Hellmuth Obrig

Beyond the Visible—Imaging the Human Brain with Light:

Optical approaches to investigate cerebral function and metabolism have long been applied in invasive studies. From the neuron cultured in vitro to the exposed cortex in the human during neurosurgical procedures, high spatial resolution can be reached and several processes such as membrane potential, cell swelling, metabolism of mitochondrial chromophores, and vascular response can be monitored, depending on the respective preparation. The authors focus on an extension of optical methods to the noninvasive application in the human. Starting with the pioneering work of Jöbsis 25 years ago, near-infrared spectroscopy (NIRS) has been used to investigate functional activation of the human cerebral cortex. Recently, several groups have started to use imaging systems that allow the generation of images of a larger area of the subjects head and, thereby, the production of maps of cortical oxygenation changes. Such images have a much lower spatial resolution compared with the invasively obtained optical images. The noninvasive NIRS images, however, can be obtained in undemanding set-ups that can be easily combined with other functional methods, in particular EEG. Moreover, NIRS is applicable to bedside use. The authors briefly review some of the abundant literature on intrinsic optical signals and the NIRS imaging studies of the past few years. The weaknesses and strengths of the approach are critically discussed. The authors conclude that NIRS imaging has two major advantages: it can address issues concerning neurovascular coupling in the human adult and can extend functional imaging approaches to the investigation of the diseased brain.

Correlates of alpha rhythm in functional magnetic resonance imaging and near infrared spectroscopy

We used simultaneous electroencephalogram-functional magnetic resonance imaging (EEG-fMRI) and EEG-near infrared spectroscopy (NIRS) to investigate whether changes of the posterior EEG alpha rhythm are correlated with changes in local cerebral blood oxygenation. Cross-correlation analysis of slowly fluctuating, spontaneous rhythms in the EEG and the fMRI signal revealed an inverse relationship between alpha activity and the fMRI-blood oxygen level dependent signal in the occipital cortex. The NIRS-EEG measurements demonstrated a positive cross-correlation in occipital cortex between alpha activity and concentration changes of deoxygenated hemoglobin, which peaked at a relative shift of about 8 s. Our data suggest that alpha activity in the occipital cortex is associated with metabolic deactivation. Mapping of spontaneously synchronizing distributed neuronal networks is thus shown to be feasible.

Spontaneous low frequency oscillations of cerebral hemodynamics and metabolism in human adults.

UNLABELLED We investigated slow spontaneous oscillations in cerebral oxygenation in the human adults visual cortex. The rationale was (1) to demonstrate their detectability by near infrared spectroscopy (NIRS); (2) to analyze the spectral power of as well as the phase relationship between the different NIRS parameters (oxygenated and deoxygenated hemoglobin and cytochrome-oxidase; oxy-Hb/deoxy-Hb/Cyt-ox). Also (3) influences of functional stimulation and hypercapnia on power and phase shifts were investigated. The results show that-in line with the literature-low frequency oscillations (LFO) centred around 0.1 s(-1) and even slower oscillations at about 0.04 s(-1) (very low frequency, VLFO) can be distinguished. Their respective power differs between oxy-Hb, deoxy-Hb, and Cyt-ox. Either frequency (LFO and VLFO) is altered in magnitude by functional stimulation of the cortical area examined. Also we find a change of the phase shift between the vascular parameters (oxy-Hb, tot-Hb) and the metabolic parameter (Cyt-ox) evoked by the stimulation. It is shown that hypercapnia attenuates the LFO in oxy-Hb and deoxy-Hb. CONCLUSIONS (1) spontaneous vascular and metabolic LFO and VLFO can be reproducibly detected by NIRS in the human adult. (2) Their spectral characteristics and their response to hypercapnia are in line with those described in exposed cortex (for review see (Hudetz et al., 1998)) and correspond to findings with transcranial doppler sonography (TCD) (Diehl et al., 1995) and fMRI (Biswal et al., 1997). (3) The magnitude of and phase relation between NIRS-parameters at the LFO may allow for a local noninvasive assessment of autoregulatory mechanisms in the adult brain.

Simultaneous recording of cerebral blood oxygenation changes during human brain activation by magnetic resonance imaging and near-infrared spectroscopy

Changes in cerebral blood oxygenation due to functional activation of the primary sensorimotor cortex during a unilateral finger opposition task were simultaneously mapped by deoxyhemoglobin-sensitive magnetic resonance imaging (MRI) and monitored by near-infrared spectroscopy (NIRS). Activation foci along the contralateral central sulcus displayed task-associated increases in MRI signal intensity, indicating a concomitant decrease of the focal concentration of deoxyhemoglobin. This interpretation was confirmed by simultaneous reductions in deoxyhemoglobin measured optically. Since observation of the latter effect required exact spatial matching of the MRI-detected activation foci and position of the fiber optic bundles (“optodes”) used for transmitting and receiving light, it may be concluded that optical recordings of changes in deoxyhemoglobin during functional challenge probe only a restricted brain tissue region. While deoxyhemoglobin responses seen by NIRS were smaller for ipsi- than for contralateral finger movements, task-related increases in oxyhemoglobin were rather similar between both conditions and, thus, seem to be less specific. Furthermore, no consistent changes were obtained for total hemoglobin during task performance, possibly due to the short timing of the repetitive protocol. In general, results underline, in humans, the hitherto assumed signal physiology for functional brain mapping by oxygenation-sensitive MRI and allow assessment of both constraints and practicability of functional studies by NIRS.

Noninvasive Functional Imaging of Human Brain Using Light

Analysis of photon transit time for low-power light passing into the head, and through both skull and brain, of human subjects allowed for tomographic imaging of cerebral hemoglobin oxygenation based on photon diffusion theory. In healthy adults, imaging of changes in hemoglobin saturation during hand movement revealed focal, contralateral increases in motor cortex oxygenation with spatial agreement to activation maps determined by functional magnetic resonance imaging; in ill neonates, imaging of hemoglobin saturation revealed focal regions of low oxygenation after acute stroke, with spatial overlap to injury location determined by computed tomography scan. Because such slow optical changes occur over seconds and co-localize with magnetic resonance imaging vascular signals whereas fast activation-related optical changes occur over milliseconds and co-localize with EEG electrical signals, optical methods offer a single modality for exploring the spatio-temporal relationship between electrical and vascular responses in the brain in vivo, as well as for mapping cortical activation and oxygenation at the bedside in real-time for clinical monitoring.

Determining changes in NIR absorption using a layered model of the human head

A theoretical approach is presented to determine absorption changes in different compartments of a layered structure from distributions of times of flight of photons. In addition resulting changes in spatial profiles of time-integrated intensity and mean time of flight are calculated. The capability of a single-distance, time-domain method to determine absorption changes with depth resolution is tested on a layered phantom. We apply this method to in vivo measurements on the human head (motor stimulation, Valsalva manoeuvre) and introduce a small-sized time-domain experimental set-up suitable for bedside monitoring.

Time-resolved multidistance near-infrared spectroscopy of the adult head: intracerebral and extracerebral absorption changes from moments of distribution of times of flight of photons

We report on multidistance time-resolved diffuse reflectance spectroscopy of the head of a healthy adult after intravenous administration of a bolus of indocyanine green. Intracerebral and extracerebral changes in absorption are deduced from moments (integral, mean time of flight, and variance) of the distributions of times of flight of photons (DTOFs), recorded simultaneously at four different source-detector separations. We calculate the sensitivity factors converting depth-dependent changes in absorption into changes of moments of DTOFs by Monte Carlo simulations by using a layered model of the head. We validate our method by analyzing moments of DTOFs simulated for the assumed changes in absorption in different layers of the head model.

Sensitivity of Newborn Auditory Cortex to the Temporal Structure of Sounds

Understanding the rapidly developing building blocks of speech perception in infancy requires a close look at the auditory prerequisites for speech sound processing. Pioneering studies have demonstrated that hemispheric specializations for language processing are already present in early infancy. However, whether these computational asymmetries can be considered a function of linguistic attributes or a consequence of basic temporal signal properties is under debate. Several studies in adults link hemispheric specialization for certain aspects of speech perception to an asymmetry in cortical tuning and reveal that the auditory cortices are differentially sensitive to spectrotemporal features of speech. Applying concurrent electrophysiological (EEG) and hemodynamic (near-infrared spectroscopy) recording to newborn infants listening to temporally structured nonspeech signals, we provide evidence that newborns process nonlinguistic acoustic stimuli that share critical temporal features with language in a differential manner. The newborn brain preferentially processes temporal modulations especially relevant for phoneme perception. In line with multi-time-resolution conceptions, modulations on the time scale of phonemes elicit strong bilateral cortical responses. Our data furthermore suggest that responses to slow acoustic modulations are lateralized to the right hemisphere. That is, the newborn auditory cortex is sensitive to the temporal structure of the auditory input and shows an emerging tendency for functional asymmetry. Hence, our findings support the hypothesis that development of speech perception is linked to basic capacities in auditory processing. From birth, the brain is tuned to critical temporal properties of linguistic signals to facilitate one of the major needs of humans: to communicate.

Bed-side assessment of cerebral perfusion in stroke patients based on optical monitoring of a dye bolus by time-resolved diffuse reflectance

We present a minimally invasive optical method, that is, multi-channel time-domain diffuse near-infrared reflectometry of the head to assess cerebral blood perfusion that is applicable at the bed-side and repetitively at short intervals. Following intravenous injection of an ICG bolus, its transit through intra- and extracerebral tissue is monitored based on changes in moments of distributions of times of flight of photons, recorded with a 4-channel instrument simultaneously on both hemispheres. In healthy volunteers, we found that variance of distributions of times of flight of photons is well suited to assess latency and initial slope of the increase in absorption of intracerebral tissue due to the bolus. We successfully applied our method in two patients demonstrating a reversible cerebral perfusion deficit in an ischemic stroke patient who was treated by thrombolysis and in another patient with a permanent impaired unilateral perfusion due to ipsilateral internal carotid artery occlusion. In either case, we observed a difference in bolus transit time between the hemispheres. In the stroke patient, this difference resolved when re-evaluated 1 day after thrombolysis. The study demonstrates the necessity of a technique with sub-nanosecond time resolution to allow for depth discrimination if clinical perfusion monitoring of cerebrovascular diseases is addressed by optical methods.

A wearable multi-channel fNIRS system for brain imaging in freely moving subjects.

Functional near infrared spectroscopy (fNIRS) is a versatile neuroimaging tool with an increasing acceptance in the neuroimaging community. While often lauded for its portability, most of the fNIRS setups employed in neuroscientific research still impose usage in a laboratory environment. We present a wearable, multi-channel fNIRS imaging system for functional brain imaging in unrestrained settings. The system operates without optical fiber bundles, using eight dual wavelength light emitting diodes and eight electro-optical sensors, which can be placed freely on the subjects head for direct illumination and detection. Its performance is tested on N=8 subjects in a motor execution paradigm performed under three different exercising conditions: (i) during outdoor bicycle riding, (ii) while pedaling on a stationary training bicycle, and (iii) sitting still on the training bicycle. Following left hand gripping, we observe a significant decrease in the deoxyhemoglobin concentration over the contralateral motor cortex in all three conditions. A significant task-related ΔHbO2 increase was seen for the non-pedaling condition. Although the gross movements involved in pedaling and steering a bike induced more motion artifacts than carrying out the same task while sitting still, we found no significant differences in the shape or amplitude of the HbR time courses for outdoor or indoor cycling and sitting still. We demonstrate the general feasibility of using wearable multi-channel NIRS during strenuous exercise in natural, unrestrained settings and discuss the origins and effects of data artifacts. We provide quantitative guidelines for taking condition-dependent signal quality into account to allow the comparison of data across various levels of physical exercise. To the best of our knowledge, this is the first demonstration of functional NIRS brain imaging during an outdoor activity in a real life situation in humans.