Copy number variants at 4q31.3 affecting the regulatory region of FBXW7 associated with neurodevelopmental delay.

Emerging research has demonstrated that genomic alterations disrupting topologically associated domains (TADs) and chromatin interactions underlie the pathogenic mechanisms of specific copy number variants (CNVs) in neurodevelopmental disorders. We report two patients with a de novo deletion and a duplication in chromosome 4q31, potentially causing FBX-related neurodevelopmental syndrome by affecting the regulatory region of FBXW7. High-throughput chromosome conformation capture (Hi-C) analysis using available capture data in neural progenitor cells revealed the rewiring of the TAD boundary close to FBXW7. Both patients exhibited facial dysmorphisms, cardiac and limb abnormalities, and neurodevelopmental delays, showing significant clinical overlap with previously reported FBXW7-related features. We also included an additional 10 patients with CNVs in the 4q31 region from the literature and the DECIPHER database for Hi-C analysis, which confirmed that disruption of the regulatory region of FBXW7 likely contributes to the developmental defects observed in these patients.

Application of the Hammersmith Infant Neurological Examination in the developmental follow-up of high-risk infants.

AIM: To investigate the independent influences affecting the global score of the Hammersmith Infant Neurological Examination (HINE) in the early life of high-risk infants and to provide evidence for early effective screening and for evaluating interventions. METHOD: We conducted a prospective cohort study of 258 high-risk infants assessed by the HINE and Gesell Developmental Diagnosis Schedule at 3, 6, 9, and 12 months corrected age. A multiple linear regression model was developed to investigate independent influences on HINE global score at 3 months corrected age. The accuracy of the HINE global score was analysed by calculating the discriminant, concurrent, and predictive validities according to ages. RESULTS: There were nine independent influences affecting the HINE global score at 3 months corrected age in high-risk infants. The discriminant, concurrent, and predictive validities of the HINE for gross motor developmental delays at 12 months corrected age were all statistically significant (p < 0.05). INTERPRETATION: Different neonatal clinical settings are related to the HINE global score of high-risk infants early in life. The HINE can be used for longitudinal monitoring of neurological development in the first year of life in a typical Chinese clinical setting and the findings at all four ages tested relate to neuromotor outcomes at 12 months corrected age.

Diagnostic yield and novel candidate genes for neurodevelopmental disorders by exome sequencing in an unselected cohort with microcephaly.

OBJECTIVES: Microcephaly is caused by reduced brain volume and most usually associated with a variety of neurodevelopmental disorders (NDDs). To provide an overview of the diagnostic yield of whole exome sequencing (WES) and promote novel candidates in genetically unsolved families, we studied the clinical and genetic landscape of an unselected Chinese cohort of patients with microcephaly. METHODS: We performed WES in an unselected cohort of 103 NDDs patients with microcephaly as one of the features. Full evaluation of potential novel candidate genes was applied in genetically undiagnosed families. Functional validations of selected variants were conducted in cultured cells. To augment the discovery of novel candidates, we queried our genomic sequencing data repository for additional likely disease-causing variants in the identified candidate genes. RESULTS: In 65 families (63.1%), causative sequence variants (SVs) and clinically relevant copy number variants (CNVs) with a pathogenic or likely pathogenic (P/LP) level were identified. By incorporating coverage analysis to WES, a pathogenic or likely pathogenic CNV was detected in 15 families (16/103, 15.5%). In another eight families (8/103, 7.8%), we identified variants in newly reported gene (CCND2) and potential novel neurodevelopmental disorders /microcephaly candidate genes, which involved in cell cycle and division (PWP2, CCND2), CDC42/RAC signaling related actin cytoskeletal organization (DOCK9, RHOF), neurogenesis (ELAVL3, PPP1R9B, KCNH3) and transcription regulation (IRF2BP1). By looking into our data repository of 5066 families with NDDs, we identified additional two cases with variants in DOCK9 and PPP1R9B, respectively. CONCLUSION: Our results expand the morbid genome of monogenic neurodevelopmental disorders and support the adoption of WES as a first-tier test for individuals with microcephaly.

A de novo 10q11.23q22.1 deletion detected by whole genome mate-pair sequencing: a case report.

BACKGROUND: Interstitial deletions of chromosome band 10q11-q22 was a genomic disorder distinguished by developmental delay, congenital cleft palate and muscular hypotonia. The phenotypes involved were heterogeneous, hinge on the variable breakpoints and size. CASE PRESENTATION: Here, we presented a patient with soft palate cleft, growth and development delay. The patient was a 2 years and 5 months girl who was not able to walk unless using a children's crutches to support herself. Whole-exome sequencing (WES) and whole-genome mate-pair sequencing (WGMS) were both performed by next generation sequencing (NGS). A 20.76 Mb deletion at 10q11.23q22.1 (seq[GRCh37/hg19]del(10)(50,319,387-71,083,899) × 1) was revealed by the WGMS, which was verified as de novo by quantitative polymerase chain reaction (QPCR). CONCLUSION: Children with 10q11-q22 deletions greater than 20 MB have never been reported before, and we are the first to report and provide a detailed clinical phenotype, which brings further knowledge of 10q11-q22 deletions.

Case report: Expansion of phenotypic and genotypic data in TENM3-related syndrome: Report of two cases.

Biallelic TENM3 variants were recently reported to cause non-syndromic microphthalmia with coloboma-9 (MCOPCB9) and microphthalmia and/or coloboma with developmental delay (MCOPS15). To date, only eight syndromic and non-syndromic microphthalmia cases with recessive TENM3 variants have been reported. Herein, we report two unrelated new cases with biallelic variants in TENM3, widening the molecular and clinical spectrum. Regarding patient 1, WES revealed compound heterozygous variants in the TENM3 gene: c.3847_3855del; p.Leu1283_Ser1285del and c.3698_3699insA; p.Thr1233Thrfs*20 in the index patient, who was presenting with bilateral microphthalmia, congenital cataract, microcephaly, and global developmental delay. Regarding patient 2, compound missense heterozygous variants in the TENM3 gene were identified: c.941C > T; p.Ala314Val and c.6464T > C; p.Leu2155Pro in the 3-year-old boy, who presented with congenital esotropia, speech delay, and motor developmental delay. The clinical features of these two cases revealed high concordance with the previously reported cases, including microphthalmia and developmental delay. The presence of microcephaly in our patient potentially expands the neurologic phenotype associated with loss of function variants in TENM3, as microcephaly has not previously been described. Furthermore, we present evidence that missense variants in TENM3 are associated with similar, but milder, ocular features.

Novel variants in the CLCN4 gene associated with syndromic X-linked intellectual disability.

Objective: The dysfunction of the CLCN4 gene can lead to X-linked intellectual disability and Raynaud-Claes syndrome (MRXSRC), characterized by severe cognitive impairment and mental disorders. This study aimed to investigate the genetic defects and clinical features of Chinese children with CLCN4 variants and explore the effect of mutant ClC-4 on the protein expression level and subcellular localization through in vitro experiments. Methods: A total of 401 children with intellectual disabilities were screened for genetic variability using whole-exome sequencing (WES). Clinical data, including age, sex, perinatal conditions, and environmental exposure, were collected. Cognitive, verbal, motor, and social behavioral abilities were evaluated. Candidate variants were verified using Sanger sequencing, and their pathogenicity and conservation were analyzed using in silico prediction tools. Protein expression and localization of mutant ClC-4 were measured using Western blotting (WB) and immunofluorescence microscopy. The impact of a splice site variant was assessed with a minigene assay. Results: Exome analysis identified five rare CLCN4 variants in six unrelated patients with intellectual disabilities, including two recurrent heterozygous de novo missense variants (p.D89N and p.A555V) in three female patients, and two hemizygous missense variants (p.N141S and p.R694Q) and a splicing variant (c.1390-12T > G) that are maternally inherited in three male patients. The p.N141S variant and the splicing variant c.1390-12(T > G were novel, while p.R694Q was identified in two asymptomatic heterozygous female patients. The six children with CLCN4 variants exhibited a neurodevelopmental spectrum disease characterized by intellectual disability (ID), delayed speech, autism spectrum disorders (ASD), microcephaly, hypertonia, and abnormal imaging findings. The minigene splicing result indicated that the c.1390-12T > G did not affect the splicing of CLCN4 mRNA. In vitro experiments showed that the mutant protein level and localization of mutant protein are similar to the wild type. Conclusion: The study identified six probands with CLCN4 gene variants associated with X-linked ID. It expanded the gene and phenotype spectrum of CLCN4 variants. The bioinformatic analysis supported the pathogenicity of CLCN4 variants. However, these CLCN4 gene variants did not affect the ClC-4 expression levels and protein location, consistent with previous studies. Further investigations are necessary to investigate the pathogenetic mechanism.

Machine Learning-Based Evaluation on Craniodentofacial Morphological Harmony of Patients After Orthodontic Treatment.

Objectives: Machine learning is increasingly being used in the medical field. Based on machine learning models, the present study aims to improve the prediction performance of craniodentofacial morphological harmony judgment after orthodontic treatment and to determine the most significant factors. Methods: A dataset of 180 subjects was randomly selected from a large sample of 3,706 finished orthodontic cases from six top orthodontic treatment centers around China. Thirteen algorithms were used to predict the value of the cephalometric morphological harmony score of each subject and to search for the optimal model. Based on the feature importance ranking and by removing features, the regression models of machine learning (including the Adaboost, ExtraTree, XGBoost, and linear regression models) were used to predict and compare the score of harmony for each subject from the dataset with cross validations. By analyzing the prediction values, the most optimal model and the most significant cephalometric characteristics were determined. Results: When nine features were included, the performance of the XGBoost regression model was MAE = 0.267, RMSE = 0.341, and Pearson correlation coefficient = 0.683, which indicated that the XGBoost regression model exhibited the best fitting and predicting performance for craniodentofacial morphological harmony judgment. Nine cephalometric features including L1/NB (inclination of the lower central incisors), ANB (sagittal position between the maxilla and mandible), LL-EP (distance from the point of the prominence of the lower lip to the aesthetic plane), SN/OP (inclination of the occlusal plane), SNB (sagittal position of the mandible in relation to the cranial base), U1/SN (inclination of the upper incisors to the cranial base), L1-NB (protrusion of the lower central incisors), Ns-Prn-Pos (nasal protrusion), and U1/L1 (relationship between the protrusions of the upper and lower central incisors) were revealed to significantly influence the judgment. Conclusion: The application of the XGBoost regression model enhanced the predictive ability regarding the craniodentofacial morphological harmony evaluation by experts after orthodontic treatment. Teeth position, teeth alignment, jaw position, and soft tissue morphology would be the most significant factors influencing the judgment. The methodology also provided guidance for the application of machine learning models to resolve medical problems characterized by limited sample size.

Virtual Reality-Based Sensory Stimulation for Pediatric Disorders of Consciousness: A Pilot Study.

Objective: The purpose of this study was to determine whether virtual reality-based sensory stimulation has the ability to improve the level of consciousness in pediatric disorders of consciousness compared with general rehabilitation. Methods: Thirty subjects were divided into a virtual reality (VR) group (n = 15) and a control group (n = 15). Subjects in the VR group received both general rehabilitation and exposure to VR videos; the control group received only general rehabilitation. The Glasgow Coma Scale (GCS), Coma Recovery Scale-Revised (CRS-R), and amplitude-integrated electroencephalogram (EEG) (aEEG) were used to measure the clinical behavioral response and neuroelectrophysiology before and after the treatment. The Glasgow Outcome Scale Extended Pediatric Revised (GOS-E Peds) was used to measure the social and personal functional ability after 3 months. Results: After 2 weeks of treatment, the CRS-R and GCS improved in both groups. However, the VR group had better results than the control group in the CRS-R (p = 0.003) and GCS (p = 0.045). There were no significant differences on aEEG in the two groups after treatment. According to the GOS-E Peds, the improvement of social and personal functional ability had no significant differences in the two groups. Additionally, there were no obvious adverse reactions in the two group during the treatment. Conclusions: This pilot study indicates potential benefit from the addition of VR to standard rehabilitation in pediatric disorders of consciousness. To further explore the efficacy of VR, a large-sample randomized controlled trial is warranted.

Number comparison under the Ebbinghaus illusion.

A series of studies show interest in how visual attributes affect the estimate of object numbers in a scene. In comparison tasks, it is suggested that larger patches are perceived as more numerous. However, the inequality of density, which changes inversely with the area when numerosity remains constant, may mediate the influence of area on numerosity perception. This study aims to explore the role of area and density in the judgment of numerosity. The Ebbinghaus illusion paradigm was adopted to induce differences in the perceived, rather than the physical, area of the two patches to be compared. Participants were asked to compare the area, density, and the number of the two patches in three tasks. To this end, no PSE (point of subjective equality) bias was found in number comparison with randomly distributed dots, although a significant difference was revealed in the perceived area of the two patches. No PSE bias was found in the density comparison, either. For a comparison, density and number tasks were also conducted with regularly distributed dots. No PSE bias was found in density comparison. By contrast, significant PSE bias showed up in number comparison, and larger patches appeared to be more numerous than smaller patches. The density mechanism was proposed as the basis for number comparison with regular patterns. The individual Weber fractions for regular patterns were not correlated with those for random patterns in the number task, but they were correlated with those for both patterns in the density task. To summarize, numerosity is directly sensed, and numerosity perception is not affected by area inequality induced by the Ebbinghaus illusion. In contrast, density and area are combined to infer numerosity when the approximate numerosity mechanism is disrupted by dot distribution.

Case report: Novel compound heterozygous missense mutations in the DDHD2 gene in a Chinese patient associated with spastic paraplegia type 54.

Background: Spastic paraplegia type 54 (SPG54) is a rare inherited autosomal recessive disorder, and a complex hereditary spastic paraplegia (HSP) caused by mutations in the phospholipase DDHD2 gene. SPG54 is characterized by early onset of spastic paraplegia, intellectual disability and dysplasia of corpus callosum. Case presentation: We report a 9 years and 5 months old Chinese girl with progressive spasm of the lower limbs, muscle weakness and intellectual disability. Brain magnetic resonance imaging (MRI) showed periventricular leukomalacia and thinning of the corpus callosum. According to the Wechsler Intelligence Scale, her IQ is 42. By whole exome sequencing, novel compound heterozygous missense mutations in the DDHD2 gene [c.168G>C, p.(Trp56Cys) and c.1505T>C, p.(Phe502Ser)] were identified in the proband. Comparative amino acid sequence alignment across different species revealed that Trp56 and Phe502 in the DDHD2 protein were highly conserved during evolution. And multiple in silico prediction tools suggested that both mutations were deleterious. Conclusions: Our study reports a very rare case of complicated HSP caused by two novel compound heterozygous mutations in the DDHD2 gene. Our findings expand the genetic spectrum of SPG54.

New Approach to Intelligence Screening for Children With Global Development Delay Using Eye-Tracking Technology: A Pilot Study.

Objective: There has become a consensus for detecting intellectual disability in its early stages and implementing effective intervention. However, there are many difficulties and limitations in the evaluation of intelligence-related scales in low-age children. Eye-tracking technology may effectively solve some of the pain points in the evaluation. Method: We used an eye-tracking technology for cognitive assessment. The subjects looked at a series of task pictures and short videos, the fixation points of which were recorded by the eye-movement analyzer, and the data were statistically analyzed. A total of 120 children aged between 1.5 and 4 years participated in the study, including 60 typically developing children and 60 children with global development delay, all of whom were assessed via the Bayley scale, Peabody Picture Vocabulary Test (PPVT), and Gesell scale. Results: Cognitive scores from eye-tracking technology are closely related to the scores of neuropsychological tests, which shows that the technique performs well as an early diagnostic test of children's intelligence. Conclusions: The results show that children's cognitive development can be quickly screened using eye-tracking technology and that it can track quantitative intelligence scores and sensitively detect intellectual impairment.

Changes of Structural Brain Network Following Repetitive Transcranial Magnetic Stimulation in Children With Bilateral Spastic Cerebral Palsy: A Diffusion Tensor Imaging Study.

Introduction: Bilateral spastic cerebral palsy (BSCP) is the most common subtype of cerebral palsy (CP), which is characterized by various motor and cognitive impairments, as well as emotional instability. However, the neural basis of these problems and how repetitive transcranial magnetic stimulation (rTMS) can make potential impacts on the disrupted structural brain network in BSCP remain unclear. This study was aimed to explore the topological characteristics of the structural brain network in BSCP following the treatment of rTMS. Methods: Fourteen children with BSCP underwent 4 weeks of TMS and 15 matched healthy children (HC) were enrolled. Diffusion tensor imaging (DTI) data were acquired from children with bilateral spastic cerebral palsy before treatment (CP1), children with bilateral spastic cerebral palsy following treatment (CP2) and HC. The graph theory analysis was applied to construct the structural brain network. Then nodal clustering coefficient (C i ) and shortest path length (L i ) were measured and compared among groups. Results: Brain regions with significant group differences in C i were located in the left precental gyrus, middle frontal gyrus, calcarine fissure, cuneus, lingual gyrus, postcentral gyrus, inferior parietal gyri, angular gyrus, precuneus, paracentral lobule and the right inferior frontal gyrus (triangular part), insula, posterior cingulate gyrus, precuneus, paracentral lobule, pallidum. In addition, significant differences were detected in the L i of the left precental gyrus, lingual gyrus, superior occipital gyrus, middle occipital gyrus, superior parietal gyrus, precuneus and the right median cingulate gyrus, posterior cingulate gyrus, hippocampus, putamen, thalamus. Post hoc t-test revealed that the CP2 group exhibited increased C i in the right inferior frontal gyrus, pallidum and decreased L i in the right putamen, thalamus when compared with the CP1 group. Conclusion: Significant differences of node-level metrics were found in various brain regions of BSCP, which indicated a disruption in structural brain connectivity in BSCP. The alterations of the structural brain network provided a basis for understanding of the pathophysiological mechanisms of motor and cognitive impairments in BSCP. Moreover, the right inferior frontal gyrus, putamen, thalamus could potentially be biomarkers for predicting the efficacy of TMS.

[Exploration of design and practice of disaster medical rescue monitoring system with privacy protection mechanism].

OBJECTIVE: On the premise of fully studying the disaster medical rescue monitoring mechanism in emergencies at home and abroad, the functional requirements of the domestic disaster medical rescue monitoring system was analyzed in this paper, the logical framework and data structure of disaster medical rescue monitoring system with privacy protection mechanism was designed by department of emergency in Chinese PLA General Hospital, department of information management in School of Economics and Management of Beijing Jiaotong University, the School of Information Management of Nanjing University. Three major functional modules were realized in the system: reporter information management, disaster medical rescue data upload, and disaster medical rescue data search. Android client and Web client were developed for easy access to the system. The system also had the function of privacy protection. Based on symmetric searchable encryption algorithm, the system realized the encryption storage of untrusted servers and ensured the security of medical and health data. It is beneficial for the further development and improvement of disaster medical rescue data collection in China.

[Big data in emergency and clinical decision support system].

OBJECTIVE: Medical big data is a hot research topic in China, and it is also the main research direction in the field of emergency medicine. The current situation of the construction of the first-aid big data platform and the construction of the first-aid clinical decision support system were analyzed, the problems existing in the development of the first-aid big data research field were enumerated, to explore the theoretical methods for promoting the development of domestic first-aid big data, so as to provide references for the research in related fields.

[Enlightenment from the surveillance in post extreme emergencies and disasters].

OBJECTIVE: The detailed analysis of the surveillance in post extreme emergencies and disasters (SPEED) provides practical reference for China to establish a disaster medical rescue information monitoring system with Chinese characteristics. METHODS: The SPEED system under the scene of disaster medical rescue information monitoring is analyzed in detail. The SPEED system design, work flows, system implementation and other aspects are analyzed and summarized in this paper, and suggests the enlightenment of SPEED system for Chinese disaster medical rescue information monitoring work. RESULTS: The SPEED system is an information monitoring system for the early stages of disasters. It provides monitoring for diseases caused by disasters, and life and health trends. It has a complete data collection mechanism, a comprehensive personnel training system, a complete system function, and an implementation strategy involving multi-layer, multi-region, and multi -sector. It is a powerful tool for disaster medical rescue and management personnel to obtain information in time. In the field of disaster medical rescue, a similar public-facing information monitoring system in China is still not perfect. CONCLUSIONS: Learning the design flows and establishment mode of the SPEED system can provide reference for China to establish a disaster medical rescue information monitoring system with Chinese characteristics.

Efficient and Robust Learning for Sustainable and Reacquisition-Enabled Hand Tracking.

The use of machine learning approaches for long-term hand tracking poses some major challenges such as attaining robustness to inconsistencies in lighting, scale and object appearances, background clutter, and total object occlusion/disappearance. To address these issues in this paper, we present a robust machine learning approach based on enhanced particle filter trackers. The inherent drawbacks associated with the particle filter approach, i.e., sample degeneration and sample impoverishment, are minimized by infusing the particle filter with the mean shift approach. Moreover, to instill our tracker with reacquisition ability, we propose a rotation invariant and efficient detection framework named beta histograms of oriented gradients. Our robust appearance model operates on the red, green, blue color histogram and our newly proposed rotation invariant noise compensated local binary patterns descriptor, which is a noise compensated, rotation invariant version of the local binary patterns descriptor. Through our experiments, we demonstrate that our proposed hand tracker performs favorably against state-of-the-art algorithms on numerous challenging video sequences of hand postures, and overcomes the largely unsolved problem of redetecting hands after they vanish and reappear into the frame.

Neonatal repetitive pain in rats leads to impaired spatial learning and dysregulated hypothalamic-pituitary-adrenal axis function in later life.

Preterm birth is a major health issue. As part of their life-saving care, most preterm infants require hospitalization and are inevitably exposed to repetitive skin-breaking procedures. The long-term effects of neonatal repetitive pain on cognitive and emotional behaviors involving hypothalamic-pituitary-adrenal (HPA) axis function in young and adult rats are unknown. From P8 to P85, mechanical hypersensitivity of the bilateral hindpaws was observed in the Needle group (P < 0.001). Compared with the Tactile group, the Needle group took longer to find the platform on P30 than on P29 (P = 0.03), with a decreased number of original platform site crossings during the probe trial of the Morris water maze test (P = 0.026). Moreover, the Needle group spent more time and took longer distances in the central area than the Tactile group in the Open-field test, both in prepubertal and adult rats (P < 0.05). The HPA axis function in the Needle group differed from the Tactile group (P < 0.05), with decreased stress responsiveness in prepuberty and puberty (P < 0.05) and increased stress responsiveness in adulthood (P < 0.05). This study indicates that repetitive pain that occurs during a critical period may cause severe consequences, with behavioral and neuroendocrine disturbances developing through prepuberty to adult life.

Risk-Benefit Profile of Gastric vs Transpyloric Feeding in Mechanically Ventilated Patients: A Meta-Analysis.

BACKGROUND: The risk-benefit profile of transpyloric vs gastric feeding in mechanically ventilated (MV) patients has not been definitively established. OBJECTIVE: To evaluate the risks and benefits of transpyloric feeding compared with gastric feeding in mechanically ventilated patients. DESIGN: We systematically searched MEDLINE, Google Scholar, EMBASE, and the Cochrane Central Register of Controlled Trials databases for eligible articles through June 21, 2013. Randomized controlled trials (RCTs) that reported a comparison between gastric and transpyloric feeding in MV patients were selected. Two reviewers independently extracted data on populations, methods, outcomes, and risk of bias. Ventilator-associated pneumonia (VAP) was considered the primary outcome. RESULTS: A total of 8 RCTs, including 835 MV patients, were identified and analyzed. Our pooled findings indicated that there was a significant reduction in VAP through transpyloric feeding compared with gastric feeding (relative risk [RR], 0.67; 95% confidence interval [CI], 0.53 to 0.85; P = .001) but not in mortality (RR, 1.08; 95% CI, 0.86 to 1.36; P = .49), length of mechanical ventilation (mean difference [MD], -0.16; 95% CI, -0.75 to 0.43; P = .59), length of stay in the intensive care unit (MD, -0.91; 95% CI, -2.75 to 0.94; P = .34), incidence of diarrhea (RR, 0.9; 95% CI, 0.66 to 1.23; P = .50), and incidence of vomiting (RR, 0.82; 95% CI, 0.25 to 2.72; P = .75). CONCLUSIONS: Transpyloric feeding in MV adults was associated with significantly less incidence of VAP compared with gastric feeding. No differences were observed in other outcomes, suggesting that the difference observed in the incidence of VAP may be spurious and needs confirmation.

Evaluation of stress and pain in young children with cerebral palsy during early developmental intervention programs: a descriptive study.

OBJECTIVE: The aim of this study was to use the Face, Legs, Activity, Cry, Consolability Scale; salivary cortisol levels; and withdrawal reflex thresholds to assess pain, stress, and pain sensitivity in young children with cerebral palsy during early developmental intervention programs. DESIGN: A total of 40 children with cerebral palsy (age range, 1-4 yrs) participated in the early intervention programs, which included neurodevelopmental treatment, neuromuscular electrical stimulation, occupational therapy, head acupuncture, and Chinese traditional manipulation five times per week for 3 wks. The Face, Legs, Activity, Cry, Consolability Scale was applied during the course of each treatment, and salivary cortisol samples were obtained from each child 10 mins before and 10 mins after each treatment. Withdrawal reflex thresholds were assessed via mechanical stimulation of the foot with von Frey hairs. RESULTS: All treatment programs caused some degree of pain. In descending order, the extents of the pain caused by each treatment were head acupuncture, neurodevelopmental treatment, neuromuscular electrical stimulation, Chinese traditional manipulation, and occupational therapy. There were statistically significant increases in salivary cortisol levels after the head acupuncture (P < 0.001), neurodevelopmental treatment (P < 0.001), neuromuscular electrical stimulation (P < 0.001), and Chinese traditional manipulation (P < 0.001) treatments. No significant changes were found in the withdrawal reflex thresholds during the study (P > 0.05). CONCLUSIONS: The results of this study demonstrate that early developmental intervention programs cause pain and stress in young children with cerebral palsy.