Effect of Brief Training to Identify Autism Spectrum Disorder During Toddler Well-Child Care Visits.

OBJECTIVE: To examine the effect of a brief Enhanced training using the information-motivation-behavior (IMB) change model on improving providers' surveillance rates and accuracy of autism spectrum disorder (ASD) detection. METHOD: Toddlers (n = 5,672) were screened for ASD during their pediatric well-child visits. Pediatric providers (n = 120) were randomized to receive Enhanced (incorporating components of the IMB model) or Control training. Providers indicated whether they had an ASD concern at each well-child visit. Toddlers who were positive on any screener and/or whose provider indicated ASD concern were invited for a diagnostic evaluation. Differences in provider-indicated ASD concerns before and after training were evaluated using log-linear analyses. RESULTS: The Enhanced training did not have a significant effect on provider-endorsed ASD concerns (p = 0.615) or accuracy of endorsing concerns (p = 0.619). Providers in the Control training showed a significant reduction in indicating whether or not they had concerns after the training (from 71.9% to 64.3%), which did not occur in the Enhanced group. The Enhanced training led to more frequent endorsements of language (χ2 = 8.772, p = 0.003) and restricted and repetitive behavior (χ2 = 7.918, p = 0.005) concerns for children seen after training. CONCLUSION: Provider training had limited impact on ASD surveillance, indicating the importance of using formal screening instruments that rely on parent report during well-child visits to complement developmental surveillance. Future research should examine whether providers who indicate specific concerns are more likely to accurately refer children for ASD evaluations.

Early and Repeated Screening Detects Autism Spectrum Disorder.

OBJECTIVE: To evaluate timing and accuracy of early and repeated screening for autism spectrum disorder (ASD) during well-child visits. STUDY DESIGN: Using a longitudinal study design, toddlers (n = 5784) were initially screened at 12 (n = 1504), 15 (n = 1228), or 18 (n = 3052) months during well-child visits, and rescreened at 18, 24, and 36 months. Of those screened, 368 toddlers attended an ASD evaluation after a positive screen and/or a provider concern for ASD at any visit. RESULTS: Screens initiated at 12 months yielded an ASD diagnosis significantly earlier than at 15 months (P = .003, d = 0.99) and 18 months (P < .001, d = 0.97). Cross-group overall sensitivity of the initial screen was .715 and specificity was .959. Repeat screening improves sensitivity (82.1%), without notably decreasing specificity (all >93.5%). Screening at 18 months resulted in significantly higher positive predictive value than at 12 months (X2 (1, n = 221) = 9.87, P = .002, OR = 2.60) and 15 months (X2 (1, n = 208) = 14.57, P < .001, OR = 3.67). With repeat screening, positive predictive value increased for all screen groups, but the increase was not significant. CONCLUSIONS: Screening as early as 12 months effectively identifies many children at risk for ASD. Children screened at 12 months receive a diagnosis of ASD significantly earlier than peers who are first screened at later ages, facilitating earlier intervention. However, as the sensitivity is lower for a single screen, screening needs to be repeated.

Long-range gamma phase synchronization as a compensatory strategy during working memory in high-performing patients with schizophrenia.

Working memory deficits in schizophrenia may be associated with impairments in the integration of neural activity across a distributed network of cortical areas. However, evaluation of the contribution of this integration to working memory impairments in patients is severely confounded by behavioral performance. In the present multidimensional-neuroimaging study, measures of neural oscillations at baseline and during a working memory task, baseline gamma-aminobutyric acid (GABA) level in the left dorsolateral prefrontal cortex (DLPFC), and behavioral performance were obtained. Controlling behavioral performance by recruiting only "high-performing" patients with schizophrenia, we investigated whether the strength of cross-area communications differs between patients with schizophrenia and healthy participants under accurate and equivalent behavioral performance. Results of phase-locking value indicated that these high-performing patients recruited significantly more between frontal and occipital regions in the left hemisphere, t(13) = -2.16, p = .05, Cohen's d = -1.20, and between frontal and temporal regions in the right hemisphere, t(13) = -2.63, p = .02, Cohen's d = -1.46. These cross-area communication patterns may be associated with visuoverbal and visuospatial working memory networks of the left and right hemispheres, respectively. Moreover, correlations of patient's cross-area communication with in vivo GABA levels of the left DLPFC revealed a significant positive relationship (r = .77, p = .04), demonstrating that the critical role of GABA functions in gamma band oscillations may go beyond local neuronal assemblies in the left DLPFC. Altogether, these exploratory findings point to the heterogeneity among schizophrenia patients and highlight the notion that high-performing patients may engage in potential compensatory mechanisms and may represent a subgroup of patients that may be categorically or dimensionally divergent in psychopathology.

Effects of chronic ketamine on hippocampal cross-frequency coupling: implications for schizophrenia pathophysiology.

Disrupted neuronal oscillations have been identified as a potentially important biomarker for the perceptual and cognitive symptoms of schizophrenia. Emerging evidences suggest that interactions between different frequency bands, cross-frequency coupling (CFC), serve an important role in integrating sensory and cognitive information and may contribute to disease pathophysiology. In this study, we investigated the effects of 14-day consecutive administration of ketamine (30 mg/kg i.p.) vs. saline on alterations in amplitude and changes in the coupling of low-frequency (0-30 Hz) phase and high-frequency (30-115 Hz) amplitude in the CA1 hippocampus of Long Evans rats. Intracranial electrode recordings were conducted pre- and post-injection while the animals performed a foraging task on a four-arm rectangular maze. Permutation analysis of frequency band-specific change in amplitudes revealed between-group differences in theta (6-12 Hz) and slow gamma (25-50 Hz) but not fast gamma (65-100 Hz) bands at both slow and fast speeds. Chronic ketamine challenge resulted in decreased coupling (pre to post) at slow speeds but increased coupling at faster speeds, compared to either no or modest increased coupling in the saline group. These results demonstrate that chronic ketamine administration alters the interaction of low-frequency phase and high-frequency oscillations chronically and that such coupling varies as a function of locomotive speed. These findings provide evidence for the potential relevance of CFC to the pathophysiology of schizophrenia.

Machine learning identification of EEG features predicting working memory performance in schizophrenia and healthy adults.

BACKGROUND: With millisecond-level resolution, electroencephalographic (EEG) recording provides a sensitive tool to assay neural dynamics of human cognition. However, selection of EEG features used to answer experimental questions is typically determined a priori. The utility of machine learning was investigated as a computational framework for extracting the most relevant features from EEG data empirically. METHODS: Schizophrenia (SZ; n = 40) and healthy community (HC; n = 12) subjects completed a Sternberg Working Memory Task (SWMT) during EEG recording. EEG was analyzed to extract 5 frequency components (theta1, theta2, alpha, beta, gamma) at 4 processing stages (baseline, encoding, retention, retrieval) and 3 scalp sites (frontal-Fz, central-Cz, occipital-Oz) separately for correctly and incorrectly answered trials. The 1-norm support vector machine (SVM) method was used to build EEG classifiers of SWMT trial accuracy (correct vs. incorrect; Model 1) and diagnosis (HC vs. SZ; Model 2). External validity of SVM models was examined in relation to neuropsychological test performance and diagnostic classification using conventional regression-based analyses. RESULTS: SWMT performance was significantly reduced in SZ (p < .001). Model 1 correctly classified trial accuracy at 84 % in HC, and at 74 % when cross-validated in SZ data. Frontal gamma at encoding and central theta at retention provided highest weightings, accounting for 76 % of variance in SWMT scores and 42 % variance in neuropsychological test performance across samples. Model 2 identified frontal theta at baseline and frontal alpha during retrieval as primary classifiers of diagnosis, providing 87 % classification accuracy as a discriminant function. CONCLUSIONS: EEG features derived by SVM are consistent with literature reports of gamma's role in memory encoding, engagement of theta during memory retention, and elevated resting low-frequency activity in schizophrenia. Tests of model performance and cross-validation support the stability and generalizability of results, and utility of SVM as an analytic approach for EEG feature selection.

Development of sensory gamma oscillations and cross-frequency coupling from childhood to early adulthood.

Given the importance of gamma oscillations in normal and disturbed cognition, there has been growing interest in their developmental trajectory. In the current study, age-related changes in sensory cortical gamma were studied using the auditory steady-state response (ASSR), indexing cortical activity entrained to a periodic auditory stimulus. A large sample (n = 188) aged 8-22 years had electroencephalography recording of ASSR during 20-, 30-, and 40-Hz click trains, analyzed for evoked amplitude, phase-locking factor (PLF) and cross-frequency coupling (CFC) with lower frequency oscillations. Both 40-Hz evoked power and PLF increased monotonically from 8 through 16 years, and subsequently decreased toward ages 20-22 years. CFC followed a similar pattern, with strongest age-related modulation of 40-Hz amplitude by the phase of delta oscillations. In contrast, the evoked power, PLF and CFC for the 20- and 30-Hz stimulation were distinct from the 40-Hz condition, with flat or decreasing profiles from childhood to early adulthood. The inverted U-shaped developmental trajectory of gamma oscillations may be consistent with interacting maturational processes-such as increasing fast GABA inhibition that enhances gamma activity and synaptic pruning that decreases gamma activity-that may continue from childhood through to adulthood.

Novel acoustic stimuli can alter locomotor speed to hippocampal theta relationship.

Hippocampal theta (6-12 Hz) plays a critical role in synchronizing the discharge of action potentials, ultimately orchestrating individual neurons into large-scale ensembles. Alterations in theta dynamics may reflect variations in sensorimotor integration, the flow of sensory input, and/or cognitive processing. Previously we have investigated septotemporal variation in the locomotor speed to theta amplitude relationship as well as how that relationship is systematically altered as a function of novel, physical space. In the present study, we ask, beyond physical space, whether persistent and passive sound delivery can alter septal theta local field potential rhythm dynamics. Results indicate pronounced alterations in the slope of the speed to theta amplitude relationship as a function of sound presentation and location. Further, this reduction in slope habituates across days. The current findings highlight that moment-to-moment alterations in theta amplitude is a rich dynamic index that is quantitatively related to both alterations in motor behavior and sensory experience. The implications of these phenomena are discussed with respect to emergent cognitive functions subserved by hippocampal circuits.

GABA level, gamma oscillation, and working memory performance in schizophrenia.

A relationship between working memory impairment, disordered neuronal oscillations, and abnormal prefrontal GABA function has been hypothesized in schizophrenia; however, in vivo GABA measurements and gamma band neural synchrony have not yet been compared in schizophrenia. This case-control pilot study (N = 24) compared baseline and working memory task-induced neuronal oscillations acquired with high-density electroencephalograms (EEGs) to GABA levels measured in vivo with magnetic resonance spectroscopy. Working memory performance, baseline GABA level in the left dorsolateral prefrontal cortex (DLPFC), and measures of gamma oscillations from EEGs at baseline and during a working memory task were obtained. A major limitation of this study is a relatively small sample size for several analyses due to the integration of diverse methodologies and participant compliance. Working memory performance was significantly lower for patients than for controls. During the working memory task, patients (n = 7) had significantly lower amplitudes in gamma oscillations than controls (n = 9). However, both at rest and across working memory stages, there were significant correlations between gamma oscillation amplitude and left DLPFC GABA level. Peak gamma frequency during the encoding stage of the working memory task (n = 16) significantly correlated with GABA level and working memory performance. Despite gamma band amplitude deficits in patients across working memory stages, both baseline and working memory-induced gamma oscillations showed strong dependence on baseline GABA levels in patients and controls. These findings suggest a critical role for GABA function in gamma band oscillations, even under conditions of system and cognitive impairments as seen in schizophrenia.

Validation of the modified checklist for Autism in toddlers, revised with follow-up (M-CHAT-R/F).

OBJECTIVE: This study validates the Modified Checklist for Autism in Toddlers, Revised with Follow-up (M-CHAT-R/F), a screening tool for low-risk toddlers, and demonstrates improved utility compared with the original M-CHAT. METHODS: Toddlers (N = 16,071) were screened during 18- and 24-month well-child care visits in metropolitan Atlanta and Connecticut. Parents of toddlers at risk on M-CHAT-R completed follow-up; those who continued to show risk were evaluated. RESULTS: The reliability and validity of the M-CHAT-R/F were demonstrated, and optimal scoring was determined by using receiver operating characteristic curves. Children whose total score was ≥ 3 initially and ≥ 2 after follow-up had a 47.5% risk of being diagnosed with autism spectrum disorder (ASD; confidence interval [95% CI]: 0.41-0.54) and a 94.6% risk of any developmental delay or concern (95% CI: 0.92-0.98). Total score was more effective than alternative scores. An algorithm based on 3 risk levels is recommended to maximize clinical utility and to reduce age of diagnosis and onset of early intervention. The M-CHAT-R detects ASD at a higher rate compared with the M-CHAT while also reducing the number of children needing the follow-up. Children in the current study were diagnosed 2 years younger than the national median age of diagnosis. CONCLUSIONS: The M-CHAT-R/F detects many cases of ASD in toddlers; physicians using the 2-stage screener can be confident that most screen-positive cases warrant evaluation and referral for early intervention. Widespread implementation of universal screening can lower the age of ASD diagnosis by 2 years compared with recent surveillance findings, increasing time available for early intervention.

The corollary discharge in humans is related to synchronous neural oscillations.

How do animals distinguish between sensations coming from external sources and those resulting from their own actions? A corollary discharge system has evolved that involves the transmission of a copy of motor commands to sensory cortex, where the expected sensation is generated. Through this mechanism, sensations are tagged as coming from self, and responsiveness to them is minimized. The present study investigated whether neural phase synchrony between motor command and auditory cortical areas is related to the suppression of the auditory cortical response. We recorded electrocorticograms from the human brain during a vocalizing/listening task. Neural phase synchrony between Broca's area and auditory cortex in the gamma band (35 to ∼50 Hz) in the 50-msec time window preceding speech onset was greater during vocalizing than during listening to a playback of the same spoken sounds. Because prespeech neural synchrony was correlated (r = -.83, p = .006), with the subsequent suppression of the auditory cortical response to the spoken sound, we hypothesize that phase synchrony in the gamma band between Broca's area and auditory cortex is the neural instantiation of the transmission of a copy of motor commands. We suggest that neural phase synchrony of gamma frequencies may contribute to transmission of corollary discharges in humans.