Real-time gait biofeedback is a promising rehabilitation strategy for improving biomechanical deficits in walking patterns of post-stroke individuals. Because wearable sensor technologies are creating avenues for novel applications of gait biofeedback, including use in tele-health, there is a need to evaluate the state of the current evidence regarding the effectiveness of biofeedback for post-stroke gait training. The objectives of this review are to: (1) evaluate the current state of biofeedback literature pertaining to post-stroke gait training; and (2) determine future research directions related to gait biofeedback in context of evolving technologies. Our overall goal was to determine whether gait biofeedback is effective at improving stroke gait deficits while also probing why and for whom gait biofeedback may be an efficacious treatment modality. Our literature review showed that the effects of gait biofeedback on post-stroke walking dysfunction are promising but are inconsistent in methodology and therefore results. We summarize sources of methodological heterogeneity in previous literature, such as inconsistencies in feedback target, feedback mode, dosage, practice structure, feedback structure, and patient characteristics. There is a need for larger-sample studies that directly compare different feedback parameters, employ more uniform experimental designs, and evaluate characteristics of potential responders. However, as these uncertainties in existing literature are resolved, the application of gait biofeedback has potential to extend neurorehabilitation clinicians' cues to individuals with post-stroke gait deficits during ambulation in clinical, home, and community settings, thereby increasing the quantity and quality of skilled repetitions during task-oriented stepping training. In addition to identifying gaps in previous research, we posit that future research directions should comprise an amalgam of mechanism-focused and clinical research studies, to develop evidence-informed decision-making guidelines for gait biofeedback strategies that are tailored to individual-specific gait and sensorimotor impairments. Wearable sensor technologies have the potential to transform gait biofeedback and provide greater access and wider array of options for clinicians while lowering rehabilitation costs. Novel sensing technologies will be particularly valuable for telehealth and home-based stepping exercise programs. In summary, gait biofeedback is a promising intervention strategy that can enhance efficacy of post-stroke gait rehabilitation in both clinical and tele-rehabilitation settings and warrants more in-depth research. Biofeedback is a process by which an external stimulus derived from previously covert physiological or motor performance data is provided to an individual in real time to induce self-modification of a behavior –6. AppliStroke is a leading cause of adult disability and a majority of stroke survivors present with post-stroke gait dysfunction resulting in compromised community participation and quality of life , 12–14. While there is little research on barriers limiting clinical use of biofeedback, costly and cumbersome equipment combined with a lack of research consensus may be contributing factors. However, technological advances, including the evolution of wearable sensors, may resolve the former problem and serve to make biofeedback gait training a more realistic intervention choice for clinicians . An addiTherefore, the objectives of this review are 2-fold: (1) to evaluate the current state of biofeedback literature that pertains to post-stroke gait training; and (2) to determine future research directions related to gait biofeedback with a special focus on application of new technologies. To achieve these objectives, the literature search was designed to include multiple feedback modes, target parameters for gait retraining, and methods of post-stroke gait biofeedback as possible, with the intent to synthesize our current knowledge regarding the methodological parameters and effects of post-stroke gait biofeedback, while also outlining areas for future research.This literature review categorizes the factors that influence the efficacy of biofeedback as a gait training intervention for post-stroke individuals and identifies knowledge gaps in the evidence landscape. The literature review included searches of databases, including PubMed and PEDro. All articles available on PEDro were categorized based on their PEDro score. The following search terms were used in PubMed:  AND (“stroke rehabilitation”[tw] OR “Stroke Rehabilitation” [Mesh] OR “Stroke/rehabilitation” [Mesh]) AND  AND English[lang] AND (“1970/1/1”[Date - Publication]: “2020/4/1”[Date - Publication]) NOT .All articles that appeared in the initial database search were evaluated for relevance by author JS. Randomized Control Trials (RCTs) scoring >6/10 on the PEDro scale were given preference. Because our goal was to capture a wide variety of experiment designs lower scoring RCTs and non-RCTs were also included if they used unique or rigorous methodology. Articles exclusively involving biofeedback provided during static standing or marching in place as well as provided in conjunction with robotic gait training were excluded.We were unable to find systematic reviews specifically addressing biofeedback for post-stroke gait rehabilitation, although two reviews covered somewhat related topics and merit mention. Woodford and Price  performeWhile there have been a few literature reviews on biofeedback as a rehabilitation modality, previous work has not focused exclusively on stroke as a neuropathology and biofeedback as a basis for specifically targeting gait deficits. Because a goal of the current review was to capture a wide variety of potential methods for providing biofeedback during post-stroke gait retraining, our inclusion criteria that relate to quality and study design are broader, including both RCTs and non-RCTs, with the intent of evaluating a greater number of studies Previously, Tate and Milner  identifiThere are fewer studies from which conclusions can be drawn using other forms of gait biofeedback. Morris et al.  and BasaKinetic biofeedback most commonly involves the use of force sensors placed either in the shoe or embedded within the surface over which the individual is ambulating, such as the floor or a treadmill. Sungkarat et al.  and a piIn summary, a review of previous biofeedback studies reveals that multiple target gait parameters have been utilized with the goal of improving post-stroke gait impairments with mixed results. Several additional methodological factors discussed in subsequent subsections can impact the efficacy of gait biofeedback.via surface electrodes, has been studied in conjunction with wearable plantar force sensors , Afzal et al. . In repeated measures study  and feedback schedule  are important factors impacting the magnitude of locomotor learning ; yet fewThere is little research evaluating the effect of dosage on gait biofeedback training. In fact, “dose” is often an ill-defined a term in stroke rehabilitation studies . Here, dBernhardt et al. outlined the chronological stages of stroke recovery from a rehabilitation perspective as follows: hyper acute 0–24 h), acute (1–7 days), early subacute (7 days to 3 months), late subacute (3–6 months), and chronic (>6 months) . The maj4 h, acutThe severity of sensorimotor deficits of stroke participants is another source of variability between studies . BecauseDue to the varied and often conflicting nature of evidence, more research is needed to prove the efficacy of gait biofeedback for post-stroke individuals , 4. HoweOur review of previous literature provides several indications of where to begin such future investigations. First, modes of feedback and target parameters could be compared directly across multiple patient populations. Second, motor learning strategies, such as faded feedback or variable practice structure, could be tested against more conventional procedures for the application of biofeedback. Third, greater efforts should be made to identify characteristics of responders and non-responders. Fourth, studies aimed at evaluating dose-response relationships are needed. Fifth, large-sample RCTs are needed, especially for stroke survivors in more acute stages of recovery to compare the relative efficacy of biofeedback for different stages of recovery.As is true for a majority of neuro-rehabilitation treatments, the efficacy of biofeedback as a gait training intervention stands to benefit from a better understanding of the underlying neurophysiological, biomechanical, and motor learning mechanisms of gait biofeedback. There is a research gap related to short-term and long-term changes in cortical and spinal circuitry following gait biofeedback interventions. As an illustration of a study exploring both the biomechanical and neural processes of gait biofeedback, Pietrosimone et al.  demonstrBased on the review of previous research, our long-term vision is that cumulative evidence derived from a series of mechanism-focused and translational gait feedback studies will facilitate the development of clinical prediction rules or decision-making guidelines for more effective and individualized rehabilitation of post-stroke walking function. Completing the studies needed to systematically and individually delineate the multiple variables affecting the success of biofeedback gait training may be time consuming, but the efforts involved would be outweighed by the potential reward of one or more highly effective biofeedback interventions that can later leverage novel wearable sensor technologies.via portable, non-obtrusive, non-restrictive, user-friendly sensor units on their person, enabling decrease in the cost and increase in the usability of gait biofeedback , feedback modes , practice structure, dosage, and patient characteristics. Based on our analyses of the gaps in the previous research, we suggest that more favorable and conclusive evidence supporting gait biofeedback can be achieved if larger-sample studies are conducted to directly compare different feedback parameters, employ more uniformity in experimental design, and evaluate patient characteristics of potential responders. The cumulative research evidence gained from an amalgam of mechanism-focused and clinical research will yield clinical prediction rules and decision-making algorithms for optimization of gait biofeedback parameters. Wearable sensor technologies have the potential to transform gait biofeedback and provide greater access and wider array of options for the clinicians while lowering costs. Sensing technologies will be particularly valuable for telehealth and home-based stepping exercise programs. High-quality, portable, user-friendly gait biofeedback systems will provide patients with clinician-determined cues regarding gait performance resulting in a greater number of high-quality repetitions during walking practice. In summary, gait biofeedback has strong potential as a post-stroke gait training tool and warrants further research.JS developed the manuscript draft, conducted the review of literature, and summarized the findings of the review. SW was involved in editing and finalizing the manuscript. TK assisted JS with the literature review, conceptualized the study, and was involved with editing and finalizing the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Due to social distancing and isolation recommendations, COVID-19 resulted in older adults’ greater reliance on technology to contact friends and families. While the mental health of older adults during COVID-19 has been well explored, less is known about how changes in modes and frequency of social contact is associated with loneliness. Using the National Health and Aging Trends Study COVID-19 data, this study assessed how the frequency of varying modes of contact  during the pandemic was associated with feelings of loneliness during COVID-19 among community-dwelling Medicare beneficiaries (n = 2149). Participants were asked if they felt lonely "more often," "less often," or "about the same" compared to before the outbreak started. Multinomial regression analyses indicated that, compared to those who reported daily in-person visits, the odds of having more feelings of loneliness as compared to about the same as pre-COVID-19 was significantly higher among those who reported having in-person visits a few times , at least once , and never/less than once a week  while controlling for demographics, household, and social network size. Compared to daily use, use of phone/email/text at least once  or a few times  a week was associated with lower odds of reporting more feelings of loneliness versus about the same. Results suggest that greater use of technology that promote social engagement improves social connectedness and decreases COVID-19 related loneliness among older adults, and highlights the importance of older adults’ access to technology, including reliable internet.


Perioperative neurocognitive disorder (PND) frequently occurs in the elderly as a severe postoperative complication and is characterized by a decline in cognitive function that impairs memory, attention, and other cognitive domains. Currently, the exact pathogenic mechanism of PND is multifaceted and remains unclear. The glymphatic system is a newly discovered glial-dependent perivascular network that subserves a pseudo-lymphatic function in the brain. Recent studies have highlighted the significant role of the glymphatic system in the removal of harmful metabolites in the brain. Dysfunction of the glymphatic system can reduce metabolic waste removal, leading to neuroinflammation and neurological disorders. We speculate that there is a causal relationship between the glymphatic system and symptomatic progression in PND. This paper reviews the current literature on the glymphatic system and some perioperative factors to discuss the role of the glymphatic system in PND. Perioperative neurocognitive disorder (PND), which encompasses delirium and postoperative cognitive dysfunction, commonly occurs in the elderly after anesthesia and surgery. Previously, all forms of postoperative cognitive impairments were called “postoperative cognitive dysfunction,” but more recently, the use of “perioperative neurocognitive disorder” is recommended as an overarching term for cognitive impairment identified in the preoperative or postoperative period  combined with xylazine (20 mg·kg−1) significantly increased the influx of the CSF tracer in all mice analyzed  inhibited CSF circulation and waste clearance in the brain  is another αPropofol is a widely used intravenous anesthetic in humans with anti-inflammatory (Ren et al., Interestingly, these animal studies on glymphatic dysfunction agree with those of clinical studies on PND. Anesthetics are a risk factor for postoperative cognitive decline or neuropathological changes (Schenning et al., The mechanisms that regulate glymphatic function under normal physiological conditions include arterial pulsatility, respiration, and neural activity. However, these mechanisms may be disrupted during anesthesia, including general anesthesia and spinal anesthesia Scott, . During 1-, α2-, and non-selective β-adrenergic receptor antagonists, as well as some anesthetics, including isoflurane, ketamine, and xylazine (Liu G. et al., The sympathetic, stellate ganglion, and subcutaneous sympathetic nerves are all suppressed by most anesthesia types, including general, neuraxial, epidural, and lumbar anesthesia. Anesthesia suppresses blood pressure and heart rate by causing dose-dependent vasodilation or vasoplegia. Hypotension occurs due to anesthesia-induced reduction in heart rate, vasodilation, reduced afterload, and circulating volume. Furthermore, a lower heart rate has a strong positive association with glymphatic influx (Hablitz et al., Perioperative hemodynamic optimization is crucial for improving outcomes after surgery and anesthesia. Anesthesia management often includes the administration of catecholamine vasoactive drugs such as norepinephrine, dopamine, and phenylephrine to maintain stable hemodynamics throughout surgery (Foss and Kehlet, Theoretically, any changes in cardiovascular parameters induced by anesthesia can impair the cardiac pulsation mechanism, resulting in waste accumulation. Hence, understanding the processes contributing to pulsatility and how these components drive waste clearance by the glymphatic system continues to evolve. Further research is needed to determine the most appropriate management of glymphatic function during clinical anesthesia.During experimental testing in mouse or rat models described above, spontaneous respiration was inhibited but still preserved in research involving the glymphatic system. Spontaneous respiration in anesthetized animals is very different from that in controlled or assisted respiration under clinical anesthesia. During clinical anesthesia, positive-pressure mechanical ventilation is often used to replace spontaneous respiration. Mechanical ventilation differs from spontaneous breathing in terms of physiology, and its effect on glymphatic system transport in the brain is currently unknown. Ventilators are inspiratory assist devices that deliver tidal breath under positive pressure. Positive pressure ventilation, including positive end-expiratory pressure, may increase intrathoracic pressure and reduce venous return, subsequently causing increased ICP (Chen et al., Although the administration of local anesthetics through the spinal or epidural canal can provide anesthesia without the need for mechanical ventilation, there are still additional effects on the sympathetic nervous system, parasympathetic nervous system, and motor control, resulting in respiratory impairment (Wink et al., Preclinical and clinical evidence suggests that mechanical ventilation induces adverse neurocognitive effects (Wang et al., Some studies have demonstrated that arousal state correlates with the glymphatic system (Hablitz et al., However, accurate estimation of the depth of anesthesia remains an important issue in clinical or animal anesthesia. Non-invasive EEG or evoked potential indices, such as the bispectral index, narcotrend index, state entropy, and response entropy, for monitoring anesthesia depth are widely used in clinical research. High EEG delta power is positively associated with glymphatic activity, while beta power is negatively corelated in animal models (Hablitz et al., in vivo two-photon imaging demonstrated that calcium signaling in astrocytes is associated with the selective transport of small lipophilic molecules and rapid ISF movement throughout the glymphatic system (Rangroo Thrane et al., 2+ currents in cultured astrocytes (Maneshi et al., 2+ signaling (Duman et al., 2+ currents acutely and chronically (Zhou et al., 2+ signaling and impair glymphatic lipid transport, consequently increasing intracellular lipid accumulation (Rangroo Thrane et al., The use of + after neuronal activity (Jo et al., AQP4 colocalizes the inwardly rectifying potassium channel Kir4.1 and contributes to the coupled influx of water and KPersistent systemic inflammation caused by surgery can disrupt the integrity of the BBB (Vacas et al., Researchers have studied the effects of body position on glymphatic function and Aβ clearance using optical imaging, CSF radiotracers, and fluorescent tracers in the brains of anesthetized rodents. According to previous studies, glymphatic transport is most effective in the lateral position, inferior in the supine position, and least efficient in the prone position (Lee et al., Although PND was initially described as a complication after cardiac surgery, many recent studies have found that some patients undergoing non-cardiac surgeries, such as orthopedic surgery, also suffered cognitive decline (Evered and Silbert, The clearance of the glymphatic system is closely related to the sleep-wake cycle, with sleep promoting faster metabolite removal (Xie L. et al., Postoperative pain remains a significant health care issue that disturbs sleep in the postoperative period, and sleep disturbances may, in turn, exacerbate postoperative pain (Chouchou et al., Currently, in animal models of glymphatic function, sleep is simulated by anesthesia or sleep deprivation. Owing to technical limitations, it is difficult to perform such experiments on naturally sleeping mice (Xie L. et al., Notably, the adverse cerebral effects of anesthesia were primarily reported in the elderly Bedford, . It is nDue to technical limitations, few previous studies have used non-invasive methods to investigate glymphatic function in humans, particularly hospitalized surgical patients susceptible to PND. Recent advances in imaging, such as real-time MRI (Ding et al., Recent discoveries concerning the glymphatic system anatomy and mechanisms have contributed to a better understanding of CSF circulation and waste removal. Furthermore, the glymphatic system has an immune function and may affect the onset and progression of PND, either directly or indirectly. Because clinical research on perioperative glymphatic changes is still lacking, scientists and clinicians, particularly gerontologists, neurologists, psychiatrists, anesthesiologists, and surgeons, can collaborate to uncover the etiological mechanisms of perioperative glymphatic changes. The glymphatic concept may provide a strategic breakthrough in rethinking, treating, and, most importantly, preventing PND.Human studies exploring the physiological and pathological mechanisms between the glymphatic system and brain cognition over time have greatly improved our knowledge; however, some key issues still need to be addressed by future research. First, the definition of normal or healthy glymphatic function may be one of the biggest challenges. A simpler and quicker intraoperative monitoring method remains to be developed. A better description of glymphatic dynamics will help demarcate “normal” and “abnormal” glymphatic function in humans and identify preventive strategies for PND. Second, perioperative factors such as anesthetic type, intraoperative hemodynamics, surgery position, surgical inflammation, and previous health status may confound research on the glymphatic system and PND. Cross-sectional clinical studies have demonstrated specific changes in the glymphatic transport of patients susceptible to neurological diseases, which is helpful in predicting the incidence of PND. Third, more clinical studies should be conducted instead of purely animal studies. Although association analysis may provide critical information for cause-effect deductions, correlation does not necessarily mean causation. Fourth, basic research targeting the perioperative glymphatic system in PND merits optimization; specifically, appropriate model systems should be carefully selected. Finally, the translation of basic research results into clinically relevant effects in humans should be expedited. Most data on the role of the glymphatic system are based on animal studies. Preclinical animal studies frequently result in unexpected failures during clinical transition due to unidentified reasons. Alternatively, future therapeutic interventions will likely be based on individual factors due to significant differences in anatomical variation and disease complexity among human populations.XR, GZ, LL, and CL contributed significantly to conception of the review and edited the review. XR undertook the literature, drafted, and corrected most of the manuscript and tables. SL, KL, and HL assisted with part of the pictures and manuscript. CL contributed to the sections of glymphatic system and anaesthetics. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Youth with chronic pain often report executive functioning difficulties, many of which have been linked to poor treatment adherence and health-related quality of life in adults with chronic pain, as well as in other pediatric chronic health populations. Despite the extensive implications for functional impairment, executive functioning remains understudied in pediatric chronic pain. Measurement approaches have lacked clear theoretical guidance, resulting in only some domains of executive functioning being investigated. To date, the methods used to measure executive functioning have been inconsistent, ranging from self-report measures of everyday executive functioning in home and school contexts to standardized neuropsychological tests. We argue for enhanced measure validation efforts and increased clarity in the approaches chosen to measure executive functioning in pediatric chronic pain to better guide research efforts in this area, thus yielding clearer clinical implications. Pediatric chronic pain is a prevalent condition affecting nearly 23 percent of young people . It is wPediatric chronic pain is complex, involving dynamic interactions among myriad biological, psychological, and socio-cultural influences ,4,5,6,7.Executive functioning (EF) is defined as a collection of higher-order cognitive processes underlying goal-directed behavior and is often referred to as the “conductor” that controls, organizes, and directs cognitive activity, emotional responses, and behavior ,24,25,26Inhibitory control (IC) is characterized by one’s ability to exhibit mental control over their thoughts, feelings, and behaviors in order to override external distractors and rather engage with or in the more appropriate or necessary task . IC is aUnsurprisingly, difficulties related to the processes of inhibitory control, working memory, and cognitive flexibility often result in marked functional impairment . EF diffUnderstanding the exact nature of EF deficits in pediatric chronic pain has direct implications for functional impairment . For youEF is an essential part of treatment adherence, as youth with chronic medical conditions often need to make difficult and important decisions regarding their treatment and practice flexibility and adaptability when their treatment changes ,34,35. RYouth with chronic pain often experience emotional impairment. Specifically, pediatric chronic pain has been linked to a variety of mental health conditions, such as anxiety and depressive disorders ,38. ReseGiven the complex, multifaceted nature of EF it is perhaps not surprising that those studying cognitive difficulties in the context of pediatric chronic pain have utilized a variety of measurement approaches . Some haMeasurement methods generally fall into the following categories: youth self-report, parent-proxy report, experimental performance-based tasks, and standardized neuropsychological tests (often including intelligence quotient (IQ) and academic achievement tests as part of the assessment battery) .To date, only one youth self-report and parent-proxy EF questionnaire has been utilized in research measuring EF in youth with chronic pain. Specifically, the Behavior Rating Inventory of Executive Function  , the Rey Complex Figure Test (RCFT), and the Delis-Kaplan Executive Function System (D-KEFS).Anti-saccade tasks  assess iNeuropsychological tests are tasks designed to assess a particular psychological function that has been linked to a specific neurological pathway or brain structure. One battery of neuropsychological tests used to assess EF in pediatric chronic pain was the TEA-Ch battery , which cThe Wide Range Assessment of Memory and Learning (WRAML-2) has also been used in one study of EF in pediatric chronic pain . The WRAIQ and Achievement tests have also been used to measure specific domains of EF in pediatric chronic pain. Cruz and colleagues  used theDespite an increased interest in EF in pediatric populations, numerous challenges remain in understanding EF in pediatric chronic pain. To date, although findings have been fairly consistent in showing a link between EF and impairment in chronic pain , researcAnother limiting factor inhibiting research in this area is a lack of validation efforts establishing the appropriateness of existing EF measures for use in pediatric chronic pain and without establishing the psychometric properties of available EF measures for use with pediatric chronic pain patients. Although extant questionnaires, such as the BRIEF-2, and neuropsychological tests of EF domains have been validated in child psychiatric populations , Autism Spectrum Disorder (ASD)), it is unknown whether these measures adequately capture the nature of EF—and are helpful in predicting functional impairment—in youth with chronic pain. Therefore, research is needed to solidify both the content of EF measures as well as the construct validity  of experimental measures among youth with chronic pain. Without establishing the psychometric properties of existing—or newly developed—EF measures in pediatric pain populations, conclusions drawn from EF studies remain equivocal.Another potential challenge in understanding EF in pediatric chronic pain is the inherent variability across chronic pain conditions. Thus, individual study findings may not widely generalize. Previous studies examining EF in pediatric chronic pain have included small samples (ranging from N = 13 to 57) of youth between the ages of 8 and 19 with a variety of primary pain conditions , ,55, 54,5Including multiple informants in the assessment of EF in youth with chronic pain would bolster the evidence for impairment in particular domains of EF if similar difficulties were reported by multiple sources. Unlike parents and teachers, youth with chronic pain experience the direct impact of executive dysfunction on their daily life. In pediatric chronic pain, it has been established that the youth self-report is often a useful method of assessment ,54,55. FFrom a developmental perspective, children and adolescents have varying introspective abilities. EF difficulties may be particularly challenging for some young people to accurately report . To addrn = 26 youth with chronic pain), thus generalizability is limited. Without careful examinations of multiple EF domains, it will be challenging to accurately determine the domains of EF that are most impacted in pediatric chronic pain. Therefore, future studies should also incorporate multiple measurement methods with larger samples—both community- and clinic-based—in a systematic and theory-informed manner.Though multifaceted definitions of EF have generally been referenced, the measurement methods used in pediatric pain research have rarely examined multiple domains of EF in a single study. For example, Verhoeven and colleagues  measuredOnce researchers have (1) established the reliability and validity of EF measures for use in pediatric chronic pain, (2) determined which domains of EF are most impaired in pediatric chronic pain patients, and (3) identified the specific measures that best distinguish between youth with chronic pain and healthy controls, then we must (4) establish which EF measures best predict key clinical and functional outcomes in youth with chronic pain. To date, research that has included both a pediatric chronic pain sample and healthy controls has focused—rightly so—on establishing group differences. This is a helpful starting off point, and much more in this area is necessary. However, even if relatively consistent group differences emerge , elevated scores alone do not guide clinical practice and do not necessarily shed light on the degree to which EF deficits are associated with clinical outcomes. Rather, we need to establish which domains of EF are specifically linked to particular areas of functional impairment  and clinical outcomes . It remains unclear whether there are unique EF risk profiles associated with certain areas of functional impairment.Youth with chronic pain often report cognitive difficulties, specifically when it comes to inhibition, cognitive flexibility, and working memory ,16,17,58


Low diet quality is a significant public health problem in the United States, especially among low-income populations. The food environment influences dietary choices. When applied to eating behavior, behavioral economics (BE) recognizes that decision biases instigated by a food environment saturated with unhealthy foods may lead people to purchase such foods, even when they possess the necessary information and skills to make healthy dietary choices. Choice architecture, a BE concept that involves modifying the appeal or availability of choices to “nudge” people toward a certain choice, retains freedom of choice but makes unhealthy options less convenient or visible. Choice architecture has been demonstrated to influence food choices in various settings, including supermarkets, convenience stores, and food pantries. These modifications are low-cost and feasible to implement, making them a viable strategy to help “nudge” patrons toward healthier choices in food establishments serving low-income populations, including food pantries and retailers accepting the Supplemental Nutrition Assistance Program. This narrative review searched, appraised, and underscored the strengths and limitations of extant research studies that used choice architecture adaptations to influence food choices among low-income populations in the United States. Findings from studies in food pantry settings suggest the potential of BE strategies to improve the healthfulness of food choices and dietary intake in low-income populations. In food retail settings, research suggests that BE strategies increase sales of healthy foods, like fruits and vegetables. We identify new areas of research needed to determine if BE-based modifications in low-income settings have sustained impacts on diet quality. Low diet quality represents a significant public health problem in the United States (US). Estimates state that 82% of US adults aged 20–49 years and 73% of adults over 50 years score poorly on measures of diet . Low-incTheory in behavioral economics recognizes that even when people possess the necessary information and skills, decision biases and other pitfalls may lead them to make decisions that are not in their best interest . BehavioAccess to nutritious food is considered an essential social determinant of health due to the direct impact of nutrition on health . An estiThis mini-review summarizes the strengths and limitations of behavioral economics strategies, specifically choice architecture adaptations, to improve the quality of foods chosen by low-income populations in food retail settings and pantries. We searched PubMed using terms such as “behavioral economics,” “choice architecture,” “nudging,” “food choices,” “diet quality,” “food pantries,” and “SNAP.” Although behavioral economics strategies have been examined in health promotion and healthcare contexts , and choResearch suggests that low-income households tend to purchase and consume foods that are less healthy than higher-income households , 16, 17.The mechanisms driving unhealthy dietary choices among low-income populations are complex and not limited to individual choices. A disproportionately higher presence of marketing for unhealthy foods in low-income communities is a main contributor . For exaSNAP serves over 42 million individuals in the US and provides a major source of nutrition assistance for low-income populations. Most SNAP-approved vendors are small grocery and convenience stores (78.0% of SNAP vendors); however, the majority of benefits are redeemed at superstores and supermarkets (82.5% of SNAP redemptions), which together make up 15.4% of SNAP retailers , 25. WhiIntervention studies evaluating the effects of changes to choice architecture on consumer food choices have been conducted in various settings, including food pantries, convenience stores, and supermarkets. These interventions have demonstrated the potential to nudge people to make healthier food choices in food pantries and retailers in underserved, low-income communities .Feeding America's network of 58,000 food pantries serves ~46.5 million individuals in the US every year . AlthougDespite promising findings, the current evidence base is limited, including a lack of randomized trials and longitudinal studies examining the long-term effects of nudges on food pantry patrons' food choices . Also, tChanges to choice architecture have been shown to promote sales of healthy foods in retail stores that accept SNAP redemption, often located in low-income communities. A cluster-randomized controlled trial showed that increasing healthy product visibility and signage in supermarkets located in low-income neighborhoods, most of which were SNAP retailers, resulted in significantly greater sales of several targeted options  compared to stores with no intervention within 6 months . AnotherThe success of these choice architecture changes at supermarkets, convenience stores, corner stores, and grocery stores in nudging consumers to choose healthier options demonstrates potential in using these inexpensive strategies to promote sales of healthy foods at food retailers , 24, 25.The recent expansion of online ordering capabilities to SNAP retailers presents an opportunity to implement behavioral nudges online. The SNAP Online Purchasing Pilot, a program testing online grocery purchasing in SNAP, was launched in April 2019. By early 2021, online purchasing became available as an option for SNAP beneficiaries in 48 states at large nationwide retailers . A recenIn contrast to nutrition education or other dietary interventions that put the onus on the individual, behavioral economics strategies may reduce effort and improve the convenience of making healthier food choices. Choice architecture nudges individuals toward healthier options without restricting their choices by making certain options more convenient or visible , 48. BehDespite these advantages, there are potential shortcomings of using changes to choice architecture as a nutrition intervention. Individuals make food choices in various settings beyond retail food establishments, including at home, schools, and worksites. While behavioral nudges may influence behavior at the moment, in another environment without such nudges, people may continue to make unhealthy choices . In addiA challenge to implementing behavioral economics-based interventions in food retail settings is establishing partnerships with food retailers. At smaller stores, managers are most often responsible for the layout and selection of the products available at their stores . HoweverResearch evaluating the efficacy of interventions aimed at promoting healthy food choices in low-income settings using behavioral economics-informed approaches, most of which has been conducted in food pantry settings, suggests that such approaches may improve the healthfulness of food purchases and dietary intake in low-income populations. However, more research is needed to determine the optimal design of interventions that leverage behavioral economics in retailers serving low-income consumers , 20, 32.Low diet quality is a public health concern that disproportionately impacts low-income populations , 62. BecEA, RW, and BL conceptualized the topic, researched and analyzed the background literature, wrote the manuscript, and including interpretations. RP and HK researched and analyzed the background literature, wrote portions of the manuscript, and including interpretations. AM, MT, SB, and JM provided substantial scholarly guidance on the conception of the topic, manuscript draft and interpretation, and revised the manuscript critically for intellectual content. All the authors approved the final version of the manuscript, ensured the accuracy and integrity of the work, and agreed to be accountable for all aspects of the work.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The COVID-19 pandemic has disrupted the provision of essential reproductive, maternal, newborn, and child health (RMNCH) services in sub-Saharan Africa to varying degrees. Original models estimated as many as 1,157,000 additional child and 56,700 maternal deaths globally due to health service interruptions. To reduce potential impacts to populations related to RMNCH service delivery, national governments in Kenya, Mozambique, Uganda, and Zimbabwe swiftly issued policy guidelines related to essential RMNCH services during COVID-19. The World Health Organization (WHO) issued recommendations to guide countries in preserving essential health services by June of 2020.We reviewed and extracted content related to family planning (FP), antenatal care (ANC), intrapartum and postpartum care and immunization in national policies from Kenya, Uganda, Mozambique, and Zimbabwe from March 2020 to February 2021, related to continuation of essential RMNCH services during the COVID-19 pandemic. Using a standardized tool, two to three analysts independently extracted content, and in-country experts reviewed outputs to verify observations. Findings were entered into NVivo software and categorized using pre-defined themes and codes. The content of each national policy guideline was compared to WHO guidance related to RMNCH essential services during COVID-19.All four country policy guidelines considered ANC, intrapartum care, FP, and immunization to be essential services and issued policy guidance for continuation of these services. Guidelines were issued in April 2020 by Mozambique, Kenya, and Uganda, and in June 2020 by Zimbabwe. Many elements of WHO’s 2020 recommendations were included in country policies, with some notable exceptions. Each policy guideline was more detailed in some aspects than others — for example, Kenya’s guidelines were particularly detailed regarding FP service provision, while Uganda’s guidelines were explicit about immediate breastfeeding. All policy guidance documents contained a balance of measures to preserve essential RMNCH services while reducing COVID-19 transmission risk within these services.The national policy guidelines to preserve essential RMNCH services in these four countries reflected WHO recommendations, with some notable exceptions for ANC and birth companionship. Ongoing revision of country policy guidelines to adapt to changing pandemic conditions is recommended, as is further analysis of subnational-level policies. Emerging empirical evidence along with modeling projections suggest that the COVID-19 pandemic is significantly impacting RMNCH services and health outcomes in many low- and middle-income countries (LMICs) . One repImportantly, the majority of these additional deaths and unintended pregnancies was thought to be due to disruptions of health services . During The COVID-19 pandemic has placed massive pressure on health systems in Africa particularly . For AfrWhile many countries in sub-Saharan Africa have achieved significant reductions in maternal and child mortality over the past decade, COVID-19 has threatened to slow this progress. To reach global mortality reduction targets established for the 2030 Sustainable Development Goals (SDGs), countries must continue to ensure that essential health services, information, and commodities reach women, newborns, infants, and children and their families, without unduly increasing the risks of COVID-19 transmission while doing so.Different possible approaches have been identified to mitigate exposure to COVID-19 during health service interactions. In the context of HIV service delivery, WHO’s call for differentiated service delivery (DSD)  pre-dateTo successfully adapt service delivery models to pandemic-related threats, changes to national policy guidelines are required. These changes provide health care providers and administrators with an operational and legal framework for essential RMNCH service provision. Some of the most relevant policy factors to be addressed during the COVID-19 pandemic include: health care provider shortages and absenteeism; supply chain for RMNCH commodities, including contraceptives; reluctance of clients to seek care because of perceived risk of COVID-19 infection; travel or transport restrictions; and economic difficulties of users of the health system , 13, 23.Starting in March 2020, policymakers in Kenya, Mozambique, Uganda and Zimbabwe as in so many other countries were tasked with continuing essential, life-saving RMNCH services in a way that was least likely to contribute to new COVID-19 infections among both health care providers and clients. This analysis systematically describes how these four countries balanced continuation of RMNCH services — specifically, ANC, FP, intrapartum and postnatal care (PNC) and immunization services — with prevention of COVID-19 transmission. The purpose of this analysis is to describe the key policy elements driving service delivery in Kenya, Mozambique, Uganda, and Zimbabwe, including comparing with examples from HIV’s differentiated service delivery (DSD) models. We also compare WHO recommendations to what was described in each of the four countries’ national policies. In addition to filling the gap in systematic analysis of RMNCH service policy, this article will also provide contextual information to help interpret trends in service delivery during the pandemic in these four countries.We conducted a systematic review and analysis of policy guideline content related to RMNCH service provision during the COVID-19 pandemic to elucidate key policy approaches across Kenya, Mozambique, Uganda, and Zimbabwe. These four countries were conveniently selected because in each country, a USAID-funded technical assistance program led by FHI 360 was supporting the government to improve RMNCH service quality.The analysis catalogued policy adaptations to RMNCH services and linked the adaptations either to continuation of a service  or prevention of COVID-19 transmission within service delivery. The analysis was conducted using national-level RMNCH policy guidelines issued specifically to address RMNCH service delivery — subnational-level RMNCH policy guidelines were not included.In each country, we formed a committee that included technical experts from USAID-funded RMNCH programs . This committee proposed relevant policy guidelines for inclusion in the review and subsequently requested input from Ministry of Health (MOH) staff. Policies were included if they met two criteria:  issued bTwo analysts  used a standardized tool to extract content from the policy guidelines using pre-assigned categories, which fit under either “continuation of services” or “prevention of COVID-19 transmission.” The tool also had a category for “other” to allow for emerging in addition to pre-defined themes. Following the Grounded Theory approach , we inclMaintaining essential health services: operational guidance for the COVID-19 context [Two analysts  reviewed WHO’s  context  of June This study was reviewed by FHI 360’s Office of International Research Protection institutional review board and received a non-research determination. All policies reviewed were in the public domain. No people were interviewed as part of this study, so no informed consent was necessary.The governments of Kenya, Mozambique, Uganda, and Zimbabwe all issued national-level policy guidance related to RMNCH service continuity Table . PolicieThe analysis grouped policy recommendations into two (overlapping) aims: continuing services and preventing COVID-19 transmission during provision of these services. Summarized findings from the four countries are presented in Fig. The key policy aspects supporting continuation of FP services included multimonth dispensing  and telemedicine . Multimonth dispensing of short-term FP methods was described in Kenya, Uganda, and Zimbabwe Table . In bothMaintaining essential health services: operational guidance for the COVID-19 context, WHO makes recommendations on maintaining essential RMNCH services, including FP. All four countries included guidance which aligned with WHO’s recommendation of multimonth dispensing of FP  reflects policy makers’ understanding of the immediate, life-changing and life-threatening impacts of disruptions to RMNCH services. Unavailability of contraceptives can quickly lead to unintended pregnancies; unavailability of condoms can immediately lead to new HIV infections; restrictions on access to skilled birth attendance can directly lead to maternal and newborn deaths. Our analysis describes country-level recommendations for FP, ANC, intrapartum and postpartum care, and immunization services during the COVID-19 pandemic, so that countries can learn from these policy responses as they face the ever-evolving challenges associated with COVID-19. Our analysis suggests that i) the RMNCH service package is complex; ii) gaps exist in original policy guidelines to varying extents in the four countries when compared to WHO guidance, and iii) policy guidance for RMNCH service delivery should be revisited given changing public health responses, mutations to the virus, vaccination availability, and new understanding of interactions between HIV and COVID-19.As we have compared selected WHO recommendations for service delivery to the country policy guidelines, it is important to note that in Kenya, Mozambique, and Uganda, country policy guidelines were issued before the WHO guidelines, and in Zimbabwe, the policy guidelines were issued in the same month as WHO guidelines. The comparison is thus not meant to suggest deficiencies in content of country policy guidelines, but rather to highlight considerations for policy-makers as revisions are made to policy guidelines. In “normal” processes, WHO guidance comes first, then countries adapt the global guidance to local context, but during the COVID-19 public health emergency, this timing was altered . While tGlobally, the majority of maternal and newborn deaths occur in the intrapartum period , and thiOne area of great alignment between WHO recommendations and country policy guidelines was the promotion of immediate breastfeeding of the newborn. All four countries’ policies specifically promoted immediate breastfeeding of newborns, with prevention measures to reduce risks of COVID-19 transmission. This has not been the case in all countries – case reports  as well The cancellation of outreach services, most disruptive to immunization and FP services, is a very difficult decision for countries. Overall, 69% of WHO member states reported disruption to outreach services for immunization . This diAs the pandemic continues to unroll in Africa, the need for integration of COVID-19 vaccination for people living with HIV (PLHIV) is becoming more urgent, for multiple reasons. PLHIV in SSA appear to have heightened morbidity and mortality related to COVID-19, with one study showing up to four times higher likelihood of death among people with advanced or uncontrolled HIV . AdditioPrior to the COVID-19 pandemic, the HIV community had introduced models of differentiated service delivery (DSD), which involves tailoring services to take into consideration clinical needs and characteristics affecting the population . As the While differences between HIV and RMNCH are notable – for example, intrapartum care must take place in the health facility and is not a schedulable service - the principle of adapting services to account for peoples’ needs, environment, and circumstances is not only admirable, but also necessary to achieve continuity of essential RMNCH services. Policymakers are encouraged to incorporate “DSD thinking” into the policy and planning of RMNCH services, integrating RMNCH and HIV services, particularly in regard to reaching PLHIV with COVID-19 vaccines, and replicating the creativity and urgency with which the HIV community is adapting to mitigate the effects of COVID-19 on service delivery.While our analysis has revealed much disruption to RMNCH health services, a perspective is emerging that perhaps not all health system impacts of the pandemic will be negative. Some COVID-19 policy guidance may serve to improve efficiencies of health systems, translating into beneficial effects for clients , 48. WHOThe need for rapid mechanisms to adapt policy guidelines in the case of pandemics has been increasingly highlighted, with multiple mechanisms suggested, including increasing academic and government collaboration and creating multiple “templates” which could be rapidly applied . A burgeThe results of this analysis should be considered in light of the following limitations. The four countries were conveniently selected as countries in which the authors’ team had access to policy guidance and MOH colleagues to verify findings. Given the variation of content found in each country’s policy guidelines, findings may have limited applicability to other LMICs. However, we believe that our approach to the systematic review may be applicable to other country stakeholders who wish to apply an analytic lens to policy guidance on RMNCH services during the COVID-19 pandemic, particularly during policy revisions. Additionally, while our analysis only focused on national-level policies, we recognize that in many cases, subnational policy guidance may have had more immediate effect on service delivery. Indeed, colleagues in Kenya shared memos and circulars from county-level health authorities; these documents adjusted national-level policy to meet needs for immunization and other outreach services at the county level. We highly encourage more in-depth analyses that take subnational variations in policy into account.Provide more specific guidance on making telemedicine operational for RMNCH services. While all four country policy guidelines mentioned use of telemedicine for expanding access to health services, none of the reviewed policy guidelines contained instructions sufficient to guide health system administrators in how to use telephone technology to effectively deliver RMNCH services.Increase intention for multimonth dispensing in ANC. Multimonth dispensing for ANC medicines or supplements was only mentioned in Kenya’s policy guidelines. As per WHO recommendations, this is a recommended approach and an area of potential efficiency. Relevant approaches may include building upon suggested content areas and modes of service delivery for ANC mentioned in Zimbabwe’s policy guidance, which recommended visit content and mode of ANC service delivery by gestational age.Apply examples from DSD implemented for HIV services to rapidly learn how to tailor RMNCH services. While service platforms, content of services, and resource availability differ between HIV and RMNCH, the need for integration has become apparent, and both are served by the same health system. Existing analyses have started to draw lessons from HIV rollout to COVID-19 prevention services rollout . PolicymRevisit WHO’s recommendations to see where those not currently addressed within country guidelines may be applied. For example, allowing birth companions, which aligns with the countries’ own stated desire for improving respectful maternity care, may be revisited in areas where resources allow for screening for COVID-19.Bolster recommendations for PNC. In all four countries’ policy guidelines, PNC was not explicitly addressed, and in all four cases, the main recommendations by WHO for maintaining PNC were not seen in country guidelinesRollout of COVID-19 vaccines  and new In the first year of response to the COVID-19 pandemic, national policies from Kenya, Mozambique, Uganda, and Zimbabwe reflected a balance between the need to continue essential RMNCH services and the need to prevent transmission of COVID-19 in these services. For facility-based services that cannot be scheduled, such as intrapartum and immediate postpartum care, the focus was on triaging clients into categories of risk and setting up separated spaces. For services that included significant outreach components, the largest changes involved canceling outreach services and centralizing services at the health facility. Country policy makers will need to update RMNCH policy guidelines to adapt to vaccine availability and increased understanding of HIV and COVID-19, and incorporate global guidance from WHO during these revisions. Policymakers in these four countries are also urged to look to the DSD approach in HIV services for examples of how to adapt services to the needs of users during the COVID-19 pandemic, and to revisit WHO recommendations as they revise RMNCH policies to respond to the evolving conditions of the pandemic.


Spinal cord injury (SCI) produces paralysis and a unique form of neurogenic disuse osteoporosis that dramatically increases fracture risk at the distal femur and proximal tibia. This bone loss is driven by heightened bone resorption and near-absent bone formation during the acute post-SCI recovery phase and by a more traditional high-turnover osteopenia that emerges more chronically, which is likely influenced by the continual neural impairment and musculoskeletal unloading. These observations have stimulated interest in specialized exercise or activity-based physical therapy (ABPT) modalities  that reload the paralyzed limbs and promote muscle recovery and use-dependent neuroplasticity. However, only sparse and relatively inconsistent evidence supports the ability of these physical rehabilitation regimens to influence bone metabolism or to increase bone mineral density (BMD) at the most fracture-prone sites in persons with severe SCI. This review discusses the pathophysiology and cellular/molecular mechanisms that influence bone loss after SCI, describes studies evaluating bone turnover and BMD responses to ABPTs during acute versus chronic SCI, identifies factors that may impact the bone responses to ABPT, and provides recommendations to optimize ABPTs for bone recovery. An estimated 250,000 to 500,000 new spinal cord injuries (SCI) occur worldwide each year , with maBone loss after SCI is termed neurogenic or disuse osteoporosis and is confined to the sublesional skeleton ,11,12, wAfter SCI, fractures are usually non-traumatic, due to the mobility limitations in persons with SCI, and result from low-velocity compressive forces or torsional stresses  that dev3) and distal tibia epiphysis (<71 mg/cm3) in persons with SCI [Dual-energy X-ray absorptiometry (DXA) is the standard to assess osteoporosis and fracture risk at traditional osteoporosis sites , via the quantification of areal (a)BMD and T-scores . Specialwith SCI . High-rewith SCI  can alsowith SCI ,35. For with SCI , likely with SCI . RegardlWithin the SCI population, persons with complete paralysis display the most extensive bone loss ,26 and hBone undergoes continuous remodeling throughout the lifespan, which is balanced during homeostasis via integrated resorption and formation processes that maintain skeletal integrity. However, after severe SCI, a unique form of unopposed bone resorption drives bone loss . As evidThe molecular mechanisms that propagate the uncoupled bone turnover that is present in the paralyzed limbs after SCI and that drive the exceedingly rapid bone loss in this population, in comparison with other disuse conditions, require further elucidation. Given that disuse is a factor that mediates SCI-induced bone loss, it is likely that osteocytes (primary bone mechanosensor) influence neurogenic osteoporosis. Osteocytes reside within the calcified bone matrix and communicate with other osteocytes and with osteoclasts, osteoblasts, and other cells that reside on bone surfaces via dendritic projections that emerge from the osteocyte cell body to form an interconnected dendritic network. Dendrites provide one means by which the osteocytes sense alterations in localized bone strains that result from disuse or imposed loading and transduce this information to the osteocyte cell body, a process that is referred to as mechanotransduction. In response to this stimulus, osteocytes release a host of nuclear-derived signaling molecules , osteoprotegrin (OPG), sclerostin, and others) that orchestrate osteoclastic and/or osteoblastic bone remodeling. Readers are directed to the following reviews that discuss osteocyte mechanosensors and mechanotransduction-associated signaling pathways ,61.While it is likely that osteocytes orchestrate the skeletal responses to SCI, few studies have directly assessed this possibility or described how osteocytes respond to paralysis or to imposed bone loading after SCI. Qin et al. observed osteocyte morphological aberrations in rats within seven-weeks of spinal transition, including reductions in the dendritic length and dendritic number, along with altered osteocyte cell body shape . The molRANKL is an osteocyte-derived protein that is necessary for the differentiation of hematopoietic progenitors of the monocyte-macrophage lineage into osteoclasts. RANKL stimulates osteoclastogenesis and bone resorption by binding RANK receptors on the cell surfaces of osteoclast precursors and osteoclasts, respectively . RANKL-mSigns of altered RANKL signaling coexist with bone loss in rodent SCI models. For example, cultured bone marrow mesenchymal or stromal cells that were isolated from spinalized mice exhibit higher RANKL and lower OPG vs. the controls, which may underlie the two- to three-fold increase in tartrate-resistant acid phosphatase (TRAP)+ osteoclast-like cells that develop in bone marrow culture that are derived from spinalized mice . SimilarRecently, RANK  and RANKThe canonical Wnt/β-catenin signaling cascade promotes bone formation by stimulating osteoblast differentiation and osteoblast growth rate, by inhibiting osteoblast apoptosis, and by stimulating osteoblast activity. This signaling pathway is initiated when the various Wnt ligands  bind the low-density lipoprotein receptor-related protein (LRP)5/6 and Frizzled receptor complex on osteoblasts and prevent the Axin-adenomatous polyposis coli-glycogen synthase kinase 3-casein kinase 1 (APC-GSK-3-Ck1) complex from phosphorylating cytoplasmic β-catenin, which traditionally marks β-catenin for proteasomal degradation. In response, unphosphorylated β-catenin accumulates within the cytoplasm, where it can be shuttled to the nucleus to interact with DNA binding proteins  to promote the activation of Wnt responsive gene transcription pathways . SeveralAlterations in Wnt signaling accompany bone loss in the paralyzed limbs in rodent SCI models. For example, several proteins that are involved in Wnt signaling  are repressed at the distal femur and proximal tibia within a few weeks of SCI, while the number of osteocytes that stain for sclerostin are increased  and SOSTGiven the role of disuse in mediating the musculoskeletal decline after SCI, a large body of research has focused on ABPTs and other exercise-based regimens that reload the impaired limbs to restore muscle integrity . Common In uninjured persons, weight-bearing exercise that produces high peak strains and/or high strain rates increases BMD  and prevRelatively few preclinical SCI studies have evaluated the possibility that ABPTs alter bone turnover or improve BMD, likely because few preclinical modalities exist to reload the paralyzed limbs. In this regard, Qin et al. developed an implantable electrical stimulation (ES) system that elicited unilateral near-maximal contractions of the paralyzed soleus and plantaris muscles in spinal transected rats, with ES delivered 60 min/day for one-week , 1.5 V) . This brBeyond the studies that are described above, we are aware of only a few others assessing bone responses to loading in preclinical SCI models. Zamarioli et al.  evaluateBased on the evidence that is presented above, it remains unknown whether ABPTs that reload the impaired limbs after SCI alter bone turnover in a manner that is sufficient to improve BMD. With the above considered, the next sections summarize the findings of clinical studies that met the following criteria: (1) enrolled adults with incomplete and/or complete SCI and (2) reported BMD at the distal femur or proximal tibia, or BMD or T-scores at other sublesional sites, both before and after an ABPT intervention regardless of other study characteristics. In doing so, we considered several important questions. First, did the study enroll persons with acute to subacute (0–12-months) SCI when bone loss is the most rapid, or during the chronic (>12-month) period when bone loss is more gradual? Secondly, did the study assess the bone changes at the relevant fracture-prone sites after SCI  or at other bone sites? Thirdly, did the study report that an ABPT attenuated bone loss or increased BMD? We considered trials that reported attenuated bone loss or increased BMD vs. the baseline or a control group to have demonstrated improvement, while those not meeting these criteria were considered to have shown no effect. For studies that combined an ABPT with a pharmacologic intervention, we only discuss the groups that were receiving ABPT alone. Case studies, case series, and cross-sectional studies that did not statistically assess the pre-post differences are discussed from a qualitative perspective.A visual summary of the studies examining the effects of different ABPT modalities at knee and non-knee sites in acute and subacute SCI is presented in No trial without a control comparator ,108 nor In comparison, 6 of the 11 controlled trials reported that an ABPT attenuated BMD loss at different sublesional sites ,113,115.A visual summary of studies examining the effects of different ABPT modalities at knee and non-knee sites in chronic SCI is presented in Inconsistent results also exist in uncontrolled and controlled trials that evaluated the effects of ABPT on bone in persons with chronic SCI. In total, we identified 14 trials without a control comparator group , which rIn total, five uncontrolled ,100,103 Several common parameters existed among studies that reported improved proximal tibia or distal femur BMD or increased BMD at other sites. First, studies that reported attenuated BMD loss at the knee all enrolled persons with acute/subacute SCI and used FES-based modalities that were performed 3–5 days/week, 20–60 min/day, for ≥3-months ,106,113 Several other factors that were associated with BMD improvements were also identified. First, higher total work output was associated with greater BMD gain. For example, Lambach et al.  reportedWhat are the optimal FES and modality-specific parameters  to stimulate and/or maintain bone improvements?What is the optimal training frequency (number of sessions per day or per week) and training duration (time per bout and intervention length) to improve bone parameters?What is the minimum training frequency and duration to maintain bone after SCI?Is the magnitude of BMD or bone microstructural gains that result from FES sufficient to improve bone strength or bone mechanical characteristics and/or to reduce the fracture risk at the distal femur and/or proximal tibia after SCI?As discussed above, only limited evidence supports the notion that ABPTs attenuate BMD loss in persons with acute/subacute SCI or increase BMD in the paralyzed limbs after chronic SCI, especially when considering the most fracture-prone sites that surround the knee. Moreover, few studies have evaluated whether ABPTs improve trabecular or cortical bone microstructure at the distal femur or proximal tibia  and noneClinical trials focused on optimizing FES would require a large, concerted effort over many years to discern optimal parameters, due to the relatively slow bone remodeling in humans and the number of potential parameter combinations. To lessen this burden, percutaneous ES ,145,146 Regardless of the intervention that is used, we suggest the following practices be implemented when evaluating bone changes after SCI. First, studies should quantify the distal femur and/or proximal tibia bone parameters before and after an intervention using an established imaging modality  and a validated protocol, instead of assessing surrogate bone sites. We recognize that DXA is used to quantify whole-body fat-free mass or fat mass changes, and thus, aBMD that is assessed in the whole-body or at other traditional osteoporosis sites may be reported out of convenience. Future work should explain the relevance of BMD changes at these traditional osteoporosis sites in relation to the more fracture-prone distal femur and proximal tibia sites after SCI. Second, clinical trials should last a minimum of 6–12 months with ABPT performed ≥3 days/week for ≥30 min/day across the intervention, given the slow bone turnover and BMD improvements that are present in humans in response to loading. Third, a control group or control comparator  should be assessed to ensure the appropriate data interpretation. Fourth, interventions should attempt to quantify the tibio-femoral forces during training, as has been previously reported , and/or A visual summary of all the reviewed studies examining the effects of ABPT modalities at knee and non-knee sites in acute and chronic SCI is presented in


The speech we hear every day is typically “degraded” by competing sounds and the idiosyncratic vocal characteristics of individual speakers. While the comprehension of “degraded” speech is normally automatic, it depends on dynamic and adaptive processing across distributed neural networks. This presents the brain with an immense computational challenge, making degraded speech processing vulnerable to a range of brain disorders. Therefore, it is likely to be a sensitive marker of neural circuit dysfunction and an index of retained neural plasticity. Considering experimental methods for studying degraded speech and factors that affect its processing in healthy individuals, we review the evidence for altered degraded speech processing in major neurodegenerative diseases, traumatic brain injury and stroke. We develop a predictive coding framework for understanding deficits of degraded speech processing in these disorders, focussing on the “language-led dementias”—the primary progressive aphasias. We conclude by considering prospects for using degraded speech as a probe of language network pathophysiology, a diagnostic tool and a target for therapeutic intervention. Speech is arguably the most complex of all sensory signals and yet the healthy brain processes it with an apparent ease that belies the complexities of its neurobiological and computational underpinnings. Speech signals arrive at the ears with widely varying acoustic characteristics, reflecting such factors as speech rate, morphology, and in particular, the presence of competing sounds ,2. The cVarious computational models have been proposed to explain how a speech signal is normally efficiently disambiguated from auditory “noise”, entailing the extraction of specific acoustic features, phonemes, words, syntax, and ultimately, meaning ,5,6,7,8.Predictive coding theory, a current highly influential theory of perception, postulates that the brain models the causes of sensory input by iteratively comparing top-down predictions to bottom-up inputs and updating those predictions to reduce the disparity between prediction and experience  ,12. The According to this predictive coding framework, degraded speech perception depends on hierarchical reciprocal processing in which each stage passes down predictions, and prediction errors  are passed up the hierarchy ,15. Our From a neuroanatomical perspective, it is well established that the representation and analysis of intelligible speech occur chiefly in a processing network surrounding primary auditory cortex in Heschl’s gyrus, with processing “streams” projecting ventrally along superior temporal gyrus and sulcus (STG/STS) and dorsally to inferior frontal gyrus (IFG) in the left (dominant) cerebral hemisphere ,18,19. MBroadly similar regions have been consistently identified in neuroimaging studies of degraded speech processing, including superior temporal sulcus/gyrus  and magneto-encephalography (MEG) have revealed dynamic, oscillatory activity that synchronises neural circuits and large-scale networks . By deliAccurate and flexible understanding of speech depends critically on the capacity of speech processing circuitry to respond efficiently, dynamically, and adaptively to diverse auditory inputs in multiple contexts and environments . DegradeIn this review, we consider how and why the processing of degraded speech is affected in some major acquired brain disorders. Experimentally, many different types of speech degradation have been employed to study degraded speech processing: we summarise some of these in Healthy ageing importantly influences the perception of degraded speech ,95,96,97These alterations in auditory pathway function tend to be amplified by age-related decline in additional cognitive functions relevant to degraded speech perception. Ageing affects domains such as episodic memory, working memory, and attention ,104,105.The auditory system is dynamic and highly integrated with cognitive function more broadly ,110. ExeAttention, a key cognitive factor in most sensory predictive coding models, modulates the intelligibility of degraded speech, and functional magnetic resonance imaging (fMRI) research suggests that additional frontal cortical regions are recruited when listeners attend to degraded speech signals . AttentiAccumulated experience of speech signals and auditory environments over the course of the lifetime leads to the development and refinement of internal models that direct predictions about auditory input, facilitating faster neural encoding and integration . CertainBilingual speakers have more difficulty perceiving speech-in-noise in their non-native language than their monolingual counterparts, even when they consider themselves proficient in their non-native language ,138,139,Improved accuracy of degraded speech processing is associated with sustained exposure to the stimulus ,54,144: Although perceptual learning of degraded speech is strongest and most consistent if trained and tested with the same single speaker ,152,153,The functional consequences of degraded speech processing on communication cannot be fully appreciated without considering how perceptual alterations influence speech output. In the healthy brain, there is an intimate interplay between speech input and output processing, both functionally and neuroanatomically ,165: braThe various factors that affect the processing of degraded speech in the healthy brain are all potentially impacted by brain diseases. Brain disorders often affect executive function, speech production, perceptual learning and other general cognitive capacities, with many becoming more frequent with age and their expression may be heavily modified by life experience.We now consider some acquired neurological conditions that are associated with particular profiles of degraded speech processing; key studies are summarised in Traumatic brain injury (TBI) refers to any alteration in brain function or structure caused by an external physical force. It therefore encompasses a wide spectrum of insults, pathological mechanisms and transient and permanent cognitive deficits ,172. IndPeople with TBI frequently report difficulties understanding speech under challenging listening conditions and a variety of central auditory deficits have been documented, including impaired speech-in-noise perception and dichotic listening ,175,176;A number of abnormalities of degraded speech processing have been described in the context of aphasia following stroke. People with different forms of stroke-related aphasia have difficulties comprehending sentences spoken in an unfamiliar accent . As mighParkinson’s disease (PD), a neurodegenerative disorder caused primarily by the loss of dopaminergic neurons from the basal ganglia, is typically led by “extrapyramidal” motor symptoms including tremor, bradykinesia, and rigidity ,181. HowTaken together, the available evidence points to abnormal auditory-motor integration in PD that tends to impair the perception of degraded speech and to promote dysfunctional communication under challenging listening conditions. Candidate neuroanatomical substrates have been identified: enhanced evoked (P2) potentials in response to FAF in PD relative to healthy controls have been localised to activity in left superior and inferior frontal gyrus, premotor cortex, inferior parietal lobule, and superior temporal gyrus .Alzheimer’s disease (AD), the most common form of dementia, is typically considered to be an amnestic clinical syndrome underpinned by the degeneration of posterior hippocampus, entorhinal cortex, posterior cingulate, medial and lateral parietal regions within the so-called “default mode network” ,193. PeoPeople with AD have difficulty understanding non-native accents ,202 and Speech and language problems are leading features of the primary progressive aphasias (PPA). These “language-led dementias” constitute a heterogeneous group of disorders, comprising three cardinal clinico-anatomical syndromic variants. The nonfluent/agrammatic variant (nfvPPA) is characterised by disrupted speech and connected language production due to selective degeneration of a peri-Sylvian network centred on inferior frontal cortex and insula; the phenotype is quite variable between individual patients . The semWhile people with AD have relatively greater difficulty processing less familiar non-native accents, particularly at the level of phrases and sentences, those with nfvPPA show a more pervasive pattern of impairment affecting more and less familiar accents at the level of single words . People The structural and functional neuroanatomy of degraded speech processing has been addressed in somewhat more detail in PPA than in other brain disorders. Using a MEG paradigm in which noise-vocoded words were presented to participants alongside written text that either matched or mismatched the degraded words, Cope and colleagues  found thEmerging evidence in PPA suggests a framework for applying predictive coding theory as outlined for the healthy brain  to formuAccording to this model, nfvPPA—which affects inferior frontal and more posterior peri-Sylvian cortices—is associated with a “double-hit” to the degraded speech processing network. The most clearly established consequence is overly precise, top-down predictions due to neuronal dysfunction and loss in inferior frontal cortex . The topIn svPPA, the primary focus of atrophy in anterior temporal lobe principally affects the top-down integration of contextual and stored semantic information. This reduces neural capacity to modify semantic predictions about less predictable verbal signals , in line with experimental observations .In lvPPA, atrophy predominantly involving temporo-parietal cortex is anticipated to impair phonemic decoding and earlier stages in the representation of acoustic features in auditory cortex and brainstem due to altered top-down influences from the temporal parietal junction on auditory cortex and brainstem: this could be via altered precision weighting of prediction errors conveyed by the auditory efferent pathways, or inaccurate priors. This formulation has some experimental support ,215.Improved understanding of the pathophysiology of degraded speech processing in brain disorders is the path to effective therapeutic interventions. Several physiologically informed therapeutic approaches are in current use or have shown early promise. In a clinical context, it is important not to overlook ancillary nonverbal strategies to compensate for reduced capacity to process degraded speech: examples include the minimisation of environmental noise, training speakers to face the patient to maximise visual support and aid speech sound discrimination, and using gestures to support semantic context ,217. A rMore specifically, the finding that perceptual learning of degraded speech is retained in diverse brain disorders including dementias  and stroOther therapeutic approaches have focused on training auditory working memory. These have yielded mixed results , though Pharmacological approaches are potentially complementary to behavioural interventions or transcranial stimulation. In healthy individuals, dopamine has been shown to enhance the perception of spectrally shifted noise-vocoded speech . In patiLike any scientific paradigm, predictive coding demands a critical evaluation of falsifiable hypotheses. The issues in relation to the auditory system have been usefully reviewed previously in Heilbron and Chait . While iFirstly, to what extent is the processing of degraded speech generically underpinned by predictive coding? While the predictive coding paradigm is committed to finding optimal computational solutions to perceptual perturbations, much natural language use relies on acoustic or articulatory characteristics that are “sub-optimal” . More fuSecondly, how is the predictive coding of degraded speech instantiated in the brain? Although macroscopic neural network substrates that could support the required hierarchical and reciprocal information exchange have been delineated , the preThe perception and ultimately understanding of degraded speech relies upon flexible and dynamic neural interactions across distributed brain networks. These physiological and anatomical substrates are intrinsically vulnerable to the disruptive effects of brain disorders, particularly neurodegenerative pathologies that preferentially blight the core circuitry responsible for representing and decoding speech signals. Predictive coding offers an intuitive framework within which to consider degraded speech processing, both in the healthy brain  and in bFrom a neurobiological perspective, building on the model outlined for PPA in From a clinical perspective, the processing of degraded speech  might facilitate the early diagnosis of brain disorders. Neurodegenerative pathologies, in particular, often elude diagnosis in their early stages: degraded speech stimuli might be adapted to constitute dynamic, physiological “stress tests” to detect such pathologies. Similar pathophysiological principles should inform the design of behavioural and pharmacological therapies, such as those that harness neural plasticity: looking forward, such interventions could be particularly powerful if combined with disease modifying therapies, as integrated cognitive neurorehabilitation strategies motivated by neurobiological principles.