Epidural electrical stimulation (EES) applied over the human lumbosacral spinal cord provides access to afferent fibers from virtually all lower-extremity nerves. These afferents connect to spinal networks that play a pivotal role in the control of locomotion. Studying EES-evoked responses mediated through these networks can identify some of their functional components. We here analyzed electromyographic (EMG) responses evoked by low-frequency (2–6 Hz) EES derived from eight individuals with chronic, motor complete spinal cord injury. We identified and separately analyzed three previously undescribed response types: first, crossed reflexes with onset latencies of ~55 ms evoked in the hamstrings; second, oligosynaptic reflexes within 50 ms post-stimulus superimposed on the monosynaptic posterior root-muscle reflexes in the flexor muscle tibialis anterior, but with higher thresholds and no rate-sensitive depression; third, polysynaptic responses with variable EMG shapes within 50–450 ms post-stimulus evoked in the tibialis anterior and triceps surae, some of which demonstrated consistent changes in latencies with graded EES. Our observations suggest the activation of commissural neurons, lumbar propriospinal interneurons, and components of the late flexion reflex circuits through group I and II proprioceptive afferent inputs. These potential neural underpinnings have all been related to spinal locomotion in experimental studies. A growing number of studies have demonstrated that epidural electrical stimulation (EES) can engage spinal neural circuits to enable overground walking in individuals with severe spinal cord injury (SCI) ,2,3,4. CHere, our objective was to explore and characterize non-monosynaptic EMG responses to EES in individuals with chronic, motor-complete SCI with the aim of revealing some of the circuit components potentially mediating the motor effects in functional EES applications. EMG data from lower-extremity muscles evoked by EES at the lowest available stimulation frequencies (2–6 Hz) were analyzed to enable the investigation of responses evoked by individual pulses within continuous trains of stimuli. Using an exploratory approach, we identified three previously undescribed ipsilateral and contralateral oligo- and polysynaptic response types. We then investigated their EMG features and identified characteristic EES amplitude-dependent and rate-sensitive behaviors that were specific to each response type, which suggested candidate neural underpinnings. While these structures cannot be unequivocally unveiled in humans, our data propose the recruitment of commissural neurons, lumbar propriospinal interneurons, and components of the late flexion reflex within circuits that are associated with spinal locomotor activity.Data were derived from eight individuals with a median age  of 25.0 years (21.8–26.5 years) who had been referred to a clinical program for the treatment of lower-extremity spasticity by EES of the lumbar spinal cord . All subEES was applied through percutaneous linear leads  placed in the posterior epidural space  with absolute values >2 were considered to indicate significant deviations from independence.Data were analyzed using Matlab R2019a  and NumPy 1.19.2  for PythEffective EES sites were classified into three categories based on the relative thresholds of PRM reflexes in RF and TS evoked at the lowest programmable stimulation frequencies. Threshold was defined as the lowest EES amplitude that evoked a mean EMG peak-to-peak amplitude ≥50 µV across available responses. The categories were: RF bias, threshold RF < threshold TS, indicating mid-lumbar stimulation; non-selective, threshold RF = threshold TS, lower lumbar stimulation; and TS bias, threshold RF > threshold TS, lower lumbar/upper sacral stimulation . EMG responses to unilateral EES at ~6 Hz in subject 4, recordings 1–3, and subject 7, recording 1, were analyzed within time windows of 0–100 ms following each pulse within the stimulus train. For each electrode setup and EES amplitude, EMG peak-to-peak amplitudes were separately calculated for PRM reflexes occurring within 0–50 ms and for crossed reflexes within 50–100 ms post-stimulus  and the late EMG components of the composite responses (lowest EES amplitude at which a late EMG component was detected based on the Q3 latency) and compared using a paired Student’s t-test. To test for associations between the elicitation of composite TA responses and (i) stimulation site category  as well as (ii) EES amplitudes, categorized into 1.0 × lowest TA response threshold; . Linear mixed models with response groups as fixed factors and subject and recording as random factors were separately run on the onset, offset, and Q3 latencies as well as the numbers of major potential peaks. For the assessment of post-activation depression and low-frequency depression of the monosynaptic PRM reflexes and, separately, of the monosynaptic and the late EMG components of the composite responses, datasets with EES at frequencies of 2 Hz, 5 Hz, 11 Hz, 16 Hz, and 21 Hz derived from subjects 3 and 6–8, one recording each, were available . For post-tests. Responses in RF, TA, and TS to EES at ~2 Hz derived from six subjects, 13 recordings (1–4 per subject), were analyzed within time windows of 0–450 ms post-stimulus  values were calculated for time windows of 0–50 ms, 50–100 ms, 100–150 ms, 150–200 ms and 200–450 ms. To estimate balanced mean values, a generalized linear mixed model with muscle, time window, and EES amplitude category as fixed effects was run on the EMG-RMS values. Nested random effects for subject, recording, limb , and electrode setup were included. The full-factorial dispersion model was estimated to account for heteroscedasticity; a Gamma distribution with a log-link was used. The model was fit using Template Model Builder interfaced through the glmmTMB 1.0.1 for R 4.0.0 . BackwarIn subjects 4 and 7, two percutaneous linear leads were additionally placed left and right to the midline lead during the trial phase of stimulation a. In subp < 0.001, r = 1.000  confirmed the suppression of the crossed reflexes from 245.6 µV (172.8–313.46 µV) at 5.86 ± 0.22 Hz to 8.7 µV (8.0–23.5 µV) at 9.33 ± 0.76 Hz, W = 0.000, p = 0.002, r = 1.0, while the ipsilateral PRM reflexes demonstrated no statistical changes, 1322.5 µV (944.7–2439.2 µV) and 1307.9 µV (541.5–2866.3 µV), W = 26.000, p = 0.922, r = 0.200  = 9.743, p = 0.008, Cramer’s V = 0.176. Non-selective stimulation sites contributed more than expected under the null hypothesis , while TS-bias stimulation sites contributed less than expected . No difference in the observation frequency between composite TA responses and monosynaptic PRM reflexes was found for RF-bias stimulation sites . The mean threshold ± SD of the late EMG components was significantly higher by a factor of 1.8 ± 1.2 than the TA response threshold, irrespective of the response type. Considering all electrode setups resulting in composite TA responses with at least one stimulation amplitude, mean thresholds were 3.8 ± 2.3 V for TA responses and 5.5 ± 2.3 V for the late EMG components, t(167) = −11.173, p < 0.001, r = 0.865. There was a significant association between the elicitation of the late EMG components and the EES amplitude, classified into five categories: 1.0 × TA response threshold;  = 36.796, p < 0.001, Cramer’s V = 0.223. Stimulation at threshold contributed less  and at >3.0 × threshold more  than expected under the null hypothesis. A specific behavior of monosynaptic PRM reflexes is the increase in response size with graded EES amplitudes without changes in characteristic features of their EMG shapes b. They w2(4) = 37.409, p < 0.001, r = 0.225 (p = 0.019); to the .TA responses with late EMG components were generally inconsistently evoked by repetitive stimulation with constant parameters a. Their  = 0.225 b. Post-hnce of 1 c. The men = 728; cf. n = 262; cf. n = 278; cf. p = 0.831, p < 0.001, p < 0.001, p < 0.001). We additionally analyzed the number of major peaks of the EMG potentials and identified response group as significant factor, F = 29.757, p < 0.001, p < 0.001) as well as group 2 . In summary, the composite responses identified by the Q3 latency had monosynaptic onset latencies but featured additional EMG peaks and prolonged offset latencies.For the analysis of temporal parameters , we clasThe late EMG components were never evoked without a preceding monosynaptic PRM reflex and therefore, their onset latencies could not be directly detected in the EMG signals. We estimated their EMG signals by subtracting the averaged EMG waveforms of the monosynaptic PRM reflexes from the composite responses considering datasets with proportional occurrences of 0.1–0.9  at an interstimulus interval of 56 ms. Low-frequency depression of the three response types was investigated for EES frequencies of 5, 11, 16 and 21 Hz  as well as the monosynaptic components of the composite responses  at the two highest frequencies tested. At these frequencies, the late components were rather facilitated.We investigated post-activation depression of the monosynaptic PRM reflexes and, separately, of the monosynaptic and late EMG components of the composite responses (three response categories) tested by paired pulses at interstimulus intervals of 41, 56, 85, 175, and 443 ms  = 45.570, p < 0.001) as well as in TS than RF  = 36.618, p < 0.001). Within all other time windows, EMG-RMS values of both TA and TS were significantly larger than those of RF . Further, EES amplitude category had a significant effect on the RMS-EMG values produced in all three muscles studied within each time window. Within time windows >50 ms, EMG-RMS values of TA either plateaued (50–100 ms and 100–150 ms) or increased (150–200 ms and >200 ms) with graded stimulation, while EMG-RMS values of TS plateaued  or decreased (150–200 ms). 2-Hz EES applied from RF-bias stimulation sites evoked long-latency responses in TA and TS, but not the thigh muscles, with variable EMG shapes and latencies within 50–450 ms post-stimulus a. Data dt(136) = −18.926, p < 0.001. Monosynaptic PRM reflex threshold in TA was 7.3 ± 2.2 V. Thresholds of the long-latency responses were, TA, 5.3 ± 1.8 V, and TS, 4.9 ± 1.8 V, and were significantly lower than those of the respective monosynaptic PRM reflexes, TA, t(110) = −16.870, p < 0.001, and TS, t(136) = −22.750, p < 0.001. The difference between the thresholds of the long-latency TA responses and the monosynaptic PRM reflex in RF amounted to 0.3 ± 0.7 V, yet was significant, t(110) = −5.175, p < 0.001. The mean difference between the thresholds of the long-latency TS responses and the monosynaptic PRM reflex in RF was −0.1 ± 0.9 V and not significant, t(136) = 1.729, p = 0.086. The long-latency responses were elicited in TA with 111 (62.4%) and in TS with 137 (77.0%) of the electrode setups tested. They could be elicited concomitantly in the antagonistic TA and TS  or in one of these muscles only . With the electrode setups leading to the long-latency TA and TS responses, mean thresholds ± SD for the elicitation of monosynaptic PRM reflexes were, RF, 5.0 ± 1.8 V, and TS, 6.9 ± 2.3 V, and were significantly different between these two muscles, While we did not attempt to classify the long-latency responses, two different types could be differentiated by their compelling behavior with graded EES . We idenWe propose that the contralateral Ham responses with onset latencies of ~55 ms were initiated within unilateral, upper lumbar posterior roots and were crossed reflexes. Upper lumbar stimulation sites were documented by the relative PRM reflex thresholds of the L2−L4 innervated RF and the L5−S2 innervated TS , togetheRemarkably, with an increase in EES frequency to ~9 Hz, the crossed reflexes were completely depressed. The absence of attenuation of the monosynaptic PRM reflexes in Ham could have been related to reduced homosynaptic depression at the synapse between group Ia muscle spindle afferents and α-motoneurons following SCI ,40. HomoRecent studies in humans with intact nervous systems identified excitatory crossed actions on background EMG activity of the contralateral Ham. Ipsilateral knee flexion activating proprioceptive afferents from the quadriceps evoked a facilitatory response in the contralateral biceps femoris (BF) with an onset latency of 43.7 ± 7.2 ms during isometric contraction, thought to be induced by group II afferents . HoweverThe rostral EES sites leading to the crossed reflexes as well as the occasional concomitant elicitation of ipsilateral Ham responses with similar latency were reminiscent of findings in animal experiments. In the cat, interneurons located in lamina VIII in the L4−L5 spinal cord segments receive monosynaptic inputs from group I and II afferents and project caudally to the contralateral motor nuclei of Ham located in the L7 segment . AnotherWe propose that the late EMG components of the composite TA responses represented homonymous oligosynaptic reflexes evoked by electrical stimulation of group ll muscle spindle afferents. Compatible with the fact that group II fibers cannot be electrically recruited in isolation from group Ia, the late EMG components never occurred in the absence of a monosynaptic PRM reflex . SeveralWe estimated a delay of 8.0 ms of the late EMG components with respect to the monosynaptic PRM reflex in TA, which is consistent with an oligosynaptic reflex. Previous studies had estimated the central delay of the oligosynaptic group II reflexes in humans to be longer than the monosynaptic transmission by 5.3 ms  and 13.0The composite EMG waveform of the monosynaptic and the late EMG components shared some similarities with the MR and LR evoked by single-pulse EES in hindlimb muscles in normal and spinal rats ,30,31. HNon-monosynaptic group I and group II excitation of human lower-extremity motoneurons, including those of TA, were suggested to be relayed through rostral interneurons located in the upper lumbar spinal cord ,58. TheySimilar observations to which we could directly relate our findings of long-latency responses in TA and TS have not been described in literature to the best of our knowledge, hence we can only speculate about their neural underpinning. Thresholds of the long-latency responses were significantly lower than those of the monosynaptic PRM reflexes in the same muscle. At the same time, relative thresholds of PRM reflexes in RF and TS suggested that stimulation sites were located close to the L2−L4 posterior roots . FurtherThe long latencies could not be explained by reafferent inflow following a previous muscle contraction ,62 as thA striking characteristic of two types of long-latency responses cf.  was the The facilitation of walking function by EES applied below a (near-) complete lesion in previous studies had suggested the recruitment of locomotor-related spinal neural circuits through proprioceptive afferent projections in humans. Here, previously undescribed lower-extremity muscle responses evoked by single pulses of low-frequency EES revealed the activation of neural circuits, all of which could be components linked to spinal locomotor control. Our data suggested the recruitment of specific pathways mediating the crossed reflex in Ham and the oligosynaptic reflex in TA, respectively, as well as of more complex sets of circuits involved in the long-latency activation of TA and TS. Common to all response types was their initiation within lumbar proprioceptive afferents and the mediation of their activity, most likely through upper lumbar interneurons, including those connecting the two halves and different segments of the spinal cord. Increasing use of EES in investigational studies will not only continue to shift the boundaries of functional recovery to levels previously deemed impossible, but will also provide new approaches to further delineate the neural mechanisms underlying locomotor control in humans.


Cerebral palsy is the most common physical disability of childhood, but the rate is falling, and severity is lessening. We conducted a systematic overview of best available evidence (2012–2019), appraising evidence using GRADE and the Evidence Alert Traffic Light System and then aggregated the new findings with our previous 2013 findings. This article summarizes the best available evidence interventions for preventing and managing cerebral palsy in 2019.Effective prevention strategies include antenatal corticosteroids, magnesium sulfate, caffeine, and neonatal hypothermia. Effective allied health interventions include acceptance and commitment therapy, action observations, bimanual training, casting, constraint-induced movement therapy, environmental enrichment, fitness training, goal-directed training, hippotherapy, home programs, literacy interventions, mobility training, oral sensorimotor, oral sensorimotor plus electrical stimulation, pressure care, stepping stones triple P, strength training, task-specific training, treadmill training, partial body weight support treadmill training, and weight-bearing. Effective medical and surgical interventions include anti-convulsants, bisphosphonates, botulinum toxin, botulinum toxin plus occupational therapy, botulinum toxin plus casting, diazepam, dentistry, hip surveillance, intrathecal baclofen, scoliosis correction, selective dorsal rhizotomy, and umbilical cord blood cell therapy.We have provided guidance about what works and what does not to inform decision-making, and highlighted areas for more research.The online version of this article (10.1007/s11910-020-1022-z) contains supplementary material, which is available to authorized users. Cerebral palsy is the most common physical disability of childhood. In the last decade, major discoveries have been made in early diagnosis, prevention, and treatment, altering incidence, prognosis, and treatment responsivity. In high-income countries such as Australia, motor severity has lessened and the incidence of cerebral palsy has fallen by a staggering 30% . Non-ambIn recent years, the cerebral palsy treatment evidence base has continued to expand rapidly, providing clinicians and families with the possibility of newer, safer, and more effective interventions. Since we last provided a comprehensive summary of the cerebral palsy intervention evidence in 2013, another 200+ systematic reviews have been published .This paper aimed to systematically describe the best available evidence for cerebral palsy interventions in 2019. We searched for the best available evidence published after 2012 and aggregated the new findings with our previous 2013 summary of evidence, using the updated GRADE system and the Evidence Alert Traffic Light System , 6. The We conducted a systematic overview of best available evidence using the systematic review of systematic reviews methodology in order to provide an overview of the current state of the evidence .www.cochrane.org]; EMBASE (2012 to 2019); ERIC (2012 to 2019); PubMED (2012 to 2019), PsycINFO (2012 to 2019), MEDLINE (2012 to 2019), OTSeeker [www.otseeker.com]; Physiotherapy Evidence Database (PEDro) [www.pedro.fhs.usyd.edu.au]; Psychological database for Brain Impairment Treatment Efficacy (PsycBITE) [www.psycbite.com]; PsycINFO (1935 to 2012); PubMED; and Speech Pathology Database for Best Interventions and Treatment Efficacy (speechBITE) [www.speechbite.com]. We sought to update and amalgamate the findings of our 2013 original paper , any topography , and any functional ability level . IThe main results are detailed in the online table, which outlines the citation, the name of the intervention, the intervention indicator, the types of participants the intervention had been tested on, the dose/intensity used within the research studies, the GRADE ratings, the panels reflections on the evidence to decision recommendation process, and the clinical nuance of findings and considerations for interpretation. We strongly urge readers to read the detailed online resource to gain the necessary specifics for understanding the evidence base.y-axis of the graph corresponds to the GRADE system rating and estimate of effect . The color of the circle correlates to the Evidence Alert System  only; size 2, 1–3 RCTs; size 3, 4–15 RCTs; and size 4, 15+ RCTs. The location of the circle on the High levels of evidence exist in the literature summarizing effective preventive strategies and intervention options for children with cerebral palsy. There was an exponential increase in the number of systematic reviews and clinical trials published about cerebral palsy interventions since our last review. We observed a substantial increase in the number of systematic reviews published about acupuncture, pharmacological agents for managing tone, orthopedic surgery, dysphagia management, physical activity, participation, and clinical trials in regenerative medicine.Undoubtedly, the most notable breakthroughs in the field of cerebral palsy research in the last decade have been made in the area of prevention ••, 12–18In recent years, our understanding of the genetic basis for cerebral palsy has advanced substantially . A genetThe field has also started to critically examine whether repair of a brain injury might be possible using regenerative medicine treatments, paving the way towards finding a cure. Our review found that erythropoietin has promising effects as a neuro-regenerative treatment in the preterm population  and erythropoietin trials are underway in a population with hypoxic ischemic encephalopathy ••. In adAn intervention may target multiple desirable treatment outcomes, e.g., reduction of spasticity and improvement in function, and thus outcomes and levels of evidence could vary between outcomes. For most instances, the treatment outcome matched with the appropriate mechanism of action, e.g., pharmacological agent to reduce spasticity effectively reduced spasticity. There was often less convincing evidence  to support upstream effects for other treatment outcomes for other levels of the ICF, e.g., improvement in functional mobility. These are not surprising results; however, they provide an important reminder to clinicians to select interventions that address a child’s specific goal based on the intervention’s mechanism of action. Also, to be cognizant that applying more than one intervention simultaneously might be beneficial to achieve a goal where multiple goal-limiting factors are present. If the goal is to improve functional mobility: a pharmacological agent to reduce background spasticity (green light)  might maAll children with cerebral palsy have, by definition, a motor impairment and difficulties with tasks involving motor performance . In highThere are also several adjunctive interventions that when combined with task-specific motor training may augment the positive effects of training. These include electrical stimulation , 92–94, The available studies about complementary and alternative medicine interventions for childhood cerebral palsy aimed to improve motor skills. Trials suggested efficacy with acupuncture , 228 andEighty-five percent of children with cerebral palsy have spasticity as their primary motor type and 7% have dyskinesia (including either dystonia or athetosis) as their primary motor type . Many chAgainst the backdrop of spasticity management, there is a now an intense research focus on improved understanding of pathology, histochemistry, and muscle architecture in cerebral palsy . ChildreContracture is a common complication, particularly for children with spastic cerebral palsy. A longitudinal population-based study in Sweden has demonstrated that comprehensive multidisciplinary intervention at the right time can prevent contracture . Contrachttps://www.ausacpdm.org.au/resources/australian-hip-surveillance-guidelines/).One in three children in high-income countries experience progressive hip displacement as a complication of their cerebral palsy, except in the Nordic countries where rates are substantially lower , 262. ThPhysical activity is essential for improving health but designing and implementing moderate to vigorous exercise programs for children with severe physical disabilities, who have limited movement and move slowly, is complex . RecommeWe observed a shift in interventions that affected a child’s participation within their community. Most importantly, we noticed that interventions had been developed since 2013, which were specifically designed to target participation, and address barriers that prohibit participation and their effects were being studied in trials underway . In otheHalf of all children with cerebral palsy have dysphagia and the prevalence is even higher in the infant population . One in Rates of cerebral palsy following prematurity, encephalopathy, and neonatal surgery are well understood. It is now possible to accurately detect and diagnose cerebral palsy as early as three months of age (corrected), enabling much earlier intervention . PreviouIn contrast, the feasibility and preliminary efficacy trials of a novel parent coaching-based approach (COPCA) disappointingly did not confer any gains over and above passive neurodevelopmental therapy within traditional physiotherapy  –90. LikeAlmost half of all children with cerebral palsy have co-occurring intellectual disability (46%) of varying severities, but notably, the prevalence of this comorbidity declining , 2, 262.Another innovation has been to test the feasibility, acceptability, and preliminary efficacy of a cognitive-based intervention known as cognitive orientation to occupational performance (CO-OP) . CO-OP wParenting a child with cerebral palsy is known to be isolating and stressful. Supporting parents is essential both to optimize the child’s development and to protect a parent’s mental health. We observed that two interventions for parents of children with cerebral palsy, stepping stones triple P and acceptance and commitment therapy (ACT), now have empirical evidence of effectiveness (green lights) . SteppinThis paper is not the personal opinions of the authors; instead, it is a summary of the best available published evidence in 2019. This paper does not, therefore, invalidate observations of a child’s response to interventions, even if they differ to average treatment responses measured in trials. Furthermore, it does not seek to criticize therapy choices of families or critique health care providers. Where evidence is not available, more well-designed trials are necessary. As cerebral palsy is a heterogeneous condition, the interpretation of the results from randomized controlled trials is complex.n of 1 trial may accommodate the issue of heterogeneity.Randomized controlled trials by their nature summarize the average response to an experimental treatment compared with that of a controlled comparison. In any given trial or real-world clinical scenario, an individual with cerebral palsy may respond better, or worse, than the average trial data. Heterogeneity is why many of the included trials have wide confidence intervals, indicating varied responses. We observed that often the trials with most robust treatment effects focused on homogeneous sub-groups of cerebral palsy . In the future, alternative methodologies such as the To use the findings of this paper within clinical practice, we recommend the following: First, ask the child and family to define intervention goals. Second, match their goals to the outcome indicator headings and look up the corresponding intervention options with the associated levels of evidence. Third, select the intervention with the highest level of evidence and explain to families that on average, X intervention is most likely to help someone achieve their goals, and offer it. Monitor the individual effects of the intervention for the goal. Fourth, if the intervention is ineffective or unavailable, or the family declines , select the second most effective intervention and explain that on average, Y intervention is next most likely to help reach goals. Continue with this transparent conversation, compassionately acknowledging the disappointment if the child does not respond. Collectively problem solve a plan that matches the child’s capabilities and optimizes inclusion.Augmentative and Alternative Communication) due to participant numbers not reaching the required threshold. Some of the studies included in the reviews have reported on cerebral palsy but that may not be the primary outcomes of those studies.Our study has several limitations. First, a systematic review of systematic reviews is a study limitation in its own right because the methodology does not create any new knowledge that was not already published. In addition, the methodology of systematic reviews established by Cochrane favors the inclusion of randomized controlled trials, which may mean important observational studies are excluded or under-emphasized. Second, any summary lacks key details. Our helicopter view synthesis means that specific details about intervention fidelity, key ingredients, and best responders or non-responders are not reported or described in depth. We therefore advise clinicians and researchers to read additional literature to obtain this information, especially when adopting new interventions not previously used. Third, systematic reviews, despite being the highest level of evidence, are not without bias. Even though our review aimed to be unbiased, it included inherent biases. Publication bias may be at work within the included data we appraised, since trials with no between-group differences are less likely to be published in the first place, positively weighting the evidence base towards interventions that work. In addition, systematic reviews can be of varying methodological quality. Review authors may elect to include and review lower level evidence within their reviews to provide a more comprehensive picture of the evidence, but in doing so, provide a summary of highly biased data. We then have further summarized potentially biased data. The review authors may also have excluded relevant data, based on their inclusion criteria and the question they were seeking to answer. Fourth, in some of the included systematic reviews, we identified statistical errors, which we reinterpreted or reanalyzed where possible. For example, an accidental reversal of forest plots meaning the analysis was the opposite of the way the authors reported it. Another example was a misinterpretation of meta-analyses, where the confidence intervals around the standardized mean difference crossed the line of no effect, but the authors had made their interpretations based on the standardized mean difference alone and erroneously interpreted the intervention as effective. Fifth, despite our thorough search strategy, there is no guarantee that we retrieved and included all relevant systematic reviews, or important data published after the included reviews that might have changed our confidence in the estimate of the effects. Sixth, as we excluded articles not published in English and adhered to strict inclusion criteria regarding % of participants identified as having cerebral palsy, we may have overlooked important data and/or excluded recent reviews exploring relevant, non-CP-specific interventions  to effective (green): Botulinum toxin plus adjunctive casting for increasing range of motion; goal-directed training for improving gross motor skills; hippotherapy for increasing symmetry; stepping stones triple P for improving child behavior; and strength training for improving muscle strength. There is a lack of robust clinical efficacy evidence for a large proportion of the interventions in use within standard care for people with cerebral palsy, and more research would increase our confidence in the estimate of effect. Thus, we have highlighted the need for more research using rigorous methodologies to advance the evidence base about interventions for cerebral palsy, to better inform decision-making by families and clinicians.ESM 1(PDF 1569 kb)


Active design is an emerging concept to incorporate physical activity into daily life through thoughtful design, and is often implemented in new building designs. It is, however, not known what evidence base there is to support the claims. Through this systematic review, the current evidence for active design was investigated. Seven databases were searched. A range of search terms relating to active design, physical activity, sitting, performance and wellbeing were used. After title and abstract screening of 1174 papers and full-text screening, 17 were selected for inclusion. The papers provided promising evidence of active design aiding a reduction in sitting and increase in standing time. Limited evidence was found for physical activity; a few studies reported an increase in step counts. Musculoskeletal effects were investigated in few studies, but there is some evidence of benefits to lower back pain. There was consistent evidence for better light and air quality, but no evidence for other features of the workplace environment. No conclusive evidence was found on associations between active design features and work performance. There is hence some evidence to support the benefit of active design on physical health; however, the dearth and heterogeneity of the study designs, measures and findings warrant further research. Physical activity has great proven benefits to physical and mental health. Conversely, physical inactivity has been recognised as a significant risk factor for obesity, chronic disease and premature death ,2. A recHowever, excessive sitting has also emerged as a related risk factor for ill health and mortality ,5. Both Workplace health promotion activities targeting physical activity have typically focused on work-based exercise and wellness programs and ergonomic furniture , such asThe concept of active design is a holistic approach that incorporates the structural design elements necessary for promoting physical activity and wellbeing, as well as the policies, workplace cultures, work styles and personal factors that promote these, in line with ecological models ,16. The Active design hence works on the basis that behaviour can be influenced at an individual and population level by altering the environments within which people make choices (choice architecture). Choice architecture can be broadly defined as the organisation or presentation of options to help people make decisions, and thus may accomplish two things: it may make it easier for the user/building occupant to navigate complex choices, but it may also influence the choices they make. It is proposed that interventions, such as thoughtful design, provision and placement of stairs, kitchens and end of trip facilities typically require little conscious engagement on the part of the individual to realise their intended effects, mainly working via automatic or non-conscious psychological processes ,19,20.Active design is a relatively new concept and it is not clear how much is known about its impact on health- and work performance-related outcomes. The implementation of active design is in many cases a large investment, but can also have the potential to be applied to many occupants and visitors. As an emerging field with possible implications for public health, efforts must be made to continue to support active design with scientific evidence, such that a strong case can be made to governments and the private sector to broaden its implementation.In order to chart the state of evidence for active design on healthy behaviour, wellbeing and work performance in the workplace, I performed a systematic review, presented in the following sections on this paper.A rapid literature review was conducted in September 2016 to examine the feasibility of the research question: “Can active building design support increased physical activity and reduced sitting at work, and how does it impact on worker wellbeing and productivity?” A small evidence base was found to support suggestions that active design could support less sitting and more movement in offices, with uncertain impacts on wellbeing and productivity. A comprehensive search strategy was carried out in December 2018 for the purposes of this systematic review. Systematic review registration number: PROSPERO CRD42016048165.www.covidence.org), in which title and abstract screening, followed by full-text screening by two reviewers were conducted.The author searched Scopus, Pubmed, CINAHL, Business Source Ultimate, ProQuest Central, PsycInfo, Web of Science and Cochrane Library. This set of databases was selected to ensure a wide search across disciplines. The search results were collated into an online systematic review platform, Covidence (Search terms used in the systematic review can be found in Inclusion criteria for the studies were human studies (children or adults); English language papers; intervention or exposure involving the built indoor environment; intervention or exposure in a workplace or educational building; outcome(s) involving perceived or actual physical activity, movement, sitting, health, well-being, productivity or other factors relating to work performance; all study types ; and full-text paper available. Exclusion criteria were non-human subjects; not in English; intervention or exposure in residential buildings only; intervention or exposure involving only behavioural elements ; intervention or exposure involving only ergonomic furniture ; intervention or exposure involving only the outdoor built environment; intervention or exposure involving only open-plan office design, activity-based working design or green design, without genuine active design elements; papers with no documented intervention or exposure; papers with no documented outcomes; and full-text paper not available.www.prisma-statement.org). A total of 1174 articles were added to Covidence for title/abstract screening, of which 1087 were deemed irrelevant; 5 additional papers were found through citation review, leaving 92 articles for full-text screen. Of these 92 articles, 75 articles were excluded at full-text screen by two independent reviewers, due to the full-text not being available (3 articles); irrelevant intervention (54 articles); and no or irrelevant outcomes (17 articles); protocol paper (1 article)—leaving 17 for data extraction.Data extraction included summarising the study design, population, intervention(s) or exposure(s), outcome(s), exposure and outcome measures, overall results and practical implications. These results were categorized by the outcome measured and are presented descriptively below.Quality assessment was done using a checklist developed specifically for this review, with elements taken from the National Heart, Lung and Blood Institute (NIH) Quality Assessment Tools for Before–After (Pre–Post) Studies  and ObseSeventeen  studies Seven pre–post studies were found ,27,28,39Seven cross-sectional analytic studies employing mixed method approaches were found, with four investigating the impacts of stair and elevator design ,33,34,36Three qualitative studies were included, with two investigating employee attitudes toward sitting reduction strategies, including elements of active design ,38, and There is evidence for beneficial effects on standing and sitting, with four of the studies reporting beneficial effects on standing time (increase) ,26,28,39From this review there is inconclusive evidence that active design buildings are related to higher overall physical activity. Two studies by Engelen et al. ,26 used In contrast, findings from one cross-sectional study, in which 99 university staff across three buildings wore accelerometers for a working week, indicates the beneficial effects of active design buildings on occupants’ MVPA and step counts , althougTwo cross-sectional studies that focused on stair use found increased stair use when the stair wells were accessible and well lit ,36. BassNicoll et al. (2009)  also repA study using a variety of qualitative and quantitative methods to investigate the impact of layout on collaboration of scientists in two university research buildings, found that researchers were more likely to move if spaces were well-integrated and easily visible via thoughtfully designed corridors . SimilarOne study conducted semi-structured interviews with 20 employees and managers from a range of industries , and theOnly two studies, both by Engelen and colleagues ,26, asseThere is some evidence that aspects of work performance and health were positively related with active design buildings. Data suggests positive effects on finding work motivating and looking forward to going to work ,26, but Four studies, three pre–post studies ,25,26 anImproved perceptions of air quality and light in the new building were fairly consistent across the studies. Engelen et al. (2017)  found imIn this systematic review on the evidence of active design strategies’ influence on health and work performance measures in the workplace, 17 papers were identified that met the inclusion criteria. This relatively low number is not surprising, given the emerging nature of the topic. There is good evidence for sitting and standing. Consistent evidence that active design strategies increase standing and reduce sitting during the workday was found throughout the studies. Given the emphasis on stair design in these buildings, it is surprising that the pre–post studies did not report increased stair use; however, the cross-sectional studies generally found positive associations between improved stair design and stair use.The evidence for increased walking or stepping in active design buildings was inconclusive in the present review, with the one study that found evidence for increased walking  attributThe research revealed paradoxical impacts of active design strategies, such as an unexpected increase in workers identifying as disabled when moving to a building with a skip–stop elevator , and theOnly a small number of studies reported productivity or motivational outcomes; some positive effects on finding work motivating and looking forward to going to work were found, but not much evidence for effects on work performance. A previous study by Dole and Schroeder (2001) stated that, in the workplace, it is often assumed that employees who are more satisfied with the physical environment are more likely to produce better work outcomes . This waper se [There was consistent evidence for perceived better light and air quality in active design buildings, but no evidence for other features. This outcome is likely more related to the buildings being relatively new and fresh, rather than the active design strategies per se . Howeverper se ; hence, The built structures alone may not change behaviours of its users ,48. To bAs some managers identified in one qualitative study ; it is nThis systematic review highlights the multitude of disciplines that study active design for various reasons. The diversity of disciplines conducting and reporting on active design settings and its effects is a strength in this field, but this also raises a number of issues that make it hard to draw solid conclusions based on the studies included for review. One challenge is the variation in research methods due to the nature of the multidisciplinary backgrounds of researchers investigating active design. While more rigorous scientific methods including pre–post-studies with comparison groups may generate usable evidence, such studies are often limited in scale. In comparison, post-only studies involving large samples, common to the architecture and corporate property fields, may provide more generalisable data, but with weaker evidence of causality . Other studies just assess the use and implementation of active design, and provide process measures, but not evidence of actual impacts. For these reasons, cross-disciplinary reviews have challenges in reaching clear conclusions, and this is a limitation of the current review.While some studies used objective outcome measures, such as accelerometers and handrail sensors, there was a general reliance upon subjective self-reported outcome measures, which may have reduced validity of the results and introduced bias. Generalisability may be limited by the high proportion of studies conducted in academic or research buildings, and an absence of studies involving blue-collar workers.A limitation of this review was that the search methods may not have uncovered the full evidence base, due to exclusion of non-English studies, review of a finite number of databases and a decision to not actively contact researchers to request unpublished papers.Based on the outcomes of this review, it is evident that a number of gaps in the literature around active design exist, and especially the lack of objective measures and of evidence on health and work performance effects. Going forward, future studies should attempt to measure a range of outcomes across a variety of settings. To progress with strengthening the evidence base, further emphasis should be placed on using consistent and appropriate evidence-generating research methods and designs across disciplines, to ensure comparability. Health outcomes need to be more specific than “overall health”, to tease out if the effects are physical, mental or whether they are a reflection of the organisation.Active Design is a recent concept and is often incorporated in many new office building designs. It has some proven and a range of other potential benefits for health, wellbeing and productivity. The evidence base for active design is limited, although at this stage the evidence to support the benefit of active design on sitting, standing, step count and musculoskeletal issues seems quite convincing. The range of studies is often characterised by non-comparable measures, but this is reflective of real-world settings. The implementation of active design is often accompanied by significant investments, both in terms of time and planning as well as finance. It is therefore important to support claims of efficacy with further evidence to ensure the best investments for public health are made. Future research to build the evidence base of the effects of active design on health, perceptions and productivity is warranted.