Physiological origin for the BOLD poststimulus undershoot in human brain: Vascular compliance versus oxygen metabolism

The poststimulus blood oxygenation level-dependent (BOLD) undershoot has been attributed to two main plausible origins: delayed vascular compliance based on delayed cerebral blood volume (CBV) recovery and a sustained increased oxygen metabolism after stimulus cessation. To investigate these contributions, multimodal functional magnetic resonance imaging was employed to monitor responses of BOLD, cerebral blood flow (CBF), total CBV, and arterial CBV (CBVa) in human visual cortex after brief breath hold and visual stimulation. In visual experiments, after stimulus cessation, CBVa was restored to baseline in 7.9 ± 3.4 seconds, and CBF and CBV in 14.8 ± 5.0 seconds and 16.1 ± 5.8 seconds, respectively, all significantly faster than BOLD signal recovery after undershoot (28.1 ± 5.5 seconds). During the BOLD undershoot, postarterial CBV (CBVpa, capillaries and venules) was slightly elevated (2.4 ± 1.8%), and cerebral metabolic rate of oxygen ( CMRO2) was above baseline (10.6 ± 7.4%). Following breath hold, however, CBF, CBV, CBVa and BOLD signals all returned to baseline in ∼20 seconds. No significant BOLD undershoot, and residual CBVpa dilation were observed, and CMRO2 did not substantially differ from baseline. These data suggest that both delayed CBVpa recovery and enduring increased oxidative metabolism impact the BOLD undershoot. Using a biophysical model, their relative contributions were estimated to be 19.7 ± 15.9% and 78.7 ± 18.6%, respectively.

Download Full-text

Hemodynamic Changes after Visual Stimulation and Breath Holding Provide Evidence for an Uncoupling of Cerebral Blood Flow and Volume from Oxygen Metabolism

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2008.109 ◽

2008 ◽

Vol 29 (1) ◽

pp. 176-185 ◽

Cited By ~ 48

Author(s):

Manus J Donahue ◽

Robert D Stevens ◽

Michiel de Boorder ◽

James J Pekar ◽

Jeroen Hendrikse ◽

...

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

Cerebral Blood Volume ◽

Visual Stimulation ◽

Functional Neuroimaging ◽

Oxygen Metabolism ◽

Blood Oxygenation ◽

Breath Holding ◽

Breath Hold ◽

Bold Signal

Functional neuroimaging is most commonly performed using the blood-oxygenation-level-dependent (BOLD) approach, which is sensitive to changes in cerebral blood flow (CBF), cerebral blood volume (CBV), and the cerebral metabolic rate of oxygen (CMRO2). However, the precise mechanism by which neuronal activity elicits a hemodynamic response remains controversial. Here, visual stimulation (14 secs flashing checkerboard) and breath-hold (4 secs exhale + 14 secs breath hold) experiments were performed in alternating sequence on healthy volunteers using BOLD, CBV-weighted, and CBF-weighted fMRI. After visual stimulation, the BOLD signal persisted for 33 ± 5 secs (n = 9) and was biphasic with a negative component (undershoot), whereas CBV and CBF returned to baseline without an undershoot at 20 ± 5 and 20 ± 3 secs, respectively. After breath hold, the BOLD signal returned to baseline (23 ±7 secs) at the same time ( P < 0.05) as CBV (21 ± 6 secs) and CBF (18 ±3 secs), without a poststimulus undershoot. These data suggest that the BOLD undershoot after visual activation reflects a persistent increase in CMRO2. These observations support the view that CBV and CBF responses elicited by neuronal activation are not necessarily coupled to local tissue metabolism.

Download Full-text

Basal Cerebral Blood Volume during the Poststimulation Undershoot in BOLD MRI of the Human Brain

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2010.133 ◽

2010 ◽

Vol 31 (1) ◽

pp. 82-89 ◽

Cited By ~ 13

Author(s):

Peter Dechent ◽

Gunther Schütze ◽

Gunther Helms ◽

Klaus Dietmar Merboldt ◽

Jens Frahm

Keyword(s):

Contrast Agent ◽

Blood Volume ◽

Animal Studies ◽

Cerebral Blood Volume ◽

Visual Stimulation ◽

Three Dimensional ◽

Blood Pool ◽

Blood Oxygenation ◽

Bold Mri ◽

Oxygenation Level

One of the characteristics of the blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI) response to functional challenges of the brain is the poststimulation undershoot, which has been suggested to originate from a delayed recovery of either cerebral blood volume (CBV) or cerebral metabolic rate of oxygen to baseline. Using bolus-tracking MRI in humans, we recently showed that relative CBV rapidly normalizes after the end of stimulation. As this observation contradicts at least part of the blood-pool contrast agent studies performed in animals, we reinvestigated the CBV contribution by dynamic T1-weighted three-dimensional MRI (8 seconds temporal resolution) and Vasovist at 3 T (12 subjects). Initially, we determined the time constants of individual BOLD responses. After injection of Vasovist, CBV-related T1-weighted signal changes revealed a signal increase during visual stimulation (1.7%±0.4%), but no change relative to baseline in the poststimulation phase (0.2%±0.3%). This finding renders the specific nature of the contrast agent unlikely to be responsible for the discrepancy between human and animal studies. With the assumption of normalized cerebral blood flow after stimulus cessation, a normalized CBV lends support to the idea that the BOLD MRI undershoot reflects a prolonged elevation of oxidative metabolism.

Download Full-text

Effects of aging on cerebral blood flow, oxygen metabolism, and blood oxygenation level dependent responses to visual stimulation

Human Brain Mapping ◽

10.1002/hbm.20574 ◽

2009 ◽

Vol 30 (4) ◽

pp. 1120-1132 ◽

Cited By ~ 136

Author(s):

Beau M. Ances ◽

Christine L. Liang ◽

Oleg Leontiev ◽

Joanna E. Perthen ◽

Adam S. Fleisher ◽

...

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

Visual Stimulation ◽

Oxygen Metabolism ◽

Blood Oxygenation Level Dependent ◽

Blood Oxygenation ◽

Blood Oxygenation Level ◽

Oxygenation Level ◽

Effects Of Aging

Download Full-text

Hemodynamic and metabolic changes during hypercapnia with normoxia and hyperoxia using pCASL and TRUST MRI in healthy adults

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x211064572 ◽

2021 ◽

pp. 0271678X2110645

Author(s):

Pieter T Deckers ◽

Alex A Bhogal ◽

Mathijs BJ Dijsselhof ◽

Carlos C Faraco ◽

Peiying Liu ◽

...

Keyword(s):

Arterial Spin Labeling ◽

Oxygen Metabolism ◽

Blood Oxygenation Level Dependent ◽

Blood Oxygenation ◽

Cerebrovascular Reactivity ◽

Oxygen Extraction Fraction ◽

Mixed Effect ◽

Cerebral Oxygen Metabolism ◽

Extraction Fraction ◽

Oxygenation Level

Blood oxygenation level-dependent (BOLD) or arterial spin labeling (ASL) MRI with hypercapnic stimuli allow for measuring cerebrovascular reactivity (CVR). Hypercapnic stimuli are also employed in calibrated BOLD functional MRI for quantifying neuronally-evoked changes in cerebral oxygen metabolism (CMRO2). It is often assumed that hypercapnic stimuli (with or without hyperoxia) are iso-metabolic; increasing arterial CO2 or O2 does not affect CMRO2. We evaluated the null hypothesis that two common hypercapnic stimuli, ‘CO2 in air’ and carbogen, are iso-metabolic. TRUST and ASL MRI were used to measure the cerebral venous oxygenation and cerebral blood flow (CBF), from which the oxygen extraction fraction (OEF) and CMRO2 were calculated for room-air, ‘CO2 in air’ and carbogen. As expected, CBF significantly increased (9.9% ± 9.3% and 12.1% ± 8.8% for ‘CO2 in air’ and carbogen, respectively). CMRO2 decreased for ‘CO2 in air’ (−13.4% ± 13.0%, p < 0.01) compared to room-air, while the CMRO2 during carbogen did not significantly change. Our findings indicate that ‘CO2 in air’ is not iso-metabolic, while carbogen appears to elicit a mixed effect; the CMRO2 reduction during hypercapnia is mitigated when including hyperoxia. These findings can be important for interpreting measurements using hypercapnic or hypercapnic-hyperoxic (carbogen) stimuli.

Download Full-text

Multimodal Measurements of Blood Plasma and Red Blood Cell Volumes during Functional Brain Activation

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2008.100 ◽

2008 ◽

Vol 29 (1) ◽

pp. 19-24 ◽

Cited By ~ 24

Author(s):

Peter Herman ◽

Basavaraju G Sanganahalli ◽

Fahmeed Hyder

Keyword(s):

Magnetic Resonance Imaging ◽

Magnetic Resonance ◽

Blood Plasma ◽

Cerebral Blood Volume ◽

Superparamagnetic Iron Oxide ◽

Blood Oxygenation ◽

Mri Contrast Agent ◽

Resonance Imaging ◽

Doppler Flowmetry ◽

Oxygenation Level

As an alternative to functional magnetic resonance imaging (fMRI) with blood oxygenation level dependent (BOLD) contrast, cerebral blood volume (CBV)-weighted fMRI with intravascular contrast agents in animal models have become popular. In this study, dynamic measurements of CBV were performed by magnetic resonance imaging (MRI) and laser-Doppler flowmetry (LDF) in α-chloralose anesthetized rats during forepaw stimulation. All recordings were localized to the contralateral primary somatosensory cortex as revealed by BOLD at 11.7 T. Ultra-small superparamagnetic iron oxide (15mg/kg)—a plasma-borne MRI contrast agent with a half-life of several hours in blood circulation—was used to quantify changes in magnetic field inhomogeneity in blood plasma. The LDF backscattered laser light (805 nm), which reflects the amount of red blood cells, was used to measure alterations in the non-plasma compartment. Dynamic and layer-specific comparisons of the two CBV signals during functional hyperemia revealed excellent correlations (> 0.86). These results suggest that CBV measurements from either compartment may be used to reflect dynamic changes in total CBV. Furthermore, by assuming steady-state mass balance and negligible counter flow, these results indicate that volume hematocrit is not appreciably affected during functional activation.

Download Full-text

Relationship of the BOLD Signal with VEP for Ultrashort Duration Visual Stimuli (0.1 to 5 ms) in Humans

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2009.224 ◽

2009 ◽

Vol 30 (2) ◽

pp. 449-458 ◽

Cited By ~ 20

Author(s):

Barış Yeşilyurt ◽

Kevin Whittingstall ◽

Kâmil Uğurbil ◽

Nikos K Logothetis ◽

Kâmil Uludağ

Keyword(s):

Brain Function ◽

Temporal Dynamics ◽

Visual Stimulation ◽

Impulse Response Function ◽

Blood Oxygenation ◽

Context Dependency ◽

Oxygenation Level ◽

Relationship Of ◽

The Relationship ◽

The Brain

There is currently a great interest to combine electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) to study brain function. Earlier studies have shown different EEG components to correlate well with the fMRI signal arguing for a complex relationship between both measurements. In this study, using separate EEG and fMRI measurements, we show that (1) 0.1 ms visual stimulation evokes detectable hemodynamic and visual-evoked potential (VEP) responses, (2) the negative VEP deflection at ∼80 ms (N2) co-varies with stimulus duration/intensity such as with blood oxygenation level-dependent (BOLD) response; the positive deflection at ∼120 ms (P2) does not, and (3) although the N2 VEP–BOLD relationship is approximately linear, deviation is evident at the limit of zero N2 VEP. The latter finding argues that, although EEG and fMRI measurements can co-vary, they reflect partially independent processes in the brain tissue. Finally, it is shown that the stimulus-induced impulse response function (IRF) at 0.1 ms and the intrinsic IRF during rest have different temporal dynamics, possibly due to predominance of neuromodulation during rest as compared with neurotransmission during stimulation. These results extend earlier findings regarding VEP–BOLD coupling and highlight the component- and context-dependency of the relationship between evoked potentials and hemodynamic responses.

Download Full-text

Sex Differences in Blood-Oxygenation-Level-Dependent Functional MRI With Primary Visual Stimulation

American Journal of Psychiatry ◽

10.1176/ajp.155.3.434 ◽

1998 ◽

Vol 155 (3) ◽

pp. 434-436 ◽

Cited By ~ 45

Author(s):

Jonathan M. Levin ◽

Marjorie H. Ross ◽

Jack H. Mendelson ◽

Nancy K. Mello ◽

Bruce M. Cohen ◽

...

Keyword(s):

Sex Differences ◽

Functional Mri ◽

Visual Stimulation ◽

Blood Oxygenation Level Dependent ◽

Blood Oxygenation ◽

Blood Oxygenation Level ◽

Oxygenation Level

Download Full-text

Perception affects the brain's metabolic response to sensory stimulation

10.1101/2021.09.17.460759 ◽

2021 ◽

Author(s):

Mauro DiNuzzo ◽

Silvia Mangia ◽

Marta Moraschi ◽

Daniele Mascali ◽

Gisela E. Hagberg ◽

...

Keyword(s):

Metabolic Response ◽

Visual Stimulation ◽

Aerobic Glycolysis ◽

Sensory Stimulation ◽

Blood Oxygenation ◽

Bold Fmri ◽

Physiological Variables ◽

Fmri Signal ◽

Oxygenation Level ◽

Neurochemical Profile

Processing of incoming sensory stimulation triggers an increase of cerebral perfusion and blood oxygenation (neurovascular response) as well as an alteration of the metabolic neurochemical profile (neurometabolic response). Here we show that perceived and unperceived isoluminant chromatic flickering stimuli designed to have similar neurovascular responses as measured by blood oxygenation level dependent functional MRI (BOLD-fMRI) in primary visual cortex (V1) have markedly different neurometabolic responses as measured by functional MRS. In particular, a significant regional buildup of lactate, an index of aerobic glycolysis, and glutamate, an index of malate-aspartate shuttle, occurred in V1 only when the flickering is perceived, without any relation with behavioral or physiological variables. Wheras the BOLD-fMRI signal in V1, a proxy for input to V1, was insensitive to flickering perception by design, the BOLD-fMRI signal in secondary visual areas was larger during perceived than unperceived flickering indicating increased output from V1. These results indicate that the upregulation of energy metabolism induced by visual stimulation depends on the type of information processing taking place in V1, and that 1H-fMRS provides unique information about local input/output balance that is not measured by BOLD-fMRI.

Download Full-text