Functional Neuroimaging of Recovery from Focal …...ii Functional Neuroimaging of Recovery from Focal Ischemic Stroke Evelyn MR Lake Doctor of Philosophy Medical Biophysics University
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
Functional Neuroimaging of Recovery from Focal
Ischemic Stroke
by
Evelyn MR Lake
A thesis submitted in conformity with the requirements
2 The effects of delayed reduction of tonic inhibition on ischemic lesion and sensorimotor function 2.1 Physiological parameters during stroke induction and imaging 2.2 Injury characterization 2.3 Skilled reaching ability 2.4 Animal body weight
3 Neurovascular unit remodelling in the subacute stage of stroke recovery 3.1 Physiological monitoring data 3.2 Inclusion criteria for behaviour and imaging protocols 3.3 Channel-wise ipsi-/contra-lateral spontaneous activity power ratio 3.4 Spontaneous activity power ratios 3.5 Stroke volumes on T2-weighted MRI 3.6 Sections used for each ROI in the immunofluorescence analysis 3.7 Optical density ratios on immunofluorescence
4 The effects of delayed COX-1 inhibition on recovery from focal ischemic injury 4.1 Physiological monitoring 4.2 Number of animals 4.3 ROI volumes 4.4 Cortical hemodynamics
ix
List of Figures
2 The effects of delayed reduction of tonic inhibition on ischemic lesion and sensorimotor function 2.1 MRI data segmentation 2.2 Decrease in the volume of injury with treatment 2.3 Amelioration of skilled reaching deficit with treatment 2.4 Relationship between skilled reaching ability and volume of injury 2.5 H&E staining 2.6 Animal body weight 2.7 T2-weighted MRI in sham stroke with L-655,708 2.8 GFAP and NeuN immunohistochemistry
3 Neurovascular unit remodelling in the subacute stage of stroke recovery 3.1 MINCTools classify results 3.2 Somatosensory evoked potentials 3.3 Montoya staircase performance 3.4 Electrophysiological recordings of spontaneous activity 3.5 Evoked LFP responses in the contralateral hemisphere 3.6 Electrophysiological recordings of evoked responses 3.7 Stroke volumes on T2-weighted MRI 3.8 Resting blood flow and cerebrovascular reactivity to 10% CO2 3.9 GFAP and Iba-1 immunofluorescence 3.10 NeuN and RECA-1 immunofluorescence 3.11 Immunofluorescence and corresponding T2-weighted MRI
4 The effects of delayed COX-1 inhibition on recovery from focal ischemic injury 4.1 Schematic of ALZET-pump implantation 4.2 Resting perfusion 4.3 Blood flow response to hypercapnia 4.4 Iba-1 and GFAP immunohistochemistry 4.5 NeuN and RECA-1 immunohistochemistry
1
Chapter 1
1.1 Global stroke burden
Stroke is the leading cause of adult neurological disability worldwide, with the
majority of patients suffering moderate to severe disabilities, and up to one third
requiring institutionalization [Evenson et al. 2001]. With a lifetime cost between $59,800
and $230,000 USD per patient (estimated in 13 countries including Canada and the
United States), the socio-economic burden on patients, family members, and health
care services is already daunting [Feigin et al. 2003, Caro et al. 2000]. Moreover, it is
estimated that by 2020, demographic and epidemiological changes will result in
stroke/coronary-artery disease emerging as the leading cause of lost healthy life-years
worldwide [Feigin et al. 2003, WHO 2000]. If the hitherto trends continue, in the year
2030, there will be almost 12 million stroke deaths, 70 million new stroke survivors, and
more than 200 million disability-adjusted life-years lost globally [Feigin et al. 2014].
There is a clear need to identify ways through which stroke can be prevented, and
means to improve recovery following injury [Krueger et al. 2015].
1.2 Ischemic stroke burden and treatment in North America
Over 85% of all strokes that occur in Canada are ischemic, arising from an
occlusion in a cerebral vessel by a blood clot [Statistics Canada CANSIM 2012]. The
majority of ischemic stroke patients (approximately 90%) arrive at a care facility beyond
the window opportunity for acute stage recanalization treatment [Harsany et al. 2014].
Furthermore, approximately one third do not benefit [Bhatia et al. 2010, Mazighi et al.
2009, Riedel et al. 2011, Smith et al. 2008]. This leaves most patients with
physiotherapy as the only available means to improve long-term outcome [Mikulik et al.
2015, Hill et al. 2005]. That there are not more effective means to rehabilitate this
patient population largely reflects our uncertainty surrounding the underlying
mechanisms that govern recovery following ischemic injury [Teasell et al. 2014].
2
1.3 Neuroprotection and STAIRs
During the last three decades, the search for ischemic stroke therapeutic agents
has focused on neuroprotection [Moretti et al. 2015]. Some examples include: free
radical scavengers, gamma-aminobutyric acid (GABA) agonists, competitive or non-
competitive N-methyl-D-aspartate (NMDA) antagonists, and growth factors [Wahlgren et
al. 2004]. Unfortunately, despite dozens of clinical trials, no neuroprotective agent has
shown success in clinical trials, which has spurred much discussion among basic
researchers and clinicians as to how translation might be improved [Wahlgren et al.
2004, AIadecola et al. 2011]. Limitations of preclinical stroke modelling has been
proposed as a possible reason for the failure of so many therapeutics in clinical trials
that were successful in preclinical experiments [Wahlgren et al. 2004, AIadecola et al.
2011].
Notably, stroke is closely associated with numerous comorbidities (e.g. diabetes,
hypertension, or obesity), whereas the animals in preclinical trials are typically young,
lean and healthy [Wahlgren et al. 2004, Sutherland et al. 2012]. Additionally, it is
common for preclinical studies to examine only male animals [Wahlgren et al. 2004,
Sutherland et al. 2012]. Furthermore, despite the high frequency of late arrivals in
hospital, treatment is often administered within 1-2 hours following the onset of ischemia
in preclinical models [Wahlgren et al. 2004, Sutherland et al. 2012]. Upon re-
examination, many candidate neuroprotective treatments were administered to patients
much longer after the onset of ischemia than they had been given to animals in
successful preclinical experiments [Wahlgren et al. 2004]. Thus, neuroprotection is most
effective within a short time window, much like recanalization treatments, which greatly
restricts the number of patients who stand to benefit from these strategies. In addition,
many preclinical studies were confounded by drugs which caused hypothermia (which
itself is neuroprotective through several pathways: e.g. reducing free radical formation,
attenuating protein kinase C activity, and slowing cellular metabolism [Sutherland et al.
2012, Yenari et al. 2008, Berger et al. 2002, Globus et al. 1995]). Moreover, it is likely
that hypothermia is effective because so many pathways are affected which promote
cell survival; whereas many neuroprotective treatment strategies affect only one of
many targets in the cell death cascade [AIadecola et al. 2011]. Finally, outcome is most
3
commonly evaluated using tests of gross motor function and quality of life assessments
in clinical practice; whereas stroke volume is the most common outcome metric in
preclinical research [Wahlgren et al. 2004, Sutherland et al. 2012]. In addition,
evaluation of outcome in preclinical models is often early; therefore, delayed cell death
has been mistaken for cell survival [Xu et al. 2013]. Upon re-evaluation, when body
temperature is controlled and therapeutic intervention and evaluation of outcome are
delayed, the majority of neuroprotectants show no preclinical benefit. Therefore, it has
been suggested that to overcome the translational roadblock, preclinical trials that test
novel therapeutics need to adhere to a more strict set of guidelines to better model the
patient population.
To address these shortcomings, The Stroke Therapy Academic Industry
Roundtable (STAIR) working group has provided an initial (1999) and updated (2009)
set of recommendations to improve translation. Some of the recommendations from
revealed that treated rats exhibited increased neuronal survival, and attenuated peri-
lesional inflammation. These findings suggest that COX-1 inhibition in the subacute
stage may ameliorate some of the effects of focal ischemia induced injury. Inflammation
plays an as-of-yet incompletely understood role in subacute ischemic injury progression.
To-date, no anti-inflammatory therapeutics have been successfully translated to the
clinic [Yagami et al. 2015]. Again, many previous studies have been confounded by
testing candidate therapeutics at times that are inaccessible in the majority of patients
and by choosing models which do not capture critical characteristics of stroke pathology
[Hossmann 2012, Yagami et al. 2015]. As discussed above, in the present work we
employed a model which better recapitulates key features of stroke pathology, and
tested COX-1 inhibition in the subacute stage which increases the translational potential
of the present findings. Further, FR122047 has to-date not been tested as a candidate
treatment strategy for selective COX-1 inhibition in the subacute stage of ischemic injury
progression in vivo.
In summary, these studies yielded an unprecedented level of detailed in vivo
characterization of neurogliovascular changes in relation to behavioural performance
during endogenous recovery and in the presence of pharmacological interventions
during the subacute stage of ischemic injury progression. Through further study of the
underlying mechanisms and therapeutic strategies investigated in the present work,
greatly needed therapeutic strategies for ischemic stroke patients effective during an
extended time-window post stroke stand to be realized.
22
List of Contributions
Chapter 2: The effects of delayed reduction of tonic inhibition on ischemic lesion and sensorimotor function. Evelyn MR Lake, Joydeep Chaudhuri, Lynsie AM Thomason, Rafal Janik, Milan Ganguly, Dale Corbett, Greg J Stanisz, and Bojana Stefanovic
Published in Journal of Cerebral Blood Flow and Metabolism
Chapter 3: Neurovascular function in the subacute stage of focal cerebral ischemia. Evelyn MR Lake, Paolo Bazzigaluppi, James Mester, Lynsie AM Thomason, Rafal Janik, Mary Brown, JoAnne McLaurin, Peter L Carlen, Dale Corbett, Greg J Stanisz and Bojana Stefanovic
Under review with NeuroImage
Chapter 4: The effects of delayed COX-1 inhibition on recovery from focal ischemic injury. Evelyn MR Lake, James Mester, Lynsie AM Thomason, Conner Adams, Paolo Bazzigaluppi, Margaret Koletar, Rafal Janik, JoAnne McLaurin, Greg J Stanisz and Bojana Stefanovic
Under review with Journal of Magnetic Resonance Imaging Chapter 6: Functional MRI in chronic ischemic stroke (Review). Evelyn MR Lake,
Paolo Bazzigaluppi and Bojana Stefanovic
In press in Philosophical Transactions B
23
Text reproduced from publication in JCBFM
Chapter 2
The Effect of Delayed Reduction of Tonic Inhibition on Ischemic
Lesion and Sensorimotor Function
Abstract
To aid in development of chronic stage treatments for sensorimotor deficits induced by
ischemic stroke, we investigated the effects of GABA antagonism on brain structure and
fine skilled reaching in a rat model of focal ischemia induced via cortical micro-injections
of endothelin-1 (ET-1). Beginning 7 days after stroke, animals were administered a
novel GABAA inverse-agonist, L-655,708, at a dose low enough to afford α5-GABAA
receptor specificity. A week following stroke, the ischemic lesion comprised a small
hypointense necrotic core (6 ± 1 mm3) surrounded by a large (62 ± 11 mm3)
hyperintense peri-lesional region; the skilled reaching ability on the Montoya staircase
test was decreased to 34 ± 2% of the animals’ pre-stroke performance level. Upon L-
655,708 treatment, animals showed a progressive decrease in total stroke volume (13 ±
4 mm3/week, p=0.002), with no change in animals receiving placebo (p>0.3).
Concomitantly, treated animals’ skilled reaching progressively improved, by 9 ± 1% per
week, so that after two weeks of treatment, these animals performed at 65 ± 6% of their
baseline ability, which was 25 ± 11% better than animals given placebo (p=0.04). These
data indicate beneficial effects of delayed, sustained low-dose GABAA antagonism on
neuroanatomical injury and skilled reaching in the chronic stage of stroke recovery in an
ET-1 rat model of focal ischemia.
24
2.1 Introduction
The majority of ischemic stroke patients (as much as 92% in some centres)
arrive at a care facility beyond the window of opportunity (i.e., 3-4.5 hrs after the onset
of symptoms) for acute treatment with tissue plasminogen activator (t-PA), leaving
rehabilitation as the only means to improve outcome [Statistics Canada CANSIM 2012,
Hill et al. 2005]. In the long term, most ischemic stroke patients suffer moderate to
severe disabilities, and up to one third require institutionalization [Evenson et al. 2001].
The need for restorative treatments that may be administered during the chronic stage
(days to weeks following an ischemic event) is thus pressing.
It is now widely believed that the chronic stage recovery involves tissue
remodelling - through the generation of new neurons and glia, axonal sprouting, and/or
synaptogenesis [Witte et al. 2000] - in the peri-infarct zone, a surviving meta-stable
region of “at-risk” tissue that exhibits heterogeneity in both acute stage perfusion deficit
and long-term tissue fate [Wieloch et al. 2006]. Indeed animal studies suggest that the
period to support and/or enhance remapping of sensorimotor function within the peri-
infarct zone may be sufficiently long to enable effective treatment in the sub-acute and
chronic stages [Clarkson et al. 2010, Brown et al. 2009]. Although neurons in the peri-
infarct zone had long been considered hyper-excitable [Schiene et al. 1996], a recent
study in a mouse photothrombic model of focal ischemia by Clarkson et al. (2010)
reports that the initial acute phase of hyper-excitability is followed (on the third day after
photo-thrombosis) by abnormally high levels of tonic inhibition (proposed to be mediated
by decreased extra-synaptic GABA-uptake) resulting in neuronal hypo-excitability
[Clarkson et al. 2010]. Clarkson et al. (2010) show that infusing L-655,708, a GABAA-
receptor inverse agonist, using ALZET-1002 mini-pumps 3 days post-stroke improves
sensorimotor function on the grid-walking and cylinder tasks. By 7 days following stroke,
animals treated with 400 μg/kg/day of L-655,708 have fewer foot-faults on grid walking
task (1.8 times the forelimb foot faults before stroke in the treated group vs. 2.5 times in
the control group) and lower affected-to-unaffected forelimb use difference on cylinder
task (19% discrepancy in the treated group vs. 35% discrepancy in the control group).
Spurred by this report and in keeping with the recommendations of the Stroke
Treatment Academic Industry Roundtable (STAIR) [Khale et al. 2012], we investigated
25
the effects of L-655,708 on brain anatomy and forelimb skilled reaching over three
weeks following focal ischemia induced by cortical micro-injection of endothelin-1 (ET-
1).
We used rats to evaluate the effects of L-655,708 in higher-order species and to
enable the utilization of the Montoya skilled reaching task which has been shown highly
sensitive to sensorimotor injury while exhibiting much less spontaneous recovery than
that seen with measures of spontaneous activity and neurological test batteries [Murphy
& Corbett 2009]. Cortical micro-injection of ET-1 was performed to more faithfully
recapitulate the kinetics of flow impairment observed in human stroke, and to produce a
lesion comprised of a substantial peri-infarct zone surrounding the necrotic core, as
frequently observed in patients, where peri-infarct region comprises up to 35% of the
total volume of injury [Heiss et al. 2000, Windle et al. 2006, Carmichael et al. 2005,
Olsen et al. 1984, Mohr et al. 1986, ABiernaskie et al. 2001]. In contrast to Clarkson et
al. (2010), we implanted the L,655-708 tablets subcutaneously and used a dosing
regimen, following Atack et al. (2006), that results in a steady-state plasma drug
concentration that is low enough to produce selective α5-subunit-containing GABAA-
receptor occupancy during the course of treatment [Atack et al. 2006]. We thereby
assessed drug effects following a clinically relevant delivery method at a dose that
minimizes side-effects by preserving receptor subtype specificity [Atack et al. 2006].
2.2 Methods
2.2.1 Subjects
All experimental procedures in this study were approved by the Animal Care
Committee at the Sunnybrook Research Institute. Thirty-seven adult male Sprague-
Dawley rats (Charles River, Montreal, Canada) weighing 340±50g (mean ± standard
deviation, SD) at the time of stroke induction were included in this study. Animals were
housed in pairs on a 12 hour light/dark cycle. Administration of drug, MR imaging and
behaviour trials were performed during the light phase. Food and water were freely
available except during behavioural test periods (14 consecutive days prior to stroke,
and on days 4-6, 11-13, and 18-20) when food was restricted to 12-15g per day.
26
Throughout the study, the body weight of each animal was maintained at above 90% of
the free-feeding weight.
2.2.2 Stroke induction
All animals underwent the same stroke induction procedure under isoflurane
anesthesia (5% induction and 2-2.5% maintenance). Continuous physiological
monitoring was conducted throughout the surgical procedure (see Table 2.1) to ensure
physiological stability. An ischemic injury was induced via two intra-cortical micro-
injections of ET-1, into the forelimb area of the right primary sensorimotor cortex, as
described in detail below [Windle et al. 2006].
Animals were secured in a small animal stereotaxic apparatus (David KOPF
Instruments). Under aseptic condition, a midline incision was made, and two burr holes
(2mm in diameter) were drilled (relative to Bregma) at 0.0mm AP, -2.5mm ML; and at
2.3mm AP, -2.5mm ML over the right sensorimotor cortex using a high-speed micro-drill
(Foredom Electric Co., Bethel Connecticut) [Windle et al. 2006]. A 10-μl Hamilton
Syringe was used to deliver 800 picomoles of ET-1 suspended in 4μl of phosphate
buffered saline (PBS) at -2.3mm DV: 400 picomoles were delivered in 2μl aliquots
through each burr hole. After lowering the needle to -2.5mm and retracting it to -2.3mm
DV, a one-minute delay was allowed before injection began. A further one-minute delay
was kept between the delivery of each μl, and a two-minute delay preceded needle
retraction. ET-1 was injected at a rate of 1μl per minute, for a total delivery time
(including 4, one-minute delays, and 2, two-minute) of 12 minutes. Burr holes were
closed with bone wax and the scalp was sutured over the skull. For analgesia, animals
were given a subcutaneous dose of Marcaine (0.2mg/kg) suspended in PBS at the
reperfusion) decreases neuronal loss in a gerbil model of global ischemia [Candelario-
Jalil et al. 2003]. This effect has been suggested to result from a reduction in PG-D2
production – largely mediated by COX-1 post ischemia [Song et al. 2008] – that reduces
the PG-D2-induced increase in neuronal apoptosis by activation of poly ADP ribose
polymerase and caspase-3 [Liu et al. 2013].
Pruning, recruitment of mural cells, the generation of an extracellular matrix,
specialization of the vessel wall, and the functional integration of nascent vasculature
are highly dependent on the spatio-temporal interaction of nascent vessels with
surrounding neurons and glia [cf. Review Korn et al. 2015]. Increased peri-lesional
neuronal survival may thus have promoted the integration and maturation of the nascent
peri-lesional vessels, hence contributing to persistent peri-lesional hyperperfusion in
FR122047 treated rats. In contrast, greater peri-lesional neuronal loss in the placebo
rats may have led to more extensive pruning during the maturation of the nascent
vessels, thus rendering some of them non-perfused [Korn et al. 2015], accounting for
the reduction in peri-lesional perfusion with time in the placebo animals. Peri-lesional
hyper-reactivity to hypercapnia similarly may have been due to the lower resistance of
nascent vessels [White et al. 1992]. Persistent peri-lesional hyperperfusion in treated
rats may have also been influenced by an FR122047-mediated reduction in PGs that
promote vaso-constriction and are predominately produced via COX-1 in activated
microglia [Yagami et al. 2015, Kobayashi et al. 2004, McAdam et al. 1999, Giulian et al.
1996], whose peri-lesional density was decreased in FR122047 treated relative to
placebo rats. Reduced microglial/macrophage density in FR122047 treated rats is in
general agreement with previous reports on COX-1 inhibition effects in other models of
chronic inflammatory responses [Choi et al. 2009, McKee et al. 2008, Nomura et al.
2011].
The present study provided evidence of beneficial effects of delayed, selective,
cerebral COX-1 inhibition on the neurogliovascular unit in the peri-infarct zone.
Treatment resulted in increased peri-lesional neuronal survival, decreased recruitment
of microglia/macrophages, and sustained elevation in peri-lesional perfusion. These
histopathological and imaging findings warrant further investigation of the effect of
selective COX-1 inhibition on functional outcome in the chronic stage of stroke recovery.
Furthermore, future measurements of PGs levels post COX-1 inhibition, along with in
117
vivo measurements of changes in vascular architecture and function as well as neuronal
excitability will further the mechanistic understanding of the observed effects. In
addition, future studies which include behavioural testing to evaluate the effects of
FR122047 treatment on functional outcome are needed as metrics of behavioural
changes are the gold standard outcome measure of recovery from ischemic injury
[Murphy & Corbett 2009].
118
Chapter 5
There is a pressing need to identify strategies to improve functional recovery
over weeks and months- following ischemic injury [Teasell et al. 2014]. That there are
not more effective means to rehabilitate this growing patient population largely reflects
the uncertainty surrounding the underlying mechanisms that govern long-term recovery
following ischemic injury. The present work investigated the complex relationship
between structure and function of brain neuronal and vascular networks during the
weeks following unilateral focal ischemic stroke. Observations of concomitant structural,
functional, and behavioural changes over several weeks following ischemic insult were
reported during both endogenous recovery as well as with the application of L-655,708,
a GABA-receptor inverse agonist to increase neuronal excitability and FR122047, a
selective COX-1 inhibitor.
5.1 Modulating excitability
Following an ischemic injury, some sensory and motor function performed by
injured tissue prior to infarction is remapped to contra-lesional as well as peri-lesional
areas. Remapping is manifested as gross physiological changes in the responsiveness
of neuronal networks demonstrating widespread functional plasticity during the weeks-
months following injury [Murphy & Corbett 2009, Carmichael et al. 2012]. There is
growing interest in the potential that modulating excitability may have in facilitating
remapping; particularly given the evidence of improved recovery in patients receiving
trans-cranial direct current stimulation (tDCS) treatment [cf. Review by Khedr et al.
2010, Floel 2014 and Jones et al. 2015]. tDCS is thought to enhance motor learning and
increase synaptic plasticity [Fritsch et al. 2010, Monte-Silva et al. 2013, Stagg et al.
2009] by inducing subthreshold membrane depolarization (anodal tDCS), and/or
hyperpolarization (cathodal tDCS) [cf. Review by Savic et al. 2016]. These effects are
governed by altered NMDA and GABA receptor activity [Fritsch et al. 2010, Stagg et al.
2009]. Although, tDCS treatment remains to be optimized [Khedr et al. 2010], the
119
prevailing opinion is that higher session frequency results in greater functional benefit
[Jones et al. 2015, Monte-Silva et al. 2013, Floel 2014].
Pharmacological manipulations designed to enhance neuronal plasticity by
modulating excitability following stroke have also been proposed as a means to improve
outcome (e.g. blockers of tonic GABA activity and positive allosteric modulators of
AMPA (α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate) receptors) [cf. Review by
Carmichael et al. 2012]. Agents that target α-5 containing GABAA receptors (which
spare phasic GABA signalling) regulate cognitive processing, and play key roles in
memory acquisition, consolidation, and retrieval [Glykys et al. 2007, Gabriella et al.
2010, Carmichael et al. 2012]. The work presented in Chapter 2 investigated the effects
of L-655,708 (an inverse α-5 containing GABAA receptor agonist) and found that in the
subacute stage, L-655,708 elicits a decrease in stroke volume and improves skilled
reaching ability. This work provides further evidence that modulating excitability in the
subacute stage may be a promising therapeutic strategy for ischemic stroke.
A potential avenue of future investigations would be to combine L-655,708
treatment with tDCS and physical therapy (e.g. enriched environment and/or daily reach
training [BBiernaskie et al. 2001, Clarke et al. 2014]). It is conceivable that the combined
therapeutic effect would exceed the sum of the functional gains from either strategy
does alone. Moreover, fMRI measurements (e.g. BOLD and/or ASL) and
electrophysiological recordings could reveal more widespread evidence of remodelling
facilitated by L-655,708 treatment, or evidence of contra- or ipsi-lesional
remapping/recruitment, furthering our understanding of the underlying processes of
remodelling. A review of the strengths and challenges in applying fMRI in preclinical
modeling of stroke is presented in Appendix 2. Finally, it would be of great utility for the
development of GABA inhibition based intervention to examine changes in local
concentration of GABA with magnetic resonance spectroscopy (MRS), which has been
previously employed to demonstrate tDCS-mediated changes in GABA [Stagg et al.
2009]. These data would offer insight into downstream effects of GABA antagonism and
help to identify the therapeutic window for treatments which modulate excitability.
120
5.2 Endogenous neuro/angio-genesis
Brain exhibits endogenous angio- and neuro-genesis post-stroke [cf. Reviews by
Wiltrout et al. 2007, Liu et al. 2014, Sawada et al. 2014, Ruan et al. 2015, Marlier et al.
2015, Yu et al., 2016]. Promoting endogenous repair following neuronal loss caused by
injury or disease is thought to have great potential to improve outcome for many
patients [cf. Review by Jessberger et al. 2016]. Specifically, stroke induces significant
vascular outgrowth [Ruan et al. 2015], which creates a unique micro-environment
necessary for neurogenesis in the adult brain [Sawada et al. 2014, Thored et al. 2007,
Kojima et al. 2010, Grade et al. 2013, Ohab et al. 2006, Gerlai et al. 2000, Marlier et al.
2015, Nishijima et al. 2010, Greenberg et al. 2013, Jin et al. 2002, Shen et al. 2004,
Zhang et al. 2015]. Thus, enhancing injury-induced angiogenesis has been studied as a
potential therapeutic strategy in preclinical models of ischemia [Ding et al. 2006, Hu et
al. 2010, Wang et al. 2015, Tang et al. 2010, Sun et al. 2003]. For example, exercise
(either before or after stroke) increases vessel density in the peri-infarct zone and
improves functional outcome. In addition, a handful of pharmacological agents have
been identified to enhance neuro-/angio-genesis when administered 24 hours following
ischemia in animal models [Zhou et al. 2001, Manwani et al. 2013, Selvin et al. 2008,
Jin et al. 2014, Mantovani et al. 2013, Kiegerl et al. 2009, Corbett et al. 2015, Hu et al.
2016]. However, insight into endogenous neuro-/angio-genesis in preclinical models has
predominantly been gleaned from invasive or terminal experiments (e.g. microscopy,
and histochemistry) [cf. Review by Jiang et al. 2016]. Neuroimaging assays that may be
conducted both preclinically and in patients may likely help translate what has been
learnt in animal models to the clinic. Further, non-invasive methodologies allow the
assessment of tissue remodelling longitudinally and can provide valuable in vivo
measurements of function, which is currently not well characterized [Jiang et al. 2016].
Chapter 3 built upon a handful of preclinical studies that have reported transient
increases in CBF and/or CBV in peri-lesional tissue during the weeks following focal
ischemia and linked these findings to injury-induced angiogenesis on
immunohistochemistry. Concomitant to marked hemodynamic changes on in vivo ASL,
we observed evidence of both evoked and spontaneous neuronal activity that are likely
manifestations of remapping. However, the presently observed neurophysiological and
121
hemodynamic changes were not accompanied by improved skilled reaching ability,
which may be due to a highly non-linear relationship between neurophysiological state
and behaviour. Moreover, functional gains may had been apparent on other behavioural
tests.
Future investigations examining the time course of neuronal activity changes
following injury would profit from being conducted in awake and behaving animals with
permanently implanted intra-cranial electrodes [cf. Review by Oliveira et al. 2008]. Such
an experiment would reveal more precisely when changes in evoked and spontaneous
neuronal activity arise and thus more clearly define when interventions (to spur
angiogenesis or raise excitability) might be most beneficial. Alternatively, investigating
the effects of pro-angiogenic treatment (e.g. VEGF or Ang-1), exercise (endogenously
pro-angiogenic) or enhancers of neuronal excitability (e.g. L-655,708 as in Chapter 2)
on CBF and CBF elicited changes, neuronal-excitability and behaviour may reveal
neuro-imaging biomarkers of functional improvement. Finally, as a plateau was not
observed, the observation period should be extended to assess longer term changes.
5.3 Inflammation
Hitherto, the majority of candidate anti-inflammatory therapeutics have been
applied in the acute period [cf. Review by Spite et al. 2010, BIadecola et al. 2011 and
Kim et al. 2014]. Chronically, continued inflammatory processes have both deleterious
and beneficial effects on remodelling and repair [BIadecola et al. 2011, Spite et al.
2010]. Among the anti-inflammatories preclinical studies, a large proportoin find COX-2
inhibition to improve outcome [cf. Reviews by Spite et al. 2010, Yagami et al. 2015].
However, long-term placebo-controlled clinical studies reveal unfortunate cardiovascular
side-effects of COX-2 inhibition [Ott et al 2003, Nussmeier et al. 2005, Cannon et al.
2006, Blobaum et al. 2006], curbing translation of these agents. In the study presented
in Chapter 4, we reproduced the fMRI results presented in Chapter 3 in the vehicle-only
control group and demonstrated that 12 days of intracerebroventricular administration of
FR122047 (a selective COX-1 inhibitor) preserved peri-lesional hyperperfusion,
increased neuronal survival, and decreased microglia and macrophage recruitment and
activation. To the best of our knowledge, the present work is the first to examine
122
selective pharmacological COX-1 inhibition as a focal ischemic stroke treatment
strategy in the subacute phase in vivo. These findings warrant further investigation of
the effect of selective COX-1 inhibition on functional outcome, treatment optimization,
and the underlying mechanisms of FR122047-mediated changes in the
neurogliovascular unit, especially the underlying effects on PG-D2 and TX-A2
production. Furthermore, we presently administered FR122047 intracerebroventricularly
to avoid off-target effects (as COX-1 is expressed throughout the body) [Perrone et al.
2010]. However, in an effort to increase the translational potential of this treatment
strategy, future work should endeavour to test a less invasive means of delivering
FR122047 treatment. In addition, combining L-655,708 and FR122047 treatment to
simultaneously combat the deleterious effects of hyper-excitability and neuro-
inflammation might prove to be a powerful combinatorial subacute intervention and
should also be investigated.
The present work was conducted exclusively in male animals. Before
menopause, women suffer fewer strokes than do men [Stagmeyr et al. 1997, Sudlow
and Warlow et al. 1997]. Following menopause the incidence of stroke equalizes
between women and men [Anderson et al. 1991, Hurn and Macrea 2000] possibly as a
result of the lost neuroprotective effects of estrogen [Hurn and Macrea 2000] and/or the
associated higher cerebral blood flow of pre-menopausal women [Esposito et al. 1996].
However, sex differences are present in the pediatric population and persist following
menopause suggesting that the prescence of reproductive steroids do not wholly
account for the sexual dimorphism in stroke [cf. Review by Liu et al. 2009]. Notably,
outcome after an ischemic injury in post-menopausal women is worse than men
[Bushnell 2008]. Specifically, women suffer from more severe disabilities [Bushnell
2008], are more likely to be institutionalized [Bushnell 2008], and less likely to reach
independence in instrumental activities [Lai et al. 2005]. Furthermore, there are sex
differences in neuroprotection and cell death [Liu et al. 2009], auto-regulation by
immune cells [Tipton & Sullivan 2014] and response to rehabilitation [Langdon et al.
2014]. Future investigations of the present findings should thus be conducted in both
male and female animals. These investigations may address behavioural phenotyping
differences both between sexes and across straing [Meziane et al. 2007].
123
5.4 Limitations of Normalization
In the present work, functional MRI measures (perfusion and reactivity)
presented in Chapters 3 and 4 were obtained by dividing the average parameter
estimate within the ipsilateral ROI by the average parameter estimate within the
contralateral ROI in each animal. These ratios were then averaged within groups. This
division was necessary in Chapter 3 due to variation in the signal-to-noise ratio between
recordings on different imaging days. In Chapter 4, we report both the absolute signal
change in right and left ROIs as well as the inter-hemispheric ratio. Although commonly
employed, use of the contralateral hemisphere signal as an 'internal reference' is
confounding as the contralateral hemisphere has been shown to be involved in the
progression of ischemic injury [c.f. Review in Appendix 2]. Notwithstanding, comparing
the ipsilateral measurements to the whole brain parameter estimates (as was done in
Chapter 3), or contrasting the non-normalized signal changes (Chapter 4) yielded the
same contrasts. While preferable, absolute quantification of CBF was not undertaken in
the present work. It would have entailed T1 relaxometry and inversion efficiency
measurements in each subject, in addition to the quantification of steady-state arterial
magnetization, thus significantly prolonging the MRI protocol, which would have likely
increased the attrition given the fragile state of these animals.
In Chapter 3 we report normalized electrophysiological data on evoked and
spontaneous activity. In these experiments, the signal from neighbouring electrodes
was first subtracted to increase sensitivity to changes in the neighbourhood of each
electrode. In the evoked activity experiment, each pairwise difference signal traces was
then averaged across 10 stimulus presentations and the response amplitude of that
average trace estimated; and divided by the maximum response amplitude recorded by
that array. These values were then averaged across spatially corresponding positions in
different animals and resulting across-subject averages plotted as a function of distance
from Bregma. In the spontaneous activity experiment, the FFT of the recorded signal
was computed for each electrode and the power within each frequency band of interest
averaged across all electrodes of the array. In each animal, the average power
recorded by the ipsilateral array was then divided by the average power recorded by the
contra-lateral array. The sources of noise in these experiments were differences
124
between the right and left craniotomies, the hardware differences between the two
MEAs, as well as environmental noise sources, necessitating normalization. To reduce
systematic error, we randomized the placement of each MEA between right vs. left
hemisphere.
In Chapter 3, the area occupied by positively stained cells in
immunohistochemical analysis was also normalized. For the ipsilateral and contralateral
ROIs in each animal, the fractional area occupied by positively stained cells was
computed and the ipsilateral ROI value was then divided by the contralateral ROI value.
The inter-hemispheric ratios were then averaged across animals within each group. For
each stain, all sections were prepared simultaneously. Furthermore, all imaging and
data processing parameters were held constant for all sections. As with the fMRI
analysis, normalization of the immunohistochemical data thus used the contralateral
hemisphere value as an internal control. In Chapter 4, we reported the fractional area
occupied by the cell types of interest without normalization, yet observed the same
contrasts in the placebo animals as those observed in untreated animals of Chapter 3.
Future work should further characterize the immunohistochemical results reported in the
present work using a more rigorous methodology (e.g., stereology).
5.5 Conclusion
As the vast majority of patients arrive at a care facility well outside of the window
of opportunity for treatment using current therapies, identifying ways through which
outcome can be improved during the subacute and chronic stages is of utmost
importance. The present work investigated endogenous neurovascular processes of
subacute recovery as well as two pharmacological interventions: sustained low-dose
GABAA antagonism (L-655,708) and selective cyclooxygenase-1 (COX-1) inhibition
(FR122047). On the whole, the present work shows the complexity of the relationship
between neurovascular structure, function, and behaviour, and emphasized the need for
multi-modal characterization of neurophysiological state over prolonged observation
periods following ischemic insult. Furthermore, the beneficial effects of L-655,708 and
FR122047 when administered in the subacute stage of injury progression warrant
further investigation of the underlying mechanisms of action. All together, these data
125
show new evidence of highly dynamic structural and functional remodelling within the
neurogliolvascular network over the weeks following ischemic injury and the successful
pharmacological modulation of these processes to improve outcome.
126
References
Ahmad M, Ahmad AS, Zhuang H, et al. Stimulation of prostaglandin E2-EP3 receptors exacerbates stroke and excitotoxic injury. J Neuroimmunol. 2007;184:172–179
Aid S, Bosetti F. Targeting cyclooxygenases-1 and -2 in neuro-inflammation: Therapeutic implications. Biochimie. 2011;93:46–51
Alexandrov AV, Clack SE, Ehrlich LE, Bladin CF, Smurawska LT, Pirisi A, Caldwell CB. Simple visual analysis of brain perfusion on HMPAO SPECT predicts early outcome in acute stroke. Stroke. 1996;26:1537-42
Allan SM, Rothwell NJ. Cytokines and acute neurodegeneration. Nat Rev Neurosci. 2001: 734–744
Altamura C, Torquati K, Zappasodi F, Ferretti A, Pizzella V, Tibuzzi F, Vernieri F, Pasqualetti P, Landi D, Del Gratta C et al. fMRI-vs-MEG evaluation of post-stroke interhemispheric asymmetries in primary sensorimotor hand areas. Exp Neurol. 2007;204(2):631-9
Anderson KM, Wilson PW, Odell PM, Kannel WB. An updated coronary risk profile. I statement for health professionals. Circulation. 1991;83:356-62
Atack JR, Pike A, Clarke A, Cook SM, Sohal B, McKernan RM et al. Rat pharmacokinetics and pharmacodynamics of a sustained release formulation of the GABA(A) Alpha-5-selective compound L-655,708. Drug Metab Dispos. 2006;34:887-93
Atochin DN, Wang A, Liu VW, Critchlow JD, Dantas AP, Looft-Wilson R, Murata T, Salomone S, Shin HK, Ayata C, Moskowitz MA, Michel T, Sessa WC, Huang PL. The phosphorylation state of eNOS modulates vascular reactivity and outcome of cerebral ischemia in vivo. J Clin Invest. 2007;117(7):1961-7
Astrakas LG, Naqvi SHA, Kateb B, Tzika AA. Functional MRI using robotic MRI compatible devices for monitoring rehabilitation from chronic stroke in the molecular medicine era (review). Int J Mol Med. 2012; 29(6):963-73
Baaven RH, Davidson DJ, Bates DM. Mixed-effects modelling with crossed random effects for subjects and items. J Mem Lang. 2008:390-412
Barreca S, Gowland C, Stratford P, et al. Development of the Chedoke arm and hand activity inventory: item selection. Physiother Can. 1999;209-11
Basu A, Lazovic J, Krady JK, Mauger DT, Rothstein RP, Smith MB, Levison SW. Interleukin-1 and the interleukin-1 type 1 receptor are essential for the progressive neurodegeneration that ensues subsequent to a mild hypoxic/ischemic injury. 2005
Becker K, Kindrick D, Relton J, Harlan J, Winn R. Antibody to the alpha4 integrin decreases infarct size in transient focal cerebral ischemia in rats. Stroke. 2001;32(1):206–211
Beech JS, Williams SC, Campbell CA, Bath PM, Parsons AA, Hunter AJ, et al. Further characterisation of a thromboembolic model of stroke in the rat. Brain Res. 2001;895:18 –24
Berger C, Schabitz WR, Georgiadis D, Steiner T, Aschoff A, Schwab S. Effects of hypothermia on excitatory amino acids and metabolism in stroke patients: a microdialysis study. Stroke 2002;33:519–24
127
Berrouschot J, Sterker M, Bettin S, Koster J, Schneider D. Mortal of space-occupying (“malignant”) middle cerebral artery infarction under conservative intensive care. Intensive Care Med. 1998;24:620–3
Bhatia R, Hill MD, Shobha N, Menon B, Bal S, Kochar P, Watson T, Goyal M, Demchuk AM. Low rates of acute recanalization with intravenous recombinant tissue plasminogen activator in ischemic stroke: real-world experience and a call for action. Stroke 2010;41:2254–8
ABiernaskie J, Corbett D, Peeling J, Wells J, Lei H. A serial MR study of cerebral blood flow changes and lesion development following endothelin-1-induced ischemia in rats. Magn Reson Med. 2001;46:827-30
BBiernaskie J, Corbett D. Enriched rehabilitative training promotes improved forelimb motor function and enhanced dendritic growth following focal ischemic injury. J Neurosci. 2001;21: 5272–80
Biernaskie J, Chernenko G, Corbett D. Efficacy of rehabilitative experience declines with time after focal ischemic brain injury. J Neurosci. 2004;24:1245–4
Binkofski F, Seitz RJ. Modulation of the BOLD- response in early recovery from sensorimotor stroke. Neurology. 2004;63(7):1223-9
Blicher JU, Stagg CJ, O’Shea J, Østergaard L, MacIntosh BJ, Johansen-Berg H, Jezzard P, Donahue MJ. Visualization of altered neurovascular coupling in chronic stroke patients using multi-modal functional MRI. J Cereb Blood Flow Metab. 2012(11):2044-54
Blobaum AL, Marnett LJ. NSAID action and the foundations for cardiovascular toxicity. Cardiotoxicity Non-Cardiovascular Drugs. 2010;257–285
Bolay H, Dalkara T. Mechanisms of motor dysfunction after transient MCA occlusion: persistent transmission failure in cortical synapses is a major determinant. Stroke. 1998;29(9):1988-93
Bours MJ, Swennen EL, Di Virgilio F, Cronstein BN, Dagnelie PC. Adenosine 5'-triphosphate and adenosine as endogenous signaling molecules in immunity and inflammation. Pharmacol Ther. 2006;112:358–404
Boutin H, LeFeuvre RA, Horai R, Asano M, Iwakura Y, Rothwell NJ. Role of IL-1alpha and IL-1beta in ischemic brain damage. J Neurosci. 2001;21(15):5528–5534
Brown CE, Aminoltejari K, Erb H, Winship IR, Murphy TH. In vivo voltage-sensitive dye imaging in adult mice reveals that somatosensory maps lost to stroke are replaced over weeks by new structural and functional circuits with prolonged modes of activation within both the peri-infarct zone and distant sites. J Neurosci. 2009;29:1719-34
Buetefisch CM. Role of the Contralesional Hemisphere in Post-Stroke Recovery of Upper Extremity Motor Function. Front Neurol. 2015;6:214
Buga AM, Di Napoli M, Popa-Wagner A. Preclinical models of stroke in aged animals with or without comorbidities: role of neuro-inflammation. Biogerontology. 2013;14(6):651-62
Buma FE, Lindeman E, Ramsey NF, Kwakkel G. Functional neuroimaging studies of early upper limb recovery after stroke: a systematic review of the literature. Neurorehabil Neural Repair. 2010;24(7):589-608
Bune LT, Thaning P, Johansson PI, Bochsen L, Rosenmeier JB. Effects of nucleotides and nucleosides on coagulation. Blood Coagul Fibrinolysis. 2010;21:436–41
Burnstock G, Ralevic V. Purinergic signaling and blood vessels in health and disease. Pharmacol Rev. 2013;66(1):102-92
128
Bushnell CD. Stroke and the female brain. Nature Clinical Practice Neurology. 2008;4:22-33
Buxton RB,Wong EC, Frank LR. Dynamics of blood flow and oxygenation changes during brain activation: the balloon model. Magn Reson Med. 1998;39(6):855–64
Candelario-Jalil E, González-Falcón A, García-Cabrera M, Álvarez D, Al-Dalain S, Martínez-Sánchez G, León OS, Sprinter JE. Assessment of the relative contribution of COX-1 and COX-2 isoforms to ischemia-induced oxidative damage and eurodegeneration following transient global cerebral ischemia. J Neurochem. 2003;86(3):545-55
Candelario-Jalil E, Pinheiro de Oliveira AC, Gräf S, Bhatia HS, Hüll M, Muñoz E, Fiebich BL. Resveratrol potently reduces prostaglandin E2 production and free radical formation in lipopolysaccharide-activated primary rat microglia. J neuro-inflammation. 2007;4:25
Cannon CP, Curtis SP, FitzGerald GA, Krum H, Kaur A, Bolognese JA, Reicin AS, Bombardier C, Weinblatt ME, van der Heijde D, Erdmann E, Laine L. Cardiovascular outcomes with etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the multinational etoricoxib and diclofenac arthritis long-term (MEDAL) programme: A randomized comparison. Lancet 2006;368:1771–1781
Cao Y, D’Olhaberriague L, Vikingstad EM, Levine SR, Welch KM. Pilot study of functional MRI to assess cerebral activation of motor function after poststroke hemiparesis. Stroke. 1998;29(1):112-22
Cardona AE, et al. Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci. 2006;9:917–24
Carey JR, Kimberley TJ, Lewis SM, Auerbach E, Dorsey L, Rundquist P, Ugurbil K. Analysis of fMRI and finger tracking training in subjects with chronic stroke. Brain. 2002;125:773–788
Carmichael ST, Wei L, Rovainen CM, Woolsey TA. New patterns of intracortical projections after focal cortical stroke. Neurobiol Dis. 2001;8(5):910-22
Carmichael ST. Rodent models of focal stroke: size, mechanism and purpose. NeuroRx. 2005;2:396-409
Carmichael ST. Translating the frontiers of brain repair to treatments: starting not to break the rules. Neurobiol Dis. 2010;37:237–42
Carmichael TS, Brain excitability in stroke: the yin and yang of stroke progression. Arch. Neurol. 2012;69:161-7
Caro JJ, Huybrechts KF, Duchesne I. Management patterns and costs of acute ischemic stroke : an international study. Stroke. 2000;31:582–90
Center for Biologics Evaluation and Research. US License 1048: Activase ® . Rockville, Food and Drug Administration, 2003
Chapman GA, et al. Fractalkine cleavage from neuronal membranes represents an acute event in the inflammatory response to excitotoxic brain damage. J Neurosci. 2000;20:RC87
Chang CH, et al. High resolution structural and functional assessments of cerebral microvasculature using 3D Gas delta-R2*-mMRA. PLoS One. 2013;8:1-10
Chen JJ, Pike GB. Global cerebral oxidative metabolism during hypercapnia and
129
hypocapnia in humans: implications for BOLD fMRI. J Cereb Blood Flow Metab, 2010;6:1094-9
Chen J, Venkat P, Zacharek A, Chopp M. Neurorestorative therapy for stroke. Front Hum Neurosci. 2014:8(318);1-12
Choi SH, Bosetti F. Cyclooxygenase-1 null mice show reduced neuro-inflammation in response to β-amyloid. Aging 2009;1:234–244
Cinelli P, Madani R, Tsuzuki N, Vallet P, Arras M, Zhao CN, Osterwalder T, Rulicke T, Sonderegger P. Neuroserpin, a neuroprotective factor in focal ischemic stroke. Mol Cell Neurosci. 2001;18(5):443–457
Clark WM, Rinker LG, Lessov NS, Hazel K, Hill JK, Stenzel-Poore M, Eckenstein F. Lack of interleukin-6 expression is not protective against focal central nervous system ischemia. Stroke. 2000;31(7):1715–1720
Clarke J, Langdon KD, Corbett D. Early poststroke experience differentially alters periinfarct layer II and III cortex. J Cereb Blood Flow Metab. 2014;34(4):630-7
Clarkson AN, Huang BS, Macisaac SE, Mody I, Carmichael T. Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke. Nature. 2010;468:305-9
Committee for Proprietary Medicinal Products (CPMP): Actilyse. Annex I. Amended Summary of Product Characteristics of the Reference Member State. The European Agency for the Evaluation of Medical Products (EMEA). 2002
Corbett AM, Sieber S, Wyatt N, Lizzi J, Flannery T, Sibbit B, Sanghvi S. Increasing neurogenesis with fluoxetine, simvastatin and ascorbic Acid leads to functional recovery in ischemic stroke. Recent Pat Drug Deliv Formul. 2015;9(2):158-66
Cox RW. AFNI: software for analysis and visualization of functional magnetic resonance neuroimages. Comput Biomed Res. 1996;29:162-73
Cramer SC, Nelles G, Benson RR, Kaplan JD, Parker RA, Kwong KK, Kennedy DN, Finklestein SP, Rosen BR. A functional MRI study of subjects recovered from hemiparetic stroke. Stroke 1997; 28:2518–27
Chung S, You J, Tack G, Yi J, Lee B. The mean intensity of activation than the number of activated voxels is a better index to reflect the levels of visuospatial performance. Conf Proc IEEE Eng Med Biol Soc. 2005;5:5298–5301
Chung SC, Sohn JH, Lee B, Tack GR, Yi JH, You JH, Kwon JH, Kim HJ, Lee SY. A comparison of the mean signal change method and the voxel count method to evaluate the sensitivity of individual variability in visuospatial performance. Neurosci Lett. 2007;418:138–142
Da Fonseca ACC, Matias D, Garcia C, et al. The impact of microglial activation on blood-brain barrier in brain diseases. Frontiers in Cellular Neuroscience. 2014;8:362
Davis TL, Kwong KK,Weisskoff RM, Rosen BR. Calibrated functional MRI: mapping the dynamics of oxidative metabolism. Proc Natl Acad Sci USA. 1998;95(4):1834–9
De Felipe L, Alonso-Nanclares L, Arellano JL. Microstructure of the neocortex: Comparative aspects. J Neurocytol. 2002;31(3-5):299-316
De Girolami U, Crowell RM, Marcoux FW. Selective necrosis and total necrosis in focal cerebral ischemia: neuropathologic observations on experimental middle cerebral artery occlusion in the macaque monkey. J Neuropathol Exp Neurol.
130
1984;43(1):57-71 del Zoppo GJ, Schmid-Schonbein GW, Mori E, Copeland BR, Chang CM.
Polymorphonuclear leukocytes occlude capillaries following middle cerebral artery occlusion and reperfusion in baboons. Stroke. 1991;22:1276–83
del Zoppo GJ. Inflammation and the neurovascular unit in the setting of focal cerebral ischemia. Neuroscience. 2009;158(3):972-82
den Haan JMM, Arens R, van Zelm MC. The activation of the adaptive immune system: Cross-talk between antigen-presenting cells, T cells and B cells. Immunology Letters. 2014;162(2):103–12
Dietrich WD, Ginsberg MD, Busto R, Watson BD. Photochemically induced cortical infarction in the rat. 2. Acute and subacute alterations in local glucose utilization. J Cereb Blood Flow Metab . 1986;6:195–202
Dietrich WD, Watson BD, Busto R, Ginsberg MD. Metabolic plasticity following cortical infarction: a 2-deoxyglucose study. In: Cerebrovascular disorders (Raichel ME, Powers WJ, eds). New York: Raven Press. 1987;285–95
Dijkhuizen RM, Singhal AB, Mandeville JB, Wu O, Halpern EF, Finklestein SP, Rosen BR, Lo EH. Correlation between brain reorganization, ischemic damage, and neurologic status after transient focal cerebral ischemia in rats: a functional magnetic resonance imaging study. J Neurosci. 2003;23(2):510-7
Ding YH, Li J, Yao WX, Rafols JA, Clark JC, Ding Y. Exercise preconditioning upregulates cerebral integrins and enhances cerebrovascular integrity in ischemic rats. Acta Neuropathol. 2006;112:74–84
Ding G, Jiang Q, Li L, Zhang L, Wang Y, Zhang ZG et al. Cerebral tissue repair and atrophy after embolic stroke in rat: a magnetic resonance imaging study of erythropoietin therapy. J Neurosci Res. 2010;88(14): 3206-14
Dittmar M, Spruss T, Schuierer G, Horn M. External carotid artery territory ischemia impairs outcome in the endovascular filament model of middle cerebral artery occlusion in rats. Stroke. 2003;34:2252-7
Donovan NJ, Kendall DL, Heaton SC, Kwon S, Velozo CA, Duncan PW. Conceptualizing functional cognition in stroke. Neurorehabil Neural Repair. 2008;22(2):122–35
Duncan PW, Lai SM, Keighley J. Defining post-stroke recovery: implications for design and interpretation of drug trials. Neuropharmacology. 2000;39(5):835–41
Eltzschig HK, Carmeliet P. Hypoxia and inflammation. N Engl J Med. 2011;364:656–65 Endres M, Engelhardt, B, Koistinaho, J, Lindvall, O, Meairs, S, Mohr, JP, Planas, A,
Rothwell, N, Schwaninger, M, Schwab, ME, Vivien, D, Wieloch, T, Dirnagl U. Improving outcome after stroke: overcoming the translational roadblock. Cerebrovasc Dis. 2008;25(3):268-78
Engelhardt B, Sorokin L. The blood-brain and the blood-cerebrospinal fluid barriers: function and dysfunction. Semin Immunopathol. 2009;31:497–511
Esposito G, Van Horn JD, Weinberger DR, Berman KF. Gender differences in cerebral blood flow as a function of cognitive state with PET. Journal of nuclear medicine: official publication Society of Nuclear Medicine 1996;37:559-64
Evenson KR, Rosamond WD, Morris DL. Prehospital and in-hospital delays in acute stroke care. Neuroepidemiology. 2001;20:65-76
Fallon JH. The islands of Calleja complex of rat basal forebrain II: connections of medium and largesized cells. Brain Resb. Bull. 1983;10:775–93
131
Fasoli SE, Krebs HI, Stein J, Frontera WR and Hogan N: Effects of robotic therapy on motor impairment and recovery in chronic stroke. Arch Phys Med Rehabil. 2003;84(4):477-82
Fasoli SE, Krebs HI, Stein J, Frontera WR, Hughes R and Hogan N. Robotic therapy for chronic motor impairments after stroke: follow-up results. Arch Phys Med
Rehabil. 2004;85(7): 1106‐11 Feigin VL, Carlene MM Lawes, Derrick A Bennett, and Craig S Anderson. Stroke
epidemiology: a review of population- based studies of incidence, prevalence, and case-fatality in the late 20th century . Lancet Neurology 2003;2:43-553
Feigin VL, Forouzanfar MH, Krishnamurthi R, et al. Global and regional burden of stroke during 1990–2010: findings from the Global Burden of Disease Study 2010. Lancet. 2014;383(9913):245-54
Félétou M, Huang Y, Vanhoutte PM. Endothelium-mediated control of vascular tone: COX-1 and COX-2 products. Br J Pharmacol. 2011;164(3):894-912
Feydy A, Carlier R, Roby-Brami A, Bussel B, Cazalis F, Pierot L, Burnod Y, Maier MA. Longitudinal study of motor recovery after stroke: recruitment and focusing of brain activation. Stroke. 2002;33(6):1610-7
Floel A. tDCS-enhanced motor and cognitive function in neurological diseases. Neuroimage 2014;85: 934-47
Frank-Cannon TC, Alto LT, McAlpine FE, Tansey MG. Does neuro-inflammation fan the flame in neurodegenerative diseases? Mol Neurodegener. 2009;4:47
Fritsch B, Reis J, Martinowich K, Schambra HM, Ji Y, Cohen LG, Lu B. Direct current stimulation promotes BDNF-dependent synaptic plasticity: potential implications for motor learning. Neuron . 2010;66:198-204
Gabriella G, Giovanna C. γ-Aminobutyric acid type A (GABA(A)) receptor subtype inverse agonists as therapeutic agents in cognition. Methods Enzymol. 2010;485:197–211
Gerlai R, Thibodeaux H, Palmer JT, van Lookeren Campagne M, Van Bruggen N. Transient focal cerebral ischemia induces sensorimotor deficits in mice. Behav Brain Res. 2000;108:63–71
AGerriets T, Stolz E, Walberer M, Kaps M, Bachmann G, Fisher M. Neuroprotective effects of MK-801 in different rat stroke models for permanent middle cerebral artery occlusion: adverse effects of hypothalamic damage and strategies for its avoidance. Stroke. 2003;34:2234 –9
BGerriets T, Li F, Silva MD, Meng X, Brevard M, Sotak CH, Fisher M. The macrosphere model: evaluation of a new stroke model for permanent middle cerebral artery occlusion in rats. J Neurosci Methods. 2003;122:201–11
Gerriets T, Stolz E, Walberer M, Mȕller C, Rottger C, Kluge A, Manfred K , Fisher M, Bachmann G. Complications and pitfalls in rat stroke models for middle cerebral artery occlusion. Stroke. 2004;35:2372-7
Gertz K, Kronenberg G, Kalin RE, Baldinger T, Werner C, Balkaya M, Eom GD, Hellmann- Regen J, Krober J, Miller KR, Lindauer U, Laufs U, Dirnagl U, Heppner FL, Endres M. Essential role of interleukin-6 in post-stroke angiogenesis. Brain. 2012;135(Pt 6):1964–1980
Giulian D, Corpuz M, Richmond B, Wendt E, Hall ER. Activated microglia are the principal glial source of thromboxane in the central nervous system. Neurochem Int. 1996; 29(1):65–76
132
Gladstone DJ, Danells CJ, Black SE. The fugl-meyer assessment of motor recovery after stroke: a critical review of its measurement properties. Neurorehabil Neural Repair. 2002;16(3):232-40
Globus MY, Alonso O, Dietrich WD, Busto R, Ginsberg MD. Glutamate release and free radical production following brain injury: effects of posttraumatic hypothermia. J Neurochem 1995;65:1704–11
Glykys J, Mody I. Activation of GABAA receptors: views from outside the synaptic cleft. Neron. 2007;56(5):763–70
Goussev AV, Zhang Z, Anderson DC, Chopp M. P-selectin antibody reduces hemorrhage and infarct volume resulting from MCA occlusion in the rat. J Neurol Sci. 1998;161(1):16–22
Gowland C, VanHullenaar S, Torresin W, et al. Chedoke-McMaster stroke assessment: development, validation and administration manual. Hamilton (ON), Canada: Chedoke-McMaster Hospitals and McMaster University; 1995
Grade S, Weng YC, Snapyan M, Kriz J, Malva JO, Saghatelyan A. Brain-derived neurotrophic factor promotes vasculature-associated migration of neuronal precursors toward the ischemic striatum. PLoS One. 2013;8(1):e55039
Greenberg DA, Jin K. Growth factors and stroke. NeuroRx. 2006;3:458–65 Greenberg DA, Jin K. Vascular endothelial growth factors (VEGFs) and stroke. Cell Mol
Life Sci. 2013;70(10):1753-61 Griffin KM, Blau CW, Kelly ME, O'Herlihy C, O'Connell PR, Jones JF, Kerskens CM.
Propofol allows precise quantitative arterial spin labelling functional magnetic resonance imaging in the rat. Neuroimage. 2010;51(4):1395-404.
Grotta JC, Jacobs TP, Koroshetz WJ, Moskowitz MA. Stroke Program Reviews Group: An interim report. Stroke; 2008(39):1364-70
Gualtieri F, Curia G, Marinelli C, Biagini G. Increased perivascular laminin redicts damage to astrocytes in CA3 and piriform cortex following chemoconvulsive treatments. Neurosci. 2012;218:278-94
Guegan C, Sola B. Early and sequential recruitment of apoptotic effectors after focal permanent ischemia in mice. Brain Res. 2000;856: 93–100
Gunther A, Kuppers-Tiedt L, Schneider PM, Kunert I, Berrouschot J, Schneider D, Rossner S. Reduced infarct volume and differential effects on glial cell activation after hyperbaric oxygen treatment in rat permanent focal cerebral ischaemia. Eur J Neurosci. 2005;21(11):3189–3194
Hacke W, Schwab S, Horn M, Spranger M, De Georgia M, von Kummer R. “Malignant” middle cerebral artery territory infarction: clinical course and prognostic signs. Arch Neurol. 1996;53:309 –315
Haensel JX, Spain A, Martin C. A systematic review of physiological methods in rodent pharmacological MRI studies. Psychopharmacology (Berl). 2015;232(3):489-99
Hallenbeck JM. The many faces of tumor necrosis factor in stroke. Nat Med. 2002;8(12):1363– 1368
Hallett M. Plasticity of the human motor cortex and recovery from stroke. Brain Res Brain Res Rev. 2001;36(2-3):169-74
Harsany M, Tsivgoulis G, Alexandrov AV. Intravenous thrombolysis in acute ischemic stroke: standard and potential future applications. Expert Rev Neurother. 2014;14(8):879-92
Harston G, Tee Y, Blockley N, Okell TW, Thandeswaran S, Shaya G, Sheerin F,
133
Cellerini M, Payne S, Jezzard P, Chappell, Kennedy J. Identifying the ischaemic penumbra using pH-weighted magnetic resonance imaging. Brain. 2015;138:36-42
Hast A. Simple filter design for first and second order derivatives by a double filtering approach. Pattern Recognition Letters. 2014;42;65-71
Hayashi T, Sakurai M, Itoyama Y, Abe K. Oxidative damage and breakage of DNA in rat brain after transient MCA occlusion. Brain Res. 1999;832:159 –63
Hayward NM, Yanev P, Haapasalo A, Miettinen R, Hiltunen M, Gröhn O, Jolkkonen J. Chronic hyperperfusion and angiogenesis follow subacute hypo-perfusion in the thalamus of rats with focal cerebral ischemia. J Cereb Blood Flow Metab. 2011;31(4):1119-32
Heiss WD, Graf R, Löttgen J, Ohta K, Fujita T, Wagner R, Grond M, Weinhard K. Repeat positron emission tomographic studies in transient middle cerebral artery occlusion in cats: residual perfusion and efficacy of postischemic reperfusion. J Cereb Blood Flow Metab 1997;17:388-400
Heiss WD. Ischemic Penumbra: Evidence from functional imaging in man. J Cereb Blood F Met. 2000;20:1276-93
Herrmann O, Tarabin V, Suzuki S, Attigah N, Coserea I, Schneider A, Vogel J, Prinz S, Schwab S, Monyer H, Brombacher F, Schwaninger M. Regulation of body temperature and neuroprotection by endogenous interleukin-6 in cerebral ischemia. J Cereb Blood Flow Metab. 2003; 23(4):406–415
Hill MD, Buchan AM. Thrombolysis for acute ischemic stroke: results of the Canadian Alteplase for Stroke Effectiveness Study. Can Med Assoc J. 2005;172:1307-12
Hoge RD. Calibrated fMRI. Neuroimage. 2012;62(2):930-7 Hosp JA, et al. Thin-film epidural microelectrode arrays for somatosensory and motor
cortex mapping in rat. J. Neurosci. Methods. 2008;172:255-62 Hossmann KA. The two pathophysiologies of focal brain ischemia: implications for
translational stroke research. J. Cereb. Blood Flow Metab. 2012;32:1310-16 Howells DW, Macleod MR. Evidence-based translational medicine. Stroke .
2013;44:1466–71 Hu X, Wester P, Brannstrom T, Watson BD, Gu W. Progressive and reproducible focal
cortical ischemia with or without late spontaneous reperfusion generated by a ring-shaped, laser-driven photothrombotic lesion in rats. Brain Res Brain Res Protoc. 2001;7:76- 85
Hu X, Zheng H, Yan T, Pan S, Fang J, Jiang R, Ma S. Physical exercise induces expression of CD31 and facilitates neural function recovery in rats with focal cerebral infarction. Neurol Res. 2010;32:397–402
Hu S, Cao Q, Xu P, Ji W, Wang G, Zhang Y. Rolipram stimulates angiogenesis and attenuates neuronal apoptosis through the cAMP/cAMP-responsive element binding protein pathway following ischemic stroke in rats. Exp Ther Med. 2016;11(3):1005-10
Huang J, Choudhri TF, Winfree CJ, McTaggart RA, Kiss S, Mocco J, Kim LJ, Protopsaltis TS, Zhang Y, Pinsky DJ, Connolly ES Jr. Postischemic cerebrovascular E-selectin expression mediates tissue injury in murine stroke. Stroke. 2000;31(12):3047–3053
Hunter AJ, Hatcher J, Virley D, Nelson P, Irving E, Hadingham SJ, Parsons AA. Functional assessments in mice and rats after focal stroke.
134
Neuropharmacology. 2000;39(5):806-16 Hurn PD, Macrae IM. Estrogen as a neuroprotectant in stroke. I Cereb Blood Flow
Metab. 2000;20:631-52 Hyder F, Rothman DL, Bennett MR. Cortical energy demands of signaling and
nonsignaling components in brain are conserved across mammalian species and activity levels. Proc Natl Acad Sci USA. 2013;110(9):3549-54
Hyman MC, et al. Self-regulation of inflammatory cell trafficking in mice by the leukocyte surface apyrase CD39. J Clin Invest. 2009;119:1136–49
AIadecola C, Zhang F, Xu S, Casey R, Ross ME. Inducible nitric oxide synthase gene expression in brain following cerebral ischemia. J Cereb Blood Flow Metab. 1995;15(3):378–384
Iadecola C, Sugimoto K, Niwa K, et al. Increased susceptibility to ischemic brain injury in cyclooxygenase-1-deficient mice. J Cereb Blood Flow Metab. 2001;21:1436-41
Iadecola C. Neurovascular regulation in the normal brain and in Alzheimer's disease. Nat Rev Neurosci. 2004;5(5):347-60
AIadecola C, Anrather J. Stroke research at a crossroad: asking the brain for directions. Nat Neurosci. 2011;14(11):1363-8
BIadecola C, Anrather J. The immunology of stroke: from mechanisms to translation. Nat Med. 2011;17:796–808
ImageMagick Studio LLC. http://www.imagemagick.org/script/index.php. Copyright 1999-2013 Non-profit organization dedicated to making software imaging solutions freely available. 2013
Ishikawa M, Zhang JH, Nanda A, Granger DN. Inflammatory responses to ischemia and reperfusion in the cerebral microcirculation. Front Biosci. 2004;9:1339–47
Jander S, Schroeter M, Stoll G. Role of NMDA receptor signaling in the regulation of inflammatory gene expression after focal brain ischemia. J Neuroimmunol. 2007;109:181–7
Jeffers MS, Hoyles A, Morshead C, Corbett D. Epidermal growth factor and erythropoietin infusion accelerate functional recovery in combination with rehabilitation. Stroke. 2014;45(6):1856-8
Jessberger S. Neural repair in the adult brain. F1000Res. 2016;5 Jiang Q. Magnetic resonance imaging and cell-based neurorestorative therapy after
brain injury. Neural Regen Res. 2016;11(1):7-14 Jin K, Zhu Y, Sun Y, Mao XO, Xie L, Greenberg DA. Vascular endothelial growth factor
(VEGF) stimulates neurogenesis in vitro and in vivo. Proc Natl Acad Sci USA. 2002;99(18):11946-50
Jin K, Sun Y, Xie L, Childs J, Mao XO, Greenberg DA. Post-ischemic administration of heparin-binding epidermal growth factor-like growth factor (HB-EGF reduces infarct size and modifies neurogenesis after focal cerebral ischemia in the rat. J Cereb Blood F Met. 2004;24:399-408
Jin R, Yang G, Li G. Molecular insights and therapeutic targets for blood-brain barrier disruption in ischemic stroke: critical role of matrix metalloproteinases and tissue-type plasminogen activator. Neurobiol Dis. 2010;38(3):376–385
AJin R, Yang G, Li G. Inflammatory mechanisms in ischemic stroke: role of inflammatory cells. J Leukoc Biol. 2010;87(5):779-89
135
BJin R, Yang G, Li G. Molecular insights and therapeutic targets for blood-brain barrier disruption in ischemic stroke: critical role of matrix metalloproteinases and tissue-type plasminogen activator. Neurobiol Dis. 2010;38(3):376–385
Jin Q, Cheng J, Liu Y, Wu J, Wang X, Wei S, Zhou X, Qin Z, Jia J, Zhen X. Improvement of functional recovery by chronic metformin treatment is associated with enhanced alternative activation of microglia/macrophages and increased angiogenesis and neurogenesis following experimental stroke. Brain Behav Immun. 2014;40:131-42
Jones TA, Schallert T. Use-dependent growth of pyramidal neurons after neocortical damage. J Neurosci. 1994;14:2140–52
Jones TA, Adkins DL. Motor System Reorganization After Stroke: Stimulating and Training Toward Perfection. Physiology (Bethesda). 2015;30(5):358-70
Jung JE, Kim GS, Chan PH. Neuroprotection by interleukin-6 is mediated by signal transducer and activator of transcription 3 and antioxidative signaling in ischemic stroke. Stroke. 2011;42(12):3574–3579
Kakuta H, Zheng X, Oda H, Harada S, Sugimoto Y, Sasaki K, Tai A. Cyclooxygenase-1-Selective Inhibitors Are Attractive Candidates for Analgesics That Do Not Cause Gastric Damage. Design and in Vitro/in Vivo Evaluation of a Benzamide-Type Cyclooxygenase-1 Selective Inhibitor. J Med Chem. 2008;51:2400-11
Kanemitsu H, Nakagomi T, Tamura A, Tsuchiya T, Kono G, Sano K. Differences in the extent of primary ischemic damage between middle cerebral artery coagulation and intraluminal occlusion models. J Cereb Blood Flow Metab. 2002 ;22:1196 –204
Kanemoto Y, Nakase H, Akita N, Sakaki T. Effects of anti-intercellular adhesion molecule-1antibody on reperfusion injury induced by late reperfusion in the rat middle cerebral artery occlusion model. Neurosurgery. 2002;51(4):1034–1041
Kang JK, Bénar C, Al-Asmi A, et al. Using patient-specific hemodynamic response functions in combined EEG-fMRI studies in epilepsy. Neuroimage. 2003;20:1162-70
Katsman D, Zheng J, Spinelli K, Carmichael ST. Tissue micro-environments within functional cortical subdivisions adjacent to focal stroke. J Cereb Blood Flow Metab. 2003;23:997–1009
Katz JA. COX-2 inhibition: what we learned--a controversial update on safety data. Pain Med 2013;14:29-34
Kawabori M, Yenari MA. The role of the microglia in acute CNS injury.Metab Brain Dis. 2015;30(2):381-92
Kawano T, Anrather J, Zhou P, Park L, Wang G, Frys KA, Kunz A, Cho S Orio M, Iadecola C. Prostaglandin E2 EP1 receptors: down- stream effectors of COX-2 neurotoxicity. Nat Med 2006;12(2):225– 229
Khale MP, Bix GJ. Successfully climbing the “STAIRs”: Surmounting failed translation of experimental ischemic stroke treatments. Stroke Research and Treatment. 2012;2013:374098
Khedr EM, Fetoh NA. Short- and long-term effect of rTMS on motor function recovery after ischemic stroke. Restor Neurol Neurosci. 2010;28(4):545-59
Kidwell CS, Alger JR, Saver JL. Beyond mismatch: evolving paradigms in imaging the ischemic penumbra with multi-modal magnetic resonance imaging. Stroke.
136
2003;34:2729- 35 Kigerl KA, Gensel JC, Ankeny DP, Alexander JK, Donnelly DJ, Popovich PG.
Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J. Neurosci. 2009;29(43):13435–44
Kim GW, Sugawara T, Chan PH. Involvement of oxidative stress and caspase-3 in cortical infarction after photothrombotic ischemia in mice. J Cereb Blood Flow Metab. 2000;20:1690 –1701
Kim JY, Kawabori M, Yenari MA. Innate inflammatory responses in stroke: mechanisms and potential therapeutic targets. Curr Med Chem. 2014;21(18):2076-97
Kimberley TJ, Lewis SM. Understanding Neuroimaging. Phys Ther. 2007;87:670–683 Kimberley TJ, Khandekar G, Borig M. fMRI reliability in subjects with stroke. Exp Brain
res. 2008;186:183–190 Kirilina E, Lutti A, Poser BA, Blankenburg F, Weiskopf N. The quest for the best: The
impact of different EPI sequences on the sensitivity of random effect fMRI group analyses. NeuroImage. 2015;126:49-59
Kleim JA, Boychuk JA, Adkins DL. Rat models of upper extremity impairment in stroke. ILAR J. 2007;48(4):374-84
Kobayashi T, Tahara Y, Matsumoto M, Iguchi M, Sano H, Murayama T, Arai H, Oida H, Yurugi-Kobayashi T, Yamashita JK, Katagiri H, Majima M, Yokode M, Kita T, Narumiya S. Roles of thromboxane A(2) and prostacyclin in the development of atherosclerosis in apoE-deficient mice. J Clin Invest. 2004;114(6):784-94
Kojima T, Hirota Y, Ema M, Takahashi S, Miyoshi I, Okano H, Sawamoto K. SVZ-derived neural progenitor cells migrate along a blood vessel scaffold toward the post-stroke striatum. Stem Cells. 2010;28(3):545-54
Kono H, Rock KL. How dying cells alert the immune system to danger. Nat Rev Immunol. 2008;8:279–89
Konsman JP, Drukarch B, Van Dam AM. (Peri)vascular production and action of proinflammatory cytokines in brain pathology. Clin Sci (Lond). 2007;112:1–25
Korn C, Augustin HG. Mechanisms of Vessel Pruning and Regression. Dev Cell. 2015;34(1):5-17
Krafft PR, Bailey EL, Lekic T, Rolland WB, Altay O, Tang J, Wardlaw JM, Zhang JH, Sudlow CL. Etiology of stroke and choice of models. Int J Stroke. 2012;7(5):398-406
Krainik A, Hund-Georgiadis M, Zysset S, von Cramon DY. Regional impairment of cerebrovascular reactivity and BOLD signal in adults after stroke. Stroke. 2005;36(6):1146-52
Krishnamurthi RV, Feigin VL, Forouzanfas MH, Mensah GA, Connor M, Bennett DA, Moran AE, Sacco RL, Anderson LM, Truelsen T, et al. Global and regional burden of first-ever ischaemic and haemorrhagic stroke during 1990-2010: findings from the Global Burden of Disease Study 2010. Lancet Glob Health. 2013;1(5):259-81
Krueger H, Koot J, Hall RE, O'Callaghan C, Bayley M, Corbett D. Prevalence of Individuals Experiencing the Effects of Stroke in Canada: Trends and Projections. Stroke. 2015;46(8):2226-31
Krupiński J, Kaluza J, Kumar P, Kumar S, Wang JM. Some remarks on the growth-rate and angiogenesis of microvessels in ischemic stroke. Morphometric and immunocytochemical studies. Patol Pol. 1993;44:203–9
137
Krupiński J, et al. Role of angiogenesis in patients with cerebral ischemic stroke. Stroke. 1994;25:1794-8
Kwakkel G, Veerbeek JM, van Wegen EE, Wolf SL. Constraint-induced movement therapy after stroke. Lancet Neurol. 2015;14(2):224-34
Kwakkel G, Winters C, van Wegen EE, Nijland RH, van Kuijk AA, Visser-Meily A, de Groot J, de Vlugt E, Arendzen JH, Geurts AC, Meskers CG. Effects of Unilateral Upper Limb Training in Two Distinct Prognostic Groups Early After Stroke: The EXPLICIT-Stroke Randomized Clinical Trial. Neurorehabil Neural Repair. 2016.
Lai SM, Studenski S, Duncan PW, Perera S. Persisting consequences of stroke measured by the Stroke Impact Scale. Stroke. 2002;33(7):1840-4
Lai AY, Todd KG. Microglia in cerebral ischemia: molecular actions and interactions. Can J Physiol Pharmacol. 2006;84(1):49–59
Laird NM and JH Ware. Random-effects models for longitudinal data. Biometrics. 1982;38(4):963-74
Lake EM, Chaudhuri J, Thomason L, et al. The effects of delayed reduction of tonic inhibition on ischemic lesion and sensorimotor function. J Cereb Blood Flow Metab. 2015;35:1601-9
Lalancette-Hebert M, Gowing G, Simard A, Weng YC, Kriz J. Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain. J Neurosci. 2007;27:2596–605
Lambertsen KL, Gregersen R, Finsen B. Microglial-macrophage synthesis of tumor necrosis factor after focal cerebral ischemia in mice is strain dependent. J Cereb Blood Flow Metab. 2002 ;22:785–97
Lambrechts D Zacchigna S, Carmeliet P. Neurovascular signalling defects in neurodegeneration. Nature reviews. 2008;9:169–81
Langdon KD, Granter-Button S, Harley CW, Moody-Corbett F, Peeling J, Corbett D. A cognitive rehabilitation paradigm effective in male rats lacks efficacy in female rats. J Cereb Flow Metab. 2014;34:1673-80
Lee RG, van Donkelaar P. Mechanisms underlying functional recovery following stroke. Can J Neurol Sci. 1995;22(4):257-63
Lee VM, Burdett NG, Carpenter A, Hall LD, Pambakian PS, Patel S, Wood NI, James MF. Evolution of photochemically induced focal cerebral ischemia in the rat. Magnetic resonance imaging and histology. Stroke. 1996;27:2110–8
Lee JK, Kim JE, Sivula M, Strittmatter SM. Nogo receptor antagonism promotes stroke recovery by enhancing axonal plasticity. J Neurosci. 2004;24(27):6209–17
Li YF, Cheng YF, Huang Y, Conti M, Wilson SP, O'Donnell JM, Zhang HT. Phosphodiesterase-4D knock-out and RNA interference-mediated knock-down enhance memory and increase hippocampal neurogenesis via increased cAMP signaling. J Neurosci. 2011;31(1):172-83
Li C, Wang J, Fang Y, Liu Y, Chen T, Sun H, Zhou XF, Liao H. Nafamostat Mesilate Improves Function Recovery after Stroke by Inhibiting neuro-inflammation in Rats. Brain Behav Immun. 2016
138
Liang X, Lin L, Woodling NS, et al. Signaling via the prostaglandin E(2) receptor EP4 exerts neuronal and vascular protection in a mouse model of cerebral ischemia. J Clin Invest. 2011;121:4362– 4371
Liedtke AJ, Crews BC, Daniel CM, Blobaum AL, Kingsley PJ, Ghebreselasie K, Marnett LJ. Cyclooxygenase-1-selective inhibitors based on the (E)-2'-des-methyl-sulindac sulfide scaffold. J Med Chem. 2012;55(5):2287-300
Liepert J, Bauder H, Wolfgang HR, Miltner WH, Taub E, Weiller C: Treatment-induced cortical reorganization after stroke in humans. Stroke. 2000;31(6):1210-6
Liesz A, Zhou W, Mracsko E, Karcher S, Bauer H, Schwarting S, Sun L, Bruder D, Stegemann S, Cerwenka A, Sommer C, Dalpke AH, Veltkamp R. Inhibition of lymphocyte trafficking shields the brain against deleterious neuro-inflammation after stroke. Brain. 2011;134(Pt 3):704–720
Lin TN, Sun SW, Cheng WM, Li F, Chang C. Dynamic changes in cerebral blood flow and angiogenesis after transient focal cerebral ischemia in rats: evaluation with serial magnetic resonance imaging. Stroke. 2002;33(12):2985-91
Lin CY, Chang C, Cheung WM, Lin MH, Chen JJ, Hsu CY, Chen JH, Lin TN. Dynamic changes in vascular permeability, cerebral blood volume, vascular density, and size after transient focal cerebral ischemia in rats: evaluation with contrast-enhanced magnetic resonance imaging. J Cereb Blood Flow Metab. 2008;28(8):1491-501
Lindsberg PJ, Strbian D, Karjalainen-Lindsberg ML. Mast cells as early responders in the regulation of acute blood-brain barrier changes after cerebral ischemia and hemorrhage. J Cereb Blood Flow Metab. 2010;30:689–702
Liu XS, Zhang ZG, Zhang RL, Gregg S, Morris DC, Wang Y, Chopp M. Stroke induces gene profile changes associated with neurogenesis and angiogenesis in adult SVZ progenitor cells. J Cereb Blood Flow Metab. 2007;27(3):564-74
Liu M, Dziennis S, Hurn PD, Alkayed NJ. Mechanisms of gender-linked ischemic brain injury. Restor Neurol Neurosci. 2009;27:163-79
Liu H, Li W, Rose ME, Pascoe JL, Miller TM, Ahmad M, Poloyac SM, Hickey RW, Graham SH. Prostaglandin D2 toxicity in primary neurons is mediated through its bioactive cyclopentenone metabolites. Neurotoxicology. 2013;39:35–44
Liu J, Wang Y, Akamatsu Y, Lee CC, Stetler RA, Lawton MT, Yang GY. Vascular remodelling after ischemic stroke: mechanisms and therapeutic potentials. Prog Neurobiol. 2014;115:138-56
Lively S, Moxon-Emre I, Schlichter CL. SC1/Hevin and Reactive Gliosis after Transient Ischemic stroke in young and aged rats. J Neuropathol Exp Neurol. 2011;70:913-29
Logothetis NK. What we can do and what we cannot do with fMRI. Nature. 2008; 453(7197):869-78
Lu YZ, Lin CH, Cheng FC, Hsueh CM. Molecular mechanisms responsible for microglia-derived protection of Sprague-Dawley rat brain cells during in vitro ischemia. Neurosci Lett. 2005; 373(2):159–164
Lum PS, Burgar CG, Shor PC, Majmundar M and van der Loos M. Robot-assisted movement training compared with conventional therapy techniques for the rehabilitation of upper-limb motor function after stroke. Arch Phys Med Rehabil. 2002;83(7):952-9
Effects of moderate caloric restriction on cortical microvascular density and local cerebral blood flow in aged rats. Neurobiol Aging. 1999;20(2):191-200S
Mantovani A, Biswas SK, Galdiero MR, Sica A, Locati M. Macrophage plasticity and polarization in tissue repair and remodelling. J Pathol. 2013;229(2):176–85
Manwani B, McCullough LD. Function of the master energy regulator adenosine monophosphate-activated protein kinase in stroke. J. Neurosci. Res. 2013;91(8):1018–29
Mao L, Jia J, Zhou X, Xiao Y, Wang Y, Mao X, Zhen X, Guan Y, Alkayed NJ, Cheng J. Delayed administration of a PTEN inhibitor BPV improves functional recovery after experimental stroke. Neuroscience. 2013;231:272–81
Marlier Q, Verteneuil S, Vandenbosch R, Malgrange B. Mechanisms and Functional Significance of Stroke-Induced Neurogenesis. Front Neurosci. 2015;9:458
Martin A, et al. Imaging of perfusion, angiogenesis, and tissue elasticity after stroke. J. Cereb. Blood Flow Metab. 2012;32:1496-1507
Martirosian P, Boss A, Schraml C, Schwenzer NF, Graf H, Claussen CD, Schick F. Magnetic resonance perfusion imaging without contrast media. Eur J Nucl Med Mol Imaging. 2010;37(1):52-64
Matsumoto H, Kumon Y, Watanabe H, Ohnishi T, Takahashi H, Imai Y, Tanaka J. Expression of CD200 by macrophage-like cells in ischemic core of rat brain after transient middle cerebral artery occlusion. Neurosci Lett. 2007;418:44–8
Metz GA, Whishaw IQ. Cortical and subcortical lesions impair skilled walking in the ladder rung walking test: a new task to evaluate fore- and hindlimb stepping, placing, and co-ordination. J Neurosci Methods. 2002;115:169–179
Marsh BJ, Williams-Karnesky RL, Stenzel-Poore MP. Toll-like receptor signaling in endogenous neuroprotection and stroke. Neuroscience. 2009;158:1007–20
Marshall RS, Perera GM, Lazar RM, Krakauer JW, Constantine RC, DeLaPaz RL. Evolution of cortical activation during recovery from corticospinal tract infarction. Stroke. 2000;31(3):656-61
Mayzel-Oreg O, Omae T, Kazemi M, Li F, Fisher M, Cohen Y, et al. Microsphere-induced embolic stroke: an MRI study. Magn Reson Med. 2004;51:1232–8
Mazighi M, Serfaty JM, Labreuche J, Laissy JP, Meseguer E, Lavallee PC, et al. Comparison of intravenous alteplase with a combined intravenous-endovascular approach in patients with stroke and confirmed arterial occlusion (RECANALISE study): a prospective cohort study. Lancet Neurol. 2009;8:802-9
McAdam BF, Catella-Lawson F, Mardini IA, Kapoor S, Lawson JA, FitzGerald GA. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci U S A. 1999;96(1):272-7
McKee AC, Carreras I, Hossain L, Ryu H, Klein W. L, Oddo S, LaFerla F. M, Jenkins B. G, Kowall N. W, Dedeoglu A. Ibuprofen reduces Aβ, hyperphosphorylated tau and memory deficits in Alzheimer mice. Brain Res. 2008;1207:225–236
Meziane H, Ouagazzal AM, Aubert L, Wietrzych M, Krezel W. Estrous cycle effects on behavior of C57BL/6J and BALB/cB-gamma-J female mice: implications for phenotyping strategies. Genes, Brain and Behavior. 2007;6:192-200
Mikulik R, Wahlgren N. Treatment of acute stroke: an update. Journal of Internal Medicine. 2015;145:165
Milidonis X, Marshall I, Macleod MR, Sena ES. Magnetic resonance imaging in
140
experimental stroke and comparison with histology: systematic review and meta-analysis. Stroke. 2015;46(3):843-51
Miltner WH, Bauder H, Sommer M, Dettmers C and Taub E. Effects of constraint-induced movement therapy on patients with chronic motor deficits after stroke: a replication. Stroke. 1999;30(3):586-92
Miyake M, Takeo S, Kaijihara H. Sustained decrease in regional blood flow after microsphere injection in rats. Stroke. 1993 ;24:415– 20
Mocco J, Choudhri T, Huang J, Harfeldt E, Efros L, Klingbeil C, Vexler V, Hall W, Zhang Y, Mack W, Popilskis S, Pinsky DJ, Connolly ES Jr. HuEP5C7 as a humanized monoclonal anti-E/P- selectin neurovascular protective strategy in a blinded placebo-controlled trial of nonhuman primate stroke. Circ Res. 2002;91(10):907–914
Mogensen TH. Pathogen Recognition and Inflammatory Signaling in Innate Immune Defenses. Clin Microbiol Rev. 2009;22(2):240-73
Mohr JP, Gautier JC, Hier D, Stein RW. Middle cerebral artery disease. Stroke: Pathophysiology, Diagnosis and Management. 1986;1:377-450
Monte-Silva K, Kuo MF, Hessenthaler S, Fresnoza S, Liebetanz D, Paulus W, Nitsche MA. Induction of late LTP-like plasticity in the human motor cortex by repeated non-invasive brain stimulation. Brain Stimul. 2013;6:424-32
Montoya CP, Campbell-Hope LJ, Pemberton KD, Dunnett SB. The “staircase test”: a measure of independent forelimb reaching and grasping abilities in rats. J Neurosci Methods. 1991;36(2-3):219-28
Mohr JP, Grotta JC, Wolf PA, Moskowitz MA, Mayberg MR, Von Kummer R. Stroke: pathophysiology, diagnosis, and management. Elsevier Health Sciences. 2011
Moretti A, Ferrari F, Villa RF. Neuroprotection for ischaemic stroke: Current status and challenges . Pharmacol Ther. 2015;146:23-34
Morris DC, Yeich T, Khalighi MM, Soltanian-Zadeh H, Zhang ZG, Chopp M. Microvascular structure after embolic focal cerebral ischemia in the rat. Brain Res. 2003;972(1-2):31-7
Murphy TH, Corbett D. Plasticity during stroke recovery: from synapse to behaviour. Nat Rev Neurosci. 2009;10(12):861-72
Mulcahy NJ, Ross J, Rothwell NJ, Loddick SA. Delayed administration of interleukin-1 receptor antagonist protects against transient cerebral ischaemia in the rat. Br J Pharmacol. 2003;140(3): 471–476
Nagayama T, Lan J, Henshall DC, Chen D, O’Horo C, Simon RP, Chen J Induction of oxidative DNA damage in the peri-infarct region after permanent focal cerebral ischemia. J Neurochem. 2000;75:1716 –28
Nathan C, Ding A. Nonresolving inflammation. Cell. 2010;140:871–82 Nedergaard M, Ransom B, Goldman SA. New roles for astrocytes: redefining the
MINCTools. http://www.bic.mni.mcgill.ca/ServicesSoftware/MINC Neumann-Haefelin T, Kastrup A, de Crespigny A, Yenari MA, Ringer T, Sun GH et al.
Serial MRI after transient focal cerebral ischemia in rats: dynamics of tissue injury, blood-brain barrier damage, and edema formation. Stroke. 2000;31:1965-72
Newton J, Sunderland A, Butterworth SE, Peters AM, Peck KK, Gowland PA. A pilot
141
study of event- related functional magnetic resonance imaging of monitored wrist movements in patients with partial recovery. Stroke. 2002;33(12):2881-7
Nguemeni C, Gomez-Smith M, Jeffers MS, Schuch CP, Corbett D. Time course of neuronal death following endothelin-1 induced focal ischemia in rats. J. Neurosci. Methods. 2015;242:72-6
Nishibe M, Urban ET 3rd, Barbay S, Nudo RJ. Rehabilitative training promotes rapid motor recovery but delayed motor map reorganization in a rat cortical ischemic infarct model. Neurorehabil Neural Repair. 2015;29(5):472-82
Nishijima T, Piriz J, Duflot S, Fernandez AM, Gaitan G, Gomez-Pinedo U, Verdugo JM, Leroy F, Soya H, Nuñez A, Torres-Aleman I. Neuronal activity drives localized blood-brain-barrier transport of serum insulin-like growth factor-I into the CNS. Neuron. 2010;67(5):834-46
Niwa K, Haensel C, Ross ME, Iadecola C. Cyclooxygenase-1 participates in selected vasodilator responses of the cerebral circulation. Circ Res. 2001;88(6):600-8
Nowicka D, Rogozinska K, Aleksy M, Witte OW, Skangiel-Kramska J. spatio-temporal dynamics of astroglial and microglial responses after photothrombotic stroke in the rat brain. Acta Neurobiol Exp (Wars). 2008;68(2):155–168
Nussmeier NA, Whelton AA, Brown MT, Langford RM, Hoeft A, Parlow JL, Boyce SW, Verburg KM. Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med. 2005;352:1081–1091
O’Collins VE, Macleod MR, Donnan GA, Horky LL, van der Worp BH, Howells DW. 1,026 experimental treatments in acute stroke. Ann Neurol. 2006;59:467–77
Ohab JJ, Fleming S, Blesch A, Carmichael ST. A neurovascular niche for neurogenesis after stroke. J Neurosci. 2006;26(50):13007-16
Oliveira LMO, Dimitrov D. Surgical Techniques for Chronic Implantation of Microwire Arrays in Rodents and Primates. In: Nicolelis MAL, editor. Methods for Neural Ensemble Recordings. 2nd edition. Boca Raton (FL): CRC Press/Taylor & Francis; 2008. Chapter 2.
Olsen TS, Lassen NA. A dynamic concept of middle cerebral artery occlusion and cerebral infarction in the acute state based on interpreting severe hyperemia as a sign of embolic migration. Stroke. 1984;15:458-68
Ott E, Nussmeier NA, Duke PC, Feneck RO, Alston RP, Snabes MC, Hubbard RC, Hsu PH, Saidman LJ, Mangano DT. Efficacy and safety of the cyclooxygenase 2 inhibitors parecoxib and valdecoxib in patients undergoing coronary artery bypass surgery. J Thorac Cardiovasc Surg. 2003;125:1481–1492
Pan W, Kastin AJ. Tumor necrosis factor and stroke: role of the blood-brain barrier. Prog Neurobiol. 2007;83(6):363–374
Pang L, Ye W, Che XM, Roessler BJ, Betz AL, Yang GY. Reduction of inflammatory response in the mouse brain with adenoviral-mediated transforming growth factor-ss1 expression. Stroke. 2001;32(2):544–552
Parkes LM, Tofts PS. Improved accuracy of human cerebral blood perfusion measurements using arterial spin labeling: accounting for capillary water permeability. Magn Reson Med. 2002;48(1):27-41
142
Paxinos G, Watson C. The Rat Brain in Stereotaxic Coordinates. Fifth Edition. 2005 Peachell P. Regulation of mast cells by β-agonists. Clin Rev Allergy Immunol.
2006;31:131–42 Peerschke EI, Yin W, Ghebrehiwet B. Complement activation on platelets: implications
for vascular inflammation and thrombosis. Mol Immunol. 2010;47:2170–5 Peng SL, Ravi H, Sheng M, Thomas BP, Lu H. Searching for a truly “iso-metabolic” gas
challenge in physiological fMRI. J Cereb Blood Flow Metabol. 2016 Perrone MG, Scilimati A, Simone L, Vitale P. Selective COX-1 Inhibition: A Therapeutic
Target to be Reconsidered. Curr Med Chem. 2010;17(32):3769-805 Pineiro R, Pendlebury S, Johansen-Berg H, Matthews PM. Altered hemodynamic
responses in patients after subcortical stroke measured by functional MRI. Stroke. 2002;33:103-9
Pinsky DJ, et al. Hypoxia-induced exocytosis of endothelial cell Weibel-Palade bodies. A mechanism for rapid neutrophil recruitment after cardiac preservation. J Clin Invest. 1996;97:493–500
Pinteaux E, Rothwell NJ, Boutin H. Neuroprotective actions of endogenous interleukin-1 receptor antagonist (IL-1ra) are mediated by glia. Glia. 2006;53(5):551–556
Pocock JM, Kettenmann H. Neurotransmitter receptors on microglia. Trends Neurosci. 2007; 30:527–35
Pomeroy V, Aglioti SM, Mark VW, McFarland D, Stinear C, Wolf SL et al. Neurological principles and rehabilitation of action disorders: rehabilitation interventions. Neurorehab Neural Re. 2011;5:35-43
Pradillo JM, Denes A, Greenhalgh AD, Boutin H, Drake C, McColl BW, Barton E, Proctor SD, Russell JC, Rothwell NJ, Allan SM. Delayed administration of interleukin-1 receptor antagonist reduces ischemic brain damage and inflammation in comorbid rats. J Cereb Blood Flow Metab. 2012;32(9):1810–1819
Provenzale JM, Jahan R, Naidich TP, Fox AJ. Assessment of the patient with hyperacute stroke: imaging and therapy. Radiology . 2003;229:347–59
Que M, Schiene K, Witte OW, Zilles K. Widespread up-regulation of N-methyl-D-aspartate receptors after focal photothrombotic lesion in rat brain. Neurosci Lett. 1999;273:77– 80
Rainsford KD. Anti-inflammatory drugs in the 21st century. Subcell Biochem. 2007;42:3–27
Reid JL, Dawson D, Macrae IM. Endothelin, cerebral ischaemia and infarction. Clin Exp Hypertens. 1995;(1-2):399-407
Relton JK, Sloan KE, Frew EM, Whalley ET, Adams SP, Lobb RR. Inhibition of alpha4 integrin protects against transient focal cerebral ischemia in normotensive and hypertensive rats. Stroke. 2001;32(1):199–205
Riedel CH, Zimmermann P, Jensen-Kondering U, Stingele R, Deuschl G, Jansen O. The importance of size: successful recanalization by intravenous thrombolysis in acute anterior stroke depends on thrombus length. Stroke. 2011;42:1775–7
Roc AC, Wang J, Ances BM, Liebeskind DS, Kasner SE, Detre JA. Altered hemodynamics and regional cerebral blood flow in patients with hemodynamically significant stenoses. Stroke. 2006;37(2):382-7
Rossini PM, et al. Interhemispheric difference of sensory hand area after monohemispheric stroke: MEG/MRI integrative study. NeuroImage.
143
2001;14:474-85 Rossini C, Altamura A, Ferretti F, Vernieri F, Zappasodi M, Caulo, Pizzella V. Does
cerebrovascular disease affect the coupling between neuronal activity and local haemodynamics? Brain. 2004;127(1):99-110
Ruan L, Wang B, ZhuGe Q, Jin K. Coupling of neurogenesis and angiogenesis after ischemic stroke. Brain Res. 2015;1623:166-73
Sahin B, et al. Brain volumes of the lamb, rat and bird do not show hemispheric asymmetry: a stereological study. Image Anal. Sterol. 2001;20:9-13
Sairanen TR, Lindsberg PJ, Brenner M, Siren AL. Global forebrain ischemia results in differential cellular expression of interleukin-1beta (IL-1beta) and its receptor at mRNA and protein level. J Cereb Blood Flow Metab. 1997;17:1107–20
Saleem S, Ahmad AS, Maruyama T, Narumiya S, Dore S. PGF(2alpha) FP receptor contributes to brain damage following transient focal brain ischemia. Neurotox Res. 2009;15(1):62–70
Salter K, Campbell N, Richardson M, Mehta S, Jutai J, Zettler L, Moses M, McClure A, Mays R, Foley N, Teasell R. Evidence-Based Review of Stroke Rehabilitation Chapter 21: Outcome measures in stroke rehabilitation 2013. Heart and stroke foundation Canadian partnership for stroke recovery. Evidence Based Review of Stroke Rehabilitation, London Ontario Canada. 2013
Samson MT, et al. Differential roles of CB1 and CB2 cannabinoid receptors in mast cells. J Immunol. 2003;170:4953–62
Sanchez-Moreno C, Dashe JF, Scott T, Thaler D, Folstein MF, Martin A. Decreased levels of plasma vitamin C and increased concentrations of inflammatory and oxidative stress markers after stroke. Stroke J Cereb Circ. 2004;35(1):163–168
Savic B, Meier B. How Transcranial Direct Current Stimulation Can Modulate Implicit Motor Sequence Learning and Consolidation: A Brief Review. Front Hum Neurosci. 2016;10:26
Sawada M, Matsumoto M, Sawamoto K. Vascular regulation of adult neurogenesis under physiological and pathological conditions. Front Neurosci. 2014;8:53
Schiene K, Bruehl C, Zilles K, Qu M, Hagemann G, Kraemer M et al. Neuronal hyper-excitability and reduction of GABAA-receptor expression in the surround of cerebral photo-thrombosis. J Cereb Blood F Met. 1996;16:906-14
Schroeter M, Jander S, Huitinga I, Witte OW, Stoll G. Phagocytic response in photochemically induced infarction of rat cerebral cortex. The role of resident microglia. Stroke. 1997;28:382–6
Schwab S, Steiner T, Aschoff A, Schwarz S, Steiner HH, Jansen O, et al. Early hemicraniectomy in patients with complete middle cerebral artery infarction. Stroke. 1998;29:1888–93
Schwab JM, Nguyen TD, Postler E, Meyermann R, Schluesener HJ. Selectiveaccumulation of cyclooxygenase-1-expressing microglial cells/macrophages in lesions of human focal cerebral ischemia. Acta Neuropathol. 2000;99(6):609-14
Seil FJ. Recovery and repair issues after stroke from the scientific perspective. Curr Opin Neurol. 1997;10(1):49-51
Selvin E, Hirsch A. Contemporary risk factor control and walking dysfunction in individuals with peripheral arterial disease: NHANES 1999– 2004. Atherosclerosis. 2008;201(2)425–33
144
Shen Q, Goderie SK, Jin L, Karanth N, Sun Y, Abramova N, Vincent P, Pumiglia K, Temple S. Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science. 2004;304(5675):1338-40
Shen Q, Du F, Huang S, Duong TQ. spatio-temporal characteristics of postischemic hyperperfusion with respect to changes in T1, T2, diffusion, angiography, and blood-brain barrier permeability. J Cereb Blood Flow Metab. 2011;31(10):2076-85
Shen Q, Huang S, Duong TQ. Ultra-high spatial resolution basal and evoked cerebral blood flow MRI of the rat brain. Brain Res. 2015;1599:126-36
Shih YY, Huang S, Chen YY, Lai HY, Kao YC, Du F, Hui ES, Duong TQ. Imaging neurovascular function and functional recovery after stroke in the rat striatum using forepaw stimulation. J Cereb Blood Flow Metab. 2014(9):1483-92
Shu CY, Herman P , Coman D, Sanganahalli BG , Wang H, Juchem W, Rothman DL, de Graaf RA, Hyder F. Brain region and activity-dependent properties of M for calibrated fMRI. Neuroimage. 2016;125:846:856
Shyu WC, Lin SZ, Yang HI, Tzeng YS, Pang CY,Yen PS et al. Functional recovery of stroke rat induced by granulocyte colony-neurogenesis and angiogenesis and improves neurological function in rats. Circulation. 2004;110:1847-54
Simon AB, Buxton RB. Understanding the dynamic relationship between cerebral blood flow and the BOLD signal: implications for quantitative functional fMRI. Neuroimage 2015;116:158:161
Smith WS, Sung G, Saver J, Budzik R, Duckwiler G, Liebeskind DS, Lutsep HL, Rymer MM, Higashida RT, Starkman S, Gobin YP. Multi MERCI Investigators; Frei D, Grobelny T, Hellinger F, Huddle D, Kidwell C, Koroshetz W, Marks M, Nesbit G, Silverman IE: Mechanical thrombectomy for acute ischemic stroke: final results of the Multi MERCI trial. Stroke. 2008;39:1205–12
Song WL, Wang M, Ricciotti E, Fries S, Yu Y, Grosser T, Reilly M, Lawson JA, FitzGerald GA. Tetranor PGDM, an abundant urinary metabolite reflects biosynthesis of prostaglandin D2 in mice and humans. J Biol Chem. 2008; 283(2):1179-88
Speliotes EK, et al. Increased expression of basic fibroblast growth factor (bFGF) following focal cerebral infarction in the rat. Brain Res. Mol. Brain Res. 1995;29:31-42
Spite M, Serhan CN. Novel lipid mediators promote resolution of acute inflammation: impact of aspirin and statins. Circ Res. 2010;107:1170–84
Stagg CJ, Best JG, Stephenson MC, O'Shea J, Wylezinska M, Kincses ZT, Morris PG, Matthews PM, Johansen-Berg H. Polarity-sensitive modulation of cortical neurotransmitters by transcranial stimulation. J Neurosci. 2009; 29(16):5202-6
Stanimirovic D, Satoh K. Inflammatory mediators of cerebral endothelium: a role in ischemic brain inflammation. Brain Pathol. 2000;10(1):113-26
Statistics Canada CANSIM Table 102-0529: deaths, by cause: diseases of the circulatory system. 2012, 2000–2006
Stegmayr B, Asplund K, Kuulasmaa K, Rajakangas AM, Thorvaldsen P, Tuomilehto J. Stroke incidence and mortality correlated to stroke risk factors in the WHO MONICA Project. An ecological study of 18 populations. Stroke. 1997;28:1367-74
Steinberg BA, Augustine JR. behavioural, anatomical, and physiological aspects of
145
recovery of motor function following stroke. Brain Res Brain Res Rev. 1997;25(1):125-32
regulate early ischemic brain swelling and neutrophil accumulation. J Cereb Blood Flow Metab. 2006;26:605–12
Strle K, Zhou JH, Shen WH, Broussard SR, Johnson RW, Freund GG, Dantzer R, Kelley KW. Interleukin-10 in the brain. Crit Rev Immunol. 2001;21(5):427–449
Stroemer RP, Kent TA, Hulsebosch CE. Increase in synaptophysin immunoreactivity following cortical infarction. Neurosci Lett. 1992;147(1):21-4
Stroemer RP, Kent TA, Hulsebosch CE. Acute increase in expression of growth associated protein GAP-43 following cortical ischemia in rat. Neurosci Lett. 1993;162(1-2):51-4
Stroemer RP, Kent TA, Hulsebosch CE. Neocortical neural sprouting, synaptogenesis and behavioural recovery following neocortical infarction in rats. Stroke. 1998;29(11):2381-93
Sudlow CL, Warlow CP. Comparable studies of the incidence of stroke and its pathological types: results from an international collaboration. International Stroke Inschidence Collaboration. Stroke. 1997;28:491-9
Sun Y, Jin K, Xie L, Childs J, Mao XO, Logvinova A et al. VEGF-induced neuro-protection, neurogenesis and angiogenesis after focal cerebral ischemia. J Clin Invest. 2003;111:1843-51
Sutherland BA, Minnerup J, Balami JS, Arba F, Buchan AM, Kleinschnitz C. Neuroprotection for ischaemic stroke: translation from the bench to the bedside. Int J Stroke. 2012;7:407–18
Swanson LW. Mapping the human brain: past, present, and future. Trends Neurosci. 1995;18:471-4
Szpak GM, et al. Border zone neovascularization in cerebral ischemic infarct. Folia Neuropathol. 1999;37:264–8
Taguchi A, Soma T, Tanaka H, Kanda T, Nishimura H, Yoshikawa H et al. Administration of CD34+ cells after stroke enhances neurogenesis via angiogenesis in a mouse model. J Clin Invest. 2004;114:330–8
Taub E, Miller NE, Novack TA, Cook EW 3rd, Fleming WC, Nepomuceno CS, Connell JS, Crago JE. Technique to improve chronic motor deficit after stroke. Arch Phys Med Rehabil. 1993;74(4):347-54
Taub E, Uswatte G, King DK, Morris D, Crago JE, Chatterjee A. A placebo-controlled trial of constraint-induced movement therapy for upper extremity after stroke. Stroke. 2006;37(4):1045-9
Teasell R, Rice D, Richardson M, Campbell N, Madady M, Hussein N, Murie-Fernandez M, Page S. The next revolution in stroke care. Expert Rev Neurother. 2014:14(11):1307-14
Tecchio F, et al. Brain plasticity in recovery from stroke: An MEG assessment. NeuroImage. 2006;32:1326-34
Thored P, Wood J, Arvidsson A, Cammenga J, Kokaia Z, Lindvall O. Long-term
146
neuroblast migration along blood vessels in an area with transient angiogenesis and increased vascularization after stroke. Stroke. 2007;38(11):3032-9
Tipton AJ, Sullivan JP. Sex differences in T cells in hypertension. Clin Ther. 2014;36:1882-900
Turner RC, Lucke-Wold B, Lucke-Wold N, Elliott AS, Logsdon AF, Rosen CL, et al. Neuroprotection for ischemic stroke: moving past shortcomings and identifying promising directions. Int J Mol Sci. 2013;14:1890–917
Ueki M, Linn F, Hossmann KA. Functional activation of cerebral blood flow and metabolism before and after global ischemia of rat brain. J Crebe Blood Flow and metab. 1988;8:486:494
van Bruggen N, Cullen BM, King MD, Doran M, Williams SR, Gadian DG, et al. T2- and diffusion-weighted magnetic resonance imaging of a focal ischemic lesion in rat brain. Stroke. 1992;23:576–82
van der Zijden JP, van der Toorn A, van der Marel K, Dijhuizen RM. Longitudinal in vivo MRI of alterations in peri-lesional tissue after transient ischemic stroke in rats. Exp Neurol. 2008;212:207-12
van Lookeren CM, et al. Secondary reduction in the apparent diffusion coefficient of water, increase in cerebral blood volume, and delayed neuronal death after middle cerebral artery occlusion and early repercussion in the rat. J. Cereb. Blood Flow Metab. 1999;19:1354-64
Veerbeek JM, van Wegen E, van Peppen R, van der Wees PJ, Hendriks E, Rietberg M, Kwakkel G. What is the evidence for physical therapy poststroke? A systematic review and meta-analysis. PLoS One. 2014;9(2)
Vemuganti R, Dempsey RJ, Bowen KK. Inhibition of intercellular adhesion molecule-1 protein expression by antisense oligonucleotides is neuroprotective after transient middle cerebral artery occlusion in rat. Stroke. 2004;35(1):179–184
Virley D, Beech JS, Smart SC, Williams SC, Hodges H, Hunter AJ. A temporal MRI assessment of neuropathology after transient middle cerebral artery occlusion in the rat: correlations with behaviour. J Cereb Blood Flow Metab. 2000;20:563-82
Wahlgren NG, Ahmed N. Neuroprotection in cerebral ischemia: facts and fancies – the need for new approaches. Cerebrovasc Dis. 2004;17(1):153-66
Wang L, Yushmanov VE, Liachenko SM, Tang P, Hamilton RL, Xu Y. Late reversal of cerebral and water diffusion after transient focal ischemia in rats. J. Cereb. Blood Flow Metab. 2002;22:253-61
Wang Y, Cooke MJ, Morshead CM, Shoichet MS. Hydrogel delivery of erythropoietin to the brain for endogenous stem cell stimulation after stroke injury. Biomaterials. 2012(33):2681-62
Wang Y, Li M, Dong F, Zhang J, Zhang F. Physical exercise-induced protection on ischemic cardiovascular and cerebrovascular diseases. Int J Clin Exp Med. 2015:15;8(11):19859-66
Ward NS, Brown MM, Thompson AJ, Frackowiak RS: Neural correlates of outcome after stroke: a cross-sectional fMRI study. Brain. 2003;126(6):1430-48
Watson BD, Dietrich WD, Busto R, Wachtel MS, Ginsberg MD. Induction of reproducible brain infarction by photochemically initiated thrombosis. Ann Neurol. 1985;17:497–504
Weber R, Ramos-Cabrer P, Wiedermann D, van Camp N, Hoehn M. A fully non-
147
invasive and robust experimental protocol for longitudinal fMRI studies in the rat. Neuroimage. 2006;29(4):1303-10
Weber R, Ramos-Cabrer P, Justicia C, Wiedermann D, Strecker C, Sprenger C, Hoehn M. Early prediction of functional recovery after experimental stroke: functional magnetic resonance imaging, electrophysiology, and behavioural testing in rats. J Neurosci. 2008;28(5):1022-9
Wegener S, Weber R, Ramos-Cabrer P, Uhlenkueken U, Sprenger C, Wiedermann D et al. Temporal profile of T2-weighted MRI distinguishes between pannecrosis and selective neuronal death after transient focal cerebral ischemia in the rat. J Cereb Blood F Met. 2006;26:38-47
Wegener S, Artmann J, Luft AR, Buxton RB, Weller M, Wong EC. The time of maximum post-ischemic hyperperfusion indicates infarct growth following transient experimental ischemia. PLoS One. 2013;8(5)
Wesson DW, Wilson DA. Sniffing out the contributions of the olfactory tubercle to the sense of smell: hedonics, sensory integration, and more? Neurosci. Biobehav. Rev. 2011;35:655-68
Weston RM, Jones NM, Jarrott B, Callaway JK. Inflammatory cell infiltration after endothelin-1- induced cerebral ischemia: histochemical and myeloperoxidase correlation with temporal changes in brain injury. J Cereb Blood Flow Metab. 2007;27(1):100–114
Whishaw IQ, Pellis SM, Gorny B, Kolb B, Tetzlaff W. Proximal and distal impairments in rat forelimb use in reaching follow unilateral pyramidal tract lesions. Behav Brain Res. 1993;56:59–76
White FC, Bloor CM. Coronary vascular remodelling and coronary resistance during chronic ischemia. Am J Cardiovasc Pathol. 1992; 4:193-202
WHO. The world health report 2000: Health systems - improving performance. Geneva: WHO, 2000
Wieloch T, Nikolich K. Mechanisms of neural plasticity following brain injury. Curr Opin Neurobiol. 2006;16:258-64
Wiltrout C, Lang B, Yan Y, Dempsey RJ, Vemuganti R. Repairing brain after stroke: a review on post-ischemic neurogenesis. Neurochem Int. 2007;50(7-8):1028-41
Windle V, Szymanska A, Granter-Button S, White C, Buist R, Peeling J et al. An analysis of four different methods of producing focal cerebral ischemia with endothelin-1 in the rat. Exp Neurol. 2006;201:324-34
Witte OW, Bidmon HJ, Schiene K, Redecker C, Hagemann G. Functional differentiation of multiple peri-lesional zones after focal cerebral ischemia. J Cereb Blood F Met. 2000;20:1149-65
Womelsdorf T, Valiante TA, Sahin NT, Miller KJ, Tiesinga P. Dynamic circuit motifs underlying rhythmic gain control, gating and integration. Nat Neurosci. 2014;17(8):1031-9
Wong EC. An introduction to ASL labeling techniques. J Magn Reson Imaging. 2014;40(1):1-10
Woodruff TM, Thundyil J, Tang SC, Sobey CG, Taylor SM, Arumugam TV. Pathophysiology, treatment, and animal and cellular models of human ischemic stroke. Molecular degeneration. 2011;6-11
Xiong X, Barreto GE, Xu L, Ouyang YB, Xie X, Giffard RG. Increased brain injury and worsened neurological outcome in interleukin-4 knockout mice after transient
148
focal cerebral ischemia. Stroke. 2011;42(7):2026–2032 Xiong Y, Zhu WZ, Zhang Q, Wang W. Observation of post-MCAO cortical inflammatory
edema in rats by 7.0Tesla MRI. J Huazhong Univ Sci Technol Med Sci. 2014;34(1):120-4
Xu SY, Pan SY. The failure of animal models of neuroprotection in acute ischemic stroke to translate to clinical efficacy. Med Sci Monit Basic Res. 2013;19:37-45
Yagami T, Koma H, Yamamoto Y. Pathophysiological Roles of Cyclooxygenases and PG in the Central Nervous System. Mol Neurobiol. 2015
Yamashita K, Busch E, Wiessner C, Hossmann KA. Thread occlusion but not electrocoagulation of the middle cerebral artery causes hypothalamic damage with subsequent hyperthermia. Neurol Med Chir. 1997;37:723–7
Yamashita T, Sawamoto K, Suzuki S, Suzuki N, Adachi K, Kawase T, Mihara M, Ohsugi Y, Abe K, Okano H. Blockade of interleukin-6 signaling aggravates ischemic cerebral damage in mice: possible involvement of Stat3 activation in the protection of neurons. J Neurochem. 2005;94(2): 459–468
Yang Y, Yang T, Li Q, Wang CX, Shuaib A. A new reproducible focal cerebral ischemia model by introduction of polyvinylsiloxane into the middle cerebral artery: a comparison study. Neurosci Methods. 2002;118(2):199-206
Yang Y, Estrada EY, Thompson JF, Liu W, Rosenberg GA. Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. J Cereb Blood Flow Metab. 2007;27(4):697– 709
Yemisci M, et al. Pericyte contraction induced by oxidative-nitrative stress impairs capillary reflow despite successful opening of an occluded cerebral artery. Nat Med. 2009;15:1031–7
Yenari M, Kitagawa K, Lyden P, Perez-Pinzon M. Metabolic down-regulation: a key to successful neuroprotection? Stroke. 2008;39:2910–7
Yepes M, Sandkvist M, Wong MK, Coleman TA, Smith E, Cohan SL, Lawrence DA. Neuroserpin reduces cerebral infarct volume and protects neurons from ischemia-induced apoptosis. Blood. 2000;96(2):569–576
Yrjanheikki J, Keinanen R, Pellikka M, Hokfelt T, Koistinaho J. Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proc Natl Acad Sci U S A. 1998;95(26):15769–15774
Yrjanheikki J, Tikka T, Keinanen R, Goldsteins G, Chan PH, Koistinaho J. A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proc Natl Acad Sci U S A. 1999;96(23):13496–13500
Yu SW, Friedman B, Cheng Q, Lyden PD. Stroke-evoked angiogenesis results in a transient population of microvessels. Cereb Blood Flow Metab. 2007;27(4):755-63
Yu CW, Liang X, Lipsky S, Karaaslan C, Kozakewich H, Hotamisligil GS, Bischoff J, Cataltepe S. Dual role of fatty acid-binding protein 5 on endothelial cell fate: a potential link between lipid metabolism and angiogenic responses. Angiogenesis. 2016;19(1):95-106
Zhang Z, Zhang RL, Jiang Q, Raman SB, Cantwell L, Chopp M. A new rat model of
Zhang Z, Chopp M. Vascular endothelial growth factor and angiopoietins in focal cerebral ischemia. Trends Cardiovasc Med. 2002;12(2):62-6
Zhang L, Schallert T, Zhang ZG, Jiang Q, Arniego P, Li Q, Lu M, Chopp M. A test for detecting long-term sensorimotor dysfunction in the mouse after focal cerebral ischemia. J. Neurosci. Methods. 2002;117(2):207–14
Zhang N, Komine-Kobayashi M, Tanaka R, Liu M, Mizuno Y, Urabe T. Edaravone reduces early accumulation of oxidative products and sequential inflammatory responses after transient focal ischemia in mice brain. Stroke. 2005;36(10):2220–2225
Zhang P, et al. Early exercise improves cerebral blood flow through increased angiogenesis in experimental stroke rat model. J Neuroeng. Rehabil. 2013;10;1-10
Zhang ZG, Chopp M. Promoting brain remodelling to aid in stroke recovery. Trends Mol Med. 2015;21(9):543-8
Zhao X, Haensel C, Araki E, Ross ME, Iadecola C. Gene-dosing effect and persistence of reduction in ischemic brain injury in mice lacking inducible nitric oxide synthase. Brain Res. 2000; 872(1–2):215–218
Zhe-Sun P, Zhou J, Sun W, J Huang, van Zijl P. Detection of the ischemic penumbra using pH weighted fMRI. J Cereb Blood Flow Metabol. 2007;27:1129-1136
Zhe-Sun P, Benner T, Copen WA, Sorensen G. Early experience of translating pH-weighted MRI to image human subject at 3 Tesla. Stroke, 2010:147-155
Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001:108(8):1167–74
150
Appendix 1 – Continuous ASL
An MR image can be sensitized to the effect of in-flowing blood spins if those
spins are in a different magnetic state (“labelled”) than the static tissue [Martirosian et
al. 2010]. When magnetically labelled spins diffuse into the extracellular space and
exchange with the unperturbed tissue spins, the result is a net reduction of tissue
magnetization [Parkes & Tofts 2002]. Repeating the experiment in a “control” condition
(in which arterial spins are not labelled [Martirosian et al. 2010]) and comparing the
signal between conditions results in a direct measurement of perfusion [Parkes & Tofts
2002].
In the continuous ASL experiment (CASL, employed in the present work) the
“label” is created by inverting the magnetization of arterial protons using a long radio
frequency (RF) pulse in combination with a slice-selective gradient for a flow-driven
adiabatic inversion of arterial magnetization [Parkes & Tofts 2002]. During adiabatic
labeling, the magnetization of spins crossing the labeling plane are inverted. The net
result being the creation of a continuous stream of inverted or 'labelled' protons which
flow towards the imaging plane placed downstream of the labelling plane [Martirosian et
al. 2010]. The ASL labeling pulse consists of a lengthy (~1-2 second long) constant
gradient ('Gz') (applied parallel to the direction of flow) and an RF pulse ('B1') applied
perpendicular to the gradient (along the transverse plane). In the present work the
direction of flow is parallel to the main magnetic field where labelling occurs at the level
of carotid arteries [Wong 2014]. From the perspective of the moving spin, the effective
field ('Beff' – from B1 and Gz) rotates at the frequency of the applied RF pulse: B1 is fixed
(in the transverse plane), while the longitudinal component is proportional to the position
of the spin [Wong 2014]. As the spin travels across the labelling plane Beff (beginning at
a magnitude of '+Z') reduces to zero then grows to reach '-Z' causing an inversion of the
spin if rotation of Beff is slow compared to the precession frequency (this is the adiabatic
condition) [1] – reproduced from Wong 2014. In Equation [1], 'Ɣ' denotes the
gyromagnetic ratio (the constant nucleus-specific MR frequency at a given field
strength).
151
[1]
A cartoon of the labelling (difference in signal achieved between a labeled image
and a control image) and labelling/imaging planes overlaid on an image of a rat head
are shown in the figure below. The plot below shows the signal difference with the
passage of the label during the CASL experiment. In the first part, (1), there is no signal
change as the label has yet to reach the imaging plane. In time (denoted tA), the label
begins to reach the imaging plane resulting in a non-zero difference in signal. The signal
difference increases as the label continues to arrive at the imaging plane during the
second part (2) of the experiment. Relaxation and outflow after labelling stops (at a time
denoted: tA + tL), result in a reduction of the signal difference during the final part of the
experiment (3). Adapted from Parkes & Tofts (2002).
For ASL experiments, the in-flow/out-flow arterial/venous magnetization (denoted
by 'ma' and 'mv' in equation [2]) are included in the Bloch equation (which expresses net
nuclear magnetization (M) as a function of relaxation times) [Parkes & Tofts 2002]. The
152
simplest description of ASL theory uses a single compartment model where within an
imaging voxel spins instantaneously cross from intra-vascular to extra vascular space:
ie there's only one compartment effectively. There are two key assumptions in this
model: (1) water enters and exits through exchanging arteries/veins, (2) the
compartment is well mixed. Therefore, within a voxel inside the imaging plane, spins
cross between the intra- and extra-vascular compartments at a perfusion rate (f: blood
perfusion, ml blood/min/100ml tissue) [Parkes & Tofts 2002]. Spins relax at the tissue
relaxation rate 'T1' (or the longitudinal relaxation time of water in tissue). Equation [2]