Longitudinal EEG power in the first postnatal year differentiates autism outcomes

An aim of autism spectrum disorder (ASD) research is to identify early biomarkers that inform ASD pathophysiology and expedite detection. Brain oscillations captured in electroencephalography (EEG) are thought to be disrupted as core ASD pathophysiology. We leverage longitudinal EEG power measurements from 3 to 36 months of age in infants at low- and high-risk for ASD to test how and when power distinguishes ASD risk and diagnosis by age 3-years. Power trajectories across the first year, second year, or first three years postnatally were submitted to data-driven modeling to differentiate ASD outcomes. Power dynamics during the first postnatal year best differentiate ASD diagnoses. Delta and gamma frequency power trajectories consistently distinguish infants with ASD diagnoses from others. There is also a developmental shift across timescales towards including higher-frequency power to differentiate outcomes. These findings reveal the importance of developmental timing and trajectory in understanding pathophysiology and classifying ASD outcomes.R01 DC010290 - NIDCD NIH HHS; T32 MH112510 - NIMH NIH HHS; U54 HD090255 - NICHD NIH HHSPublished versio

Differential rates of perinatal maturation of human primary and nonprimary auditory cortex

Abstract Primary and nonprimary cerebral cortex mature along different timescales; however, the differences between the rates of maturation of primary and nonprimary cortex are unclear. Cortical maturation can be measured through changes in tissue microstructure detectable by diffusion magnetic resonance imaging (MRI). In this study, diffusion tensor imaging (DTI) was used to characterize the maturation of Heschl’s gyrus (HG), which contains both primary auditory cortex (pAC) and nonprimary auditory cortex (nAC), in 90 preterm infants between 26 and 42 weeks postmenstrual age (PMA). The preterm infants were in different acoustical environments during their hospitalization: 46 in open ward beds and 44 in single rooms. A control group consisted of 15 term-born infants. Diffusion parameters revealed that (1) changes in cortical microstructure that accompany cortical maturation had largely already occurred in pAC by 28 weeks PMA, and (2) rapid changes were taking place in nAC between 26 and 42 weeks PMA. At term equivalent PMA, diffusion parameters for auditory cortex were different between preterm infants and term control infants, reflecting either delayed maturation or injury. No effect of room type was observed. For the preterm group, disturbed maturation of nonprimary (but not primary) auditory cortex was associated with poorer language performance at age two years

Neurobehavioral Abnormalities in Firest-Degree Relative of Individuals With Autism

CONTEXT: Studying sensorimotor and neurocognitive impairments in unaffected family members of individuals with autism may help identify familial pathophysiological mechanisms associated with the disorder. OBJECTIVE: To determine whether atypical sensorimotor or neurocognitive characteristics associated with autism are present in first-degree relatives of individuals with autism. DESIGN: Case-control comparison of neurobehavioral functions. SETTING: University medical center. PARTICIPANTS: Fifty-seven first-degree relatives of individuals with autism and 40 age-, sex-, and IQ-matched healthy control participants (aged 8-54 years). MAIN OUTCOME MEASURES: Oculomotor tests of sensorimotor responses (saccades and smooth pursuit); procedural learning and response inhibition; neuropsychological tests of motor, memory, and executive functions; and psychological measures of social behavior, communication skills, and obsessive-compulsive behaviors. RESULTS: On eye movement testing, family members demonstrated saccadic hypometria, reduced steady-state pursuit gain, and a higher rate of voluntary response inhibition errors relative to controls. They also showed lateralized deficits in procedural learning and open-loop pursuit gain (initial 100 milliseconds of pursuit) and increased variability in the accuracy of large-amplitude saccades that were confined to rightward movements. In neuropsychological studies, only executive functions were impaired relative to those of controls. Family members reported more communication abnormalities and obsessive-compulsive behaviors than controls. Deficits across oculomotor, neuropsychological, and psychological domains were relatively independent from one another. CONCLUSIONS: Family members of individuals with autism demonstrate oculomotor abnormalities implicating pontocerebellar and frontostriatal circuits and left-lateralized alterations of frontotemporal circuitry and striatum. The left-lateralized alterations have not been identified in other neuropsychiatric disorders and are of interest given atypical brain lateralization and language development associated with the disorder. Similar oculomotor deficits have been reported in individuals with autism, suggesting that they may be familial and useful for studies of neurophysiological and genetic mechanisms in autism

Electrical impedance myography for reducing sample size in Duchenne muscular dystrophy trials

OBJECTIVE: To evaluate the sensitivity of electrical impedance myography (EIM) to disease progression in both ambulatory and non-ambulatory boys with DMD. METHODS AND PARTICIPANTS: A non-blinded, longitudinal cohort study of 29 ambulatory and 15 non-ambulatory boys with DMD and age-similar healthy boys. Subjects were followed for up to 1 year and assessed using the Myolex((R)) mView(TM) EIM system as part of a multicenter study. RESULTS: In the ambulatory group, EIM 100 kHz resistance values showed significant change compared to the healthy boys. For example, in lower extremity muscles, the average change in EIM 100 kHz resistance values over 12 months led to an estimated effect size of 1.58. Based on these results, 26 DMD patients/arm would be needed for a 12-month clinical trial assuming a 50% treatment effect. In non-ambulatory boys, EIM changes were greater in upper limb muscles. For example, biceps at 100kHz resistance gave an estimated effect size of 1.92 at 12 months. Based on these results, 18 non-ambulatory DMD patients/arm would be needed for a 12-month clinical trial assuming a 50% treatment effect. Longitudinal changes in the 100 kHz resistance values for the ambulatory boys correlated with the longitudinal changes in the timed supine-to-stand test. EIM was well-tolerated throughout the study. INTERPRETATION: This study supports that EIM 100 kHz resistance is sensitive to DMD progression in both ambulatory and non-ambulatory boys. Given the technology\u27s ease of use and broad age range of utility it should be employed as an exploratory endpoint in future clinical therapeutic trials in DMD. TRIAL REGISTRATION: Clincialtrials.gov registration #NCT02340923

Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome

Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder mainly affecting females and is associated with mutations in MECP2, the gene encoding methyl CpG-binding protein 2. Mouse models suggest that recombinant human insulin-like growth factor 1 (IGF-1) (rhIGF1) (mecasermin) may improve many clinical features. We evaluated the safety, tolerability, and pharmacokinetic profiles of IGF-1 in 12 girls with MECP2 mutations (9 with RTT). In addition, we performed a preliminary assessment of efficacy using automated cardiorespiratory measures, EEG, a set of RTT-oriented clinical assessments, and two standardized behavioral questionnaires. This phase 1 trial included a 4-wk multiple ascending dose (MAD) (40–120 μg/kg twice daily) period and a 20-wk open-label extension (OLE) at the maximum dose. Twelve subjects completed the MAD and 10 the entire study, without evidence of hypoglycemia or serious adverse events. Mecasermin reached the CNS compartment as evidenced by the increase in cerebrospinal fluid IGF-1 levels at the end of the MAD. The drug followed nonlinear kinetics, with greater distribution in the peripheral compartment. Cardiorespiratory measures showed that apnea improved during the OLE. Some neurobehavioral parameters, specifically measures of anxiety and mood also improved during the OLE. These improvements in mood and anxiety scores were supported by reversal of right frontal alpha band asymmetry on EEG, an index of anxiety and depression. Our data indicate that IGF-1 is safe and well tolerated in girls with RTT and, as demonstrated in preclinical studies, ameliorates certain breathing and behavioral abnormalities

Modeling pain in vitro using nociceptor neurons reprogrammed from fibroblasts

Reprogramming somatic cells from one cell fate to another can generate specific neurons suitable for disease modeling. To maximize the utility of patient-derived neurons, they must model not only disease-relevant cell classes but also the diversity of neuronal subtypes found in vivo and the pathophysiological changes that underlie specific clinical diseases. Here, we identify five transcription factors that reprogram mouse and human fibroblasts into noxious stimulus-detecting (nociceptor) neurons that recapitulate the expression of quintessential nociceptor-specific functional receptors and channels found in adult mouse nociceptor neurons as well as native subtype diversity. Moreover, the derived nociceptor neurons exhibit TrpV1 sensitization to the inflammatory mediator prostaglandin E2 and the chemotherapeutic drug oxaliplatin, modeling the inherent mechanisms underlying inflammatory pain hypersensitivity and painful chemotherapy-induced neuropathy. Using fibroblasts from patients with familial dysautonomia (hereditary sensory and autonomic neuropathy type III), we show that the technique can reveal novel aspects of human disease phenotypes in vitro

Hypothesis testing, power and sample size determination for health science data.

Hypothesis testing, power and sample size determination for health science data

Biophysical Variation within the M1 Type of Ganglion Cell Photoreceptor

Summary: Intrinsically photosensitive retinal ganglion cells of the M1 type encode environmental irradiance for functions that include circadian and pupillary regulation. Their distinct role, morphology, and molecular markers indicate that they are stereotyped circuit elements, but their physiological uniformity has not been investigated in a systematic fashion. We have profiled the biophysical parameters of mouse M1s and found that extreme variation is their hallmark. Most parameters span 1–3 log units, and the full range is evident in M1s that innervate brain regions serving divergent functions. Biophysical profiles differ among cells possessing similar morphology and between neighboring M1s recorded simultaneously. Variation in each parameter is largely independent of that in others, allowing for flexible individualization. Accordingly, a common stimulus drives heterogeneous spike outputs across cells. By contrast, a population of directionally selective retinal ganglion cells appeared physiologically uniform under similar conditions. Thus, M1s lack biophysical constancy and send diverse signals downstream. : Emanuel et al. demonstrate that a type of sensory cell with a defined role and morphology nevertheless exhibits log units of variation in its biophysical parameters. Variation drives functional individualization, even in spike outputs, and is fully available to downstream brain regions serving divergent functions. Keywords: cell type, melanopsin, photoreceptor, retinal ganglion cell, phototransduction, heterogeneity, membrane excitability, directionally selective retinal ganglion cell, Hb

Impaired memory consolidation in children with obstructive sleep disordered breathing

Memory consolidation is stabilized and even enhanced by sleep (and particularly by 12–15 Hz sleep spindles in NREM stage 2 sleep) in healthy children but it is unclear what happens to these processes when sleep is disturbed by obstructive sleep disordered breathing. This cross-sectional study investigates differences in declarative memory consolidation among children with primary snoring (PS) and obstructive sleep apnea (OSA) compared to controls. We further investigate whether memory consolidation group differences are associated with NREM stage 2 (N2) sigma (12–15 Hz) or NREM slow oscillation (0.5–1 Hz) spectral power bands. In this study, we trained and tested participants on a spatial declarative memory task with cued recall. Retest occurred after a period of daytime wake (Wake) or a night of sleep (Sleep) with in-lab polysomnography. 36 participants ages 5–9 years completed the protocol: 14 with OSA as defined by respiratory disturbance index (RDI) > 1/hour, 12 with primary snoring (PS) and 10 controls. OSA participants had poorer overall memory consolidation than controls across Wake and Sleep conditions [OSA: mean = -18.7% (5.8), controls: mean = 1.9% (7.2), t = -2.20, P = 0.04]. In contrast, PS participants and controls had comparable memory consolidation across conditions (t = 0.41; P = 0.38). We did not detect a main effect for condition (Sleep, Wake) or group x condition interaction on memory consolidation. OSA participants had lower N2 sigma power than PS (P = 0.03) and controls (P = 0.004) and N2 sigma power inversely correlated with percentage of time snoring on the study night (r = -0.33, P<0.05). Across all participants, N2 sigma power modestly correlated with memory consolidation in both Sleep (r = 0.37, P = 0.03) and Wake conditions (r = 0.44, P = 0.009). Further observed variable path analysis showed that N2 sigma power mediated the relationship between group and mean memory consolidation across Sleep and Wake states [Bindirect = 6.76(3.5), z = 2.03, P = 0.04]. NREM slow oscillation power did not correlate with memory consolidation. All results retained significance after controlling for age and BMI. In sum, participants with mild OSA had impaired memory consolidation and results were mediated by N2 sigma power. These results suggest that N2 sigma power could serve as biomarker of risk for cognitive dysfunction in children with sleep disordered breathing