Functional magnetic resonance imaging in chronic ischaemic stroke rstb.royalsocietypublishing.org

Evelyn M. R. Lake1, Paolo Bazzigaluppi1,4 and Bojana Stefanovic1,2,3 1

Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada Physical Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada 3 Heart and Stroke Foundation Centre for Stroke Recovery, Ottawa, Canada 4 Fundamental Neurobiology, Krembil Research Institute, University Health Network, Toronto, Ontario, Canada 2

Review Cite this article: Lake EMR, Bazzigaluppi P, Stefanovic B. 2016 Functional magnetic resonance imaging in chronic ischaemic stroke. Phil. Trans. R. Soc. B 371: 20150353. http://dx.doi.org/10.1098/rstb.2015.0353 Accepted: 1 June 2016 One contribution of 15 to a Theo Murphy meeting issue ‘Interpreting BOLD: a dialogue between cognitive and cellular neuroscience’. Subject Areas: neuroscience Keywords: stroke recovery, functional magnetic resonance imaging, blood oxygen level dependent, arterial spin labelling, electrophysiology Author for correspondence: Bojana Stefanovic e-mail: [email protected]

Ischaemic stroke is the leading cause of adult disability worldwide. Effective rehabilitation is hindered by uncertainty surrounding the underlying mechanisms that govern long-term ischaemic injury progression. Despite its potential as a sensitive non-invasive in vivo marker of brain function that may aid in the development of new treatments, blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) has found limited application in the clinical research on chronic stage stroke progression. Stroke affects each of the physiological parameters underlying the BOLD contrast, markedly complicating the interpretation of BOLD fMRI data. This review summarizes current progress on application of BOLD fMRI in the chronic stage of ischaemic injury progression and discusses means by which more information may be gained from such BOLD fMRI measurements. Concomitant measurements of vascular reactivity, neuronal activity and metabolism in preclinical models of stroke are reviewed along with illustrative examples of post-ischaemic evolution in neuronal, glial and vascular function. The realization of the BOLD fMRI potential to propel stroke research is predicated on the carefully designed preclinical research establishing an ischaemia-specific quantitative model of BOLD signal contrast to provide the framework for interpretation of fMRI findings in clinical populations. This article is part of the themed issue ‘Interpreting BOLD: a dialogue between cognitive and cellular neuroscience’.

1. Introduction Although widely used in neuroscience for the study of healthy human brain function, blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) has found limited application in clinical research on brain disorders and diseases. Indeed, the perceived clinical potential of BOLD fMRI remains unrealized. In this review, we focus on the application of fMRI to studies of brain function in the chronic stage of stroke progression. The large societal and personal burden of stroke, the mechanistic basis of stroke in vascular injury and the strong dependence of BOLD signal on blood flow make fMRI application to the chronic stage of stroke a particularly significant research direction. Indeed, BOLD neuroimaging has been proposed to be a robust in vivo marker of ischaemia-induced brain dysfunction/stroke recovery that could aid in identification of the determinants of prognosis, and guide the development of new ischaemic stroke treatments [1– 4]. The positive BOLD response is robustly observed in various brain regions under a variety of input tasks/stimuli across many physiological conditions and in many species. It reflects a focal decrease in deoxyhaemoglobin (dHb) content, which due to the paramagnetism of dHb, its sequestration to red blood cells, and the geometry of the focal vascular architecture, results in the decrease of local microscopic magnetic field heterogeneities and thus lengthening of the apparent tissue spin–spin relaxation time during periods of increased neuronal activity. The BOLD fMRI signal is hence a function of dHb concentration, which is in turn driven by adjustments in cerebral blood flow (CBF), cerebral blood volume (CBV) and cerebral metabolic rate of

& 2016 The Author(s) Published by the Royal Society. All rights reserved.

In clinical practice, stroke recovery is evaluated using one or more structured neuropsychological tests, which incorporate simple physical tasks and quality of life assessments [29]. Although neuropsychological tests are carefully designed to evaluate whether a patient is improving, they are confounded by self-reporting bias and high incidence of very gradual gains (recovery over a long period often results in a flawed perception of progress). Further, they offer little insight into the underlying processes driving or impeding recovery [30]. To address this gap, several studies have tested whether fMRI can provide a more objective metric of behavioural impairment and/or functional recovery while still correlating with performance on neuropsychological assessments.

3. Behavioural correlates of blood oxygenation level-dependent functional magnetic resonance imaging response On the whole, evoked BOLD fMRI response measurements following ischaemic stroke have shown pronounced alterations in amplitude and kinetics of the BOLD signal both in

4. Mechanistic basis of blood oxygenation leveldependent functional magnetic resonance imaging response in stroke recovery Notwithstanding the lack of correlation between BOLD fMRI alterations and behavioural performance, researchers have also attempted to use BOLD fMRI measurements to gain insight into the neurobiological changes in the chronic stage of ischaemic injury progression. Delayed, low amplitude, absent or negative BOLD responses have been purported to indicate dysfunction. BOLD response attenuation was thus proposed to result from compromised local perfusion due to structural damage to the vasculature (caused by either ischaemia itself or pre-existing comorbidities) [33], exhausted vasomotor reactivity due to chronically maximally dilated vasculature [34,35] or absent neuronal activity [31,36,37]. To test these hypotheses, some fMRI studies probed neuronal activity while others assessed cerebrovascular reactivity [34,35,38]. Employing tactile exploration of objects to elicit BOLD signal changes and motor evoked potentials (assessed with transcranial magnetic stimulation; TMS), Binkofski et al. [38] conducted a longitudinal multimodal neuroimaging study in patients imaged at one, two to four weeks and one month following injury [38]. One week after stroke, BOLD signal change and TMS revealed the representation of the paretic hand fingers to be remapped to the adjacent cortical

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2. Clinical functional magnetic resonance imaging research on ischaemic stroke recovery

the ipsi- and in the contralesional cortex months after the ischaemic insult. In the majority of patients studied to date, however, BOLD response was altered whether or not the patient had made a good recovery, suggesting BOLD fMRI may not be a sensitive marker of functional recovery. For example, in patients with residual paralysis 9 –57 months after stroke, Blicher et al. [31] used unilateral isolated wrist extension –flexion and observed a positive BOLD response in 55%, negative BOLD response in 9% and no BOLD response in 36% of patients [31]. In patients with poor outcome, imaged more than 270 days after stroke, Newton et al. [32] employed near-isometric wrist extension movements and found the peak BOLD response in ipsilesional M1 to be delayed relative to contralesional M1 responses during movement of either wrist. The patients exhibited abnormally delayed M1 responses in the ipsilesional hemisphere when moving the paretic wrist. In mildly impaired patients performing a finger- or hand-tapping task (4 –660 days after stroke), Pineriro et al. [33] observed the rate of BOLD signal increase and maximum BOLD signal change in the sensorimotor cortex of both hemispheres to be decreased by approximately 30% in patients relative to controls. Rossini et al. [34] and Altamura et al. [35] studied individuals who experienced a good recovery: 12 months following injury, direct median nerve stimulation elicited no BOLD activation in either hemisphere in 25% of these patients, while in 45% of the patients, activation was present only in the contralesional hemisphere [34,35]. In another study of patients with good recovery 1–2 years after stroke, a visually guided bilateral handball squeeze task produced a biphasic BOLD response, with patients showing earlier onset and extended duration of the initial, negative BOLD response followed by a positive BOLD response with a delayed time-to-peak but normal peak magnitude [36].

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O2 consumption (CMRO2); as well as the distribution of dHb in the tissue, as determined by the microvascular architecture [5,6]. Stroke affects each of the physiological parameters underlying BOLD contrast: ischaemia triggers perilesional angiogenesis (preceded acutely by vessel loss) thus changing microvascular architecture and affecting CBF and CBV; and modulates CMRO2 due to neuronal loss [7], glial recruitment and activation [8], generation of new vessels [9–12], axonal sprouting [13], and synaptogenesis [14–16]. Consequently, BOLD may be a sensitive and widely accessible marker of ischaemic sequelae. On the other hand, because all the parameters dictating the BOLD signal are differentially affected by ischaemic injury progression, the interpretation of BOLD signal change following ischaemic injury is complex [17] and BOLD neuroimaging in isolation has been challenged to impact clinical research on stroke recovery. This review summarizes progress on clinical and preclinical application of BOLD fMRI in the chronic stage of ischaemic injury progression, and discusses means by which more information may be gained from such BOLD fMRI measurements. The focus on the chronic stage is motivated by an increasingly recognized need for interventions in the weeks to months following ischaemic injury as the majority of ischaemic stroke patients (as many as 97% in some centres) arrive at a care facility beyond the therapeutic window for safe application of currently available treatments [18]. This research direction is further supported by the incidence and temporal evolution of spontaneous recovery: as many as 25% of ischaemic stroke patients show improvement with physical therapy and continue to recover function more than 12 months following stroke [4,19 –26]. The therapeutic window for novel treatments, aimed at enhancement of endogenous healing, may thus be much longer than is often assumed [1– 3,26–28]. BOLD fMRI may thus also be valuable for elucidation of the mechanisms which govern recovery in the long-term and for identification of new, chronic stage treatment targets to improve recovery in a much wider population of patients.

vasculature in the perilesional tissue could modulate blood flow and volume and alter vascular reserve capacity and/or neurovascular coupling [31,37]. Further, BOLD attenuation may be secondary to increases in basal CBF of the peri-infarct zone due to persistent collateral perfusion [37].

In addition to BOLD response attenuation, BOLD fMRI studies of ischaemic injury progression have also shown evidence of an altered spatial pattern of BOLD responses. In particular, focal signal enhancement within the primary motor cortex, increased activity in non-primary sensorimotor areas, and/or increased activity in the contralateral hemisphere have all been reported [32,39–43]. However, whether such remapping of the BOLD response provides salient insight and if so, whether it signifies recovery or is a manifestation of dysfunction remains controversial [32,43,44]. Some studies have provided evidence of BOLD response remapping, but such remapping was not found to correlate with outcome. For instance, employing the finger opposition task in patients 5–43 months after injury, with varied NIHSS and Rankin scores, Cao et al. [43] examined event related BOLD responses [43]. Seventy five per cent of patients showed extended activation of the contralesional sensorimotor cortex; 50% showed bilateral activation of the primary sensorimotor cortex; 50% showed contralesional activation alone during paretic hand movement; 25% showed activation in contralesional premotor and dorsolateral prefrontal cortex, and 25% of patients exhibited activation in the contralesional supramarginal gyrus and premotor cortex during paretic hand movement. Despite such extensive BOLD response reorganization in the patients, no correlation between degree of remapping and neuropsychological test scores was observed. In contrast, some authors have postulated that fMRI response remapping, namely activation in the contralesional motor cortex, increased sensorimotor activation volume and activation within the perilesional tissue indicate remapping of neuronal activity patterns and/or recruitment of additional neurons and are manifestations of recovery. In particular, Cramer et al. [39] employed a finger- or handtapping task to measure BOLD responses in recovered stroke patients between 11 days and 15 months following ischaemia [39]. Seventy per cent of the patients were found to have a greater activation volume in the contralesional sensorimotor cortex than that observed in control subjects. Most patients with greater activation volumes in the contralesional sensorimotor cortex also showed increased activation in the contralesional cerebellum, premotor cortex and both the ipsilesional and contralesional supplementary motor areas [39]. In addition, degree of peri-infarct activation correlated with clinical improvement. Similarly, Marshall et al. [40] used the finger –thumb opposition task to measure BOLD responses in patients within the first few days of stroke onset and again 3–6 months thereafter [40]. In the first few days of injury and in the chronic phase after stroke, patients showed greater activation in the ipsilesional sensorimotor cortex, ipsilesional posterior parietal and bilateral prefrontal regions than did the control subjects. Moreover, ipsilesional

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5. Blood oxygenation level-dependent functional magnetic resonance imaging response remapping

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areas. At 2–4 weeks, there was a transient lack of BOLD responses despite clinical improvement of hand function and preserved motor evoked potentials on TMS. At one month after ischaemia, BOLD responses were again detected; motor evoked potentials were still present, and further clinical improvement was made. Similarly, Rossini et al. [34] and Altamura et al. [35] observed absent or reduced BOLD responses in both hemispheres, yet measured stereotypical somatosensory evoked fields from ipsi- and contralesional hemispheres via magnetoencephalography (MEG) [34,35]. Combined, these data provide evidence that at least in the well-recovering patients BOLD fMRI attenuation was not due to an absence of neuronal activity. With respect to impairment in cerebrovascular reactivity, some studies did not, while others did, find it correlated with BOLD attenuation. Rossini et al. [34] measured cerebrovascular reactivity to hypercapnia (inhalation of 7% CO2) with transcranial doppler colour-coded duplex sonography [34]. In 25% of the patients, missing BOLD fMRI activation was accompanied by impaired vascular reactivity to hypercapnia. In the remaining 75% of patients, who exhibited some BOLD response, no correlation was found between the amplitude of the BOLD response and the degree of hypercapnic reactivity of the major arterial vessels, though impaired microvascular reactivity was thus not excluded. Moreover, Blicher et al. [31] observed no BOLD signal change, on average, in M1 in response to unilateral isolated wrist extension–flexion in patients with residual paralysis, yet arterial spin labelling (ASL) and VASO-FLAIR (vascular-spaceoccupancy fluid attenuated inversion recovery) showed this task elicited CBF and CBV increases that were indistinguishable from those observed in control subjects [31]. Krainik et al. [37] used fMRI to estimate cerebrovascular reactivity by comparing BOLD signal between normal breathing and hyperventilation-elicited hypocapnia (which increases oxygen extraction, induces vasoconstriction and reduces CBF) in fully recovered patients with frontal lobe stroke 11–85 days after injury [37]. Hyperventilation resulted in a smaller BOLD signal decrease in the ipsilesional primary sensorimotor cortex and supplementary motor areas relative to contralesional hemispheres and relative to control subjects (bilaterally). Hyperventilation-elicited BOLD signal decrease in the contralesional supplementary motor areas was larger than that in the control subjects. In a separate experiment in the same study, BOLD response during a repeated hand grip task was decreased in the ipsilesional primary sensorimotor cortex and ipsilesional supplementary motor areas despite a full clinical recovery and no evidence of lesions in the primary sensorimotor cortex, supplementary motor areas, cerebellum, basal ganglia or thalamus on three-dimensional T1-weighted MRI [37]. The authors suggested that impaired cerebrovascular reactivity was a predictor of impaired motor-related BOLD response in the sensorimotorcortex during contralateral movements [37]. The discrepancy between this study and those by Rossini [34] and Blicher [31] may be attributed to methodological differences. Preceding reports of persistent neuronal activity, vascular reactivity impairment and alterations in BOLD response amplitude and temporal profile have prompted further mechanistic hypotheses of modified neurovascular coupling due to abnormal vascular anatomy and/or changes in tissue metabolic needs. Ultrastructural changes in cerebral vessels caused by atherosclerosis, perilesional gliosis, and/or disruption of aminergic and cholinergic fibres that innervate the

Preclinical studies offer well-controlled experimental conditions including tightly regulated ischaemic injury parameters as well

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6. Preclinical functional magnetic resonance imaging research on ischaemic stroke recovery

as careful control of comorbidities, and thus provide a powerful means for examining the neurobiological determinants of stroke recovery and establishing a quantitative model of BOLD signal contrast post-ischaemic injury. However, translation potential of preclinical findings critically depends on careful experimental design and thoughtful consideration of salient interspecies differences. Of note, there are structural, functional and hence metabolic differences between humans and animals in addition to differences in preclinical versus clinical BOLD fMRI implementation. The higher nominal spatial resolution used in preclinical fMRI (e.g. 0.32 mm3 as in Weber et al. [46]) versus clinical fMRI (e.g. 27 mm3) research is to be evaluated in the light of three orders of magnitude smaller rodent versus human total brain volume [46,47]. A preclinical BOLD fMRI voxel thus represents a 100 times larger relative brain volume than that comprising a clinical BOLD fMRI voxel. Additionally, cortical neuronal density in rats is approximately twice that of humans, whereas the ratio of glia to neurons is lower in rats (approx. 1 : 1) than in humans [48,49]. Interestingly, fundamental cortical communication processes (e.g. action potentials, pre- and post-synaptic potentials, glial neurotransmitter and Kþ clearance) were estimated to have the same relative energy costs in rats and in humans [50]. On a final methodological note, the sensitivity of BOLD fMRI to magnetic susceptibility gradients limits the invasiveness of manipulations that can be performed on the animals and hence the spectrum of complementary techniques that can be done in combination with fMRI. As combining fMRI with other methodologies represents a major technical challenge, there are only a few multimodal preclinical fMRI reports which monitor ischaemia-induced neurovascular remodelling during the chronic period (more than 7 days after the injury): further, their conclusions with respect to neurovascular coupling post-ischaemia have not been consistent. In particular, Shih et al. [51] measured intra-cortical local field potentials (LFPs) and CBF and CBV fMRI signal changes with forepaw stimulation up to four weeks following a 20-min middle carotid artery (MCA) occlusion [51]. Noxious forepaw stimulation-elicited negative fMRI responses were associated with LFP recovery 28 days following ischaemic insult. Negative fMRI responses were interpreted as evidence of uncoupling between neuronal activity and local vascular reactivity. However, when Weber et al. [46] performed the adhesive tape removal test, BOLD fMRI and electroencephalography (EEG; through skull) up to seven weeks following MCA occlusion [46] they found that at 2–7 days after ischaemia, rats were impaired and showed attenuated BOLD responses to forepaw stimulation, but within 1–4 weeks they exhibited recovery on the adhesive tape removal test and showed reestablishment of normal BOLD responses, suggesting that BOLD fMRI could be used as an indicator of functional loss and restoration. Moreover, they observed a tight coupling of electrical brain activity and haemodynamic responses in early and late phases after stroke, suggesting preservation of neurovascular coupling in the somatosensory cortex in this model. The complexity of the perilesional neurovascular changes induced by focal ischaemia is further exemplified by two multimodal preclinical fMRI examinations from our own work. Using intra-cortical microinjection of endothelin-1 into the right sensorimotor cortex of adult Sprague Dawley rats, we induced ischaemic lesions of 50 + 10 mm3 volume on T2-weighted MRI. Three weeks following stroke, BOLD and continuous ASL readings were

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(relative to contralesional) activity in the sensorimotor cortex increased progressively as the paretic hand regained function [40]. Combined, these studies suggest that a dynamic bihemispheric reorganization of motor networks probably contributes to recovery following focal ischaemia [39,40]. Some authors suggested that remapping of the BOLD response correlates with a poor prognosis. For instance, Ward et al. [41] employed a dynamic visually paced handgrip task at least three months after stroke in patients with documented deficits lasting a minimum of 48 h following stroke, and with a varied degree of recovery at the time of imaging [41]. Patients with poor recovery were more likely to recruit a number of motor-related brain regions over and above those activated in the control group, whereas patients showing recovery were more likely to show an fMRI activation pattern similar to control subjects [41]. Across the entire patient group, Ward et al. [41] were able to demonstrate a negative correlation between outcome and the degree of task-related activation in the supplementary motor areas, cingulate motor areas, premotor cortex, posterior parietal cortex and cerebellum [41]. In another example, Feydy et al. [42] used repetitive first clench (n ¼ 10), or a modified movement for those unable to fist clench (n ¼ 4), to measure evoked BOLD responses at three imaging sessions over a period of 1–6 months following ischaemic stroke [42]. At earlier time points, patients showed contralateral and ipsilateral recruitment of sensorimotor cortex, supplementary motor areas, frontal premotor cortex, frontal premotor areas and, less commonly, posterior parietal areas. By latter imaging time points, this recruitment subsided in 66% of patients; the remaining 34% of the patients showed a higher incidence of M1 lesions [42]. The authors suggested that ipsilateral recruitment after stroke corresponds to a compensatory corticocortical process, which may be due to a decrease in inhibition caused by an M1 lesion and damage to the underlying reciprocal corticocortical connections from M1 to the secondary motor areas, leading to more extensive ipsilateral and contralateral activation in worse-off patients. In summary, clinical research has provided ample evidence of BOLD modulation post-ischaemic injury, but findings on the correlation between BOLD fMRI response features (magnitude, kinetics or spatial pattern) and clinical outcome have been inconsistent [44]. Mechanistically, there has been some, though still varied, support for BOLD modulation resulting from alterations in impairment in cerebrovascular reactivity and alterations in neurovascular coupling, though details of these mechanisms remain uncertain. Concomitant measurements of metabolism, haemodynamics and BOLD in ischaemic stroke patients during the weeks to months following injury need to be more widely employed [45] to improve our understanding of the natural progression of the disease in patients and facilitate interpretation of BOLD response signals in studies of novel therapeutic agents. At the same time, a detailed mechanistic understanding of the determinants of BOLD contrast postischaemic injury will necessitate measurements of changes in morphology and function of specific cellular populations and hence calls for studies in preclinical models of ischaemic stroke.

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Figure 1. Functional MRI and immunohistochemistry in a rat model of focal sensorimotor ischaemia. One week following right sensorimotor cortex injection of endothelin-1, BOLD fMRI responses (a(i)) and blood flow changes (a(ii)) elicited by hypercapnia (10% CO2), as well as resting perfusion (a(iii)) are shown overlaid on the corresponding structural T2-weighted images. Perilesional M1/M2 BOLD response (1.09 + 0.07%) was attenuated by approximately 60% relative to its level in the contralesional cortex (2.5 + 0.1%), with an ipsi- to contralesional ratio of cortical DBOLD of 0.44 + 0.02. Perilesionally, blood flow increase in the M1/M2 ROI in response to hypercapnia, of 39 + 5%, was strongly potentiated (ratio: 3.25 + 0.04) relative to the contralateral M1/M2 ROI (12 + 2%). Similarly, perilesional resting perfusion (1.66 + 0.09%) was doubled (ratio: 1.95 + 0.01) relative to that of the contralesional cortex. Post-mortem immunohistochemistry was performed in the same animals immediately following imaging, with Iba-1 staining for microglia (b(i)), GFAP for astrocytic activation (b(ii)), and RECA-1 for blood vessel endothelium (b(iii)). Microglial recruitment (b(i)) as well as a pronounced astrocytic activation (b(ii)) were evident in the peri-infarct zone. Endogenous angiogenesis was also observed in the perilesional tissue (b(iii)). Scale bar in (a) 2 mm; scale bar in (b) 500 mm. acquired to measure BOLD and CBF signal changes elicited by hypercapnia (10% CO2), while skilled reaching ability was evaluated using the Montoya Staircase skilled reaching task [52]. In addition, we recorded intra-cortical spontaneous LFP responses simultaneously from both hemispheres using a pair of multi-electrode arrays composed of 16 (2  8) Pl/Ir electrodes ( placed within the cortex such that the anterior pair of electrodes was within the core of the lesion) or performed immunohistochemical analysis post-mortem. These data allowed the investigation of BOLD signal changes, cerebrovascular reactivity, motor recovery and neuronal functioning, as well as post-mortem changes in select cellular populations.

In the first example, we considered the subacute period (7 days following ischaemic injury). Representative fMRI and immunohistochemical results are shown in figure 1. At this time point, hypercapnia elicited an attenuated BOLD response in the perilesional M1/M2 region of interest (ROI) relative to the contralesional M1/M2 ROI. The perilesional BOLD response was attenuated by approximately 60%: 1.09 + 0.07% in the perilesional cortex versus 2.5 + 0.1% in the contralesional cortex. However, perfusion increases with hypercapnia in the perilesional M1/M2 cortex were triple those in the contralesional M1/M2 (39 + 5% perilesionally versus 12 + 2% contralesionally). Perilesional resting perfusion was twice the contralesional perfusion: 1.66 + 0.09% versus 0.85 + 0.04%.

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7. Conclusion and future work Notwithstanding the complexities, BOLD fMRI still has significant potential to advance the research of neurophysiological changes in the chronic stage of stroke recovery, due to its easy implementation in patient populations and its robustness. Longitudinal BOLD fMRI measurements based on signal intensity changes have consistently proven more reliable than activation volumes in ischaemia patients [61] and in healthy subjects [62–65]. For the potential of fMRI to be fully realized, however, a much more comprehensive understanding of the neurovascular coupling over this period is needed. Such understanding necessitates that BOLD fMRI data be widely acquired and combined with other, more specific cellular measures as infarct affects all cell types (neurons, glia and vascular endothelial cells) both

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time, ongoing perilesional vascular remodelling catches up with the metabolic demands of the tissue. To examine the attenuation of the BOLD response perilesionally in the FR122047-treated animal, despite the increase in vascular reactivity, we performed intracranial array electrode recordings in the same animals (figure 3). During rest, the brain generates oscillations in different frequency bands, which are believed to be the neuronal correlate of different behaviours and cognitive states (for review, see Womelsdorf et al. [59]). We found high coherence in the contralesional cortex of both animals (green traces in figure 3a(iii) and b(iii)). In the perilesional cortices (black traces in figure 3a(iii) and b(iii)), the coherence was lower, indicating stroke-induced impairment in neuronal functioning; the treated animal, however, exhibited a smaller degree of attenuation across all frequency bands (figure 3b(iii)) than did the placebo administered animal (figure 3a(iii)). Notwithstanding the attenuated BOLD response, these data suggest COX-1 inhibition in the chronic phase after ischaemia may exert a beneficial effect on neuronal communication and putative cortical reorganization. To examine underlying neuronal metabolic activity, we estimated neuronal power as a correlate of neuronal metabolic intake. In both animals, the average neuronal power was attenuated in the perilesional relative to that in the contralesional cortex in each frequency band. However, in all frequency bands this attenuation was smaller in the FR122047-treated animal than in the placebo administered animal (control versus treated): u, 73% versus 90%; a, 37% versus 58%; b, 21% versus 31%; low g, 12% versus 13%; and g, 24% versus 28% (cf. Figure 3a(iv) and b(iv)). In summary, the treated animal exhibited higher relative ( perilesional versus contralesional) coherence and higher relative neuronal power. The perilesional BOLD response attenuation in the FR122047-treated animal was thus associated with improved neuronal function and may be attributable to high oxygen extraction accompanying elevated neuronal activity, spurred on by inhibition of microglial invasion by COX-1. These examples are in line with the acute phase observations of depressed CBF and metabolic responses despite the recovery of somatosensory evoked potentials [60]. Combined, these findings emphasize the need for multimodal examination of neuronal, vascular and glial function as well as metabolism over the course of ischaemic injury progression to establish a framework for interpreting BOLD signal changes in the highly dynamic peri-infarct region.

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Perilesional BOLD fMRI response attenuation thus accompanied vascular hyper-reactivity. Immunohistochemical analysis of these brains demonstrated perilesional neuroinflammation, with dense microglial invasion (figure 1b(i)) and pronounced astrocytic reactivity (figure 1b(ii)). Proximal to the site of injury, RECA-1 staining (figure 1b(iii)) showed an increase in vascular endothelial density indicating endogenous angiogenesis, as previously reported [9–12]. In parallel experiments, Montoya staircase testing demonstrated approximately 70–80% impairment in skilled reaching ability of the left forepaw. Intra-cortical LFP recordings collected 7 days after injury showed a 10–30% lower ipsi- to contralesional power ratio (across all frequency bands), suggesting silencing of the neuronal network in the peri-infarct zone. BOLD response attenuation and motor impairment were thus accompanied by a hyper-reactive and proliferating vasculature on the one hand, and neuronal hypoactivity on the other. We hypothesized that the pronounced increase in perilesional vascular reactivity and local baseline perfusion were triggered by increased metabolic needs (O2 consumption and glutamate/glutamine cycling) of the densely packed neuroinflammatory cells. Direct measurements of tissue metabolism are needed to examine this hypothesis. In the second example, we considered the neurovascular state three weeks following the endothelin-1 elicited ischaemic insult. Representative fMRI and electrophysiological results are shown in figures 2 and 3, respectively. In these experiments, we investigated the effects of selective cyclooxygenase-1 (COX-1) inhibition through the chronic administration of FR122047 (Cedarlane Laboratories, Burlington, ON, Canada) from 7 to 19 days following stroke, followed by fMRI or electrophysiological recordings 20 or 21 days after stroke. In clinical and preclinical ischaemic stroke studies, COX-1 metabolites have been shown to contribute to injury during the chronic phase of stroke [53,54]. In preclinical studies, COX-1 inhibition has been shown to prevent neuronal loss [55], reduce oxidative stress (by disrupting free radical production) [56,57], attenuate neuroinflammation [53] and increase resting vascular tone [58]. By sustained inhibition of COX-1 in the chronic stage of stroke, we expected to ameliorate neurovascular function through reduction in microglial invasion. We therefore measured BOLD and flow responses to hypercapnia (figure 2) in vehicle-administered and FR122047-treated animals, and subsequently recorded neuronal activity via intracranial electrophysiology (figure 3). Twenty-one days after stroke, the BOLD response to hypercapnia in the vehicle-administered animal was not lateralized (2.6 + 0.1% versus 2.8 + 0.1%). However, perilesional blood flow increase to hypercapnia was double that of the contralesional cortex (ratio of 2.3 + 0.1). In the FR122047-treated animal, BOLD response to hypercapnia was attenuated by 40% perilesionally (3.7 + 0.3% in the peri- versus 6.1 + 0.3% in the contralesional cortex). Nonetheless, its perilesional perfusion response to hypercapnia was elevated by 20% over the contralesional level (ratio of 1.2 + 0.1). Although perilesional vascular reactivity was elevated in both animals, the control animal exhibited no BOLD response lateralization whereas the FR122047 rat showed attenuated BOLD response in the perilesional tissue. Moreover, the non-lateralized BOLD response of the control animal is in contrast with the attenuated BOLD response in the subacute study, though both are accompanied by elevated perilesional vascular reactivity. It is possible that with

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Figure 2. Functional MRI following chronic COX-1 inhibition in a rat model of focal sensorimotor ischaemia. Maps of BOLD signal changes elicited by hypercapnia (10% CO2) in two representative rats after ALZET-mini pump intracerebroventricular administration of vehicle (a(i)) or FR122047 (a(ii)) are shown overlaid on the corresponding T2-weighted structural images (SI, signal intensity). The treatment was initiated 7 days following injection of endothelin-1 into the right sensorimotor cortex and terminated after 10 days, with imaging performed 24 h following treatment cessation. The average normalized SI in the M1/M2 ROIs (top, black trace: contralateral ROI; bottom, blue trace: perilesional ROI) for the vehicle-administered control subject are plotted in (a(iii)) and for the FR122047-treated animal are displayed in (a(iv)). These traces were normalized, animal-wise, to the maximum signal in that animal’s contralateral M1/M2 ROI. Periods during which 10% CO2 was delivered are indicated by grey rectangles. Concomitant blood flow changes are shown in (b(i)) for a vehicle-administered rat; and in (b(ii)) for a FR122047treated animal. The control animal showed no lateralization in DBOLD (2.6 + 0.1% versus 2.8 + 0.1%), with a peri- to contralesional ratio of 0.9 + 0.1; and doubled peri- versus contralesional DCBF, with a peri- to contralesional ratio of 2.3 + 0.1. In the FR122047-treated animal, BOLD response was attenuated peri- (3.7 + 0.3%) versus contralesionally (6.1 + 0.3%); whereas perilesional Dperfusion was increased by 20% relative to that of the contralesional cortex (ratio of 1.2 + 0.1). Scale bar (a(i) and b(i)) 2 mm. Although the across-brain average BOLD responses were higher in the treated rat than in the vehicle-administered rat, this inter-subject variability was not significant cohort-wise; but it did motivate the interhemispheric normalization within each subject. acutely and chronically. As was the case with BOLD fMRI applications to neuroscientific research in physiological conditions, multimodal preclinical studies can be used to quantitatively characterize neurovascular state in ischaemic progression and yield an ischaemia-specific model of BOLD signal contrast to support the interpretation of fMRI findings in clinical research. In particular, combining BOLD fMRI with in vivo measurements of glucose and oxygen metabolism in

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addition to direct measures of vascular state will provide important insight into the determinants of BOLD contrast in ischaemic injury progression. In addition, combining BOLD with CBF measurements in calibrated fMRI experiments may provide quantitative estimates of the relative oxygen consumption during the execution of a task [66 –69]. This approach relies on CMRO2 measurements during iso-metabolic perturbation and the conservation of

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Figure 3. (Caption opposite.) the assumed blood flow and volume coupling between iso-metabolic stimulation and the functional stimulus/task under investigation. The identification of clinically translatable iso-metabolic perturbers remains an active area of research [70], as does the relationship between flow and volume changes under various ( patho)physiological

conditions. Further insight into the metabolic changes in the peri-infarct tissue may be attained by combining BOLD fMRI with complementary MRI approaches such as amide proton transfer imaging to assess tissue pH. Its preclinical applications have shown that MCAO-induced pH deficits extend beyond the region of diffusion changes, but are

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comprehensive characterization of treatment effects. Another important aspect in treatment development for stroke is elucidating the contributors to subacute reperfusion damage/ oedema. Recent research suggests that reperfusion-induced injury in the subacute stage may be prevented by inhibiting microglial and astrocytic production of matrix metalloproteinases responsible for delayed blood–brain barrier breakdown (reviewed in [79]). fMRI is particularly beneficial for these investigations due to its robustness, sensitivity and easy repeatability, all the while providing whole brain coverage and thus affording the interpretation of signal changes in affected areas in relation to those in distal (notionally intact) brain regions. fMRI use in the development of such interventions may yield indispensable information on spatio-temporal changes in neurovascular functioning (e.g. oxygen extraction with calibrated BOLD) by at-risk tissue, furthering our understanding of the mechanisms of subacute reperfusion injury, which may allow the extension of the time-window for safe and effective application of thrombolytics.

Ethics. All experimental procedures discussed in this paper were approved by the Animal Care Committee of the Sunnybrook Research Institute, which adheres to the Policies and Guidelines of the Canadian Council on Animal Care and meets all the requirements of the Provincial Statute of Ontario, Animals for Research Act as well as those of the Canadian Federal Health of Animals Act. Authors’ contributions. All authors conceived and wrote the review. Competing interests. The authors have no competing interests to declare. Funding. The authors would like to acknowledge the funding sources: CIHR, CCNA, Heart and Stroke Canadian Partnership for Stroke Recovery, Heart and Stroke Foundation of Canada.

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more circumscribed than hypoperfusion [71], and promising preliminary results have also been obtained in stroke patients [72,73]. Owing to the spatial heterogeneity of the metastable peri-infarct zone, these studies will profit from improved spatial resolution [74]. Moreover, such assessments will need to be undertaken longitudinally, at multiple time points following injury due to the highly dynamic neurovascular changes in the chronic stage of ischaemic injury progression. Finally, the generalizability of the preclinical findings will be greatly extended by careful consideration of the appropriateness of the preclinical model of ischaemia [75], modelling of relevant comorbidities that are known to exert a profound impact on outcomes in patients [76], as well as standardization of these protocols to enable the integration of data across different studies and centres [77]. The mechanistic understanding of ischaemic injury and recovery ensuing from the careful application of BOLD fMRI in combination with other modalities in preclinical models will be invaluable in the development of new therapeutic treatments for stroke. In particular, fMRI may prove a valuable tool in the preclinical development of novel pleiotropic therapeutic approaches, called for by the evidence of perilesional plasticity and thus potential for functional recovery and the hitherto poor efficacy of exclusively neuroprotective approaches [78]. In addition to affecting neuronal populations, these treatments will target inflammatory cells and cerebral vasculature in the chronic stage of stroke [58], making multimodal fMRI (combining BOLD fMRI with MRI-based measurements of blood flow, glucose metabolism, pH and inflammation) a useful tool for the

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Figure 3. (Opposite.) Neuronal activity following chronic COX-1 inhibition in a rat model of focal sensorimotor ischaemia. Intracranial array electrophysiological recordings were done in the same animals shown in figure 2. Coherence and power estimates were evaluated in the control animal (a) and in the FR122047treated animal (b). Normalized heat-plots of the multi-electrode array recordings from contralesional (left (i)), and ipsilesional (right (ii)) hemispheres. We recorded from 0 to 1.75 mm from Bregma and plotted distance along the x-axis, and from 0.3 Hz to 100 Hz and plotted frequency along the y-axis. The contralesional hemispheres (a(i) and b(i)) magnitude squared coherence (msc) estimates between neighbouring electrodes showed a high degree of coherence across the cortex throughout the frequency spectrum in the right (contralesional) hemispheres. In the placebo administered animal, the ipsilesional hemisphere (a(ii)) msc was reduced, especially immediately proximal to the site of injury (within 0 – 0.25 mm of Bregma). In the FR122047-treated animal, the msc reduction in the perilesional tissue was less pronounced. The cross-electrode averaged msc is plotted for the contralesional hemisphere (in green) and for the ipsilesional hemisphere (in black) for the control animal (a(iii)) and for the FR122047-treated animal (b(iii)). The contralesional hemispheres (green in a(iii) and b(iii)) showed a higher coherence than the ipsilesional hemispheres (black in a(iii) and b(iii)) across all frequency bands. Contra- versus ipsilesional msc ratios in each band are quoted below and above the corresponding traces in panels (a(iii)) and (b(iii)). The ipsi- to contralesional ratio of the average neuronal power within each frequency band is plotted in (a(iv)) and (b(iv)). In both animals, the average neuronal power was attenuated in the ipsilesional hemisphere relative to contralesional hemisphere in each frequency band. However, in all frequency bands, this attenuation was greater in the vehicle-only administered animal relative to the FR122047-treated animal: u, 73% versus 90%; a, 37% versus 58%; b, 21% versus 31%; low g, 12% versus 13%; g, 24% versus 28%.

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Functional magnetic resonance imaging in chronic ischaemic stroke.

Ischaemic stroke is the leading cause of adult disability worldwide. Effective rehabilitation is hindered by uncertainty surrounding the underlying me...
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