Clinical Recovery from CNS Damage

H. Naritomi, D. W. Krieger

• Publisher: S. Karger
• Year: 2013
• ISBN:
  9783318023091
• Topic: Medicine
• Subtopic: Neurosurgery

After decades of focusing on how to alleviate and prevent recurrence of acute CNS injuries, the emphasis has finally shifted towards repairing such devastating events and rehabilitation. This development has been made possible by substantial progress in understanding the scientific underpinnings of recovery as well as by novel diagnostic tools, and most importantly, by emerging therapies awaiting clinical trials. In this publication, several international experts introduce novel areas of neurological reorganization and repair following CNS damage. Principles and methods to monitor and augment neuroplasticity are explored in depth and supplemented by a critical appraisal of neurological repair mechanisms and possibilities to curtail disability using computer or robotic interfaces. Rather than providing a textbook approach of CNS restoration, the editors selected topics where progress is most imminent in this labyrinthine domain of medicine. Moreover, the varied background and origins of the contributors lend this book a truly global perspective on the current state of affairs in neurological recovery.

Naritomi H, Krieger DW (eds): Clinical Recovery from CNS Damage.
Front Neurol Neurosci. Basel, Karger, 2013, vol 32, pp 9–25 (DOI: 10.1159/000346408)

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Diagnostic Approach to Functional Recovery: Functional Magnetic Resonance Imaging after Stroke

Inger Havsteen^a · Kristoffer H. Madsen^c · Hanne Christensen^b · Anders Christensen^a · Hartwig R. Siebner^c

Departments of ^aRadiology and ^bNeurology, Copenhagen University Hospital Bispebjerg, Copenhagen, and ^cDanish Research Center for Magnetic Resonance, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark

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Abstract

Stroke remains the most frequent cause of handicap in adult life and according to the WHO the second cause of death in the Western world. In the peracute phase, intravenous thrombolysis and in some cases endovascular therapy may induce early revascularization and hereby improve prognosis. However, only up to 20-25% of patients are eligible to causal treatment. Further, care in a specialized stroke unit improves prognosis in all patients independent of age and stroke severity. Even when it is not possible to prevent tissue loss, the surviving brain areas of functional brain networks have a substantial capacity to reorganize after a focal ischemic (or hemorrhagic) brain lesion.This functional reorganization contributes to functional recovery after stroke. Functional magnetic resonance imaging (fMRI) provides a valuable tool to capture the spatial and temporal activity changes in response to an acute ischemic lesion. Task-related as well as resting-state fMRI have been successfully applied to elucidate post-stroke remodeling of functional brain networks. This includes regional changes in neuronal activation as well as distributed changes in functional brain connectivity. Since fMRI is readily available and does not pose any adverse effects, repeated fMRI measurements provide unprecedented possibilities to prospectively assess the time course of reorganization in functional neural networks after stroke and relate the temporospatial dynamics of reorganization at the systems level to functional recovery. Here we review the current status and future perspectives of fMRI as a means of studying functional brain reorganization after stroke. We summarize (a) how fMRI has advanced our knowledge regarding the recovery mechanisms after stroke, and (b) how fMRI has been applied to document the effects of therapeutical interventions on post-stroke functional reorganization.

Copyright © 2013 S. Karger AG, Basel

Background

Stroke and other cerebrovascular diseases remain the world's second leading cause of death [1] and stroke is the leading cause for acquired disability in adults, including hemiparesis, dysphasia, neglect or other focal neurological deficits. Recent advances in neuroimaging enable rapid and precise diagnosis and new treatment options have become available for patients with acute ischemic stroke, if diagnosis is made within the first hours after the onset of ischemia [2, 3]. However, the majority of patients have either only limited effect or are uneligible for revascularization therapy and long-term rehabilitation remains the most important treatment option. In patients with acute stroke, it is difficult to predict functional recovery and the long-term functional outcome varies from patient to patient [4]. A detailed assessment of lesion location and size with structural magnetic resonance imaging (MRI) is often of limited value in terms of explaining or predicting interindividual differences in long-term recovery because structural MRI provides only little information regarding the potential of the nondamaged brain regions to promote recovery of function [5-7].

Here functional MRI (fMRI) comes into the picture because the distributed neural activity of functional brain networks can be readily studied with fMRI at rest and while patients perform a specific task [8]. In healthy individuals, fMRI has proven to be a valuable tool to study functional brain reorganization due to learning and long-term practice [9, 10] or associated with brain maturation during childhood and adolescence [11] or healthy aging [12]. In a wide range of diseases, fMRI has been extensively used to study how a given brain disease changes the functional neuro-architecture at the systems level [13-15]. In the last 10 years, cross-sectional as well as longitudinal fMRI studies after stroke have provided important insights into changes of the brain in recovery after stroke.

In this chapter, we review the application of fMRI to study the reorganization of functional brain networks after stroke.

What Is Functional Magnetic Resonance Imaging?

When stroke patients undergo fMRI, we measure local changes in regional neural activity using the blood-oxygenation-level-dependent (BOLD) signal [16]. A regional increase in neural activity triggers an increase in local blood perfusion. Under normal physiological conditions, regional oxygen supply increases as a consequence of increasing perfusion, exceeding the local activity-dependent increase in oxygen consumption. Accordingly, an increase in regional neural activity leads to a rise in the local oxyhemoglobin concentration and a decrease in the local concentration of deoxyhemoglobin. The activity-driven reduction of paramagnetic deoxyhemoglobin causes the regional increase in the BOLD signal. Hence, the BOLD signal provides an endogenous contrast which is sensitive to regional changes in neural activity, yet it needs to be borne in mind that the BOLD signal is an indirect (vascular) measure of neural activity which relies on neurovascular coupling [16, 17]. This explains why fMRI can identify functional brain networks, which show a temporally correlated BOLD signal increase in response to a stimulus or in relation to an experimental task [18, 19].

How Can Functional Magnetic Resonance Imaging Be Used to Assess Brain Function after Stroke?

A given brain function is maintained by the functional integration of neural processing among specialized brain regions. Stroke causes a focal brain lesion, which involves one or more specialized brain regions and their interaction with the remaining nodes of the functional network. In other words, the post-stroke brain is characterized by an altered functional network architecture, one which is less effective as opposed to the intact brain, but which will use its remaining processing capacities to maintain as much as possible functional integrity. The altered neural processing within poststroke brain networks can be studied with BOLD fMRI which can reveal altered levels of regional brain activation within the network as well as changes in the functional interactions between the remaining network nodes.

In stroke patients, fMRI can either be performed while patients are ‘at rest’ (i.e., resting-state fMRI) or while patients are exposed to sensory stimuli (i.e., stimulus-related fMRI) or perform a well-defined task in response to a sensory stimulus (i.e., task-related fMRI). These fMRI techniques have been successfully applied in poststroke patients to assess functional remodeling of brain networks as reflected by regional changes in neuronal activation and distributed changes in functional brain connectivity. Stimulus-related, task-related and resting-state fMRI capture different aspects of functional reorganization and should be considered as complementary techniques with specific strengths and weaknesses. For resting-state and stimulus-related fMRI, it is not necessary that patients can perform a specific task. This has the advantage that these fMRI examinations are feasible even in severely affected stroke patients and can be used to study spontaneous fluctuations in regional BOLD levels (i.e., resting-state fMRI) or changes in regional BOLD signal driven by ‘passive’ sensory stimulation (i.e., stimulus-related fMRI).

Resting-state fMRI can be used to study alterations in functional brain connectivity after stroke because the low-frequency (<0.1 Hz) BOLD signal fluctuations at rest are temporally correlated in functional brain networks [8, 20]. The resting-state BOLD signal correlations are sensitive to head movements [21]. Moreover, comprehensive filtering should be applied because physiological noise from cardiac and respiratory cycles causes BOLD signal changes resembling those observed in resting-state fMRI [22]. A resting-state fMRI time series can reveal functional connectivity of several functional brain networks, including the so-called default mode network and the motor network [8]. Studies on healthy resting subjects have shown that brain networks which display correlated resting-state activity strongly overlap with the topography of brain networks as identified by task-related fMRI [8].

In contrast, task-related fMRI offers the possibility to identify changes in the task-specific activation pattern after stroke and to examine how task-specific activation patterns dynamically change during the course of recovery. Task-related fMRI studies offer better possibilities to directly relate specific activity or connec-tivity changes in the relevant brain networks to the degree of functional impairment and to recovery of a specific brain function such as hand paresis, aphasia or neglect. In summary, resting-state, stimulus-related and task-related fMRI measure different aspects of functional integration and therefore, should be used as complementary approaches when assessing functional brain reorganization after stroke.

The above-mentioned fMRI approaches can be combined with an intervention. For instance, focal transcranial brain stimulation might be combined with fMRI to experimentally manipulate the function of one or more of the nonaffected cortical areas [23, 24]. This combined brain stimulation-fMRI approach is particularly interesting if one wishes to test the functional relevance of a specific cortical area for recovery of a specific brain function. Another interventional approach is to map distributed changes in the BOLD signal in response to an acute pharmacological intervention compared to placebo. Pharmacological fMRI might be useful to examine how the pharmacological manipulation of a specific neurotransmitter or ion channel alters the functional integration within brain networks and hereby promotes recovery of function [25].

Feasibility of Functional Magnetic Resonance Imaging in a Clinical Post-Stroke Setting

Stroke patients frequently undergo MRI as part of their diagnostic workup. fMRI carries the same contraindications as conventional MRI scans, that is metal implants, claustrophobia etc. Artifacts induced by head movements remain a limiting problem in the acute phase [26]. Here prospective motion correction of head movements using data from optical tracking systems might significantly help to reduce motion artifacts in future studies [27].

As pointed out above, resting-state fMRI is suited for patients with any neurological deficit of any severity as there is no task to perform. The only practical limitation might be related to spontaneous body movements during the resting-state fMRI session. The estimation of resting-state functional connectivity becomes more reliable the more time points (i.e., brain volumes) are acquired during a single resting state, because resting-state connectivity describes the temporal correlation of spontaneous BOLD signal fluctuations within functional brain networks. Van Dijk et al. [28] reported that a scanning session of 5 min is sufficient to acquire reliable resting-state fMRI data with a TR of 2.5 s and a spatial resolution of 2-3 mm. Usually, a resting-state fMRI session lasts between 5 and 10 min which allows resting-state fMRI to be incorporated into existing clini...