HIV-Specific Antibodies Capable of ADCC Are Common in Breastmilk and Are Associated with Reduced Risk of Transmission in Women with High Viral Loads

There are limited data describing the functional characteristics of HIV-1 specific antibodies in breast milk (BM) and their role in breastfeeding transmission. The ability of BM antibodies to bind HIV-1 envelope, neutralize heterologous and autologous viruses and direct antibody-dependent cell cytotoxicity (ADCC) were analyzed in BM and plasma obtained soon after delivery from 10 non-transmitting and 9 transmitting women with high systemic viral loads and plasma neutralizing antibodies (NAbs). Because subtype A is the dominant subtype in this cohort, a subtype A envelope variant that was sensitive to plasma NAbs was used to assess the different antibody activities. We found that NAbs against the subtype A heterologous virus and/or the woman's autologous viruses were rare in IgG and IgA purified from breast milk supernatant (BMS) – only 4 of 19 women had any detectable NAb activity against either virus. Detected NAbs were of low potency (median IC50 value of 10 versus 647 for the corresponding plasma) and were not associated with infant infection (p = 0.58). The low NAb activity in BMS versus plasma was reflected in binding antibody levels: HIV-1 envelope specific IgG titers were 2.2 log10 lower (compared to 0.59 log10 lower for IgA) in BMS versus plasma. In contrast, antibodies capable of ADCC were common and could be detected in the BMS from all 19 women. BMS envelope-specific IgG titers were associated with both detection of IgG NAbs (p = 0.0001)and BMS ADCC activity (p = 0.014). Importantly, BMS ADCC capacity was inversely associated with infant infection risk (p = 0.039). Our findings indicate that BMS has low levels of envelope specific IgG and IgA with limited neutralizing activity. However, this small study of women with high plasma viral loads suggests that breastmilk ADCC activity is a correlate of transmission that may impact infant infection risk

Impaired proprioception and magnified scaling of proprioceptive error responses in chronic stroke

Abstract Background Previous work has shown that ~ 50–60% of individuals have impaired proprioception after stroke. Typically, these studies have identified proprioceptive impairments using a narrow range of reference movements. While this has been important for identifying the prevalence of proprioceptive impairments, it is unknown whether these error responses are consistent for a broad range of reference movements. The objective of this study was to characterize proprioceptive accuracy as function of movement speed and distance in stroke. Methods Stroke (N = 25) and controls (N = 21) completed a robotic proprioception test that varied movement speed and distance. Participants mirror-matched various reference movement speeds (0.1–0.4 m/s) and distances (7.5–17.5 cm). Spatial and temporal parameters known to quantify proprioception were used to determine group differences in proprioceptive accuracy, and whether patterns of proprioceptive error were consistent across testing conditions within and across groups. Results Overall, we found that stroke participants had impaired proprioception compared to controls. Proprioceptive errors related to tested reference movement scaled similarly to controls, but some errors showed amplified scaling (e.g., significantly overshooting or undershooting reference speed). Further, interaction effects were present for speed and distance reference combinations at the extremes of the testing distribution. Conclusions We found that stroke participants have impaired proprioception and that some proprioceptive errors were dependent on characteristics of the movement (e.g., speed) and that reference movements at the extremes of the testing distribution resulted in significantly larger proprioceptive errors for the stroke group. Understanding how sensory information is utilized across a broad spectrum of movements after stroke may aid design of rehabilitation programs

Presentation_1_Aging increases proprioceptive error for a broad range of movement speed and distance estimates in the upper limb.pptx

Previous work has identified age-related declines in proprioception within a narrow range of limb movements. It is unclear whether these declines are consistent across a broad range of movement characteristics that more closely represent daily living. Here we aim to characterize upper limb error in younger and older adults across a range of movement speeds and distances. The objective of this study was to determine how proprioceptive matching accuracy changes as a function of movement speed and distance, as well as understand the effects of aging on these accuracies. We used an upper limb robotic test of proprioception to vary the speed and distance of movement in two groups: younger (n = 20, 24.25 ± 3.34 years) and older adults (n = 21, 63 ± 10.74 years). The robot moved one arm and the participant was instructed to mirror-match the movement with their opposite arm. Participants matched seven different movement speeds (0.1–0.4 m/s) and five distances (7.5–17.5 cm) over 350 trials. Spatial (e.g., End Point Error) and temporal (e.g., Peak Speed Ratio) outcomes were used to quantify proprioceptive accuracy. Regardless of the speed or distance of movement, we found that older controls had significantly reduced proprioceptive matching accuracy compared to younger control participants (p ≤ 0.05). When movement speed was varied, we observed that errors in proprioceptive matching estimates of spatial and temporal measures were significantly higher for older adults for all but the slowest tested speed (0.1 m/s) for the majority of parameters. When movement distance was varied, we observed that errors in proprioceptive matching estimates were significantly higher for all distances, except for the longest distance (17.5 cm) for older adults compared to younger adults. We found that the magnitude of proprioceptive matching errors was dependent on the characteristics of the reference movement, and that these errors scaled increasingly with age. Our results suggest that aging significantly negatively impacts proprioceptive matching accuracy and that proprioceptive matching errors made by both groups lies along a continuum that depends on movement characteristics and that these errors are amplified due to the typical aging process.</p

Kinesthetic deficits after perinatal stroke: robotic measurement in hemiparetic children

Abstract Background While sensory dysfunction is common in children with hemiparetic cerebral palsy (CP) secondary to perinatal stroke, it is an understudied contributor to disability with limited objective measurement tools. Robotic technology offers the potential to objectively measure complex sensorimotor function but has been understudied in perinatal stroke. The present study aimed to quantify kinesthetic deficits in hemiparetic children with perinatal stroke and determine their association with clinical function. Methods Case–control study. Participants were 6–19 years of age. Stroke participants had MRI confirmed unilateral perinatal arterial ischemic stroke or periventricular venous infarction, and symptomatic hemiparetic cerebral palsy. Participants completed a robotic assessment of upper extremity kinesthesia using a robotic exoskeleton (KINARM). Four kinesthetic parameters (response latency, initial direction error, peak speed ratio, and path length ratio) and their variabilities were measured with and without vision. Robotic outcomes were compared across stroke groups and controls and to clinical measures of sensorimotor function. Results Forty-three stroke participants (23 arterial, 20 venous, median age 12 years, 42% female) were compared to 106 healthy controls. Stroke cases displayed significantly impaired kinesthesia that remained when vision was restored. Kinesthesia was more impaired in arterial versus venous lesions and correlated with clinical measures. Conclusions Robotic assessment of kinesthesia is feasible in children with perinatal stroke. Kinesthetic impairment is common and associated with stroke type. Failure to correct with vision suggests sensory network dysfunction

Relative independence of upper limb position sense and reaching in children with hemiparetic perinatal stroke

Abstract Background Studies using clinical measures have suggested that proprioceptive dysfunction is related to motor impairment of the upper extremity following adult stroke. We used robotic technology and clinical measures to assess the relationship between position sense and reaching with the hemiparetic upper limb in children with perinatal stroke. Methods Prospective term-born children with magnetic resonance imaging-confirmed perinatal ischemic stroke and upper extremity deficits were recruited from a population-based cohort. Neurotypical controls were recruited from the community. Participants completed two tasks in the Kinarm robot: arm position-matching (three parameters: variability [Varxy], contraction/expansion [Areaxy], systematic spatial shift [Shiftxy]) and visually guided reaching (five parameters: posture speed [PS], reaction time [RT], initial direction error [IDE], speed maxima count [SMC], movement time [MT]). Additional clinical assessments of sensory (thumb localization test) and motor impairment (Assisting Hand Assessment, Chedoke-McMaster Stroke Assessment) were completed and compared to robotic measures. Results Forty-eight children with stroke (26 arterial, 22 venous, mean age: 12.0 ± 4.0 years) and 145 controls (mean age: 12.8 ± 3.9 years) completed both tasks. Position-matching performance in children with stroke did not correlate with performance on the visually guided reaching task. Robotic sensory and motor measures correlated with only some clinical tests. For example, AHA scores correlated with reaction time (R = − 0.61, p < 0.001), initial direction error (R = − 0.64, p < 0.001), and movement time (R = − 0.62, p < 0.001). Conclusions Robotic technology can quantify complex, discrete aspects of upper limb sensory and motor function in hemiparetic children. Robot-measured deficits in position sense and reaching with the contralesional limb appear to be relatively independent of each other and correlations for both with clinical measures are modest. Knowledge of the relationship between sensory and motor impairment may inform future rehabilitation strategies and improve outcomes for children with hemiparetic cerebral palsy

Bilateral reaching deficits after unilateral perinatal ischemic stroke: a population-based case-control study

Abstract Background Detailed kinematics of motor impairment of the contralesional (“affected”) and ipsilesional (“unaffected”) limbs in children with hemiparetic cerebral palsy are not well understood. We aimed to 1) quantify the kinematics of reaching in both arms of hemiparetic children with perinatal stroke using a robotic exoskeleton, and 2) assess the correlation of kinematic reaching parameters with clinical motor assessments. Methods This prospective, case-control study involved the Alberta Perinatal Stroke Project, a population-based research cohort, and the Foothills Medical Center Stroke Robotics Laboratory in Calgary, Alberta over a four year period. Prospective cases were collected through the Calgary Stroke Program and included term-born children with magnetic resonance imaging confirmed perinatal ischemic stroke and upper extremity deficits. Control participants were recruited from the community. Participants completed a visually guided reaching task in the KINARM robot with each arm separately, with 10 parameters quantifying motor function. Kinematic measures were compared to clinical assessments and stroke type. Results Fifty children with perinatal ischemic stroke (28 arterial, mean age: 12.5 ± 3.9 years; 22 venous, mean age: 11.5 ± 3.8 years) and upper extremity deficits were compared to healthy controls (n = 147, mean age: 12.7 ± 3.9 years). Perinatal stroke groups demonstrated contralesional motor impairments compared to controls when reaching out (arterial = 10/10, venous = 8/10), and back (arterial = 10/10, venous = 6/10) with largest errors in reaction time, initial direction error, movement length and time. Ipsilesional impairments were also found when reaching out (arterial = 7/10, venous = 1/10) and back (arterial = 6/10). The arterial group performed worse than venous on both contralesional and ipsilesional parameters. Contralesional reaching parameters showed modest correlations with clinical measures in the arterial group. Conclusions Robotic assessment of reaching behavior can quantify complex, upper limb dysfunction in children with perinatal ischemic stroke. The ipsilesional, “unaffected” limb is often abnormal and may be a target for therapeutic interventions in stroke-induced hemiparetic cerebral palsy

Impairments of the ipsilesional upper-extremity in the first 6-months post-stroke

Abstract Background Ipsilesional motor impairments of the arm are common after stroke. Previous studies have suggested that severity of contralesional arm impairment and/or hemisphere of lesion may predict the severity of ipsilesional arm impairments. Historically, these impairments have been assessed using clinical scales, which are less sensitive than robot-based measures of sensorimotor performance. Therefore, the objective of this study was to characterize progression of ipsilesional arm motor impairments using a robot-based assessment of motor function over the first 6-months post-stroke and quantify their relationship to (1) contralesional arm impairment severity and (2) stroke-lesioned hemisphere. Methods A total of 106 participants with first-time, unilateral stroke completed a unilateral assessment of arm motor impairment (visually guided reaching task) using the Kinarm Exoskeleton. Participants completed the assessment along with a battery of clinical measures with both ipsilesional and contralesional arms at 1-, 6-, 12-, and 26-weeks post-stroke. Results Robotic assessment of arm motor function revealed a higher incidence of ipsilesional arm impairment than clinical measures immediately post-stroke. The incidence of ipsilesional arm impairments decreased from 47 to 14% across the study period. Kolmogorov–Smirnov tests revealed that ipsilesional arm impairment severity, as measured by our task, was not related to which hemisphere was lesioned. The severity of ipsilesional arm impairments was variable but displayed moderate significant relationships to contralesional arm impairment severity with some robot-based parameters. Conclusions Ipsilesional arm impairments were variable. They displayed relationships of varying strength with contralesional impairments and were not well predicted by lesioned hemisphere. With standard clinical care, 86% of ipsilesional impairments recovered by 6-months post-stroke

Disruption in proprioception from long-term thalamic deep brain stimulation: A pilot study

Deep brain stimulation (DBS) is an excellent treatment for tremor and is generally thought to be reversible by turning off stimulation. For tremor, DBS is implanted in the ventrointermedius (Vim) nucleus of the thalamus, a region that relays proprioceptive information for movement sensation (kinaesthesia). Gait disturbances have been observed with bilateral Vim DBS, but the long-term effects on proprioceptive processing are unknown. We aimed to determine whether Vim DBS surgical implantation or stimulation leads to proprioceptive deficits in the upper limb. We assessed two groups of tremor subjects on measures of proprioception (kinaesthesia, position sense) and motor function using a robotic exoskeleton. In the first group (Surgery), we tested patients before and after implantation of Vim DBS, but before DBS was turned on to determine if proprioceptive deficits were inherent to tremor or caused by DBS implantation. In the second group (Stim), we tested subjects with chronically implanted Vim DBS ON and OFF stimulation. Compared to controls, there were no proprioceptive deficits before or after DBS implantation in the Surgery group. Surprisingly, those that received chronic long-term stimulation (LT-stim, 3-10 years) displayed significant proprioceptive deficits ON and OFF stimulation not present in subjects with chronic short-term stimulation (ST-stim, 0.5-2 years). LT-stim had significantly larger variability and reduced workspace area during the position sense assessment. During the kinesthetic assessment, LT-stim made significantly larger directional errors and consistently underestimated the speed of the robot, despite generating normal movement speeds during motor assessment. Chronic long-term Vim DBS may potentially disrupt proprioceptive processing, possibly inducing irreversible plasticity in the Vim nucleus and/or its network connections. Our findings in the upper limb may help explain some of the gait disturbances seen by others following Vim DB

Inter-rater reliability of kinesthetic measurements with the KINARM robotic exoskeleton

Abstract Background Kinesthesia (sense of limb movement) has been extremely difficult to measure objectively, especially in individuals who have survived a stroke. The development of valid and reliable measurements for proprioception is important to developing a better understanding of proprioceptive impairments after stroke and their impact on the ability to perform daily activities. We recently developed a robotic task to evaluate kinesthetic deficits after stroke and found that the majority (~60%) of stroke survivors exhibit significant deficits in kinesthesia within the first 10 days post-stroke. Here we aim to determine the inter-rater reliability of this robotic kinesthetic matching task. Methods Twenty-five neurologically intact control subjects and 15 individuals with first-time stroke were evaluated on a robotic kinesthetic matching task (KIN). Subjects sat in a robotic exoskeleton with their arms supported against gravity. In the KIN task, the robot moved the subjects’ stroke-affected arm at a preset speed, direction and distance. As soon as subjects felt the robot begin to move their affected arm, they matched the robot movement with the unaffected arm. Subjects were tested in two sessions on the KIN task: initial session and then a second session (within an average of 18.2 ± 13.8 h of the initial session for stroke subjects), which were supervised by different technicians. The task was performed both with and without the use of vision in both sessions. We evaluated intra-class correlations of spatial and temporal parameters derived from the KIN task to determine the reliability of the robotic task. Results We evaluated 8 spatial and temporal parameters that quantify kinesthetic behavior. We found that the parameters exhibited moderate to high intra-class correlations between the initial and retest conditions (Range, r-value = [0.53–0.97]). Conclusions The robotic KIN task exhibited good inter-rater reliability. This validates the KIN task as a reliable, objective method for quantifying kinesthesia after stroke