Increased cortical reactivity to repeated tones at 8 months in infants with later ASD.

Dysregulation of cortical excitation/inhibition (E/I) has been proposed as a neuropathological mechanism underlying core symptoms of autism spectrum disorder (ASD). Determining whether dysregulated E/I could contribute to the emergence of behavioural symptoms of ASD requires evidence from human infants prior to diagnosis. In this prospective longitudinal study, we examine differences in neural responses to auditory repetition in infants later diagnosed with ASD. Eight-month-old infants with (high-risk: n = 116) and without (low-risk: n = 27) an older sibling with ASD were tested in a non-linguistic auditory oddball paradigm. Relative to high-risk infants with typical development (n = 44), infants with later ASD (n = 14) showed reduced repetition suppression of 40-60 Hz evoked gamma and significantly greater 10-20 Hz inter-trial coherence (ITC) for repeated tones. Reduced repetition suppression of cortical gamma and increased phase-locking to repeated tones are consistent with cortical hyper-reactivity, which could in turn reflect disturbed E/I balance. Across the whole high-risk sample, a combined index of cortical reactivity (cortical gamma amplitude and ITC) was dimensionally associated with reduced growth in language skills between 8 months and 3 years, as well as elevated levels of parent-rated social communication symptoms at 3 years. Our data show that cortical 'hyper-reactivity' may precede the onset of behavioural traits of ASD in development, potentially affecting experience-dependent specialisation of the developing brain.

Non-invasive measurement of a metabolic marker of infant brain function.

While near-infrared spectroscopy (NIRS) haemodynamic measures have proven to be vastly useful in investigating human brain development, the haemodynamic response function (HRF) in infants is not yet fully understood. NIRS measurements of the oxidation state of mitochondrial enzyme cytochrome-c-oxidase (oxCCO) have the potential to yield key information about cellular oxygen utilisation and therefore energy metabolism. We used a broadband NIRS system to measure changes in oxCCO, in addition to haemodynamic changes, during functional activation in a group of 33 typically developing infants aged between 4 and 6 months. The responses were recorded over the right temporal lobe while the infants were presented with engaging videos containing social content. A significant increase in oxCCO was found in response to the social stimuli, with maximum increase of 0.238 ± 0.13 µM. These results are the first reported significant change in oxCCO in response to stimulus-evoked activation in human infants and open new vistas for investigating human infant brain function and its energy metabolism.

Atypical processing of voice sounds in infants at risk for autism spectrum disorder.

Adults diagnosed with autism spectrum disorder (ASD) show a reduced sensitivity (degree of selective response) to social stimuli such as human voices. In order to determine whether this reduced sensitivity is a consequence of years of poor social interaction and communication or is present prior to significant experience, we used functional MRI to examine cortical sensitivity to auditory stimuli in infants at high familial risk for later emerging ASD (HR group, N = 15), and compared this to infants with no family history of ASD (LR group, N = 18). The infants (aged between 4 and 7 months) were presented with voice and environmental sounds while asleep in the scanner and their behaviour was also examined in the context of observed parent-infant interaction. Whereas LR infants showed early specialisation for human voice processing in right temporal and medial frontal regions, the HR infants did not. Similarly, LR infants showed stronger sensitivity than HR infants to sad vocalisations in the right fusiform gyrus and left hippocampus. Also, in the HR group only, there was an association between each infant's degree of engagement during social interaction and the degree of voice sensitivity in key cortical regions. These results suggest that at least some infants at high-risk for ASD have atypical neural responses to human voice with and without emotional valence. Further exploration of the relationship between behaviour during social interaction and voice processing may help better understand the mechanisms that lead to different outcomes in at risk populations.

Differential habituation to repeated sounds in infants at high risk for autism.

It has been suggested that poor habituation to stimuli might explain atypical sensory behaviours in autism. We investigated habituation to repeated sounds using an oddball paradigm in 9-month-old infants with an older sibling with autism and hence at high risk for developing autism. Auditory-evoked responses to repeated sounds in control infants (at low risk of developing autism) decreased over time, demonstrating habituation, and their responses to deviant sounds were larger than responses to standard sounds, indicating discrimination. In contrast, neural responses in infants at high risk showed less habituation and a reduced sensitivity to changes in frequency. Reduced sensory habituation may be present at a younger age than the emergence of autistic behaviour in some individuals, and we propose that this could play a role in the over responsiveness to some stimuli and undersensitivity to others observed in autism.

Early specialization for voice and emotion processing in the infant brain.

Human voices play a fundamental role in social communication, and areas of the adult "social brain" show specialization for processing voices and their emotional content (superior temporal sulcus, inferior prefrontal cortex, premotor cortical regions, amygdala, and insula). However, it is unclear when this specialization develops. Functional magnetic resonance (fMRI) studies suggest that the infant temporal cortex does not differentiate speech from music or backward speech, but a prior study with functional near-infrared spectroscopy revealed preferential activation for human voices in 7-month-olds, in a more posterior location of the temporal cortex than in adults. However, the brain networks involved in processing nonspeech human vocalizations in early development are still unknown. To address this issue, in the present fMRI study, 3- to 7-month-olds were presented with adult nonspeech vocalizations (emotionally neutral, emotionally positive, and emotionally negative) and nonvocal environmental sounds. Infants displayed significant differential activation in the anterior portion of the temporal cortex, similarly to adults. Moreover, sad vocalizations modulated the activity of brain regions involved in processing affective stimuli such as the orbitofrontal cortex and insula. These results suggest remarkably early functional specialization for processing human voice and negative emotions.