Neuromagnetic representation of musical roundness in chord progressions.

Introduction: Musical roundness perception relies on consonance/dissonance within a rule-based harmonic context, but also on individual characteristics of the listener. The present work tackles these aspects in a combined psychoacoustic and neurophysiological study, taking into account participant's musical aptitude. Methods: Our paradigm employed cadence-like four-chord progressions, based on Western music theory. Chord progressions comprised naturalistic and artificial sounds; moreover, their single chords varied regarding consonance/dissonance and harmonic function. Thirty participants listened to the chord progressions while their cortical activity was measured with magnetoencephalography; afterwards, they rated the individual chord progressions with respect to their perceived roundness. Results: Roundness ratings differed according to the degree of dissonance in the dominant chord at the progression's third position; this effect was pronounced in listeners with high musical aptitude. Interestingly, a corresponding pattern occurred in the neuromagnetic N1m response to the fourth chord (i.e., at the progression's resolution), again with somewhat stronger differentiation among musical listeners. The N1m magnitude seemed to increase during chord progressions that were considered particularly round, with the maximum difference after the final chord; here, however, the musical aptitude effect just missed significance. Discussion: The roundness of chord progressions is reflected in participant's psychoacoustic ratings and in their transient cortical activity, with stronger differentiation among listeners with high musical aptitude. The concept of roundness might help to reframe consonance/dissonance to a more holistic, gestalt-like understanding that covers chord relations in Western music.

Predictive value of the General Movements Assessment and Standardized Infant NeuroDevelopmental Assessment in infants at high risk of neurodevelopmental disorders.

AIM: To compare the predictive values of the General Movements Assessment (GMA) and the Standardized Infant NeuroDevelopmental Assessment (SINDA) neurological scale for atypical neurodevelopmental outcome in 3-month-old at-risk infants. METHOD: A total of 109 infants (gestational age 30 weeks; range: 24-41; 52 males) attending a non-academic outpatient clinic were assessed with the GMA and the SINDA at 3 (2-4) months corrected age. The GMA pays attention to the complexity of general movements and presence of fidgety movements. Atypical neurodevelopmental outcome at 24 months corrected age (and older) implied cerebral palsy (CP) or a Bayley Mental Development Index or Bayley Psychomotor Development Index lower than 70. RESULTS: At 24 months corrected (and older) age, 16 children had an atypical outcome, including 14 children with CP. Regarding markedly reduced general movement complexity in combination with absent or sporadic fidgety movements, the GMA predicted an atypical outcome with specificity, positive, and negative predictive values greater than 0.900, and sensitivity of 0.687 (95% confidence interval [CI] = 0.460-0.915). SINDA predicted an atypical outcome with sensitivity, specificity, and negative predictive value greater than 0.900 and a positive predictive value of 0.652 (95% CI = 0.457-0.847). Regarding absent fidgety movements only or markedly reduced general movement complexity, the GMA predicted the outcome less well than both general movement criteria. INTERPRETATION: The SINDA and GMA both predict neurodevelopmental outcome well, but SINDA is easier to learn than the GMA; being a non-video-based assessment, it allows caregiver feedback during the consultation whereas the GMA usually does not.

Altered binaural hearing in pre-ataxic and ataxic mutation carriers of spinocerebellar ataxia type 3.

Brainstem degeneration is a prominent feature of spinocerebellar ataxia type 3 (SCA3), involving structures that execute binaural synchronization with microsecond precision. As a consequence, auditory processing may deteriorate during the course of disease. We tested whether the binaural "Huggins pitch" effect is suitable to study the temporal precision of brainstem functioning in SCA3 mutation carriers. We expected that they would have difficulties perceiving Huggins pitch at high frequencies, and that they would show attenuated neuromagnetic responses to Huggins pitch. The upper limit of Huggins pitch perception was psychoacoustically determined in 18 pre-ataxic and ataxic SCA3 mutation carriers and in 18 age-matched healthy controls. Moreover, the cortical N100 response following Huggins pitch onset was acquired by means of magnetoencephalography (MEG). MEG recordings were analyzed using dipole source modeling and comprised a monaural pitch condition and a no-pitch condition with simple binaural correlation changes. Compared with age-matched controls, ataxic but not pre-ataxic SCA3 mutation carriers had significantly lower frequency limits up to which Huggins pitch could be heard. Listeners with lower frequency limits also showed diminished MEG responses to Huggins pitch, but not in the two control conditions. Huggins pitch is a promising tool to assess brainstem functioning in ataxic SCA3 patients. Future studies should refine the psychophysiological setup to capture possible performance decrements also in pre-ataxic mutation carriers. Longitudinal observations will be needed to prove the potential of the assessment of Huggins pitch as a biomarker to track brainstem functioning during the disease course in SCA3.

Neuromagnetic representation of melodic contour processing in human auditory cortex.

The pattern of ups and downs in a sequence with varying pitch can be heard as a melodic contour. Contrary to single pitch, the neural representation of melodic contour information in the auditory cortex is rarely investigated, and it is not clear whether the processing entails a hemispheric asymmetry. The present magnetoencephalography study assessed the neuromagnetic responses of N = 18 normal-hearing adults to four-note sequences with fixed vs. varying pitch that were presented either monaurally or diotically; data were analyzed using minimum-norm reconstructions. The first note of the sequences elicited prominent transient activity in posterior auditory regions (Planum temporale), especially contralateral to the ear of entry. In contrast, the response to the subsequent notes originated from more anterior areas (Planum polare) and was larger for melodic contours than for fixed pitch sequences, independent from the ear of entry and without hemispheric asymmetry. Together, the results point to a gradient in the early cortical processing of melodic contours, both in spatial and functional terms, where posterior auditory activity reflects the onset of a pitch sequence and anterior activity reflects its subsequent notes, including the difference between sequences with fixed pitch and melodic contours.

A direct comparison of voice pitch processing in acoustic and electric hearing.

In single-sided deafness patients fitted with a cochlear implant (CI) in the affected ear and preserved normal hearing in the other ear, acoustic and electric hearing can be directly compared without the need for an external control group. Although poor pitch perception is a crucial limitation when listening through CIs, it remains unclear how exactly the cortical processing of pitch information differs between acoustic and electric hearing. Hence, we separately presented both ears of 20 of these patients with vowel sequences in which the pitch contours were either repetitive or variable, while simultaneously recording functional near-infrared spectroscopy (fNIRS) and EEG data. Overall, the results showed smaller and delayed auditory cortex activity in electric hearing, particularly for the P2 event-related potential component, which appears to reflect the processing of voice pitch information. Both the fNIRS data and EEG source reconstructions furthermore showed that vowel sequences with variable pitch contours evoked additional activity in posterior right auditory cortex in electric but not acoustic hearing. This surprising discrepancy demonstrates, firstly, that the acoustic detail transmitted by CIs is sufficient to distinguish between speech sounds that only vary regarding their pitch information. Secondly, the absence of a condition difference when stimulating the normal-hearing ears suggests a saturation of cortical activity levels following unilateral deafness. Taken together, these results provide strong evidence in favour of using CIs in this patient group.

Simultaneous EEG/MEG yields complementary information of nociceptive evoked responses.

OBJECTIVE: Nociceptive stimuli have been studied either by dipolar modelling using electroencephalography (EEG) or magnetoencephalography (MEG), but rarely using both techniques simultaneously. This study aims to investigate the spatiotemporal representation of cortical activity in response to non-nociceptive (tactile) and nociceptive (laser) stimuli using parallel EEG-MEG recordings. METHODS: We performed simultaneous EEG and MEG recordings in 12 healthy subjects by applying pneumatic tactile and nociceptive laser stimuli on the right- and left-hand dorsum. We analyzed brain responses for both modalities and methods by means of global field power (GFP), and dipole source locations, strengths and orientations calculated in the depth to identify similarities and differences. RESULTS: Prominent GFP peaks were similar in EEG and MEG for tactile responses but different for nociceptive responses. CONCLUSIONS: Methodically, MEG was superior to EEG in detecting the earliest nociceptive laser-evoked components with earlier latency in primary- and secondary somatosensory cortices, whereas EEG was superior to MEG in detecting late nociceptive components due to radially oriented deeper cortical activity. SIGNIFICANCE: EEG and MEG revealed in part differential nociceptive waveform patterns, peak latencies, and source orientations, making combined recordings favorable to examine pain-related activity as a whole in high temporal-spatial resolution.

Behavioral and neurophysiological correlates of emotional face processing in borderline personality disorder: are there differences between men and women?

Emotional dysregulation is a core feature of borderline personality disorder (BPD); it is, for example, known to influence one's ability to read other people's facial expressions. We investigated behavioral and neurophysiological foundations of emotional face processing in individuals with BPD and in healthy controls, taking participants' sex into account. 62 individuals with BPD (25 men, 37 women) and 49 healthy controls (20 men, 29 women) completed an emotion classification task with faces depicting blends of angry and happy expressions while the electroencephalogram was recorded. The cortical activity (late positive potential, P3/LPP) was evaluated using source modeling. Compared to healthy controls, individuals with BPD responded slower to happy but not to angry faces; further, they showed more anger ratings in happy but not in angry faces, especially in those with high ambiguity. Men had lower anger ratings than women and responded slower to angry but not happy faces. The P3/LPP was larger in healthy controls than in individuals with BPD, and larger in women than in men; moreover, women but not men produced enlarged P3/LPP responses to angry vs. happy faces. Sex did not interact with behavioral or P3/LPP-related differences between healthy controls and individuals with BPD. Together, BPD-related alterations in behavioral and P3/LPP correlates of emotional face processing exist in both men and women, supposedly without sex-related interactions. Results point to a general 'negativity bias' in women. Source modeling is well suited to investigate effects of participant and stimulus characteristics on the P3/LPP generators.

Cortical activity evoked by voice pitch changes: A combined fNIRS and EEG study.

Functional near-infrared spectroscopy (fNIRS) and electroencephalography (EEG) data were simultaneously obtained from normal-hearing listeners presented with continuous natural vowel sequences to study the interrelation of the haemodynamic and electrophysiological cortical responses evoked by voice pitch changes. fNIRS topographies and distributed ERP source reconstructions both indicated additional activity in the right superior temporal cortex if the prosodic contours varied between successive vowels, rather than being the same throughout the sequences. The source-level ERPs furthermore revealed two temporally and spatially separable adaptation processes in superior temporal cortex: Firstly, the early P1 component was bilaterally attenuated when vowels with the same prosodic contours were presented repeatedly, reflecting sensory adaptation. Secondly, the later P2 and sustained potential components were smaller in the right hemisphere during sequences without prosodic changes, which is taken to represent an attention-based adaptation effect. The present results demonstrate the convergence of both methods and demonstrate which ERPs underlie the right-lateralised activity in superior temporal cortex evoked in response to pitch changes that has been observed in many neuroimaging studies.

Correction: Modeling and MEG evidence of early consonance processing in auditory cortex.

[This corrects the article DOI: 10.1371/journal.pcbi.1006820.].

Posterior insular activity contributes to the late laser-evoked potential component in EEG recordings.

OBJECTIVE: Nociceptive activity in some brain areas has concordantly been reported in EEG source models, such as the anterior/mid-cingulate cortex and the parasylvian area. Whereas the posterior insula has been constantly reported to be active in intracortical and fMRI studies, non-invasive EEG and MEG recordings mostly failed to detect activity in this region. This study aimed to determine an appropriate inverse modeling approach in EEG recordings to model posterior insular activity, assuming the late LEP (laser evoked potential) time window to yield a better separation from other ongoing cortical activity. METHODS: In 12 healthy volunteers, nociceptive stimuli of three intensities were applied. LEP were recorded using 32-channel EEG recordings. Source analysis was performed in specific time windows defined in the grand-average dataset. Two distinct dipole-pairs located close to the operculo-insular area were compared. RESULTS: Our results show that posterior insular activity yields a substantial contribution to the latest part (positive component) of the LEP. CONCLUSIONS: Even though the initial insular activity onset is in the early LEP time window,modelingthe insular activity in the late LEP time window might result in better separation from other ongoing cortical activity. SIGNIFICANCE: Modeling the late LEP activity might enable to distinguish posterior insular activity.

Early cortical processing of pitch height and the role of adaptation and musicality.

Pitch is an important perceptual feature; however, it is poorly understood how its cortical correlates are shaped by absolute vs relative fundamental frequency (f0), and by neural adaptation. In this study, we assessed transient and sustained auditory evoked fields (AEFs) at the onset, progression, and offset of short pitch height sequences, taking into account the listener's musicality. We show that neuromagnetic activity reflects absolute f0 at pitch onset and offset, and relative f0 at transitions within pitch sequences; further, sequences with fixed f0 lead to larger response suppression than sequences with variable f0 contour, and to enhanced offset activity. Musical listeners exhibit stronger f0-related AEFs and larger differences between their responses to fixed vs variable sequences, both within sequences and at pitch offset. The results resemble prominent psychoacoustic phenomena in the perception of pitch contours; moreover, they suggest a strong influence of adaptive mechanisms on cortical pitch processing which, in turn, might be modulated by a listener's musical expertise.

Auditory cortex activity measured using functional near-infrared spectroscopy (fNIRS) appears to be susceptible to masking by cortical blood stealing.

To validate the use of functional near-infrared spectroscopy (fNIRS) in auditory perception experiments, combined fNIRS and electroencephalography (EEG) data were obtained from normal-hearing subjects passively listening to speech-like stimuli without linguistic content. The fNIRS oxy-haemoglobin (HbO) results were found to be inconsistent with the deoxy-haemoglobin (HbR) and EEG data, as they were dominated by increasingly more negative responses along a diagonal axis running in posterior-superior to anterior-inferior direction. This large-scale bilateral gradient in the HbO data masked the right-lateralised neural activity in the auditory cortex that was clearly evident in the HbR data and EEG source reconstructions and is most likely due to cerebral blood stealing. When the subjects were subsequently split into subgroups with more positive or more negative HbO responses in the right auditory cortex, the former group surprisingly showed smaller event-related potentials and increased EEG alpha power, indicating reduced attention and vigilance. These findings thus suggest that positive HbO responses in the auditory cortex may not necessarily be a favourable result when investigating auditory perception using fNIRS. More generally, the results show that the interpretation of fNIRS HbO signals can be misleading and demonstrate the benefits of combined fNIRS-EEG analyses.

Transient and sustained processing of musical consonance in auditory cortex and the effect of musicality.

In recent years, electroencephalography and magnetoencephalography (MEG) have both been used to investigate the response in human auditory cortex to musical sounds that are perceived as consonant or dissonant. These studies have typically focused on the transient components of the physiological activity at sound onset, specifically, the N1 wave of the auditory evoked potential and the auditory evoked field, respectively. Unfortunately, the morphology of the N1 wave is confounded by the prominent neural response to energy onset at stimulus onset. It is also the case that the perception of pitch is not limited to sound onset; the perception lasts as long as the note producing it. This suggests that consonance studies should also consider the sustained activity that appears after the transient components die away. The current MEG study shows how energy-balanced sounds can focus the response waves on the consonance-dissonance distinction rather than energy changes and how source modeling techniques can be used to measure the sustained field associated with extended consonant and dissonant sounds. The study shows that musical dyads evoke distinct transient and sustained neuromagnetic responses in auditory cortex. The form of the response depends on both whether the dyads are consonant or dissonant and whether the listeners are musical or nonmusical. The results also show that auditory cortex requires more time for the early transient processing of dissonant dyads than it does for consonant dyads and that the continuous representation of temporal regularity in auditory cortex might be modulated by processes beyond auditory cortex.NEW & NOTEWORTHY We report a magnetoencephalography (MEG) study on transient and sustained cortical consonance processing. Stimuli were long-duration, energy-balanced, musical dyads that were either consonant or dissonant. Spatiotemporal source analysis revealed specific transient and sustained neuromagnetic activity in response to the dyads; in particular, the morphology of the responses was shaped by the dyad's consonance and the listener's musicality. Our results also suggest that the sustained representation of stimulus regularity might be modulated by processes beyond auditory cortex.

Standardized Infant NeuroDevelopmental Assessment developmental and socio-emotional scales: reliability and predictive value in an at-risk population.

AIM: To assess the reliability and predictive validity of the developmental and socio-emotional scales of the Standardized Infant NeuroDevelopmental Assessment (SINDA). METHOD: To assess reliability, two sets of three assessors forming eight assessor-pairs independently rated the developmental and socio-emotional scales of 60 infants. To evaluate predictive validity, 223 infants (gestational age 30wks [range 23-41wks]; 117 males, 106 females) attending a non-academic outpatient clinic were assessed by different assessors with SINDA's neurological, developmental, and socio-emotional scales. Atypical neurodevelopmental outcome at a corrected age of 24 months or older implied a Bayley Mental or Psychomotor Developmental Index score of less than 70 or neurological disorder (including cerebral palsy). Behavioural and emotional disorders were classified according to the International Classification of Diseases, 10th Revision. Predictive values were calculated from SINDA (2-12mo corrected age, median 7mo) and typical versus atypical outcome, and for intellectual disability only (Mental Developmental Index <70). RESULTS: Assessors highly agreed on the developmental and socio-emotional assessments (developmental scores: Spearman's rank correlation coefficient ρ=0.972; single socio-emotional behaviour items: Cohen's κ=0.783-0.896). At 24 months or older, 65 children had atypical outcome. Atypical neurological scores predicted atypical outcome (sensitivity 83%, specificity 96%); atypical developmental scores predicted intellectual disability (sensitivity 77%, specificity 92%). Atypical emotionality and atypical self-regulation were associated with behavioural and emotional disorders. INTERPRETATION: SINDA's three scales are reliable, and have a satisfactory predictive validity for atypical developmental outcome at 24 months or older in a non-academic outpatient setting. SINDA's developmental scale has promising predictive validity for intellectual disability. SINDA's socio-emotional scale is a tool for caregiver counselling. WHAT THIS PAPER ADDS: Standardized Infant NeuroDevelopmental Assessment (SINDA)'s developmental and socio-emotional scales have excellent interrater reliability. Replication of the satisfactory validity of SINDA's neurological scale for atypical outcome.

Modeling and MEG evidence of early consonance processing in auditory cortex.

Pitch is a fundamental attribute of auditory perception. The interaction of concurrent pitches gives rise to a sensation that can be characterized by its degree of consonance or dissonance. In this work, we propose that human auditory cortex (AC) processes pitch and consonance through a common neural network mechanism operating at early cortical levels. First, we developed a new model of neural ensembles incorporating realistic neuronal and synaptic parameters to assess pitch processing mechanisms at early stages of AC. Next, we designed a magnetoencephalography (MEG) experiment to measure the neuromagnetic activity evoked by dyads with varying degrees of consonance or dissonance. MEG results show that dissonant dyads evoke a pitch onset response (POR) with a latency up to 36 ms longer than consonant dyads. Additionally, we used the model to predict the processing time of concurrent pitches; here, consonant pitch combinations were decoded faster than dissonant combinations, in line with the experimental observations. Specifically, we found a striking match between the predicted and the observed latency of the POR as elicited by the dyads. These novel results suggest that consonance processing starts early in human auditory cortex and may share the network mechanisms that are responsible for (single) pitch processing.

Reliability and predictive validity of the Standardized Infant NeuroDevelopmental Assessment neurological scale.

AIM: To assess reliability and predictive validity of the neurological scale of the Standardized Infant NeuroDevelopmental Assessment (SINDA), a recently developed assessment for infants aged 6 weeks to 12 months. METHOD: To assess reliability, three assessors independently rated video-recorded neurological assessments of 24 infants twice. Item difficulty and discrimination were determined. To evaluate predictive validity, 181 infants (median gestational age 30wks [range 22-41wks]; 92 males, 89 females) attending a non-academic outpatient clinic were assessed with SINDA's neurological scale (28 dichotomized items). Atypical neurodevelopmental outcome at 24 months or older corrected age implied a Bayley Mental Developmental Index or Psychomotor Developmental Index lower than 70 or a diagnosis of cerebral palsy (CP). Predictive values were calculated from SINDA (2-12mo corrected age, median 3mo) and typical versus atypical outcome. RESULTS: Intraclass correlation coefficients of intrarater and interrater agreement of the neurological score varied between 0.923 and 0.965. Item difficulty and discrimination were satisfactory. At 24 months or older, 56 children (31%) had an atypical outcome (29 had CP). Atypical neurological scores (below 25th centile, ≤21) predicted atypical outcome and CP with sensitivities of 89% and 100%, and specificities of 94% and 81% respectively. INTERPRETATION: SINDA's neurological scale is reliable and in a non-academic outpatient setting has a satisfactory predictive validity for atypical developmental outcome, including CP, at 24 months or older. WHAT THIS PAPER ADDS: The Standardized Infant NeuroDevelopmental Assessment's neurological scale has a good to excellent reliability. The scale has promising predictive validity for cerebral palsy. The scale has promising predictive validity for other types of atypical developmental outcome.

CONFIABILIDAD Y VALIDEZ PREDICTIVA DE LA ESCALA NEUROLÓGICA DE LA EVALUACIÓN DEL NEURODESARROLLO INFANTIL ESTANDARIZADA: OBJETIVO: Evaluar la confiabilidad y la validez predictiva de la escala neurológica de la Evaluación del Neurodesarrollo Infantil Estandarizada (SINDA), una evaluación desarrollada recientemente para bebés de 6 semanas a 12 meses. MÉTODO: Para evaluar la confiabilidad, tres evaluadores evaluaron dos veces, de forma independiente, las evaluaciones neurológicas grabadas en videos de 24 recién nacidos. Se determinaron la dificultad del ítem y la discriminación. Para evaluar la validez predictiva, se evaluaron 181 neonatos (mediana de edad gestacional de 30 semanas [rango 22-41 semanas], 92 varones, 89 mujeres) que asisten a una clínica ambulatoria no académica con la escala neurológica de SINDA (28 ítems dicotomizados). El resultado del desarrollo neurológico atípico a los 24 meses o mayor edad corregida implicaba un índice de desarrollo mental o índice de desarrollo psicomotor Bayley inferior a 70 o un diagnóstico de parálisis cerebral (PC). Los valores predictivos se calcularon a partir de SINDA (edad corregida 2-12mo, mediana 3meses) y resultado típico versus a atípico. RESULTADOS: Los coeficientes de correlación intraclase de la concordancia intra e inter codificador del puntaje neurológico variaron entre 0.923 y 0.965. La dificultad del item y la discriminación fueron satisfactorias. A los 24 meses o más, 56 niños (31%) tuvieron un resultado atípico (29 tuvieron PC). Las puntuaciones neurológicas atípicas (por debajo del percentil 25, ≤21) predijeron un resultado atípico y PC con sensibilidades del 89% y del 100%, y especificidades del 94% y del 81%, respectivamente. INTERPRETACIÓN: La escala neurológica de SINDA es confiable y en un entorno ambulatorio no académico tiene una validez predictiva satisfactoria para la detección del desarrollo atípico, incluido la PC, a los 24 meses o más.

CONFIABILIDADE E VALIDADE PREDITIVA DA ESCALA NEUROLÓGICA DE AVALIAÇÃO PADRONIZADA NEURODESENVOLVIMENTAL INFANTIL: OBJETIVO: Avaliar a confiabilidade e validade preditiva da escala neurológica Avaliação Padronizada Neurodesenvolvimental Infantil (SINDA), uma avaliação desenvolvida recentemente para lactentes de 6 semanas a 12 meses de idade. MÉTODO: Para avaliar a confiabilidade, por duas vezes três avaliadores pontuaram independentemente avaliações neurológicas de 24 lactentes registradas em vídeo. Para avaliar a validade preditiva, 181 lactentes (idade gestacional mediana de 30 semanas[variação de 22 a 41 semanas]); 92 do sexo masculino; 89 do sexo feminino) que frequentavam uma clínica não acadêmica foram avaliados com a escala neurológica da SINDA (28 itens dicotomizados). O neurodesenvolvimento atípico na idade de 24 meses de idade corrigida ou mais tarde foi determinado por índice desenvolvimental mental da Bayley ou Item desenvolvimental psicomotor menor do que 70 ou diagnóstico de paralisia cerebral (PC). Os valores preditivos foram calculados para o SINDA (2-12 meses de idade corrigida, mediana de 3 m) e resultado típico versus atípico. RESULTADOS: Os coeficientes de correlação intraclasse de concordância intra ou inter-examinadores do escore neurológico variaram de 0,923 a 0,965. A dificuldade e discriminação do item foram satisfatórias. Aos 24 meses de idade ou mais, 56 crianças (31%) tiveram resultado atípico (29 tinham PC). Os escores neurológicos atípicos (abaixo do percentil 25, ≤21) foram preditivos de resultado atípico e PC com sensibilidades de 89% e 100%, e especificidades de 94% e 81%, respectivamente. INTERPRETAÇÃO: A escala neurológica SINDA é confiável e em um ambiente não acadêmico tem validade preditiva satisfatória para resultado atípico do desenvolvimento, incluindo PC, aos 24 meses de idade ou mais.

Limitations of Specific Coagulation Tests for Direct Oral Anticoagulants: A Critical Analysis.

Background During treatment with direct oral anticoagulants ( DOAC ), coagulation assessment is required before thrombolysis, surgery, and if anticoagulation reversal is evaluated. Limited data support the accuracy of DOAC -specific coagulation assays around the current safe-for-treatment threshold of 30 ng/ mL . Methods and Results In 481 samples obtained from 96 patients enrolled at a single center, DOAC concentrations were measured using Hemoclot direct thrombin inhibitor assay, Biophen direct thrombin inhibitor assay or ecarin clotting time for dabigatran, chromogenic anti-Xa assay ( AXA ) for factor Xa inhibitors (rivaroxaban, apixaban) and ultraperformance liquid chromatography-tandem mass spectrometry as reference. All dabigatran-specific assays had high sensitivity to concentrations >30 ng/ mL , but specificity was lower for Hemoclot direct thrombin inhibitor assay (78.2%) than for Biophen direct thrombin inhibitor assay (98.9%) and ecarin clotting time (94.6%). AXA provided high sensitivity and specificity for rivaroxaban, but low sensitivity for apixaban (73.8%; concentrations up to 82 ng/ mL were misclassified as <30 ng/ mL ). If no DOAC -specific calibration for AXA is available, results 2-fold above the upper limit of normal indicate relevant rivaroxaban concentrations. For apixaban, all elevated results should raise suspicion of relevant anticoagulation. Conclusions DOAC -specific tests differ considerably in diagnostic performance for concentrations close to the currently accepted safe-for-treatment threshold. Compared with Biophen direct thrombin inhibitor assay and ecarin clotting time, limited specificity of Hemoclot direct thrombin inhibitor assay poses a high risk of unnecessary anticoagulation reversal or treatment delays in patients on dabigatran. While AXA accurately detected rivaroxaban, the impact of low apixaban levels on the assay was weak. Hence, AXA results need to be interpreted with extreme caution when used to assess hemostatic function in patients on apixaban. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifiers: NCT 02371044, NCT 02371070.

Intravenous thrombolysis in acute central retinal artery occlusion - A prospective interventional case series.

BACKGROUND: No evidence-based therapy exists for non-arteritic central retinal artery occlusion (NA-CRAO). Retinal ischemic tolerance is low; irreversible damage occurs within four hours of experimental NA-CRAO. In previous randomized trials evaluating intra-arterial or intravenous thrombolysis (IVT) in NA-CRAO, only one patient was treated this early. In December 2013, the Departments of Neurology & Stroke and Ophthalmology at University Hospital Tuebingen, Germany, decided to treat patients using IVT within 4.5 hours of NA-CRAO, the therapeutic window established for ischemic stroke. MATERIALS AND METHODS: Consecutive NA-CRAO patients with severe visual loss received IVT after exclusion of intracranial hemorrhage. Follow-up was conducted at day 5 (d5) and day 30 (d30). Visual outcomes were compared to the conservative standard treatment (CST) arm of the EAGLE-trial. RESULTS: Until August 2016, 20 patients received IVT within 4.5 hours after NA-CRAO with a median onset-to-treatment time of 210 minutes (IQR 120-240). Visual acuity improved from baseline mean logarithm of the minimum angle of resolution 2.46±0.33 (SD) (light perception) to 1.52±1.09 (Snellen equivalent: 6/200) at d5 (p = 0.002) and 1.60±1.08 (Snellen equivalent: 6/240) at d30. Compared to the EAGLE CST-arm, functional recovery to reading ability occurred more frequently after IVT: 6/20 (30%) versus 1/39 (3%) at d5 (p = 0.005) and at d30 5/20 (25%) versus 2/37 (5%) (p = 0.045). Two patients experienced serious adverse events (one angioedema and one bleeding from an abdominal aortic aneurysm) but recovered without sequelae. CONCLUSIONS: IVT within 4.5 hours after symptom onset may represent an effective treatment of NA-CRAO. Randomized trials are warranted to evaluate efficacy and safety of early IVT in acute NA-CRAO.

Evidence Integration in Natural Acoustic Textures during Active and Passive Listening.

Many natural sounds can be well described on a statistical level, for example, wind, rain, or applause. Even though the spectro-temporal profile of these acoustic textures is highly dynamic, changes in their statistics are indicative of relevant changes in the environment. Here, we investigated the neural representation of change detection in natural textures in humans, and specifically addressed whether active task engagement is required for the neural representation of this change in statistics. Subjects listened to natural textures whose spectro-temporal statistics were modified at variable times by a variable amount. Subjects were instructed to either report the detection of changes (active) or to passively listen to the stimuli. A subset of passive subjects had performed the active task before (passive-aware vs passive-naive). Psychophysically, longer exposure to pre-change statistics was correlated with faster reaction times and better discrimination performance. EEG recordings revealed that the build-up rate and size of parieto-occipital (PO) potentials reflected change size and change time. Reduced effects were observed in the passive conditions. While P2 responses were comparable across conditions, slope and height of PO potentials scaled with task involvement. Neural source localization identified a parietal source as the main contributor of change-specific potentials, in addition to more limited contributions from auditory and frontal sources. In summary, the detection of statistical changes in natural acoustic textures is predominantly reflected in parietal locations both on the skull and source level. The scaling in magnitude across different levels of task involvement suggests a context-dependent degree of evidence integration.