Electroencephalographic Correlates of Clinical Severity in the Natural history study of RTT and Related Disorders.

OBJECTIVE: This study was undertaken to characterize quantitative electroencephalographic (EEG) features in participants from the Natural history study of RTT and Related Disorders and to assess the potential for these features to act as objective measures of cortical function for Rett syndrome (RTT). METHODS: EEG amplitude and power features were derived from the resting EEG of 60 females with RTT (median age = 10.7 years) and 26 neurotypical females (median age = 10.6 years). Analyses focus on group differences and within the RTT group, associations between the EEG parameters and clinical severity. For a subset of participants (n = 20), follow-up data were available for assessing the reproducibility of the results and the stability in the parameters over 1 year. RESULTS: Compared to neurotypical participants, participants with RTT had greater amplitude variability and greater low-frequency activity as reflected by greater delta power, more negative 1/f slope, and lower theta/delta, alpha/delta, beta/delta, alpha/theta, and beta/theta ratios. Greater delta power, more negative 1/f slope, and lower power ratios were associated with greater severity. Analyses of year 1 data replicated the associations between 1/f slope and power ratios and clinical severity and demonstrated good within-subject consistency in these measures. INTERPRETATION: Overall, group comparisons reflected a greater predominance of lower versus higher frequency activity in participants with RTT, which is consistent with prior clinical interpretations of resting EEG in this population. The observed associations between the EEG power measures and clinical assessments and the repeatability of these measures underscore the potential for EEG to provide an objective measure of cortical function and clinical severity for RTT. ANN NEUROL 2024;96:175-186.

Multisite Study of Evoked Potentials in Rett Syndrome.

OBJECTIVE: The aim of the current study was to evaluate the utility of evoked potentials as a biomarker of cortical function in Rett syndrome (RTT). As a number of disease-modifying therapeutics are currently under development, there is a pressing need for biomarkers to objectively and precisely assess the effectiveness of these treatments. METHOD: Yearly visual evoked potentials (VEPs) and auditory evoked potentials (AEPs) were acquired from individuals with RTT, aged 2 to 37 years, and control participants across 5 sites as part of the Rett Syndrome and Related Disorders Natural History Study. Baseline and year 1 data, when available, were analyzed and the repeatability of the results was tested. Two syndrome-specific measures from the Natural History Study were used for evaluating the clinical relevance of the VEP and AEP parameters. RESULTS: At the baseline study, group level comparisons revealed reduced VEP and AEP amplitude in RTT compared to control participants. Further analyses within the RTT group indicated that this reduction was associated with RTT-related symptoms, with greater severity associated with lower VEP and AEP amplitude. In participants with RTT, VEP and AEP amplitude was also negatively associated with age. Year 1 follow-up data analyses yielded similar findings and evidence of repeatability of EPs at the individual level. INTERPRETATION: The present findings indicate the promise of evoked potentials (EPs) as an objective measure of disease severity in individuals with RTT. Our multisite approach demonstrates potential research and clinical applications to provide unbiased assessment of disease staging, prognosis, and response to therapy. ANN NEUROL 2021;89:790-802.

Neural representations of the body in 60-day-old human infants.

The organization of body representations in the adult brain has been well documented. Little is understood about this aspect of brain organization in human infancy. The current study employed electroencephalography (EEG) with 60-day-old infants to test the distribution of brain responses to tactile stimulation of three different body parts: hand, foot, and lip. Analyses focused on a prominent positive response occurring at 150-200 ms in the somatosensory evoked potential at central and parietal electrode sites. The results show differential electrophysiological signatures for touch of these three body parts. Stimulation of the left hand was associated with greater positive amplitude over the lateral central region contralateral to the side stimulated. Left foot stimulation was associated with greater positivity over the midline parietal site. Stimulation of the midline of the upper lip was associated with a strong bilateral response over the central region. These findings provide new insights into the neural representation of the body in infancy and shed light on research and theories about the involvement of somatosensory cortex in infant imitation and social perception.

Infant brain responses to felt and observed touch of hands and feet: an MEG study.

There is growing interest concerning the ways in which the human body, both one's own and that of others, is represented in the developing human brain. In two experiments with 7-month-old infants, we employed advances in infant magnetoencephalography (MEG) brain imaging to address novel questions concerning body representations in early development. Experiment 1 evaluated the spatiotemporal organization of infants' brain responses to being touched. A punctate touch to infants' hands and feet produced significant activation in the hand and foot areas of contralateral primary somatosensory cortex as well as in other parietal and frontal areas. Experiment 2 explored infant brain responses to visually perceiving another person's hand or foot being touched. Results showed significant activation in early visual regions and also in regions thought to be involved in multisensory body and self-other processing. Furthermore, observed touch of the hand and foot activated the infant's own primary somatosensory cortex, although less consistently than felt touch. These findings shed light on aspects of early social cognition, including action imitation, which may build, at least in part, on infant neural representations that map equivalences between the bodies of self and other.

Neural body maps in human infants: Somatotopic responses to tactile stimulation in 7-month-olds.

A large literature has examined somatotopic representations of the body in the adult brain, but little attention has been paid to the development of somatotopic neural organization in human infants. In the present study we examined whether the somatosensory evoked potential (SEP) elicited by brief tactile stimulation of infants' hands and feet shows a somatotopic response pattern at 7months postnatal age. The tactile stimuli elicited a prominent positive component in the SEP at central sites that peaked around 175ms after stimulus onset. Consistent with a somatotopic response pattern, the amplitude of the response to hand stimulation was greater at lateral central electrodes (C3 and C4) than at the midline central electrode (Cz). As expected, the opposite pattern was obtained to foot stimulation, with greater peak amplitude at Cz than at C3 and C4. These results provide evidence of somatotopy in human infants and suggest that the developing body map can be delineated using readily available methods such as EEG. These findings open up possibilities for further work investigating the organization and plasticity of infant body maps.

Comparison of evoked potentials across four related developmental encephalopathies.

BACKGROUND: Developing biomarkers is a priority for drug development for all conditions, but vital in the rare neurodevelopmental disorders where sensitive outcome measures are lacking. We have previously demonstrated the feasibility and tracking of evoked potentials to disease severity in Rett syndrome and CDKL5 deficiency disorder. The aim of the current study is to characterize evoked potentials in two related developmental encephalopathies, MECP2 duplication syndrome and FOXG1 syndrome, and compare across all four groups to better understand the potential of these measures to serve as biomarkers of clinical severity for the developmental encephalopathies. METHODS: Visual and auditory evoked potentials were acquired from participants with MECP2 duplication syndrome and FOXG1 syndrome across five sites of the Rett Syndrome and Rett-Related Disorders Natural History Study. A group of age-matched individuals (mean = 7.8 years; range = 1-17) with Rett syndrome, CDKL5 deficiency disorder, and typically-developing participants served as a comparison group. The analysis focused on group-level differences as well as associations between the evoked potentials and measures of clinical severity from the Natural History Study. RESULTS: As reported previously, group-level comparisons revealed attenuated visual evoked potentials (VEPs) in participants with Rett syndrome (n = 43) and CDKL5 deficiency disorder (n = 16) compared to typically-developing participants. VEP amplitude was also attenuated in participants with MECP2 duplication syndrome (n = 15) compared to the typically-developing group. VEP amplitude correlated with clinical severity for Rett syndrome and FOXG1 syndrome (n = 5). Auditory evoked potential (AEP) amplitude did not differ between groups, but AEP latency was prolonged in individuals with MECP2 duplication syndrome (n = 14) and FOXG1 syndrome (n = 6) compared to individuals with Rett syndrome (n = 51) and CDKL5 deficiency disorder (n = 14). AEP amplitude correlated with severity in Rett syndrome and CDKL5 deficiency disorder. AEP latency correlated with severity in CDKL5 deficiency disorder, MECP2 duplication syndrome, and FOXG1 syndrome. CONCLUSIONS: There are consistent abnormalities in the evoked potentials in four developmental encephalopathies some of which correlate with clinical severity. While there are consistent changes amongst these four disorders, there are also condition specific findings that need to be further refined and validated. Overall, these results provide a foundation for further refinement of these measures for use in future clinical trials for these conditions.

Electrophysiological biomarkers of brain function in CDKL5 deficiency disorder.

CDKL5 deficiency disorder is a debilitating developmental and epileptic encephalopathy for which no targeted treatment exists. A number of promising therapeutics are under development for CDKL5 deficiency disorder but a lack of validated biomarkers of brain function and clinical severity may limit the ability to objectively assess the efficacy of new treatments as they become available. To address this need, the current study quantified electrophysiological measures in individuals with CDKL5 deficiency disorder and the association between these parameters and clinical severity. Visual and auditory evoked potentials, as well as resting EEG, were acquired across 5 clinical sites from 26 individuals with CDKL5 deficiency disorder. Evoked potential and quantitative EEG features were calculated and compared with typically developing individuals in an age- and sex-matched cohort. Baseline and Year 1 data, when available, were analysed and the repeatability of the results was tested. Two clinician-completed severity scales were used for evaluating the clinical relevance of the electrophysiological parameters. Group-level comparisons revealed reduced visual evoked potential amplitude in CDKL5 deficiency disorder individuals versus typically developing individuals. There were no group differences in the latency of the visual evoked potentials or in the latency or amplitude of the auditory evoked potentials. Within the CDKL5 deficiency disorder group, auditory evoked potential amplitude correlated with disease severity at baseline as well as Year 1. Multiple quantitative EEG features differed between CDKL5 deficiency disorder and typically developing participants, including amplitude standard deviation, 1/f slope and global delta, theta, alpha and beta power. Several quantitative EEG features correlated with clinical severity, including amplitude skewness, theta/delta ratio and alpha/delta ratio. The theta/delta ratio was the overall strongest predictor of severity and also among the most repeatable qEEG measures from baseline to Year 1. Together, the present findings point to the utility of evoked potentials and quantitative EEG parameters as objective measures of brain function and disease severity in future clinical trials for CDKL5 deficiency disorder. The results also underscore the utility of the current methods, which could be similarly applied to the identification and validation of electrophysiological biomarkers of brain function for other developmental encephalopathies.

Evoked Potentials and EEG Analysis in Rett Syndrome and Related Developmental Encephalopathies: Towards a Biomarker for Translational Research.

Rett syndrome is a debilitating neurodevelopmental disorder for which no disease-modifying treatment is available. Fortunately, advances in our understanding of the genetics and pathophysiology of Rett syndrome has led to the development of promising new therapeutics for the condition. Several of these therapeutics are currently being tested in clinical trials with others likely to progress to clinical trials in the coming years. The failure of recent clinical trials for Rett syndrome and other neurodevelopmental disorders has highlighted the need for electrophysiological or other objective biological markers of treatment response to support the success of clinical trials moving forward. The purpose of this review is to describe the existing studies of electroencephalography (EEG) and evoked potentials (EPs) in Rett syndrome and discuss the open questions that must be addressed before the field can adopt these measures as surrogate endpoints in clinical trials. In addition to summarizing the human work on Rett syndrome, we also describe relevant studies with animal models and the limited research that has been carried out on Rett-related disorders, particularly methyl-CpG binding protein 2 (MECP2) duplication syndrome, CDKL5 deficiency disorder, and FOXG1 disorder.

Exploring potential social influences on brain potentials during anticipation of tactile stimulation.

This study explored interpersonal influences on electrophysiological responses during the anticipation of tactile stimulation. It is well-known that broad, negative-going potentials are present in the event-related potential (ERP) between a forewarning cue and a tactile stimulus. It has also been shown that the alpha-range mu rhythm shows a lateralized desynchronization over central electrode sites during anticipation of tactile stimulation of the hand. The current study used a tactile discrimination task in which a visual cue signaled that an upcoming stimulus would either be delivered 1500ms later to the participant's hand, to a task partner's hand, or to neither person. For the condition in which participants anticipated the tactile stimulation to their own hand, a negative potential (contingent negative variation, CNV) was observed in the ERP at central sites in the 1000ms prior to the tactile stimulus. Significant mu rhythm desynchronization was also present in the same time window. The magnitudes of the ERPs and of the mu desynchronization were greater in the contralateral than in the ipsilateral hemisphere prior to right hand stimulation. Similar ERP and EEG changes were not present when the visual cue indicated that stimulation would be delivered to the task partner or to neither person. The absence of social influences during anticipation of tactile stimulation, and the relationship between the two brain signatures of anticipatory attention (CNV and mu rhythm) are discussed.

Beyond the N1: A review of late somatosensory evoked responses in human infants.

Somatosensory evoked potentials (SEPs) have been used for decades to study the development of somatosensory processing in human infants. Research on infant SEPs has focused on the initial cortical component (N1) and its clinical utility for predicting neurological outcome in at-risk infants. However, recent studies suggest that examining the later components in the infant somatosensory evoked response will greatly advance our understanding of somatosensory processing in infancy. The purpose of this review is to synthesize the existing electroencephalography (EEG) and magnetoencephalography (MEG) studies on late somatosensory evoked responses in infants. We describe the late responses that have been reported and discuss the utility of such responses for illuminating key aspects of somatosensory processing in typical and atypical development.

Infants' somatotopic neural responses to seeing human actions: I've got you under my skin.

Human infants rapidly learn new skills and customs via imitation, but the neural linkages between action perception and production are not well understood. Neuroscience studies in adults suggest that a key component of imitation-identifying the corresponding body part used in the acts of self and other-has an organized neural signature. In adults, perceiving someone using a specific body part (e.g., hand vs. foot) is associated with activation of the corresponding area of the sensory and/or motor strip in the observer's brain-a phenomenon called neural somatotopy. Here we examine whether preverbal infants also exhibit somatotopic neural responses during the observation of others' actions. 14-month-old infants were randomly assigned to watch an adult reach towards and touch an object using either her hand or her foot. The scalp electroencephalogram (EEG) was recorded and event-related changes in the sensorimotor mu rhythm were analyzed. Mu rhythm desynchronization was greater over hand areas of sensorimotor cortex during observation of hand actions and was greater over the foot area for observation of foot actions. This provides the first evidence that infants' observation of someone else using a particular body part activates the corresponding areas of sensorimotor cortex. We hypothesize that this somatotopic organization in the developing brain supports imitation and cultural learning. The findings connect developmental cognitive neuroscience, adult neuroscience, action representation, and behavioral imitation.

Imitation and the Developing Social Brain: Infants' Somatotopic EEG Patterns for Acts of Self and Other.

A leading question in developmental social-cognitive neuroscience concerns the nature and function of neural links between action perception and production in early human development. Here we document a somatotopic pattern of activity of the sensorimotor EEG mu rhythm in 14-month-old infants. EEG was recorded during interactive trials in which infants activated a novel object using their own hands or feet ("execution" trials) and watched an experimenter use her hands or feet to achieve the same goal ("observation" trials). At central electrodes overlying sensorimotor hand areas (C3/C4), mu rhythm power was reduced (indicating greater cortical activation) during infants' execution of hand acts compared to foot acts. For the central electrode overlying the sensorimotor foot area (Cz), mu power was reduced during the execution of foot versus hand acts. Strikingly similar somatotopic patterns were found in both the action execution and observation conditions. We hypothesize that these somatotopic patterns index an intercorporeal mapping of corresponding body parts between self and other. We further propose that infants' ability to identify self-other equivalences at the level of body parts underlies infant imitation and is an ontogenetic building block for the feelings of intersubjectivity we experience when socially engaged with other people.

Infant Brain Responses to Object Weight: Exploring Goal-Directed Actions and Self-Experience.

Recent work has suggested the value of electroencephalographic (EEG) measures in the study of infants' processing of human action. Studies in this area have investigated desynchronization of the sensorimotor mu rhythm during action execution and action observation in infancy. Untested but critical to theory is whether the mu rhythm shows a differential response to actions which share similar goals but have different motor requirements or sensory outcomes. By varying the invisible property of object weight, we controlled for the abstract goal (reach, grasp, and lift the object), while allowing other aspects of the action to vary. The mu response during 14-month-old infants' own executed actions showed a differential hemispheric response between acting on heavier and lighter objects. EEG responses also showed sensitivity to "expected object weight" when infants simply observed an experimenter reach for objects that the infants' prior experience indicated were heavier versus lighter. Crucially, this neural reactivity was predictive - during the observation of the other reaching toward the object, before lifting occurred. This suggests that infants' own self-experience with a particular object's weight influences their processing of others' actions on the object, with implications for developmental social-cognitive neuroscience.

The utility of EEG band power analysis in the study of infancy and early childhood.

Research employing electroencephalographic (EEG) techniques with infants and young children has flourished in recent years due to increased interest in understanding the neural processes involved in early social and cognitive development. This review focuses on the functional characteristics of the alpha, theta, and gamma frequency bands in the developing EEG. Examples of how analyses of EEG band power have been applied to specific lines of developmental research are also discussed. These examples include recent work on the infant mu rhythm and action processing, frontal alpha asymmetry and approach-withdrawal tendencies, and EEG power measures in the study of early psychosocial adversity.

Neural correlates of being imitated: an EEG study in preverbal infants.

A foundational aspect of early social-emotional development is the ability to detect and respond to the actions of others who are coordinating their behavior with that of the self. Behavioral work in this area has found that infants show particular preferences for adults who are imitating them rather than adults who are carrying out noncontingent or mismatching actions. Here, we explore the neural processes related to this tendency of infants to prefer others who act like the self. Electroencephalographic (EEG) signals were recorded from 14-month-old infants while they were observing actions that either matched or mismatched the action the infant had just executed. Desynchronization of the EEG mu rhythm was greater when infants observed an action that matched their own most recently executed action. This effect was strongest immediately prior to the culmination of the goal of the observed action, which is consistent with recent ideas about the predictive nature of brain responses during action observation.

An investigation of the determinants of motor contagion in preschool children.

The influence of action perception on action execution has been demonstrated by studies of motor contagion in which the observation of an action interferes with the concurrent execution of a different action. The current study extends prior work on the extent of motor contagion in early childhood, a period of development when the effects of action observation on action execution may be particularly salient. During a classroom story reading, children (mean age 4.8 years) were familiarized with two different-colored bears, one of which was used as a seemingly animate hand puppet while the other bear remained lifeless and inanimate. Children then completed a task in which they were instructed to move a stylus on a graphics tablet in the presence of background videos of each bear making horizontal arm movements which had biological (human-moved) or non-biological (machine-moved) origins. Motor contagion was assessed as the variability of stylus movements in the horizontal axis when children were instructed to produce vertical stylus movements. Significant levels of motor contagion were seen when children observed the previously animate bear in the non-biological motion condition and when they observed the previously inanimate bear in the biological motion condition. For future studies of social perception, this finding points to the potential importance of examining mismatches between prior experience with (or knowledge about) a particular agent and the subsequent behavior of that agent in a different context.