Steven C Cramer’s research while affiliated with University of California, Los Angeles and other places

Introduction: Childhood trauma exposure (CTE) is a known risk factor for poor adult mental&physical health, higher mortality, and disability. Understanding the psychosocial mechanisms by which CTE affects functional outcomes could help identify intervention targets to improve outcomes after stroke. We examine post-stroke mental health and loneliness as potential mediators of the association between CTE and functional/cognitive disability at 1-year post-stroke. Methods: Adults with a new stroke enrolled in the STRONG ( S troke, s T ress, R ehabilitati ON , and G enetics) study at 28 US sites and were assessed 4 times over 1 year. Assessments included CTE, mental health (depression, anxiety, PTSD), and loneliness 90 days post-stroke, and Stroke Impact Scale (SIS), modified Rankin Scale (mRS),&Telephone Montreal Cognitive Assessment (tMoCA) 1-year post-stroke. Analyses examined 90-d mental health and loneliness as mediators of the link between CTE and 1-year outcomes. Results: The 763 enrollees had age 63.1±14.9 years; initial NIHSS score 4 [2-9]; 41.2% Female; 69.4% White. Complete case (N=332) analysis revealed that controlling for age, gender, race, and acute NIHSS score, CTE was not directly associated with any 1-year functional outcome but was significantly associated with loneliness and mental health symptoms 3-months post-stroke. However, greater CTE was indirectly and significantly linked to worse 1-year mRS and SIS scores through 3-mo loneliness, and to worse 1-year mRS, SIS, and tMOCA scores through 3-mo mental health symptoms. Conclusions: Mental health and loneliness are pathways through which CTE is linked to post-stroke functional outcomes. Addressing mental health symptoms and loneliness early post-stroke may support improved functional outcome 1-year post-stroke in patients who have experienced CTE.

Background: Stroke is a major cause of long-term disability and has widely varying recovery outcomes. While clinical factors like stroke severity play a role, genetic factors are increasingly recognized as important contributors to stroke recovery. This study aims to identify genetic variants associated with recovery phenotypes through genome-wide association studies (GWAS) and protein-protein interaction (PPI) networks. Methods: DNA from STRONG study participants was genotyped using the Infinium Global Screening Array, resulting in 565 samples and 9,814,610 variants after quality control. GWAS were conducted on 11 recovery phenotypes using plink v1.9, including motor (Grip Strength), cognition (tMoCA), functional performance (SIS-ADL), mental health (PHQ-8 and PTSD), and disability (mRS). Models adjusted for age, sex, stroke severity acutely, and ancestry. To further examine how the identified genetic variants may relate to biological mechanisms of recovery, PPI networks and gene ontology enrichment analyses were conducted. Results: Participants’ stroke severity was mild to moderate (acute NIHSS median score 4, IQR 2 – 9). Several cross-phenotype associations were identified for genes of biological interest: Grip strength, PHQ8, and PTSD were associated with the rs138829971-C variant near DCLK2 (involved in hippocampal organization). Grip strength and tMoCA were associated with the rs149456987-T variant near UNK (crucial for cortical neuron development). The PPI networks for multiple phenotypes (including SIS ADL and mRS at 3 months, change in Grip Strength from 1-3 months, PHQ8 and PTSD measures at 12 months) were significantly enriched in protein-protein interactions, and for GO terms including Nervous System Development (SIS ADL), Post-synaptic Density (PHQ8), Neuron Projection (tMOCA) and Axon Guidance (Grip Strength). Conclusions: While some genetic variations affect specific domains of recovery, others have cross-phenotype associations that affect recovery more broadly. Our analyses identified several gene associations and biological pathways active during development, suggesting a potential shared biology with reparative processes post-stroke. Other associated genes affecting axon guidance that we identified remain expressed in adult brain tissue and could offer targets for developing drug therapies.

Introduction: Neuroplasticity is highest during the first weeks after stroke and can be studied at the bedside using EEG. However, brain mapping studies during this time are uncommon and longitudinal data are spaced weeks or months apart, which is insufficient to capture neuroplasticity and respond therapeutically. Towards this goal, a longitudinal study of frequent EEG was performed in subacute stroke patients to deeply understand neuroplasticity during this time period. Methods: Post-stroke patients were included 16 days after stroke onset and were seen four times every 2.1±0.3 days (n=2). They performed paretic hand grip contractions while 32-lead EEG and paretic flexor digitorum communis electromyography (EMG) were recorded. In the EEG beta frequency band, event-related desynchronization (ERD) was calculated as well as cortico-muscular coherence (CMC) with paretic flexor digitorum communis EMG. Cortical coherence (CC) was calculated between EEG electrodes. Longitudinal variation was quantified as % change between visits. Results: The contralesional hemisphere showed maximum plasticity between days 16 and 18. A 24% increase in ERD amplitude and a 30% decrease in CMC were seen between day 16 and 18, compared with respective variations of 0% and 4% between subsequent visits. The ipsilesional hemisphere showed maximum plasticity between days 21 and 23. A 26% decrease in ERD amplitude and a 54% increase in inter-hemispheric connectivity were seen, compared with, respectively, 12% and 11% variation between the other visits. Discussion: Findings suggest two-stage neuroplasticity, first involving the contralesional, and then the ipsilesional, hemisphere. Recruitment of the contralesional hemisphere increases, while its communication with the paretic flexor muscle decreases, suggesting its indirect involvement in motor control. Subsequently, ipsilesional hemisphere activity decreases, while its connectivity with the contralesional hemisphere increases, reinforcing the contralesional hemisphere role in movement programming early post-stroke. Frequent bedside EEG provides precise measures of sequential stages of neuroplasticity early post-stroke, finding that may ultimately inform sub-acute post-stroke rehabilitation.

Background: Cognitive factors influence motor performance, but often this is not considered when testing motor function. Here we examined this issue using 3 versions of the Box and Blocks Test (BBT), a measure of arm motor function. First, we developed 2 new, briefer versions of BBT and then tested their validity. Second, we hypothesized that cognitive factors would be more strongly related to versions of the BBT that require a longer period of testing. Methods: In 71 patients <=30 days post-stroke, 3 BBT versions were scored. BBT60 is the standard one; subjects move as many blocks as possible over a divider in 60 sec. We also counted # blocks moved in the first 10 sec (BBT10) and time to move the first 3 blocks (3-BBT). Other testing included 2 motor scores, Fugl Meyer (FM) and 9-Hole Peg (9HP); and 2 cognitive scores, Trail Making Test-A (TMT-A) and Montreal Cognitive Assessment (MoCA). First, we tested the validity of the briefer BBT versions (3-BBT and BBT10) against BBT60 and FM. Second, we compared all BBT versions to measures of sustained attention (TMT-A) and cognitive function (MoCA). Comparisons used Spearman’s rank correlation coefficient (threshold p<0.05). Results: Mean time post-stroke was 13.1±5.9 days; age, 66.9±14.9 yrs; 40.8% female. Median BBT scores: 3-BBT, 17.4 sec; BBT10, 2 blocks; and BBT60, 10 blocks. Other median scores: FM, 36 points, MoCA, 21 points; 9HP, 1 peg in 60 sec; TMT-A, 49.5 sec for 25 targets. Scores on 3-BBT (r=-0.93, p<0.0001) and BBT10 (r=0.95, p<0.0001) showed strong validity with BBT60 scores. Each BBT version, respectively, was related to FM score (r=-0.81, r=0.77, r=0.82; all p<0.0001) and to 9HP score (r=-0.77, r=0.82, r=0.82; all p<0.0001). TMT-A was not significantly related to 3-BBT (r=0.20, p=0.09), but was related to BBT10 (r=-0.24, p=0.04) and BBT60 (r=-0.24, p=0.04). MoCA was not significantly related to 3-BBT (r=-0.15, p=0.21) or BBT60 (r=0.20, p=0.09), but was to BBT10 (r=0.26, p=0.03). Conclusions: The 3-BBT and BBT10 are both valid measures of arm motor function in subacute stroke. Each is quicker and more easily assessed than BBT60. The BBT10 and BBT60 were more strongly related to TMT-A, and BBT60 to MoCA, suggesting that these 2 BBT versions are more influenced by attention or cognition compared to 3-BBT. All 3 BBT measures are valid; choice of which to use depends on whether the goal is to measure motor function with less (3-BBT) or more (BBT10 and BBT60) influence of attention or cognitive factors.

Introduction: Strokes lead to acute deficits with wide-ranging severity. Genetic variation may explain some of these inter-subject differences. The current report examined the relationship that candidate genetic variants have with acute injury and acute behavioral deficits. We hypothesized that variants known to be associated with poorer stroke recovery would also be associated with more a severe acute presentation. Methods: Infarcts were outlined on clinical scans acquired during acute stroke admission as part of the STRONG (“Stroke, sTress, RehabilitatiON, and Genetics”) study and resampled to MNI152 brain standard space. Multivariable linear regression modeling was used to examine association with genetic measures known to be related to stroke outcome: 3 single nucleotide polymorphisms (SNPs): BDNF (rs6265), ACE (rs4291), and FAAH (rs324420), plus ApoE e4 and ApoE e2; a dopamine polygene score was also explored. Acute injury (infarct volume) and acute deficits (NIHSS score, grip strength, and acute stress disorder inventory (ASDI)) were each examined as the dependent measure in separate models that used age, gender, and ancestry as covariates. To understand where in the brain these relationships occurred, voxel lesion symptom mapping (VLSM) was used to test for associations between acute injury and each genetic measure. Results: In 448 subjects (age 63.4±14.4 yr (mean±SD), 43.1% females), lesion volume ranged from 0.46 to 535.13 cc and involved cortical grey matter in 63% of patients. Larger lesion volume was associated with presence of the ACE SNP (β=8.77, p=0.03); lower NIHSS score, with ApoE e4 (β=-1.69, p=0.04); greater grip strength, with ApoE e2 SNPs (β=6.78, p=0.03); and higher ASDI, with the ACE SNP (β=0.56, p=0.05). VLSM revealed that acute injury to the postcentral gyrus was significantly more likely in the presence of the ACE SNP (z=-3.5), and that acute injury to the calcarine fissure was significantly more likely in the presence of the BDNF SNP (z=-2.53). Conclusions: Genetic variants known to be associated with differences in stroke recovery are also related to acute stroke deficits and injury. In particular, a common variant in the gene for ACE was associated with differences in lesion volume and location, findings that may suggest a personalized medicine approach to acute therapy. Measures of genetic variability may be useful to understand inter-subject differences in acute injury and symptom severity, and may have therapeutic implications.

Introduction: Restorative therapies have maximal impact when introduced early post-stroke. Dopamine modulates learning and plasticity, and its levels decrease after stroke, making it a key therapeutic candidate. For a restorative therapy to promote experience-dependent plasticity, concomitant training is needed and must be provided experimentally given low rehabilitation doses received with usual care (UC); here this was provided using an established telerehabilitation (TR) system. Current hypotheses : [H1] Adding intensive arm motor rehabilitation therapy to UC improves arm motor status more than UC alone, and [H2] Combining intensive arm motor therapy with levodopa further improves arm motor gains. Methods: Adults ≤30 days post-stroke having moderate-severe arm weakness were randomized (3:3:2) to (1) 6 wk of intensive daily arm motor TR + daily carbidopa/levodopa (25/100) before therapy (given for first 3 wk), on top of UC; (2) TR + placebo before therapy (given for first 3 wk), on top of UC, or (3) UC alone. TR was initiated in the inpatient rehabilitation facility and completed at home. Assessments were blinded and included Action Research Arm Test (ARAT; primary endpoint) and Fugl-Meyer (FM; secondary endpoint) at baseline and 10 wk later. Results: At baseline, subjects (n=25) were 13.2 days post-stroke, mean age 64.9 yr, ARAT 18.8, and FM 30.1. [H1] TR vs. UC : ARAT change from baseline to 10 wk later was 7.7 points higher in TR (23.8±2.8, n=16) vs. UC (16.1±3.2, n=9, propensity adjusted p=0.08). FM change was 12.3 points higher in TR (22.5±2.3) vs. UC (10.3±2.7, p=0.0027). [H2] TR+levodopa vs. TR+placebo vs. UC : ARAT change was not different between the 3 groups (p=0.17). However, FM change was: regression adjusted post hoc FM change with TR+levodopa (21.1±3.9) was significantly higher than change with UC (10.7±2.8, p=0.047), but FM change with TR+placebo (17.2±3.2) was not significantly higher than UC (p=0.103). Conclusions: Therapeutic trials of patients ≤30 days post-stroke can be difficult to implement, e.g., due to transitions of care. This study describes a method to study a restorative drug tightly linked with intensive rehabilitation therapy using a telehealth approach. This pilot study, though at risk of type II error, provides evidence that adding intensive rehabilitation therapy to UC early post-stroke improves outcomes, and supports the potential value of adding levodopa to intensive rehabilitation therapy in the early post-stroke population.

Background and Aims: Non-invasive, frequency-tuned, low-intensity electromagnetic network targeting field (ENTF) stimulation therapy has shown signals of reducing global disability at 90 days post-stroke in subacute ischaemic stroke patients with moderate-severe disability and upper-extremity impairment in the EMAGINE 1 randomized trial, but the pace of potential response has not been delineated. Methods: We conducted a multicenter, double-blind, randomized, sham-controlled, trial enrolling participants 4-21 days post-stroke with baseline modified Rankin Scale 3-4 and Fugl-Meyer Assessment Upper-Extremity 10-45. Participants were allocated to active or sham treatment, of stimulation paired with an evidence-based, functional, repetitive, home-based physical exercises regimen for 45 one-hour sessions, five times per week within the first 90 days from stroke. Global disability mRS was assessed at baseline, day 45, and day 90. Results: Participant age was 59.0 ( + 12.5), 33% were female, and study treatment was initiated at day 14 (IQR 12-19) post-stroke. The evolution of mRS distribution in the active and sham stimulation groups is shown in the Figure. At day 45, there was evidence of potential treatment benefit for functional independence (mRS 0-2, active vs sham 50% vs 35%, adjusted p=0.05) though not in freedom-from-disability (mRS 0-1, 5% vs 2%). By day 90, after further recovery in both treatment groups, there was evidence of potential treatment benefit for both freedom-from-disability (mRS 0-1, 26% vs 11%, adjusted p=0.03) and functional independence (mRS 0-2, 83% vs 74%, p=0.13). Shift on the mRS trichotomized at 0-1/2/3-6 similarly showed signals of benefit at day 45 (adjusted p=0.07) in addition to day 90 (adjusted p=0.02). Conclusion: ENTF therapy showed safety and preliminary efficacy in reducing global disability among subacute ischaemic stroke patients with severe baseline disability, with potential benefit accruing at mRS 0-2 by day 45 and at both mRS 0-1 and 0-2 by day 90. These results require confirmation in an adequately powered prospective trial.

BACKGROUND: Perivascular Spaces (PVS) are a marker of cerebral small vessel disease (CSVD) that are visible on brain imaging. Larger PVS has been associated with poor quality of life and cognitive impairment post-stroke. However, the association between PVS and post-stroke sensorimotor outcomes has not been investigated. METHODS: 602 individuals with a history of stroke across 24 research cohorts from the ENIGMA Stroke Recovery Working Group were included. PVS volume fractions were obtained using a validated, automated segmentation pipeline from the basal ganglia (BG) and white matter centrum semiovale (CSO), separately. Robust mixed effects regressions were used to a) examine the cross-sectional association between PVS volume fraction and post-stroke sensorimotor outcomes and b) to examine whether PVS volume fraction was associated with other measures of CSVD and overall brain health (e.g., white matter hyperintensities [WMHs], brain age [measured by predicted age difference, brain-PAD]). RESULTS: Larger PVS volume fraction in the CSO, but not BG, was associated with worse post-stroke sensorimotor outcomes (b = -0.06, p = 0.047). Higher burden of deep WMH (b = 0.25, p <0.001), periventricular WMH (b = 0.16, p <0.001) and higher brain-PAD (b = 0.09, p <0.001) were associated with larger PVS volume fraction in the CSO. CONCLUSIONS: Our data show that PVS volume fraction in the CSO is cross-sectionally associated with sensorimotor outcomes after stroke, above and beyond standard lesion metrics. PVS may provide insight into how the overall vascular health of the brain impacts inter-individual differences in post-stroke sensorimotor outcomes.

BACKGROUND Brain age, a proxy of overall brain health estimated from structural neuroimaging, has been associated with sensorimotor performance in chronic stroke. Similarly, post-stroke cognitive outcomes have been associated with accelerated brain aging. However, the relationships between brain age, sensorimotor, and cognitive outcomes in early subacute stroke (<3 months after onset) are less understood. METHODS In this work, we investigated associations between stroke survivors’ brain-predicted age difference (brain-PAD, quantified as a person’s brain age minus their chronological age) and longitudinal measurements of motor impairment (Fugl-Meyer Upper Extremity Assessment [FMUE]) and cognitive impairment (Montreal Cognitive Assessment [MoCA]) in subacute stroke. We used high-resolution T1-weighted MRIs from 44 participants at baseline and three months after stroke onset to investigate associations between brain-PAD, MoCA, and FMUE scores with robust linear mixed-effects regression models and mediation analyses. RESULTS We found negative associations between baseline brain-PAD and FMUE at baseline (β=-0.87, p=0.029) and three months (β=-0.87, p=0.011). Baseline brain-PAD was also negatively correlated with MoCA at three months (β=-0.13, p=0.015) but not at baseline (β=-0.11, p=0.141). Baseline brain-PAD was not associated with changes in FMUE (β=-0.01, p=0.930) or MoCA (β=-0.03, p=0.579). Finally, MoCA was not associated with FMUE at either time point, nor did it mediate the relationship between brain-PAD and FMUE. CONCLUSION Overall, we show that baseline brain age predicts both motor and cognitive outcomes at three months. However, motor and cognitive outcomes are not directly associated with one other. This suggests that brain age is representative of changes in multiple, distinct neurological pathways post-stroke. Further research with longer time intervals is needed to examine whether brain age also predicts chronic stroke outcomes.