Event-related potentials (ERP) have widely been used to study inhibition in adults suffering from various psychopathological states. In particular, depressive disorder has been linked to ERPs modulations, at early as well as at latter stages of the information-processing stream, when processing affective material. For instance, deficits in inhibiting negative information have been indexed by changes in the parameters (amplitudes and latencies) of early P2, P1 and N1 components while other ERP studies have shown an ability to differentiate depressed patients from normal controls based upon response inhibition difficulties in go-nogo tasks, indexed by later NoGo P3 differences. In this review, we will focus on results of ERP studies investigating inhibition and its interaction with emotional related cue processing in depressive populations. Implications for future research and theoretical perspectives will be discussed within the framework of current models of depressive disorder, based upon the hypothesis that negative ruminations are at the center of depression processes.Major depression is a serious disorder of impaired emotion regulation. Emotion hyperactivity leads to excessive negative ruminations that daily hijack the patient’s mental life, impacting their mood. Evidence from past researches suggest that depressive patients present several cognitive impairments in attention and working memory, leading to a more acute selective attention for negative stimuli and a greater accessibility of negative memories. Recently, is has been proposed that impaired inhibitory functioning with regard to emotional information processing might be one of the mechanisms of ruminations linking memory, attention and depression. It seems that inhibition deficit is present at both  Depressed patients seem to daily experience sustained negative affect and a persistent reduction in positive affect that impact their thoughts, behavior, mood and physical health. Importantly, those ones cannot just swap out of negative vibes. Current pharmacological and psychological treatments are quite effective in reducing depressive symptoms at short term, but relapse rates remain very high . ConsideMajor Depressive Disorder is a serious disorder of impaired emotional functioning. Behavioral studies investigating the emotional processing stream – which, ranges from an interpretation of the stimulus to the preparation of an appropriate behavioral response  – have sHowever, perception and recognition are not the only impaired faculties in the emotional functioning in depressed individuals. A deficit in emotion regulation - the processes that influence when and how emotions are experienced  – has wiMoreover, brain imaging studies, such as functional magnetic resonance imaging (fMRI) researches, have been conducted in order to highlight the defective brain circuitry in depression that further support the idea of an impaired emotional processing in Major Depressive Disorder. Various neuropathological and neurochemical abnormalities have been found in depressive patients within the neural systems that modulate emotional behavior . A partiImportantly, researchers have begun to explore the neural correlates of emotion regulation strategies . They obRumination – a style of information processing defined by the process of recurrent thoughts and ideas  – is a pIt’s likely that there are a number of factors that affect emotion regulation in depression. Notably, cognitive models suggest that cognitions play a crucial role in emotion regulation processing  in behavioral tasks that required participants to ignore emotional (positive or negative) material to response to a target stimulus such as the emotional Stroop Task . They are required to name colors of positive, neutral and/or negative words. Researchers then examine time responses for each emotional condition, reflecting different mechanisms of interference, which include interference inhibition. Note that this task, traditionally used in neuropsychological studies on inhibition, does not allow distinguishing between active selection of task relevant material and active inhibition of task-irrelevant  material . One of those stimuli consists in a probe trial, and the other consists in a prime trial. Subjects have to specify the valence of the probe trial as fast as possible. Accordingly, the time necessary to respond depends on the prime trial. Indeed, the probe trial is processed faster when the prime is valence-congruent, while slower when the prime is valence-incongruent. On the following trial, the previous prime may become the new probe trial (or not). In this special case, priming occurs because the prime triggers other information of the same valence  . Two conditions can occur: (1) a valid cue condition in which the target appears at the same location as the cue, and (2) an invalid cue condition in which the target appears at a different location as the cue. Cue validity is inferred if the reaction times (RTs) in the valid cue condition are significantly shorter than those in the invalid cue condition. On the contrary, an IOR effect is obtained if the RTs in the valid cue condition are not significantly shorter than those in the invalid cue condition.In a classical cue-target task, participants are required to response to the location of a target appearing after a cue . In an affective Go-NoGo task, subjects are required to respond to stimuli of one valence while inhibiting responses to stimuli of the opposite valence , which set up a prepotent response tendency and not to another one (“NoGo” stimulus), which require that prepotent response tendency to be inhibited  and late  components have been explored depending on the tasks used to assess cognitive inhibition. That is, neuronal processing related to cognitive inhibition can be examined with electroencephalography (EEG) when combined with particular paradigms from used in cognitive psychology studies.Firstly, detected around 60–140 milliseconds (ms) after stimuli onset, the P1 component consists in a positive deflection, which is thought to index the low-level features of stimuli and initial encoding for sensory information . SecondlFirstly, detected around 300–600 ms after stimuli onset, the P3 component consists in a positive deflection thought to index late evaluation stage of processing and updating in working memory . EvaluatFrom now on, behavioral studies investigating cognitive inhibition deficits in MDD, through the used of inhibitory tasks described above, have found consistent impairments both in the processing of neutral material , and in Importantly, most of those studies have suggested that the valence-specific (negative) inhibition impairment observed in MDD play a crucial role in rumination . That isOnly recently, studies have begun to explore the neural correlates associated with depression-related impaired inhibition over emotional stimuli with electroencephalography (EEG) during particular tasks in which participants have to inhibit some task-irrelevant information. Mounting ERP evidence indicates that depressive individuals display inhibitory dysfunction at the input and the higher level of the information processing-stream. We summarized here ERPs studies investigating inhibition in MDD.In another study, Furthermore, interested in exploring the neural correlates of interference inhibition ability for emotional words in MDD patients, Another research has used a cue-target task to investigate the phenomenon of inhibition of return (IOR) in depressed individuals. In this study, In summary, behavioral studies have shown that MDD patients present inhibition dysfunction for negative material. Importantly, those results are mirrored in ERPs data, which shows that it modulates the earlier attention allocation stage as well as the later evaluation stage.Depressed patients seem to daily experience sustained negative affect and a persistent reduction in positive affect. Several questions remain to find out why depressed patients cannot just swap out of negative vibes. Therefore a major research challenge is to identify contributing factors to the development, the maintenance and the recurrence of Major Depressive Disorder. It has been shown that the system that filters emotionally relevant information from irrelevant one is impaired in patients with Major Depressive Disorder and that this could underlie rumination by linking depression, attention and memory deficits observed in the disease. We reported here behavioral and ERPs results related to inhibition. Importantly, ERPs data mirror behavioral results showing that MDD patients present inhibition dysfunction for negative material, which modulates the earlier attention allocation stage as well as the later evaluation stage. Several theoretical and clinical implications for future developments arise from this.Indeed, better theoretical knowledge of Major Depressive Disorder and its underlying cognitive deficits are needed. ERPs, with its good temporal resolution, seem to be a preferred technique to study cognitive impairments at a neural level. Moreover, ERPs could allow us to further deep into inhibitory processes. For instance, recent studies have suggested that diminished inhibitory control in response to a negative stimulus might in fact stem from a breakdown in both reactive and proactive cognitive control , 2014. TIn this vein, using ERPs could be of major relevance for clinicians. Firstly, future diagnosis and treatment procedures could be facilitated by the use of ERPs as they have shown in previous studies their ability to discriminate between currently depressed patients remitted patients and never depressed controls . SecondlAn interesting question would be whether boosting inhibition in MDD patients could lead to less rumination. For instance, cognitive training  and neurWith their potential to measure the evolution of resistance to distracting interferences, ERPs could be used as a way to assess inhibitory control, when patients are processing negative emotional stimuli, from baseline to one of those treatments’s endpoint. Furthermore, in the aim to individualize treatment based on the personal characteristics of each patient, ERPs could help to predict which patient could benefit from those treatments. That is, patients who don’t display inhibition deficits, when viewing negative emotional stimuli at baseline, should presumably not benefit from inhibition improvement treatments. Therefore ERPs combined to an inhibition task at baseline of treatment could have predictive value and be useful in the selection of patients who could benefit from it. However, further investigations are needed for neurophysiological biomarkers being regularly used in clinical psychiatry, which requires multi-guidelines to be developed for ERPs recording .Major Depressive Disorder patients cannot just swap out of negative vibes. Based upon the hypothesis that negative ruminations are at the center of depression processes and are probably underlined by impaired cognitive inhibition, we would preconize a multi-disciplinary treatment approach of the disease including social, psychological and medical support/treatment. Among them, neuromodulation techniques, such as transcranial Direct Current Stimulation (tDCS), Mindfulness and cognitive inhibition training could enhance depressed patients’ abilities to inhibit negative ruminations. ERPs, given their high sensitivity for cognitive impairments, could play a crucial role by highlighting which impaired cognitive process should be trained in order to improve the patient’s clinical state.All authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication.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.


Proof-of-concept has long been gained from both Huntington's disease (HD) animal models and pilot clinical trials that transplantation of fetal striatal tissue has the potential to offer a substitutive therapy to HD patients  in the striatum is a hallmark of HD. Hence, production of this cell type from pluripotent stem cells holds promises for achieving brain repair  cells isolated from 9 to 12-week-old human fetuses, possess the machinery for long-term survival, proliferation and differentiation (Sarchielli et al., in vitro modeling and ex vivo experiments have recently provided a molecular definition of developing striatal anatomy, showing how transcriptional and functional processes converge to specify human striatal and neocortical neurons during development (Onorati et al., in vitro the differentiation of human pluripotent stem cells toward MSN, as well as when grafting fetal striatum.Caudate-putaminal transplantation of human striatal primordium is straightforward in its procedure, since just involves the injection of a dissociated cell suspension into the adult HD brain without any additional growth factors or other supply (Bachoud-Lévi and Perrier, Even if deeper understanding is needed to fully answer the question “what constitutes a functional striatal graft,” provided it is taken within the appropriate developmental stage, striatal primordium seems to fulfill the requirements for effective repair. We definitely agree that a pure MSN fate may not be sufficient for successful stem-cell based transplantation protocols, especially because multiple types of striatal neurons and glial cells are required for a full striatal reconstruction. Therefore, more sophisticated differentiation protocols will be necessary. In the meanwhile, it would be extremely important for people who are now living the dramatic condition of HD prospective trials be undertaken to assess the clinical utility of fetal-tissue based therapies. Certainly, several challenges remain to be faced, including overall optimization of graft procedure and patient management (Baizabal-Carvallo, 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.


Eye movements are a valuable window into the integrity of central nervous system structures and their changes in defined neurodegenerative conditions, that is, the oculomotor nuclei in the brainstem together with their directly activating supranuclear centers and the basal ganglia as well as cortical areas of higher cognitive control of attention.The evolution of the fovea centralis, the most central part of the retina and the area of the highest visual accuracy, requires humans to shift their gaze rapidly (saccades) to bring some object of interest within the visual field onto the fovea. In addition, humans are equipped with the ability to rotate the eye ball continuously in a highly predicting manner (smooth pursuit) to hold a moving target steadily upon the retina. The functional deficits in neurodegenerative movement disorders  involve the basal ganglia that are critical in all aspects of movement control. Moreover, neocortical structures, the cerebellum, and the midbrain may become affected by the pathological process. A broad spectrum of eye movement alterations may result, comprising smooth pursuit disturbance , saccadic dysfunction , and abnormal attempted fixation . On clinical grounds, videooculography is a sensitive noninvasive  Eye movement assessment potentially provides a valuable window into the human central nervous system function and may help to obtain insights into the structure of complex forms of human behavior including attentional control , 2. Furt10 bits/s whereas only approximately 3,000,000 bits/s are leaving the retina due to the limited number of available axons of the optic nerve and finally less than 10,000 bits/s are believed to be under attentive scrutiny [Evidence for the need of intrinsically organized brain activity associated with visual input depends on the almost infinite visual information received by the human eye from the external environment . Before scrutiny . This coscrutiny  and othescrutiny , fronto-scrutiny , and Alzscrutiny . Patholoscrutiny .Retinal structure is divided into the fovea centralis with ultimate vision in its center and the larger periphery  so that humans have developed the ability to foveate or refoveate an object of interest in the visual field. Rotating the eye ball offers a somewhat more economical strategy to shift or to maintain an object of interest on the fovea than turning the whole head . In geneThis review summarizes the fundamental mechanisms of eye movement control, considering healthy and pathological states of the brain. More specifically, we discuss the main features of the oculomotor phenotypes that are specific for different movement disorders and that can serve as model conditions to study how distinct brain areas contribute to eye movement control. In addition, we focus on fixational eye movements as presenting a continuous range from microsaccades to  square wave jerks (SWJ) . Due to During the absence of any  stimulus, healthy subjects are expected to withhold any unwanted considerable gaze shift maintaining the eyeball in its primary position. However, by performing attempted visual fixation of an unmoving target, conjugated small (<1°), jerk-like, involuntary saccades (microsaccades) and slow conjugated drifts are near-instantly observed . For cleWith respect to their amplitude, larger microsaccades are termed as SWJ and also become evident during fixation . SWJ arePatients with neurodegenerative movement disorders frequently develop abnormal SWJ which frequently interrupt fixation, within the broad spectrum of oculomotor deficits , 27. SinDuring impaired stationary fixation such as sustained abnormal eye oscillations , patients may report that vision is becoming subjectively blurred . In geneAbnormalities during fixation can be investigated with Frenzel goggles or the ophthalmoscope by asking the patients either to hold their gaze steadily at the primary position or to shift their gaze towards eccentric positions. Frenzel goggles inspection of the patient's fixation ability accounts for a sensitive instrument to address fixational dysfunction or nystagmus. Unlike the ophthalmoscope, Frenzel goggles are equipped with small lights illuminating the patient's eyes and provide high-powered positive magnifying glasses (>+15 diopter) that disable the subject to adequately fixate any target in the visual field . Hence, To overcome these limitations, computer-based recording techniques are applied to quantify subtle alterations in eye movement control, that is, electrooculography, scleral search coil systems, and videooculography (VOG). The past decades have emerged easy manageable computer-based eye trackers with integrated software environment for both stimulus design and automated data analysis for laboratory and portable usage. Scleral search coil systems and VOG emerge as the most widely used techniques to quantify eye movements, although electrooculography is yet the only device allowing recordings with closed eyes. The VOG measurement offers the best compromise between easily tolerable, noninvasive measurement and spatial and temporal resolution but requires advanced calibration techniques to be able to accurately quantify oculomotor performance. In contrast, scleral search coil systems provide optimum spatial and temporal resolution and warrant no calibration approach due to the absolute calibration by default  but are Basal oculomotor network function  is usually tested by visually guided reactive saccades , 34, 35.Parkinson's Disease (PD) is the second most common neurodegenerative disorder with cardinal motor symptoms comprising hypokinesia, tremor, rigidity, and postural impairment, while a multitude of nonmotor conditions including cognitive decline as part of the disease process has become evident , 40. AutPD onset typically incorporates motor symptoms caused by dopaminergic nigrostriatal cell degradation in the basal ganglia which are critical in locomotion including eye movements. The substantia nigra pars reticulata tonically inhibits the superior colliculus (SC) via GABA-ergic projections, whereas pausing the inhibitory SC input provides a prerequisite for saccadic release . The SC Unlike the basal ganglia, the SC remains intact until later stages in the pathological process , and botDeterioration of dopaminergically mediated pathways in the basal ganglia in PD leads to overactive SC inhibition preventing the SC to trigger the brainstem saccadic generator. This may contribute to saccadic hypometria, as depicted in Terao et al.  proposedSPEM provide an optimum strategy of maintained movement adaptation in a highly predictive manner and involve large parts of the brain cortex, comprising primary visual areas like the striate and extrastriate cortex as well as the FEF and supplementary eye fields . LikewisThe mechanism of SWJ generation appears to be similar in PD patients and healthy controls, as indicated by Otero-Millan and coworkers . MoreoveIn summary, PD patients present with a broad spectrum of disturbed oculomotor function comprising saccadic intrusions during SPEM, impaired inhibition control, and hypometric saccadic gains, while eye velocities used to be normal. Notably, these deficits manifest early in the disease course; however, they can be observed in the symptomatic rather than in presymptomatic stages of familial PD cases. In general, as the disease progresses, the oculomotor disturbances develop their full spectrum. The combination of both, the observed oculomotor phenotype and autopsy-controlled findings in PD, may increase our understanding of eye movement control as (i) the oculomotor nuclei in the brainstem appear to be spared by the PD-associated pathological process and (ii) the oculomotor deficits may primarily reflect a lack of attentional control. In the clinical context, the quantitative objective measure of eye movements by means of VOG has the potential as a possible technical surrogate marker in PD , 67.MSA is a neurodegenerative disease characterized by autonomic and pyramidal dysfunction in addition to a broad spectrum of Parkinsonism presentations and cerebellar ataxia . On neurProgressive supranuclear palsy (PSP) is characterized by Parkinsonism associated with signs like supranuclear gaze palsy, early falls, dysphagia, dysarthria, axially pronounced rigidity, and behavioral/cognitive impairment . PSP canStudy of oculomotor dysfunctions both in PSP-RS and in PSP-P revealed a similar presentation comprising slowed vertical saccades, saccadic hypometria, prolonged latencies, and impaired pursuit eye movement . In advaRemarkably, SPEM remain intact even in severely impaired PSP patients as long as a target is continuously moving in a predictive manner with low peak velocity and acceleration. This could be demonstrated when patients were asked to track a sinusoidal oscillating spot with low frequency . With inAutosomal dominant Huntington's disease (HD) is a progressive neurodegenerative disease, clinically presenting with a hyperkinetic movement disorder (chorea), cognitive decline, and behavioral symptoms . The agePresymptomatic gene carriers show subtle cognitive and motor impairment due to striatal and cortical neuropathological changes that cause increased error rates during inhibition tests such as antisaccades  and likeCerebellar signs manifest in many neurodegenerative movement disorders such as MSA and in the heterogeneous group of hereditary spinocerebellar ataxia. One prominent feature is cerebellar ataxia with impaired body posture; in addition, patients present with dysarthria, dysmetria, and dysdiadochokinesia . Cerebel In vivo examination of the oculomotor system offers a valuable window into altered brain function in the pathological state of movement disorders. Thus, we can learn about the contribution of different functional systems that may interfere with the way we direct our attention in the visual scene. In addition, oculomotor control covers large portions of the whole brain that appear to be decomposable into two major subdivisions: (i) the oculomotor nuclei responsible for the innervation of the six extraocular eye muscles and (ii) the much more complex network of higher cognitive control that is strongly associated with visual attention.In the absence of definitive biomarkers, VOG holds promise for a complementary noninvasive tool to characterize the oculomotor phenotype of distinct disease entities within the spectrum of neurodegenerative diseases. In the course of neurodegenerative disorders, disease-specific brain structures get systematically damaged. Hence, the resulting clinical condition might be considered as an investigational model for the contribution of functional components to eye movement control. in vivo method to detect alterations in oculomotion function in patients with neurodegenerative movement disorders. Malfunctioning oculomotor control appears to have some characteristic feature that can give clues to be attributed uniquely to the subtype of the movement disorder. More specifically, other neurodegenerative types of Parkinsonian syndromes can be differentiated from PD early in the course. One should keep in mind that some of the Parkinsonian-associated hallmarks such as slowed eye velocities could also manifest in other neurodegenerative (nonmovement) disorders, resulting in the necessity for careful interpretation of VOG results in the light of the clinical presentation. Particular aspects such as SWJ or larger intruding eye movements may provide motivation for future investigations  to Notably, attentional dysfunction in oculomotor control mostly presents early in the course of neurodegenerative movement disorders even while no obvious cognitive deficits exist. This finding prompts the notion that even a subtle pathology of cortical networks may cause a broad variety of oculomotor alterations. To further investigate the complex nature of visual attention and the way we direct or withhold our gaze, it might be safe to assume that we can learn much from pathological conditions related to specific functional systems. This approach offers the possibility to refine our existing models of human oculomotor networks whose functional interaction may be considered an essential framework for higher functions such as visual attention.


Self-administration of medicines is believed to increase patients' understanding about their medication and to promote their independence and autonomy in the hospital setting. The effect of inpatient self-administration of medication (SAM) schemes on patients, staff and institutions is currently unclear.To systematically review the literature relating to the effect of SAM schemes on the following outcomes: patient knowledge, patient compliance/medication errors, success in self-administration, patient satisfaction, staff satisfaction, staff workload, and costs.Keyword and text word searches of online databases were performed between January and March 2013. Included articles described and evaluated inpatient SAM schemes. Case studies and anecdotal studies were excluded.43 papers were included for final analysis. Due to the heterogeneity of results and unclear findings it was not possible to perform a quantitative synthesis of results. Participation in SAM schemes often led to increased knowledge about drugs and drug regimens, but not side effects. However, the effect of SAM schemes on patient compliance/medication errors was inconclusive. Patients and staff were highly satisfied with their involvement in SAM schemes.SAM schemes appear to provide some benefits (e.g. increased patient knowledge), but their effect on other outcomes (e.g. compliance) is unclear. Few studies of high methodological quality using validated outcome measures exist. Inconsistencies in both measuring and reporting outcomes across studies make it challenging to compare results and draw substantive conclusions about the effectiveness of SAM schemes. The Royal Pharmaceutical Society (RPS) describes patient self-administration of medication (SAM) as a ‘transfer of responsibility’ which should be dependent on a patient's ability to manage the tasks involved, as well as giving their consent to do so Hospital SAM schemes often incorporate several stages of increasing patient independence and decreasing nurse involvement as patients become more competent For many patients, it is important to be able to self-administer their medications successfully as they will often be expected to do so once they are discharged from hospital. In line with this, the UK's National Institute for Health and Care Excellence (NICE) states that prescribers should, ‘when possible, support patients to take responsibility for their medicines and self-manage their conditions' It has been proposed that patients, staff and healthcare systems will benefit from the implementation of a SAM scheme We reviewed the literature in order to answer the following questions about hospital inpatient self-administration:What types of SAM scheme interventions have been implemented by healthcare professionals among hospital inpatients?What effects have these interventions had on outcomes related to patients, staff and institutions?We undertook a systematic search of the literature and a narrative synthesis. Full details of the study protocol can be accessed via PROSPERO [reference CRD42013003498] We included randomised controlled trials (RCTs), non-RCTs, cohort studies, observational studies, cross-sectional studies, before-and-after studies, and case series. Case studies and anecdotal studies were excluded, as were those which did not evaluate the scheme or provided insufficient information about the evaluation.We included studies that reported evaluations of SAM schemes implemented in a hospital inpatient setting. We excluded texts for the following reasons: where patients were assisted by relatives or carers, as this may negate the experience of self-administering; where drugs were administered as needed by patients (PRN), as these did not follow a pre-specified regimen; studies which described outpatient or community-based interventions; or where patients would use their own (prescribed or otherwise) drugs that were not dispensed by the hospital. The reasons for excluding the latter group were that patients' own drugs are generally considered to reduce medication waste and aid the reconciliation process on admission, and is not necessarily an indicator of self-administration. In addition, we felt the use of the patient's own drugs for self-administration may be more likely to have been initiated by the patient, as opposed to a structured scheme implemented by the healthcare team, as our objective states.We included studies that provided information on at least one of the following primary outcome measures: patient knowledge and patient compliance or error. We also investigated a number of secondary outcome measures: patient success in self-administering; patient satisfaction; staff satisfaction; staff workload; and costs.We performed a comprehensive search see  based onTitles and abstracts of papers identified in the search were reviewed independently by two of four review authors , and articles that appeared to fulfil the inclusion criteria were retrieved. The degree of agreement for each pair of reviewers was calculated using Kappa coefficients. Where there were discrepancies, a decision to include or exclude the study was reached by consensus between the two reviewers, or if necessary a third reviewer was also involved. From the full text of these papers, three review authors  independently established whether studies met the inclusion criteria.Included texts were assessed for quality of reporting using a modified version of the quality assessment checklist for health care interventions developed by Downs and Black Studies were assessed independently by two of three reviewers  and the third reviewer acted as adjudicator where consensus could not be reached.For each text, two of the three aforementioned reviewers independently undertook data extraction using a piloted data extraction form. Information was collated on rationale, aims and design of intervention, population, country, study design, baselines and comparators, outcomes and reported barriers. Due to the anticipated heterogeneity of study designs and reported outcomes a narrative synthesis is presented.The searches identified 1321 articles, and from these 160 studies were independently selected by two reviewers based on titles and abstracts see . One hunThe characteristics of the 43 included studies are shown in The rationale behind implementing a SAM scheme in each study was either explicitly stated or it was possible to infer the rationale from the article. The most common reasons for implementing SAM schemes were to improve patient compliance (n = 28), to improve patient knowledge (n = 18), to increase patient independence (n = 14) and to reduce medication errors (n = 4); most studies provided multiple reasons.Of the 43 interventions, 10 SAM schemes had a single-staged approach to patient self-administration The types of drugs self-administered varied between studies, often reflecting different study populations. Most studies did not specify which drugs were self-administered (n = 23) or simply allowed all drugs to be self-administered (n = 3). Commonly described self-administered drugs included psychotropic medicines Outcome measures were assessed at a variety of time points across the 43 studies, from admission to a maximum of 24 months after patients started the SAM scheme Nineteen studies assessed patients' knowledge of their own medicines Of the five RCTs that measured patient knowledge, four found a greater increase in knowledge in SAM participants compared with control participants Twenty four studies measured patient compliance/error Four studies compared the change in compliance over time in patients who were self-administering Nineteen studies investigated patient satisfaction with SAM programmes Success within the SAM scheme was measured in 12 studies Seven studies investigated staff satisfaction with SAM schemes Seven studies investigated the effect of SAM schemes on staff workload Financial costs of implementation were not explicitly measured by any of the studies reviewed. However, anecdotal evidence from three studies suggested that SAM schemes may increase costs due to supplying individual patient medicines and memory aids In the current review we observed mixed findings concerning the effectiveness of implementing SAM schemes on a variety of patient, staff and institution-related outcomes. We were able to answer the following research questions:Types of interventions varied broadly in their specific structures (e.g. numbers of stages within a SAM scheme), but in principle were very similar in allowing patients to self-administer with increasing independence and decreasing staff involvement. This was reflected in the consistency of authors' rationales for implementing SAM schemes, which were comparable across all studies. A variety of drugs were self-administered in the included studies, and a number of different patient groups assessed. It is clear from the patient populations utilised in these studies that chronic illness is a focus for self-administration programmes.Overall the effect of SAM scheme interventions appears mixed. Some studies concluded that SAM schemes had positive effects on the various outcome measures whilst others provided neutral or inconclusive, though rarely negative, conclusions. There was some evidence to suggest that patients' medicines knowledge increases through involvement in a SAM scheme, but not whether this involvement improves compliance, as has been suggested in some research Most patients were successful in self-administering medications, and it is possible that certain patient, setting or medication factors are related to the success of SAM schemes. We noted some weak evidence that those patients with greater cognitive function were more likely to be successful There are a number of potential barriers to the implementation of and success within SAM schemes, such as the need for additional pharmacist time in preparing medicines et al argue that patient satisfaction scores are often misrepresented It may be challenging to draw extensive conclusions from the included studies as many lack methodological rigour, as reflected by the wide variation in the quality assessment scores. Similar to the previously conducted literature reviews in this area Our study has a number of limitations. Despite performing a rigorous literature search, almost half (19 out of 42) of our final studies were identified through hand-searching after our electronic searches were complete. This may suggest that our original search was not broad enough to capture all relevant papers in the first instance, or that the articles found by hand searching were not well indexed. Although our search was not restricted by language, some language bias was still inherent as our search was conducted using English-language search terms. Only two papers that were not written in the English language were assessed at full-text level; both were eventually excluded as they did not fit our inclusion criteria. It may be possible that we have excluded alternative cultural perspectives on self-administration or that the practice of self-administration itself is more prevalent in English-speaking countries. Finally, a strength of our review is that we assessed the included studies for methodological quality; despite using an adapted version of the Downs and Black quality assessment scale we still believe the adapted version provides a good indication of the relative quality of studies both within and outside of this review Overall, some significant improvements in patient knowledge and compliance due to SAM schemes were observed; however these findings were not consistent across studies. There were varied findings regarding patient and staff satisfaction with SAM schemes and the success of patients within such schemes. A number of barriers to implementing SAM schemes were identified, including increased staff workload, costs, and physical difficulties for patients. It appears that, in some situations or groups, SAM schemes may be effective in helping patients to increase their independence and regain control over some aspects of their care through improved knowledge of and greater compliance with their medication regimen. An increased sense of control may be particularly poignant for specific patient groups for whom hospital spells may be long-lasting or frequent, such as those managing chronic conditions. Further research of good methodological quality and the development of standardised measures are required to successfully evaluate the effect of SAM schemes on a variety of patient, staff and system outcomes. It is important to ensure that SAM schemes balance the benefits of patient independence and increasing knowledge with the potential for increased demands on staff time and the financial implications of implementation.Table S1Database search strategies.(DOCX)Click here for additional data file.Table S2Study characteristics by design.(DOCX)Click here for additional data file.Table S3Study outcomes and results by design.(DOCX)Click here for additional data file.Checklist S1PRISMA 2009 Checklist.(DOC)Click here for additional data file.


Social animals can identify conspecifics by many forms of sensory input. However, whether the neuronal computations that support this ability to identify individuals rely on modality-independent convergence or involve ongoing synergistic interactions along the multiple sensory streams remains controversial. Direct neuronal measurements at relevant brain sites could address such questions, but this requires better bridging the work in humans and animal models. Here, we overview recent studies in nonhuman primates on voice and face identity-sensitive pathways and evaluate the correspondences to relevant findings in humans. This synthesis provides insights into converging sensory streams in the primate anterior temporal lobe (ATL) for identity processing. Furthermore, we advance a model and suggest how alternative neuronal mechanisms could be tested. Our ability to identify unique entities, such as specific individuals, appears to depend on sensory convergence in the anterior temporal lobe.However, the neural mechanisms of sensory convergence in the anterior temporal lobe are unclear.Alternative accounts remain equivocal but could be tested by better bridging the findings in humans and animal models.Recent work in monkeys on face- and voice-identity processes is helping to close epistemic gaps between studies in humans and animal models.We synthesize recent knowledge on the convergence of auditory and visual identity-related processes in the anterior temporal lobe.This synthesis culminates in a model and insights into converging sensory streams in the primate brain, and is used to suggest how the neuronal mechanisms for identifying individuals could be tested. Certain individuals are unmistakable by their visual face or auditory voice characteristics, others by their smell or how they move. Identifying an individual, or any other unique entity, is an instance of the general problem of object identification, which is a process occurring at different levels of categorization . At a basic level, identifying objects relies on recognizing the categorical features of the object class; social animals can also perceptually categorize species membership, social rank, body size, or age amodal  Initial insights into the regions underlying the identification of individuals were provided by lesion and However, current accounts of the neural processes involved in assessing identity remain equivocal. The most common approaches can identify the large-scale neural substrates but provide limited insights into the overlap, segregation, and form of neuronal representations involved in identity processes, because neuroimaging approaches measure either surrogates of neuronal activity or large-scale neural responses. Consequently, there is a need for direct measures of localized neuronal computations to resolve alternative accounts. Direct neuronal recordings (depth electrode recordings or electrocorticography) in human patients being monitored for neurosurgery can inform on neuronal function in localized regions in the human brain, while work in animal models can describe neuronal processes at multiple scales directly from the regions of interest and offers greater specificity in neuronal manipulation (activation and/or inactivation). However, until recently the animal work had not kept apace. The current literature in humans considers multisensory interactions and convergence as a research priority, with studies often collecting data from at least two sensory modalities Here, we briefly overview two alternative neurocognitive models of identity processing developed in humans. We then review recent studies on voice- and face-identity processes and multisensory pathways conducted in nonhuman primates and evaluate the correspondences to relevant findings in humans. From this synthesis, we propose a model of primate ATL function for identity-related processes and use it to identify imminent gaps in our understanding. We conclude by suggesting how alternative neuronal mechanisms could be tested.Current theoretical models developed from human studies of face- and voice-identity perception have suggested that the related auditory and visual streams converge in the ATL sensitive regions might result in phonagnosia and affect voice–face multisensory interactions, but will not disrupt the ability to identify an individual with inputs from the preserved sensory modalities. Another ‘distributed-plus-hub’ model (or related ‘hub-plus-spoke’ models) for identity processing not only contains distributed processes, but also features the ATL as a key hub or convergence site whose function is amodal Two prominent, not mutually exclusive, models are as follows. A ‘distributed-only’ model proposes that the sensory features important for recognizing an individual engage distinct brain regions, interconnected into a network multisensory convergence sites, but differ in the processing at these sites. In this paper, we take this a step further to suggest neuronal mechanisms that could be tested even at the level of single neurons. For instance, multisensory convergence in the ATL as an amodal process suggests an ‘or gating’ function where one or another synaptic input is sufficient to result in neuronal depolarization. The alternative mechanism is a synergistic interaction of the available multisensory inputs, such that the form of neuronal representations depends on the combination of the different available inputs. It is also possible that the ‘or gating’ occurs as a side product of the converging synergistic multisensory neural process being assigned a top-down label.Both models rely on Thereby, different scientific lines have converged on questioning the neural multisensory interactions in ATL sites and the identity-related processes that they support. Although animal models cannot directly address questions of interest for lexical retrieval, since naming relies on human language, work in nonhuman animals can clarify which identity processes in the ATL are evolutionarily conserved and the cognitive functions that they support . Recent developments now allow better bridging gaps between the work in humans and other animals.First, face-sensitive neurons were identified in the monkey inferior temporal (IT) cortex as neurons that respond more strongly to face than to nonface objects voice content.Auditory studies in animal models have shown that neuronal responses typically become increasingly selective for complex sound features along the auditory processing hierarchy Regions responding more strongly to voice versus nonvoice categories of sounds were first identified in humans with functional magnetic resonance imaging (fMRI) There are multiple voice category-preferring clusters in the primate STP In monkeys, targeted neural recordings in voice identity-sensitive fMRI clusters in the ATL provided the first evidence for voice cells A [63]. Tselectivity of auditory ATL neurons is not unexpected However, the functional organization of face- and voice-sensitive clusters in the ATL may not be identical Regarding the nature of multisensory interactions underlying individual identification, there is now substantial evidence for anatomical and functional crosstalk at various stages of the sensory pathways in humans and many other animal species Several studies have also assessed the timing of neuronal responses relative to oscillatory activity, as a mechanism for routing and prioritizing sensory information Recently, the directional effective connectivity of the voice network was investigated using combined microstimulation and fMRI in monkeys, providing insights into voice-related and multisensory processing pathways in the primate ATL Surprisingly, microstimulating voice identity-sensitive cortex does not strongly activate PFC, unlike stimulation of downstream multisensory areas in the STS and upstream auditory cortical areas in the lateral belt However, there is a noted distinction between species intracranial recordings in monkeys.Human neuroimaging studies have shown that voice and face regions in the temporal lobe can be respectively influenced by the other modality beta band), whereas unisensory responses in the STG and FG were in the gamma band  of patients reported highly selective responses to pictures of known celebrities, such as Jennifer Aniston mma band . This miThus far, our understanding of how affecting neuronal processes or brain regions impacts on identity-related perception is limited. For practical reasons, recordings in monkeys and many human imaging studies are conducted with passive stimulation or a stimulus-irrelevant task, such as visual fixation. An earlier study showed that microstimulation of monkey IT neurons influenced subsequent face category judgments We propose a model of individual identity processes in primates, on the basis of the prior synthesis . PossiblThe primate model at a regional level is generally in agreement with human models on face and voice perception, whereby distinct sensory processing streams have prominent multisensory interactions between face and voice areas Furthermore, the multisensory computations underlying identity identification remain unclear. First, it is possible that, in certain ATL sites, a process resembling convergence on a larger scale might, at a finer scale, be found to be partially segregated by unisensory input While the notion of sites with amodal functions may well be disproved in the future, it is a useful concept for generating testable predictions on neuronal processes and multisensory interactions. It is also worth keeping in mind that the ATL is one of several highly multisensory convergence sites in the brain that serve various purposes. For example, the angular gyrus in humans is part of a multiple-demand, cognitive control network The proposed primate model may be generalized for testing in other nonhuman animals. Rodents identify each other by odor Outstanding QuestionsIs any sensory input at multisensory convergence sites sufficient for the identification of conspecifics, or are all incoming signals integrated and identification emerges out of their synergistic interaction?Which subregions of the human ATL support identity processes, how are they structurally and functionally interconnected, and how does this compare to data in animal models?How do ATL regions functionally interact with other brain regions, and is interaction with medial temporal lobe structures required for identity recognition and memory?Can animal studies clarify whether certain ATL processes are crucial for perception and/or conceptual knowledge? Attentional cuing tasks can be used to assess the perceptual awareness of an animal towards attended voice or face features. Also, person-specific conceptual knowledge could be modeled in nonhuman animals to assess modality-independent representations of specific individuals, using voices and/or faces of familiar animals or those with known social categories  within adaptation, oddball, or other experimental paradigms.What is the impact of degrading or inactivating a sensory input stream on the neuronal responses at face–voice convergence sites?Which subregions of the ATL have amodal representations of identity, and do these require an ‘or gate’ process or does top-down selection serve as the gating mechanism?Regardless of the nature of the multisensory mechanisms, what is the pattern of encoding at the neuronal subpopulation level in any of these regions  and how is this affected by removing sensory inputs?How do oscillatory mechanisms support identity representations in the ATL, and are these processes specifically involved in person identification or do they form part of general computational principles that apply across sensory tasks and brain regions?By reviewing recent voice- and face-related neurobiological work in nonhuman primates and humans, we suggest here several principles that may be eventually extended for modeling the basic neural processes involved in subordinate or identity perception. The proposed model highlights some possible neural mechanisms and the key areas of uncertainty between the primate and human models. We argue that the next step in understanding the neurobiology of identity perception will benefit from cross-species comparisons, direct access to local neuronal processes in different ATL subregions, and causal manipulation of sensory inputs into convergence sites. We also need information on effective connectivity and to better establish causal relations between neuronal processes and identity perception and cognition (see Outstanding Questions). All such work will need to involve more than just one sensory modality.


Understanding spontaneous transitions between dynamical modes in the neuronal networks is of great importance. For example, such transitions separate pathological and normal function of the brain. In this study, we developed a metric to capture the characteristics of such spontaneous transitions from asynchronous to synchronous dynamics and predict occurrence of these transitions in a simplified neuronal network. In this work we simulate excitatory and excitatory-inhibitory network and in these neuronal networks we examine how inhibition, network topology, noise level, and cellular heterogeneity affect network dynamics. In case of excitatory network, we saw three different types of dynamics depending on its underlying structure: 1) local connectivity leads to long propagating waves of activity, 2) small-world connectivity results in two coexisting phases of short waves of activity and episodes of synchronous activity, and 3) random connectivity pattern that provides synchronous dynamics. When the connectivity pattern is within the small-world region (Pe=0.1-0.2), firing rate is optimum and transitions into and out of the synchronous activity are frequent. Here noise is another factor that can shape dynamics, as our results indicate substantial increase in the noise level can prevent occurring of spontaneous transitions from asynchronous to synchronous dynamics.e=0.15), local inhibitory connectivity pattern significantly suppresses propagating chains of activity, even though the firing rate does not change remarkably. However, when inhibitory cells are connected randomly to other inhibitory and excitatory cells, network dynamics adopts long local traveling chains of activity with low frequency and the synchronous activity of the network was suppressed completely. Interestingly we learned that for a fixed connectivity pattern of excitatory network, when inhibition topology is in small-world region the probability that network goes under synchronous activity is maximized compare to the local and random connectivity pattern.Then, we investigated how various topologies of inhibitory connectivity affect the network’s spatio-temporal patterning. When the excitatory network has a fixed small world connectivity pattern (PUltimately, we developed and utilized different measures based on the spike timings to detect early sings of possible transitions into the bursting regime. These measures go through systematic changes prior to the onset of transitions into the bursting that can be interpreted as the early signs of incoming transition and based on that we can obtain a lead-time to predict future transitions. We show that this lead-time is a function of connectivity pattern of excitatory and inhibitory cells, and our predictability is higher when inhibitory neurons have small-world connectivity pattern rather than solely local or random connectivity.


The mechanisms of such effects are not known, but they deserve to be explored as current epidemiological findings suggest the possibility of primary prevention for inflammatory conditions such as allergy, through intervention during pregnancy.It has been proposed that helminth infection may be particularly detrimental during pregnancy, through adverse effects on maternal anaemia and on birth outcomes, and that anthelminthic treatment during pregnancy will therefore be particularly beneficial. However, the few treatment trials that have been conducted have given, but little support to this notion and further trials in settings of nutritional stress are needed. It has also been proposed that prenatal exposure to helminth infection has an important effect on the development of the foetal immune response. There is evidence that this may impact, long-term, upon responses to helminth and nonhelminth antigens, and to allergens. Exposure to helminths  Helminth infections are highly prevalent. In 2006, it was estimated that over a billion people were infected with one or more species of soil-transmitted helminth Observational studies on the effects of helminth infections in humans are fraught with strong potential for both measured and unmeasured confounding, as helminths occur in the most disadvantaged communities alongside poverty, lack of education and malnutrition. Helminth-infected pregnant women are likely to be younger, less educated and of lower socio-economic status than uninfected women Historically, pregnant and breastfeeding women have often been excluded from the treatment for helminths, due to concern about possible adverse effects of the drugs on the developing foetus. However, in 1994, the World Health Organization (WHO) recommended the treatment of pregnant women for hookworm, because of concern about hookworm-induced anaemia Trichuris trichiura are particularly important There is substantial evidence from studies in human subjects that certain species of helminth infection during pregnancy are associated with maternal anaemia, as reviewed by Brooker and colleagues in 2008 Studies in mice suggest that maternal worm infections influence foetal linear growth and the growth of lymphoid tissues and bone Schistosoma japonicum during pregnancy is in progress and scheduled for completion this year S. japonicum has been shown to be associated with inflammation in maternal, placental and foetal tissues in vitro suggest that exposure of trophoblast cells to S. japonicum egg antigen may result in impaired placentation If the hypothesis that anthelminthic treatment during pregnancy can have important benefits for maternal and infant birth outcomes is to be rigorously tested, and the policy of routine anthelminthic treatment during pregnancy is to be validated, large trials are still needed in a range of settings. It may be that anthelminthics will be found most useful in settings in which anaemia is prevalent, and where there is nutritional stress and limited access to haematinic supplementation. In such settings, single dose benzimidazoles, [which are easy to administer and have been highly effective against hookworm in most trials to date Pregnancy results in major hormonal and nutritional changes, and in immunological changes allowing successful allograft retention Studies in mice also suggest that pregnancy is associated with increased schistosome-induced pathology, related to reduced parasite-specific interferon (IFN)-γ but increased interleukin (IL)-4 production Schistosoma mansoni during pregnancy was not associated with an increased rate of miscarriage or still birth Treatment of schistosomiasis with praziquantel in nonpregnant human subjects is associated with release of worm antigen into the blood stream and with a boost in cellular and antibody responses to worm and egg antigen Helminth infections modulate the host immune response through a variety of mechanisms S. haematobium and Ascaris lumbricoides have been associated with lower malaria parasite densities Mansonella malaria associations observed in our study First, they may impact upon susceptibility to heterologous infections. Effects on susceptibility to malaria might be especially relevant during pregnancy, given its adverse impact on pregnancy outcomes Second, they may impact upon maternal metabolism – for example glucose metabolism Arguably, the most important potential impact of worm infections during pregnancy is upon long-term outcomes in the offspring.in utero to filarial antigen showed similar immunological and clinical outcomes to unexposed infants, but that children who were exposed in utero and not sensitized (suggesting the acquisition of tolerance) were slower to develop detectable cellular responses and more likely to become microfilaraemic than either sensitized or unexposed infants There is considerable evidence from studies in both animal models M. perstans infection had elevated IL-10 responses to both BCG-related and tetanus antigens, but these associations were seen only among infants of mothers who received no albendazole, suggesting that prenatal exposure to albendazole, or to its effects on maternal infections, blocked the ability of maternal M. perstans to promote regulatory responses to heterologous antigens in the infants Observational studies have also suggested that exposure to worm infections during pregnancy can alter the offspring's response to unrelated antigens, including vaccines, infectious diseases and allergens. A study in Kenya found that infants exposed and sensitized to schistosomiasis and filarial worms in utero showed a Th2 bias in their immune responses to BCG vaccine, while infants who were exposed but not sensitized showed a Th1 profile of response Besides tuberculosis, HIV infection and malaria are among the most important co-infections in helminth-endemic settings, and there is considerable controversy as to the effects of helminths on susceptibility to both M. perstans and S. mansoni were associated with increased risk of malaria incidence in the offspring In EMaBS, we also investigated associations between maternal helminth and maternal malaria infection and infant susceptibility to malaria. We found that maternal worm infections, including hookworm, Ascaris, Trichuris and Strongyloides), so the mechanism of the effect of albendazole was not clear. However, maternal hookworm showed a significant inverse association with eczema in childhood, which increased with intensity S. mansoni during pregnancy The most striking findings of EMaBS was that maternal albendazole during pregnancy was associated with an increased incidence of infantile eczema The mechanisms by which maternal helminth infection can influence outcomes in the foetus are not known. Investigation of these mechanisms might shed important light on the development on the infant immune response and inform the development of possible interventions for the primary prevention of immunologically mediated conditions, such as allergy in utero, and at first sight, this is surprising as most macromolecules and immune complexes in the maternal circulation are broken down by macrophages in the trophoblast, providing amino acids for the growth of the placenta and foetus and preventing transfer to the foetal circulation in uteroIt is clear that the human foetus can become sensitized to parasite in utero sensitization results in down-regulated responses among the offspring, on encountering the homologous antigen. As reviewed by Dauby and colleagues in vitro depletion of CD4 + CD25hi regulatory T cells in cord blood demonstrated their contribution to suppression of neonatal responses to malaria antigens in malaria-exposed infants With regard to helminth-specific immune responses, epidemiological evidence discussed above suggests that in utero sensitization down-regulates the (Th2-mediated) granuloma formation associated with pathology In addition to the possibility that antibodies facilitate the transfer of antigen across the placenta, there is evidence that maternal antibody idiotypes specific for helminth antigens can be transferred across the placenta and can themselves induce sensitization of the foetus in both animal models These possible mechanisms largely provide explanations for effects of maternal helminth infections on the offspring's response to the same helminth infection. How might maternal helminth infection influence the foetal response to unrelated antigens?Anisakis SimplexA. lumbricoidesDermatophagoides pteronyssinus; IgE, IgG and IgG4 cross-reactivity has been demonstrated between filarial antigen and cockroach allergen In the case of allergens, one possibility may be cross-reactivity between helminth antigens and allergens. There are many structural similarities between allergens and metazoan parasite immunogens Acinetobacter lwoffii was associated with reduced susceptibility to experimentally induced asthma in the offspring and that this was mediated by up-regulation of maternal Toll-like receptor (TLR) expression and circulating pro-inflammatory cytokines, and down-regulation of placental TLR expression Alternatively, maternal helminth infection might influence the foetal innate immune system in such a way as to modulate the response induced on co-exposure to a wide range of heterologous antigens including malaria, tetanus and mycobacterial antigen, as well as allergens. Allergologists have explored this possibility to investigate how prenatal exposure to a barn environment might influence the offspring's risk of allergy-related disease. Using a mouse model of experimental allergic airway inflammation, Conrad and colleagues showed that low-grade inflammation in the maternal lung induced by the cowshed-derived bacterium Helminth infection during pregnancy is common, but the benefits of anthelminthic treatment during pregnancy are not yet clear either for the mother or for the offspring. On the other hand, there is strong epidemiological evidence that prenatal exposure to maternal helminth infection tends to down-modulate the offspring's response following infection, resulting in increased susceptibility to the same helminth species, but reduced pathology. Thus, an unwanted consequence of partially successful intervention against helminths may be increased susceptibility to helminth-induced pathology in some endemic settings as prevalence during pregnancy declines. Of more interest, however, is the increasing evidence that prenatal exposure to helminths may influence the offspring's susceptibility to other conditions, and particularly to allergy-related disease. The mechanisms of this effect deserve urgent investigation as they may indicate possible routes to the primary prevention, or management, of these conditions.