Neurochemical balance and inhibition at the subacute stage after stroke.

Stroke is a leading cause of death and disability worldwide with many people left with impaired motor function. Evidence from experimental animal models of stroke indicates that reducing motor cortex inhibition may facilitate neural plasticity and motor recovery. This study compared primary motor cortex (M1) inhibition measures over the first 12 wk after stroke with a cohort of age-similar healthy controls. The excitation-inhibition ratio and gamma-aminobutyric acid (GABA) neurotransmission within M1 were assessed using magnetic resonance spectroscopy and threshold hunting paired-pulse transcranial magnetic stimulation respectively. Upper limb impairment and function were assessed with the Fugl-Meyer Upper Extremity Scale and Action Research Arm Test. Patients with a functional corticospinal pathway had motor-evoked potentials on the paretic side and exhibited better recovery from upper limb impairment and recovery of function than patients without a functional corticospinal pathway. Compared with age-similar controls, the neurochemical balance in terms of the excitation-inhibition ratio was greater within contralesional M1 in patients with a functional corticospinal pathway. There was evidence for elevated long-interval inhibition in both ipsilesional and contralesional M1 compared with controls. Short-interval inhibition measures differed between the first and second phases, with evidence for elevation of the former only in ipsilesional M1 and no evidence of disinhibition for the latter. Overall, findings from transcranial magnetic stimulation indicate an upregulation of GABA-mediated tonic inhibition in M1 early after stroke. Therapeutic approaches that aim to normalize inhibitory tone during the subacute period warrant further investigation.NEW & NOTEWORTHY Magnetic resonance spectroscopy indicated higher excitation-inhibition ratios within motor cortex during subacute recovery than age-similar healthy controls. Measures obtained from adaptive threshold hunting paired-pulse transcranial magnetic stimulation indicated greater tonic inhibition in patients compared with controls. Therapeutic approaches that aim to normalize motor cortex inhibition during the subacute stage of recovery should be explored.

PREP2: A biomarker-based algorithm for predicting upper limb function after stroke.

Objective: Recovery of motor function is important for regaining independence after stroke, but difficult to predict for individual patients. Our aim was to develop an efficient, accurate, and accessible algorithm for use in clinical settings. Clinical, neurophysiological, and neuroimaging biomarkers of corticospinal integrity obtained within days of stroke were combined to predict likely upper limb motor outcomes 3 months after stroke. Methods: Data from 207 patients recruited within 3 days of stroke [103 females (50%), median age 72 (range 18-98) years] were included in a Classification and Regression Tree analysis to predict upper limb function 3 months poststroke. Results: The analysis produced an algorithm that sequentially combined a measure of upper limb impairment; age; the presence or absence of upper limb motor evoked potentials elicited with transcranial magnetic stimulation; and stroke lesion load obtained from MRI or stroke severity assessed with the NIHSS score. The algorithm makes correct predictions for 75% of patients. A key biomarker obtained with transcranial magnetic stimulation is required for one third of patients. This biomarker combined with NIHSS score can be used in place of more costly magnetic resonance imaging, with no loss of prediction accuracy. Interpretation: The new algorithm is more accurate, efficient, and accessible than its predecessors, which may support its use in clinical practice. While further work is needed to potentially incorporate sensory and cognitive factors, the algorithm can be used within days of stroke to provide accurate predictions of upper limb functional outcomes at 3 months after stroke. www.presto.auckland.ac.nz.

Proportional Motor Recovery After Stroke: Implications for Trial Design.

BACKGROUND AND PURPOSE: Recovery of upper-limb motor impairment after first-ever ischemic stroke is proportional to the degree of initial impairment in patients with a functional corticospinal tract (CST). This study aimed to investigate whether proportional recovery occurs in a more clinically relevant sample including patients with intracerebral hemorrhage and previous stroke. METHODS: Patients with upper-limb weakness were assessed 3 days and 3 months poststroke with the Fugl-Meyer scale. Transcranial magnetic stimulation was used to test CST function, and patients were dichotomized according to the presence of motor evoked potentials in the paretic wrist extensors. Linear regression modeling of Δ Fugl-Meyer score between 3 days and 3 months was performed, with predictors including initial impairment (66 - baseline Fugl-Meyer score), age, sex, stroke type, previous stroke, comorbidities, and upper-limb therapy dose. RESULTS: One hundred ninety-two patients were recruited, and 157 completed 3-month follow-up. Patients with a functional CST made a proportional recovery of 63% (95% confidence interval, 55%-70%) of initial motor impairment. The recovery of patients without a functional CST was not proportional to initial impairment and was reduced by greater CST damage. CONCLUSIONS: Recovery of motor impairment in patients with intact CST is proportional to initial impairment and unaffected by previous stroke, type of stroke, or upper-limb therapy dose. Novel interventions that interact with the neurobiological mechanisms of recovery are needed. The generalizability of proportional recovery is such that patients with intracerebral hemorrhage and previous stroke may usefully be included in interventional rehabilitation trials. CLINICAL TRIAL REGISTRATION: URL: http://www.anzctr.org.au. Unique identifier: ANZCTR12611000755932.

Functional effects of unilateral open-angle glaucoma on the primary and extrastriate visual cortex.

The purpose of this study was to use functional magnetic resonance imaging (fMRI) to investigate the response of the visual cortex to unilateral primary open-angle glaucoma (POAG). Specifically, we assessed whether regions of V1 and V2 with lost input from the glaucomatous eye had a greater response to input from the nonaffected fellow eye. Nine participants with unilateral POAG causing paracentral visual field defects and four controls participated in the study. We found no evidence for an increased response to the fellow eye in glaucoma-affected regions of the visual cortex; however, in agreement with previous studies, there was a pronounced, retinotopically localized reduction of activation in both the primary (V1) and extrastriate visual cortex (V2), when participants viewed through their glaucomatous eye. Our results suggest a remarkable level of stability within the adult primary and extrastriate visual cortex in response to unilateral neurodegeneration of the optic nerve.

Neuroserpin regulates the density of dendritic protrusions and dendritic spine shape in cultured hippocampal neurons.

Neuroserpin is a member of the serpin superfamily that is expressed principally in neurons of the central and peripheral nervous systems. Neuroserpin's spatial-temporal expression during development and in the adult brain suggests possible roles in synaptogenesis and synaptic plasticity. This is supported by behavioral changes in transgenic mice overexpressing neuroserpin. We have used an embryonic rat primary hippocampal neuron culture model to investigate whether neuroserpin can regulate elements of synaptic morphology that may be involved in these changes in cognitive function. Neuroserpin localized to axonal and dendritic compartments in cultured neurons and accumulated in synapsin-positive presynaptic terminals. Increased expression of neuroserpin resulted in an increase in the density of dendritic protrusions and alterations in dendritic spine shape. Our results identify neuroserpin as a new regulator of structural plasticity and suggest a cellular mechanism that may contribute to neuroserpin's effects on cognition.