Paradoxical reduction of cerebral blood flow after acetazolamide loading: a hemodynamic and metabolic study with 15O PET

Paradoxical reduction of cerebral blood flow (CBF) after administration of the vasodilator acetazolamide is the most severe stage of cerebrovascular reactivity failure and is often associated with an increased oxygen extraction fraction (OEF). In this study, we aimed to reveal the mechanism underlying this phenomenon by focusing on the ratio of CBF to cerebral blood volume (CBV) as a marker of regional cerebral perfusion pressure (CPP). In 37 patients with unilateral internal carotid or middle cerebral arterial (MCA) steno-occlusive disease and 8 normal controls, the baseline CBF (CBF_b), CBV, OEF, cerebral oxygen metabolic rate (CMRO₂), and CBF after acetazolamide loading in the anterior and posterior MCA territories were measured by ¹⁵O positron emission tomography. Paradoxical CBF reduction was found in 28 of 74 regions (18 of 37 patients) in the ipsilateral hemisphere. High CBF_b (>47.6 mL/100 mL/min, n = 7) was associated with normal CBF_b/CBV, increased CBV, decreased OEF, and normal CMRO₂. Low CBF_b (<31.8 mL/100 mL/min, n = 9) was associated with decreased CBF_b/CBV, increased CBV, increased OEF, and decreased CMRO₂. These findings demonstrated that paradoxical CBF reduction is not always associated with reduction of CPP, but partly includes high-CBF_b regions with normal CPP, which has not been described in previous studies.     

Evaluation of cerebral blood flow and metabolism in childhood moyamoya disease: an investigation into “re-build-up” on EEG by positron CT

The cerebral blood flow and cerebral metabolic rate of oxygen (CBF and CMRO₂) of three cases of childhood moyamoya disease were examined by positron-emission-computed tomography for the purpose of investigating the mechanism of the re-build-up phenomenon on EEG. Decrease in both CBF and CMRO₂ were observed following hyperventilation. However, dissociation between the decrease in CBF and CMRO₂ was also observed. Arterial blood-gas analysis disclosed hypocapnea during hyperventilation and hypoxia following hyperventilation. These results clearly indicate that the re-build-up seen on EEG is the manifestation not only of ischemic hypoxia but also of hypoxic hypoxia characteristically seen in moyamoya disease.Presented at the 13th Annual Meeting of the International Society for Pediatric Neurosurgery     

Capillary dysfunction is associated with symptom severity and neurodegeneration in Alzheimer's disease

Introduction

We examined whether cortical microvascular blood volume and hemodynamics in Alzheimer's disease (AD) are consistent with tissue hypoxia and whether they correlate with cognitive performance and the degree of cortical thinning.

Striatal and cortical BOLD,blood flow,blood volume,oxygen consumption,and glucose consumption changes in noxious forepaw electrical stimulation

Recent reports showed noxious forepaw stimulation in rats evoked an unexpected sustained decrease in cerebral blood volume (CBV) in the bilateral striatum, whereas increases in spike activity and Fos-immunoreactive cells were observed. This study aimed to further evaluate the hemodynamic and metabolic needs in this model and the sources of negative functional magnetic resonance imaging (fMRI) signals by measuring blood oxygenation-level-dependent (BOLD), cerebral-blood-flow (CBF), CBV, and oxygen-consumption (i.e., cerebral metabolic rate of oxygen (CMRO₂)) changes using an 11.7-T MRI scanner, and glucose-consumption (i.e., cerebral metabolic rate of glucose (CMRglc)) changes using micro-positron emission tomography. In the contralateral somatosensory cortex, BOLD, CBF, CBV, CMRO₂ (n=7, P<0.05), and CMRglc (n=5, P<0.05) increased. In contrast, in the bilateral striatum, BOLD, CBF, and CBV decreased (P<0.05), CMRO₂ decreased slightly, although not significantly from baseline, and CMRglc was not statistically significant from baseline (P>0.05). These multimodal functional imaging findings corroborate the unexpected negative hemodynamic changes in the striatum during noxious forepaw stimulation, and support the hypothesis that striatal hemodynamic response is dominated by neurotransmitter-mediated vasoconstriction, overriding the stimulus-evoked fMRI signal increases commonly accompany elevated neuronal activity. Multimodal functional imaging approach offers a means to probe the unique attributes of the striatum, providing novel insights into the neurovascular coupling in the striatum. These findings may have strong implications in fMRI studies of pain.     

Cerebral blood flow changes during pilocarpine-induced status epilepticus activity in the rat hippocampus

Introduction

There is a known relationship between convulsive status epilepticus (SE) and hippocampal injury. Although the precise causes of this hippocampal vulnerability remains uncertain, potential mechanisms include excitotoxicity and ischaemia. It has been hypothesised that during the early phase of seizures, cerebral blood flow (CBF) increases in the cortex to meet energy demand, but it is unclear whether these compensatory mechanisms occur in the hippocampus. In this study we investigated CBF changes using perfusion MRI during SE in the pilocarpine rat.

Methods

First, we determined whether SE could be induced under anaesthesia. Two anaesthetic protocols were investigated: isoflurane (n = 6) and fentanyl/medetomidine (n = 7). Intrahippocampal EEG electrodes were used to determine seizure activity and reflex behaviours were used to assess anaesthesia. Pilocarpine was administered to induce status epilepticus. For CBF measurements, MRI arterial spin labelling was performed continuously for up to 3 h. Either pilocarpine (375 mg/kg) (n = 7) for induction of SE or saline (n = 6) was administered. Diazepam (10 mg/kg) was administered i.p. 90 min after the onset of SE.

Results and discussion

We demonstrated time-dependent significant (p < 0.05) differences between the CBF responses in the parietal cortex and the hippocampus during SE. This regional response indicates a preferential distribution of flow to certain regions of the brain and may contribute to the selective vulnerability observed in the hippocampus in humans.     

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 (CBV_a) in human visual cortex after brief breath hold and visual stimulation. In visual experiments, after stimulus cessation, CBV_a 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 (CBV_pa, 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, CBV_a and BOLD signals all returned to baseline in ∼20 seconds. No significant BOLD undershoot, and residual CBV_pa dilation were observed, and CMRO₂ did not substantially differ from baseline. These data suggest that both delayed CBV_pa 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.     

Impaired cerebral vascular and metabolic responses to parametric N-back tasks in subjective cognitive decline

Previous studies reported abnormally increased and/or decreased blood oxygen level-dependent (BOLD) activations during functional tasks in subjective cognitive decline (SCD). The neurophysiological basis underlying these functional aberrations remains debated. This study aims to investigate vascular and metabolic responses and their dependence on cognitive processing loads during functional tasks in SCD. Twenty-one SCD and 18 control subjects performed parametric N-back working-memory tasks during MRI scans. Task-evoked percentage changes (denoted as δ) in cerebral blood volume (δCBV), cerebral blood flow (δCBF), BOLD signal (δBOLD) and cerebral metabolic rate of oxygen (δCMRO₂) were evaluated. In the frontal lobe, trends of decreased δCBV, δCBF and δCMRO₂ and increased δBOLD were observed in SCD compared with control subjects under lower loads, and these trends increased to significant differences under the 3-back load. δCBF was significantly correlated with δCMRO₂ in controls, but not in SCD subjects. As N-back loads increased, the differences between SCD and control subjects in δCBF and δCMRO₂ tended to enlarge. In the parietal lobe, no significant between-group difference was observed. Our findings suggested that impaired vascular and metabolic responses to functional tasks occurred in the frontal lobe of SCD, which contributed to unusual BOLD hyperactivation and was modulated by cognitive processing loads.     

Measurement of CMRO2 and its relationship with CBF in hypoxia with an extended calibrated BOLD method

Cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO₂) are physiological parameters that not only reflect brain health and disease but also jointly contribute to blood oxygen level-dependent (BOLD) signals. Nevertheless, unsolved issues remain concerning the CBF–CMRO₂ relationship in the working brain under various oxygen conditions. In particular, the CMRO₂ responses to functional tasks in hypoxia are less studied. We extended the calibrated BOLD model to incorporate CMRO₂ measurements in hypoxia. The extended model, which was cross-validated with a multicompartment BOLD model, considers the influences of the reduced arterial saturation level and increased baseline cerebral blood volume (CBV) and deoxyhemoglobin concentration on the changes of BOLD signals in hypoxia. By implementing a pulse sequence to simultaneously acquire the CBV-, CBF- and BOLD-weighted signals, we investigated the effects of mild hypoxia on the CBF and CMRO₂ responses to graded visual stimuli. Compared with normoxia, mild hypoxia caused significant alterations in both the amplitude and the trend of the CMRO₂ responses but did not impact the corresponding CBF responses. Our observations suggested that the flow-metabolism coupling strategies in the brain during mild hypoxia were different from those during normoxia.     

Model of the transient neurovascular response based on prompt arterial dilation

Brief neural stimulation results in a stereotypical pattern of vascular and metabolic response that is the basis for popular brain-imaging methods such as functional magnetic resonance imagine. However, the mechanisms of transient oxygen transport and its coupling to cerebral blood flow (CBF) and oxygen metabolism (CMRO₂) are poorly understood. Recent experiments show that brief stimulation produces prompt arterial vasodilation rather than venous vasodilation. This work provides a neurovascular response model for brief stimulation based on transient arterial effects using one-dimensional convection–diffusion transport. Hemoglobin oxygen dissociation is included to enable predictions of absolute oxygen concentrations. Arterial CBF response is modeled using a lumped linear flow model, and CMRO₂ response is modeled using a gamma function. Using six parameters, the model successfully fit 161/166 measured extravascular oxygen time courses obtained for brief visual stimulation in cat cerebral cortex. Results show how CBF and CMRO₂ responses compete to produce the observed features of the hemodynamic response: initial dip, hyperoxic peak, undershoot, and ringing. Predicted CBF and CMRO₂ response amplitudes are consistent with experimental measurements. This model provides a powerful framework to quantitatively interpret oxygen transport in the brain; in particular, its intravascular oxygen concentration predictions provide a new model for fMRI responses.     

Acute vagus nerve stimulation using different pulse widths produces varying brain effects

Background

Vagus nerve stimulation (VNS) is an approved treatment for epilepsy and has been investigated in clinical trials of depression. Little is known about the relationship of VNS parameters to brain function. Using the interleaved VNS /functional magnetic resonance imaging (fMRI) technique, we tested whether variations of VNS pulse width (PW) would produce different immediate brain activation in a manner consistent with single neuron PW studies.

Methods

Twelve adult patients with major depression, treated with VNS, underwent three consecutive VNS/fMRI scans, each randomly using one of three PWs (130 μs, 250 μs, or 500 μs). The data were analyzed with SPM2.

Results

Global activations induced by PWs 250 and 500 were both significantly greater than that induced by PW 130 but not significantly different from each other. For global deactivation, PWs 130 and 250 were both significantly greater than PW 500 but not significantly different from each other. Regional similarities and differences were also seen with the various PWs.

Conclusions

The data confirm our hypothesis that VNS at PW 500 globally produces no more activation than does PW 250, and PW 130 is insufficient for activation of some regions. These data suggest that PW is an important variable in producing VNS brain effects.     

Accounting for the role of hematocrit in between‐subject variations of MRI‐derived baseline cerebral hemodynamic parameters and functional BOLD responses

Baseline hematocrit fraction (Hct) is a determinant for baseline cerebral blood flow (CBF) and between‐subject variation of Hct thus causes variation in task‐based BOLD fMRI signal changes. We first verified in healthy volunteers (n = 12) that Hct values can be derived reliably from venous blood T₁ values by comparison with the conventional lab test. Together with CBF measured using phase‐contrast MRI, this noninvasive estimation of Hct, instead of using a population‐averaged Hct value, enabled more individual determination of oxygen delivery (DO₂), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO₂). The inverse correlation of CBF and Hct explained about 80% of between‐subject variation of CBF in this relatively uniform cohort of subjects, as expected based on the regulation of DO₂ to maintain constant CMRO₂. Furthermore, we compared the relationships of visual task‐evoked BOLD response with Hct and CBF. We showed that Hct and CBF contributed 22%–33% of variance in BOLD signal and removing the positive correlation with Hct and negative correlation with CBF allowed normalization of BOLD signal with 16%–22% lower variability. The results of this study suggest that adjustment for Hct effects is useful for studies of MRI perfusion and BOLD fMRI. Hum Brain Mapp 39:344–353, 2018. © 2017 Wiley Periodicals, Inc.     

Differential effects of anesthetics on cocaine's pharmacokinetic and pharmacodynamic effects in brain

Most studies of the effect of cocaine on brain activity in laboratory animals are preformed under anesthesia, which could potentially affect the physiological responses to cocaine. Here we assessed the effects of two commonly used anesthetics [α‐chloralose (α‐CHLOR) and isofluorane (ISO)] on the effects of acute cocaine (1 mg/kg i.v.) on cerebral blood flow (CBF), cerebral blood volume (CBV), and tissue hemoglobin oxygenation (S_tO₂) using optical techniques and cocaine’s pharmacokinetics (PK) and binding in the rat brain using (PET) and [¹¹C]cocaine. We showed that acute cocaine at a dose abused by cocaine abusers decreased CBF, CBV and S_tO₂ in rats anesthetized with ISO, whereas it increased these parameters in rats anesthetized with α‐CHLOR. Importantly, in ISO‐anesthetized animals cocaine‐induced changes in CBF and S_tO₂ were coupled, whereas for α‐CHLOR these measures were uncoupled. Moreover, the clearance of [¹¹C]cocaine from the brain was faster for ISO (peak half‐clearance 15.8 ± 2.8 min) than for α‐CHLOR (27.5 ± 0.6 min), and the ratio of specific to non‐specific binding of [¹¹C]cocaine in the brain was higher for ISO‐ (3.37 ± 0.32) than for α‐CHLOR‐anesthetized rats (2.24 ± 0.4). For both anesthetics, cocaine‐induced changes in CBF followed the fast uptake of [¹¹C]cocaine in the brain (peaking at ～2.5–4 min), but only for ISO did the duration of the CBV and S_tO₂ changes correspond to the rate of [¹¹C]cocaine’s clearance from the brain. These results demonstrate that anesthetics influence cocaine’s hemodynamic and metabolic changes in the brain, and its binding and PK, which highlights the need to better understand the interactions between anesthetics and pharmacological challenges in brain functional imaging studies.     

Impaired response of cerebral oxygen metabolism to visual stimulation in Huntington’s disease

Huntington’s disease (HD) is a neurodegenerative disease caused by a CAG triplet repeat expansion in the Huntingtin gene. Metabolic and microvascular abnormalities in the brain may contribute to early physiological changes that subserve the functional impairments in HD. This study is intended to investigate potential abnormality in dynamic changes in cerebral blood volume (CBV) and cerebral blood flow (CBF), and cerebral metabolic rate of oxygen (CMRO₂) in the brain in response to functional stimulation in premanifest and early manifest HD patients. A recently developed 3-D-TRiple-acquisition-after-Inversion-Preparation magnetic resonance imaging (MRI) approach was used to measure dynamic responses in CBV, CBF, and CMRO₂ during visual stimulation in one single MRI scan. Experiments were conducted in 23 HD patients and 16 healthy controls. Decreased occipital cortex CMRO₂ responses were observed in premanifest and early manifest HD patients compared to controls (P < 0.001), correlating with the CAG-Age Product scores in these patients (R² = 0.4, P = 0.001). The results suggest the potential value of this reduced CMRO₂ response during visual stimulation as a biomarker for HD and may illuminate the role of metabolic alterations in the pathophysiology of HD.     

Correlation between the arterial pulse wave of the cerebral microcirculation and CBF during breath holding and hyperventilation in human

Objective

To evaluate if relative changes in the amplitude of the arterial pulse wave of the cerebral microcirculation (APWCM) measured by near-infrared spectroscopy (NIRS) may provide information about relative changes of cerebral blood flow (CBF) in cerebral cortex.

Methods

In 10 healthy human volunteers, through simultaneous recording of the APWCM amplitude by means of NIRS and the mean blood flow velocity (MBFV) of middle cerebral artery by means of transcranial Doppler (TCD) at rest and during breath holding and hyperventilation, we evaluate a possible correlation between relative changes of the mean APWCM amplitude and relative changes of MBFV.

Results

We found a significant linear correlation: breath holding: R² 0.84, p < 0.001, hyperventilation: R² 0.81, p < 0.001.

Conclusion

The relative changes of the mean APWCM amplitude seem able to provide information about relative changes of CBF of cerebral cortex in healthy adult humans during breath holding and hyperventilation.

Significance

APWCM detected by NIRS, a safe, repeatable, inexpensive technology and at the bedside may improve the study of cerebral cortex microcirculation in neurological diseases.     

Cerebrovascular reactivity over time-course - From major depressive episode to remission

Introduction

Depression is a prospective risk factor for stroke. Little is known, however, about the pathophysiologic links leading to this association. Cerebrovascular reactivity (CVR) reflects the compensatory dilatory capacity of cerebral arterioles to a dilatory stimulus and is an important mechanism to provide constant cerebral blood flow. In the absence of major arterial stenosis, an impaired CVR has been associated with a higher risk of stroke. We hypothesized that CVR might be continuously reduced in patients with major depression even after successful remission thus contributing to the association between depression and stroke.

Materials and methods

We investigated CVR in a group of patients (N = 29) in the acute episode of depressive illness and after 21 months under euthymic condition. A healthy control group (N = 33) was investigated at comparable time intervals. All patients and controls were otherwise healthy. CVR was investigated by calculating the increase in cerebral blood flow velocity after stimulation with acetazolamide. Blood flow velocities were measured by transcranial doppler ultrasound.

Results

A group of acutely depressed patients presented a significantly reduced CVR compared to controls. On follow-up 21 months later after treatment and remission, CVR in the patient group had significantly improved, whereas CVR in the control group remained unchanged. Confounding factors had no significant influence.

Discussion

CVR is impaired during major depression. Since CVR seems to improve after treatment of depression, the contribution to an increased stroke risk among depressive patients may be true for a subgroup only and needs to be further investigated.     

Metabolic control of resting hemispheric cerebral blood flow is oxidative,not glycolytic

Although the close regional coupling of resting cerebral blood flow (CBF) with both cerebral metabolic rate of oxygen (CMRO₂) and cerebral metabolic rate of glucose (CMRglc) within individuals is well documented, there are few data regarding the coupling between whole brain flow and metabolism among different subjects. To investigate the metabolic control of resting whole brain CBF, we performed multivariate analysis of hemispheric CMRO₂, CMRglc, and other covariates as predictors of resting CBF among 23 normal humans. The univariate analysis showed that only CMRO₂ was a significant predictor of CBF. The final multivariate model contained two additional terms in addition to CMRO₂: arterial oxygen content and oxygen extraction fraction. Notably, arterial plasma glucose concentration and CMRglc were not included in the final model. Our data demonstrate that the metabolic factor controlling hemispheric CBF in the normal resting brain is CMRO₂ and that CMRglc does not make a contribution. Our findings provide evidence for compartmentalization of brain metabolism into a basal component in which CBF is coupled to oxygen metabolism and an activation component in which CBF is controlled by another mechanism.     

Dual role of cerebral blood flow in regional brain temperature control in the healthy newborn infant

Small shifts in brain temperature after hypoxia–ischaemia affect cell viability. The main determinants of brain temperature are cerebral metabolism, which contributes to local heat production, and brain perfusion, which removes heat. However, few studies have addressed the effect of cerebral metabolism and perfusion on regional brain temperature in human neonates because of the lack of non-invasive cot-side monitors. This study aimed (i) to determine non-invasive monitoring tools of cerebral metabolism and perfusion by combining near-infrared spectroscopy and echocardiography, and (ii) to investigate the dependence of brain temperature on cerebral metabolism and perfusion in unsedated newborn infants.Thirty-two healthy newborn infants were recruited. They were studied with cerebral near-infrared spectroscopy, echocardiography, and a zero-heat flux tissue thermometer. A surrogate of cerebral blood flow (CBF) was measured using superior vena cava flow adjusted for cerebral volume (rSVC flow). The tissue oxygenation index, fractional oxygen extraction (FOE), and the cerebral metabolic rate of oxygen relative to rSVC flow (CMRO₂ index) were also estimated.A greater rSVC flow was positively associated with higher brain temperatures, particularly for superficial structures. The CMRO₂ index and rSVC flow were positively coupled. However, brain temperature was independent of FOE and the CMRO₂ index. A cooler ambient temperature was associated with a greater temperature gradient between the scalp surface and the body core.Cerebral oxygen metabolism and perfusion were monitored in newborn infants without using tracers. In these healthy newborn infants, cerebral perfusion and ambient temperature were significant independent variables of brain temperature. CBF has primarily been associated with heat removal from the brain. However, our results suggest that CBF is likely to deliver heat specifically to the superficial brain. Further studies are required to assess the effect of cerebral metabolism and perfusion on regional brain temperature in low-cardiac output conditions, fever, and with therapeutic hypothermia.     

Method for rapid MRI quantification of global cerebral metabolic rate of oxygen

A recently reported quantitative magnetic resonance imaging (MRI) method denoted OxFlow has been shown to be able to quantify whole-brain cerebral metabolic rate of oxygen (CMRO₂) by simultaneously measuring oxygen saturation (S_vO₂) in the superior sagittal sinus and cerebral blood flow (CBF) in the arteries feeding the brain in 30 seconds, which is adequate for measurement at baseline but not necessarily in response to neuronal activation. Here, we present an accelerated version of the method (referred to as F-OxFlow) that quantifies CMRO₂ in 8 seconds scan time under full retention of the parent method''s capabilities and compared it with its predecessor at baseline in 10 healthy subjects. Results indicate excellent agreement between both sequences, with mean bias of 2.2% (P=0.18, two-tailed t-test), 3.4% (P=0.08, two-tailed t-test), and 2.0% (P=0.56, two-tailed t-test) for S_vO₂, CBF, and CMRO₂, respectively. F-OxFlow''s potential to monitor dynamic changes in S_vO₂, CBF, and CMRO₂ is illustrated in a paradigm of volitional apnea applied to five of the study subjects. The sequence captured an average increase in S_vO₂, CBF, and CMRO₂ of 10.1±2.5%, 43.2±9.2%, and 7.1±2.2%, respectively, in good agreement with literature values. The method may therefore be suited for monitoring alterations in CBF and S_vO₂ in response to neurovascular stimuli.     

Interindividual variations of cerebral blood flow, oxygen delivery, and metabolism in relation to hemoglobin concentration measured by positron emission tomography in humans

Regional cerebral blood flow (CBF) and oxygen metabolism can be measured by positron emission tomography (PET) with ¹⁵O-labeled compounds. Hemoglobin (Hb) concentration of blood, a primary determinant of arterial oxygen content (C_aO₂), influences cerebral circulation. We investigated interindividual variations of CBF, cerebral blood volume (CBV), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO₂) in relation to Hb concentration in healthy human volunteers (n=17) and in patients with unilateral steno-occlusive disease (n=44). For the patients, data obtained only from the contralateral hemisphere (normal side) were analyzed. The CBF and OEF were inversely correlated with Hb concentration, but CMRO₂ was independent of Hb concentration. Oxygen delivery defined as a product of C_aO₂ and CBF (C_aO₂ CBF) increased with a rise of Hb concentration. The analysis with a simple oxygen model showed that oxygen diffusion parameter (L) was constant over the range of Hb concentration, indicating that a homeostatic mechanism controlling CBF is necessary to maintain CMRO₂. The current findings provide important knowledge to understand the control mechanism of cerebral circulation and to interpret the ¹⁵O PET data in clinical practice.     

Altered task-induced cerebral blood flow and oxygen metabolism underlies motor impairment in multiple sclerosis

The neural mechanisms underlying motor impairment in multiple sclerosis (MS) remain unknown. Motor cortex dysfunction is implicated in blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) studies, but the role of neural–vascular coupling underlying BOLD changes remains unknown. We sought to independently measure the physiologic factors (i.e., cerebral blood flow (ΔCBF), cerebral metabolic rate of oxygen (ΔCMRO₂), and flow–metabolism coupling (ΔCBF/ΔCMRO₂), utilizing dual-echo calibrated fMRI (cfMRI) during a bilateral finger-tapping task. We utilized cfMRI to measure physiologic responses in 17 healthy volunteers and 32 MS patients (MSP) with and without motor impairment during a thumb-button-press task in thumb-related (task-central) and surrounding primary motor cortex (task-surround) regions of interest (ROIs). We observed significant ΔCBF and ΔCMRO₂ increases in all MSP compared to healthy volunteers in the task-central ROI and increased flow–metabolism coupling (ΔCBF/ΔCMRO₂) in the MSP without motor impairment. In the task-surround ROI, we observed decreases in ΔCBF and ΔCMRO₂ in MSP with motor impairment. Additionally, ΔCBF and ΔCMRO₂ responses in the task-surround ROI were associated with motor function and white matter damage in MSP. These results suggest an important role for task-surround recruitment in the primary motor cortex to maintain motor dexterity and its dependence on intact white matter microstructure and neural–vascular coupling.