Classical analytical approaches for examining multisensory processing in individual neurons have relied heavily on changes in mean firing rate to assess the presence and magnitude of multisensory interaction. However, neurophysiological studies within individual sensory systems have illustrated that important sensory and perceptual information is encoded in forms that go beyond these traditional spike-based measures. Here we review analytical tools as they are used within individual sensory systems  to advance our understanding of how sensory cues are effectively integrated across modalities . Specifically, we discuss how methods used to assess response variability , local field potentials (LFPs), current source density (CSD), oscillatory coherence, spike synchrony, and receiver operating characteristics (ROC) represent particularly promising tools for understanding the neural encoding of multisensory stimulus features. The utility of each approach and how it might optimally be applied toward understanding multisensory processing is placed within the context of exciting new data that is just beginning to be generated. Finally, we address how underlying encoding mechanisms might shape—and be tested alongside with—the known behavioral and perceptual benefits that accompany multisensory processing. Because we live in a world composed of a complex amalgam of sensory information, it is only through the ability to combine the various forms of this information that a meaningful behavioral and perceptual gestalt (an organized “whole” greater than the sum of its parts) can be formed. Furthermore, the adaptive advantages that multisensory integration confers are critical to survival, and often allow appropriate behavioral responses to be generated under circumstances in which information from one sense is inadequate. Enhanced orientation  of cats and ferrets, or the posterior parietal cortex, particularly the superior temporal sulcus (STS) of primates , response depression , or no interaction between the sensory modalities   of response attributable to the presence of a stimulus in a second sensory modality—thereby demonstrating the presence or absence of a multisensory interaction—a measure with undeniable ethological validity.The focus of these early neurophysiological response analyses of multisensory neurons [defined as neurons that respond to, or are influenced by, stimuli from more than one sensory modality  measure:SA is the spontaneous activity, SM1 is the first single-modality response , SM2 is the second single-modality response , CM is the combined-modality response, and n is the number of trials. In each case the response is defined as the mean number of spikes per trial evoked for the duration specific to each response  while SA is the average spikes per trial during 500 ms interval prior to stimulus onset. Using this equation, only responses that exceed the level of spontaneous activity affect the mean statistical contrast. This model assumes independence between inputs from each sensory modality and utilizes additive factors logic to distinguish between superadditive (contrast > 0) and subadditive (contrast < 0) responses , it must be recognized that these metrics still rely on changes in the mean firing profile of the neurons under study. Studies within sensory systems have illustrated that information can be encoded in forms that differ from these traditional spike-based measures—a series of findings that are beginning to be extended into multisensory systems. Alternative measures such as mean response duration, response latency (measured either as mean response latency or first spike latency), and peak firing rate (measured from the time bin in which the maximum number of spikes occurred post-stimulus) are also used to quantify multisensory integration. These measures provide valuable insights into temporal response dynamics and their effect on the integrative capacity of multisensory neurons  calculation:2) to the mean (μ) of spike counts is computed across trials and averaged over a specific time window of single unit neuronal response  systems is that of reliability. In psychophysical studies, reliability is generally framed from the perspective of cue weighting, with the relative cue weights being a function of the reliability of the various sensory inputs  between the maximum unisensory response  and the multisensory response :Recent studies from our laboratory have begun to highlight the utility of FF analysis as a tool for elucidating information content in multisensory systems. In recordings from the SC of both awake and anesthetized cats, different modes of multisensory interactions  were discovered to be associated with distinctly different changes in FF. Thus, whereas response enhancements are accompanied by an increase in response variability under multisensory conditions, response depressions are characterized by decreased variability Figure  Sarko e. We asseFF-value indicates unisensory responses that are more variable (less reliable) than multisensory responses, a negative ΔFF-value indicates the reverse. On average, neuronal responses that demonstrated response enhancements under multisensory conditions were less reliable  compared to unisensory responses, resulting in negative ΔFF-values  similar to those characteristic of electroencephalogram (EEG) studies. Spectral analysis of the LFP signal further assesses changes in the power spectrum of particular frequency bands that coincide with distinct stimulus conditions  elucidates subthreshold influences through sampling pooled voltage changes  of awake macaques  and vertical  spread of the LFP  to motivational processes, reward, and deep sleep  to working memory, emotional arousal, and fear conditioning  to working memory and awake resting state in the absence of sensory inputs  to sensorimotor processing  to a variety of cortical functions including visual feature integration  between states of high and low excitability on a more global scale  external noise, such as that generated within the environment, and (2) internal noise, such as that generated within the nervous system. Signal detection theory :Discrimination of a signal from noise depends primarily on the Numerous studies performed in the visual system have used analyses derived from signal detection theory to test the ability of neuronal responses to predict stimulus characteristics and/or behavior  seen for cross-modal trials would be predicted to coincide with increased ROC areas computed from neuronal recordings as the animal performed a task . Additionally, the time course of the neuronal response plotted as a function of ROC area would help to distinguish the contribution of neuronal activity to different stages of the task being performed, thereby directly relating multisensory neural activity to behaviorally and perceptually relevant outcomes. Recent studies have begun to study such neurometric/psychometric relationships using ROC analysis in a multisensory context. For instance, simultaneous recording of neuronal activity in the dorsal medial superior temporal (MSTd) area of monkeys was performed during a multisensory discrimination task using visual and vestibular cues to discriminate heading , and measures of signal detection outcomes  are integral in relating the reliability and efficacy of neural processing to behavioral gains such as improved target detection under multisensory conditions. Sensory integration, in part, also requires binding of unisensory representations through interactions between sensory cortices. This in turn requires widely distributed functional coupling, poising slow frequency bands of LFP or CSD signals as a promising experimental focus, given that these bands have been particularly implicated in long-range interactions. Future studies should address direct links between oscillatory activity, perception and behavior as it relates to cross-modal processing. Furthermore, using multisite and multiarea recordings in behaving animals to examine cross-talk between neurons of different sensory areas through increased or decreased spike synchrony, independent of changes in firing rate, might elucidate how cue weighting of significant sensory events works to perceptually bind stimuli as a unified percept or dissociate them (Fetsch et al., This work was supported by National Institute of Mental Health Grant MH-63861 and Vanderbilt Kennedy Center Development Funds to Mark T. Wallace.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The development of Colorectal Cancer (CRC) follows a sequential progression from adenoma to the carcinoma. Therefore, opportunities exist to interfere with the natural course of disease development and progression. Dysregulation of microRNAs (miRNAs) in cancer cells indirectly results in higher levels of messenger RNA (mRNA) specific to tumour promoter genes or tumour suppressor genes. This narrative review aims to provide a comprehensive review of the literature about the manipulation of oncogenic or tumour suppressor miRNAs in colorectal cancer cells for the purpose of development of anticancer therapies. A literature search identified studies describing manipulation of miRNAs in colorectal cancer cells in vivo and in vitro. Studies were also included to provide an update on the role of miRNAs in CRC development, progression and diagnosis. Strategy based on restoration of silenced miRNAs or inhibition of over expressed miRNAs has opened a new area of research in cancer therapy. In this review article different techniques for miRNA manipulation are reviewed and their utility for colorectal cancer therapy has been discussed in detail. Restoration of normal equilibrium for cancer related miRNAs can result in inhibition of tumour growth, apoptosis, blocking of invasion, angiogenesis and metastasis. Furthermore, drug resistant cancer cells can be turned into drug sensitive cells on alteration of specific miRNAs in cancer cells. MiRNA modulation in cancer cells holds great potential to replace current anticancer therapies. However, further work is needed on tissue specific delivery systems and strategies to avoid side effects. Colorectal cancer (CRC) is the third most common neoplasm worldwide. According to the International Agency for Research on Cancer, approximately 1.24 million new cases of CRC were detected worldwide in 2008 . The lifA search was performed using Medline, PubMed and The Cochrane Library databases from 2000 to 2011 to identify articles reporting the role of miRNAs in colorectal cancer development, diagnosis and therapy. The following MeSH search headings were used: ‘microRNA’ and ‘colorectal cancer’. The search was further extended by using the following text words and their combinations: ‘microRNA’, ‘blood’, ‘circulation’, ‘diagnosis’, ‘screening’, ‘therapy’, ‘manipulation’, ‘modulation’, ‘stem cells’ and ‘miRNAs’. ‘The related articles’ function in PubMed was used to broaden the search. All the abstracts, studies and citations found were reviewed. The most recent date of the search was 16 July 2011. Information about colorectal cancer related miRNAs was extracted on the following areas: cancer development & progression; diagnostic utility; manipulation in vitro and vivo; development of therapies. Detailed information was extracted from studies that met the inclusion criteria: Studies conducted on human and non-human cells or tissues; blood-based miRNAs- in colorectal cancers and studies published in the English literature. Because of the lack of randomized controlled trials and the heterogeneous nature of the available data, no attempt was made to perform quantitative meta-analyses. In the absence of standard criteria for the quality assessment of laboratory-based, observational studies on miRNA and heterogeneity of outcome measures included in this narrative review, no quality assessment of included studies was carried out. As the study is only a narrative review, no ethical permission or approval was required.The literature search identified 48 original scientific studies and review articles in which some or all of the outcomes of interest were reported. 18 additional articles and web-based information sites were selected to provide a general background to miRNA and colorectal neoplasia. 36 additional studies were included to supplement the information in colorectal cancer development, detection of circulating miRNAs, and principles of miRNA therapy, design and delivery. This article provides a comprehensive review of the different approaches for restoration of tumour suppressor miRNAs expression and methods of knocking down the tumour promoter miRNAs in cancer cells. Not all the methodologies of miRNA manipulation have been applied to CRC cells and some have been experimented only on other solid organ cancers. As description and elaboration of these methods might provide an insight to future CRC therapies designed on miRNA manipulations, the authors have included principle studies focussing on mechanisms of such manipulation.miRNAs are single-stranded, evolutionarily conserved, small (17–25 ribonucleotides) noncoding  RNA moleMiRNAs play an important role in colorectal tumour biology including; oncogenesis; progression; invasion; metastasis and angiogenesis -22. InitAnother cancer pathway- the second serrated neoplasia pathway has recently gained acceptance and is for the most part, APC and TP53 mutation independent. It involves distinct molecular features of somatic BRAF mutation concordance with high CpG islands methylation phenotype (CIMP-H) and microsatellite instability (MSI+) associated with mutt homologue 1 (MLH1) methylation ,35. InvoFunctional and mechanistic studies of miRNAs have shown that the replacement or knockdown of distinct miRNAs in vitro resulted in distinct cytogenetic abnormalities leading to either tumour cell proliferation or apoptosis . That’s Recent studies have shown that tumour-derived miRNAs are present in human body fluids in a remarkably stable form and are protected from endogenous ribonuclease activity. In three different studies researchers have evaluated the suitability of circulating miRNAs as a diagnostic biomarker for CRC . PrelimiThe fact that miRNAs regulate multiple genes in a molecular pathway, makes them excellent candidates for gene therapy. One of the most appealing properties of miRNAs as therapeutic agents is their ability to target multiple genes, frequently in the context of a network, making them extremely efficient in regulating distinct biological cell processes relevant to normal and malignant cell homeostasis. The rationale for using miRNAs as anticancer drugs is based on two major principles:1. MiRNA expression is deregulated in cancer compared with normal tissues2. Cancer phenotype can be changed by targeting miRNA expressionMiRNA based gene therapy is based on these two principles where manipulation of miRNA expression levels in cancer tissue results in inhibition of tumour growth, apoptosis, blocking of invasion, angiogenesis and metastasis. Restoration of the normal equilibrium for cancer related miRNA expression levels can result in growth retardation and reduced cell viability both in vivo and in vitro experiments. The major obstacle in gene therapy is the safe delivery to specific target tissue without side effects. Rapid degradation by body nucleases and poor cellular uptake owing to the unfavourable chemical structure of synthetic miRNAs have forced researchers to try chemical modifications of synthetic oligonucleotides as well as a more effective means of delivery. To overcome these delivery hurdles, viral and non-viral strategies have been developed. Restoration of tumour-suppressor miRNAs in cancer cells is usually achieved in vitro by using adenovirus-associated vectors (AAV). These vectors do not integrate into the genome and are eliminated efficiently with minimal toxicity. There are multiple AAV serotypes available, allowing for the efficient targeting of specific tissues including colorectal tissue. The ability of miRNAs to regulate several genes, does create potential problem in terms of side effects. This is a major concern in miRNA therapeutics as such interactions may lead to toxic phenotypes formation in targeted cells . This haThe demonstration that oncogenic miRNAs are upregulated in cancer provided a rationale to investigate the use of antisense oligonucleotides to block their expression. Antisense oligonucleotides work as competitive inhibitors of miRNAs, presumably by annealing to the mature miRNA guide strand and inducing degradation of mature miRNAs Figure . The staLNA construct based anti-miR therapeutic strategy has been extensively explored by researchers studying the miRNA based antiviral therapy for chronic hepatitis-C . LNA nucmiRNA sponges based techniques to manipulate oncogenic miRNAs is still in its infancy and has not been studied in detail in CRC cells. miRNA sponges are transcripts that contain multiple tandem-binding sites to a miRNA of interest and are transcribed from mammalian expression vectors. Ebert and colleagues recently reported the use of miRNA sponges in mammalian cells . The autMiRNA masking effect strategy is designed to target single signalling cancer pathways. miR-mask (miRNA-masking antisense oligonucleotides) technology has been developed by Xiao and colleagues . In contSeveral drugs may have the ability to modulate the expression of miRNAs by targeting signalling pathways that ultimately converge on the activation of transcription factors which in turn regulate miRNA encoding genes. Furthermore, it is possible to modulate the machinery that contributes to miRNA maturation and degradation processes. The identification of these compounds, however, is not straightforward and requires efficient screening of chemical libraries. Recently, Gumireddy and colleagues identified a method to screen for small-molecule inhibitors of miRNAs . As a prThe loss or downregulation of a tumour-suppressor miRNA could be overcome by introducing synthetic oligonucleotides i.e. mature miRNA mimics, miRNA precursors or pre-miRNA mimics into the CRC cellsFigure . IntroduAlterations in miRNA processing machinery have also been implicated in cancer development and modulation of this machinery in part or in general can potentially lead to the discovery of new anticancer therapies. Researchers have investigated the global repression of miRNA maturation process in cells and have identified that the abrogation of miRNA processing pathway promotes the cellular transformation and tumorigenesis . The inhCancer stem cells or tumor-initiating cells have recently gained enormous attention. According to this hypothesis a subpopulation of cancer cells possesses unique characteristics of self renewal and multipotent differentiation; fundamental characteristics of embryonic and somatic stem cells . As cancIn summary, there is strong evidence that miRNAs play a significant role in CRC development and progression. There is emerging evidence that miRNAs interact with different cancer signalling pathways and control cellular homeostasis. Changes in miRNAs expression levels results in alteration of this homeostasis and significantly contribute in cancer development and progression. Cancer specific miRNAs are detectable in body fluids and can potentially be used as novel biomarkers for CRC detection and prediction of cancer specific survival. MiRNAs influence oncogenic potential and therefore strategies to manipulate oncogenic or tumour suppressor miRNAs can successfully halt tumour progression. Furthermore, miRNA manipulation strategies can potentially be used as an adjuvant to other forms of anticancer therapies as miRNA manipulation can be used to sensitise drug resistant tumours. Finally, stem cell directed miRNA based therapies can be used to control stemness and latency of cancer stem cells in order to prevent the recurrence of tumour. However, miRNA based gene therapy is still in its infancy, but does hold great potential to replace current anticancer therapies. Further work is needed on an efficient, tissue specific delivery system and strategies to avoid side effects.The authors declare that they have no competing interests.MIA: literature search, review of studies, critical analysis of studies, layout of manuscript, design of figures and tables. MP: literature search, review of studies, critical analysis of studies. JHP: critical review of manuscript and analysis of the quality of manuscript. BS:, reviewed the quality of manuscript. JSJ: Review of quality , structure and design of manuscript. All authors read and approved the manuscript.


Objectives: This article reviews the present literature on the issues encountered while coping with children with autistic spectrum disorder from the dental perspective. The autistic patient profile and external factors affecting the oral health status of this patient population are discussed upon the existing body of evidence.Material and Methods: The MEDLINE database was searched using the terms ‘Autistic Disorder’, ‘Behaviour Control/methods’, ‘Child’, ‘Dental care for disabled’, ‘Education’, ‘Oral Health’, and ‘Pediatric Dentistry’ to locate related articles published up to January 2013.Results: Most of the relevant studies indicate poor oral hygiene whereas they are inconclusive regarding the caries incidence in autistic individuals. Undergraduate dental education appears to determine the competence of dental professionals to treat developmentally disabled children and account partly for compromised access to dental care. Dental management of an autistic child requires in-depth understanding of the background of the autism and available behavioural guidance theories. The dental professional should be flexible to modify the treatment approach according to the individual patient needs. Key words:Autism spectrum disorder, dental management, children. Autism spectrum disorder (ASD) refers to a group of neurodevelopmental disabilities with a core set of defining criteria that comprise impaired social interaction, communication, and restricted or repetitive behavioural stereotypes. The spectrum consists of autism, Asperger Disorder (AD), and Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS), which differ in the number and severity of diagnostic features .The etiologic background of ASD, though not yet completely understood, is considered to implicate both genetic and environmental factors. Recent research work has elucidated that parameters such as CNTNAP2 gene, de novo mutations, mitochondrial defects  may be iThe symptomatology of ASD initiates before the third year of age and generally undergoes a steady course without remission through aging ,6. EstabFurthermore, the psychological well-being of parents of a child with diagnosed ASD is significantly influenced by the behavioural difficulties of their offspring. Synopsis of the existing literature reveals accentuated stress, more psychological distress and depressive signs, lowered living standards and increased rates of physical and mental health problems in guardians of autistic children . UpbringA MEDLINE (www.ncbi.nlm.nih.gov/pubmed) search was conducted using alternatively the Medical Subject Headings terms ‘Autistic Disorder’, ‘Behaviour Control/methods’, ‘Child’, ‘Dental care for disabled’, ‘Education’, ‘Oral Health’, and ‘Pediatric Dentistry’ combined with the Boolean operators ‘AND’ and ‘OR’. Our aim was to identify studies on the dental related problematique of children with ASD published up to January 2013. In this review article, aspects requiring attention in the management of autistic children from the dental perspective are summarized.Conflicting results have emerged by the limited number of studies that carried out normative oral health assessment in children with ASD ,5,9-16 . In thisThe underlying rationale of dental decay prevalence in autistic children has been sought in physicochemical properties of saliva, dietary and oral hygiene habits. Hence, Bassoukou and colleagues  concludeChild’s attitude towards dental procedures, expenditure and lack of insurance coverage have been acknowledged as the main burdens to oral care delivery for children with ASD by a recent large-scale parent survey . AversioApparently, the quality of dental education is highly influential on the professional functioning and self-esteem of the prospective practitioners in treating special needs patients. It is characteristic that more than 60 percent of the general dentists felt not well or not at all prepared to treat patients with special needs and mental retardation . In the To conclude, relevant research has been so far conducted using properly structured but heterogeneous questionnaires that do not allow for direct comparisons between studies. Theoretically, increase of didactic and clinical hours in the predoctoral dental education program can be translated into more effective management of the DD population at the private practice level of care, and this will eventually eliminate disparities in the overall provision of dental care. In the future, it will be interesting to carry out questionnaire-based surveys addressed to faculty members, undergraduate students and dental professionals deriving from the same institutions.Knowledge and in-depth understanding of basic behavioural patterns is salient in successfully coping with a child with ASD at the dental office. One of the earliest indicators of the autistic disorder is the failure to develop joint attention, which literally means lack of curiosity for the environment and incapability of the child to share information using spoken language, gestures and eye contact . It is cSeveral basic behaviour guidance methods have been recommended to accommodate dental therapy of autistic patients, including the presence of parents, the use of tell-show-do technique, short, clear commands, and differential verbal reinforcement . ApplicaA. Visual pedagogyIdentification of the variables that arouse aversive behaviour may contribute in establishing favourable conditions for the autistic child to cooperate at the dental practice. The process known as functional behavioural assessment  may takeB. Sensory adapted environment The importance of environmental factors in determining the comfort level of children with DD during stressful medical events has been emphasized by Shapiro and colleagues . DistracThe dental clinic per se represents an anxiety-provoking environment with bright fluorescent lights, devices generating sharp noises like dental drill, and materials of unfamiliar texture, taste, and smell. Noise disturbances may be exaggerated in busy dental facilities with multiple operating units in the same room . EmotionC. Applied Behaviour Analysis (ABA) Applied Behaviour Analysis is the branch of psychology that through the analysis of the relationship of behaviour and the environment intends to modify behaviours to achieve desired effects . PracticD. Advanced behaviour guidance methodsUnder certain circumstances, dental management of these patients may be performed in combination with advanced behaviour guidance techniques. Antipsychotic medications are most commonly prescribed for ASD patients to alleviate symptoms of irritability, distress, self-injurious behaviour, aggression and delusions . The denEmphasis should be placed also on training parents in management policies focused on changing the nature or self-perception of the stress-inducing factors. The dental team should aim to navigate parents to accredited professional and social care support networks. Hence, access to rigid scientific evidence will render the parents active participants in therapy decision making and reinforce their confidence in handling the child’s attitude. The Internet has nowadays become the second most popular source of health care consultation for families following their physicians . HoweverDental care should be viewed as integral part of comprehensive health care program coordinated by the medical home . Based oFurther insight of the exact association between the primary care provider’s and dentist’ perception of the child’s behaviour in the dental chair should be gained by future interdisciplinary research. Evidence-based coping regimes for patients with ASD also need to be developed to improve compliance with oral care procedures. Taking this for granted, the dental practitioner will be provided with the opportunity to deliver health services in a personalized and appropriate manner.The dental management of a child with ASD requires in-depth understanding of the autistic behavioural profile. Based on well-established behavioural guidance techniques, the therapeutic approach should be individualized for each patient. The role of continuous education of dental professionals and parents is essential in overcoming the difficulties encountered by the autistic child in the dental chair.


However, FAS is only the most serious possible consequence of heavy prenatal alcohol exposure, and many individuals who do not meet diagnostic criteria for FAS also are severely impacted by gestational alcohol exposure. The term fetal alcohol spectrum disorders (FASD) is used to encompass a spectrum of effects that includes FAS towards the extreme end as well as conditions such as alcohol-related neurodevelopmental disorder (ARND) and alcohol-related birth defects (ARBD). The term ARND  are well established, and, as a leading cause of intellectual disabilities , FAS haserm ARND  refers term ARND . ClinicaAlthough the main goal of the quest for a neurobehavioral profile of heavy prenatal alcohol exposure is improved identification of alcohol-affected individuals, additional benefits include enhanced intervention and treatment opportunities for these individuals as well as improved accuracy of incidence estimates. Thus far, accurate identification of individuals who are affected by alcohol exposure has proven difficult for several reasons. First, clinicians cannot rely only on external markers because the majority of alcohol-affected people do not meet the physical criteria for FAS. Second, the full range of effects of prenatal alcohol exposure is not currently known; therefore, individuals with less striking or atypical manifestations may be misdiagnosed or fail to get a diagnosis altogether. Third, individual neurobehavioral features, including decreases in an individual’s intelligence quotient (IQ), also may result from clinical conditions or disorders other than FASD, further decreasing the ability to accurately identify individuals as alcohol affected. Finally, individual differences in factors that influence the consequences of prenatal alcohol exposure, such as the dose or timing of exposure, genetic variability, nutritional status, or postnatal factors, might interfere with developing a unifying neurobehavioral profile.There currently are two main avenues for identifying individuals with prenatal alcohol exposure: maternal reports of drinking in pregnancy and dysmorphology exams. Maternal reports of exposure, if accurate, are ideal for identifying people who have been exposed to alcohol prenatally. Such data can be collected during pregnancy  or afterwards . Recent research suggests that compared with prospective reports, retrospective maternal reports of gestational alcohol use indicate higher levels of exposure and are better predictors of behavioral outcomes in teenagers with histories of prenatal alcohol exposure . However4–14.) Although the combination of these markers is relatively specific to prenatal alcohol exposure and the diagnosis of FAS can be made even if the person’s history of prenatal alcohol exposure is unknown, it is not sufficiently sensitive to detect all affected individuals because not all affected persons show the physical features associated with FAS. In fact, the number of nondysmorphic individuals born to heavy-drinking women likely is at least three times greater than the number of cases of FAS —is standard practice for identifying affected individuals. This examination typically documents physical markers associated with exposure to substances that can harm the embryo  such as alcohol, or with other genetic or medical conditions. The physical markers of alcohol exposure are well documented and include short palpebral fissures, a smooth philtrum, a thin vermillion border, and small brain size .  in the meconiumConsequently, development of a neurobehavioral profile that characterizes the effects of heavy prenatal alcohol exposure in affected individuals regardless of the presence of physical features (and therefore the diagnosis of FAS) has the potential to overcome the limitations of the aforementioned methods of identifying alcohol-affected individuals. It also would allow a more accurate assessment of the neurobehavioral effects across the spectrum of FASD.The quest for a disorder-specific neurobehavioral profile is not without precedent. For example, the understanding of Williams syndromeTo provide all these benefits, a neurobehavioral profile associated with heavy prenatal alcohol exposure must be both sensitive  and specific . Identification of a profile with good sensitivity is fairly straightforward in principle; it involves identifying a cognitive ability or set of abilities that are deficient in alcohol-affected individuals. Nearly four decades of research have detailed numerous neurobehavioral deficits in alcohol-affected individuals  similar to alcohol-affected individuals. These comparisons can help identify characteristics that differ between groups and therefore are specific to alcohol-affected individuals. Thus far, these efforts have focused on two primary effects of heavy prenatal alcohol exposure: low IQ score and a diagnosis of ADHD. When children with heavy prenatal alcohol exposure are compared with contrast groups with similar IQ scores, both similarities and differences emerge. Similarities  include performance on measures of internalizing behavior , expressOther research has documented both similarities and differences between children with heavy prenatal alcohol exposure and nonexposed children with ADHD. These studies found that some aspects of executive function may prove useful in profile development because deficits in this domain are not entirely overlapping in these two groups. For example, children with ADHD or FASD show deficits on measures of nonverbal problem solving and worse letter fluency than category fluency, but only alcohol-affected children demonstrate greater impairment on letter fluency and set-switching . Other sOne weakness of this approach of comparing alcohol-affected children with other clinical contrast groups  is that these studies have proceeded, by necessity, in a piecemeal fashion, and no one study can simultaneously account for all aspects of the alcohol phenotype. To date, only two pieces of the FASD puzzle have been addressed, and additional research addressing other potential contributory factors or including other comparisons is needed. Another important consideration in the development of a neurobehavioral profile for individuals affected by heavy prenatal alcohol exposure is the possibility that more than one profile may exist. For example, differences in the patterns  or timing of alcohol exposure e.g.,  may resuThe quest for a neurobehavioral profile of heavy prenatal alcohol exposure is essential for enhancing understanding of the effectsofthis exposure and will result in improvements in intervention and incidence estimates. Although the search already has been fruitful, a reliable profile has been elusive. Additional research is necessary to further clarify the sensitivity and specificity of the emerging profile as well as to continue to address the confounding effects of myriad complicating factors.


The load theory of selective attention hypothesizes that distractor interference is suppressed after perceptual processing  at low perceptual load of the central task, but in the early stage of perceptual processing at high perceptual load. Consistently, studies on the neural correlates of attention have found a smaller distractor-related activation in the sensory cortex at high relative to low perceptual load. However, it is not clear whether the distractor-related activation in brain regions linked to later stages of central processing  is also smaller at high rather than low perceptual load, as might be predicted based on the load theory.We studied 24 healthy participants using functional magnetic resonance imaging (fMRI) during a visual target identification task with two perceptual loads (low vs. high). Participants showed distractor-related increases in activation in the midbrain, striatum, occipital and medial and lateral prefrontal cortices at low load, but distractor-related decreases in activation in the midbrain ventral tegmental area and substantia nigra (VTA/SN), striatum, thalamus, and extensive sensory cortices at high load.Multiple levels of central processing involving midbrain and frontostriatal circuits participate in suppressing distractor interference at either low or high perceptual load. For suppressing distractor interference, the processing of sensory inputs in both early and late stages of central processing are enhanced at low load but inhibited at high load. Early selection theory proposes that attention filters irrelevant information during perceptual processing late selection theory proposes that attention selects relevant information for response and/or memory storage after perceptual processing load theory of selective attention proposed that the neural substrates underlying inhibition of distractor interference is dependent on the perceptual load of goal-directed tasks. It proposes that attention prevents distractor interference during perceptual processing at high perceptual load and after perceptual processing at low load Attention facilitates goal-directed behavior by focusing on targets and inhibiting interference from distractors. Several theories have been proposed to explain the brain mechanisms underlying inhibition of distractor interference. When considering the load theory, one might pose the following hypotheses. First, the early stage  of central processing will process distractors at low load because the spared processing resources from the central task will spill over to distractors. Second, the late stage  will actively differentiate perceived distractors from targets at low load. Third, the central processing passively excludes distractors from processing at high load because central tasks may consume all processing resources While fMRI studies consistently support the prediction of a greater distractor-related activation in the early stages of central processing at low relative to high load, there is little evidence supporting the prediction of a greater distractor-related activation in later stages at low relative to high load. Data suggest that the neural correlates of later stages of central processing involve frontostriatal circuits To investigate further the influence of perceptual load on distractor-evoked activation in the frontostriatal circuits, we assessed the whole-brain activity of 24 healthy participants using fMRI as they performed a novel visual target-identification task under varying load and distractor conditions. The task features two different perceptual loads , and each load has two distractor conditions . Based on the load theory, as well as the fMRI studies reviewed above, we predicted that distractors would be associated with a greater increase in activity not only in the occipital cortex, but also in frontostriatal regions at low relative to high load. We examined this prediction by comparing distractor-related changes in blood oxygen level dependent (BOLD) signal at different perceptual loads. Data confirming or refuting this prediction would not only have theoretical implications with respect to the validity of the load theory, but also provide empirical data on the neural mechanisms underlying selective attention in different environmental contexts.Twenty-seven healthy adults from the community of the University of California Los Angeles (UCLA) gave written informed consent to participate in this study, which was approved by the Institutional Review Board at the UCLA. Data from three subjects were excluded from analysis because one subject fell asleep and the other two reported inadequate vision correction in the scanner. The final sample size included 24 participants .The task used 16 schematic faces as targets and 64 scene pictures as background distractors . Becausehttp://psychtoolbox.org/PTB-2/osx.html) and displayed on the screen of a Macintosh laptop.The task used a 2×2 factorial design with two perceptual loads  and two distractor conditions . At low load, any face with an elongated nose was a target; participants could simply search features to identify the target . At highStimuli for each condition were grouped into blocks with the same 16 faces used in every trial block. These 16 face images, either alone or overlaid on a distractor image, were presented one by one in random sequence within each block. Each image was presented once for 100 ms. The interstimulus interval was 1.1 s, and the duration of each block was 19.2 s ×16 = 19.2). The instruction, “Please identify,” was presented for 5 s before each trial block above an instruction image specifying the facial features for the targets in the following task block . ParticiPrior to scanning, each participant was trained until he or she achieved three consecutive performances of the task each with error rates less than 50% for both commission and omission errors at high perceptual load. During scanning, each subject performed three functional runs using three different task scripts. No feedback on task performance was provided during the entire scanning period. Within each run, each blocked condition was repeated four times, and the whole run lasted 387.2s. The order of blocks was randomized within each run, and the order of runs was counterbalanced across subjects. Each condition within one run  consisted of 64 stimuli . In the distractor condition at each load level within each run, each stimulus had a different distractor, but the same 64 pictures were used for both low and high load conditions to avoid potential differences in brain activation induced by different physical stimuli between perceptual loads. Task performance was assessed using reaction time (RT), rate of omission error, and rate of commission error. It has been suggested that omission and commission errors reflect deficits in different central processes  Functional images were acquired using gradient-echo EPI scanning sequence  with a Siemens Allegra 3T system. The scanning plane was off the AC-PC line rostrally at 20°. The thin scanning slice and tilted scanning plane were used to reduce susceptibility-related signal loss at the basal forebrain Each BOLD time series was motion-corrected, normalized to the MNI  template, and smoothed with a 5-mm kernel using SPM2 . After the functional images were filtered with a 128-s high-pass temporal filter, model time courses for each block condition were constructed by convolving a boxcar waveform representing the times of the presentation of each block with the canonical hemodynamic response function offered by SPM2. The functional data were analyzed using a standard GLM.Statistical tests had two levels, first at single subject level (fixed effects) and then at group level (random effects). For each subject, SPM (T} maps with the following contrasts were created first: high load vs. low load (collapsed across distractor conditions), low load (with distractor vs. without distractor), high load (with distractor vs. without distractor), and [low load (with distractor vs. without distractor) vs. high load (with distractor vs. without distractor)]. Then, these contrast maps were fed into the second level, one-sample t-tests to acquire group means for each contrast. Unless specified otherwise in the result section, we employed FWE cluster-level correction for multiple comparisons of the voxel-wise whole brain analysis throughout this study, and used cluster p<.05 (FWE corrected) in conjunction with voxel height threshold p<.01 to identify significant changes in BOLD signal between task conditions. Marsbar toolbox Participants showed increases in BOLD signal in brain regions implicated in attentional processing, including the lateral PFC (LPFC), parietal cortex, occipital cortex including the fusiform gyrus, thalamus, basal ganglia, and midbrain, at high relative to low perceptual load, across distractor conditions . They shFive clusters showed significant increases in BOLD signal in the distractor relative to the no–distractor condition at low perceptual load . One cluOne cluster across the occipital cortex including cuneus and lingual gyrus, parahippocampus, and cerebellum, bilaterally, showed significant increases in BOLD signal at the distractor relative to no-distractor condition at high perceptual load . Three cEight clusters showed significant differences in distractor-related changes in BOLD signal at low vs. high perceptual load as assessed by the contrast [low load (with distractor vs. without distractor) vs. high load (with distractor vs. without distractor)] . These cThe main aim of this study was to test our hypothesis that distractors would induce greater activation in frontostriatal regions at a low relative to a high perceptual load of a central task. Our main findings include: 1) distractors induced a greater decrease in commission errors and a trend towards a greater increase in omission errors at high as compared to low perceptual load; 2) distractors induced an increase in activation in the occipital cortex and parahippocampus at both low and high loads, and the increases were greater at low than high load, consistent with prior work; 3) distractors induced an increase in activation in multiple brain regions including the IFG, caudate head, and midbrain PAG/RF at low load; and, 4) distractors induced a decrease in activation in the striatum, midbrain VTA/SN, and multiple sensory cortices at high load. These findings support our prediction that distractors would induce a greater increase in activation in frontostriatal regions at low relative to high load.In this study, distractors showed a marginal main effect on RT. This effect is weaker than the significant distractor-related RT increases typically reported by prior load theory studies In the current study, distractors were associated with increased omission errors and decreased commission errors. The distractor-induced opposite changes in the errors of omission and commission are consistent with a previous hypothesis that they are associated with different central processes, i.e., processes related to attention vs. impulsivity The distractor-related changes in omission and commission errors did not correlate with each other at either perceptual load. The lack of such a correlation suggests that the opposite changes in the two types of errors are probably not due to a tradeoff between them. The significant two-way interaction between perceptual load and distractors on commission error suggests that the effects of distractors on commission errors are dependent on perceptual load, and probably reflect different neural correlates of suppressing distractor interference at different perceptual loads (see below). However, we cannot exclude the potential contribution of a “floor effect” with respect to the two-way interaction, because the commission error rate was very low in the condition of low perceptual load without distractor  and therefore might not allow assessment of further decreases.solely in distractor processing and not involved in processing of relevant stimuli . The current design did not allow us to isolate BOLD signal in the frontostriatal circuits associated with distractors only  from BOLD signal associated with relevant stimuli only, or with both distractors and relevant stimuli.Throughout this paper we use the phrases “distractor-related activation”, “distractor-related deactivation”, and “distractor-related changes in activation” to refer to the observed statistically significant increases, decreases, and differences, respectively, in BOLD signal between conditions with and without distractors at each level of perceptual load. By using these phrases we do not imply that these changes in BOLD signal are involved The participants in this study showed distractor-related increases in activation in the visual cortex, parahippocampus and frontostriatal regions including IFG and caudate heads at low perceptual load. The distractor-related activation in the parahippocampus is consistent with a previous finding that the parahippocampus is specifically sensitive to stimuli of houses and/or scenes The MPFC, a major component of the brain default-mode network, often shows relative deactivation while healthy participants perform cognitively demanding tasks relative to a control condition The TPJs are often relatively deactivated while healthy subjects perform cognitive tasks, and this deactivation has been proposed to reflect suppression of distractor processing in the brain The above-discussed findings together suggest that three sets of different neural events operate to prevent interference from task-introduced distractors at low perceptual load. The first may involve increasing activity in the midbrain PAG/FR and MPFC to increase arousal and attention to external stimuli; the second may involve increasing activity in the visual cortex and frontostriatal circuits, which may reflect increased processing of sensory inputs at both early and late stages of central processing; and the third may involve decreasing activity in the TPJs to filter distractors.The cuneus, lingual gyrus, and parahippocampus showed increased activation in the condition with distractors relative to without distractors at high load. This increase could be accounted for by distractor-related processing in the visual cortices. Furthermore, distractors induced diminished activation  in the middle and inferior occipital gyri at high load. In this instance, “deactivation” refers to the finding of reduced BOLD signal in the condition with distractors relative to without distractors at high perceptual load. This pattern of activation and deactivation together results in smaller distractor-related net increases in activation in the cuneus and middle occipital gyri at high relative to low load. These data are consistent with findings of prior studies of the load theory that the occipital cortex shows smaller distractor-related increases in activation at high relative to low load.The distractors at high load were also associated with deactivation in the parietal, temporal, and posterior insular cortices, which receive somatosensory, auditory, and visceral sensory inputs, respectively At high load, distractors were not associated with increases in activation in frontostriatal regions, but with relative decreases in activation in the caudate heads and thalamus. This finding is consistent with our prediction that distractors will evoke a smaller increase in activation in the frontostriatal circuits at high relative to low load. The precise neural mechanisms underlying distractor-induced deactivation in the caudate, thalamus, and extensive sensory cortices  at high load are not clear at present. They might relate to top-town attentional control, which might inhibit the processing of irrelevant information in the sensory cortices and thus prevent it from reaching frontostriatal regions when most or all processing resources of the frontostriatal regions are consumed by high-demanding central tasks.An unexpected finding of this study was the distractor-related deactivation in the VTA/SN at high load. Previous studies reported that the level of BOLD signal change in the VTA/SN was positively correlated with levels of their DA release in the frontostriatal circuits while healthy participants performed cognitive tasks In this study, participants needed to remember more features when they tried to identify targets by searching for a junction of features in the condition of high load relative to when they tried to identify targets by searching for one feature in the condition of low load. Therefore, working memory load was greater in the condition of high relative to low load. It has been hypothesized that increasing working memory load would consume increasingly large resources of cognitive control and reduce inhibition of distractor processing A potential weakness of this study is its block design, which prevents the isolation of brain activity associated with performance errors, particularly since error rates are greater at high relative to low task load. However, block designs have been frequently used in studies investigating the neural substrates of attention, including within the context of the load theory Findings from this study indicate that distractor-related activation is greater not only in the sensory cortices, but also in frontostriatal circuits at low relative to high perceptual load. At low perceptual load, the neural mechanisms of inhibiting distractor interference may include increasing arousal by increasing activation in the midbrain PAG/FR and MPFC, filtering distractors by decreasing activation in the TPJ, and rejecting distractors and/or selecting appropriate responses by increasing activation in frontostriatal circuitry. At high perceptual load, increased top-down attentional control appears to contribute to the inhibition of distractor interference, as suggested by distractor-related concurrent deactivation in the frontostriatal circuits, midbrain VTA/SN, and extensive sensory cortices. Therefore, the midbrain PAG/FR and VTA/SN and frontostriatal circuits may play different roles in inhibiting distractor interference at different perceptual demands of central tasks.


As successful malaria control programs move towards elimination, they must identify residual transmission foci, focus on both asymptomatic and symptomatic infections, and manage importation risk. High spatial and temporal resolution maps of malaria risk can support all of these activities, but new approaches are required to provide accurate case-based risk maps for very low prevalence countries like Swaziland, where fewer than 500 cases were reported in 2011.Household locations and travel histories of confirmed malaria patients were recorded through routine surveillance by the Swaziland National Malaria Control Programme for the higher transmission months of Jan to Apr 2011 and the lower transmission months of May to Dec. Household locations with locally-acquired infections were compared against a random set of background points with respect to variables related to environment, population density, vector control, and distance to the households of imported cases. Comparisons were made separately for the high and low transmission seasons. The regression tree classification approach Random Forest was used to generate maps predicting the probability of a locally-acquired case at 100 m resolution across Swaziland during the high and low transmission seasons.Results indicated that case households during the high transmission season tended to be located at lower elevations, closer to stream channels, in more sparsely populated areas, with higher rainfall and lower temperature than random background points . No significant difference was evident with distance to the nearest imported case household. Similar differences were evident during the low transmission season, but environmental variables like distance to stream channels and water bodies were no longer significantly different, while low season case households were located significantly nearer to those of imported cases (p = 0.02). Maps from the fit models suggested better predictive ability during the high season.The rapid, high-resolution mapping approaches described here appear useful for helping elimination programs understand the epidemiology of a disappearing disease. Generating case-based risk maps at high spatial and temporal resolution will allow control programs to direct interventions in response to evidence-based measures of risk and ensure that the impact of limited resources is maximized to achieve and maintain malaria elimination.


Vaccination has had a major impact on the control of infectious diseases. However, there are still many infectious diseases for which the development of an effective vaccine has been elusive. In many cases the failure to devise vaccines is a consequence of the inability of vaccine candidates to evoke appropriate immune responses. This is especially true where cellular immunity is required for protective immunity and this problem is compounded by the move toward devising sub-unit vaccines. Over the past decade nanoscale size (<1000 nm) materials such as virus-like particles, liposomes, ISCOMs, polymeric, and non-degradable nanospheres have received attention as potential delivery vehicles for vaccine antigens which can both stabilize vaccine antigens and act as adjuvants. Importantly, some of these nanoparticles (NPs) are able to enter antigen-presenting cells by different pathways, thereby modulating the immune response to the antigen. This may be critical for the induction of protective Th1-type immune responses to intracellular pathogens. Their properties also make them suitable for the delivery of antigens at mucosal surfaces and for intradermal administration. In this review we compare the utilities of different NP systems for the delivery of sub-unit vaccines and evaluate the potential of these delivery systems for the development of new vaccines against a range of pathogens. Traditional vaccines include live attenuated microbes, killed microbes, or components of microbes. Although many of these vaccines have been central to the control of infectious disease, some do not afford good protection against disease. In addition, some live vaccines are not safe for use in the growing population of immunocompromised individuals in society. There is also a wide range of infectious diseases for which no licensed vaccines are available. To address these challenges a range of vaccines are being developed based on isolated proteins or polysaccharides or naked DNA encoding a protective antigen. Whilst these can be safer, more defined, and less reactogenic than many existing vaccines, they are often poor immunogens, which require adjuvants to boost their efficacy. The most commonly used adjuvants are aluminium based but these can induce local reactions and may fail to generate strong cell-mediated immunity Guy, . As a coRecently attention has been directed toward the utility of nanoparticles (NPs) as delivery vehicles for vaccines. The vaccine antigen is either encapsulated within or decorated onto the surface of the NP. By encapsulating antigenic material, NPs provide a method for delivering antigens which may otherwise degrade rapidly upon injection or induce a short-lived, localized immune response. Conjugation of antigens onto NPs can allow presentation of the immunogen to the immune systems in much the same way that it would be presented by the pathogen, thereby provoking a similar response. Moreover, NPs made from some composites enable not only site directed delivery of antigens but also the prolonged release of antigens to maximize exposure to the immune system. Also being explored is the potential for NPs to deliver vaccines through non-traditional methods such as topical, inhalation, or optical delivery as well as combining several antigens to the same particle so as to protect against more than one disease.In this review we have considered VLPs, liposomes, ISCOMs, polymeric NPs, and non-degradable NPs as delivery systems for microbial proteins. The expectation is that the particulate vaccines generated using these technologies will be better at providing potent antigen-specific humoral and cellular immune responses and will allow next generation vaccines to be devised against a range of infectious diseases.Autographa california multiple nuclear polyhedrosis virus (AcMNPV) is the most extensively studied VLP component  to generate sufficient quantities of the viral protein which can then self-assemble into multimeric complexes   and saponin (most often Quil A from the tree co-glycolic acid) (PLGA) or poly(lactic acid) (PLA) which are often synthesized using a double emulsion-solvent evaporation technique  batches. Variation could arise from contamination, a polydisperse population of NPs, the accumulation of toxic components or incomplete particle formation. In order to maintain a homogenous population, several methods are employed to measure uniformity within colloidal solutions. Spatial uniformity amongst NPs is essential since the spherical volume will influence how much antigen is encapsulated or conjugated onto the surface and could vary the immunizing dose of the vaccine. Consequently, the size and shape of particles is characterized using a variety of methods including electron microscopy, dynamic light scattering, and density gradient centrifugation  , lipid A from the lipopolysaccharide of Gram-negative bacteria and unmethylated cytosine-guanine dinucleotides (CpG) found in bacterial DNA. Despite this, aluminium-based compounds  remain the most widely used adjuvants incorporated into licensed human vaccines. Until recently the mechanisms by which alum potentiates the immune response has been poorly understood and was initially believed to be due to a depot effect at the site of injection prolonging exposure of the antigen to the immune system for a better response  and tumor necrosis factor α (TNFα), whereas the predominantly anti-inflammatory role of Th2 cells is to secrete cytokines such as IL4, IL10, and IL13. Both types of Th cell also support the production of antibodies by B-cells, in either a pro-or anti-inflammatory environment, which in turn influences antibody isotype and function. However, some pathogens such as viruses and some bacteria are able to become internalized within cells via non-endocytic pathways. When this occurs, antigens derived from the pathogen are processed via proteosomes which then display peptides in the clefts of MHC class I molecules  NPs with encapsulated ovalbumin were used to immunize mice, significantly higher levels of total IgG, IgG1, and IgG2a were induced compared with the response to soluble ovalbumin, suggesting the particles have the ability to prime humoral and cellular immune responses since CD4+ and CD8+)  infection in both animal models and human clinical trials using the HPV L1 protein .A wide variety of NP delivery systems have been described, each offering advantages over current methods of vaccine delivery. Rather than conventional vaccines which use whole microbes (live or killed), this new generation of vaccines use components of microbes to elicit an immune response and mimic the way in which these antigens would be delivered during a natural infection. Often these antigens are poor immunogens on their own and thus require an adjuvant to boost the immune response. Although previously demonstrated with alum-based adjuvants, this often fails to induce a cellular immune response and can be reactogenic toward the host. NPs provide an alternate method for antigen delivery which not only activates different elements of the immune system but also have good biocompatibility. One of the ways in which NPs are able to elicit different immune responses is through their size; moving into cells via non-classical pathways and then processed as such. Delivering antigens in different ways also has a profound effect on the resulting immune response, whether the antigen is decorated on the NP surface for presentation to antigen-presenting cells or encapsulated for slow release and prolonged exposure to the immune system. NPs are also versatile and can be modified with immunostimulatory compounds to enhance the intensity of the immune response or with molecules to increase their stability Many of the NP delivery systems mentioned in this review are capable of eliciting both cellular and humoral immune responses. However, an efficient and protective vaccine is likely to induce a combination of both responses and should be tailored to the pathogen in question accordingly. Whilst these delivery vehicles may present as an exciting prospect for future vaccination strategies, it is also worth noting their potential drawbacks, particulary those associated with cytotoxicity. Since NPs have a relatively short history in medicine they do not have a longstanding safety profile in human use. It is therefore essential that further research is carried out in NP toxicity to fully address these questions if they are to be accepted as an alternative method for the delivery of novel vaccines and are licensed more widely for human use.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Facial expressions are of eminent importance for social interaction as they convey information about other individuals’ emotions and social intentions. According to the predominant “basic emotion” approach, the perception of emotion in faces is based on the rapid, automatic categorization of prototypical, universal expressions. Consequently, the perception of facial expressions has typically been investigated using isolated, de-contextualized, static pictures of facial expressions that maximize the distinction between categories. However, in everyday life, an individual’s face is not perceived in isolation, but almost always appears within a situational context, which may arise from other people, the physical environment surrounding the face, as well as multichannel information from the sender. Furthermore, situational context may be provided by the perceiver, including already present social information gained from affective learning and implicit processing biases such as race bias. Thus, the perception of facial expressions is presumably always influenced by contextual variables. In this comprehensive review, we aim at (1) systematizing the contextual variables that may influence the perception of facial expressions and (2) summarizing experimental paradigms and findings that have been used to investigate these influences. The studies reviewed here demonstrate that perception and neural processing of facial expressions are substantially modified by contextual information, including verbal, visual, and auditory information presented together with the face as well as knowledge or processing biases already present in the observer. These findings further challenge the assumption of automatic, hardwired categorical emotion extraction mechanisms predicted by basic emotion theories. Taking into account a recent model on face processing, we discuss where and when these different contextual influences may take place, thus outlining potential avenues in future research. Dating back to Darwin  it has bAs a consequence, experimental work on the perception of emotional facial expressions has often relied on a set of isolated, de-contextualized, static photographs of actors posing facial expressions that maximize the distinction between categories  or ends  may constitute important non-emotional context cues. It has been demonstrated several times that dynamically evolving facial expressions are much better recognized, rated as more arousing, elicit larger emotion-congruent facial muscle responses . Meeren et al.  found thEmotion research frequently uses language in form of emotion labels, both to instruct participants and to assess recognition performance. As the following examples demonstrate, language can guide and even bias participants on how to read facial expressions in this kind of research. For example, when participants were asked to repeat an emotion word such as “anger” aloud either three times (temporarily increasing its accessibility) or 30 times (temporarily reducing its accessibility), reduced accessibility of the meaning of the word led to slower and less accurate emotion recognition, even when participants were not required to verbally label the target faces  serving as unconditioned stimulus (UCS). For example, in one study, participants learned that faces predicted negative social outcomes , positive social outcomes , or neutral social outcomes  showed higher increases in amygdala activation toward black faces compared to participants with lower bias , within-sender features , environmental features , or within-perceiver features  seems to dramatically influence how we perceive a facial expression. The studies as reviewed above altogether point at the notion that efficient emotion perception is not solely driven by the structural features present in a face. In addition, as the studies on affective learning and verbal descriptions of contexts show, contextual influences seem to be especially influential when the facial expression is either ambiguous  or no facial expression is shown . The latter effects not only highlight the notion of contextual influences but also pinpoint the issues of using so-called neutral faces as baseline condition in the research of facial expressions perception. Thus, using neutral faces as baseline, researchers have to be aware that these are probably influenced by the preceding faces . Whereas some of the effects observed here can be explained by affective priming mechanisms , other effects  point to a supramodal emotion perception which rapidly integrates cues from the facial expression and affective contextual cues. Particularly the influences on surprised (ambiguous) and neutral faces show that contextual effects may play an even more important role when the emotional information is difficult to derive from the facial features alone. The latter is also in line with recent models of impression forming of other people based on minimal information Todorov, .Beyond the scope of this paper, cultural influences obviously also define a major context for the perception of facial expressions , it is also essential for our further understanding of contextual influences on face processing to identify at which temporal stage of the processing stream (“when?”) the integration of context and facial expression takes place. To this end, measures with high temporal resolution like EEG are much better suited than measures with high spatial, but poor temporal resolution like fMRI (Brosch and Wieser, Altogether, the literature as reviewed above nicely fits distributed as opposed to categorical models of face processing (Haxby et al., As this review shows, different types of context influence face perception. However, a lot of questions remain unsolved, which need to be addressed in future research. It is still unknown, for example, how these various dimensions of contexts and facial expressions are coded and how they are integrated into a single representation. Moreover, given the complexity of such a process, the available models need to be refined with regard to the interconnections between the neuroanatomical structures underlying face perception as shown in Figure Taken together, the work reviewed here demonstrates that the impact of contextual cues on facial expression recognition is remarkable. At the neural level, this interconnection is implemented in widespread interactions between distributed core and extended face processing regions. As outlined earlier, many questions about these interactions are still unsolved. All the more, the time has come for social affective neuroscience research to put faces back in context.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Anaesthetic propofol, commonly used for general anaesthesia, is known to bind to GABAA receptors . It affeTo answer this question, we built a model of cortical population made of 750 excitatory and 250 inhibitory neurons whose dynamics resemble those found in biological neurons. Excitatory cells are modeled by a leaky-integrate-and-fire model of pyramidal neurons . The celWe show with our minimal model of a cortical assembly that the peak in the power spectrum of the mean membrane voltage of excitatory cells, whose spiking frequency originally is about 11 Hz without tonic inhibition, shifts towards slower frequencies with increasing tonic inhibition. This result is similar to occipital EEG recordings under propofol anesthesia. However, the amplitude of the power spectra diminishes drastically, more so than in biological recordings, in the presence of tonic inhibition compared to without tonic inhibition. This may indicate that tonic inhibition is not the only occurrence responsible for the increase in amount of delta oscillations, but that thalamic inputs may help maintaining slow cortical occipital activity under general anesthesia. We are thus planning for future works to include interactions in our model between cortical and thalamic populations.


The mere presence of irrelevant external stimuli results in interference with the fidelity of details retrieved from long-term memory (LTM). Recent studies suggest that distractibility during LTM retrieval occurs when the focus of resource-limited, top-down mechanisms that guide the selection of relevant mnemonic details is disrupted by representations of external distractors. We review findings from four studies that reveal distractibility during episodic retrieval. The approach cued participants to recall previously studied visual details when their eyes were closed, or were open and irrelevant visual information was present. The results showed a negative impact of the distractors on the fidelity of details retrieved from LTM. An fMRI experiment using the same paradigm replicated the behavioral results and found that diminished episodic memory was associated with the disruption of functional connectivity in whole-brain networks. Specifically, network connectivity supported recollection of details based on visual imagery when eyes were closed, but connectivity declined in the presence of visual distractors. Another experiment using auditory distractors found equivalent effects for auditory and visual distraction during cued recall, suggesting that the negative impact of distractibility is a domain-general phenomenon in LTM. Comparisons between older and younger adults revealed an aging-related increase in the negative impact of distractibility on retrieval of LTM. Finally, a new study that compared categorization abilities between younger and older adults suggests a cause underlying age-related decline of visual details in LTM. The sum of our findings suggests that cognitive control resources, although limited, have the capability to resolve interference from distractors during tasks of moderate effort, but these resources are overwhelmed when additional processes associated with episodic retrieval, or categorization of complex prototypes, are required. A growing body of research shows that the presence of irrelevant information, which is a common factor in our real-world environment, diminishes performance in visual working memory (WM)  interferes with free recall  buffers that are involved in processing external visual stimuli , a measure that contrasts the hit rate for targets with the false alarm rate for lures  and interruption (relevant information for a secondary task) on WM, and revealed that distinct neural mechanisms underlie these two types of interference  could be diminished due to interference from processing concurrent, although irrelevant, visual information. In this example, recollection of details would be disrupted, yet a general assessment of recognition accuracy  would not reveal an impact of distraction. Second, because attentional resources are limited /(1-p(Forgotten)] and were used to compare performance with a mixed-design, 2 distractor modality  × 3 condition  ANOVA. The results showed a main effect of condition such that retrieval of relevant visual details during the distractor conditions declined relative to both the no distractor and control distractor conditions. There was no difference in the pair-wise comparison between the no distractor and control distractor conditions. Critically, there was no main effect of distractor modality and no interaction between condition and distractor modality.A direct comparison was performed between results of the auditory distractor study with the visual distractor study  was compared between conditions using estimates of d' /(1-p(Forgotten)] and revealed a main effects of age and of condition, as well as an interaction of age and condition. To interrogate this interaction, both within-group and between-group tests were performed. Pair-wise comparisons within the older adult group showed that retrieval of relevant visual details declined significantly in VD relative to SHUT and GRAY, and there was no difference between conditional correct scores for SHUT and GRAY. Between-group comparisons, which directly compared conditions for older and younger adults, revealed an aging-related decline in episodic retrieval in VD, while there were only trends for aging-related declines in SHUT and GRAY. This finding that older adults exhibited diminished detailed LTM in the setting of visual distraction is in contrast to the absence of an age-related change on overall recognition as the impact of distraction, thus establishing the selectivity of distractibility on episodic retrieval.A mixed-design ANOVA (younger/older × SHUT/GRAY/VD) compared conditional correct scores  that exhibited greater functional connectivity in common with the left hippocampus and the left LOC seed during SHUT correct than incorrect Figure . This leNext, we evaluated the impact on this functional network from visual distraction during episodic retrieval. In comparisons of the left-lateralized hippocampus-VLPFC-LOC network between the SHUT and VD conditions, functional connectivity decreased in association with VD correct, relative to SHUT correct, and, critically, no longer supported episodic retrieval . Moreover, a regression analysis revealed that the change in network connectivity between SHUT correct and VD correct was correlated for an index of left VLPFC with left hippocampus connectivity and an index of left VLPFC with left LOC connectivity Figure . The resThe mutual functional connectivity of the left VLPFC region with an object-selective region involved in visual imagery and a memory region critical for episodic retrieval suggests that the left VLPFC may serve as a source of cognitive control in a functional network necessary for the selection of contextual mnemonic details based on visual imagery. Based on the results from the fMRI study, the causal involvement of the left VLPFC ROI in episodic retrieval was assessed using repetitive transcranial magnetic stimulation (rTMS) to perturb normal function immediately prior to test blocks in the memory test  × rTMS  × Condition (SHUT|VD) revealed a main effect of Condition and a significant interaction of Site × Condition. Correct responses decreased during VD, relative to SHUT, and this disruption of episodic retrieval was to a greater degree in the VLPFC experiment than the Vertex experiment Figure . The ANOThe fMRI study revealed for the first time that the fidelity of episodic retrieval declines in the presence of irrelevant external information and that this decline is associated with disrupted hippocampal function. Our interpretation of the fMRI results obtained during the SHUT condition is that the fidelity of episodic retrieval depends upon reinstatement of encoded representations for details relevant to memory goals, or visual imagery. This is consistent with results from previous fMRI studies that have shown reinstatement of activity associated with encoding visual stimuli when recognition was successful  showed that distractibility during categorization was greater for older than younger adults.Morph ratio was compared as a repeated measure of condition (plain|distractor) between groups (younger|older). The results showed a main effect of group, such that younger adults categorized at a lower morph ratio  than older adults. An interaction of age × condition revealed that older adults were more susceptible to visual distraction during categorization than younger adults. Critically, comparisons between age groups showed no difference in performance in the plain condition, but older adults categorized with a significantly higher morph ratio in the distractor condition than did younger adults. Results within the group of older adults suggested that distractor exemplars were categorized with a higher morph ratio than plain exemplars. We analyzed the basis for this pattern in the results by comparing the mean distractibility index between age groups. An index for each participant was calculated as morph ratio in the distractor condition minus morph ratio in the plain condition, such that a positive value showed a disruptive effect of distractibility Figure . An indeThe study examined for the first time, to the best of our knowledge, the impact of distraction on categorization learning. We found that distractors did not affect categorization of morphed exemplars for younger adults. This finding reveals that top-down processes engaged to enhance representations of relevant stimulus features during categorization are undisturbed when additional control resources are required to suppress processing of irrelevant bottom-up information during the distractor condition , the precise locus where information from bottom-up processes associated with distraction interferes with information represented from LTM stores is, as yet, unclear. A potential substrate where perceptual information might intersect with top-down selection and tuning processes necessary for representation of episodic details is illustrated by the notion of coherence fields (Serences and Yantis, We also recently examined the impact of visual distraction on categorization learning, using a task that is orthogonal to LTM retrieval yet very demanding on the fidelity of information represented in immediate memory (Jiang et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Common spatial pattern (CSP) is one of the most popular and effective feature extraction methods for motor imagery-based brain-computer interface (BCI), but the inherent drawback of CSP is that the estimation of the covariance matrices is sensitive to noise. In this work, local temporal correlation (LTC) information was introduced to further improve the covariance matrices estimation (LTCCSP). Compared to the Euclidean distance used in a previous CSP variant named local temporal CSP (LTCSP), the correlation may be a more reasonable metric to measure the similarity of activated spatial patterns existing in motor imagery period. Numerical comparisons among CSP, LTCSP, and LTCCSP were quantitatively conducted on the simulated datasets by adding outliers to Dataset IVa of BCI Competition III and Dataset IIa of BCI Competition IV, respectively. Results showed that LTCCSP achieves the highest average classification accuracies in all the outliers occurrence frequencies. The application of the three methods to the EEG dataset recorded in our laboratory also demonstrated that LTCCSP achieves the highest average accuracy. The above results consistently indicate that LTCCSP would be a promising method for practical motor imagery BCI application. Brain-computer interfaces (BCI) use electroencephalographic signals or other electrophysiological measures of brain activity to provide a new nonmuscular channel for sending messages and commands to the external world. According to the different electrophysiological signals which they use, BCI can fall into 6 groups : visual Feature extraction and classification algorithms play important roles for the performance of ERD/ERS based BCI, and there are various methods have been proposed to extract ERD/ERS related features , 12, sucxl and xm (both xl and xm are N-channel EEG recording vectors at two given time points l and m) as a weight to emphasize the covariance matrices , while the Euclidean distance distributes in a wide range, which makes LTCCSP more stable than LTCSP.Use of correlation may reduce the possibility of imposing small weight to natural EEG signal. τ in LTCCSP, while in LTCSP there are two parameters need to configure, τ and σ, which makes LTCCSP easier to implement in practical use.There is only one parameter In summary, compared with the Euclidean distance-based LTCSP, correlation-based LTCCSP may provide the following merits. It should be noted that several methods have also been proposed to improve CSP's performance. For example, adaptive CSP is developed to deal with time-varying signals ; nonlineIn this paper, we proposed a practical feature extraction method named LTCCSP, which considers local temporal correlation information in the learning process of the conventional CSP, for optimizing spatial filters. The current results confirmed that LTCCSP has the ability to obtain meaningful spatial filters from natural EEG data and noise influenced EEG data. Furthermore, LTCCSP is simple for application as there is only one parameter that needs to be configured. However, it should be noted that though LTCCSP shows its effective ability for motor imagery-related feature extraction, it still cannot completely suppress the introduced noise, and much work is still needed to promote for a more robust feature extraction.