Michele L. Pierro

Low-Frequency Spontaneous Oscillations of Cerebral Hemodynamics Investigated With Near-Infrared Spectroscopy: A Review

Hemodynamic low-frequency oscillations (LFOs), in the range 0.01-0.1 Hz, are intriguing, yet elusive phenomena, which occur spontaneously in the vascular system. More than 150 years have passed since their discovery, but the cellular mechanisms at their origin and their physiological implications have yet to be unraveled. The study of LF hemodynamic oscillations is considered to be relevant in areas of brain research such as cerebral autoregulation, functional and effective connectivity, and their related pathologies. These research areas have been traditionally investigated by transcranial Doppler (autoregulation) and functional MRI [functional connectivity (FC)]. The purpose of this paper is to review the work that has been done in this area using near-infrared spectroscopy (NIRS), which is a noninvasive technique used for monitoring and imaging tissue hemodynamics. NIRS has the advantage of being sensitive to both oxy- and deoxyhemoglobin concentration changes. Therefore, not only can it be used in autoregulation and FC studies (for broader populations of subjects), it can also help understand the local interplay between vascular and metabolic parameters. Finally, we present a novel approach to the study of LFOs and to the physiological interpretation of the amplitude and relative phase of oscillatory components of oxy- and deoxyhemoglobin concentrations.

Practical steps for applying a new dynamic model to near-infrared spectroscopy measurements of hemodynamic oscillations and transient changes: implications for cerebrovascular and functional brain studies.

RATIONALE AND OBJECTIVES Perturbations in cerebral blood volume (CBV), blood flow (CBF), and metabolic rate of oxygen (CMRO2) lead to associated changes in tissue concentrations of oxy- and deoxy-hemoglobin (ΔO and ΔD), which can be measured by near-infrared spectroscopy (NIRS). A novel hemodynamic model has been introduced to relate physiological perturbations and measured quantities. We seek to use this model to determine functional traces of cbv(t) and cbf(t) - cmro2(t) from time-varying NIRS data, and cerebrovascular physiological parameters from oscillatory NIRS data (lowercase letters denote the relative changes in CBV, CBF, and CMRO2 with respect to baseline). Such a practical implementation of a quantitative hemodynamic model is an important step toward the clinical translation of NIRS. MATERIALS AND METHODS In the time domain, we have simulated O(t) and D(t) traces induced by cerebral activation. In the frequency domain, we have performed a new analysis of frequency-resolved measurements of cerebral hemodynamic oscillations during a paced breathing paradigm. RESULTS We have demonstrated that cbv(t) and cbf(t) - cmro2(t) can be reliably obtained from O(t) and D(t) using the model, and that the functional NIRS signals are delayed with respect to cbf(t) - cmro2(t) as a result of the blood transit time in the microvasculature. In the frequency domain, we have identified physiological parameters (e.g., blood transit time, cutoff frequency of autoregulation) that can be measured by frequency-resolved measurements of hemodynamic oscillations. CONCLUSIONS The ability to perform noninvasive measurements of cerebrovascular parameters has far-reaching clinical implications. Functional brain studies rely on measurements of CBV, CBF, and CMRO2, whereas the diagnosis and assessment of neurovascular disorders, traumatic brain injury, and stroke would benefit from measurements of local cerebral hemodynamics and autoregulation.

Phase-amplitude investigation of spontaneous low-frequency oscillations of cerebral hemodynamics with near-infrared spectroscopy: A sleep study in human subjects

We have investigated the amplitude and phase of spontaneous low-frequency oscillations (LFOs) of the cerebral deoxy- and oxy-hemoglobin concentrations ([Hb] and [HbO]) in a human sleep study using near-infrared spectroscopy (NIRS). Amplitude and phase analysis was based on the analytic signal method, and phasor algebra was used to decompose measured [Hb] and [HbO] oscillations into cerebral blood volume (CBV) and flow velocity (CBFV) oscillations. We have found a greater phase lead of [Hb] vs. [HbO] LFOs during non-REM sleep with respect to the awake and REM sleep states (maximum increase in [Hb] phase lead: ~π/2). Furthermore, during non-REM sleep, the amplitudes of [Hb] and [HbO] LFOs are suppressed with respect to the awake and REM sleep states (maximum amplitude decrease: 87%). The associated cerebral blood volume and flow velocity oscillations are found to maintain their relative phase difference during sleep, whereas their amplitudes are attenuated during non-REM sleep. These results show the potential of phase-amplitude analysis of [Hb] and [HbO] oscillations measured by NIRS in the investigation of hemodynamics associated with cerebral physiology, activation, and pathological conditions.

Validation of a novel hemodynamic model for coherent hemodynamics spectroscopy (CHS) and functional brain studies with fNIRS and fMRI

We report an experimental validation and applications of the new hemodynamic model presented in the companion article (Fantini, 2014-this issue) both in the frequency domain and in the time domain. In the frequency domain, we have performed diffuse optical measurements for coherent hemodynamics spectroscopy (CHS) on the brain and calf muscle of human subjects, showing that the hemodynamic model predictions (both in terms of spectral shapes and absolute spectral values) are confirmed experimentally. We show how the quantitative analysis based on the new model allows for autoregulation measurements from brain data, and provides an analytical description of near-infrared spiroximetry from muscle data. In the time domain, we have used data from the literature to perform a comparison between brain activation signals measured with functional near-infrared spectroscopy (fNIRS) or with blood oxygenation level dependent (BOLD) fMRI, and the corresponding signals predicted by the new model. This comparison shows an excellent agreement between the model predictions and the reported fNIRS and BOLD fMRI signals. This new hemodynamic model provides a valuable tool for brain studies with hemodynamic-based techniques.

Reduced speed of microvascular blood flow in hemodialysis patients versus healthy controls: a coherent hemodynamics spectroscopy study

Abstract. We present a pilot clinical application of coherent hemodynamics spectroscopy (CHS), a technique to investigate cerebral hemodynamics at the microcirculatory level. CHS relies on frequency-resolved measurements of induced cerebral hemodynamic oscillations that are measured with near-infrared spectroscopy (NIRS) and analyzed with a hemodynamic model. We have used cyclic inflation (200 mmHg) and deflation of a pneumatic cuff placed around the subject’s thigh at seven frequencies in the range of 0.03 to 0.17 Hz to generate CHS spectra and to obtain a set of physiological parameters that include the blood transit times in the cerebral microcirculation, the cutoff frequency for cerebral autoregulation, and blood volume ratios across the three different compartments. We have investigated five hemodialysis patients, during the hemodialysis procedure, and six healthy subjects. We have found that the blood transit time in the cerebral microcirculation is significantly longer in hemodialysis patients with respect to healthy subjects. No significant differences were observed between the two groups in terms of autoregulation efficiency and blood volume ratios. The demonstration of the applicability of CHS in a clinical setting and its sensitivity to the highly important cerebral microcirculation may open up new opportunities for NIRS applications in research and in medical diagnostics and monitoring.

PHASE DIFFERENCE BETWEEN LOW-FREQUENCY OSCILLATIONS OF CEREBRAL DEOXY- AND OXY-HEMOGLOBIN CONCENTRATIONS DURING A MENTAL TASK

Hemodynamic low-frequency (~0.1 Hz) spontaneous oscillations as detected in the brain by near-infrared spectroscopy have potential applications in the study of brain activation, cerebral autoregulation, and functional connectivity. In this work, we have investigated the phase lag between oscillations of cerebral deoxy- and oxy-hemoglobin concentrations in the frequency range 0.05-0.10 Hz in a human subject during a mental workload task. We have obtained a measure of such phase lag using two different methods: (1) phase synchronization analysis as used in the theory of chaotic oscillators and (2) a novel cross-correlation phasor approach. The two methods yielded comparable initial results of a larger phase lag between low-frequency oscillations of deoxy- and oxy-hemoglobin concentrations during mental workload with respect to a control, rest condition.

Phase characterization of oscillatory components of the cerebral concentrations of oxy-hemoglobin and deoxy-hemoglobin

We present a study of the relative phase of oscillations of cerebral oxy- and deoxy-hemoglobin concentrations in the low-frequency range, namely 0.04-0.12 Hz. We have characterized the potential contributions of noise to the measured phase distributions, and we have performed phase measurements on the brain of a human subject at rest, and on the brain of a human subject during stage I sleep. While phase distributions of pseudo hemodynamic oscillations generated from noise (obtained by applying to two independent sets of random numbers the same linear transformation that converts absorption coefficients at 690 and 830 nm into concentrations of oxy- and deoxy-hemoglobin) are peaked at 180º, those associated with real hemodynamic changes can be peaked around any value depending on the underlying physiology and hemodynamics. In particular, preliminary results reported here indicate a greater phase lead of deoxy-hemoglobin vs. oxy-hemoglobin low-frequency oscillations during stage I sleep (82º ± 55º) than while the subject is awake (19º ± 58º).

COHERENT HEMODYNAMICS SPECTROSCOPY BASED ON A PACED BREATHING PARADIGM — REVISITED

A novel hemodynamic model has been recently introduced, which provides analytical relationships between the changes in cerebral blood volume (CBV), cerebral blood flow (CBF), and cerebral metabolic rate of oxygen (CMRO2), and associated changes in the tissue concentrations of oxy- and deoxy-hemoglobin (ΔO and ΔD) measured with near-infrared spectroscopy (NIRS) [S. Fantini, Neuroimage85, 202–221 (2014)]. This novel model can be applied to measurements of the amplitude and phase of induced hemodynamic oscillations as a function of the frequency of oscillation, realizing the novel technique of coherent hemodynamics spectroscopy (CHS) [S. Fantini, Neuroimage85, 202–221 (2014); M. L. Pierro et al., Neuroimage85, 222–233 (2014)]. In a previous work, we have demonstrated an in vivo application of CHS on human subjects during paced breathing [M. L. Pierro et al., Neuroimage85, 222–233 (2014)]. In this work, we present a new analysis of the collected data during paced breathing based on a slightly revised formulation of the hemodynamic model and an efficient fitting procedure. While we have initially treated all 12 model parameters as independent, we have found that, in this new implementation of CHS, the number of independent parameters is eight. In this article, we identify the eight independent model parameters and we show that our previous results are consistent with the new formulation, once the individual parameters of the earlier analysis are combined into the new set of independent parameters.

Applications of a novel hemodynamic model to functional brain studies with fNIRS and fMRI

We report time-domain applications of a new hemodynamic model by Fantini [1] that yields analytic expressions for signals that are measurable with hemodynamic-based neuroimaging techniques such as functional near-infrared spectroscopy (fNIRS) and functional magnetic resonance imaging (fMRI). We show how the model can be used to predict the perturbations in cerebral blood volume (CBV), blood flow (CBF), and metabolic rate of oxygen (CMRO2) that account for the initial dip and post-stimulus undershoot that have been reported in the fMRI and fNIRS literature. Furthermore, we have used data from the literature to perform a comparison between measured fNIRS and fMRI signals and the corresponding signals predicted by the new hemodynamic model. Results showed an excellent agreement between the model predictions and the reported measured data.

Relative phase of oscillations of cerebral oxy-hemoglobin and deoxy-hemoglobin concentrations during sleep

We present a near-infrared spectroscopy study of the instantaneous phase difference between spontaneous oscillations of cerebral deoxy-hemoglobin and oxy-hemoglobin concentrations ([Hb] and [HbO], respectively) in the low-frequency range, namely 0.04-0.12 Hz. We report phase measurements during the transitions between different sleep stages in a whole-night study of a human subject. We have found that the phase difference between [Hb] and [HbO] low-frequency oscillations tends to be greater in deep sleep (by ~96° on average) and REM sleep (by ~77° on average) compared to the awake state. In particular, we have observed progressive phase increases as the subject transitions from awake conditions into non-REM sleep stages N1, N2, and N3. Corresponding phase decreases were recorded in the reversed transitions from sleep stages N3 to N2, and N2 to awake. These results illustrate the physiological information content of phase measurements of [Hb] and [HbO] oscillations that reflect the different cerebral hemodynamic conditions of the different sleep stages, and that can find broader applicability in a wide range of near-infrared spectroscopy brain studies.