The Effect of Sensory Reweighting on Postural Control and Cortical Activity in Parkinson's Disease.

Aims: Balance requires the cortical control of visual, somatosensory, and vestibular inputs. The aim of this cross-sectional study was to compare the contributions of each of these systems on postural control and cortical activity using a sensory reweighting approach between participants with Parkinson's disease (PD) and controls. Methods: Ten participants with PD (age: 72 ± 9; 3 women; Hoehn & Yahr: 2 [1.5 - 2.50]) and 11 controls (age: 70 ± 3; 4 women) completed a sensory organization test in virtual reality (VR-SOT) while cortical activity was being recorded using electroencephalography (EEG). Conditions 1 to 3 were completed on a stable platform; conditions 4 to 6 on a foam. Conditions 1 and 4 were done with eyes open; conditions 2 and 5 in a darkened VR environment; and conditions 3 and 6 in a moving VR environment. Linear mixed models were used to evaluate changes in center of pressure (COP) displacement and EEG alpha and theta/beta ratio power between the two groups across the postural control conditions. Condition 1 was used as reference in all analyses. Results: Participants with PD showed greater COP displacement than controls in the anteroposterior (AP) direction when relying on vestibular input (condition 5; p<0.0001). The mediolateral (ML) COP sway was greater in PD than in controls when relying on the somatosensory (condition 2; p = 0.03), visual (condition 4; p = 0.002), and vestibular (condition 5; p < 0.0001) systems. Participants with PD exhibited greater alpha power compared to controls when relying on visual input (condition 2; p = 0.003) and greater theta/beta ratio power when relying on somatosensory input (condition 4; p = 0.001). Conclusions: PD affects reweighting of postural control, exemplified by greater COP displacement and increased cortical activity. Further research is needed to establish the temporal dynamics between cortical activity and COP displacement.

A Double-Blind Randomised Controlled Trial of Prebiotic Supplementation in Children with Autism: Effects on Parental Quality of Life, Child Behaviour, Gastrointestinal Symptoms, and the Microbiome.

PURPOSE: Modifying gut bacteria in children with autism may influence behaviour, with potential to improve family functioning. We conducted a randomised controlled trial to assess the effect of prebiotics on behaviour, gastrointestinal symptoms and downstream effects on parental quality of life. METHOD: Children with autism (4-10yrs) were randomised to 2.4 g/d of prebiotic (GOS) or placebo for six weeks. Pre and post stools samples were collected, and validated questionnaires used to measure change in social and mealtime behaviours, GI symptoms and pQOL. Linear mixed models evaluated group differences for behavioural variables, and Mann Whitney U tests were used to compare change between-groups for GI symptoms, differential abundance of genera and alpha diversity of the microbiome. RESULTS: Thirty-three parent-child dyads completed the trial. No group difference was seen for behavioural variables but both groups improved significantly from baseline. There was a medium effect size between groups for GI symptoms (d = 0.47) and pQOL (d = 0.44) driven by greater improvements in the prebiotic group. Bifidobacterium increased threefold following prebiotics (1.4-5.9%, p < 0.001) with no change in controls. Supplements were well tolerated, compliance with dose 94%. CONCLUSION: Prebiotics modify levels of Bifidobacterium and prove well tolerated but in this instance, resulted in only marginal effects on GI symptoms and pQOL. A larger sample of children with more severe symptoms could help to determine the potential of prebiotics in autism. TRIAL REGISTRATION: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12619000615189 .

Aerobic Exercise Improves Cortical Inhibitory Function After Stroke: A Preliminary Investigation.

BACKGROUND AND PURPOSE: Aerobic exercise can elicit positive effects on neuroplasticity and cognitive executive function but is poorly understood after stroke. We tested the effect of 4 weeks of aerobic exercise training on inhibitory and facilitatory elements of cognitive executive function and electroencephalography markers of cortical inhibition and facilitation. We investigated relationships between stimulus-evoked cortical responses, blood lactate levels during training, and aerobic fitness postintervention. METHODS: Twelve individuals with chronic (>6 months) stroke completed an aerobic exercise intervention (40 minutes, 3×/wk). Electroencephalography and motor response times were assessed during congruent (response facilitation) and incongruent (response inhibition) stimuli of a Flanker task. Aerobic fitness capacity was assessed as o2peak during a treadmill test pre- and postintervention. Blood lactate was assessed acutely (<1 minute) after exercise each week. Cortical inhibition (N2) and facilitation (frontal P3) were quantified as peak amplitudes and latencies of stimulus-evoked electroencephalographic activity over the frontal cortical region. RESULTS: Following exercise training, the response inhibition speed increased while response facilitation remained unchanged. A relationship between earlier cortical N2 response and faster response inhibition emerged postintervention. Individuals who produced higher lactate during exercise training achieved faster response inhibition and tended to show earlier cortical N2 responses postintervention. There were no associations between o2peak and metrics of behavioral or neurophysiologic function. DISCUSSION AND CONCLUSIONS: These preliminary findings provide novel evidence for selective benefits of aerobic exercise on inhibitory control during the initial 4-week period after initiation of exercise training and implicate a potential therapeutic effect of lactate on poststroke inhibitory control.

Delayed cortical engagement associated with balance dysfunction after stroke.

Cortical resources are typically engaged for balance and mobility in older adults, but these resources are impaired post-stroke. Although slowed balance and mobility after stroke have been well-characterized, the effects of unilateral cortical lesions due to stroke on neuromechanical control of balance is poorly understood. Our central hypothesis is that stroke impairs the ability to rapidly and effectively engage the cerebral cortex during balance and mobility behaviors, resulting in asymmetrical contributions of each limb to balance control. Using electroencephalography (EEG), we assessed cortical N1 responses evoked over fronto-midline regions (Cz) during balance recovery in response to backward support-surface perturbations loading both legs, as well as posterior-lateral directions that preferentially load the paretic or nonparetic leg. Cortical N1 responses were smaller and delayed in the stroke group. While older adults exhibited weak or absent relationships between cortical responses and clinical function, stroke survivors exhibited strong associations between slower N1 latencies and slower walking, lower clinical mobility, and lower balance function. We further assessed kinetics of balance recovery during perturbations using center of pressure rate of rise. During backward support-surface perturbations that loaded the legs bilaterally, balance recovery kinetics were not different between stroke and control groups and were not associated with cortical response latency. However, lateralized perturbations revealed slower kinetic reactions during paretic loading compared to controls, and to non-paretic loading within stroke participants. Individuals post stroke had similar nonparetic-loaded kinetic reactions to controls implicating that they effectively compensate for impaired paretic leg kinetics when relying on the non-paretic leg. In contrast, paretic-loaded balance recovery revealed time-synchronized associations between slower cortical responses and slower kinetic reactions only in the stroke group, potentially reflecting the limits of cortical engagement for balance recovery revealed within the behavioral context of paretic motor capacity. Overall, our results implicate individuals after stroke may be uniquely limited in their balance ability by the slowed speed of their cortical engagement, particularly under challenging balance conditions that rely on the paretic leg. We expect this neuromechanical insight will enable progress toward an individualized framework for the assessment and treatment of balance impairments based on the interaction between neuropathology and behavioral context.

Optimal Intensity and Duration of Walking Rehabilitation in Patients With Chronic Stroke: A Randomized Clinical Trial.

Importance: For walking rehabilitation after stroke, training intensity and duration are critical dosing parameters that lack optimization. Objective: To assess the optimal training intensity (vigorous vs moderate) and minimum training duration (4, 8, or 12 weeks) needed to maximize immediate improvement in walking capacity in patients with chronic stroke. Design, Setting, and Participants: This multicenter randomized clinical trial using an intent-to-treat analysis was conducted from January 2019 to April 2022 at rehabilitation and exercise research laboratories. Survivors of a single stroke who were aged 40 to 80 years and had persistent walking limitations 6 months or more after the stroke were enrolled. Interventions: Participants were randomized 1:1 to high-intensity interval training (HIIT) or moderate-intensity aerobic training (MAT), each involving 45 minutes of walking practice 3 times per week for 12 weeks. The HIIT protocol used repeated 30-second bursts of walking at maximum safe speed, alternated with 30- to 60-second rest periods, targeting a mean aerobic intensity above 60% of the heart rate reserve (HRR). The MAT protocol used continuous walking with speed adjusted to maintain an initial target of 40% of the HRR, progressing up to 60% of the HRR as tolerated. Main Outcomes and Measures: The main outcome was 6-minute walk test distance. Outcomes were assessed by blinded raters after 4, 8, and 12 weeks of training. Results: Of 55 participants (mean [SD] age, 63 [10] years; 36 male [65.5%]), 27 were randomized to HIIT and 28 to MAT. The mean (SD) time since stroke was 2.5 (1.3) years, and mean (SD) 6-minute walk test distance at baseline was 239 (132) m. Participants attended 1675 of 1980 planned treatment visits (84.6%) and 197 of 220 planned testing visits (89.5%). No serious adverse events related to study procedures occurred. Groups had similar 6-minute walk test distance changes after 4 weeks (HIIT, 27 m [95% CI, 6-48 m]; MAT, 12 m [95% CI, -9 to 33 m]; mean difference, 15 m [95% CI, -13 to 42 m]; P = .28), but HIIT elicited greater gains after 8 weeks (58 m [95% CI, 39-76 m] vs 29 m [95% CI, 9-48 m]; mean difference, 29 m [95% CI, 5-54 m]; P = .02) and 12 weeks (71 m [95% CI, 49-94 m] vs 27 m [95% CI, 3-50 m]; mean difference, 44 m [95% CI, 14-74 m]; P = .005) of training; HIIT also showed greater improvements than MAT on some secondary measures of gait speed and fatigue. Conclusions and Relevance: These findings show proof of concept that vigorous training intensity is a critical dosing parameter for walking rehabilitation. In patients with chronic stroke, vigorous walking exercise produced significant and meaningful gains in walking capacity with only 4 weeks of training, but at least 12 weeks were needed to maximize immediate gains. Trial Registration: ClinicalTrials.gov Identifier: NCT03760016.

Computed Analysis of Retinal Vascular Growth After Bevacizumab Treatment of Retinopathy of Prematurity Until Age 3 Years.

PURPOSE: Premature infants, after anti-vascular endothelial growth factor injections for retinopathy of prematurity, have persistent peripheral avascular retina (PAR). PAR is ablated with laser; however, physiologic growth of the retinal vasculature in the long term has not been measured. The purposes of this study were to measure retinal vessel growth after treatment with intravitreal bevacizumab (IVB) for retinopathy of prematurity, using serial fluorescein angiography (FA), until age 3 years, and to assess the timing for providing laser ablation in PAR. METHODS: Data from an observational, longitudinal clinical study were collected. Angiographic images of eyes treated with IVB were included; imaging data from laser photocoagulation were excluded. All eyes underwent initial examination under general anesthesia with FA and photographic imaging. The retinal vessel length was measured from the temporal margin of the optic disc passing through the foveal center, and the lengths at subsequent FA were compared. To compare the changes in retinal vessel length over time in individual eyes, a paired-sample t test was performed. FINDINGS: FA images from 70 eyes (35 infants) treated with IVB were available. A total of 150 FA images were available for review; data from 125 images of good quality were used for analysis. The mean postmenstrual ages (PMAs) at first, second, third, and fourth FA were 66.2, 100.9, 135.1, and 180.7 weeks, respectively. The mean retinal vessel length was 14.177 mm at first FA and 13.199 mm at fourth FA (PMA range, 42...234 weeks). Retinal vascular lengths of individual eyes compared over time showed no statistically significant growth from the first FA to age 3 years. The changes in retinal vessel length from first to second FA were -0.117 ± 0.79 mm (p = 0.42; n = 30); from first to third FA, +0.060 ± 0.85 mm (p = 0.79; n = 15); and first to fourth FA, -0.404 ± 1.32 mm (p = 0.45; n = 7). IMPLICATIONS: Beyond 65 weeks' PMA, no meaningful retinal vascular growth occurred after IVB up to age 3 years, guiding the timing for physicians if laser photocoagulation is being considered. Future studies are needed to address retinal growth changes in the growing eyes of infants.

Hippocampal blood flow rapidly and preferentially increases after a bout of moderate-intensity exercise in older adults with poor cerebrovascular health.

Over the course of aging, there is an early degradation of cerebrovascular health, which may be attenuated with aerobic exercise training. Yet, the acute cerebrovascular response to a single bout of exercise remains elusive, particularly within key brain regions most affected by age-related disease processes. We investigated the acute global and region-specific cerebral blood flow (CBF) response to 15 minutes of moderate-intensity aerobic exercise in older adults (≥65 years; n = 60) using arterial spin labeling magnetic resonance imaging. Within 0-6 min post-exercise, CBF decreased across all regions, an effect that was attenuated in the hippocampus. The exercise-induced CBF drop was followed by a rebound effect over the 24-minute postexercise assessment period, an effect that was most robust in the hippocampus. Individuals with low baseline perfusion demonstrated the greatest hippocampal-specific CBF effect post-exercise, showing no immediate drop and a rapid increase in CBF that exceeded baseline levels within 6-12 minutes postexercise. Gains in domain-specific cognitive performance postexercise were not associated with changes in regional CBF, suggesting dissociable effects of exercise on acute neural and vascular plasticity. Together, the present findings support a precision-medicine framework for the use of exercise to target brain health that carefully considers age-related changes in the cerebrovascular system.

Sex Differences in Resilience and Resistance to Brain Pathology and Dysfunction Moderated by Cerebrovascular Response to Exercise and Genetic Risk for Alzheimer's Disease.

Sex as a biological variable appears to contribute to the multifactorial etiology of Alzheimer's disease. We tested sex-based interactions between cerebrovascular function and APOE4 genotype on resistance and resilience to brain pathology and cognitive executive dysfunction in cognitively-normal older adults. Female APOE4 carriers had higher amyloid-ß deposition yet achieved similar cognitive performance to males and female noncarriers. Further, female APOE4 carriers with robust cerebrovascular responses to exercise possessed lower amyloid-ß. These results suggest a unique cognitive resilience and identify cerebrovascular function as a key mechanism for resistance to age-related brain pathology in females with high genetic vulnerability to Alzheimer's disease.

Dementia risk and dynamic response to exercise: A non-randomized clinical trial.

BACKGROUND: Physical exercise may support brain health and cognition over the course of typical aging. The goal of this nonrandomized clinical trial was to examine the effect of an acute bout of aerobic exercise on brain blood flow and blood neurotrophic factors associated with exercise response and brain function in older adults with and without possession of the Apolipoprotein epsilon 4 (APOE4) allele, a genetic risk factor for developing Alzheimer's. We hypothesized that older adult APOE4 carriers would have lower cerebral blood flow regulation and would demonstrate blunted neurotrophic response to exercise compared to noncarriers. METHODS: Sixty-two older adults (73±5 years old, 41 female [67%]) consented to this prospectively enrolling clinical trial, utilizing a single arm, single visit, experimental design, with post-hoc assessment of difference in outcomes based on APOE4 carriership. All participants completed a single 15-minute bout of moderate-intensity aerobic exercise. The primary outcome measure was change in cortical gray matter cerebral blood flow in cortical gray matter measured by magnetic resonance imaging (MRI) arterial spin labeling (ASL), defined as the total perfusion (area under the curve, AUC) following exercise. Secondary outcomes were changes in blood neurotrophin concentrations of insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), and brain derived neurotrophic factor (BDNF). RESULTS: Genotyping failed in one individual (n = 23 APOE4 carriers and n = 38 APOE4 non-carriers) and two participants could not complete primary outcome testing. Cerebral blood flow AUC increased immediately following exercise, regardless of APOE4 carrier status. In an exploratory regional analyses, we found that cerebral blood flow increased in hippocampal brain regions, while showing no change in cerebellum across both groups. Among high inter-individual variability, there were no significant changes in any of the 3 neurotrophic factors for either group immediately following exercise. CONCLUSIONS: Our findings show that both APOE4 carriers and non-carriers show similar effects of exercise-induced increases in cerebral blood flow and neurotrophic response to acute aerobic exercise. Our results provide further evidence that acute exercise-induced increases in cerebral blood flow may be regional specific, and that exercise-induced neurotrophin release may show a differential effect in the aging cardiovascular system. Results from this study provide an initial characterization of the acute brain blood flow and neurotrophin responses to a bout of exercise in older adults with and without this known risk allele for cardiovascular disease and Alzheimer's disease. TRIAL REGISTRATION: Dementia Risk and Dynamic Response to Exercise (DYNAMIC); Identifier: NCT04009629.

Cerebrovascular response to exercise interacts with individual genotype and amyloid-beta deposition to influence response inhibition with aging.

The etiology of cognitive dysfunction associated with Alzheimer's disease (AD) and dementia is multifactorial. Yet, mechanistic interactions among key neurobiological factors linked to AD pathology are unclear. This study tested the effect of interactions between cerebrovascular function, individual genotype, and structural brain pathology on response inhibition performance, an early and sensitive indicator of cognitive executive dysfunction with aging. We quantified cerebrovascular response (CVR) to moderate-intensity aerobic exercise using transcranial doppler ultrasound and global amyloid-beta (Aß) deposition using positron emission tomography in a group of cognitively normal older adults genotyped as APOE4 carriers and noncarriers. We quantified response inhibition during a cognitive Stroop test. Individuals with blunted CVR possessed greater Aß deposition. There was CVR-by-carrier status-by-Aß interaction on response inhibition. Blunted CVR was associated with impaired response inhibition specifically in APOE4 carriers. Despite having greater Aß deposition, APOE4 carriers with higher CVR demonstrated better response inhibition. Cerebrovascular interactions with individual genotype and structural brain pathology may provide a physiologically-informed target for precision-medicine approaches for early treatment and prevention of cognitive dysfunction with aging.

Lower Cognitive Set Shifting Ability Is Associated With Stiffer Balance Recovery Behavior and Larger Perturbation-Evoked Cortical Responses in Older Adults.

The mechanisms underlying associations between cognitive set shifting impairments and balance dysfunction are unclear. Cognitive set shifting refers to the ability to flexibly adjust behavior to changes in task rules or contexts, which could be involved in flexibly adjusting balance recovery behavior to different contexts, such as the direction the body is falling. Prior studies found associations between cognitive set shifting impairments and severe balance dysfunction in populations experiencing frequent falls. The objective of this study was to test whether cognitive set shifting ability is expressed in successful balance recovery behavior in older adults with high clinical balance ability (N = 19, 71 ± 7 years, 6 female). We measured cognitive set shifting ability using the Trail Making Test and clinical balance ability using the miniBESTest. For most participants, cognitive set shifting performance (Trail Making Test B-A = 37 ± 20 s) was faster than normative averages (46 s for comparable age and education levels), and balance ability scores (miniBESTest = 25 ± 2/28) were above the threshold for fall risk (23 for people between 70 and 80 years). Reactive balance recovery in response to support-surface translations in anterior and posterior directions was assessed in terms of body motion, muscle activity, and brain activity. Across participants, lower cognitive set shifting ability was associated with smaller peak center of mass displacement during balance recovery, lower directional specificity of late phase balance-correcting muscle activity (i.e., greater antagonist muscle activity 200-300 ms after perturbation onset), and larger cortical N1 responses (100-200 ms). None of these measures were associated with clinical balance ability. Our results suggest that cognitive set shifting ability is expressed in balance recovery behavior even in the absence of profound clinical balance disability. Specifically, our results suggest that lower flexibility in cognitive task performance is associated with lower ability to incorporate the directional context into the cortically mediated later phase of the motor response. The resulting antagonist activity and stiffer balance behavior may help explain associations between cognitive set shifting impairments and frequent falls.

Motor Cortical Network Flexibility is Associated With Biomechanical Walking Impairment in Chronic Stroke.

Background: The inability to flexibly modulate motor behavior with changes in task demand or environmental context is a pervasive feature of motor impairment and dysfunctional mobility after stroke. Objective: The purpose of this study was to test the reactive and modulatory capacity of lower-limb primary motor cortical (M1) networks using electroencephalography (EEG) measures of cortical activity evoked by transcranial magnetic stimulation (TMS) and to evaluate their associations with clinical and biomechanical measures of walking function in chronic stroke. Methods: TMS assessments of motor cortex excitability were performed during rest and active ipsilateral plantarflexion in chronic stroke and age-matched controls. TMS-evoked motor cortical network interactions were quantified with simultaneous EEG as the post-TMS (0-300 ms) beta (15-30 Hz) coherence between electrodes overlying M1 bilaterally. We compared TMS-evoked coherence between groups during rest and active conditions and tested associations with poststroke motor impairment, paretic propulsive gait deficits, and the presence of paretic leg motor evoked potentials (MEPs). Results: Stroke (n = 14, 66 ± 9 years, F = 4) showed lower TMS-evoked cortical coherence and activity-dependent modulation compared to controls (n = 9, 68 ± 6 years, F = 3). Blunted reactivity and atypical modulation of TMS-evoked coherence were associated with lower paretic ankle moments for propulsive force generation during walking and absent paretic MEPs. Conclusions: Impaired flexibility of motor cortical networks to react to TMS and modulate during motor activity is distinctly associated with paretic limb biomechanical walking impairment, and may provide useful insight into the neuromechanistic underpinnings of chronic post-stroke mobility deficits.

Cortical Engagement Metrics During Reactive Balance Are Associated With Distinct Aspects of Balance Behavior in Older Adults.

Heightened reliance on the cerebral cortex for postural stability with aging is well-known, yet the cortical mechanisms for balance control, particularly in relation to balance function, remain unclear. Here we aimed to investigate motor cortical activity in relation to the level of balance challenge presented during reactive balance recovery and identify circuit-specific interactions between motor cortex and prefrontal or somatosensory regions in relation to metrics of balance function that predict fall risk. Using electroencephalography, we assessed motor cortical beta power, and beta coherence during balance reactions to perturbations in older adults. We found that individuals with greater motor cortical beta power evoked following standing balance perturbations demonstrated lower general clinical balance function. Individual older adults demonstrated a wide range of cortical responses during balance reactions at the same perturbation magnitude, showing no group-level change in prefrontal- or somatosensory-motor coherence in response to perturbations. However, older adults with the highest prefrontal-motor coherence during the post-perturbation, but not pre-perturbation, period showed greater cognitive dual-task interference (DTI) and elicited stepping reactions at lower perturbation magnitudes. Our results support motor cortical beta activity as a potential biomarker for individual level of balance challenge and implicate prefrontal-motor cortical networks in distinct aspects of balance control involving response inhibition of reactive stepping in older adults. Cortical network activity during balance may provide a neural target for precision-medicine efforts aimed at fall prevention with aging.

Cortical Beta Oscillatory Activity Evoked during Reactive Balance Recovery Scales with Perturbation Difficulty and Individual Balance Ability.

Cortical beta oscillations (13-30 Hz) reflect sensorimotor processing, but are not well understood in balance recovery. We hypothesized that sensorimotor cortical activity would increase under challenging balance conditions. We predicted greater beta power when balance was challenged, either by more difficult perturbations or by lower balance ability. In 19 young adults, we measured beta power over motor cortical areas (electroencephalography, Cz electrode) during three magnitudes of backward support -surface translations. Peak beta power was measured during early (50-150 ms), late (150-250 ms), and overall (0-400 ms) time bins, and wavelet-based analyses quantified the time course of evoked beta power. An ANOVA was used to compare peak beta power across perturbation magnitudes in each time bin. We further tested the association between perturbation-evoked beta power and individual balance ability measured in a challenging beam walking task. Beta power increased ~50 ms after perturbation, and to a greater extent in larger perturbations. Lower individual balance ability was associated with greater beta power in only the late (150-250 ms) time bin. These findings demonstrate greater sensorimotor cortical engagement under more challenging balance conditions, which may provide a biomarker for reduced automaticity in balance control that could be used in populations with neurological impairments.

Role of Interhemispheric Cortical Interactions in Poststroke Motor Function.

Background/Objective. We investigated interhemispheric interactions in stroke survivors by measuring transcranial magnetic stimulation (TMS)-evoked cortical coherence. We tested the effect of TMS on interhemispheric coherence during rest and active muscle contraction and compared coherence in stroke and older adults. We evaluated the relationships between interhemispheric coherence, paretic motor function, and the ipsilateral cortical silent period (iSP). Methods. Participants with (n = 19) and without (n = 14) chronic stroke either rested or maintained a contraction of the ipsilateral hand muscle during simultaneous recordings of evoked responses to TMS of the ipsilesional/nondominant (i/ndM1) and contralesional/dominant (c/dM1) primary motor cortex with EEG and in the hand muscle with EMG. We calculated pre- and post-TMS interhemispheric beta coherence (15-30 Hz) between motor areas in both conditions and the iSP duration during the active condition. Results. During active i/ndM1 TMS, interhemispheric coherence increased immediately following TMS in controls but not in stroke. Coherence during active cM1 TMS was greater than iM1 TMS in the stroke group. Coherence during active iM1 TMS was less in stroke participants and was negatively associated with measures of paretic arm motor function. Paretic iSP was longer compared with controls and negatively associated with clinical measures of manual dexterity. There was no relationship between coherence and. iSP for either group. No within- or between-group differences in coherence were observed at rest. Conclusions. TMS-evoked cortical coherence during hand muscle activation can index interhemispheric interactions associated with poststroke motor function and potentially offer new insights into neural mechanisms influencing functional recovery.

Modulatory Effects of Motor State During Paired Associative Stimulation on Motor Cortex Excitability and Motor Skill Learning.

Repeated pairing of electrical stimulation of a peripheral nerve with transcranial magnetic stimulation (TMS) over the primary motor cortex (M1) representation for a target muscle can induce neuroplastic adaptations in the human brain related to motor learning. The extent to which the motor state during this form of paired associative stimulation (PAS) influences the degree and mechanisms of neuroplasticity or motor learning is unclear. Here, we investigated the effect of volitional muscle contraction during PAS on: (1) measures of general corticomotor excitability and intracortical circuit excitability; and (2) motor performance and learning. We assessed measures of corticomotor excitability using TMS and motor skill performance during a serial reaction time task (SRTT) at baseline and at 0, 30, 60 min post-PAS. Participants completed a SRTT retention test 1 week following the first two PAS sessions. Following the PAS intervention where the hand muscle maintained an active muscle contraction (PASACTIVE), there was lower short interval intracortical inhibition compared to PAS during a resting motor state (PASREST) and a sham PAS condition (PASCONTROL). SRTT performance improved within the session regardless of PAS condition. SRTT retention was greater following both PASACTIVE and PASREST after 1 week compared to PASCONTROL. These findings suggest that PAS may enhance motor learning retention and that motor state may be used to target different neural mechanisms of intracortical excitation and inhibition during PAS. This observation may be important to consider for the use of therapeutic noninvasive brain stimulation in neurologic patient populations.

Higher Incidence Rates of Comorbidities in Patients with Psoriatic Arthritis Compared with the General Population Using U.S. Administrative Claims Data.

BACKGROUND: Psoriatic arthritis (PsA) is associated with multiple comorbid conditions, including cardiovascular (CV) comorbidities that impose a considerable burden on patients. Effective management of PsA requires an understanding of comorbidity profiles. OBJECTIVE: To compare the frequency and incidence rates of comorbidities and hospitalizations among newly diagnosed PsA patients and a matched general population without PsA, using large national claims databases in the United States. METHODS: This retrospective observational study used MarketScan databases from January 1, 2008, to September 30, 2015, to identify adult patients with newly diagnosed PsA (i.e., no PsA diagnosis during the 1 year before the first observed PsA diagnosis). The earliest date of PsA diagnosis was defined as the index date. Patients with no PsA diagnosis any time during the study period (controls) were directly matched to PsA patients with demographic characteristics. All patients had ≥ 2 years of medical and pharmacy coverage before the index date and ≥ 1 year of follow-up. Incident rates per 100 person-years for comorbidities of interest were evaluated. The hazard ratios of having various comorbid conditions for PsA patients were estimated by Cox proportional hazards models. All-cause and CV-related hospitalizations during the follow-up period were evaluated. RESULTS: A total of 14,898 PsA patients and 35,037 matched controls met the study criteria. Compared with controls, PsA patients had a higher risk of CV disorders (incidence rate = 6.5 vs. 5.8; HR = 1.46; 95% CI = 1.37-1.56) and a higher risk of the majority of the specific CV disorders (hypertension, hyperlipidemia, coronary artery disease, cerebrovascular disease, peripheral vascular disease). PsA patients also had a higher risk for any autoimmune disease (incidence rate = 8.4 vs. 1.6; HR = 18.26; 95% CI = 17.18-19.40) and most autoimmune categories (psoriasis, ankylosing spondylitis, rheumatoid arthritis, multiple sclerosis, and other autoimmune disorders). Rates of other PsA-related comorbidities (diabetes, anxiety, fatigue, smoking, alcohol use, obesity or overweight, depression, osteoporosis, uveitis, eczema, and gout) were also significantly higher for PsA patients. The all-cause hospitalization rate was higher among PsA patients than controls (24.9% vs. 16.2%; P < 0.001). The CV-related hospitalization rate varied depending on whether the CV condition was the primary discharge diagnosis only or was any diagnosis on the inpatient claims. The rates of coronary artery disease hospitalizations were significantly higher in PsA patients than in controls with both methods of analysis (primary diagnosis: 0.8% vs. 0.5%; P < 0.001; nonprimary diagnosis: 3.2% vs. 2.2%; P < 0.001). CONCLUSIONS: This retrospective U.S.-based claims study found that PsA patients had a high comorbidity burden. Compared with the non-PsA population, PsA patients were associated with a higher incidence of CV comorbidities, autoimmune diseases, and other PsA-related comorbidities and a higher rate of all-cause and CV-related hospitalizations. Understanding these comorbidity profiles may provide insight on the effect of comorbid conditions on disease management and health care utilization associated with PsA. DISCLOSURES: This study was funded by Novartis. Kaine is a paid consultant for Novatis. Hur and Palmer are Novartis employees and stockowners. Song and Kim work for Truven Health Analytics, which received funding from Novartis to conduct this study.

Influence of Axial Involvement on Clinical Characteristics of Psoriatic Arthritis: Analysis from the Corrona Psoriatic Arthritis/Spondyloarthritis Registry.

OBJECTIVE: We analyzed the characteristics of patients with psoriatic arthritis (PsA) with and without axial involvement in the US-based Corrona Psoriatic Arthritis/Spondyloarthritis Registry. METHODS: All patients were included who had PsA and data on axial involvement, defined as physician-reported presence of spinal involvement at enrollment, and/or radiograph or magnetic resonance imaging showing sacroiliitis. Demographics, clinical measures, patient-reported outcomes, and treatment characteristics were assessed at enrollment. RESULTS: Of 1530 patients with PsA, 192 (12.5%) had axial involvement and 1338 (87.5%) did not. Subgroups were similar in sex, race, body mass index, disease duration, presence of dactylitis, and prevalence of most comorbidities. However, patients with axial involvement were younger and more likely to have enthesitis, a history of depression, and more frequently used biologics at enrollment. They were also more likely to have moderate/severe psoriasis (body surface area ≥ 3%, 42.5% vs 31.5%) and significantly worse disease as measured by a lower prevalence of minimal disease activity (30.1% vs 46.2%) and higher nail psoriasis scores [visual analog scale (VAS) 11.4 vs 6.5], enthesitis counts (5.1 vs 3.4), Bath Ankylosing Spondylitis Disease Activity Index (4.7 vs 3.5) scores, Bath Ankylosing Spondylitis Functional Index (3.8 vs 2.5) scores, C-reactive protein levels (4.1 vs 2.4 mg/l), and scores for physical function (Health Assessment Questionnaire, 0.9 vs 0.6), pain (VAS, 47.7 vs 36.2), and fatigue (VAS, 50.2 vs 38.6). CONCLUSION: Presence of axial involvement was associated with a higher likelihood of moderate/severe psoriasis, with higher disease activity and greater effect on quality of life. These findings highlight the importance of monitoring patients with PsA for signs of axial symptoms or spinal involvement.

Direct healthcare costs and comorbidity burden among patients with psoriatic arthritis in the USA.

This study assessed the comorbidity burden and direct healthcare costs associated with psoriatic arthritis (PsA). Adults (18-64 years) with ≥ 2 claims for a PsA diagnosis ≥ 30 days apart in the Truven Health MarketScan database (July 2009-June 2014) were selected as the case group. The index date was randomly selected after the first claim for PsA. Controls free of PsA and psoriasis (PsO) in their entire claims history were assigned the same index date and were matched with the cases on age, gender, and geographic region. All patients had ≥ 12 months of continuous eligibility before and after (study period) the index date. PsA-associated comorbidities, medication use, and medical service utilization were compared between matched groups using Wilcoxon signed rank and McNemar's tests. Costs were compared using multivariable generalized linear models. The 35,061 matched pairs had a mean age of 49.11 ± 10.20 years and 52.73% were female. During the study period, PsA patients had more PsA-associated comorbidities and significantly higher medication use than controls (all-cause medications 96.64 vs. 78.95%, p < 0.0001). PsA patients had significantly greater medical service use (inpatient admissions, hospitalization days, emergency room visits, outpatient services; all p < 0.0001) and higher annual direct healthcare costs per patient than controls (adjusted cost difference [ACD] = $18,482, including higher medical costs [ACD = $6440] and all-cause pharmacy costs [ACD = $11,737]; all p < 0.0001). Overall, PsA patients had a significantly higher PsA-related comorbidity burden, healthcare utilization, and direct healthcare costs than people free of PsA and PsO, underscoring the need for more effective treatments and improved care delivery systems.