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Steven C Cramer

Publications and source records attributed to Steven C Cramer.

At least 19 recordsLinked to original sources
PubMed2026

Genomic insights into stroke recovery: cross-phenotype associations.

Stroke is a major cause of long-term disability with variable recovery. While clinical factors such as initial severity play a role, genetic factors are increasingly recognized as important contributors to stroke recovery. Genotype studies are generally focused on a single post-stroke behavioural domain, but some genes might relate to broad mechanisms of plasticity. This study therefore aimed to identify cross-phenotypic genetic variants associated across two or more stroke recovery domains. DNA from Stroke, Stress, Rehabilitation, and Genetics study participants was genotyped, resulting in 9 814 610 variants. In order to examine cross-phenotypic results, we first conducted genome-wide association studies on the six recovery domains: motor (grip force), cognition (Telephone Montreal Cognitive Assessment), depression (Patient Health Questionnaire-8), stress (Primary Care Post-Traumatic Stress Disorder Screen), functional status (Stroke Impact Scale-Activities of Daily Living), and disability (modified Rankin Scale 0-2 versus 3-6), some of which were tested longitudinally, yielding nine phenotypes. Models were adjusted for age, sex, initial severity (NIH Stroke Scale score), and ancestry. Cross-phenotype associations were identified by evaluating single nucleotide polymorphisms (SNPs) associated (P < 5e-5) with multiple phenotypes. To determine how these genetic variants may relate to biological mechanisms of recovery, we conducted gene enrichment analyses. Participants (n = 565, 59% male) had mild-moderate initial stroke severity (median acute NIH Stroke Scale score = 4). After accounting for the correlation structure among the nine phenotypes, we observed 319 cross-phenotypic SNPs, 3.45 times the expected number. Five of the cross-phenotypic SNPs were linked to genes relevant to neural development, function and plasticity, e.g. ERICH1 (rs11778883-C), FOX3 (rs55726768-G), LIFR-AS1 (rs76401391-T), RPS6KA2 (rs113518460-C) and TUBGCP2 (rs147150392-C), as were enrichments in RAB5-EEA1, CTNNA1-CTNNB1, CIN85-SH3GL2 and ELMO1-DOCK2 complexes. Multiple gene enrichments were found, e.g. Stroke Impact Scale-Activities of Daily Living and Patient Health Questionnaire 8 at 3 months were enriched for CREB phosphorylation, which is important for long-term potentiation. We identified cross-phenotypic SNPs associated with multiple behavioural domains of stroke recovery. Some of these genes encode, or regulate, druggable proteins. These genetic factors are not well captured by clinical or neuroimaging assessments and so provide a unique window into stroke recovery. These findings, if validated, suggest that some genes may be broadly important to stroke recovery.

GWAS↗
PubMed2006

Effects of motor imagery training after chronic, complete spinal cord injury.

Abnormalities in brain motor system function are present following spinal cord injury (SCI) and could reduce effectiveness of restorative interventions. Motor imagery training, which can improve motor behavior and modulate brain function, might address this concern but has not been examined in subjects with SCI. Ten subjects with SCI and complete tetra-/paraplegia plus ten healthy controls underwent assessment before and after 7 days of motor imagery training to tongue and to foot. Motor imagery training significantly improved the behavioral outcome measure, speed of movement, in non-paralyzed muscles. Training was also associated with increased fMRI activation in left putamen, an area associated with motor learning, during attempted right foot movement in both groups, despite foot movements being present in controls and absent in subjects with SCI. This fMRI change was absent in a second healthy control group serially imaged without training. In subjects with SCI, training exaggerated, rather than normalized, baseline derangement of left globus pallidus activation. The current study found that motor imagery training improves motor performance and alters brain function in subjects with complete SCI despite lack of voluntary motor control and peripheral feedback. These effects of motor imagery training on brain function have not been previously described in a neurologically impaired population, and were similar to those found in healthy controls. Motor imagery might be of value as one component of a restorative intervention.

Adult↗
PubMed2006

BDNF val66met polymorphism is associated with modified experience-dependent plasticity in human motor cortex.

Motor training can induce profound physiological plasticity within primary motor cortex, including changes in corticospinal output and motor map topography. Using transcranial magnetic stimulation, we show that training-dependent increases in the amplitude of motor-evoked potentials and motor map reorganization are reduced in healthy subjects with a val66met polymorphism in the brain-derived neurotrophic factor gene (BDNF), as compared to subjects without the polymorphism. The results suggest that BDNF is involved in mediating experience-dependent plasticity of human motor cortex.

Adult↗
PubMed2006

Association between carotid plaque characteristics and subsequent ischemic cerebrovascular events: a prospective assessment with MRI--initial results.

BACKGROUND AND PURPOSE: MRI is able to quantify carotid plaque size and composition with good accuracy and reproducibility and provides an opportunity to prospectively examine the relationship between plaque features and subsequent cerebrovascular events. We tested the hypothesis that the characteristics of carotid plaque, as assessed by MRI, are possible predictors of future ipsilateral cerebrovascular events. METHODS: A total of 154 consecutive subjects who initially had an asymptomatic 50% to 79% carotid stenosis by ultrasound with > or =12 months of follow-up were included in this study. Multicontrast-weighted carotid MRIs were performed at baseline, and participants were followed clinically every 3 months to identify symptoms of cerebrovascular events. RESULTS: Over a mean follow-up period of 38.2 months, 12 carotid cerebrovascular events occurred ipsilateral to the index carotid artery. Cox regression analysis demonstrated a significant association between baseline MRI identification of the following plaque characteristics and subsequent symptoms during follow-up: presence of a thin or ruptured fibrous cap (hazard ratio, 17.0; P< or =0.001), intraplaque hemorrhage (hazard ratio, 5.2; P=0.005), larger mean intraplaque hemorrhage area (hazard ratio for 10 mm2 increase, 2.6; P=0.006), larger maximum %lipid-rich/necrotic core (hazard ratio for 10% increase, 1.6; P=0.004), and larger maximum wall thickness (hazard ratio for a 1-mm increase, 1.6; P=0.008). CONCLUSIONS: Among patients who initially had an asymptomatic 50% to 79% carotid stenosis, arteries with thinned or ruptured fibrous caps, intraplaque hemorrhage, larger maximum %lipid-rich/necrotic cores, and larger maximum wall thickness by MRI were associated with the occurrence of subsequent cerebrovascular events. Findings from this prospective study provide a basis for larger multicenter studies to assess the risk of plaque features for subsequent ischemic events.

Aged↗
PubMed2006

Functional imaging of intervention effects in stroke motor rehabilitation.

OBJECTIVE: To assess intervention-specific effects on cortical reorganization after stroke as shown by available functional neuroimaging studies. DATA SOURCES: We searched Medline for clinical trials that contained the terms stroke, reorganization, and recovery, as well as either positron-emission tomography and PET, near-infrared spectroscopy and NIRS, single-photon emission tomography and SPECT, or functional magnetic resonance imaging and functional MRI; we reviewed primary and secondary references. STUDY SELECTION: Articles that reported neuroimaging findings as a result of a specific treatment involving more than 1 subject were included. DATA EXTRACTION: We included clinical trials that contained the terms stroke, reorganization, and recovery, as well as functional neuroimaging data findings as a result of a specific treatment involving more than 1 subject. DATA SYNTHESIS: Included studies differed clearly from one another with regard to patient characteristics, intervention protocol, and outcome measures. Most studies used functional magnetic resonance imaging and a motor paradigm. Studies were limited in size. CONCLUSIONS: Despite the methodologic differences, several common features can be identified based on the reviewed studies. Clinical improvements occurred even late after injury, after subjects were deemed to have reached a recovery plateau. This clinical improvement was accompanied by cortical reorganization that depended on the type of intervention as well as other factors. This review also suggests direction for future research studies.

Cerebral Cortex↗
PubMed2006

Imaging motor recovery after stroke.

Most patients show improvement in the weeks or months after a stroke. Recovery is incomplete, however, leaving most with significant impairment and disability. Because the brain does not grow back to an appreciable extent, this recovery occurs on the basis of change in function of surviving tissues. Brain mapping studies have characterized a number of processes and principles relevant to recovery from stroke in humans. The findings have potential application to improving therapeutics that aim to restore function after stroke.

Animals↗
PubMed2006

Automating arm movement training following severe stroke: functional exercises with quantitative feedback in a gravity-reduced environment.

An important goal in rehabilitation engineering is to develop technology that allows individuals with severe motor impairment to practice arm movement without continuous supervision from a rehabilitation therapist. This paper describes the development of such a system, called Therapy WREX or ("T-WREX"). The system consists of an orthosis that assists in arm movement across a large workspace, a grip sensor that detects hand grip pressure, and software that simulates functional activities. The arm orthosis is an instrumented, adult-sized version of the Wilmington Robotic Exoskeleton (WREX), which is a five degrees-of-freedom mechanism that passively counterbalances the weight of the arm using elastic bands. After providing a detailed design description of T-WREX, this paper describes two pilot studies of the system's capabilities. The first study demonstrated that individuals with chronic stroke whose arm function is compromised in a normal gravity environment can perform reaching and drawing movements while using T-WREX. The second study demonstrated that exercising the affected arm of five people with chronic stroke with T-WREX over an eight week period improved unassisted movement ability (mean change in Fugl-Meyer score was 5 points +/- 2 SD; mean change in range of motion of reaching was 10%, p < 0.001). These results demonstrate the feasibility of automating upper-extremity rehabilitation therapy for people with severe stroke using passive gravity assistance, a grip sensor, and simple virtual reality software.

Adult↗
PubMed2006

Motor cortex stimulation for the enhancement of recovery from stroke: a prospective, multicenter safety study.

OBJECTIVE: Functional magnetic resonance imaging and transcranial magnetic stimulation studies suggest that human cortex shows evidence of neuroplasticity. Preclinical studies in rats and monkeys suggest that motor cortical stimulation can enhance plasticity and improve recovery after stroke. This study assesses the safety and preliminary efficacy of targeted subthreshold epidural cortical stimulation delivered concurrently with intensive rehabilitation therapy while using an investigational device in patients with chronic hemiparetic stroke. METHODS: This is a prospective, multicenter, and nonblinded trial randomizing patients to rehabilitation with or without cortical stimulation. Patients aged 20 to 75 years who had had an ischemic stroke at least 4 months previously causing persistent moderate weakness of the arm were included. Functional magnetic resonance imaging localized hand motor function before surgery to place an epidural cortical electrode. Both groups then underwent rehabilitation for 3 weeks after which the electrode was removed. Outcome measures were obtained at baseline, during therapy, and at 1, 4, 8, and 12 weeks postprocedure. RESULTS: Ten patients were randomized; six patients to surgery, four to the control group. No patient deaths, neurological deterioration, or seizures occurred. There were two infections from nonprotocol-related causes. Of the eight patients completing the treatment, the stimulation plus rehabilitation group improved significantly better than controls in the Upper Extremity Fugl-Meyer (P = 0.003 overall) and the hand function score of the Stroke Impact Scale (P = 0.001 overall). CONCLUSION: The technique of cortical stimulation to enhance stroke recovery is well tolerated and safe.

Adult↗
PubMed2005

Activity in the peri-infarct rim in relation to recovery from stroke.

BACKGROUND AND PURPOSE: In the rim of tissue surrounding a cortical infarct, animal studies have described an increase in a number of growth-related processes that likely contribute to behavioral recovery. The current study hypothesized that in patients with good outcome after stroke, brain activation in peri-infarct tissue would be greater than normal. METHODS: In 15 patients with good recovery chronically after ischemic cortical stroke, activation within peri-infarct brain tissue was directly compared with activation within the same brain tissue of 13 control subjects. RESULTS: Although most patients did show activation within peri-infarct tissues, their activation compared with controls was reduced rather than increased. Evaluation of the T2*-weighted images underlying functional MRI mapping disclosed a significant gradient of increased T2* signal in peri-infarct tissues, likely attributable to tissue changes such as gliosis. CONCLUSIONS: Among well-recovered stroke patients, cortical activation is present in the area surrounding a cortical infarct but is smaller than normal. A baseline derangement of the T2*-weighted signal underlying functional MRI (fMRI) is also present in this area, which might influence interpretation of fMRI findings. The relationship between increased tissue T2* signal and fMRI activation is not known and requires further study.

Aged↗
PubMed2005

Brain motor system function after chronic, complete spinal cord injury.

Most therapies under development to restore motor function after spinal cord injury (SCI) assume intact brain motor functions. To examine this assumption, 12 patients with chronic, complete SCI and 12 controls underwent functional MRI during attempted, and during imagined, right foot movement, each at two force levels. In patients with SCI, many features of normal motor system function were preserved, however, several departures from normal were apparent: (i) volume of activation was generally much reduced, e.g. 4-8% of normal in primary sensorimotor cortex, in the setting of twice normal variance in signal change; (ii) abnormal activation patterns were present, e.g. increased pallido-thalamocortical loop activity during attempted movement and abnormal processing in primary sensorimotor cortex during imagined movement; and (iii) modulation of function with change in task or in force level did not conform to patterns seen in controls, e.g. in controls, attempted movement activated more than imagined movement did within left primary sensorimotor cortex and right dorsal cerebellum, while imagined movement activated more than attempted movement did in dorsolateral prefrontal cortex and right precentral gyrus. These modulations were absent in patients with SCI. Many features of brain motor system function during foot movement persist after chronic complete SCI. However, substantial derangements of brain activation, poor modulation of function with change in task demands and emergence of pathological brain events were present in patients. Because brain function is central to voluntary movement, interventions that aim to improve motor function after chronic SCI likely also need to attend to these abnormalities of brain function.

Adult↗
PubMed2005

Somatotopy and movement representation sites following cortical stroke.

Stroke has been associated with many changes in motor system function, but there has been limited study of changes in somatotopic organization. This was examined in a group of patients with cortical stroke affecting primary sensorimotor cortex. In 17 patients with good outcome after cortical stroke involving precentral and/or postcentral gyri, plus 14 controls, four functional MRI evaluations of brain activity were obtained: finger, shoulder, and face motor tasks plus a sensory task, passive finger motion. For each, coordinates for contralateral primary sensorimotor cortex activation site were determined, as was a measure of inter-hemispheric balance. The normal motor somatotopy measured in controls was largely preserved after stroke. The main difference found between controls and patients was that the face was lateral to finger motor activation in all controls, but face was centered medial to finger in 43% of patients. Among patients, smaller infarct volume was associated with more ventral, and larger infarct with more dorsal, contralateral primary sensorimotor cortex activation. On the other hand, better behavioral outcome was associated with a more posterior, and poorer outcome with more anterior, activation. Larger infarct and poorer behavioral outcome were each associated with a change in inter-hemispheric balance towards the non-stroke hemisphere. Shifts in contralateral movement representation site did not correlate with changes in inter-hemispheric balance. Motor somatotopy is generally preserved after injury to primary sensorimotor cortex. Greater injury and larger behavioral deficits are associated with distinct effects on movement representation sites. Changes in motor organization within and between hemispheres arise independently after stroke.

Adult↗
PubMed2005

Use of functional MRI to guide decisions in a clinical stroke trial.

BACKGROUND AND PURPOSE: An investigational trial examined safety and efficacy of targeted subthreshold cortical stimulation in patients with chronic stroke. The anatomical location for the target, hand motor area, varies across subjects, and so was localized with functional MRI (fMRI). This report describes the experience of incorporating standardized fMRI into a multisite stroke trial. METHODS: At 3 enrollment centers, patients moved (0.25 Hz) the affected hand during fMRI. Hand motor function was localized at a fourth center guiding intervention for those randomized to stimulation. RESULTS: The fMRI results were available within 24 hours. Across 12 patients, activation site variability was substantial (12, 23, and 11 mm in x, y, and z directions), exceeding stimulating electrode dimensions. CONCLUSIONS: Use of fMRI to guide decision-making in a clinical stroke trial is feasible.

Adult↗
PubMed2005

Patent foramen ovale and stroke: prognosis and treatment in young adults.

A patent foramen ovale (PFO) is found with increased frequency in patients with stroke of undetermined origin but the significance and therapeutic implications of this observation remain unclear. Several lines of evidence suggest a role for the PFO in stroke pathophysiology for some cryptogenic stroke patients, such as those whose PFO is accompanied by a prothrombotic state, atrial septal aneurysm, or lower extremity/pelvic DVT. Diagnostic evaluation of the patient with cryptogenic stroke and PFO is directed at identifying these subgroups. Appropriate therapy for primary and secondary stroke prevention in a subject with a PFO remains unclear given current uncertainties as to the pathophysiological significance of PFO. Additional studies are needed, such as those focused on lower extremity veins or the cardiac interatrial septum, to guide therapy in specific stroke subpopulations.

Adolescent↗
PubMed2005

Brain activation during execution and motor imagery of novel and skilled sequential hand movements.

This experiment used functional magnetic resonance imaging (fMRI) to compare functional neuroanatomy associated with executed and imagined hand movements in novel and skilled learning phases. We hypothesized that 1 week of intensive physical practice would strengthen the motor representation of a hand motor sequence and increase the similarity of functional neuroanatomy associated with executed and imagined hand movements. During fMRI scanning, a right-hand self-paced button press sequence was executed and imagined before (NOVEL) and after (SKILLED) 1 week of intensive physical practice (n = 54; right-hand dominant). The mean execution rate was significantly faster in the SKILLED (3.8 Hz) than the NOVEL condition (2.5 Hz) (P < 0.001), but there was no difference in execution errors. Activation foci associated with execution and imagery was congruent in both the NOVEL and SKILLED conditions, though activation features were more similar in the SKILLED versus NOVEL phase. In the NOVEL phase, activations were more extensive during execution than imagery in primary and secondary cortical motor volumes and the cerebellum, while during imagery activations were greater in the striatum. In the SKILLED phase, activation features within these same volumes became increasingly similar for execution and imagery, though imagery more heavily activated premotor areas, inferior parietal lobe, and medial temporal lobe, while execution more heavily activated the precentral/postcentral gyri, striatum, and cerebellum. This experiment demonstrated congruent activation of the cortical and subcortical motor system during both novel and skilled learning phases, supporting the effectiveness of motor imagery-based mental practice techniques for both the acquisition of new skills and the rehearsal of skilled movements.

Adult↗
PubMed2005

Stroke recovery and its imaging.

Functional imaging of stroke recovery is a unique source of information that might be useful in the development of restorative treatments. Several features of brain function change spontaneously after stroke. Current studies define many of the most common events. Key challenges for the future are to develop standardized approaches to help address certain questions, determine the psychometric qualities of these measures, and define the clinical usefulness of these methods.

Brain↗
PubMed2004

Functional imaging in stroke recovery.

Assessing neurobiology of brain systems can provide information not available from anatomic or behavioral assessment. Such information may be of value in understanding, defining, and prescribing potential therapeutic interventions that target restorative brain events after stroke. A number of methods have been used to study stroke recovery, each with its relative merits and limitations. Several studies suggest that greater injury is associated with reduced laterality of brain activity. This might be in relation to changes in interhemispheric inhibition and is a phenomenon that is likely useful for functional gains in some patients. Many other features of brain activity change in the months after a stroke, including the site and size of activation in relevant brain network nodes. While there is incomplete agreement regarding which features of altered brain activity predict and parallel better behavioral outcome, studies converge on the conclusion that best outcome is achieved by activating the brain in a pattern that most resembles the normal state.

Brain↗
PubMed2004

Blockade of central cholinergic receptors impairs new learning and increases proactive interference in a word paired-associate memory task.

Experimental data and computational models suggest that blockade of muscarinic cholinergic receptors impairs paired-associate learning and increases proactive interference (E. DeRosa & M. E. Hasselmo, 2000; M. E. Hasselmo & J. M. Bower, 1993). The results presented here provide evidence in humans supporting these hypotheses. Young healthy subjects first learned baseline word pairs (A-B) and, after a delay, learned additional overlapping (A-C) and nonoverlapping (D-E) word pairs. As predicted, when compared with subjects who received the active placebo glycopyrrolate (4 microg/kg) and subjects who were not injected, those who received scopolamine (8 microg/kg) showed (a) overall impairment in new word paired-associate learning, but no impairment in cued recall of previously learned associates; and (b) greater impairment in learning overlapping (A-C) compared with nonoverlapping (D-E) paired associates.

Adolescent↗