Nirs Neurobiologia PDF

YNIMG-10279; No.
of pages: 11; 4C: 2

NeuroImage xxx (2013) xxxxxx
Contents lists available at SciVerse ScienceDirect
NeuroImage
journal homepage: www.elsevier.com/locate/ynimg
Review
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NIRS in clinical neurology a promising tool?

Clinic for Cognitive Neurology, University Clinic Leipzig, Leipzig, Germany Max-Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany Dept. Neurology, Charit, University Medicine Berlin, Berlin, Germany
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Hellmuth Obrig
Article history: Accepted 21 March 2013 Available online xxxx Keywords: Near-infrared spectroscopy (NIRS) Clinical neurology Stroke Epilepsy Migraine Neurorehabilitation
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Near-infrared spectroscopy (NIRS) has become a relevant research tool in neuroscience. In special populations such as infants and for special tasks such as walking, NIRS has asserted itself as a low resolution functional imaging technique which prots from its ease of application, portability and the option to co-register other neurophysiological and behavioral data in a near natural environment. For clinical use in neurology this translates into the option to provide a bed-side oximeter for the brain, broadly available at comparatively low costs. However, while some potential for routine brain monitoring during cardiac and vascular surgery and in neonatology has been established, NIRS is largely unknown to clinical neurologists. The article discusses some of the reasons for this lack of use in clinical neurology. Research using NIRS in three major neurologic diseases (cerebrovascular disease, epilepsy and headache) is reviewed. Additionally the potential to exploit the established position of NIRS as a functional imaging tool with regard to clinical questions such as preoperative functional assessment and neurorehabilitation is discussed. 2013 Published by Elsevier Inc.
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Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Neurological diseases studied by NIRS . . . . . . . . . . . . . . . . . . . . . . Stroke and cerebrovascular disease . . . . . . . . . . . . . . . . . . . . . Monitoring subacute stroke . . . . . . . . . . . . . . . . . . . . . Risk assessment and prevention . . . . . . . . . . . . . . . . . . . Epileptic disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oxygenation response to epileptic activity . . . . . . . . . . . . . . Focus localization . . . . . . . . . . . . . . . . . . . . . . . . . . Presurgical mapping of language functions . . . . . . . . . . . . . . Issues of NIRS-analysis in epilepsy monitoring . . . . . . . . . . . . Idiopathic headache syndromes . . . . . . . . . . . . . . . . . . . . . . Altered vasomotor reactivity in migraine . . . . . . . . . . . . . . . Investigating cortical spreading depression (CSD) . . . . . . . . . . . Clinical aspects of migraine investigated by NIRS . . . . . . . . . . . Functional imaging of the diseased brain . . . . . . . . . . . . . . . . . . Disease differentiation by cortical activation in response to cognitive tasks Localization of eloquent cortical areas . . . . . . . . . . . . . . . . Investigating cortical plasticity in neurorehabilitation . . . . . . . . . Conclusion and perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abbreviations: ABP, arterial blood pressure; AD, Alzheimer's disease; ALS, amyotrophic lateral sclerosis; BCI, brain computer interface; CSD, cortical spreading depression; CSF, cerebrospinal uid; CT, computed tomography; CVT, cerebral venous thrombosis; DBS, deep brain stimulation; dwI, diffusion weighted imaging; ECD, extracranial Doppler sonography; ECT, electroconvulsive therapy; EP, evoked potential; ICU, intensive care unit; LP, lumbar puncture (spinal tap); MCA, middle cerebral artery; MCI, mild cognitive impairment; MEP, motor evoked potential; PFO, patent foramen ovale; pwI, perfusion weighted imaging; SpO2, partial oxygen saturation; SWI, susceptibility weighted imaging; TCD, transcranial Doppler sonography; VEP, visually evoked potential. Max-Planck Institute for Human Cognitive and Brain Sciences, Stephanstrae 1A, 04103 Leipzig, Germany. Fax: +49 341 9940 2221. E-mail address: obrig@cbs.mpg.de. 1053-8119/$ see front matter 2013 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.neuroimage.2013.03.045
Please cite this article as: Obrig, H., NIRS in clinical neurology a promising tool? NeuroImage (2013), http://dx.doi.org/10.1016/ j.neuroimage.2013.03.045
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H. Obrig / NeuroImage xxx (2013) xxxxxx
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Introduction A methodology providing continuous readings of cerebral oxygenation, applicable non-invasively at the bed side and relying on comparatively inexpensive technology should have overcome the stage of a promising tool with regard to its routine application in neurology. However, over 35 years after its rst description (Jobsis, 1977) and 25 years after the development of the rst commercial monitors (Cope and Delpy, 1988), Near-infrared spectroscopy (NIRS) is largely unknown to clinicians even in specialized neurological departments. Ironically one reason for this apparent discrepancy may be related to the versatility of the method. The list of parameters derived from changes in optical properties of brain tissue is long (Table 1). It reaches from the most straight forward assessment of concentration changes in oxygenated, deoxygenated and total hemoglobin (HbO, HbR, HbT) over the less reliable estimation of redox-changes in cytochrome oxidase (cyt-ox) (Tisdall et al., 2007) to a number of derivations yielding oxygenation indices such as regional oxygen saturation (rSaO2) or the tissue oxygenation index (TOI) (Al-Rawi and Kirkpatrick, 2006; Pocivalnik et al., 2011). Application of an optical contrast agent (indocyanine green, ICG) extends the spectrum to an index of perfusion (Terborg et al., 2004), also targeted by DCS (diffuse correlation spectroscopy) a methodology sharing many features with NIRS (Durduran et al., 2004). Finally some groups still advocate the sensitivity of non-invasive approaches to very fast changes in optical properties in response to neuronal signaling (Gratton and Fabiani, 2010). The cornucopia of parameters may be scientically rewarding but strongly limits comparability between studies from different groups and is unsuited for clinical use. This may hold in particular for neurology, a eld where diagnosis and therapy evaluation strongly rely on conating the patient's history and neurological status with the results of a large number of established instrument-based results. A second issue hampering the introduction of NIRS in clinical neurology is the fact that in adults at best half of the cerebral cortex can be interrogated. Mesial, insular and even cortex in deep sulci plus all subcortical and infratentorial parts of the brain cannot be reached (Fig. 1). Interestingly clinical use and its critical evaluation may be most advanced in brain-monitoring during cardiac and carotid artery surgery (Pennekamp et al., 2009; Vohra et al., 2009; Zheng et al., 2012) and in critical care settings (Smith, 2011). In this eld NIRS
studies largely rely on a pars pro toto approach, correlating drops in cerebral oxygenation measured in a quite limited area of the cerebral cortex to the occurrence of any post-interventional neurological decit. On the contrary neurological differential diagnosis of diseases affecting the central nervous system (CNS) usually aims at identifying a more or less circumscribed localization of the lesion or dysfunction to then differentiate between the underlying pathology. A third challenge to the establishment of any novel methodology for routine clinical use is the necessity to demonstrate a specic advantage over existing diagnostic procedures. Listing the most common diseases
Fig. 1. Coronal slice illustrating brain structures accessible to NIRS. Neocortex at the brain's surface can be interrogated by NIRS (pink ribbon). Note that besides deep brain structures (e.g. basal ganglia, BG) and white matter (WM) substantial neocortical areas cannot be reliably reached (TL: temporal lobe; IC: insular cortex; MC: mesial cortex in the interhemispheric cleft; dsC: cortex in deep sulci). The brain areas reached account to roughly half of the neocortex. Infratentorial structures such as the cerebellum and brainstem cannot be assessed.
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Abbreviation Parameter HbO HbR HbT HbD Cyt-ox rSaO2 TOI BFIICG ICGuo Oxygenated hemoglobin concentration Deoxygenated hemoglobin concentration Total Hb concentration (=HbO + HbR) Hemoglobin difference (=HbO HbR) Cytochrome-oxidase redox state Regional oxygen saturation Tissue oxygenation index
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Table 1 List of the most commonly reported parameters in studies using NIRS (near-infrared spectroscopy) and their potential in clinical neurology. Though the assessment is based on a similar principle, values may substantially differ (Pocivalnik et al., 2011). Results may support a somewhat greater sensitivity to deep layers (Liebert et al., 2006). Assessment principle Direct assessment by modied Beer Lambert approach; dual-wavelength approach sufcient Potential for clinical use Changes in cerebral hemodynamics and blood oxygenation Limitations No absolute values; combination of HbO/ HbR/HbT responses may result in 12 different response patterns
Simple derivation Requires 3 wavelengths Requires multi-distance Marker for cellular oxygenation and energy metabolism Single value to assess oxygenation, reported by many studies on intraoperative/ICU applications Perfusion in analogy to perfusion-weighted MRI Perfusion and potentially extravasation in supercial tumors or inammation May be sensitive to neuronal changes related to electrophysiological signal
Reported in few publications Low concentration, liable to crosstalk From Hb changes Strong assumptions on background optical propertiesa Requires I.V. bolus I.V. application, complex modeling of uorescence in layered tissue, as yet only feasibility studyb A number of groups doubt transcranial detectability
Blood ow index Fluorescence after injection
I.V. application of indocyanine green (ICG); bolus renders transit time based on absorption or uorescence;
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EROS
Event related optical signals fast optical changes
High frequency sampling mandatory; mostly reported for frequency domain monitors
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Note that rSaO2 and TOI are provided by different commercial monitors. Single feasibility study with a time resolved NIRS system.
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Table 2 Methodologies routinely used in clinical neurology. Methods are roughly differentiated with regard to their relevance for the respective diagnosis. ++: high, +: some relevance in the diagnostic algorithm. (+) indicates that procedure is warranted in subgroups of patients. MRI: magnetic resonance imaging; CT: computed tomography; PET: positron emission tomography; SPECT: single photon emission tomography; EEG: electroencephalography; EP: evoked potentials; TCD/ECD: transcranial/extracranial Doppler sonography; LP: lumbar puncture.
MRI Cerebrovascular disease Epileptic disorders
CT
PET/ SPECT (+)
EEG
EP
TCD/ ECD +
LP
Potential of NIRS Monitoring: oxygenation/ perfusion/ autoreg.; prim. & secondary prevention Second. hypoxic injury; focus and preoperative function localization Monitoring: oxygenation/ perfusion/autoregulation Neurovascular alterations
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(+)
High
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High
Headache
Med.
Parkinsons disease Multiple sclerosis
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CNS tumors
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(+)
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CNS infections Functional activation in brain disease
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(+)
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Low Low Med. Low High
Dementia
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Low
Vascular dementia, cognitive function
Cortical activation in DBS
Cognitive function /fatigue
Preoperative function localization
Neuro-intensive care monitoring
Assessement in natural setting; plasticity in response to rehab.
Severe brain injury
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High
affecting the central nervous system (CNS) (MacDonald et al., 2000), Table 2 provides a rough overview over the most widely established diagnostic techniques and roughly weighs their respective diagnostic relevance. Clearly neuroimaging especially magnetic resonance imaging (MRI) has become the most important cornerstone of methodbased differential diagnosis in neurology. MRI can cover the whole brain with an excellent isotropic resolution of ~1 mm for structural scans and an ever growing number of sequences provide differential sensitivity to hemorrhage, (T2* and susceptibility weighted imaging, SWI) cytotoxic edema (diffusion weighted imaging, dwI) and perfusion (perfusion weighted imaging pwI) to only name a few (Gonzalez, 2012). Computed tomography (CT) yields topographical information at a lower spatial resolution but with a number of advantages regarding the feasibility and availability in a clinical setting. Finally some diseasespecic metabolic and transmitter/receptor changes can be imaged by nuclear medicine techniques (positron emission tomography, PET/ single photon emission computed tomography, SPECT). Notably coregistration of the latter techniques with structural imaging converges structural and metabolic information with an excellent spatial resolution (Cho et al., 2008). Because NIRS will not deliver information clinically superior to any of the above imaging techniques, the option to assess pathophysiologically relevant parameters continuously at the bed-side typically motivates clinical NIRS research. These advantages are shared by electroencephalographic methods (continuous EEG and Evoked Potential, EPs) and sonographic assessment of extracerebral and intracerebral vessels (ECD/TCD, extracranial/transcranial Doppler sonography). In epileptic disorders, EEG supplies disease-specic information not available by any other standard technique. Its extremely wide use in in- and outpatient settings additionally builds on the fact that for decades it was the one technique available, although the clinical
validity as a routine-check for functional abnormalities of the CNS may be debatable (Pearce and Cock, 2006). EEG and EPs, the latter assessing integrity of afferent/efferent pathways, measure the electrical signals generated by the brain.1 It can be discussed whether the methodological underpinnings allow to consider all electrophysiological measures a direct assessment of brain activity, however, the response latency to induced or spontaneous changes is temporally concise. Some EPs even allow a differentiation of the locus of the lesion based on the latency of a component (e.g. acoustically evoked potentials). Generally, however, topographical information is limited when relying on the scalp distribution of the EP components. Therefore a combination with NIRS is helpful to allow for a rough localization of cortical generators, a potential which has been explored in neuroscientic approaches but may be extremely valuable also in the clinical context of epilepsy (see Focus localization section). Finally TCD and ECD have become standard techniques in the diagnostics of cerebrovascular disease, and like EEG they are broadly used also in out-patient settings. 2 Indications comprise the regularly performed assessment of stroke risk (atherosclerosis/ stenosis), the assessment of vasomotor reactivity (Ley-Pozo et al., 1990), and the monitoring of vasospasm after subarachnoid hemorrhage (Marshall et al., 2010) and TCD has been shown to also be useful
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1 Efferent motor pathway testing (motor evoked potential, MEP) does not rely on brain potentials like visually, auditory and somatosensory EPs. For MEP assessment transcranial magnetic stimulation over the motor cortex elicits a myographically measured response in the muscle targeted. Nonetheless the principle and its use in clinical neurology are similar. 2 In the context of methodological and technological advances it should be noted that Doppler and sonographic techniques in neurology have strongly proted from the routine use of these techniques in many other elds of medicine.
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for the assessment of the venous compartment of the cerebral vasculature (Stolz, 2008). NIRS has been advocated to be an alternative or supplementary technique especially regarding the assessment of vasomotor reactivity in occlusive carotid artery disease. The results indicate similar or lower sensitivity which may not be sufcient to broadly introduce the methodology in this eld (Palazzo et al., 2010; Vernieri et al., 2004). Nonetheless, the combination of TCD and NIRS has been used in all stages of cerebrovascular disease. The increasing use of NIRS imaging devices supplying rough topographical information may support the additional value of a combined assessment of ow-velocity in the large vessels (TCD) and an index of more focal cortical oxygenation (NIRS). Neurological diseases studied by NIRS In the following 4 sections the Introductionsection will review 3 neurologic disease complexes in which a substantial number of studies using NIRS have been published to date. Cerebrovascular disease (Stroke and cerebrovascular disease section) may be the most widely studied eld, which comes as no surprise since a change in cerebral blood oxygenation is the most directly measured parameter of NIRS. However, in epileptic disorders (Epileptic disorders section), originating from neuronal rather than vascular malfunction, the number of methodologically sound studies may be even larger. Including idiopathic headache syndromes (Idiopathic headache syndromes section) is not only motivated by the rather large body of existing literature, but nicely links the above two disease complexes by targeting pathophysiologically relevant alterations in neurovascular coupling in the morphologically largely intact brain. Also idiopathic headache is usually treated in out-patient settings, a chance to consider the clinical potential of NIRS outside specialist centers. The last section (Functional imaging of the diseased brain section) discusses functional activation studies in the diseased brain using NIRS. Such studies have been performed in a wide spectrum of CNS disease. This application shifts the focus away from the acute and subacute stages of neurological disease. Beyond scientically exciting questions regarding brain plasticity this work may contribute to clinical issues of neuro-rehabilitation. The large body of work using NIRS to monitor the brain intraoperatively and in intensive care settings in part including several hundreds of patients is not reviewed here. This work has been mostly spurred by anesthesiologists and intensivists and we may refer to excellent reviews covering the eld (Murkin and Arango, 2009; Smith, 2011). Also the quite advanced use of NIRS in monitoring the brain in the elds of neonatology and pediatrics is not included in the review (Greisen et al., 2011).
after stroke and angiographic information is available even without contrast agent application (time-of-ight approach). Contrast-agentbased perfusion weighted MRI in combination with dwI allows for a delineation of the tissue at risk based on the pathophysiological concept of the ischemic penumbra (Schlaug et al., 1999). Hence decisions on acute interventions can be guided by pathophysiologically grounded data of the individual patient (Donnan et al., 2009). The use of NIRS in the hyperacute, diagnostic stage may be limited. Methodologically NIRS can only sample the surface of the brain (Fig. 1) and hence cannot reliably differentiate between ischemia and parenchymal hemorrhage, the critical rst step before acute intervention. Similarly the delineation of the tissue at risk in substantial parts of cortical and subcortical brain tissue is beyond the method's eld of view. Not least, at this stage of stroke the credo time is brain may interfere with studies exploring alternative methodologies. However, in a recent review on NIRS in stroke research we argue that stroke can be considered a chronic disease reaching from prevention and assessment of cerebrovascular risk to the phase in which often long-term rehabilitation is regularly warranted to alleviate disability (Obrig and Steinbrink, 2011). During the subacute stage after diagnosis and initial treatment, continuous monitoring of cerebrovascular parameters can be deemed the most promising potential eld for NIRS in clinical neurology. Referring to our extensive review for a more comprehensive coverage we here discuss the most recent studies, reporting various approaches in the eld.
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Stroke and cerebrovascular disease represent the most relevant diagnosis requiring in-patient neurological care. In the acute phase admittance to specialized stroke units (Anon., 2007) and timely thrombolysis in ischemic stroke (Lees et al., 2010) have signicantly improved outcome. When the diagnosis stroke is clinically suspected it is mandatory to differentiate between ischemia and intracerebral hemorrhage. This requires imaging. CT is standard in most hospitals with a neurological department, due to availability, costs and because a number of exclusion criteria for MRI do not apply (e.g. pace-maker, claustrophobia). While a routine non-contrast CT can reliably exclude hemorrhage, the signs of ischemic stroke may be subtle in the very acute stage. However, administration of a contrast-agent renders measures of perfusion, blood volume and an angiogram. This endows CT with the option to provide pathophysiologically relevant information (Campbell et al., 2013). In larger and specialized centers MRI is regularly available for the initial decisive diagnostic work-up. MRI warrants reliable differentiation between ischemia and hemorrhage. Diffusion weighted imaging (dwI) is sensitive to tissue damage minutes
Stroke and cerebrovascular disease
Monitoring subacute stroke Exploring the potential of commercial monitors, three very recent studies demonstrate long-term monitoring in subacute stroke. Overnight recordings in 9 patients with a subacute anterior cerebral artery stroke showed that a drop in systemic (arterial blood pressure, ABP and partial oxygen saturation, SpO2) regularly caused a drop in cerebral oxygenation as monitored by NIRS (Aries et al., 2012). This was twice as common over the diseased when compared to the undiseased hemisphere. Demonstrating the feasibility of long term assessment the major shortcoming is a lack in specication of the NIRS parameter and the pathophysiological concept behind these ndings. Whether this most simple way of monitoring impaired autoregulation is sufcient to guide intervention needs to be claried in larger studies. Another study investigated the effect of sleep-associated breathing disorders in subacute stroke patients (Pizza et al., 2012). The study used two frontal probes in a multidistance approach to attenuate extracranial contamination. In 11 patients successful overnight measurements were performed and showed profound cerebral deoxygenation in response to obstructive apneas. Interestingly these changes were more prominent on the unaffected hemisphere. While the latter result requires further study the approach is another demonstration of the potential of NIRS as a straight forward monitoring technique in subacute stroke. Further illustrating the potential of NIRS in monitoring patients in the subacute stage of cerebrovascular disease, the risk for delayed stroke after subarachnoid hemorrhage was investigated using TCD and NIRS. The results of this large-scale prospective study (n = 98) underline the validity of long term NIRS-measurements in neurointensive care monitoring (Budohoski et al., 2012). Dysfunction of cerebral autoregulation in the 5 rst days correlated with the occurrence of delayed cerebral ischemia. Notably the index assessing autoregulation by means of NIRS (based on TOI), showed dysfunctional autoregulation nearly 1 day prior to its detection based on simultaneously performed TCD measurements. Risk assessment and prevention Risk assessment during primary and secondary prevention is another broadly studied eld. The two most recent studies further support the potential at this stage of cerebrovascular disease. With regard to the issue of cerebrovascular reactivity in patients with carotid artery disease a recent study reinvestigated the correlation between ow velocity (TCD) and cortical oxygenation (NIRS) in response to
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voluntary breath holding. NIRS assessed rSaO2 over bilateral frontal areas and middle cerebral arteries (MCAs) were insonated by TCD in 24 patients with variable degree of stenosis (Vasdekis et al., 2012). The correlation between methods (~ 0.6) is in the range of previously performed similar studies. It should be noted that the additional value of NIRS might be to supply a rough localization of the impaired or altered vasoreactivity. Such additional information would necessitate an imaging approach, which is generally feasible in combination with TCD. Another recent study used an ICG-bolus technique (Oldag et al., 2012) to demonstrate a delay in bolus time-to-peak in the affected versus unaffected hemisphere in patients with MCA-stenosis. The interesting novel aspect is the imaging approach successfully used, though parameters of the commercial NIRS-device were not optimized for ICG assessment. Previously reported comparisons between MRI-based pwI and NIRS-perfusion (Steinkellner et al., 2010; Terborg et al., 2009) were not performed, however the study conrms the feasibility of low resolution perfusion-imaging even when relying on commercial NIRS-imaging systems. For the chronic stage of stroke, functional imaging of the rehabilitation progress is one other potential eld, in which NIRS may establish a role. Such functional activation studies in the lesioned brain are discussed under Functional imaging of the diseased brain section. To supplement our recent review on stroke (Obrig and Steinbrink, 2011) it should be noted that in some less common cerebrovascular diseases NIRS may hold similarly strong potential for monitoring subacute disease dynamics. Cerebral venous thrombosis (CVT), for instance, is a rare but treatable cause of stroke and hemorrhage. There is a single report on a case in whom successful interventional thrombolysis was monitored by a single channel NIRS approach over the parietal area. It showed a decrease blood volume (HbT, HbO, HbR) with successful desobliteration of the transverse sinus (Witham et al., 1999). In this condition NIRS approaches targeting cerebral perfusion could deliver pseudo-continuous readings of the pathophysiological relevant parameter. In sum monitoring of subacute stroke and cerebrovascular disease may be the most relevant eld in which NIRS could reach the clinical neurologist. In this eld the methodology could be easily integrated into the diagnostic and monitoring context which is warranted to an increasing number of patients on specialized stroke units.
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while rapidly generalized seizures less consistently showed an oxygenation decrease (Sokol et al., 2000). In the latter the decrease correlated to a decrease in systemic oxygenation as measured by pulse oximetry. This highlights the necessity to somehow control for extracerebral contaminations in seizures, which often elicit quite substantial changes in ABP and SpO2. Supporting the idea of a deoxygenation in generalized seizures 3 patients with absence seizures showed a deoxygenation (HbO, HbR) over the frontal lobe. This is discussed to indicate either generalized deactivation during this seizure type or a pathological mismatch between oxygen demand and supply in generalized seizures (Buchheim et al., 2004). The pattern of a deoxygenation in response to generalized epileptic activity is also supported by a study of electroconvulsive therapy (ECT). ECT is used in drug-resistant depression and has been studied with NIRS as a model for generalized seizures in humans (Saito et al., 1995). In 90 patients induced seizures were monitored by NIRS and TCD. The results showed a decrease in oxygenation (HbO, HbT, HbR) and a reduction in cytochrome-oxidase, while TCD showed an increase in ow velocity in response to the electric shock. This is discussed to reect differences between systemic and cerebral changes in hemodynamics. The cortical deoxygenation is suggested to stem from a temporary imbalance in energy and oxygen supply induced by the seizure.
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Epileptic disorders
The diagnosis of epilepsy is clinical, based on the history of recurrent seizures usually not witnessed by a health professional (Duncan et al., 2006). Demonstration of ictal or interictal specic EEG-patterns may be the most direct demonstration of the disease but a much broader diagnostic workup including structural imaging and cerebrospinal uid (CSF) analysis is often necessary. While pharmacotherapy is effective in 6070% of all patients, drug-resistant cryptogenic or idiopathic forms may require surgery, which aims at the excision of the epileptogenic focus. NIRS studies have addressed (i) issues of cortical oxygenation during the seizure, (ii) localization of the focus and (iii) have investigated whether functional mapping prior to surgery can assist delineation of functionally eloquent brain areas.
Oxygenation response to epileptic activity The oxygenation response to epileptic activity has been most consistently investigated in NIRS studies. Early work suggested that complex partial seizures induce large increases in HbT over the frontal lobe (Villringer et al., 1994), however in two patients with temporal lobe epilepsy a deoxygenation (rSaO2) was reported over the frontal lobe ipsilateral to the focus (Steinhoff et al., 1996) and different peri-ictal patterns were reported in 3 single cases including an infant (Adelson et al., 1999). Building on such demonstrations of feasibility it was suggested that differential oxygenation patterns might be more or less specic to seizure type. In 8 patients evaluated for surgery, complex partial seizures consistently showed an increase in oxygenation
Focus localization Especially with the advent of NIRS imaging devices epileptic focus localization has become another well-studied application. 29 patients with pharmacologically intractable epilepsy underwent presurgical monitoring using simultaneous NIRS and intracranial EEG (Watanabe et al., 2002). Additionally ictal SPECT was performed. Notably NIRS identied the affected hemisphere, as dened by intracranial EEG, in 28 while SPECT showed the correct lateralization only in 20 patients. With regard to the response pattern, increases in HbO and HbR were mostly seen in clinically apparent seizures while subclinical ictal activity showed a pattern (HbO, HbR) similar to the changes expected in response to physiological functional activation. In a series of patients suffering from nonlesional drug refractory frontal lobe epilepsy, whose focus was dened by separate intracranial recordings, simultaneous scalp-EEG and NIRS recordings were performed (Nguyen et al., 2012b). In 9 patients NIRS revealed seizure-related increases in HbO, while HbR showed a less consistent decrease in concentration. Notably NIRS highlighted an episode of subclinical ictal activity which had been missed on scalp-EEG inspection. Also NIRS suggested a rapid spread of activation to homologous areas in the contralateral hemisphere. Concerning the notion of movement artifacts it is noteworthy that a case with seizure related jerks showed artifacts which could be clearly differentiated from the cerebral hemodynamic response. The same approach was used in a series of 9 patients suffering from drug-resistant temporal lobe epilepsy (Nguyen et al., 2012a). The oxygenation pattern in the 8 seizures monitored (in 3 patients) showed an initial hyperoxygenation (HbO, HbR) followed by a prolonged increase in HbR. Similar to the study in frontal lobe epilepsy a rapid spread to contralateral homologous areas is reported. It is important to note that the magnitude of the changes in response to seizures is large compared to changes expected in functional activation studies. This may be a feature of pathological neuronal activity, which makes ndings in seizures more robust. Oxygenation changes in subcortical and cortical areas may precede generalized epileptic discharges (Moeller et al., 2008). In patients with temporal lobe epilepsy a recent study showed decreases in oxygenation (HbO, HbT) up to 15 min prior to seizure onset over the frontal lobe (Slone et al., 2012). These changes were seen ipsilateral to the presumed focus. Since a 2-channel NIRS system was used, selectively sampling an area distant from the presumed focus, the pathophysiological underpinnings of such a substantial temporal delay remain elusive. Nonetheless the study underlines the potential of NIRS in long term monitoring and the potential to detect anticipatory signals of a seizure.
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Presurgical mapping of language functions Regarding presurgical evaluation of language lateralization in patients with pharmaco-resistant epilepsy a number of studies have investigated the reliability of functional NIRS assessment. The earliest study contrasting a written word-generation with a drawing task to control for motor activation showed reliable lateralization contralateral to handedness in 11 healthy volunteers. In 6 patients undergoing presurgical evaluation the lateralization correlated with the Wadatest, a test relying on unilateral angiographic application of the shortacting anesthetic amobarbital (Watanabe et al., 1998). A later study using the same task replicated the nding in 8 volunteers, but showed a less consistent picture with regard to the WadaNIRS correlation in 16 patients (Watson et al., 2004). It should be noted that diverging results between NIRS and Wada assessment were more common in the 10 patients examined after surgery. Using orally performed verbal uency (control: nonsense-syllable repetition) a good correlation of NIRS assessment with both Wada-test and fMRI results was demonstrated in 8 patients and 3 healthy controls (Gallagher et al., 2007). In sum the procedure may be a very useful additional test of language dominance and may be an alternative procedure in patients, who cannot undergo Wada, fMRI or PET imaging (Gallagher et al., 2008a, 2012). Additionally a combination with similarly non-invasive TCD assessment (Knecht et al., 1998) is readily feasible. Illustrating that NIRS may be used in different aspects of disease evaluation, an interesting case report on a 10-year-old rst assessed the oxygenation responses to seizure activity to then test language lateralization in a subsequent word generation task (Gallagher et al., 2008b). Generally seizures with a clinical correlate elicited larger changes than purely electrical seizures. The pattern consisted of a hyperoxygenation (HbO, HbR) with an initial short decrease in HbO. Issues of NIRS-analysis in epilepsy monitoring One critical issue when singular unpredictable events are to be detected is how continuous NIRS-data are analyzed. This has been formally addressed by a recent paper in which different algorithms were evaluated on simulated data and tested on data of a single patient (Machado et al., 2011). Unsurprisingly a major determinant of the detection sensitivity is signal-to-noise ratio (SNR). However, the authors could show that also short transient features in the EEG (interictal epileptiform discharges) elicit an increase in HbT and allowed for correct localization of the focus. When epileptic activity is investigated by vascular methods a related question is whether and how pathological neuronal activity translates into a vascular response. Thus standard HRF models used in the large body of fMRI and fNIRS studies to investigate functional topography of the cortex may be inappropriate to localize pathology. This has been addressed in detail for the case of epileptogenic focus localization by comparing different linear and non-linear algorithms. These were tested on simulated and data from 3 patients, suffering from drug-resistant epilepsy. It is demonstrated that nonlinear models, respecting both excitatory and inhibitory neuronal activities more adequately grasp the vascular response to ictal and interictal spike-activity. In one patient only the inclusion of non-linear extensions allowed for the correct localization of the focus in fMRI and fNIRS. The focus was identied by intracranial recordings and the success of surgery (Pouliot et al., 2012). Though this study does not provide a standard solution for the analysis of fNIRSEEG analysis in epilepsy, it is remarkable in demonstrating that careful and model based analysis of patient data is absolutely mandatory. Comparing fNIRS and fMRI data both recorded with simultaneous EEG the two methodologies largely converge with regard to the results. The apparent shortcoming of NIRS is the insensitivity to activity in deeper cortical areas.
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syndromes comprising migraine, tension-type-, cluster-headache and a number of rarer syndromes (Anon., 2004) require differential diagnosis and therapy. Migraine may be the most broadly studied primary headache syndrome and beyond the personal suffering its socio- and pharmaco-economic burden is huge (Gerth et al., 2001). The special clinical-scientic interest in this condition largely stems from the impact of the disease on both, neuronal excitability and cerebrovascular reactivity. Changes in neuronal excitability and habituation (Sand et al., 2008) especially in the visual cortex may correlate to the clinically regularly reported photophobia during the attack and aversion of migraine sufferers to strong visual stimuli (Haigh et al., 2012), which may trigger an attack. Additionally it has been controversially discussed whether excitability changes in migraine correspond to those underlying photosensitive epilepsy (Chen et al., 2011). But migraine has also been shown to impact on the vascular system (Tietjen, 2009). This latter pathophysiologic feature of migraine is reected in the rare condition of migrainous stroke (Laurell et al., 2011) and the controversially discussed enhanced risk for stroke in migraineurs (Kruit et al., 2005). NIRS studies have addressed the issue of (i) an altered vasoreactivity, (ii) the vascular response to cortical spreading depression (CSD) and (iii) some aspects of therapy or prevention of vascular events in migraine patients.
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Idiopathic headache syndromes Headache is one of the most common symptoms in neurology. If no underlying cause of headache is identied, idiopathic headache
Altered vasomotor reactivity in migraine In one of the rst studies vasomotor reactivity was assessed by a breath-holding maneuver in 6 patients suffering from migraine without aura (Akin et al., 2006). Interictally these patients showed a similar pattern of an initial decrease followed by a steep rise in HbR over the ~ 20 s of breath-holding. The pattern was qualitatively similar but the amplitude signicantly smaller when compared to healthy controls. HbO changes did not show this difference. The authors conclude that the ndings support the notion of an altered vascular reactivity in migraine. Though a multiple channel device was used (16 channels) the montage only sampled from the frontal area and only global changes are reported. Additionally breath-holding is likely to change quite a number of physiological parameters related to systemic oxygenation, which shed doubt on the clear assignment of the response pattern to the cerebrovascular system. Similarly using breath-holding as a vasoreactivity test another study showed an attenuated increase in oxygenation (HbO, HbR) in 30 patients suffering from migraine without aura when compared to age-matched controls (Liboni et al., 2007). MCA-ow velocity simultaneously monitored by TCD showed converging results. Here a single NIRS channel was applied over the left frontal area. The combination of NIRS and TCD allows for a more reliable assignment of the changes to the cerebral vascular response, however, no control for changes in systemic hemodynamics was used. Another caveat is that controls performed the breath-holding signicantly longer than the patients, which readily explains the larger response amplitude and weakens the claim of the versatility of this procedure as a diagnostic tool in migraine. Using a more controlled metabolic challenge (7% CO2 inhalation) an asymmetry of alterations in vasomotor reactivity was reported interictally in patients suffering from migraine attacks with a hemispheric dominance (Vernieri et al., 2008). The reactivity, investigated by NIRS and simultaneous TCD was larger on the dominantly affected side. Although patients were examined in the asymptomatic interictal period ndings are discussed in the light of alterations in neurovascular coupling during cortical spreading depression, the physiological counterpart of the aura preceding the headache. An even more surprising nding with regard to lateralized changes in vasoreactivity is reported in 12 patients suffering from migraine without aura (Shinoura and Yamada, 2005). In these patients a head-down tilting procedure showed a smaller increase in HbT selectively in the right hemisphere when compared to age matched controls. It remains largely elusive how such a hemisphere specic change in autoregulation could be explained and the variability of the results sheds some doubt on the versatility of the maneuver investigated. A more
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promising approach to assess vasoreactivity is the study of spontaneous low frequency oscillations (LFO). Targeting the vascular changes related to a migraine attack, the response to a glycerol nitrate injection was investigated in patients with familiar hemiplegic migraine and controls (Schytz et al., 2012). Measuring the amplitude of LFOs (assessed for HbO) over the frontal area, the authors report an increase in LFO amplitude only in migraineurs with a mixed form (i.e. hemiplegic and common migraine attacks). This may indicate that changes in neurovascular reactivity may be quite specic to subgroups of migraine patients. It would be desirable to simultaneously assess changes in systemic LFOs to more clearly differentiate between systemic (Julien et al., 2001) and truly cerebral oscillations. Interestingly a methodologically much weaker approach targeting LFOs used a breath-holding procedure in patients suffering from migraine with aura. Interictally these patients showed a lesser increase in LFO in response to the respiratory challenge selectively in the HbR measurements (Liboni et al., 2009). Investigating cortical spreading depression (CSD) CSD is a neurovascular phenomenon in response to different triggers, which has been long established in experimental animal models (Leao, 1947). Due to its pathophysiological features it has been linked to the aura preceding the headache in migraine with aura and BOLDcontrast fMRI that has provided evidence to support this hypothesis in humans (Hadjikhani et al., 2001). Interestingly early work using NIRS in a rat model has investigated the vascular response and experimental modulations of CSD (Wolf et al., 1996). Since auras are rather short lasting (~30 min) it is not trivial to investigate spontaneous auras in humans, however NIRS seems well suited to supply more data on this scientically highly interesting phenomenon. A short recent report on 8 patients with spontaneous auras describes decreases in tissue oxygenation as measured by NIRS and a decrease in diastolic ow-velocity as measured by TCD (Viola et al., 2010). These ndings are in line with the non-ischemic nature of CSD and their lateralization to the hemisphere contralateral to the symptoms supports the cerebral origin of the NIRS results. Unfortunately the details of the NIRS measurements are not provided, but the study is promising for the further elucidation of the pathophysiology of migraine auras.
Clinical aspects of migraine investigated by NIRS Few studies have studied clinically relevant aspects of migraine. One controversial issue is the enhanced vascular risk of patients suffering from migraine. In a quite large (n = 88) cohort of migraine patients NIRS was tested as a means to detect a patent foramen ovale (PFO) (Liboni et al., 2008). PFO causes microemboli and has been shown to be more common in patients suffering from migraine with aura. The study demonstrates a quite good diagnostic accuracy (84%) when the NIRS procedure is compared to a standard contrastenhanced TCD procedure. The latter identied 48 patients without and 40 patients with PFO. The pathophysiological concept behind the NIRS-parameter (PHbO = (HbO HbR) / HbT) and the criteria by which the resulting pattern was analyzed is somewhat obscure and reduces the credibility of the approach to be useful in a clinical setting. A more recent study explicitly addresses stroke risk in migraine patients. 10 patients were studied interictally and showed a longer delay between the R-wave3 of the electrocardiogram and the pulse wave recorded by NIRS when compared to age matched controls (Viola et al., 2012). Though a differentiation between extra- and intracranial contribution in the NIRS signal is not provided by the NIRS measurements (continuous wave approach) the data may indicate some alteration in cerebrovascular tone in migraineurs. The issue in how far this putative vasoconstriction predicts stroke risk in migraine patients needs further
and more rigorous evaluation. A single small scale study used NIRS to investigate oxygenation changes in response to pain reduction during the migraine attack. Sumatriptan4 was subcutaneously administered to 4 symptomatic patients while 4 controls received a sham injection of saline (Watanabe et al., 2011). The authors report simultaneous decreases in HbO measured by NIRS and skin blood ow as measured by laser Doppler owmetry only in the migraine patients receiving sumatriptan. The design controls for the effects of the injection, however it does not allow differentiation between the overall effect of pain reduction and a specic cerebral vascular response. Since changes measured by NIRS and in skin blood ow were highly correlated both methodologies may rather reect systemic then specically cerebral changes in hemodynamic parameters. An interesting study combined the idea of an altered neurovascular response and prophylactic measures in migraineurs. Building on a pre-established visual stimulation protocol (Grifn et al., 2006), 20 patients underwent various visual stimulations (checkerboard/gratings) (Coutts et al., 2012). When compared to age matched controls, patients showed a vascular response of similar amplitude but with a difference in its time-course (most prominently for the HbO). A second experiment in the same population used individually adapted color lenses, alleviating visual discomfort in the migraineurs. The use of these lters led to a normalization of the response in the patient group. The study elegantly shows how beyond a direct clinical target, therapeutic measures may be evaluated by NIRS with regard to the underlying pathophysiology. The idea of a general, interictal change in neurovascular coupling also in response to physiological stimulation has been challenged. A cognitive task taxing inhibitory control5 elicited no differences in the frontal cortex response pattern in 12 migraine patients (without aura) when compared to age matched controls (Schytz et al., 2010). Neither did behavioral measures indicate any frontal dysfunction in the patients. Interestingly the response pattern (HbO and HbR) reported in both groups is not the standard NIRS-response (HbO and HbR) expected over an activated area. Additionally potential changes in neuronal excitability need to be respected when functional stimulation is used to demonstrate changes in neurovascular response patterns in patients with migraine. In fact in the visual cortex the issue of hyper-/hypo- or normo-excitability remains controversial. A number of studies have shown a lack in habituation of the visually evoked potential (VEP) possibly indicating the lack in inhibition in migraine (Afra et al., 1998). Habituation may normalize during the attack (Judit et al., 2000) and contrary to this decit in common migraine there may be an increased habituation of the VEP in familial hemiplegic migraine (Hansen et al., 2011). Therefore the claim of an altered neurovascular coupling in migraine patients needs to respect the fact that vascular changes may simply reect an altered neuronal excitation/inhibition balance which is reected in altered vascular response amplitudes (Obrig et al., 2002). To sum up, studies targeting pathophysiological aspects of migraine may contribute to a deeper understanding of mechanisms relating to the changes in neurovascular coupling in this condition. Combined approaches with EEG and TCD and careful monitoring of systemic changes in hemodynamics may enhance the validity of such studies. With regard to a clinical use of NIRS in this eld a clear indication for differential diagnosis or therapy guidance has not been demonstrated. Since therapy mostly supplied in out-patient settings is guided by the response to medication the potential use of NIRS may be conned to diagnostic procedures warranted to exclude symptomatic headache.
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3 The R-wave is the most prominent deection in the electrocardiogram and is temporally correlated to the contraction of the ventricles.
4 Sumatriptan is a serotonin-antagonist highly effective in migraine and clusterheadache. 5 The Stroop-paradigm used in the study relies on the strong tendency in literate adults to read rather than name the color of a color-word. Thus when e.g. GREEN is printed in red letters the naming of the letter-color requires cognitive control by suppressing the tendency to read the word aloud.
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Functional imaging of the diseased brain Technology-based methods used in neurology mostly target disease processes. Imaging delineates the structural or metabolic abnormality supplemented by functional methods such as EEG which may yield pathognomonic graphoelements indicating epileptic activity. However, (ab)normal reactions to standardized stimuli or tasks constitute the backbone of the neurological status (e.g. pin-prick sensation, or pointing-tasks). In clinical routine, evoked potentials (EPs), testing the electrophysiological response to standardized visual, auditory or somatosensory stimulation, are based on the same rationale. Extending this approach to functional imaging in neurological patients opens a whole new perspective of technology-based diagnostics. Tentatively three major targets can be identied: (i) ab/normal activation patterns 6 allow for differentiation of clinically similar conditions; (ii) essential areas for endangered brain functions can be delineated e.g. prior to brain surgery and (iii) neurorehabilitation may be supervised and potentially even guided by imaging functional plasticity in the lesioned brain.
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Disease differentiation by cortical activation in response to cognitive tasks This approach has been tested in a number of studies on different dementia types. Studies usually compared healthy controls to patients with probable vascular or Alzheimer's dementia (AD). An early study using a calculation task showed an inverted response pattern (HbO, HbT) not only in AD patients when compared to normal controls but also patients suffering from depression (Hock et al., 1996). In response to a verbal uency task AD patients (n = 12) showed a less lateralized response when compared to healthy controls (Fallgatter et al., 1997). An imaging approach using the same task was applied in healthy controls, mild cognitive impairment (MCI) and AD patients. The results conrm differences in the vascular response magnitude between controls and patients. Importantly these differences show a frontoparietal distribution in AD patients (n = 15) while in MCI (n = 15) they were restricted to the right parietal region (Arai et al., 2006). Extending the work to vascular dementia and its precursors, patients with microangiopathy were tested with a modied Stroop-task, assessing inhibitory control (see footnote 3 above). Beyond the decrease in frontal activation, neurovascular coupling is shown to be altered in this patient group (Schroeter et al., 2007). This change in neurovascular coupling has been recently substantiated by an elegant approach using simultaneous fMRI and NIRS. While BOLD-contrast, HbO and HbT and also the derived estimate for cerebral blood ow (CBF) showed smaller amplitudes in response to a motor task, the derived estimate for the oxygen extraction fraction (OEF) increased in patients with vascular dementia (n = 6) when compared to healthy controls (Tak et al., 2011). The studies exemplify that NIRS can contribute to identify differences in cortical processing of motor and cognitive tasks in different dementia types. As yet the results allow describing pathophysiological alterations on a group level. This may not be an approach easily adopted in clinical practice but is an important and valuable contribution to this rapidly evolving eld.
In healthy volunteers the typical NIRS response pattern over an activated area is an increase in HbO and a smaller decrease in HbR yielding an increase in HbT. This results from the fact that in an activated area the increase in regional cerebral blood ow (rCBF) overcompensates the increase in regional cerebral metabolic rate of oxygen (rCRMO2) (FOX, P. T. & RAICHLE, M. E. 1986. Focal physiological uncoupling of cerebral blood ow and oxidative metabolism during somatosensory stimulation in human subjects. Proc Natl Acad Sci U S A, 83, 1140-4.). The increase in ow velocity leads to a more rapid washout of HbR. This decrease in HbR is the most relevant determinant of BOLD-contrast increases in functional MRI. Since regional cerebral blood volume (rCBV) increases in the activated area, NIRS is expected to show an increase in HbT (for a more detailed coverage of the topic see: Steinbrink, J., Villringer, A., Kempf, F., Haux, D., Boden, S. & Obrig, H. 2006. Illuminating the BOLD signal: combined fMRI fNIRS studies. Magn Reson Imaging, 24, 495505.).
Localization of eloquent cortical areas NIRS has been used for functional localization of eloquent cortical areas in the diseased brain. The assessment of language lateralization prior to surgery of temporal lobe epilepsy has been reviewed in Presurgical mapping of language functions section (also see (Ota et al., 2011)). Similar mapping is often performed prior to neurosurgery of brain tumors. Notably BOLD-contrast fMRI in these patients may erroneously suggest reorganization due to alterations in neurovascular coupling in the vicinity of the tumor (Ulmer et al., 2003, 2004). This is also related to angiogenesis in the tumor increasing with tumor grade (for an interesting example of intraoperative NIRS see (Asgari et al., 2003)). Combined NIRSfMRI studies have addressed such vascular response alterations. In 12 patients with different types of brain tumors a unilateral hand grasping task was investigated with NIRS and BOLD-contrast fMRI. The localization of the tumor with respect to the primary motor cortex was veried intraoperatively (Fujiwara et al., 2004). The most relevant nding is that HbO and HbT consistently increased on the affected and the unaffected side. Conversely HbR showed a variable response direction: on the unaffected side a consistent decrease was demonstrated, indicating a typical NIRS response over an activated area. However, on the side affected by the brain tumor HbR increased in 5 patients. Since HbR changes inversely correlate with BOLD-contrast (Kleinschmidt et al., 1996) the respective areas would not be considered activated according to BOLD-contrast fMRI, though NIRS demonstrates an increase in HbT and HbO. This endows NIRS with the potential to supplement pre-surgical functional imaging in patients with brain tumors. Another report highlights the relevance of alterations in the vascular response when longitudinal assessment is performed (Murata et al., 2004). In a case report the response to unilateral motor performance showed a decrease in HbR prior to tumor excision, while 2 days after the operation HbR increased and showed no changes on day 22 post-op. Alterations in vascular response were paralleled by the BOLD-contrast results. Interestingly the HbO and HbT increases remained stable at all three assessments. In patients with ischemic stroke and variable degrees of carotid artery stenosis similar alterations of the response pattern have been described (Murata et al., 2002, 2006). It has also been demonstrated that revascularization leads to a normalization of the response (Nakamura et al., 2010). While these results suggest primarily altered vascular reactivity another report highlights the complex interplay between an altered neurovascular coupling and pathological brain activity, which may both elicit increases in HbR (see Oxygenation response to epileptic activity section). Prior to surgery subdural grid electrodes for presurgical mapping were used to apply different electrical stimulations to the motor area close to the tumor (Hoshino et al., 2005). While 5 Hz stimulation yielded a typical NIRS response (HbO, HbR, HbT) the stimulation at 50 Hz inverted the response pattern of HbR (HbO, HbR, HbT). Notably differences in cortical oxygenation patterns may also result from changes in cortico-subcortical loops. This was demonstrated in patients receiving deep brain stimulation (DBS) for Parkinson's disease (n = 5) and severe essential tremor (n = 1) (Murata et al., 2000; Sakatani et al., 1999). The oxygenation over the frontal lobe (bilateral probes) showed differential response patterns depending on stimulation site. Thalamic nucleus ventralis intermedius (VIM) stimulation resulted in a typical activation pattern (HbO, HbR, HbT) while stimulation of the globus pallidus internus (GPi) resulted in a decrease in all three parameters (HbO, HbR, HbT). Though the direct clinical relevance may be limited, the assessment of functional cortical changes elicited by DBS may be a rewarding application of NIRS in this population. The potential of NIRS may lie in a less demanding and long term monitoring of changes which have been recently also investigated by fMRI (Jech et al., 2012; Kahan et al., 2012). In sum NIRS does not supply sufcient spatial resolution to allow for concise preoperative mapping of cortical functions, however, it may supply relevant supplementary information to assess altered vascular
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response patterns in the vicinity of diseased brain tissue and may allow to better understand reorganization in long term DBS. Investigating cortical plasticity in neurorehabilitation Respecting the above discussed alterations of neurovascular coupling in the diseased brain, cerebral activation patterns during rehabilitation can be addressed by NIRS. Most of the existing literature deals with post-stroke rehabilitation. In this eld an altered cortical activation pattern during gait with enhanced premotor recruitment has been demonstrated (Mihara et al., 2007). Additionally a 2-month rehabilitation changed the degree of lateralization of the NIRS response in the premotor cortex (Miyai et al., 2003). Therapeutic interventions were investigated in moderate and severely paretic stroke patients (Miyai et al., 2002, 2006) making gait one of the elds in neurorehabilitation most intensively studied by NIRS. A very recent study investigated cycling, another regularly used therapeutic intervention in hemiparesis affecting the leg. Besides a slight difference in the sensorimotor cortex for active versus passive cycling, feedback on speed-control enhanced premotor activation for the active condition. This suggests that NIRS may also be sensitive to more cognitive aspects of locomotion (Lin et al., 2012). To not reiterate the reviews which have previously covered the eld (Arenth et al., 2007; Obrig and Steinbrink, 2011) we suggest that two relevant aspects of functional reorganization can be supplied by NIRS: (i) recruitment of additional cortical areas in response to tasks not requiring extensive cognitive control in healthy controls; (ii) a lateralization index for lateralized brain functions like unilateral motor control and language. Such altered brain patterns most probably indicate compensatory processing efforts and normalization of such patterns may correlate with successful rehabilitation. The transfer from these exciting observational studies into an option to predict outcome or even guide therapeutic effort will be a challenge to be addressed in concert with other techniques assessing plasticity in the lesioned brain. Another eld with a potential in neurorehabilitation is the development of neuro-feedback systems and brain computer interfaces (BCI). Recent approaches have increasingly used NIRS for neurofeedback (Mihara et al., 2012) or incorporated NIRS as an additional means to classify brain activation patterns (Fazli et al., 2012). A case report on a patient suffering from amyotrophic lateral sclerosis (ALS) demonstrated focal oxygenation changes in response to tasks targeting cognitive function (motor imagery, covert word generation and singing). This was considered an indicator of cognitive functioning in the patient who was in a functional locked-in state due to the loss of any voluntary muscle activity (Fuchino et al., 2008). The intriguing avenue of BCIresearch (Pfurtscheller et al., 2010) may be of direct relevance in such patients to allow for communication and command over prostheses tailored to individual demands. In the eld of neurorehabilitation the major advantage of NIRS lies in the option to gather information on cortical processing in real-life scenarios and during the therapeutic intervention. To fully explore the versatility of NIRS, portability is crucial. A number of groups have successfully developed wearable devices (Atsumori et al., 2009) including solutions allowing simultaneous EEG recording (Lareau et al., 2011). Beyond very exciting research questions a routine application in neurorehabilitation depends on the demonstration that activation patterns correlate with outcome. This will be a task requiring much closer cooperation between neuroscientists and clinicians but may critically depend on integrating therapists into the research effort.
in-patient diagnosis in neurology and in most Western countries subacute treatment on specialized stroke-units is supplied to an increasing percentage of stroke patients (e.g. 15% in 2005 to 50% in 2010 in Germany (Nimptsch and Mansky, 2012)). The proof of principle for the feasibility of long term NIRS-monitoring and the correlation with some standard techniques has been supplied and can build on experience from studies in intensive-care- and intraoperative settings. What is now necessary is a large-scale, most probably multi-center study which correlates NIRS results in subacute stroke monitoring with outcome. Here the choice of the parameter (perfusion vs. oxygenation parameters), the technique (time-resolved, multidistance, etc.) and the outcome parameter (e.g. neurological deterioration, length of hospitalization) may be secondary to the need for a standardized procedure. If the protocol respects both, technical state of the art and clinical requirements I am condent that a correlation can be demonstrated. This would substantiate a claim to include NIRS into the stroke-unit protocols, in turn rendering a commercial basis for future technological advance. The second most promising application I consider to be is epilepsy. I see no reason, why the additional information supplied by (wearable) NIRSEEG devices should not help to enhance sensitivity to seizure detection and localization. The research in this eld in fact seems more advanced than in stroke, but a drawback is that the number of patients undergoing long-term monitoring is small. Additionally evaluation prior to surgery often justies invasive intracranial recordings, which can be deemed to always excel non-invasive procedures in sensitivity and specicity. The demonstration of an indication for combined NIRSEEG monitoring in the special situation of long-term seizure monitoring may, however, be the key to advocate such an inexpensive neurovascular coupling assessment also in other elds of neurology. A third quite large eld of application may be functional activation studies in chronic neurologic patients and dementia. This is a scientic eld in which the clinical setting often prevents the use of other neuroimaging methods. Exciting as this eld may be, we need to acknowledge that therapeutically relevant translation between a brain activation pattern and rehabilitative strategy is a challenge not yet met by any neuroscientific approach. However, this research eld will strongly prot from the large number of studies in which functional NIRS has been used for scientically motivated neuroimaging of healthy volunteers. In this latter eld the methodology has clearly asserted itself in the arena of neuroimaging tools and has ironically delivered on a promise much less envisaged during the early days of NIRS.
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Conclusion and perspectives Based on the above and the many not explicitly reviewed studies we may ask if and how NIRS will deliver its promise in neurology. This in essence would require the proof that beyond feasibility there is an indication for its routine use. In my opinion sub-acute stroke monitoring meets the requirements: stroke is the most common
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YNIMG-10279; No.

of pages: 11; 4C: 2

Contents lists available at SciVerse ScienceDirect

NIRS in clinical neurology a promising tool?

H. Obrig / NeuroImage xxx (2013) xxxxxx

t1:1 t1:2 t1:3

Blood ow index Fluorescence after injection

Event related optical signals fast optical changes

MRI Cerebrovascular disease Epileptic disorders

PET/ SPECT (+)

Parkinsons disease Multiple sclerosis

CNS infections Functional activation in brain disease

Vascular dementia, cognitive function

Cortical activation in DBS

Cognitive function /fatigue

Preoperative function localization

Neuro-intensive care monitoring

Assessement in natural setting; plasticity in response to rehab.

Severe brain injury

H. Obrig / NeuroImage xxx (2013) xxxxxx

Stroke and cerebrovascular disease

H. Obrig / NeuroImage xxx (2013) xxxxxx

H. Obrig / NeuroImage xxx (2013) xxxxxx

H. Obrig / NeuroImage xxx (2013) xxxxxx

H. Obrig / NeuroImage xxx (2013) xxxxxx

H. Obrig / NeuroImage xxx (2013) xxxxxx

H. Obrig / NeuroImage xxx (2013) xxxxxx

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