Increase In HbR Research Articles

The hemodynamic initial-dip consists of both volumetric and oxymetric changes reflecting localized spiking activity.

The initial-dip is a transient decrease frequently observed in functional neuroimaging signals, immediately after stimulus onset, believed to originate from a rise in deoxy-hemoglobin (HbR) caused by local neural activity. It has been shown to be more spatially specific than the hemodynamic response, and is believed to represent focal neuronal activity. However, despite being observed in various neuroimaging modalities (such as fMRI, fNIRS, etc), its origins are disputed, and its precise neuronal correlates are unknown. Here we show that the initial-dip is dominated by a decrease in total-hemoglobin (HbT). We also find a biphasic response in deoxy-Hb (HbR), with an early decrease and later rebound. Both the HbT-dip and HbR-rebound were strongly correlated to highly localized spiking activity. However, HbT decreases were always large enough to counter the spiking-induced increase in HbR. We find that the HbT-dip counters spiking induced HbR increases, imposing an upper-limit to HbR concentration in the capillaries. Building on our results, we explore the possibility of active venule dilation (purging) as a possible mechanism for the HbT dip.

Hemodynamic Changes Associated with Interictal Spikes Induced by Acute Models of Focal Epilepsy in Rats: A Simultaneous Electrocorticography and Near-Infrared Spectroscopy Study.

Interictal spikes can be generated by blocking GABAA receptor-mediated inhibition. The nature of the hemodynamic activities associated with interictal spikes in acute models of focal epilepsy based on GABA deactivation has not been determined. We analyzed systemic changes in hemodynamic signals associated with interictal spikes generated by acute models of focal epilepsy. Simultaneous ElectroCorticoGraphy (ECoG) and Near-InfraRed Spectroscopy (NIRS) recordings were obtained in vivo from adult Sprague-Dawley rat brain during semi-periodic focal interictal spikes induced by local cortical application of low doses of Penicillin G (PG) and Bicuculline Methiodide (BM) as GABA deactivation agents. The Finite Impulse Response deconvolution technique was used to estimate the profile of hemodynamic changes in oxyhemoglobin (HbO) and deoxyhemoglobin (HbR) concentrations associated with interictal ECoG spikes in each rat. Our results show that, in both acute models of focal epilepsy, the hemodynamic changes associated with interictal spikes were characterized by pre-spike and post-spike primary NIRS responses, and recovery periods with slight differences in amplitude and latency. The pre-spike period starting at least 2s prior to the onset of ECoG spikes was characterized by a significant decrease in HbO concomitant with an increase in HbR with respect to baseline. The post-spike primary NIRS response exhibited the expected changes described according to the classical view of neurovascular coupling, i.e., a significant increase in HbO and a significant decrease in HbR in response to interictal spikes. The recovery period was characterized by a decreased HbO signal and an increased HbR signal, followed by a return to baseline. Compared to the BM epilepsy model, the PG model was more stable and showed lower variability in the shape, amplitude and latency of the components of spike-related hemodynamic changes. Our findings support a prominent role for pre-spike hemodynamic changes in the initiation of interictal spikes. The mechanism of interactions between neuronal and vascular networks during the pre-spike period constitutes a complex process, resulting in increased sensitivity of the epileptogenic focus to induce neuronal spiking.

The process of change in hemodynamics after revascularization in the ischemic brain.

In patients with a high-degree of internal carotid artery stenosis, cerebral hemodynamics and metabolism are compromised during ischemia. Revascularization improves cortical hemodynamics and oxygen metabolism during functional activity, but the process by which it occurs is still controversial. Therefore, using functional near-infrared spectroscopy (fNIRS), we investigated the process by which cerebral hemodynamics improve after revascularization surgery. Eight patients with severe carotid artery stenosis were examined using fNIRS during a motor task before and after surgery. We evaluated postoperative changes in total hemoglobin and deoxyhemoglobin (HbR), at 2 weeks after surgery, and again at 3 months after surgery. Parameters measured were the TTP (time to peak) value, defined as the time taken to reach 70% of the maximum total hemoglobin concentration, and the increase in HbR during the motor task. TTP was higher in four patients preoperatively, but this was no longer evident in two of the patients at 2 weeks after surgery. An increase in HbR during the task was observed in six patients before surgery, and was maintained at 2 weeks after surgery. However, in three of these patients, this increase was no longer evident 3 months later. These changes observed using fNIRS suggest that the increase in cerebral blood flow after revascularization surgery is followed by improvement in parenchymal vasodilation and neuronal oxygen metabolism.

Non-invasive continuous EEG-fNIRS recording of temporal lobe seizures

Functional near-infrared spectroscopy (fNIRS) is a technique that allows continuous non-invasive monitoring of tissue oxygenation and haemodynamics in the brain. By using combined EEG-fNIRS recordings, we sought to better understand the pathophysiology of temporal lobe seizures. Nine patients (5 males; mean age 35 years; range 11-56 years) with refractory mesial temporal lobe epilepsy underwent combined EEG-fNIRS recordings. Eight complex partial seizures from 3 patients were successfully recorded. All seizures were associated with significant local and remote haemodynamic changes which outlasted the duration of seizures. Over the epileptogenic temporal lobe, increased oxygenation [increase in cerebral blood volume (CBV) and oxyhaemoglobin (HbO), decrease in deoxyhaemoglobin (HbR)] was followed by a deoxygenated state [increase in HbR]. A similar haemodynamic profile was seen over the contralateral temporal lobe (even without evidence of epileptic propagation) though variations generally had lower amplitudes. Heterogeneous haemodynamic changes in remote frontal and/or parietal areas were also noted early on when epileptic activity was limited to the temporal lobe. EEG-fNIRS reveals complex local and remote oxygenation changes during temporal lobe seizures.

Spatiotemporal precision and hemodynamic mechanism of optical point spreads in alert primates

In functional brain imaging there is controversy over which hemodynamic signal best represents neural activity. Intrinsic signal optical imaging (ISOI) suggests that the best signal is the early darkening observed at wavelengths absorbed preferentially by deoxyhemoglobin (HbR). It is assumed that this darkening or "initial dip" reports local conversion of oxyhemoglobin (HbO) to HbR, i.e., oxygen consumption caused by local neural activity, thus giving the most specific measure of such activity. The blood volume signal, by contrast, is believed to be more delayed and less specific. Here, we used multiwavelength ISOI to simultaneously map oxygenation and blood volume [i.e., total hemoglobin (HbT)] in primary visual cortex (V1) of the alert macaque. We found that the hemodynamic "point spread," i.e., impulse response to a minimal visual stimulus, was as rapid and retinotopically specific when imaged by using blood volume as when using the initial dip. Quantitative separation of the imaged signal into HbR, HbO, and HbT showed, moreover, that the initial dip was dominated by a fast local increase in HbT, with no increase in HbR. We found only a delayed HbR decrease that was broader in retinotopic spread than HbO or HbT. Further, we show that the multiphasic time course of typical ISOI signals and the strength of the initial dip may reflect the temporal interplay of monophasic HbO, HbR, and HbT signals. Characterizing the hemodynamic response is important for understanding neurovascular coupling and elucidating the physiological basis of imaging techniques such as fMRI.

Multimodal investigation of fMRI and fNIRS derived breath hold BOLD signals with an expanded balloon model

Multimodal investigation of blood oxygenation level-dependent (BOLD) signals, using both functional near-infrared spectroscopy (fNIRS) and functional magnetic resonance imaging (fMRI), may give further insight to the underlying physiological principles and the detailed transient dynamics of the vascular response. Utilizing a breath hold task (BHT), we measured deoxy-hemoglobin (HbR) and oxy-hemoglobin (HbO) changes via fNIRS and blood oxygen level dependent (BOLD) changes by fMRI. Measurements were taken in four volunteers asynchronously and carefully aligned for comparative analysis. In order to describe the main stimulus in BHT, partial pressure of carbon dioxide (PaCO2) parameter was integrated into the balloon model as the driving function of cerebral blood flow (CBF) which led to the development of an expanded balloon model (EBM). During BHT, the increase in HbR was observed later than the BOLD peak and coincided temporally with its post-stimulus undershoot. Further investigation of these transients with a PaCO2 integrated balloon model suggests that post-stimulus undershoot measured by fMRI is dominated by slow return of cerebral blood volume (CBV). This was confirmed by fNIRS measurements. In addition, the BOLD signal decreased with the increase of the initial level of PaCO2 derived from EBM, indicating an effect of basal CBF level on the BOLD signal. In conclusion, a multimodal approach with an appropriate biophysical model gave a comprehensive description of the hemodynamic response during BHT.

Blood volume and hemoglobin oxygenation response following electrical stimulation of human cortex

Our understanding of perfusion-based human brain mapping techniques relies on a detailed knowledge of the relationship between neuronal activity and cerebrovascular hemodynamics. We performed optical imaging of intrinsic signals at wavelengths sensitive to total hemoglobin (Hbt; which correlate with cerebral blood volume (CBV)) and deoxygenated hemoglobin (Hbr) directly in humans during neurosurgical operations and investigated the optical signals associated with bipolar cortical stimulation at a range of amplitudes. Cortical stimulation elicited a rapid focal increase in Hbr (initial dip) in all subjects. An equally rapid increase in Hbt (<200 ms), with a slightly higher signal-to-noise ratio, was also highly localized for <2 s in spite of the non-columnar nature of the stimulus, after which the signal spread to adjacent gyri. A later decrease in Hbr (>3 s), which is relevant to the blood oxygen level dependent (BOLD) signal, was poorly localized. Increasing the stimulus amplitude elicited a linear increase in the area of the optical signal for Hbt and the initial dip but not the late decrease in Hbr, and a nonlinear increase in optical signal amplitude with a plateau effect for initial dip, Hbt and late decrease in Hbr.

Neurovascular coupling investigated with two‐dimensional optical imaging spectroscopy in rat whisker barrel cortex

Optical imaging slit spectroscopy is a powerful method for estimating quantitative changes in cerebral haemodynamics, such as deoxyhaemoglobin, oxyhaemoglobin and blood volume (Hbr, HbO2 and Hbt, respectively). Its disadvantage is that there is a large loss of spatial data as one image dimension is used to encode spectral wavelength information. Single wavelength optical imaging, on the other hand, produces high-resolution spatiotemporal maps of brain activity, but yields only indirect measures of Hbr, HbO2 and Hbt. In this study we perform two-dimensional optical imaging spectroscopy (2D-OIS) in rat barrel cortex during contralateral whisker stimulation to obtain two-dimensional maps over time of Hbr, HbO2 and Hbt. The 2D-OIS was performed by illuminating the cortex with four wavelengths of light (575, 559, 495 and 587 nm), which were presented sequentially at a high frame rate (32 Hz). The contralateral whisker pad was stimulated using two different durations: 1 and 16 s (5 Hz, 1.2 mA). Control experiments used a hypercapnic (5% CO2) challenge to manipulate baseline blood flow and volume in the absence of corresponding neural activation. The 2D-OIS method allowed separation of artery, vein and parenchyma regions. The magnitude of the haemodynamic response elicited varied considerably between different vascular compartments; the largest responses in Hbt were in the arteries and the smallest in the veins. Phase lags in the HbO2 response between arteries and veins suggest that a process of upstream signalling maybe responsible for dilating the arteries. There was also a consistent increase in Hbr from arterial regions after whisker stimulation.

Functional Anatomy in Relation to Myelin Maturation

Neural organization of cerebral activity in adult and child can be investigated by means of MRI with fMRI and DTI: MRI with fMRI analyses cortical haemodynamic responses correlated to neuronal activity, whereas DTI describes the spatial orientations of the white matter fibres. The fMRI patterns of cortical activity in children more than eight years old overlap the anatomical localization in adults except for the frontal and posterior parietal cortical areas, where BOLD responses in children are often difficult to arouse. This confirms what is currently known: myelin maturation is complete in these areas only in young adulthood. In neonates and young children, depending on the higher cortical cell concentration than adults and the increase in synaptic density up to the age of four-eight years, signal changes detected by BOLD may vary drastically. BOLD signal amplitude may be lower than that found in adults due to the reduced dynamic range during haemodynamic responses, or negative due to the local increase in HbR not fully compensated by the rise in CBF. The administration of sedatives or anaesthesia in children to perform MR scans can influence the BOLD signal: signal amplitude could decrease dramatically and the activated areas could be smaller in extension, indicating a fundamental role of the level of consciousness. BOLD signal analysis can supply useful data on the maturation processes of myelin and the cerebral cortex.

Temporal dependence in uncoupling of blood volume and oxygenation during interictal epileptiform events in rat neocortex.

We investigated the dynamic spatiotemporal relationships of cerebral blood volume (CBV), deoxygenated hemoglobin (Hbr), and light scatter (LS) associated with interictal epileptiform events with multiwavelength optical recording of intrinsic signals and simultaneous field potential recording. Interictal spikes (IISs) were induced with iontophoresis of bicuculline methiodide in rat neocortex. Intrinsic signal changes appeared as early as 100 msec after the IIS at all wavelengths and could be appreciated after only a single IIS. Initially, the largest signal arose from a focal increase in deoxygenation, which lasted for approximately 2 sec, consistent with an "initial dip." An equally early focal increase in CBV had a smaller amplitude than the Hbr signal until >2 sec after the IIS, when its amplitude surpassed that of the Hbr signal but also spread to a larger, less focal area. The most spatially restricted and smallest amplitude signal was produced by LS. A later hyperoxygenation, or increase in blood oxygenation level-dependent signal, was often seen in the draining veins but inconsistently seen in the IIS focus. An inverted optical signal was recorded at all wavelengths from multiple regions in the surrounding cortex within 100 msec of the IIS. We therefore conclude that the IIS induces a rapid increase in metabolic demand, which cannot be met by a rapid, initially focal but small increase in CBV that results in a prolonged increase in Hbr (epileptic dip in oxygenated hemoglobin). The inverted optical signal in the surround arises from a decrease in CBV and a decrease in Hbr, likely resulting from a combination of shunting of CBV to the focus and decreased metabolic demand resulting from decreased neuronal activity, consistent with "surround inhibition."

Different effects between 7-nitroindazole and l-NAME on cerebral hemodynamics and hippocampal lesions during kainic acid-induced seizures in newborn rabbits

We examined the effects of 7-nitroindazole (7-NI) and N-ω-nitro- l-arginine methyl ester ( l-NAME) on the endogenous nitric oxide (NO) production in vivo, cerebral hemodynamics, and hippocampal lesions to investigate the different roles between endothelial NOS (eNOS) and neuronal NOS (nNOS) during kainic acid (KA)-induced seizures in newborn rabbits. After a pre-treatment with 7-NI (50 mg/kg, i.p.), l-NAME (20 mg/kg, i.v.) or saline (1 ml, i.v.), KA (12 mg/kg, i.v.) was administered. NO production in the brain, regional cerebral blood flow (rCBF), cerebral oxygenation (concentrations of oxyhemoglobin (HbO 2), deoxyhemoglobin (HbR), and total hemoglobin (tHb) in the brain tissue), and electroencephalography (EEG) were continuously monitored throughout the experiment lasting at least 60 min after the KA administration. There was a significant increase in NO generation in the brain during KA-induced seizures, which was inhibited by a pre-treatment with 7-NI or l-NAME. KA-induced seizures also increased rCBF significantly, which was inhibited not by 7-NI but by l-NAME. l-NAME pre-treatment caused a significant decrease in HbO 2 and a significant increase in HbR during KA-induced seizures, compared with 7-NI and saline pre-treatment. EEG abnormalities and Neuronal damages in the hippocampus were significantly lower in 7-NI- and l-NAME-treated animals respectively, than in saline-treated animals. The present data demonstrated that the selective nNOS inhibitor, 7-NI, attenuated neither rCBF nor cerebral oxygenation during the seizures, while the non-selective NOS (nNOS and eNOS) inhibitor, l-NAME, attenuated both. These findings suggest that NO, probably originating from eNOS, may play an important role in the cerebral circulation. Both 7-NI and l-NAME inhibited the NO production and EEG abnormalities during the seizures that led to less damage to the hippocampus.

Effects of nitric oxide synthase inhibition on the cerebral circulation and brain damage during kainic acid-induced seizures in newborn rabbits.

The nitric oxide (NO) synthase inhibitor, N-omega-nitro-L-arginine methyl ester (L-NAME), was used to investigate the effect of endogenous NO on the cerebral circulation and brain damage during kainic acid (KA)-induced seizures in newborn rabbits. The cerebral blood flow (CBF), by laser doppler flowmetry, cerebral oxygenation (concentrations of oxy-(HbO2), deoxy-(HbR) and total hemoglobin (tHb) in brain tissue), by near-infrared spectroscopy (NIRS), mean arterial blood pressure (MABP), electroencephalography (EEG), and hippocampal neuronal damage were evaluated. Pretreatment with L-NAME caused significant decreases in CBF, HbO2, and tHb, and a significant increase in HbR during KA-induced seizures, compared with pretreatment with saline (P < 0.05), without a significant difference in MABP. Our study also demonstrated that pretreatment with L-NAME reduced the seizure activity and neuronal cell death in the hippocampus elicited by the systemic administration of KA in the neonatal brain. These results suggest that NO is of major importance in the neurodestructive process in spite of its roles in maintaining both the CBF and cerebral oxygenation during KA-induced seizures in the neonatal brain.

Vascular imprints of neuronal activity: relationships between the dynamics of cortical blood flow, oxygenation, and volume changes following sensory stimulation.

Modern functional neuroimaging methods, such as positron-emission tomography (PET), optical imaging of intrinsic signals, and functional MRI (fMRI) utilize activity-dependent hemodynamic changes to obtain indirect maps of the evoked electrical activity in the brain. Whereas PET and flow-sensitive MRI map cerebral blood flow (CBF) changes, optical imaging and blood oxygenation level-dependent MRI map areas with changes in the concentration of deoxygenated hemoglobin (HbR). However, the relationship between CBF and HbR during functional activation has never been tested experimentally. Therefore, we investigated this relationship by using imaging spectroscopy and laser-Doppler flowmetry techniques, simultaneously, in the visual cortex of anesthetized cats during sensory stimulation. We found that the earliest microcirculatory change was indeed an increase in HbR, whereas the CBF increase lagged by more than a second after the increase in HbR. The increased HbR was accompanied by a simultaneous increase in total hemoglobin concentration (Hbt), presumably reflecting an early blood volume increase. We found that the CBF changes lagged after Hbt changes by 1 to 2 sec throughout the response. These results support the notion of active neurovascular regulation of blood volume in the capillary bed and the existence of a delayed, passive process of capillary filling.