Conditional canonical correlation estimation based on covariates with random forests.

MOTIVATION: Investigating the relationships between two sets of variables helps to understand their interactions and can be done with canonical correlation analysis (CCA). However, the correlation between the two sets can sometimes depend on a third set of covariates, often subject-related ones such as age, gender or other clinical measures. In this case, applying CCA to the whole population is not optimal and methods to estimate conditional CCA, given the covariates, can be useful. RESULTS: We propose a new method called Random Forest with Canonical Correlation Analysis (RFCCA) to estimate the conditional canonical correlations between two sets of variables given subject-related covariates. The individual trees in the forest are built with a splitting rule specifically designed to partition the data to maximize the canonical correlation heterogeneity between child nodes. We also propose a significance test to detect the global effect of the covariates on the relationship between two sets of variables. The performance of the proposed method and the global significance test is evaluated through simulation studies that show it provides accurate canonical correlation estimations and well-controlled Type-1 error. We also show an application of the proposed method with EEG data. AVAILABILITY AND IMPLEMENTATION: RFCCA is implemented in a freely available R package on CRAN (https://CRAN.R-project.org/package=RFCCA). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Infant repetition effects and change detection: Are they related to adaptive skills?

Repetition effects and change detection response have been proposed as neuro-electrophysiological correlates of fundamental learning processes. As such, they could be a good predictor of brain maturation and cognitive development. We recorded high density EEG in 71 healthy infants (32 females) aged between 3 and 9 months, while they listened to vowel sequences (standard /a/a/a/i/ [80%] and deviant /a/a/a/a/ [20%]). Adaptive skills, a surrogate of cognitive development, were measured via the parent form of the Adaptive Behavior Assessment System Second Edition (ABAS-II). Cortical auditory-evoked potentials (CAEPs) analyses, time-frequency analyses and a statistical approach using linear mixed models (LMMs) and linear regression models were performed. Age and adaptive skills were tested as predictors. Age modulation of repetition effects and change detection response was observed in theta (3-5 Hz), alpha (5-10 Hz) and high gamma (80-90 Hz) oscillations and in all CAEPs. Moreover, adaptive skills modulation of repetition effects was evidenced in theta (3-5 Hz), high gamma oscillations (80-90 Hz), N250/P350 peak-to-peak amplitude and P350 latency. Finally, adaptive skills modulation of change detection response was observed in the N250/P350 peak-to-peak amplitude. Our results confirm that repetition effects and change detection response evolve with age. Moreover, our results suggest that repetition effects and change detection response vary according to adaptive skills displayed by infants during the first year of life, demonstrating their predictive value for neurodevelopment.

NeuroPycon: An open-source python toolbox for fast multi-modal and reproducible brain connectivity pipelines.

Recent years have witnessed a massive push towards reproducible research in neuroscience. Unfortunately, this endeavor is often challenged by the large diversity of tools used, project-specific custom code and the difficulty to track all user-defined parameters. NeuroPycon is an open-source multi-modal brain data analysis toolkit which provides Python-based template pipelines for advanced multi-processing of MEG, EEG, functional and anatomical MRI data, with a focus on connectivity and graph theoretical analyses. Importantly, it provides shareable parameter files to facilitate replication of all analysis steps. NeuroPycon is based on the NiPype framework which facilitates data analyses by wrapping many commonly-used neuroimaging software tools into a common Python environment. In other words, rather than being a brain imaging software with is own implementation of standard algorithms for brain signal processing, NeuroPycon seamlessly integrates existing packages (coded in python, Matlab or other languages) into a unified python framework. Importantly, thanks to the multi-threaded processing and computational efficiency afforded by NiPype, NeuroPycon provides an easy option for fast parallel processing, which critical when handling large sets of multi-dimensional brain data. Moreover, its flexible design allows users to easily configure analysis pipelines by connecting distinct nodes to each other. Each node can be a Python-wrapped module, a user-defined function or a well-established tool (e.g. MNE-Python for MEG analysis, Radatools for graph theoretical metrics, etc.). Last but not least, the ability to use NeuroPycon parameter files to fully describe any pipeline is an important feature for reproducibility, as they can be shared and used for easy replication by others. The current implementation of NeuroPycon contains two complementary packages: The first, called ephypype, includes pipelines for electrophysiology analysis and a command-line interface for on the fly pipeline creation. Current implementations allow for MEG/EEG data import, pre-processing and cleaning by automatic removal of ocular and cardiac artefacts, in addition to sensor or source-level connectivity analyses. The second package, called graphpype, is designed to investigate functional connectivity via a wide range of graph-theoretical metrics, including modular partitions. The present article describes the philosophy, architecture, and functionalities of the toolkit and provides illustrative examples through interactive notebooks. NeuroPycon is available for download via github (https://github.com/neuropycon) and the two principal packages are documented online (https://neuropycon.github.io/ephypype/index.html, and https://neuropycon.github.io/graphpype/index.html). Future developments include fusion of multi-modal data (eg. MEG and fMRI or intracranial EEG and fMRI). We hope that the release of NeuroPycon will attract many users and new contributors, and facilitate the efforts of our community towards open source tool sharing and development, as well as scientific reproducibility.

Visual short-term memory activation patterns in adult survivors of childhood acute lymphoblastic leukemia.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Treatments against ALL might lead to later cognitive effects and alterations in brain structure in survivors but to the authors' knowledge the observed variability in the severity of neurocognitive deficits is not fully understood. The objective of the current study was to investigate abnormalities in visual short-term memory (VSTM) brain activation in survivors of childhood ALL using magnetoencephalography. METHODS: A VSTM task was completed by 40 survivors of ALL and 26 controls. VSTM capacity (Cowan K) and brain activation were assessed during the retention period of the task (400-1400 milliseconds) using a standard minimum norm source localization method. RESULTS: Performance (Cowan K) was found to be similar between survivors of ALL and controls. Atypical brain activation was found in survivors of ALL during the task, including overactivation of regions usually involved in VSTM (lateral occipital, precentral gyrus, and postcentral gyrus), recruitment of regions that typically are not involved in VSTM (superior/middle temporal gyrus and supramarginal gyrus), and lower activation of frontal brain regions (inferior frontal gyrus). These patterns of activation were modulated by the age at the time of cancer onset (P = .01) because activity was found to be reduced in participants who were younger at diagnosis. CONCLUSIONS: The results of the current study suggest a pattern of neural inefficiency and compensatory activity during VSTM in survivors of ALL.

Tracking the acquisition of anticipatory postural adjustments during a bimanual load-lifting task: A MEG study.

During bimanual coordination, that is, manipulating with the dominant hand an object held by the postural hand, anticipatory postural adjustments are required to cancel the perturbations and ensure postural stabilization. Using magnetoencephalography (MEG), we investigated changes mediating the acquisition of anticipatory postural adjustments during a bimanual load-lifting task. Participants lifted a load with their right hand, hence triggering the fall of a second load fixed to their left (postural) forearm. During Acquisition, the onset of load-lifting and the fall of the second load were experimentally delayed after few trials. During Control, load-lifting triggered the fall of the second load without delay. Upward elbow rotation decreased with trial repetition during Acquisition, hence attesting the ongoing acquisition of anticipatory postural adjustments. Bilateral event-related desynchronisation (ERD) of the alpha rhythm (8-12 Hz) was recorded. Generators of the mu rhythm were found within central and associative motor regions. Their spatial distribution within the hemisphere contralateral to the load-lifting arm was less refined and circumscribed during Acquisition compared to Control. Regression analyses emphasized the specific involvement of the precuneus in the right hemisphere contralateral to the postural forearm, and a medial prefrontal region in the left hemisphere. Analyses of the time course power showed that an increase in preunloading activation within the precuneus and a decrease in postunloading inhibition within the medial prefrontal region were associated with the acquisition of anticipatory postural adjustments. The study provides original insights into cortical activations mediating the progressive tuning of anticipatory postural adjustments during the acquisition stage of motor learning.

Mu-oscillation changes related to the development of anticipatory postural control in children and adolescents.

Anticipatory postural adjustments (APAs) cancel the destabilizing effects of movement on posture. Across development, the maturation of APAs is characterized by an accurate adjustment of the timing parameters of electromyographic (EMG) response. The study aimed at investigating the maturation of cortical oscillations involved in the improvement of APAs efficiency. Thirty-six healthy participants (8-16 yr) performed the bimanual load-lifting task in which subjects are instructed to lift a load, placed on the left forearm, with the right hand. EMG data were acquired over the biceps brachii on the postural arm to the determine EMG response onset. Electroencephalographic signals were analyzed in the time-frequency domain by convolution with complex Gaussian Morlet wavelets. Electrophysiological signature of APAs in children and adolescents consisted of a mu-rhythm desynchronization over the sensorimotor cortex contralateral to the postural arm. Across development, the mu-rhythm desynchronization was characterized by a progressive shift forward of the onset of the desynchronization, lower amplitude, and velocity. These changes occurred along with an alteration of the timing of the EMG response, as shown by an earlier onset of the flexor inhibition with increasing age. The maturational changes in the Mu-oscillations might sustain the development of APAs. A possible role of the Mu-oscillation in the generation of postural command is discussed. NEW & NOTEWORTHY Across development, our study showed a progressive shift forward of the parameters of the mu-rhythm desynchronization. These changes occurred along with an alteration of the timing parameters of the electromyographic response, as shown by an earlier onset of the flexor inhibition with increasing age. The progressive development of APAs during childhood and adolescence might therefore be sustained by maturational electrophysiological changes that include mu-rhythm oscillation modifications in the postural sensorimotor cortex.

Neurodevelopment of Posture-movement Coordination from Late Childhood to Adulthood as Assessed From Bimanual Load-lifting Task: An Event-related Potential Study.

In a bimanual task, proprioception provides information about position and movement of upper arms. Developmental studies showed improvement of proprioceptive accuracy and timing adjustments of muscular events from childhood to adulthood in bimanual tasks. However, the cortical maturational changes related to bimanual coordination is not fully understood. The aim of this study was to investigate cortical correlates underlying motor planning and upper limb stabilization performance at left (C3) and right (C4) sensorimotor cortices using event-related potential (ERP) analyses. We recruited 46 participants divided into four groups (12 children: 8-10 years, 13 early adolescents: 11-13 years, 11 late adolescents: 14-16 years and 10 young adults: 20-35 years). Participants performed a bimanual load-lifting task, where the left postural arm supported the load and the right motor arm lifted the load. Maximal amplitude of elbow rotation (MA%) of the postural arm, reaction time (RT) and EMG activity of biceps brachii bilaterally were computed. Laplacian-transformed ERPs of the electroencephalographic (EEG) signal response-locked to motor arm biceps EMG activity onset were analyzed over C3 and C4. We found a developmental effect for behavioral and EEG data denoted by significant decrease of MA% and RT with age, earlier inhibition of the biceps brachii of the postural arm in adults and earlier EEG activation/inhibition onset at C3/C4. Amplitude of the negative wave at C4 was higher in children and early adolescents compared to the other groups. In conclusion, we found a maturational process in cortical correlates related to motor planning and upper limb stabilization performance with interhemispheric lateralization appearing during adolescence. Findings may serve documenting bimanual performance in children with neurodevelopmental disorders.

Differential auditory brain response abnormalities in two intellectual disability conditions: SYNGAP1 mutations and Down syndrome.

OBJECTIVE: Altered sensory processing is common in intellectual disability (ID). Here, we study electroencephalographic responses to auditory stimulation in human subjects presenting a rare condition (mutations in SYNGAP1) which causes ID, epilepsy and autism. METHODS: Auditory evoked potentials, time-frequency and inter-trial coherence analyses were used to compare subjects with SYNGAP1 mutations with Down syndrome (DS) and neurotypical (NT) participants (N = 61 ranging from three to 19 years of age). RESULTS: Altered synchronization in the brain responses to sound were found in both ID groups. The SYNGAP1 mutations group showed less phase-locking in early time windows and lower frequency bands compared to NT, and in later time windows compared to NT and DS. Time-frequency analysis showed more power in beta-gamma in the SYNGAP1 group compared to NT participants. CONCLUSIONS: This study indicated reduced synchronization as well as more high frequencies power in SYNGAP1 mutations, while maintained synchronization was found in the DS group. These results might reflect dysfunctional sensory information processing caused by excitation/inhibition imbalance, or an imperfect compensatory mechanism in SYNGAP1 mutations individuals. SIGNIFICANCE: Our study is the first to reveal brain response abnormalities in auditory sensory processing in SYNGAP1 mutations individuals, that are distinct from DS, another ID condition.

Distinct patterns of repetition suppression in Fragile X syndrome, down syndrome, tuberous sclerosis complex and mutations in SYNGAP1.

Sensory processing is the gateway to information processing and more complex processes such as learning. Alterations in sensory processing is a common phenotype of many genetic syndromes associated with intellectual disability (ID). It is currently unknown whether sensory processing alterations converge or diverge on brain responses between syndromes. Here, we compare for the first time four genetic conditions with ID using the same basic sensory learning paradigm. One hundred and five participants, aged between 3 and 30 years old, composing four clinical ID groups and one control group, were recruited: Fragile X syndrome (FXS; n = 14), tuberous sclerosis complex (TSC; n = 9), Down syndrome (DS; n = 19), SYNGAP1 mutations (n = 8) and Neurotypical controls (NT; n = 55)). All groups included female and male participants. Brain responses were recorded using electroencephalography (EEG) during an audio-visual task that involved three repetitions of the pronunciation of the phoneme /a/. Event Related Potentials (ERP) were used to: 1) compare peak-to-peak amplitudes between groups, 2) evaluate the presence of repetition suppression within each group and 3) compare the relative repetition suppression between groups. Our results revealed larger overall amplitudes in FXS. A repetition suppression (RS) pattern was found in the NT group, FXS and DS, suggesting spared repetition suppression in a multimodal task in these two ID syndromes. Interestingly, FXS presented a stronger RS on one peak-to-peak value in comparison with the NT. The results of our study reveal the distinctiveness of ERP and RS brain responses in ID syndromes. Further studies should be conducted to understand the molecular mechanisms involved in these patterns of responses.

Prolonged and unprolonged complex febrile seizures differently affect frontal theta brain activity.

OBJECTIVE: Studies have identified mild but persistent cognitive and functional deficits, which could be linked to each other, in children with complex febrile seizures (FS). Our aim was to investigate differences in brain activity in children with a history of complex FS, through a study paradigm notably associated with the development of learning capacities and using electroencephalographic (EEG) signal. To further increase our understanding of these differences, complex FS were studied separately depending on their type. METHOD: EEG was recorded in 43 children with past FS. Brain activity associated with auditory learning was investigated using a habituation paradigm, in which repetition suppression (RS) is typically found following stimulus repetition. Auditory stimuli were repeated three times, and each presentation were analysed separately in the time-frequency (TF) domain. A mixed-analysis of variance was used to assess differences in spectral power between stimulus repetition and FS type (simple vs complex prolonged; CP vs complex unprolonged; CUP). RESULTS: Repetition effects were found in the 3-6 Hz during 150-600 ms time window after stimulus onset at frontal sites (F(2, 40) = 5.645, p = 0.007, η2p = 0.220). Moreover, an interaction effect between stimulus repetition and FS type (F(4, 80) = 2.607, p = 0.042, η2p = 0.115) was found. Children with CP FS showed greater increase in spectral power in response to the first stimulus presentation, while children with CUP FS failed to show a RS pattern. SIGNIFICANCE: Our results show distinct abnormalities in brain activity to a habituation paradigm. We argue that these changes suggest children with CP FS may be hyperexcitable, while children with CUP FS show impaired habituation processes. Still, these differences may be associated with other clinical features linked to complex FS as well. Hence, the role of these differences in complex FS incidence and prognosis should be the subject of future studies.

The relationship between acute stress and EEG repetition suppression in infants.

Over activation of the hypothalamo-pituitary-adrenal (HPA) axis in stress situations is known to influence learning and memory. In adults, an inverted-U shape relationship between acute stress, and learning and memory has been demonstrated. Whether this model fits learning performances in infants is unknown. In this study, we used EEG repetition suppression as physiological measure of learning and salivary cortisol in response to a stressor to investigate the relationship between acute stress and learning in infants. We hypothesized that EEG repetition suppression would be modulated by acute stress following an inverted-U shape relationship. Saliva samples were collected during an EEG experiment before, during and after EEG net installation in 37 healthy infants (18 males) aged between 6 and 26 months. The effect of variation in stress hormones on repetition suppression were modeled using a linear mixed model, with cortisol, age and sex as predictors. Results indicated that in healthy infants, elevations in stress hormones within the normal range are associated with a higher repetition suppression response and an increased response to the first presentation of the stimulus. The later increase could be related to vigilance. Considering that early childhood is a critical period of development, future studies should keep investigating the influence of stress on learning processes in infants.

Association between fat-soluble nutrient status and auditory and visual related potentials in newly diagnosed non-screened infants with cystic fibrosis: A case-control study.

Nutritional deficiencies often precede the diagnosis of cystic fibrosis (CF) in infants, and occur at a stage where the rapidly developing brain is more vulnerable to insult. We aim to compare fat-soluble nutrient status of newly diagnosed non-screened infants with CF to that of healthy infants, and explore the association with neurodevelopment evaluated by electroencephalography (EEG). Our results show that CF infants had lower levels of all fat-soluble vitamins and docosahexaenoic acid (DHA) compared to controls. The auditory evoked potential responses were higher in CF compared to controls whereas the visual components did not differ between groups. DHA levels were correlated with auditory evoked potential responses. Although resting state frequency power was similar between groups, we observed a negative correlation between DHA levels and low frequencies. This study emphasizes the need for long-term neurodevelopmental follow-up of CF infants and pursuing intervention strategies in the future.

Shift of the Muscular Inhibition Latency during On-Line Acquisition of Anticipatory Postural Adjustments.

During action, Anticipatory Postural Adjustments (APAs) cancel the consequences of a movement on postural stabilization. Their muscular expression is characterized by early changes in the activity of the postural muscles, before the movement begins. To explore the mechanisms enabling the acquisition of APAs, a learning paradigm was designed in which the voluntary lifting of a load with one hand triggered the unloading of another load suspended below the contralateral forearm. The aim of this study was to investigate changes in the muscular expression that uncovers the progressive learning of new APAs. A trial-by-trial analysis of kinematic and electromyographic signals recorded on the right arm was conducted in twelve adults through six sessions of learning. Kinematic results reported an enhancement of the postural stabilization across learning. The main EMG pattern found during learning consisted of a flexor inhibition, where latency was shifted towards an earlier occurrence in parallel with the improvement of the postural performance. A linear regression analysis conducted between the inhibition latency and the maximal amplitude of elbow rotation showed that the earlier the inhibition onset, the better the postural stabilization. This study revealed that the progressive shift of the postural flexor inhibition latency could be considered as a reliable neurophysiological marker of the progressive learning of new APAs. Importantly, this marker could be used to track motor learning abnormalities in pathology. We relate our findings to the update of a forward predictive model of action, defined as a system that predicts beforehand the consequences of the action on posture.

Time-Frequency and ERP Analyses of EEG to Characterize Anticipatory Postural Adjustments in a Bimanual Load-Lifting Task.

Anticipatory postural adjustments (APAs) compensate in advance for the destabilizing effect of a movement. This study investigated the specific involvement of each primary motor cortex (M1) during a bimanual load-lifting task in which subjects were required to maintain a stable forearm position during voluntary unloading. Kinematics, electromyographic, and electroencephalographic (EEG) data were recorded in eight right-handed healthy subjects lifting a load placed on their left forearm. Two EEG analyses were performed: a time-frequency (TF) analysis and an event-related potential (ERP) analysis. The TF analysis revealed a mean power decrease in the mu rhythm over the left and right M1 concomitant with lifting onset. Each decrease showed specific features: over the right M1, contralateral to the postural forearm, there was a steeper slope and a greater amplitude than over the left M1. Although a mu rhythm desynchronization has until now been the signature of cortical activity related to a motor component, we show that it can also be related to postural stabilization. We discuss the involvement of the mu rhythm desynchronization over the postural M1 in the high temporal precision enabling efficient APAs. ERP analysis showed a negative wave over the left M1 and a concomitant positive wave over the right M1. While the negative wave classically reflects M1 recruitment related to the forthcoming lifting, the novelty here is that the positive wave reflects the transmission of inhibitory commands toward the postural forearm.