A Scoping Review on Mobile Health Technology for Assessment and Intervention of Upper Limb Motor Function in Children with Motor Impairments.

Upper limb (UL) motor dysfunctions impact residual movement in hands/shoulders and limit participation in play, sports, and leisure activities. Clinical and laboratory assessments of UL movement can be time-intensive, subjective, and/or require specialized equipment and may not optimally capture a child's motor abilities. The restrictions to in-person research experienced during the COVID-19 pandemic have inspired investigators to design inclusive at-home studies with child participants and their families. Relying on the ubiquity of mobile devices, mobile health (mHealth) applications offer solutions for various clinical and research problems. This scoping review article aimed to aggregate and synthesize existing research that used health technology and mHealth approaches to evaluate and assess the hand function and UL movement in children with UL motor impairment. A scoping review based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) model was conducted in March 2023 yielding 25 articles (0.32% of 7891 studies). Assessment characteristics included game or task-based tests (13/25, 52%), primarily for neurological disorders (e.g., autism spectrum disorder [ASD], dystonia, dysgraphia) or children with cerebral palsy (CP). Although several mHealth studies were conducted in the clinical environment (10/25, 40%), studies conducted at home or in nonclinical settings (15/25, 60%) reported acceptable and highly satisfactory to the patients as minimizing the potential risks in participation. Moreover, the remaining barriers to clinical translation included object manipulation on a touch screen, offline data analysis, real-world usability, and age-appropriate application design for the wider population. However, the results emphasize the exploration of mHealth over traditional approaches, enabling user-centered study design, family-oriented methods, and large-scale sampling in future research.

Impact of Age and School Instruction Mode on Children's Occupations Early in the COVID-19 Pandemic: A Longitudinal Survey Study.

IMPORTANCE: The coronavirus disease 2019 (COVID-19) pandemic disrupted participation in routines and daily activities. It is unclear how children reengaged in activities during the pandemic, particularly as a new school year began. Differences in school instruction mode (in person, hybrid, or remote) during the pandemic could further affect activity participation. OBJECTIVE: To examine changes in sedentary and nonsedentary activity participation in children and to determine whether school instruction mode was associated with participation. SETTING: Home-based survey of U.S. residents. PARTICIPANTS: Parents of 208 children (46.2% female) between ages 5 and 18 yr were surveyed at two waves: March through April 2020 and October 2020. OUTCOMES AND MEASURES: Frequency of sedentary (indoor play, electronic device usage) and nonsedentary (outdoor play, leisure and extracurriculars) activity participation was observed. Descriptive and inferential statistics of the changes from Wave 1 to Wave 2 and linear regression were used to determine statistically significant variables associated with activity participation. RESULTS: Nonsedentary activity participation increased and sedentary activity decreased from Wave 1 to Wave 2. Instruction mode was statistically associated with nonsedentary, but not sedentary, participation. Negative mood, local COVID-19 severity, and household income were also associated with nonsedentary and sedentary participation. CONCLUSIONS AND RELEVANCE: Children's participation in sedentary and nonsedentary activities normalized during the new school year; however, many factors likely contributed to these changes. What This Article Adds: Despite differences in school instruction mode and the influence of mental health early in the pandemic, children's nonsedentary activity participation increased. Occupational therapy practitioners can reinforce the importance of reengaging in activities and regular routines to promote health and well-being during challenging situations.

Safety and feasibility of transcranial direct current stimulation stratified by corticospinal organization in children with hemiparesis.

Children with hemiparesis (CWH) due to stroke early in life face lifelong impairments in motor function. Transcranial direct current stimulation (tDCS) may be a safe and feasible adjuvant therapy to augment rehabilitation. Given the variability in outcomes following tDCS, tailored protocols of tDCS are required. We evaluated the safety, feasibility, and preliminary effects of a single session of targeted anodal tDCS based on individual corticospinal tract organization on corticospinal excitability. Fourteen CWH (age = 13.8 ± 3.63) were stratified into two corticospinal organization subgroups based on transcranial magnetic stimulation (TMS)-confirmed motor evoked potentials (MEP): ipsilesional MEP presence (MEPIL+) or absence (MEPIL-). Subgroups were randomized to real anodal or sham tDCS (1.5 mA, 20 min) applied to the ipsilesional (MEPIL + group) or contralesional (MEPIL- group) hemisphere combined with hand training. Safety was assessed with questionnaires and motor function evaluation, and corticospinal excitability was assessed at baseline and every 15 min for 1 h after tDCS. No serious adverse events occurred and anticipated minor side effects were reported and were self-limiting. Six of 14 participants had consistent ipsilesional MEPs (MEPIL + group). Paretic hand MEP amplitude increased in 5/8 participants who received real anodal tDCS to either the ipsilesional or contralesional hemisphere (+80% change). Application of tDCS based on individual corticospinal organization was safe and feasible with expected effects on excitability, indicating the potential for tailored tDCS protocols for CWH. Additional research involving expanded experimental designs is needed to confirm these effects and to determine if this approach can be translated into a clinically relevant intervention.

Anodal Contralesional tDCS Enhances CST Excitability Bilaterally in an Adolescent with Hemiparetic Cerebral Palsy: A Brief Report.

Hemiparetic cerebral palsy (HCP), weakness on one side of the body typically caused by perinatal stroke, is characterized by lifelong motor impairments related to alterations in the corticospinal tract (CST). CST reorganization could be a useful biomarker to guide applications of neuromodulatory interventions, such as transcranial direct current stimulation (tDCS), to improve the effectiveness of rehabilitation therapies. We evaluated an adolescent with HCP and CST reorganization who demonstrated persistent heightened CST excitability in both upper limbs following anodal contralesional tDCS. The results support further investigation of targeted tDCS as an adjuvant therapy to traditional neurorehabilitation for upper limb function.

Bringing Covid to College: Incoming First-Year College Students' Making Meaning of the Pandemic.

As time passes from the start of the COVID-19 pandemic in 2020, new cohorts of emerging adults transition to college, carrying with them experiences and effects of the pandemic on their lives and development. This study uses semi-structured interviews and reflexive thematic analysis to investigate how a cohort of 36 young people made narrative meaning of the pandemic in relation to their identities. Data were collected at the beginning of their first year at college and focused on their experiences of the pandemic, its impact on their lives, and the lessons they took away from it. Findings demonstrate that even amid deep and varied challenges, young people coped in nuanced ways and some built narratives of personal growth, development, new social identities, and maturing values. The study contributes to greater depth in understanding the impacts of the pandemic on young people as they develop into emerging adults.

Disrupted Access to Therapies and Impact on Well-Being During the COVID-19 Pandemic for Children With Motor Impairment and Their Caregivers.

OBJECTIVES: The aim of this study was to determine the impact of the COVID-19 pandemic on access to rehabilitation therapies and the impact of changes in therapy access on the physical and mental well-being of children with motor impairment and their caregivers. DESIGN: Caregivers of children younger than 18 yrs with childhood-onset motor impairment (primarily cerebral palsy) completed an anonymous survey through the online platform REDCap between May 5 and July 13, 2020. RESULTS: The survey was completed by 102 participants. Before the pandemic, 92 of 102 children (90%) were receiving one or more therapies; at the time surveyed, 55 children (54%) were receiving any therapies (P < 0.001). More than 40% of the sample reported increased child stress, decreased physical activity, and/or decline in mobility/movement. Participants who reported a decrease in number of therapies at the time surveyed more frequently reported lower satisfaction with treatment delivery (P < 0.001), a decline in child's mobility (P = 0.001), and increased caregiver stress (P = 0.004). Five qualitative themes were identified from open-ended question responses related to therapies and well-being. CONCLUSIONS: Access to pediatric rehabilitation therapies was disrupted during COVID-19. Disrupted access may be related to impact on physical and mental health. With the expansion of telehealth, caregiver and child feedback should be incorporated to optimize benefit.

Evaluating transcranial magnetic stimulation (TMS) induced electric fields in pediatric stroke.

Transcranial magnetic stimulation (TMS) is an increasingly popular tool for stroke rehabilitation. Consequently, researchers have started to explore the use of TMS in pediatric stroke. However, the application of TMS in a developing brain with pathologies comes with a unique set of challenges. The effect of TMS-induced electric fields has not been explored in children with stroke lesions. Here, we used finite element method (FEM) modeling to study how the electric field strength is affected by the presence of a lesion. We created individual realistic head models from MRIs (n = 6) of children with unilateral cerebral palsy due to perinatal stroke. We conducted TMS electric field simulations for coil locations over lesioned and non-lesioned hemispheres. We found that the presence of a lesion can strongly affect the electric field distribution. On the group level, the mean electric field strength did not differ between lesioned and non-lesioned hemispheres but exhibited a greater variability in the lesioned hemisphere. Other factors such as coil-to-cortex distance have a strong influence on the TMS electric field even in the presence of lesions. Our study has important implications for the delivery of TMS in children with brain lesions with respect to TMS dosing and coil placement.

Cardiovascular Effects of Transcranial Direct Current Stimulation and Bimanual Training in Children With Cerebral Palsy.

PURPOSE: To determine the influence of combined transcranial direct current stimulation (tDCS) to the motor cortex (M1) and bimanual training on cardiovascular function in children with cerebral palsy (CP). METHODS: Mean arterial pressure (MAP), heart rate (HR), and HR variability (HRV) were measured immediately before and after 20 minutes of cathodal tDCS to contralesional M1 and bimanual training on days 1, 6, and 10 of a 10-day trial in 8 participants (5 females, 7-19 years). RESULTS: Baseline MAP and HR were similar across days (93 ± 10 mm Hg and 90 ± 10 bpm, P > .05). MAP was similar from baseline to postintervention across all 3 days. Systolic pressure, diastolic pressure, nor HR significantly changed. HRV was not influenced by the 10-day intervention. CONCLUSIONS: Combined cathodal tDCS to M1 and bimanual training does not influence autonomic and cardiovascular function in children with CP due to perinatal stroke.

Ipsilateral Corticospinal Tract Excitability Contributes to the Severity of Mirror Movements in Unilateral Cerebral Palsy: A Case Series.

Mirror movements (MM) can be a clinical manifestation of unilateral cerebral palsy (UCP) causing involuntary movements when attempting to use either hand for functional activities. Atypical development of the corticospinal tract (CST) contributes to impairments in observed motor movements and functional activities. However, little is known about the underlying neurophysiology and contribution of the CST to MM. The current case study characterizes MM in 13 children and young adults with UCP ranging in age from 7 to 19 years and includes clinical and neurophysiologic variables. Clinical profiles included MM of each hand (ie, Woods and Teuber), bimanual coordination and hand use (Assisting Hand Assessment [AHA]), and perception of performance (Canadian Occupational Performance Measure [COPM]). We measured the strength of motor-evoked potentials (MEP) elicited from single-pulse transcranial magnetic stimulation (TMS) of each hemisphere to create a ratio of hemispheric responses. Our sample included three types of CST circuitry: ipsilateral (n = 5), bilateral (n = 3), and contralateral (n = 4). The MEP ratio ranged from 0 to 1.45 (median 0.11) with greater MM observed in participants with ratios greater than 0.5. We observed a positive relationship between the MEP ratio and the more-affected MM score, meaning participants with larger ipsilateral responses from contralesional stimulation (eg, the contralesional hemisphere was stimulated with TMS resulting in an ipsilateral MEP response), as compared with contralateral responses, displayed greater MM than those that did not. There was no relationship between MM and function as measured by the AHA or COPM. These findings suggest a role of the contralesional hemisphere to MM, which could serve as a therapeutic target for interventions.

A crossed-disciplinary evaluation of parental perceptions surrounding pediatric non-invasive brain stimulation research.

PURPOSE ­: Recruitment for pediatric non-invasive brain stimulation (NIBS) studies is often challenged by low enrollment. Understanding parental perceptions regarding NIBS is crucial to develop new communication strategies to increase enrollment. DESIGN/METHODOLOGY/APPROACH ­: Integrating a crossed-disciplinary approach, the authors conducted a survey at the 2018 Minnesota State Fair querying the perception of risk and preferences of current and future parents associated with pediatric NIBS research. The survey consisted of 28 closed-text questions including demographics, photographs portraying NIBS, terminologies and factors related to NIBS studies. FINDINGS ­: Complete surveys were analyzed from 622 parent participants. A significant number of participants (42.8%) perceived the photographs of NIBS as "risky." Additionally, 65.43% perceived the term "Non-invasive brain therapy" as not risky, a word combination not currently being used when recruiting potential participants. Over 90% (561/622) of participants chose the photograph of child-friendly MRI suite. RESEARCH LIMITATIONS/IMPLICATIONS ­: Although this survey identified aspects crucial in recruitment for pediatric NIBS research, there were limitations. For example, the authors did not record the sex or demographic distribution (e.g. rural versus urban setting) of the participants. These factors may also influence recruitment messaging. ORIGINALITY/VALUE ­: For important medical research to impact and improve the lives of the potential remedies, participation by the public in clinical trials is necessary. Often the general public perceives the trials as risky as a result of poor marketing communication recruitment material. This study sought to be understood if how the message is encoded has an impact on the decoding by the receiver.

Motor Evoked Potentials as Potential Biomarkers of Early Atypical Corticospinal Tract Development in Infants with Perinatal Stroke.

Diagnosis of cerebral palsy (CP) after perinatal stroke is often delayed beyond infancy, a period of rapid neuromotor development with heightened potential for rehabilitation. This study sought to assess whether the presence or absence of motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) could be an early biomarker of atypical development within the first year of life. In 10 infants with perinatal stroke, motor outcome was assessed with a standardized movement assessment. Single-pulse TMS was utilized to assess presence of MEPs. Younger infants (3-6 months CA, n = 5, 4/5 (80%)) were more likely to present with an MEP from the more-affected hemisphere (MAH) compared to older infants (7-12 months CA, n = 5, 0/5, (0%)) (p = 0.048). Atypical movement was demonstrated in the majority of infants with an absent MEP from the MAH (5/6, 83%) compared to those with a present MEP (1/4, 25%) (p = 0.191). We found that age influences the ability to elicit an MEP from the MAH, and motor outcome may be related to MAH MEP absence. Assessment of MEPs in conjunction with current practice of neuroimaging and motor assessments could promote early detection and intervention in infants at risk of CP.

Neurite orientation dispersion and density imaging quantifies corticospinal tract microstructural organization in children with unilateral cerebral palsy.

Children with unilateral cerebral palsy (UCP) due to early brain injury exhibit disrupted connectivity of corticospinal tracts (CSTs), which can be quantified using diffusion-weighted magnetic resonance imaging (DWI). Diffusion tensor imaging (DTI) is commonly used to quantify white matter organization, however, this model lacks the biological specificity to accurately describe underlying microstructural properties. Newer approaches, such as neurite orientation dispersion and density imaging (NODDI), may provide more biologically accurate information regarding CST microstructure. In this study, we directly compared metrics of CST microstructure using NODDI and DTI models to characterize the microstructural organization of corticospinal pathways. Twenty participants with UCP participating in a neuromodulation/rehabilitation intervention underwent imaging including multi-shell DWI; 10 participants' datasets were adequately completed for neuroimaging analysis. Task fMRI-guided probabilistic tractography from motor cortex to brainstem was performed at baseline and follow-up to reconstruct the CSTs. Diffusion metrics were compared between hemispheres at baseline, and between baseline and follow-up to test for intervention effects. Correlation analyses were used to compare baseline metrics to changes in hand function following the intervention. DTI results showed that mean fractional anisotropy in lesioned and nonlesioned CSTs did not significantly differ, but mean, axial, and radial diffusivity were greater in the lesioned CST. For NODDI, intracellular volume fraction (ICVF) and orientation dispersion index (ODI) were lower in the lesioned CST. Unimanual function was strongly correlated with ICVF, but not FA. NODDI may reveal distinct properties of CST microstructure that are linked to motor function, indicating their potential in characterizing brain structure and development.

Influence of Combined Transcranial Direct Current Stimulation and Motor Training on Corticospinal Excitability in Children With Unilateral Cerebral Palsy.

Combined non-invasive brain stimulation (NIBS) and rehabilitation interventions have the potential to improve function in children with unilateral cerebral palsy (UCP), however their effects on developing brain function are not well understood. In a proof-of-principle study, we used single-pulse transcranial magnetic stimulation (TMS) to measure changes in corticospinal excitability and relationships to motor performance following a randomized controlled trial consisting of 10 days of combined constraint-induced movement therapy (CIMT) and cathodal transcranial direct current stimulation (tDCS) applied to the contralesional motor cortex. Twenty children and young adults (mean age = 12 years, 9 months, range = 7 years, 7 months, 21 years, 7 months) with UCP participated. TMS testing was performed before, after, and 6 months after the intervention to measure motor evoked potential (MEP) amplitude and cortical silent period (CSP) duration. The association between neurophysiologic and motor outcomes and differences in excitability between hemispheres were examined. Contralesional MEP amplitude decreased as hypothesized in five of five participants receiving active tDCS immediately after and 6 months after the intervention, however no statistically significant differences between intervention groups were noted for MEP amplitude [mean difference = -323.9 µV, 95% CI = (-989, 341), p = 0.34] or CSP duration [mean difference = 3.9 ms, 95% CI = (-7.7, 15.5), p = 0.51]. Changes in corticospinal excitability were not statistically associated with improvements in hand function after the intervention. Across all participants, MEP amplitudes measured in the more-affected hand from both contralesional (mean difference = -474.5 µV) and ipsilesional hemispheres (-624.5 µV) were smaller compared to the less-affected hand. Assessing neurophysiologic changes after tDCS in children with UCP provides an understanding of long-term effects on brain excitability to help determine its potential as a therapeutic intervention. Additional investigation into the neurophysiologic effects of tDCS in larger samples of children with UCP are needed to confirm these findings.

Bimanual Skill Learning after Transcranial Direct Current Stimulation in Children with Unilateral Cerebral Palsy: A Brief Report.

Bimanual skills are important for goal-oriented activities. Children with unilateral cerebral palsy (UCP) have deficits in unimanual and bimanual motor control and learning. The application of non-invasive brain stimulation with existing motor training may further promote motor learning; however, the effects of stimulation on bimanual learning have not been examined. Here, we assessed the performance of a novel bimanual skill (modified Speed Stacks task) in eight children with UCP before, during, and after a combined motor training and brain stimulation intervention. Participants received 10 days (120 min/day) of goal-oriented bimanual therapy combined initially with transcranial direct current stimulation (tDCS, 20 min/day). Results showed task improvement tapered (p < 0.001) during and after the intervention and task variability decreased in 6/8 participants, indicating the potential impact of novel rehabilitation to improve skill learning in children with UCP. Future work is required to understand how both tDCS and bimanual training contribute to learning bimanual tasks.

Safety and Feasibility of Transcranial Magnetic Stimulation as an Exploratory Assessment of Corticospinal Connectivity in Infants After Perinatal Brain Injury: An Observational Study.

BACKGROUND: Perinatal brain injuries often impact the corticospinal system, leading to motor impairment and cerebral palsy. Although transcranial magnetic stimulation (TMS) has been widely used to study corticospinal connectivity in adults and older children, similar studies of young infants are limited. OBJECTIVES: The objective was to establish the safety and feasibility of advanced TMS assessments of the corticospinal connectivity of young infants with perinatal brain injury. DESIGN: This was a pilot, cross-sectional study of 3- to 12-month-old (corrected age) infants with perinatal stroke or intracranial hemorrhage. METHODS: Six participants (2 term, 4 preterm) were assessed with stereotactic neuronavigation-guided TMS. Single-pulse TMS was applied to each hemisphere and responses were recorded simultaneously from both upper limbs. During data collection, vital signs and stress responses were measured to assess safety. Developmental motor outcomes were evaluated using the General Movements Assessment and Bayley Scales of Infant and Toddler Development (3rd edition). A clinical diagnosis of cerebral palsy was recorded, if available. RESULTS: No adverse events occurred during TMS testing. All sessions were well tolerated. Contralateral motor evoked responses were detected in 4 of 6 participants. Both contralateral and ipsilateral responses were observed in 2 of 6 participants. LIMITATIONS: TMS responses were not obtained in all participants. This could be related to the location of brain injury or developmental stage of the corticospinal system controlling the wrist flexor muscle group from which responses were recorded. CONCLUSIONS: This study provides a summary of the framework for performing novel TMS assessments in infants with perinatal brain injury. Implementing this approach to measure corticospinal connectivity in hypothesis-driven studies in young infants appears to be justified. Such studies could inform the characterization of corticospinal development and the neural mechanisms driving recovery following early interventions.

Transcranial direct current stimulation and constraint-induced therapy in cerebral palsy: A randomized, blinded, sham-controlled clinical trial.

We investigated the safety, feasibility, and efficacy of transcranial direct current stimulation (tDCS) combined with constraint-induced movement therapy (CIMT) in children and young adults with unilateral cerebral palsy. Twenty participants were randomized to receive active or sham tDCS. The intervention consisted of 10 consecutive weekday sessions of tDCS applied to the non-lesioned hemisphere (20 min) concurrently with CIMT (120 min). Participants, caregivers, and interventionists were blinded to group assignment. The primary safety outcome investigated adverse events. The primary behavioral outcome was the Assisting Hand Assessment. All 20 participants (mean age = 12.7 yrs, range = 7.4-21.6 years) were evaluated for the primary outcomes. No serious adverse events occurred, and the most commonly reported minor adverse events were headache and itchiness. Both groups demonstrated a significant improvement in hand function after the intervention, although no significant effect of tDCS was observed (between-group difference = -2.18, 95% CI = [-6.48, 2.12], p = 0.30). Although hand function improved overall, no significant differences between intervention groups were found. Children with preserved corticospinal tract circuitry from the lesioned hemisphere, compared to those without, showed greater improvement in hand function (mean difference = 3.04, 95% CI = [-0.64, 6.72], p = 0.099). Our study demonstrates the safety and feasibility of serial sessions of tDCS, and presents preliminary evidence for the effect of CST circuitry on outcomes following tDCS/CIMT. Future work in children with unilateral cerebral palsy should focus on the optimal dosing and consider individual brain circuitry when describing response to combined interventions. CLINICAL TRIALS REGISTRATION: Clinicaltrials.govNCT 02250092.

Transcranial Direct Current Stimulation (tDCS) Paired with Occupation-Centered Bimanual Training in Children with Unilateral Cerebral Palsy: A Preliminary Study.

Objective: We investigated the preliminary efficacy of cathodal transcranial direct current stimulation (tDCS) combined with bimanual training in children and young adults with unilateral cerebral palsy based on the principle of exaggerated interhemispheric inhibition (IHI). Methods: Eight participants with corticospinal tract (CST) connectivity from the lesioned hemisphere participated in an open-label study of 10 sessions of cathodal tDCS to the nonlesioned hemisphere (20 minutes) concurrently with bimanual, goal-directed training (120 minutes). We measured the frequency of adverse events and intervention efficacy with performance (bimanual-Assisting Hand Assessment (AHA)-and unimanual-Box and Blocks), self-report (Canadian Occupational Performance Measure (COPM), ABILHAND), and neurophysiologic (motor-evoked potential amplitude, cortical silent period (CSP) duration, and motor mapping) assessments. Results: All participants completed the study with no serious adverse events. Three of 8 participants showed gains on the AHA, and 4 of 8 participants showed gains in Box and Blocks (more affected hand). Nonlesioned CSP duration decreased in 6 of 6 participants with analyzable data. Cortical representation of the first dorsal interosseous expanded in the nonlesioned hemisphere in 4 of 6 participants and decreased in the lesioned hemisphere in 3 of 4 participants with analyzable data. Conclusions: While goal achievement was observed, objective measures of hand function showed inconsistent gains. Neurophysiologic data suggests nonlinear responses to cathodal stimulation of the nonlesioned hemisphere. Future studies examining the contributions of activity-dependent competition and cortical excitability imbalances are indicated.

A Case of Apparent Upper-Body Freezing in Parkinsonism while Using a Wheelchair.

Freezing of gait (FOG) is a common, disabling gait disturbance in Parkinson's disease (PD) and other Parkinsonian syndromes. Freezing also occurs during non-gait movements involving the upper limbs. The mechanisms underlying freezing are complex, likely involving motor, cognitive, and sensory systems that contribute to the episodes. Here, we reported a 60-year-old female with a 24-year history of parkinsonism who experienced significant FOG when ambulatory. Disease progression resulted in her permanent use of a powered wheelchair. While using the power chair, the patient experiences apparent paroxysmal freezing in the hand and arm used to steer and propel the chair. These episodes, some lasting up to several minutes, occur only in circumstances (e.g., entering and leaving an elevator) that are similar to environments known to elicit and exacerbate FOG. Episodes are transient and can be volitionally interrupted by the patient but sometimes require external assistance. Therapeutic intervention for this type of potential freezing has yet to be determined. This case may provide insight into the complex nature of freezing behavior and suggests a need for new approaches to treating non-traditional freezing behavior.

Sexual dimorphism in myocardial acylcarnitine and triglyceride metabolism.

BACKGROUND: Cardiovascular disease is the leading cause of death among diabetic patients. Importantly, recent data highlight the apparent sexual dimorphism in the pathogenesis of cardiovascular disease in diabetics with respect to both frequency- and age-related risk factors. The disposition to cardiovascular disease among diabetic patients has been attributed, at least in part, to excess lipid supply to the heart culminating in lipotoxicity of the heart and downstream derangements. A confounding factor in obese animal models of diabetes is that increased peripheral lipid availability to the heart can induce cardio-metabolic remodeling independent of the underlying pathophysiology of diabetes, thus masking the diabetic phenotype. To that end, we hypothesized that the use of non-obese diabetic (NOD) animal models will reveal metabolic signatures of diabetes in a sex-specific manner. METHODS: To test this hypothesis, male and female NOD Goto-Kakizaki (GK) rats were used to assess the expression profile of 84 genes involved in lipid metabolism. In parallel, targeted lipidomics analysis was performed to characterize sex differences in homeostasis of non-esterified fatty acids (NEFA), acylcarnitines (AC), and triglycerides (TG). RESULTS: Our analysis revealed significant sex differences in the expression of a broad range of genes involved in transport, activation, and utilization of lipids. Furthermore, NOD male rats exhibited enhanced oxidative metabolism and accumulation of TG, whereas female NOD rats exhibited reduced TG content coupled with accumulation of AC species. Multi-dimensional statistical analysis identified saturated AC16:0, AC18:0, and AC20:0 as dominant metabolites in mediating sex differences in AC metabolism. Confocal microscopy of rat cardiomyocytes exposed to AC14:0, AC16:0, and AC18:0 confirmed induction of ROS with AC18:0 being more potent followed by AC14:0. CONCLUSION: Overall, we demonstrate sex differences in myocardial AC and TG metabolism with implications for therapy and diagnosis of diabetic cardiovascular disease.