Atypical processing of tones and phonemes in Rett Syndrome as biomarkers of disease progression.

Due to severe motor impairments and the lack of expressive language abilities seen in most patients with Rett Syndrome (RTT), it has proven extremely difficult to obtain accurate measures of auditory processing capabilities in this population. Here, we examined early auditory cortical processing of pure tones and more complex phonemes in females with Rett Syndrome (RTT), by recording high-density auditory evoked potentials (AEP), which allow for objective evaluation of the timing and severity of processing deficits along the auditory processing hierarchy. We compared AEPs of 12 females with RTT to those of 21 typically developing (TD) peers aged 4-21 years, interrogating the first four major components of the AEP (P1: 60-90 ms; N1: 100-130 ms; P2: 135-165 ms; and N2: 245-275 ms). Atypicalities were evident in RTT at the initial stage of processing. Whereas the P1 showed increased amplitude to phonemic inputs relative to tones in TD participants, this modulation by stimulus complexity was absent in RTT. Interestingly, the subsequent N1 did not differ between groups, whereas the following P2 was hugely diminished in RTT, regardless of stimulus complexity. The N2 was similarly smaller in RTT and did not differ as a function of stimulus type. The P2 effect was remarkably robust in differentiating between groups with near perfect separation between the two groups despite the wide age range of our samples. Given this robustness, along with the observation that P2 amplitude was significantly associated with RTT symptom severity, the P2 has the potential to serve as a monitoring, treatment response, or even surrogate endpoint biomarker. Compellingly, the reduction of P2 in patients with RTT mimics findings in animal models of RTT, providing a translational bridge between pre-clinical and human research.

A phase II randomized controlled trial of tiopronin for aneurysmal subarachnoid hemorrhage.

OBJECTIVE: Delayed cerebral ischemia (DCI) is a significant contributor to poor outcomes after aneurysmal subarachnoid hemorrhage (aSAH). The neurotoxin 3-aminopropanal (3-AP) is upregulated in cerebral ischemia. This phase II clinical trial evaluated the efficacy of tiopronin in reducing CSF 3-AP levels in patients with aSAH. METHODS: In this prospective, randomized, double-blind, placebo-controlled, multicenter clinical trial, 60 patients were assigned to receive tiopronin or placebo in a 1:1 ratio. Treatment was commenced within 96 hours after aSAH onset, administered at a dose of 3 g daily, and continued until 14 days after aSAH or hospital discharge, whichever occurred earlier. The primary efficacy outcome was the CSF 3-AP level at 7 ± 1 days after aSAH. RESULTS: Of the 60 enrolled patients, 29 (97%) and 27 (93%) in the tiopronin and placebo arms, respectively, received more than one dose of the study drug or placebo. At post-aSAH day 7 ± 1, CSF samples were available in 41% (n = 12/29) and 48% (n = 13/27) of patients in the tiopronin and placebo arms, respectively. No difference in CSF 3-AP levels at post-aSAH day 7 ± 1 was observed between the study arms (11 ± 12 nmol/mL vs 13 ± 18 nmol/mL; p = 0.766). Prespecified adverse events led to early treatment cessation for 4 patients in the tiopronin arm and 2 in the placebo arm. CONCLUSIONS: The power of this study was affected by missing data. Therefore, the authors could not establish or refute an effect of tiopronin on CSF 3-AP levels. Additional observational studies investigating the role of 3-AP as a biomarker for DCI may be warranted prior to its use as a molecular target in future clinical trials.Clinical trial registration no.: NCT01095731 (ClinicalTrials.gov).

Predicting delayed cerebral ischemia after subarachnoid hemorrhage using physiological time series data.

To develop and validate a prediction model for delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) using a temporal unsupervised feature engineering approach, demonstrating improved precision over standard features. 488 consecutive SAH admissions from 2006 to 2014 to a tertiary care hospital were included. Models were trained on 80%, while 20% were set aside for validation testing. Baseline information and standard grading scales were evaluated: age, sex, Hunt Hess grade, modified Fisher Scale (mFS), and Glasgow Coma Scale (GCS). An unsupervised approach applying random kernels was used to extract features from physiological time series (systolic and diastolic blood pressure, heart rate, respiratory rate, and oxygen saturation). Classifiers (Partial Least Squares, linear and kernel Support Vector Machines) were trained on feature subsets of the derivation dataset. Models were applied to the validation dataset. The performances of the best classifiers on the validation dataset are reported by feature subset. Standard grading scale (mFS): AUC 0.58. Combined demographics and grading scales: AUC 0.60. Random kernel derived physiologic features: AUC 0.74. Combined baseline and physiologic features with redundant feature reduction: AUC 0.77. Current DCI prediction tools rely on admission imaging and are advantageously simple to employ. However, using an agnostic and computationally inexpensive learning approach for high-frequency physiologic time series data, we demonstrated that our models achieve higher classification accuracy.

Incorporating High-Frequency Physiologic Data Using Computational Dictionary Learning Improves Prediction of Delayed Cerebral Ischemia Compared to Existing Methods.

PURPOSE: Accurate prediction of delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) can be critical for planning interventions to prevent poor neurological outcome. This paper presents a model using convolution dictionary learning to extract features from physiological data available from bedside monitors. We develop and validate a prediction model for DCI after SAH, demonstrating improved precision over standard methods alone. METHODS: 488 consecutive SAH admissions from 2006 to 2014 to a tertiary care hospital were included. Models were trained on 80%, while 20% were set aside for validation testing. Modified Fisher Scale was considered the standard grading scale in clinical use; baseline features also analyzed included age, sex, Hunt-Hess, and Glasgow Coma Scales. An unsupervised approach using convolution dictionary learning was used to extract features from physiological time series (systolic blood pressure and diastolic blood pressure, heart rate, respiratory rate, and oxygen saturation). Classifiers (partial least squares and linear and kernel support vector machines) were trained on feature subsets of the derivation dataset. Models were applied to the validation dataset. RESULTS: The performances of the best classifiers on the validation dataset are reported by feature subset. Standard grading scale (mFS): AUC 0.54. Combined demographics and grading scales (baseline features): AUC 0.63. Kernel derived physiologic features: AUC 0.66. Combined baseline and physiologic features with redundant feature reduction: AUC 0.71 on derivation dataset and 0.78 on validation dataset. CONCLUSION: Current DCI prediction tools rely on admission imaging and are advantageously simple to employ. However, using an agnostic and computationally inexpensive learning approach for high-frequency physiologic time series data, we demonstrated that we could incorporate individual physiologic data to achieve higher classification accuracy.

Duration of Agitation, Fluctuations of Consciousness, and Associations with Outcome in Patients with Subarachnoid Hemorrhage.

BACKGROUND: Agitation is common after subarachnoid hemorrhage (SAH) and may be independently associated with outcomes. We sought to determine whether the duration of agitation and fluctuating consciousness were also associated with outcomes in patients with SAH. METHODS: We identified all patients with positive Richmond Agitation Sedation Scale (RASS) scores from a prospective observational cohort of patients with SAH from 2011 to 2015. Total duration of agitation was extrapolated for each patient using available RASS scores, and 24-h mean and standard deviation (SD) of RASS scores were calculated for each patient. We also calculated each patient's duration of substantial fluctuation of consciousness, defined as the number of days with 24-h RASS SD > 1. Patients were stratified by 3-month outcome using the modified Rankin scale, and associations with outcome were assessed via logistic regression. RESULTS: There were 98 patients with at least one positive RASS score, with median total duration of agitation 8 h (interquartile range [IQR] 4-18), and median duration of substantially fluctuating consciousness 2 days (IQR 1-3). Unfavorable 3-month outcome was significantly associated with a longer duration of fluctuating consciousness (odds ratio [OR] per day, 1.51; 95% confidence interval [CI], 1.04-2.20; p = 0.031), but a briefer duration of agitation (OR per hour, 0.94; 95% CI, 0.89-0.99; p = 0.031). CONCLUSION: Though a longer duration of fluctuating consciousness was associated with worse outcomes in our cohort, total duration of agitation was not, and may have had the opposite effect. Our findings should therefore challenge the intensity with which agitation is often treated in SAH patients.

Hunt-Hess 5 subarachnoid haemorrhage presenting with cardiac arrest is associated with larger volume bleeds.

AIMS: The mechanism, effects, and outcomes of cardiac arrest (CA) caused by subarachnoid haemorrhage (SAH) remain unclear. We compared SAH patients presenting with CA to other high-grade SAH patients presenting without CA in order to better understand (1) the cause of CA, (2) cerebral pathophysiology following CA, and (3) outcomes of CA in patients with SAH. METHODS: We performed a retrospective analysis of a prospectively collected observational cohort. 31 Hunt-Hess 5 patients that presented with CA were compared to 146 Hunt-Hess 5 patients that presented without CA. Clinical and imaging findings were predefined and adjudicated. Cerebral physiology measures were available for a subset of patients, matched 1:1 by age. RESULTS: Twenty-two (71%) CA patients had pulseless electrical activity/asystole compared to 2 (6%) with a shockable rhythm. The CA patients were younger (OR 0.96, 95% CI 0.93-0.99, p=0.009), had more SAH on CT (OR 1.07, 95% CI 1.01-1.13, p=0.02), and had higher in-hospital mortality (87% vs. 58%, OR 6.2 (2.1-26.6), p=0.004). There were no differences in aneurysm location, cerebral herniation, or ictal seizures. Despite similar cerebral perfusion pressure, CA patients had pathologically lower brain tissue oxygenation, lower glucose, and higher lactate to pyruvate ratios. CONCLUSIONS: CA in SAH is associated with larger volume bleeds. Despite normal cerebral perfusion pressures, CA patients show compromised cerebral physiology.

Prognosticating Functional Outcome After Intracerebral Hemorrhage: The ICHOP Score.

BACKGROUND: The morbidity, mortality, and monetary cost associated with intracerebral hemorrhage (ICH) is devastatingly high. Several scoring systems have been proposed to prognosticate outcomes after ICH, although the original ICH Score is still the most widely used. However, recent research suggests that systemic physiologic factors, such as those included in the Acute Physiology and Chronic Health Evaluation II score, may also influence outcome. In addition, no scoring systems to date have included premorbid functional status. Therefore, we propose a scoring system that incorporates these factors to prognosticate 3-month and 12-month functional outcomes. METHODS: We used the Random Forest machine-learning technique to identify factors from a dataset of more than 200 data points per patient that were most strongly affiliated with functional outcome. We then used linear regression to create an initial model based on these factors and modified weightings to improve accuracy. Our scoring system was compared with the ICH Score for prognosticating functional outcomes. RESULTS: Two separate scoring systems (Intracerebral Hemorrhage Outcomes Project 3 [ICHOP3] and ICHOP12) were developed for 3-month and 12-month functional outcomes using Glasgow Coma Scale, National Institutes of Health Stroke Scale, Acute Physiology and Chronic Health Evaluation II, premorbid modified Rankin Scale (mRS), and hematoma volume (3-month only). Patient outcomes were dichotomized into good (mRS score, 0-3) and poor (mRS score, 4-6) categories based on functional status. Areas under the curve in the derivation cohort for predicting mRS score were 0.89 (3-month) and 0.87 (12-month); both were significantly more discriminatory than the original ICH Score. CONCLUSIONS: The ICHOP scores may provide more comprehensive evaluation of a patient's long-term functional prognosis by taking into account systemic physiologic factors as well as premorbid functional status.

Dynamic regimes of neocortical activity linked to corticothalamic integrity correlate with outcomes in acute anoxic brain injury after cardiac arrest.

OBJECTIVE: Recognition of potential for neurological recovery in patients who remain comatose after cardiac arrest is challenging and strains clinical decision making. Here, we utilize an approach that is based on physiological principles underlying recovery of consciousness and show correlation with clinical recovery after acute anoxic brain injury. METHODS: A cohort study of 54 patients admitted to an Intensive Care Unit after cardiac arrest who underwent standardized bedside behavioral testing (Coma Recovery Scale - Revised [CRS-R]) during EEG monitoring. Blinded to all clinical variables, artifact-free EEG segments were selected around maximally aroused states and analyzed using a multi-taper method to assess frequency spectral content. EEG spectral features were assessed based on pre-defined categories that are linked to anterior forebrain corticothalamic integrity. Clinical outcomes were determined at the time of hospital discharge, using Cerebral Performance Categories (CPC). RESULTS: Ten patients with ongoing seizures, myogenic artifacts or technical limitations obscuring recognition of underlying cortical dynamic activity were excluded from primary analysis. Of the 44 remaining patients with distinct EEG spectral features, 39 (88%) fit into our predefined categories. In these patients, spectral features corresponding to higher levels of anterior forebrain corticothalamic integrity correlated with higher levels of consciousness and favorable clinical outcome at the time of hospital discharge (P = 0.014). INTERPRETATION: Predicted transitions of neocortical dynamics that indicate functional integrity of anterior forebrain corticothalamic circuitry correlate with clinical outcomes in postcardiac-arrest patients. Our results support a new biologically driven approach toward better understanding of neurological recovery after cardiac arrest.

Electroencephalographic Periodic Discharges and Frequency-Dependent Brain Tissue Hypoxia in Acute Brain Injury.

Importance: Periodic discharges (PDs) that do not meet seizure criteria, also termed the ictal interictal continuum, are pervasive on electroencephalographic (EEG) recordings after acute brain injury. However, their association with brain homeostasis and the need for clinical intervention remain unknown. Objective: To determine whether distinct PD patterns can be identified that, similar to electrographic seizures, cause brain tissue hypoxia, a measure of ongoing brain injury. Design, Setting, and Participants: This prospective cohort study included 90 comatose patients with high-grade spontaneous subarachnoid hemorrhage who underwent continuous surface (scalp) EEG (sEEG) recording and multimodality monitoring, including invasive measurements of intracortical (depth) EEG (dEEG), partial pressure of oxygen in interstitial brain tissue (Pbto2), and regional cerebral blood flow (CBF). Patient data were collected from June 1, 2006, to September 1, 2014, at a single tertiary care center. The retrospective analysis was performed from September 1, 2014, to May 1, 2016, with a hypothesis that the effect on brain tissue oxygenation was primarily dependent on the discharge frequency. Main Outcomes and Measures: Electroencephalographic recordings were visually classified based on PD frequency and spatial distribution of discharges. Correlations between mean multimodality monitoring data and change-point analyses were performed to characterize electrophysiological changes by applying bootstrapping. Results: Of the 90 patients included in the study (26 men and 64 women; mean [SD] age, 55 [15] years), 32 (36%) had PDs on sEEG and dEEG recordings and 21 (23%) on dEEG recordings only. Frequencies of PDs ranged from 0.5 to 2.5 Hz. Median Pbto2 was 23 mm Hg without PDs compared with 16 mm Hg at 2.0 Hz and 14 mm Hg at 2.5 Hz (differences were significant for 0 vs 2.5 Hz based on bootstrapping). Change-point analysis confirmed a temporal association of high-frequency PD onset (≥2.0 Hz) and Pbto2 reduction (median normalized Pbto2 decreased by 25% 5-10 minutes after onset). Increased regional CBF of 21.0 mL/100 g/min for 0 Hz, 25.9 mL/100 g/min for 1.0 Hz, 27.5 mL/100 g/min for 1.5 Hz, and 34.7 mL/100 g/min for 2.0 Hz and increased global cerebral perfusion pressure of 91 mm Hg for 0 Hz, 100.5 mm Hg for 0.5 Hz, 95.5 mm Hg for 1.0 Hz, 97.0 mm Hg for 2.0 Hz, 98.0 mm Hg for 2.5 Hz, 95.0 mm Hg for 2.5 Hz, and 67.8 mm Hg for 3.0 Hz were seen for higher PD frequencies. Conclusions and Relevance: These data give some support to consider redefining the continuum between seizures and PDs, suggesting that additional damage after acute brain injury may be reflected by frequency changes in electrocerebral recordings. Similar to seizures, cerebral blood flow increases in patients with PDs to compensate for the increased metabolic demand but higher-frequency PDs (>2 per second) may be inadequately compensated without an additional rise in CBF and associated with brain tissue hypoxia, or higher-frequency PDs may reflect inadequacies in brain compensatory mechanisms.

Ultra-early angiographic vasospasm associated with delayed cerebral ischemia and infarction following aneurysmal subarachnoid hemorrhage.

OBJECTIVE The clinical significance of cerebral ultra-early angiographic vasospasm (UEAV), defined as cerebral arterial narrowing within the first 48 hours of aneurysmal subarachnoid hemorrhage (aSAH), remains poorly characterized. The authors sought to determine its frequency, predictors, and impact on functional outcome. METHODS The authors prospectively studied UEAV in a cohort of 1286 consecutively admitted patients with aSAH between August 1996 and June 2013. Admission clinical, radiographic, and acute clinical course information was documented during patient hospitalization. Functional outcome was assessed at 3 months using the modified Rankin Scale. Logistic regression and Cox proportional hazards models were generated to assess predictors of UEAV and its relationship to delayed cerebral ischemia (DCI) and outcome. Multiple imputation methods were used to address data lost to follow-up. RESULTS The cohort incidence rate of UEAV was 4.6%. Multivariable logistic regression analysis revealed that younger age, sentinel bleed, and poor admission clinical grade were significantly associated with UEAV. Patients with UEAV had a 2-fold increased risk of DCI (odds ratio [OR] 2.3, 95% confidence interval [CI] 1.4-3.9, p = 0.002) and cerebral infarction (OR 2.0, 95% CI 1.0-3.9, p = 0.04), after adjusting for known predictors. Excluding patients who experienced sentinel bleeding did not change this effect. Patients with UEAV also had a significantly higher hazard for DCI in a multivariable model. UEAV was not found to be significantly associated with poor functional outcome (OR 0.8, 95% CI 0.4-1.6, p = 0.5). CONCLUSIONS UEAV may be less frequent than has been reported previously. Patients who exhibit UEAV are at higher risk for refractory DCI that results in cerebral infarction. These patients may benefit from earlier monitoring for signs of DCI and more aggressive treatment. Further study is needed to determine the long-term functional significance of UEAV.

Agitation After Subarachnoid Hemorrhage: A Frequent Omen of Hospital Complications Associated with Worse Outcomes.

BACKGROUND: Agitated delirium is frequent following acute brain injury, but data are limited in patients with subarachnoid hemorrhage (SAH). We examined incidence, risk factors, and consequences of agitation in these patients in a single-center retrospective study. METHODS: We identified all patients treated with antipsychotics or dexmedetomidine from a prospective observational cohort of patients with spontaneous SAH. Agitation was confirmed by chart review. Outcomes were assessed at 12 months using the modified Rankin Scale (mRS), Telephone Interview for Cognitive Status (TICS), and Lawton IADL (Instrumental Activities of Daily Living) scores. Independent predictors were identified using logistic regression. RESULTS: From 309 SAH patients admitted between January 2011 and December 2015, 52 (17 %) developed agitation, frequently in the first 72 h (50 %) and in patients with Hunt-Hess grades 3-4 (12 % of grades 1-2, 28 % of grades 3-4, 8 % of grade 5). There was also a significant association between agitation and a history of cocaine use or prior psychiatric diagnosis. Agitated patients were more likely to develop multiple hospital complications; and in half of these patients, complications were diagnosed within 24 h of agitation onset. Agitation was associated with IADL impairment at 12 months (Lawton >8; p = 0.03, OR 2.7, 95 % CI, 1.1-6.8) in non-comatose patients (Hunt-Hess 1-4), but not with functional outcome (mRS >3), cognitive impairment (TICS ≤30), or ICU/hospital length of stay after controlling for other predictors. CONCLUSION: Agitation occurs frequently after SAH, especially in non-comatose patients with higher clinical grades. It is associated with the development of multiple hospital complications and may have an independent impact on long-term outcomes.

Automatic cortical representation of auditory pitch changes in Rett syndrome.

BACKGROUND: Over the typical course of Rett syndrome, initial language and communication abilities deteriorate dramatically between the ages of 1 and 4 years, and a majority of these children go on to lose all oral communication abilities. It becomes extremely difficult for clinicians and caretakers to accurately assess the level of preserved auditory functioning in these children, an issue of obvious clinical import. Non-invasive electrophysiological techniques allow for the interrogation of auditory cortical processing without the need for overt behavioral responses. In particular, the mismatch negativity (MMN) component of the auditory evoked potential (AEP) provides an excellent and robust dependent measure of change detection and auditory sensory memory. Here, we asked whether females with Rett syndrome would produce the MMN to occasional changes in pitch in a regularly occurring stream of auditory tones. METHODS: Fourteen girls with genetically confirmed Rett syndrome and 22 age-matched neurotypical controls participated (ages 3.9-21.1 years). High-density electrophysiological recordings from 64 scalp electrodes were made while participants passively listened to a regularly occurring stream of 503-Hz auditory tone pips that was occasionally (15 % of presentations) interrupted by a higher-pitched deviant tone of 996 Hz. The MMN was derived by subtracting the AEP to these deviants from the AEP produced to the standard. RESULTS: Despite clearly anomalous morphology and latency of the AEP to simple pure-tone inputs in Rett syndrome, the MMN response was evident in both neurotypicals and Rett patients. However, we found that the pitch-evoked MMN was both delayed and protracted in duration in Rett, pointing to slowing of auditory responsiveness. CONCLUSIONS: The presence of the MMN in Rett patients suggests preserved abilities to process pitch changes in auditory sensory memory. This work represents a beginning step in an effort to comprehensively map the extent of auditory cortical functioning in Rett syndrome. These easily obtained objective brain measures of auditory processing have promise as biomarkers against which future therapeutic efforts can be assayed.

Bedside quantitative electroencephalography improves assessment of consciousness in comatose subarachnoid hemorrhage patients.

OBJECTIVE: Accurate behavioral assessments of consciousness carry tremendous significance in guiding management, but are extremely challenging in acutely brain-injured patients. We evaluated whether electroencephalography (EEG) and multimodality monitoring parameters may facilitate assessment of consciousness in patients with subarachnoid hemorrhage. METHODS: A retrospective analysis was performed of 83 consecutively treated adults with subarachnoid hemorrhage. All patients were initially comatose and had invasive brain monitoring placed. Behavioral assessments were performed during daily interruption of sedation and categorized into 3 groups based on their best examination as (1) comatose, (2) arousable (eye opening or attending toward a stimulus), and (3) aware (command following). EEG features included spectral power and complexity measures. Comparisons were made using bootstrapping methods and partial least squares regression. RESULTS: We identified 389 artifact-free EEG clips following behavioral assessments. Increasing central gamma, posterior alpha, and diffuse theta-delta oscillations differentiated patients who were arousable from those in coma. Command following was characterized by a further increase in central gamma and posterior alpha, as well as an increase in alpha permutation entropy. These EEG features together with basic neurological examinations (eg, pupillary light reflex) contributed heavily to a linear model predicting behavioral state, whereas brain physiology measures (eg, brain oxygenation), structural injury, and clinical course added less. INTERPRETATION: EEG measures of behavioral states provide distinctive signatures that complement behavioral assessments of patients with subarachnoid hemorrhage shortly after the injury. Our data support the hypothesis that impaired connectivity of cortex with both central thalamus and basal forebrain underlies decreasing levels of consciousness. Ann Neurol 2016;80:541-553.

Prognostication of long-term outcomes after subarachnoid hemorrhage: The FRESH score.

OBJECTIVE: To create a multidimensional tool to prognosticate long-term functional, cognitive, and quality of life outcomes after spontaneous subarachnoid hemorrhage (SAH) using data up to 48 hours after admission. METHODS: Data were prospectively collected for 1,619 consecutive patients enrolled in the SAH outcome project July 1996 to March 2014. Linear models (LMs) were applied to identify factors associated with outcome in 1,526 patients with complete data. Twelve-month functional, cognitive, and quality of life outcomes were measured using the modified Rankin scale (mRS), Telephone Interview for Cognitive Status, and Sickness Impact Profile. Based on the LM residuals, we constructed the FRESH score (Functional Recovery Expected after Subarachnoid Hemorrhage). Score performance, discrimination, and internal validity were tested using the area under the receiver operating characteristic curve (AUC), Nagelkerke and Cox/Snell R(2) , and bootstrapping. For external validation, we used a control population of SAH patients from the CONSCIOUS-1 study (n = 413). RESULTS: The FRESH score was composed of Hunt & Hess and APACHE-II physiologic scores on admission, age, and aneurysmal rebleed within 48 hours. Separate scores to prognosticate 1-year cognition (FRESH-cog) and quality of life (FRESH-quol) were developed controlling for education and premorbid disability. Poor functional outcome (mRS = 4-6) for score levels 1 through 9 respectively was present in 3, 6, 12, 38, 61, 83, 92, 98, and 100% at 1-year follow-up. Performance of FRESH (AUC = 0.90), FRESH-cog (AUC = 0.80), and FRESH-quol (AUC = 0.78) was high. External validation of our cohort using mRS as endpoint showed satisfactory results (AUC = 0.77). To allow for convenient score calculation, we built a smartphone app available for free download. INTERPRETATION: FRESH is the first clinical tool to prognosticate long-term outcome after spontaneous SAH in a multidimensional manner. Ann Neurol 2016;80:46-58.

Causal Structure of Brain Physiology after Brain Injury from Subarachnoid Hemorrhage.

High frequency physiologic data are routinely generated for intensive care patients. While massive amounts of data make it difficult for clinicians to extract meaningful signals, these data could provide insight into the state of critically ill patients and guide interventions. We develop uniquely customized computational methods to uncover the causal structure within systemic and brain physiologic measures recorded in a neurological intensive care unit after subarachnoid hemorrhage. While the data have many missing values, poor signal-to-noise ratio, and are composed from a heterogeneous patient population, our advanced imputation and causal inference techniques enable physiologic models to be learned for individuals. Our analyses confirm that complex physiologic relationships including demand and supply of oxygen underlie brain oxygen measurements and that mechanisms for brain swelling early after injury may differ from those that develop in a delayed fashion. These inference methods will enable wider use of ICU data to understand patient physiology.

Sex differences in multisensory speech processing in both typically developing children and those on the autism spectrum.

BACKGROUND: Previous work has revealed sizeable deficits in the abilities of children with an autism spectrum disorder (ASD) to integrate auditory and visual speech signals, with clear implications for social communication in this population. There is a strong male preponderance in ASD, with approximately four affected males for every female. The presence of sex differences in ASD symptoms suggests a sexual dimorphism in the ASD phenotype, and raises the question of whether this dimorphism extends to ASD traits in the neurotypical population. Here, we investigated possible sexual dimorphism in multisensory speech integration in both ASD and neurotypical individuals. METHODS: We assessed whether males and females differed in their ability to benefit from visual speech when target words were presented under varying levels of signal-to-noise, in samples of neurotypical children and adults, and in children diagnosed with an ASD. RESULTS: In typically developing (TD) children and children with ASD, females (n = 47 and n = 15, respectively) were significantly superior in their ability to recognize words under audiovisual listening conditions compared to males (n = 55 and n = 58, respectively). This sex difference was absent in our sample of neurotypical adults (n = 28 females; n = 28 males). CONCLUSIONS: We propose that the development of audiovisual integration is delayed in male relative to female children, a delay that is also observed in ASD. In neurotypicals, these sex differences disappear in early adulthood when females approach their performance maximum and males "catch up." Our findings underline the importance of considering sex differences in the search for autism endophenotypes and strongly encourage increased efforts to study the underrepresented population of females within ASD.

Oscillatory recruitment of bilateral visual cortex during spatial attention to competing rhythmic inputs.

Selective attention uses temporal regularity of relevant inputs to bias the phase of ongoing population-level neuronal oscillations. This phase entrainment streamlines processing, allowing attended information to arrive at moments of high neural excitability. How entrainment resolves competition between spatially segregated inputs during visuospatial tasks is not yet established. Using high-density electroencephalography in humans, a bilateral entrainment response to the rhythm (1.3 or 1.5 Hz) of an attended stimulation stream was observed, concurrent with a considerably weaker contralateral entrainment to a competing rhythm. That ipsilateral visual areas strongly entrained to the attended stimulus is notable because competitive inputs to these regions were being driven at an entirely different rhythm. Strong modulations of phase locking and weak modulations of single-trial power suggest that entrainment was primarily driven by phase-alignment of ongoing oscillatory activity. In addition, interhemispheric differences in entrained phase were found to be modulated by attended hemifield, implying that the bilateral nature of the response reflected a functional flow of information between hemispheres. This modulation was strongest at the third of at least four harmonics that were strongly entrained. Ipsilateral increases in alpha-band (8-12 Hz) power were also observed during bilateral entrainment, reflecting suppression of the ignored stimulation stream. Furthermore, both entrainment and alpha lateralization significantly affected task performance. We conclude that oscillatory entrainment is a functionally relevant mechanism that synchronizes endogenous activity across the cortical hierarchy to resolve spatial competition. We further speculate that concurrent suppression of ignored input might facilitate the widespread propagation of attended information during spatial attention.

Interests shape how adolescents pay attention: the interaction of motivation and top-down attentional processes in biasing sensory activations to anticipated events.

The voluntary allocation of attention to environmental inputs is a crucial mechanism of healthy cognitive functioning, and is probably influenced by an observer's level of interest in a stimulus. For example, an individual who is passionate about soccer but bored by botany will obviously be more attentive at a soccer match than an orchid show. The influence of monetary rewards on attention has been examined, but the impact of more common motivating factors (i.e. the level of interest in the materials under observation) remains unclear, especially during development. Here, stimulus sets were designed based on survey measures of the level of interest of adolescent participants in several item classes. High-density electroencephalography was recorded during a cued spatial attention task in which stimuli of high or low interest were presented in separate blocks. The motivational impact on performance of a spatial attention task was assessed, along with event-related potential measures of anticipatory top-down attention. As predicted, performance was improved for the spatial target detection of high interest items. Further, the impact of motivation was observed in parieto-occipital processes associated with anticipatory top-down spatial attention. The anticipatory activity over these regions was also increased for high vs. low interest stimuli, irrespective of the direction of spatial attention. The results also showed stronger anticipatory attentional and motivational modulations over the right vs. left parieto-occipital cortex. These data suggest that motivation enhances top-down attentional processes, and can independently shape activations in sensory regions in anticipation of events. They also suggest that attentional functions across hemispheres may not fully mature until late adolescence.

Neurophysiological indices of atypical auditory processing and multisensory integration are associated with symptom severity in autism.

Atypical processing and integration of sensory inputs are hypothesized to play a role in unusual sensory reactions and social-cognitive deficits in autism spectrum disorder (ASD). Reports on the relationship between objective metrics of sensory processing and clinical symptoms, however, are surprisingly sparse. Here we examined the relationship between neurophysiological assays of sensory processing and (1) autism severity and (2) sensory sensitivities, in individuals with ASD aged 6-17. Multiple linear regression indicated significant associations between neural markers of auditory processing and multisensory integration, and autism severity. No such relationships were apparent for clinical measures of visual/auditory sensitivities. These data support that aberrant early sensory processing contributes to autism symptoms, and reveal the potential of electrophysiology to objectively subtype autism.