were instructed to play in order to win either against a human-like competitor (human-human competition) or against a non-human competitor (human-machine competition). Only the human-human competition requires ToM as this type of competition is performed under social interaction. We identified first the classical network of executive regions activated by Stroop. Secondly, we identified the social (human-human) competition regions, represented by the bilateral superior and inferior frontal gyri, the anterior cingulate, the insula, the superior and anterior temporal, the hippocampus, the fusiform gyrus, the cuneus and the precuneus. Finally, we identified the executive regions that were modulated by the human-human competition, i.e., the executive control regions additionally activated when mentalizing in the context of social competition. They constituted a network predominant to the right and composed of the superior and middle frontal, anterior cingulate, insula and fusiform gyrus. We suggest that our experimental paradigm may be useful in exploration of the cerebral correlates of social adjustments in several situations such as psychiatric disorders presenting executive and social dysfunctions.

Silence is golden: transient neural deactivation in the prefrontal cortex during attentive reading.

It is becoming increasingly clear that attention-demanding tasks engage not only activation of specific cortical regions but also deactivation of other regions that could interfere with the task at hand. At the same time, electrophysiological studies in animals and humans have found that the participation of cortical regions to cognitive processes translates into local synchronization of rhythmic neural activity at frequencies above 40 Hz (so-called gamma-band synchronization). Such synchronization is seen as a potential facilitator of neural communication and synaptic plasticity. We found evidence that cognitive processes can also involve the disruption of gamma-band activity in high-order brain regions. Intracerebral electroencephalograms were recorded in 3 epileptic patients during 2 reading tasks. Visual presentation of words induced a strong deactivation in a broad (20-150 Hz) frequency range in the left ventral lateral prefrontal cortex, in parallel with gamma-band activations within the reading network, including Broca's area. The observed energy decrease in neural signals was reproducible across patients. It peaked around 500 ms after stimulus onset and appeared subject to attention-modulated amplification. Our results suggest that cognition might be mediated by a coordinated interaction between regional gamma-band synchronizations and desynchronizations, possibly reflecting enhanced versus reduced local neural communication.

A comprehensive, time-resolved SANS investigation of temperature-change-induced sponge-to-lamellar and lamellar-to-sponge phase transformations in comparison with 2H -NMR results.

Time-resolved small-angle neutron scattering (TR-SANS) was employed to observe temperature-induced phase transitions from the sponge (L (3) to the lamellar ( L (alpha) phase, and vice versa, in the water-oil (n -decane)-non-ionic surfactant ( C(12)E(5) system using both bulk and film contrast. Samples of different bilayer volume fractions phi and solvent viscosities eta were investigated applying various amplitudes of temperature jump DeltaT . The findings of a previous (2)H -NMR study could be confirmed, where the lamellar phase formation was determined to occur through a nucleation and growth process, while it was concluded that the L (3) -phase develops in a mechanistically different and more rapid manner involving uncorrelated passage formation. Likewise, the kinetic trends of the nucleation and growth transition (decreased transition time with increase of phi and DeltaT were witnessed once again. Additionally, NMR and SANS data that demonstrate a strong dependency of that process on solvent viscosity eta are presented. Contrariwise, it is made evident via both SANS and NMR results that the L (alpha) -to-L (3) transition time is independent (within experimental sensitivity) of the varied parameters (phi , DeltaT , eta . Unusual scattering evolution in one experiment, originating from a highly ordered lamellar phase, intriguingly hints that a major rate determining factor is the disruption of long-range order. Furthermore, the bulk contrast investigations give insight into structure peak shifts/development during the transitions, while the film contrast experiments prove the bilayer thickness to be constant throughout the phase transitions and show that there is no evidence for a change in the short-range order of the bilayer structure. The latter was considered possible, due to the different topology of the L (3) and L (alpha) phases. Lastly, an unexpected yet consistent appearance of anisotropic scattering is detected in the L (3) -to- L (alpha) transitions.

Using membrane stress to our advantage.

The nature of the bilayer motif coupled with the ability of lipids and proteins to diffuse freely through this structure is crucial to the viability of cells and their ability to compartmentalize domains contained therein. It seems surprising to find then that biological as well as model membranes exist in a dynamic state of mechanical stress. The stresses within such membranes are surprisingly large, typically reaching up to 50 atm (1 atm=101.325 kPa) at the core of the membrane and vary as a function of depth. The uneven distribution of lateral pressures within monolayer leaflets causes them to bend away from or towards the water interface. This can result in the formation of complex, self-assembled mesophases, many of which occur in vivo. Our knowledge of the principles underlying membrane mechanics has reached the point where we are now able to manipulate them and create nano-structures with reasonable predictability. In addition, they can be used both to explain and control the partitioning of amphipathic proteins on to membranes. The dependence of the dynamics of membrane-bound proteins and the chemical reactivity of amphipathic drug molecules on membrane stresses suggests that Nature itself takes advantage of this. Understanding and manipulating these internal forces will be a key element in creating self-assembled, biocompatible, nanoscale cell-like systems.