A multidisciplinary approach and consensus statement to establish standards of care for Angelman syndrome.

BACKGROUND: Angelman syndrome (AS) is a rare neurogenetic disorder present in approximately 1/12,000 individuals and characterized by developmental delay, cognitive impairment, motor dysfunction, seizures, gastrointestinal concerns, and abnormal electroencephalographic background. AS is caused by absent expression of the paternally imprinted gene UBE3A in the central nervous system. Disparities in the management of AS are a major problem in preparing for precision therapies and occur even in patients with access to experts and recognized clinics. AS patients receive care based on collective provider experience due to limited evidence-based literature. We present a consensus statement and comprehensive literature review that proposes a standard of care practices for the management of AS at a critical time when therapeutics to alter the natural history of the disease are on the horizon. METHODS: We compiled the key recognized clinical features of AS based on consensus from a team of specialists managing patients with AS. Working groups were established to address each focus area with committees comprised of providers who manage >5 individuals. Committees developed management guidelines for their area of expertise. These were compiled into a final document to provide a framework for standardizing management. Evidence from the medical literature was also comprehensively reviewed. RESULTS: Areas covered by working groups in the consensus document include genetics, developmental medicine, psychology, general health concerns, neurology (including movement disorders), sleep, psychiatry, orthopedics, ophthalmology, communication, early intervention and therapies, and caregiver health. Working groups created frameworks, including flowcharts and tables, to help with quick access for providers. Data from the literature were incorporated to ensure providers had review of experiential versus evidence-based care guidelines. CONCLUSION: Standards of care in the management of AS are keys to ensure optimal care at a critical time when new disease-modifying therapies are emerging. This document is a framework for providers of all familiarity levels.

Benefits of direct patient discharge to outpatient physical therapy after total knee arthroplasty.

Purpose: To investigate the effectiveness of home health physical therapy followed by outpatient physical therapy as compared to patients discharged directly to outpatient physical therapy in improving functional performance, strength/activation and residual knee pain outcomes among patients who received a total knee arthroplasty.Materials and methods: A secondary analysis of longitudinal data in which patients with total knee arthroplasty underwent home health physical therapy or were discharged directly to outpatient physical therapy. Main outcome measures included the stair climb test, timed up and go, 6-min walk test, quadriceps and hamstring strength, quadriceps activation and residual knee pain.Results: Patients referred to home health physical therapy prior to outpatient physical therapy demonstrated significantly greater declines in stair climb test (10.3; 95% CI [6.5, 14.1]; t = 5.41; p < 0.0001), timed up and go (2.0; 95% CI [1.0, 3.0]; t = 4.10; p < 0.0001), 6-min walk (53.8; 95% CI [29.4, 78.2]; t = 4.35; p < 0.0001), quadriceps strength (21.7%; 95% CI [19.3%, 24.9%]; t = 2.53; p = 0.01), hamstring strength (44.7%; 95% CI [43.4%, 45.7%], t = 3.17; p = 0.002) and higher residual knee pain (0.53; 95% CI [0.04, 1.03]; t = 2.17; p = 0.03) 1 month after total knee arthroplasty compared to those referred directly to outpatient physical therapy.Conclusions: These findings suggest that patients discharged directly to outpatient physical therapy had a more rapid recovery 1 month after total knee arthroplasty. Additional research is needed to investigate the potential causal relation between care pathways and clinical outcomes following total knee arthroplasty.Implications for rehabilitationTotal knee arthroplasty, typically performed to alleviate end-stage knee osteoarthritis, is the most commonly performed elective surgery in the United States.Despite improvement in pain, objective measurements of functional performance and strength often remain at preoperative levels one year after total knee arthroplasty.Patients discharged directly to higher intensity outpatient physical therapy have a more rapid recovery after total knee arthroplasty compared with those patients who received two weeks of home health prior to undergoing outpatient physical therapy.

Functional Mobility Improved After Intensive Progressive Resistance Exercise in an Adolescent With Spina Bifida.

PURPOSE: To describe the use and effectiveness of a novel intensive progressive resistance exercise (PRE) approach to address the functional goals of a 14-year-old adolescent with a myelomeningocele. SUMMARY OF KEY POINTS: The child had lower extremity weakness, knee and hip flexion contractures, impaired somatosensation, and cardiopulmonary deconditioning, affecting gait mechanics and functional ambulation. An 8-week intensive PRE-based intervention was designed to improve walking in the home by targeting both power-generating and stabilizing lower extremity musculature. Secondary intervention focused on cardiopulmonary endurance training. CONCLUSIONS: The child demonstrated improvements in gait speed, walking endurance, and functional lower extremity strength. Knee contracture was moderately responsive to sustained stretching and positioning. WHAT THIS CASE ADDS TO EVIDENCE-BASED PRACTICE: This intensive PRE training approach had been effective for improving function among youth with cerebral palsy, and to our knowledge it had not yet been applied to youth with other neurological conditions.

Performance on a Clinical Quadriceps Activation Battery Is Related to a Laboratory Measure of Activation and Recovery After Total Knee Arthroplasty.

OBJECTIVE: To determine the relation between performance on a clinical quadriceps activation battery with (1) activation measured by doublet interpolation and (2) recovery of quadriceps strength and functional performance after total knee arthroplasty (TKA). DESIGN: Planned secondary analysis of a randomized controlled trial. SETTING: University research laboratory. PARTICIPANTS: Patients (N=162; mean age, 63±7y; 89 women) undergoing TKA. MAIN OUTCOME MEASURES: Patients were classified as high (quadriceps activation battery ≥4/6) or low (quadriceps activation battery ≤3/6) based on performance on the quadriceps activation battery measured 4 days after TKA. Differences between groups in activation and recovery at 1, 2, 3, 6, and 12 months after TKA were compared using a repeated-measures maximum likelihood model. RESULTS: The low quadriceps activation battery group demonstrated poorer quadriceps activation via doublet interpolation (P=.01), greater quadriceps strength loss (P=.01), and greater functional performance decline (all P<.001) at 1 month after TKA compared with the high quadriceps activation battery group. Differences between low and high quadriceps activation battery groups on all measures did not persist at 3 and 12 months (all P>.05). CONCLUSIONS: Poor performance on the quadriceps activation battery early after TKA is related to poor quadriceps activation and poor recovery in the early postoperative period. Patients in the low quadriceps activation battery group took 3 months to recover to the same level as the high quadriceps activation battery group. The quadriceps activation battery may be useful in identifying individuals who need specific interventions to target activation deficits or different care pathways in the early postoperative period to speed recovery after TKA.

Adolescent Changes in Aerobic Fitness Are Related to Changes in Academic Achievement.

There is a growing trend of decreasing physical fitness among adolescents, which may result not only in poorer physical health, but also in poorer academic achievement. PURPOSE: The purpose of this study was to investigate the changes in aerobic fitness and academic achievement in reading and mathematics during middle school. METHODS: This study employed a prospective, longitudinal cross-sectional design. Fifty-two adolescents were followed from sixth grade through eighth grade. In the spring, sixth-, seventh-, and eighth-grade students completed Progressive Aerobic Cardiovascular Endurance Run tests measuring aerobic fitness. In addition, students also completed Illinois Standards Achievement Test academic achievement tests in reading and mathematics. RESULTS: Changes in aerobic fitness between sixth and eighth grade were positively related to changes in academic achievement in both reading and mathematics between sixth and eighth grade. CONCLUSION: These data suggest that changes in aerobic fitness may modulate changes in academic achievement. These findings highlight the importance of physical activity and have broad relevance for educational systems and policies.

Central adiposity is negatively associated with hippocampal-dependent relational memory among overweight and obese children.

OBJECTIVE: To assess associations between adiposity and hippocampal-dependent and hippocampal-independent memory forms among prepubertal children. STUDY DESIGN: Prepubertal children (age 7-9 years; n = 126), classified as non-overweight (<85th percentile body mass index [BMI]-for-age [n = 73]) or overweight/obese (≥85th percentile BMI-for-age [n = 53]), completed relational (hippocampal-dependent) and item (hippocampal-independent) memory tasks. Performance was assessed with both direct (behavioral accuracy) and indirect (preferential disproportionate viewing [PDV]) measures. Adiposity (ie, percent whole-body fat mass, subcutaneous abdominal adipose tissue, visceral adipose tissue, and total abdominal adipose tissue) was assessed by dual-energy X-ray absorptiometry. Backward regression identified significant (P < .05) predictive models of memory performance. Covariates included age, sex, pubertal timing, socioeconomic status (SES), IQ, oxygen consumption, and BMI z-score. RESULTS: Among overweight/obese children, total abdominal adipose tissue was a significant negative predictor of relational memory behavioral accuracy, and pubertal timing together with SES jointly predicted the PDV measure of relational memory. In contrast, among non-overweight children, male sex predicted item memory behavioral accuracy, and a model consisting of SES and BMI z-score jointly predicted the PDV measure of relational memory. CONCLUSION: Regional, but not whole-body, fat deposition was selectively and negatively associated with hippocampal-dependent relational memory among overweight/obese prepubertal children.

Aerobic fitness predicts relational memory but not item memory performance in healthy young adults.

Health factors such as an active lifestyle and aerobic fitness have long been linked to decreased risk of cardiovascular disease, stroke, and other adverse health outcomes. Only more recently have researchers begun to investigate the relationship between aerobic fitness and memory function. Based on recent findings in behavioral and cognitive neuroscience showing that the hippocampus might be especially sensitive to the effects of exercise and fitness, the current study assessed hippocampal-dependent relational memory and non-hippocampal-dependent item memory in young adults across a range of aerobic fitness levels. Aerobic fitness was assessed using a graded exercise test to measure oxygen consumption during maximal exercise (VO2max), and relational and item memory were assessed using behavioral and eye movement measures. Behavioral results indicated that aerobic fitness was positively correlated with relational memory performance but not item memory performance, suggesting that the beneficial effects of aerobic fitness selectively affect hippocampal function and not that of the surrounding medial temporal lobe cortex. Eye movement results further supported the specificity of this fitness effect to hippocampal function, in that aerobic fitness predicted disproportionate preferential viewing of previously studied relational associations but not of previously viewed items. Potential mechanisms underlying this pattern of results, including neurogenesis, are discussed.

Identifying and characterizing the effects of nutrition on hippocampal memory.

In this review we provide evidence linking relational memory to the hippocampus, as well as examples of sensitive relational memory tasks that may help characterize the subtle effects of nutrition on learning and memory. Research into dietary effects on cognition is in its nascent stages, and many studies have cast a wide net with respect to areas of cognition to investigate. However, it may be that nutrition will have a disproportionate effect on particular cognitive domains. Thus, researchers interested in nutrition-cognition interactions may wish to apply a more targeted approach when selecting cognitive domains. We suggest that hippocampus-based relational memory may be extraordinarily sensitive to the effects of nutrition. The hippocampus shows unique plastic capabilities, making its structure and function responsive to an array of lifestyle factors and environmental conditions, including dietary intake. A major function of the hippocampus is relational memory, defined as learning and memory for the constituent elements and facts that comprise events. Here we identify several sensitive tests of relational memory that may be used to examine what may be subtle effects of nutrition on hippocampus and memory. We then turn to the literature on aerobic exercise and cognition to provide examples of translational research programs that have successfully applied this targeted approach centering on the hippocampus and sensitive relational memory tools. Finally, we discuss selected findings from animal and human research on nutrition and the hippocampus and advocate for the role of relational memory tasks in future research.

Dietary lipids are differentially associated with hippocampal-dependent relational memory in prepubescent children.

BACKGROUND: Studies in rodents and older humans have shown that the hippocampus-a brain structure critical to relational/associative memory-has remarkable plasticity as a result of lifestyle factors (eg, exercise). However, the effect of dietary intake on hippocampal-dependent memory during childhood has remained unexamined. OBJECTIVE: We investigated the cross-sectional relation of dietary components characteristic of the Western diet, including saturated fatty acids (SFAs), omega-3 (n-3) fatty acids, and refined sugar, with hippocampal-dependent relational memory in prepubescent children. DESIGN: Participants aged 7-9 y (n = 52) reported their dietary intake by using the Youth-Adolescent Food-Frequency Questionnaire and completed memory tasks designed to assess relational (hippocampal-dependent) and item (hippocampal-independent) memory. Performance on the memory tasks was assessed with both direct (accuracy) and indirect (eye movement) measures. RESULTS: Partial correlations adjusted for body mass index showed a positive relation between relational memory accuracy and intake of omega-3 fatty acids and a negative relation of both relational and item memory accuracy with intake of SFAs. Potential confounding factors of age, sex, intelligence quotient, socioeconomic status, pubertal timing, and aerobic fitness (maximal oxygen volume) were not significantly related to any of the dietary intake measures. Eye movement measures of relational memory (preferential viewing to the target stimulus) showed a negative relation with intake of added sugar. CONCLUSIONS: SFA intake was negatively associated with both forms of memory, whereas omega-3 fatty acid intake was selectively positively associated with hippocampal-dependent relational memory. These findings are among the first to show a link between habitual dietary intake and cognitive health as pertaining to hippocampal function in childhood. The Fitness Improves Thinking Kids (FITKids) and FITKids2 trials were registered at www.clinicaltrials.gov as NCT01334359 and NCT01619826, respectively.

Flexible rule use: common neural substrates in children and adults.

Flexible rule-guided behavior develops gradually, and requires the ability to remember the rules, switch between them as needed, and implement them in the face of competing information. Our goals for this study were twofold: first, to assess whether these components of rule-guided behavior are separable at the neural level, and second, to identify age-related differences in one or more component that could support the emergence of increasingly accurate and flexible rule use over development. We collected event-related fMRI data while 36 children aged 8-13 and adults aged 20-27 performed a task that manipulated rule representation, rule switching, and stimulus incongruency. Several regions - left dorsolateral prefrontal cortex (DLPFC), left posterior parietal cortex, and pre-supplementary motor area - were engaged by both the rule representation and the rule-switching manipulations. These regions were engaged similarly across age groups, though contrasting timecourses of activation in left DLPFC suggest that children updated task rules more slowly than did adults. These findings support the idea that common networks can contribute to a variety of executive functions, and that some developmental changes take the form of changes in temporal dynamics rather than qualitative changes in the network of brain regions engaged.

The eyes know: eye movements as a veridical index of memory.

In two experiments, we examined whether observers' eye movements distinguish studied faces from highly similar novel faces. Participants' eye movements were monitored while they viewed three-face displays. Target-present displays contained a studied face and two morphed faces that were visually similar to it; target-absent displays contained three morphed faces that were visually similar to a studied, but not tested, face. On each trial in a test session, participants were instructed to choose the studied face if it was present or a random face if it was not and then to indicate whether the chosen face was studied. Whereas manipulating visual similarity in target-absent displays influenced the rate of false endorsements of nonstudied items as studied, eye movements proved impervious to this manipulation. Studied faces were viewed disproportionately from 1,000 to 2,000 ms after display onset and from 1,000 to 500 ms before explicit identification. Early viewing also distinguished studied faces from faces incorrectly endorsed as studied. Our findings show that eye movements provide a relatively pure index of past experience that is uninfluenced by explicit response strategies, and suggest that eye movement measures may be of practical use in applied settings.

Comparison of neural activity that leads to true memories, false memories, and forgetting: An fMRI study of the misinformation effect.

False memories can occur when people are exposed to misinformation about a past event. Of interest here are the neural mechanisms of this type of memory failure. In the present study, participants viewed photographic vignettes of common activities during an original event phase (OEP), while we monitored their brain activity using fMRI. Later, in a misinformation phase, participants viewed sentences describing the studied photographs, some of which contained information conflicting with that depicted in the photographs. One day later, participants returned for a surprise item memory recognition test for the content of the photographs. Results showed reliable creation of false memories, in that participants reported information that had been presented in the verbal misinformation but not in the photographs. Several regions were more active during the OEP for later accurate memory than for forgetting, but they were also more active for later false memories, indicating that false memories in this paradigm are not simply caused by failure to encode the original event. There was greater activation in the ventral visual stream for subsequent true memories than for subsequent false memories, however, suggesting that differences in encoding may contribute to later susceptibility to misinformation.

Accurate forced-choice recognition without awareness of memory retrieval.

Recognition confidence and the explicit awareness of memory retrieval commonly accompany accurate responding in recognition tests. Memory performance in recognition tests is widely assumed to measure explicit memory, but the generality of this assumption is questionable. Indeed, whether recognition in nonhumans is always supported by explicit memory is highly controversial. Here we identified circumstances wherein highly accurate recognition was unaccompanied by hallmark features of explicit memory. When memory for kaleidoscopes was tested using a two-alternative forced-choice recognition test with similar foils, recognition was enhanced by an attentional manipulation at encoding known to degrade explicit memory. Moreover, explicit recognition was most accurate when the awareness of retrieval was absent. These dissociations between accuracy and phenomenological features of explicit memory are consistent with the notion that correct responding resulted from experience-dependent enhancements of perceptual fluency with specific stimuli--the putative mechanism for perceptual priming effects in implicit memory tests. This mechanism may contribute to recognition performance in a variety of frequently-employed testing circumstances. Our results thus argue for a novel view of recognition, in that analyses of its neurocognitive foundations must take into account the potential for both (1) recognition mechanisms allied with implicit memory and (2) recognition mechanisms allied with explicit memory.

Neural correlates of fluid reasoning in children and adults.

Fluid reasoning, or the capacity to think logically and solve novel problems, is central to the development of human cognition, but little is known about the underlying neural changes. During the acquisition of event-related fMRI data, children aged 6-13 (N = 16) and young adults (N = 17) performed a task in which they were asked to identify semantic relationships between drawings of common objects. On semantic problems, participants indicated which of five objects was most closely semantically related to a cued object. On analogy problems, participants solved a visual propositional analogy (e.g., shoe is to foot as glove is to...?) by indicating which of four objects would complete the problem; these problems required integration of two semantic relations, or relational integration. Our prior research on analogical reasoning in adults implicated left anterior ventrolateral prefrontal cortex (VLPFC) in the controlled retrieval of individual semantic relationships, and rostrolateral prefrontal cortex (RLPFC) in relational integration. In this study, age-related changes in the recruitment of VLPFC, temporal cortex, and other cortical regions were observed during the retrieval of individual semantic relations. In contrast, age-related changes in RLPFC function were observed during relational integration. Children aged 6-13 engage RLPFC too late in the analogy trials to influence their behavioral responses, suggesting that important changes in RLPFC function take place during adolescence.