Prospective collection of blood plasma samples to identify potential biomarkers for the prehospital stroke diagnosis (ProGrEss-Bio): study protocol for a multicenter prospective observational study.

Introduction: Intravenous thrombolysis (IVT) and mechanical thrombectomy (MT) are well-established, evidence-based, time-critical therapies that reduce morbidity and mortality in acute ischemic stroke (AIS) patients. The exclusion of intracerebral hemorrhage (ICH) is mandatory and has been performed by cerebral imaging to date. Mobile stroke units (MSUs) have been shown to improve functional outcomes by bringing cerebral imaging and IVT directly to the patient, but they have limited coverage. Blood biomarkers clearly distinguishing between AIS, ICH, and stroke mimics (SM) could provide an alternative to cerebral imaging if concentration changes are detectable in the hyperacute phase after stroke with high diagnostic accuracy. In this study, we will take blood samples in a prehospital setting to evaluate potential biomarkers. The study was registered in the German Clinical Trials Register (https://drks.de/search/de) with the identifier DRKS00023063. Methods and analysis: We plan a prospective, observational study involving 300 patients with suspected stroke and symptom onset of ≤4.5 h before the collection of biomarkers. Study participants will be recruited from three sites in Berlin, Germany during MSU deployments. The focus of the study is the collection of blood samples from participants at the prehospital scene and from participants with AIS or ICH at a second-time point. All samples will be analyzed using targeted and untargeted analytical approaches. Study-related information about participants, including medical information and discharge diagnoses from the subsequent treating hospital, will be collected and documented in an electronic case report form (eCRF). Discussion: This study will evaluate whether a single blood biomarker or a combination of biomarkers can distinguish patients with AIS and ICH from patients with stroke and SM in the early phase after symptom onset in the prehospital setting. In addition, the kinetics of blood biomarkers in AIS and ICH patients will be investigated. Our goal is to evaluate new ways to reliably diagnose stroke in the prehospital setting and thus accelerate the application of evidence-based therapies to stroke patients.

Impact of emotional valence on mismatch negativity in the course of cortical face processing.

Various aspects of cortical face processing have been studied by assessing event related potentials (ERP). It has been described in the literature that mismatch negativity (MMN), a well-studied ERP, is not only modulated by sensory features but also emotional valence. However, the exact impact of emotion on the temporo-spatial profile of visual MMN during face processing remains inconsistent. By employing a sequential oddball paradigm using both neutral and emotional deviants, we were able to differentiate two distinct vMMN subcomponents. While an early subcomponent at 150-250 ms is elicited by emotional salient facial stimuli, the later subcomponent at 250-400 ms seems to reflect the detection of regularity violations in facial recognition per se, unaffected by emotional salience. Our results suggest that emotional valence is encoded in vMMN signal strength at an early stage of facial processing. Furthermore, we assume that of facial processing consists of temporo-spatially distinct, partially overlapping levels concerning different facial aspects.

Motor cognition in schizophrenia: Control of automatic imitation and mapping of action context are reduced.

The ability to imitate is considered impaired in schizophrenia patients. This assumption, however, is based on heterogeneous studies mostly targeting voluntary imitation, e.g., pantomime. Studies on automatic imitation, however, and on underlying mechanisms of top-down inhibition of automatic imitation and contextual modulation in schizophrenia are highly limited. We employed two sensorimotor paradigms to examine imitation-inhibition and action context mapping in 37 schizophrenia patients and 36 matched controls. In the first experiment, participants performed finger lifts while observing a hand executing compatible or incompatible finger lifts from the third-person perspective. The compatibility or incompatibility of these finger lifts affected participants' reaction times (RTs). The comparison of between-condition RT differences shows a larger movement compatibility effect in schizophrenia than in controls. The second experiment involved finger lifts while watching a still hand, from the first-person perspective, with constrained fingers that either corresponded or did not correspond to the participants' response fingers. Here, schizophrenia patients showed a diminished RT slowing in corresponding constraint trials. While the former results provide evidence for an impaired control of imitation in patients with schizophrenia, the latter results indicate a reduced encoding of action context. In conclusion, this study provides the first evidence for deficits of top-down control of imitation and motor context processing in the same sample of schizophrenia patients.

Amyloid Peptide Scaffolds Coordinate with Alzheimer's Disease Drugs.

Functional amyloid materials can combine the self-assembly of peptide scaffolds into amyloid fibrils with binding capacities for ions or compounds of pharmaceutical interest, endowed by mutable non-ß-sheet-forming residues at the termini. Herein, we report the first to our knowledge amyloid materials, encompassing a GAIIG amyloidogenic core, which bind to Alzheimer's disease (AD) drugs, by mimicking the mechanism by which the same AD drugs bind to enzymes according to experimentally resolved structures, including the target enzyme acetylcholinesterase (AChE). The computationally designed amyloid scaffolds are experimentally shown to coordinate with AD drugs, using two techniques, both in dilute solutions and at higher peptide concentrations, with a higher binding capacity for donepezil and tacrine compared to that for memantine and galantamine. The binding for some of the AD drugs is strong and stable even after extensive subsequent aqueous washings, denoting high capturing efficiency by the designed biomaterials, even after incubation under physiological conditions. Our findings constitute starting points to design novel drug delivery carriers binding to one or combinations of AD drugs (e.g., NMDA and cholinesterase inhibitors).

Mapping adaptation, deviance detection, and prediction error in auditory processing.

Various studies have suggested that auditory deviance detection is organized in a hierarchical manner with ascending levels of complexity. Event-related potentials (ERP) are considered to reflect different cortical processing stages. In the current electroencephalographic study, we employed an auditory sequence oddball paradigm to investigate different levels of cortical auditory processing and the contribution of neuronal habituation and prediction error mechanism to N1 and Mismatch Negativity (MMN). Our findings suggest that N1 reflects a lower cortical process primarily involved in the encoding of simple physical features and is thus mainly modulated by neuronal attenuation and not complex top-down mechanisms. By analyzing within-sequence signal differences, we divided the MMN into distinct subcomponents reflecting different hierachical levels of auditory processing. We determined a "first-order" MMN that reflects the processing of simple deviant features (such as frequency) and "higher-order" MMNs that occur at regularity violation of complex patterns or unexpected inputs that do not allow further predictions. In our source localization analysis, both the primary auditory cortex and left IFG were primarily involved in the detection of simple, physically deviant features, while the right IFG was associated with the processing of novel, unexpected auditory inputs and the ACC with regularity violation of known patterns. Summarizing, our results might contribute to a better understanding of the different complexities of neuronal habituation and prediction error mechanisms at different levels of cortical auditory processing.

Face identity is encoded in the duration of N170 adaptation.

Previous studies assessing the involvement of the face-sensitive N170 component of the event-related potential (ERP) in the processing of face identity have shown controversial results when assessing N170 amplitude in repetition suppression (RS) designs. On the other hand, N170 adaptation is robustly associated with the inter-stimulus interval (ISI) between immediate face repetitions. Interestingly, interactions of face identity and ISI could provide valuable information on early encoding of face identity, but have not been investigated so far. We employed a repetition suppression paradigm using identical and non-identical repetitions as well as parametrically varied ISIs between 500 msec and 2,000 msec in 27 healthy subjects to investigate N170 adaptation effects. Both face identity and varying ISIs significantly influenced N170 adaptation effects, albeit with small effects sizes. Most importantly, however, face identity and ISIs strongly interacted with rapid N170 amplitude recovery in non-identical trials, but sustained N170 adaptation in identical trials. We excluded low-level sensory contributions to the N170 adaptation effect by analyzing the P1 component and by running an additional experiment employing different stimulus sizes. This specific result strongly argues in favor of neuronal sensitivity to face identity, which is primarily mirrored in the N170 temporal decay function that essentially differentiates identical and non-identical face trials. In general, taking advantage of the temporal dimension of adaptation processes, i.e., their decay over time, provides additional dissections of neuronal function into feature-specific selectivity versus non-selectivity.

Mirror neuron deficit in schizophrenia: Evidence from repetition suppression.

BACKGROUND: Schizophrenia is associated with impaired cognition, especially cognition in social contexts. The mirror neuron system (MNS) serves as an important neuronal basis for social cognitive skills; however, previous investigations on the integrity of MNS function in schizophrenia remain approximate. METHODS: We employed a repetition suppression paradigm that allows for measuring neuronal responses to gesture observation and gesture execution. Cross-modal repetition suppression, i.e., adaptation between observe/execute and execute/observe conditions, was defined as the decisive experimental condition characterizing the unique sensori-motor properties of mirror neurons. Event-related potentials (ERPs) were assessed in 15 schizophrenia patients and 15 matched controls. RESULTS: We isolated an ERP signature of specific adaptation effects to identical hand gestures. Of critical importance, this ERP signature indicated intact intra-modal adaptive pattern, i.e., observe/observe and execute/execute, of comparable magnitude between groups, but deficient cross-modal adaptation, i.e., observe/execute and execute/observe, in schizophrenia patients. CONCLUSION: Our data provide robust evidence that pure perception and execution of hand gestures are relatively intact in schizophrenia. In contrast, visuo-motor transformation processes mediated by the MNS seem to be specifically disturbed in schizophrenia. These results unambiguously demonstrate MNS deficits in schizophrenia and extend our understanding of the neuronal bases of social dysfunction in this disorder.

Emotional context facilitates cortical prediction error responses.

In the predictive coding framework, mismatch negativity (MMN) is regarded a correlate of the prediction error that occurs when top-down predictions conflict with bottom-up sensory inputs. Expression-related MMN is a relatively novel construct thought to reflect a prediction error specific to emotional processing, which, however, has not yet been tested directly. Our paradigm includes both neutral and emotional deviants, thereby allowing for investigating whether expression-related MMN is emotion-specific or unspecifically arises from violations of a given sequence. Twenty healthy participants completed a visual sequence oddball task where they were presented with (1) sequence deviants, (2) emotional sequence deviants, and (3) emotional deviants. Mismatch components were assessed at ventral occipitotemporal scalp sites and analyzed regarding their amplitudes, spatiotemporal profiles, and neuronal sources. Expression-related MMN could be clearly separated from its neutral counterpart in all investigated aspects. Specifically, expression-related MMN showed enhanced amplitude, shorter latency, and different neuronal sources. Our results, therefore, provide converging evidence for a quantitative specificity of expression-related MMN and seems to provide an opportunity to study prediction error during preattentive emotional processing. Our neurophysiological evidence ultimately suggests that a basic cognitive operator, the prediction error, is enhanced at the cortical level by processing of emotionally salient stimuli.

Auditory mismatch negativity and repetition suppression deficits in schizophrenia explained by irregular computation of prediction error.

BACKGROUND: The predictive coding model is rapidly gaining attention in schizophrenia research. It posits the neuronal computation of residual variance ('prediction error') between sensory information and top-down expectation through multiple hierarchical levels. Event-related potentials (ERP) reflect cortical processing stages that are increasingly interpreted in the light of the predictive coding hypothesis. Both mismatch negativity (MMN) and repetition suppression (RS) measures are considered a prediction error correlates based on error detection and error minimization, respectively. METHODS: Twenty-five schizophrenia patients and 25 healthy controls completed auditory tasks designed to elicit MMN and RS responses that were investigated using repeated measures models and strong spatio-temporal a priori hypothesis based on previous research. Separate correlations were performed for controls and schizophrenia patients, using age and clinical variables as covariates. RESULTS: MMN and RS deficits were largely replicated in our sample of schizophrenia patients. Moreover, MMN and RS measures were strongly correlated in healthy controls, while no correlation was found in schizophrenia patients. Single-trial analyses indicated significantly lower signal-to-noise ratio during prediction error computation in schizophrenia. CONCLUSIONS: This study provides evidence that auditory ERP components relevant for schizophrenia research can be reconciled in the light of the predictive coding framework. The lack of any correlation between the investigated measures in schizophrenia patients suggests a disruption of predictive coding mechanisms in general. More specifically, these results suggest that schizophrenia is associated with an irregular computation of residual variance between sensory input and top-down models, i.e. prediction error.

Spatiotemporal dynamics of early cortical gesture processing.

Gesture processing has been consistently shown to be associated with activation of the inferior parietal lobe (IPL); however, little is known about the integration of IPL activation into the temporal dynamics of early sensory areas. Using a temporally graded repetition suppression paradigm, we examined the activation and time course of brain areas involved in hand gesture processing. We recorded event-related potentials in response to stimulus pairs of static hand images forming gestures of the popular rock-paper-scissors game and estimated their neuronal generators. We identified two main components associated with adaptive patterns related to stimulus repetition. The N190 component elicited at temporo-parietal sites adapted to repetitions of the same gesture and was associated with right-hemispheric extrastriate body area activation. A later component at parieto-occipital sites demonstrated temporally graded adaptation effects for all gestures with a left-hemispheric dominance. Source localization revealed concurrent activations of the right extrastriate body area, fusiform gyri bilaterally, and the left IPL at about 250 ms. The adaptation pattern derived from the graded repetition suppression paradigm demonstrates the functional sensitivity of these sources to gesture processing. Given the literature on IPL contribution to imitation, action recognition, and action execution, IPL activation at about 250 ms may represent the access into specific cognitive routes for gesture processing and may thus be involved in integrating sensory information from cortical body areas into subsequent visuo-motor transformation processes.

Neurocognitive pattern analysis reveals classificatory hierarchy of attention deficits in schizophrenia.

Attention deficits, among other cognitive deficits, are frequently observed in schizophrenia. Although valid and reliable neurocognitive tasks have been established to assess attention deficits in schizophrenia, the hierarchical value of those tests as diagnostic discriminants on a single-subject level remains unclear. Thus, much research is devoted to attention deficits that are unlikely to be translated into clinical practice. On the other hand, a clear hierarchy of attention deficits in schizophrenia could considerably aid diagnostic decisions and may prove beneficial for longitudinal monitoring of therapeutic advances. To propose a diagnostic hierarchy of attention deficits in schizophrenia, we investigated several facets of attention in 86 schizophrenia patients and 86 healthy controls using a set of established attention tests. We applied state-of-the-art machine learning algorithms to determine attentive test variables that enable an automated differentiation between schizophrenia patients and healthy controls. After feature preranking, hypothesis building, and hypothesis validation, the polynomial support vector machine classifier achieved a classification accuracy of 90.70% ± 2.9% using psychomotor speed and 3 different attention parameters derived from sustained and divided attention tasks. Our study proposes, to the best of our knowledge, the first hierarchy of attention deficits in schizophrenia by identifying the most discriminative attention parameters among a variety of attention deficits found in schizophrenia patients. Our results offer a starting point for hierarchy building of schizophrenia-associated attention deficits and contribute to translating these concepts into diagnostic and therapeutic practice on a single-subject level.

Pediatric trauma at a government referral hospital in The Gambia.

OBJECTIVE: To determine the pattern of childhood injuries at a government referral hospital in sub-Saharan Africa. METHODS: Twenty-nine month hospital based study at the Royal Victoria Hospital (RVH) in Banjul, The Gambia. Children with injuries were identified from a prospectively recorded pediatric surgery database. Rate of pediatric trauma presenting to RVH was calculated for an urban population of 270,540 (32.3% aged 0-14 years) living within 25 km of the hospital. RESULTS: From January 1996 to June 1998, 798 children aged 0-14 years were admitted for treatment of injuries. Injuries accounted for 4.8% of all pediatric admissions. Burns (38.7%), fractures (20.9%), head injuries (16.2%) and soft tissue injuries (9.4%) were the most common injuries--together responsible for 85% of admissions and 74% of total hospital days. Average length of stay was 20.6 days, with injuries accounting for 16,696 total hospital days. Seventeen percent of injured children required a surgical procedure. The most common surgical procedures were burn contracture release (20%), reduction of fracture and dislocations (20%) and skin grafts (18.7%). In hospital mortality was 5.5%, with 71% of deaths related to burns. The annual cases of trauma presenting to RVH from the Greater Banjul Area was 181 admissions, 3317 hospital days, 28 surgical procedures and 7 deaths per 100,000 children aged 0-14 years. CONCLUSION: Childhood injuries, particularly burns place a significant burden on inpatient services. While accounting for a small fraction of pediatric admissions, injuries account for long hospital stays and surgical procedures.