Brain-Mapping Techniques for Evaluating Poststroke Recovery and Rehabilitation

I could easily see researchers needing to use something like this to be able to describe case studies.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2663338/


Brain-mapping techniques have proven to be vital in understanding the molecular, cellular, and functional mechanisms of recovery after stroke. This article briefly summarizes the current molecular and functional concepts of stroke recovery and addresses how various neuroimaging techniques can be used to observe these changes. The authors provide an overview of various techniques including diffusion-tensor imaging (DTI), magnetic resonance spectroscopy (MRS), ligand-based positron emission tomography (PET), single-photon emission computed tomography (SPECT), regional cerebral blood flow (rCBF) and regional metabolic rate of glucose (rCMRglc) PET and SPECT, functional magnetic resonance imaging (fMRI), near infrared spectroscopy (NIRS), electroencephalography (EEG), magnetoencephalography (MEG), and transcranial magnetic stimulation (TMS). Discussion in the context of poststroke recovery research informs about the applications and limitations of the techniques in the area of rehabilitation research. The authors also provide suggestions on using these techniques in tandem to more thoroughly address the outstanding questions in the field.Keywords: DTI, EEG, fMRI, MEG, NIRS, PET, poststroke recovery, rehabilitation, SPECT, stroke, TMS
Other Sections?
Abstract
Details of Cellular and Molecular Techniques
Details of Functional Techniques
Summary and Discussion
References
Stroke affects over 780,000 people each year in the United States. Further, in 1999 more than 1,100,000 Americans reported negative impact of stroke on their daily lives including significant functional limitations.1 Major efforts are underway to find better ways to improve the outcomes of stroke in the motor and cognitive arenas. Despite these efforts, many patients experience insufficient or only partial recovery; they are left with significant functional and/or cognitive deficits. Recent developments in neuroimaging have shed light on the reasons why some patients recover well while some do poorly. Although major progress in poststroke recovery research has been made with help from brain-mapping techniques, there are many obstacles that need to be addressed before we can develop better and more effective strategies that address the needs of stroke victims.There is no consensus on the exact mechanisms involved in regaining the functions lost due to stroke. Major routes that have been implicated include changes at the molecular and cellular levels in the periinfarct and remote brain areas, involvement of the contralateral homologues via unmasking of the previously inhibited connections, and recruitment of other compensatory brain areas.2–12 This review will focus on neuroimaging techniques that can be used to study these cellular and functional mechanisms of poststroke recovery.In the healthy brain, mechanisms that inhibit axonal sprouting predominate. Inhibition of axonal sprouting is controlled by myelin-associated proteins, extracellular matrix proteins, and growth cone inhibitors. These growth-inhibiting factors continue to be expressed in traumatic brain injury but not in stroke. However, ischemic neuronal injury induces axonal sprouting.6,10 In rodent models of stroke, ischemia initiates the formation of a glial scar directly adjacent to the damaged area in which numerous neurotrophic factors are expressed.2,4,13–15 Bordering this glial scar is a larger “growth-permissive zone” of the periinfarct cortex that expresses reduced levels of growth-inhibiting factors.4,5 In some human neuroimaging studies, increased signal in the periinfarct zone correlates with good functional recovery.16 According to experimental models of stroke, this improved recovery may be due to axonal sprouting.5Variability in poststroke recovery has been suggested to be due, in part, to the influence of the directionality of axonal sprouting through activation of task-specific cortical areas. These experiences may help determine the destination of newly sprouting axons.2,3 For example, ischemic lesions in the adult rat cortex induce axonal sprouting that follows a specific biological time course; sprouting is “triggered” at 1–3 days after insult, “initiation and maintenance” of the sprouting response occurs between 7–14 days after insult, and at 28 days after stroke formation of new patterns of connections can be observed.4,5Most evidence indicates that functional recovery after stroke occurs primarily through reorganization of cortical activity in the vicinity of or connected to the infarct.4 Recent studies also suggest that recovery of motor function may involve alteration of intracortical wiring patterns. One potential role of these novel wiring patterns may be the recruitment of compensatory areas or areas of the brain that are not directly related to the damaged area. For example, Dancause et al. found evidence not only of axonal sprouting but also of the establishment of novel connections distant to the lesion and intracortical connections with the site of cortical injury.2,10 Further, Chen et al. have shown purine nucleoside inosine-stimulated projections from undamaged cortex into denervated regions of the mid-brain and spinal cord. This expansion coincides with improved behavioral performance.11 The results of human neuroimaging studies mirror the results of animal studies suggesting the formation of new connections between the periinfarct cortex and the premotor, motor, and somatosensory cortical areas.17–20 Further, in patients with subcortical stroke, the pattern of recovery first involves activation of both hemispheres of the cortex to sensory or motor stimulation of the affected limb, followed by reorganization and restriction of the activation pattern to the infarcted hemisphere, contralateral to the affected limb.21 This reorganization is accompanied by increased activity in the supplementary motor areas of the damaged side.Mechanisms of poststroke language recovery appear to be similar to the recovery after motor stroke; there is evidence of periinfarct zone and contralateral homologue contributions to language recovery. Saur et al. suggest that language reorganization after stroke occurs in three phases.9 First, there is reduced activation of remaining areas followed by upregulation of the entire language network, including contralesional homologues, and eventual “normalization of activation” or re-shifting of activation to the hemisphere affected by stroke. It is not clear if this finding is affected by the size of the lesion, because larger areas of damage were found to be associated with increased activation of the contralateral cortex. However, in some patients, improvement in language function after stroke relates to contralateral shift and not periinfarct zone recovery.22 Recent studies in younger patients who suffered peri- or prenatal stroke in the dominant left hemisphere show that recovery of language functions after stroke may result from transfer of these functions to the contralesional, healthy homologues.12,23 For example, Tillema et al. show that activation of anatomically identical areas in the unaffected hemisphere follows perinatal left middle cerebral artery stroke.12 This mechanism may be specific to children; adults do not recover after stroke as well as children and are usually left with more deficits24 despite reliable shifts of the language-related functional magnetic resonance imaging (fMRI) signal to the contralateral homologues.25,26 In the case of adults, the recovery of function may depend more on the periinfarct areas than in children.16 Further support for this age difference arises from functional neuroimaging studies showing that language in children becomes more left-hemispheric with age.27–29As this brief overview suggests, multiple mechanisms may exist for recovery of function after stroke. Evidence shows that recovery depends on the involvement of areas unaffected by stroke, either proximal to the damaged areas or in contralateral homologues. Among the many variables that influence recovery, the ones discussed here include the age at the time of the stroke, the size of the stroke, and the poststroke environment, including training or therapy.Brain-mapping techniques have dual roles in tracking recovery after stroke. They provide information about the cellular and molecular processes arising naturally during stroke recovery and allow for the investigation of poststroke brain plasticity that may result from therapeutic interventions. Although functional changes are likely an expression of underlying cellular changes, here we define functional changes to be those that are observed either by manipulating behavior during brain mapping or by measuring regional brain metabolism if no task is being performed. The cellular and molecular mechanisms discussed previously – dendritic sprouting, axonal regrowth, and cell migration – would change the microscopic structure of brain tissue. Magnetic resonance spectroscopy (MRS), diffusion-tensor imaging (DTI), and ligand-based positron emission tomography (PET) or single-photon emission computed tomography (SPECT) techniques can provide insight into these cellular processes. DTI enables the visualization of white matter fiber tracts and the quantification of fiber tract integrity.30 MRS allows for the detection and quantification of specific biochemicals in the brain, including a limited number of compounds with either a hydrogen (proton) or phosphorus spectroscopic signature. Finally, PET and SPECT offer the opportunity to investigate the binding of specific neurotransmitter-like ligands to cell surface proteins, such as the GABA receptor or the dopamine transporter.Brain-mapping techniques that measure brain function during recovery and rehabilitation include regional cerebral blood flow (rCBF), regional metabolic rate of glucose (rCMRglc) PET or SPECT, fMRI, near infrared spectroscopy (NIRS), electroencephalography (EEG), magnetoencephalography (MEG), and transcranial magnetic stimulation (TMS). The word function, as used here, implies either the manipulation of a person’s behavior in order to influence signal amplitude or the measurement of regional blood flow or metabolism in the absence of behavioral manipulations. In either case, the signal is assumed to relate to the ability of nearby neurons to process information, that is, to function. The way in which brain function is assessed depends upon the technique in question. For fMRI, function is assessed by measuring changes in blood flow that vary with the changing metabolic demands of neurons nearby. PET can measure not only blood flow but also oxygen and sugar metabolism directly. TMS can be used to determine the electrical excitability of brain tissue by measuring the muscular response to stimulation. EEG and MEG measure an electrical or magnetic signature of cortical pyramidal neuron excitation. NIRS senses the variation in intracranial absorption and reflectance of two specific near-infrared wavelengths of visible light, which are differentially absorbed by oxy- and deoxy-hemoglobin. Roughly speaking, fMRI, PET, and NIRS measure blood flow–related signals, whereas EEG and MEG record brain electrical activity and TMS directly induces brain electrical activity.The specific research question dictates the experimenter’s choice of technique. Brain condition can be examined at one or more points during rehabilitation or recovery; three basic approaches exist. The first approach involves assessing the severity of brain injury at the outset of the experiment as a predictor of recovery or rehabilitation success. For example, TMS resting motor threshold at 24 hours following a stroke has been shown to predict the degree of recovery, with normal resting thresholds predicting good outcome and abnormal thresholds predicting poor outcome.31 The second approach assesses brain function at study termination to define attributes associated with better or worse outcomes, that is, markers of recovery.19 In the third approach, by combining before and after measurements, one can identify longitudinal changes that track recovery.29,32 The study of stroke rehabilitation is relatively new, having suffered from the longstanding view that lost functions were not recoverable. The field is rapidly evolving, but there are few standardized approaches to the use of brain-mapping methods. This article is intended to illustrate ways in which several widely used brain-mapping techniques may aid stroke rehabilitation research.