MRI Mapping of Cerebrovascular Reactivity via Gas Inhalation Challenges

The brain is a spatially heterogeneous and temporally dynamic organ, with different regions requiring different amount of blood supply at different time. ...

University of Texas Southwestern Medical Center

Cerebrovascular reactivity (CVR) reflects the capacity of blood vessels to dilate and is an important marker for brain vascular reserve. It may provide a useful addition to the traditional baseline blood flow measurement when assessing vascular factors in brain disorders. Blood-oxygenation-level-dependent MRI under CO(2) inhalation offers a non-invasive and quantitative means to estimate CVR in humans. In this study, we investigated several important methodological aspects of this technique with the goal of optimizing the experimental and data processing strategies for clinical use. Comparing 4 min of 5% CO(2) inhalation (less comfortable) to a 1 min inhalation (more comfortable) duration, it was found that the CVR values were 0.31 +/- 0.05%/mmHg (N = 11) and 0.31 +/- 0.08%/mmHg (N = 9), respectively, showing no significant differences between the two breathing paradigms. Therefore, the 1 min paradigm is recommended for future application studies for patient comfort and tolerability. Furthermore, we have found that end-tidal CO(2) recording was useful for accurate quantification of CVR because it provided both timing and amplitude information regarding the input function to the brain vascular system, which can be subject-dependent. Finally, we show that inter-subject variations in CVR are of physiologic origin and affect the whole brain in a similar fashion. Based on this, it is proposed that relative CVR (normalized against the CVR of the whole brain or a reference tissue) may be a more sensitive biomarker than absolute CVR in clinical applications as it minimizes inter-subject variations. With these technological optimizations, CVR mapping may become a useful method for studies of neurological and psychiatric diseases.

On the assessment of cerebrovascular reactivity using hypercapnia BOLD MRI.

The power of fMRI in assessing neural activities is hampered by inter-subject variations in basal physiologic parameters, which may not be related to neural activation but has a modulatory effect on fMRI signals. Therefore, normalization of fMRI signals with these parameters is useful in reducing variations and improving sensitivity of this important technique. Recently, we have shown that basal venous oxygenation is a significant modulator of fMRI signals and individuals with higher venous oxygenation tend to have lower fMRI signals. In this study, we aim to test the utility of venous oxygenation normalization in distinguishing subject groups. A "model" condition was used in which two visual stimuli with different flashing frequencies were used to stimulate two subject groups, respectively, thereby simulating the situation of control and patient groups. It was found that visual-evoked BOLD signal is significantly correlated with baseline venous T2 (P = 0.0003) and inclusion of physiologic modulator in the regression analysis can substantially reduce P values of group-level statistical tests. When applied to voxel-wise analysis, the normalization process can allow the detection of more significant voxels. The utility of other basal parameters, including blood pressure, heart rate, arterial oxygenation, and end-tidal CO(2), in BOLD normalization was also assessed and it was found that the improvement was less significant. Time-to-peak of the BOLD responses was also studied and it was found that subjects with higher basal venous oxygenation tend to slower BOLD responses.

Improving fMRI sensitivity by normalization of basal physiologic state.

Pseudocontinuous arterial spin labeling MRI is a new arterial spin labeling technique that has the potential of combining advantages of continuous arterial spin labeling and pulsed arterial spin labeling. However, unlike continuous arterial spin labeling, the labeling process of pseudocontinuous arterial spin labeling is not strictly an adiabatic inversion and the efficiency of labeling may be subject specific. Here, three experiments were performed to study the labeling efficiency in pseudocontinuous arterial spin labeling MRI. First, the optimal labeling position was determined empirically to be approximately 84 mm below the anterior commissure-posterior commissure line in order to achieve the highest sensitivity. Second, an experimental method was developed to utilize phase-contrast velocity MRI as a normalization factor and to estimate the labeling efficiency in vivo, which was founded to be 0.86 +/- 0.06 (n = 10, mean +/- standard deviation). Third, we compared the labeling efficiency of pseudocontinuous arterial spin labeling MRI under normocapnic and hypercapnic (inhalation of 5% CO(2)) conditions and showed that a higher flow velocity in the feeding arteries resulted in a reduction in the labeling efficiency. In summary, our results suggest that labeling efficiency is a critical parameter in pseudocontinuous arterial spin labeling MRI not only in terms of achieving highest sensitivity but also in quantification of absolute cerebral blood flow in milliliters per minute per 100 g. We propose that the labeling efficiency should be estimated using phase-contrast velocity MRI on a subject-specific basis.

Estimation of labeling efficiency in pseudocontinuous arterial spin labeling.

Epidemiologic evidence and postmortem studies of cerebral amyloid angiopathy suggest that vascular dysfunction may play an important role in the pathogenesis of Alzheimer's disease (AD). However, alterations in vascular function under in vivo conditions are poorly understood. In this study, we assessed cerebrovascular-reactivity (CVR) in AD patients and age-matched controls using CO(2)-inhalation while simultaneously acquiring Blood-Oxygenation-Level-Dependent (BOLD) MR images. Compared with controls, AD patients had widespread reduction in CVR in the rostral brain including prefrontal, anterior cingulate, and insular cortex (p < 0.01). The deficits could not be explained by cardiovascular risk factors. The spatial distribution of the CVR deficits differed drastically from the regions of cerebral blood flow (CBF) deficits, which were found in temporal and parietal cortices. Individuals with greater CVR deficit tended to have a greater volume of leukoaraiosis as seen on FLAIR MRI (p = 0.004). Our data suggest that early AD subjects have evidence of significant forebrain vascular contractility deficits. The localization, while differing from CBF findings, appears to be spatially similar to PIB amyloid imaging findings.

Forebrain-dominant deficit in cerebrovascular reactivity in Alzheimer's disease.

To characterize multiple patterns of vascular changes in leukoaraiosis using in vivo magnetic resonance imaging (MRI) techniques.

In vivo vascular hallmarks of diffuse leukoaraiosis.

A better understanding of carbon dioxide (CO(2)) effect on brain activity may have a profound impact on clinical studies using CO(2) manipulation to assess cerebrovascular reserve and on the use of hypercapnia as a means to calibrate functional magnetic resonance imaging (fMRI) signal. This study investigates how an increase in blood CO(2), via inhalation of 5% CO(2), may alter brain activity in humans. Dynamic measurement of brain metabolism revealed that mild hypercapnia resulted in a suppression of cerebral metabolic rate of oxygen (CMRO(2)) by 13.4% ± 2.3% (N=14) and, furthermore, the CMRO(2) change was proportional to the subject's end-tidal CO(2) (Et-CO(2)) change. When using functional connectivity MRI (fcMRI) to assess the changes in resting-state neural activity, it was found that hypercapnia resulted in a reduction in all fcMRI indices assessed including cluster volume, cross-correlation coefficient, and amplitude of the fcMRI signal in the default-mode network (DMN). The extent of the reduction was more pronounced than similar indices obtained in visual-evoked fMRI, suggesting a selective suppression effect on resting-state neural activity. Scalp electroencephalogram (EEG) studies comparing hypercapnia with normocapnia conditions showed a relative increase in low frequency power in the EEG spectra, suggesting that the brain is entering a low arousal state on CO(2) inhalation.

The influence of carbon dioxide on brain activity and metabolism in conscious humans.

Client language (change talk [CT] and counterchange talk [CCT]) is gaining increasing support as an active ingredient of psychosocial interventions. Preliminary work with adults suggests that there may be a neural basis for this. With a diverse sample of adolescent cannabis users, we evaluated the influence of CT and CCT on blood oxygen level dependent (BOLD) response during an fMRI cannabis cue-exposure paradigm. We also investigated how BOLD activation related to treatment outcomes. Adolescent cannabis users (N = 43; 83.7% male; 53.5% Hispanic; M age = 16 years) were presented with CT and CCT derived from their prescan intervention session during the fMRI paradigm. Additionally, BOLD activation during CT (vs. CCT) was tested as a predictor of 1-month follow-up cannabis use behavior (frequency of cannabis use, cannabis problems, cannabis dependence). We observed a significant interaction, with greater activation during CT (vs. CCT) during the cannabis (but not control) cues in several areas key to self-referential processes (uncorrected p < 0.001; medial frontal gyrus, insula). Furthermore, BOLD activation during CT (vs. CCT) during cannabis (but not control) cues in areas that underlie introspection (posterior cingulate, precuneus) was significantly related to youths' 1-month follow-up cannabis use behavior (frequency of cannabis use, cannabis problems, cannabis dependence; uncorrected p < 0.001). These data indicate a unique interaction pattern, whereby CT (vs. CCT) during the cannabis (but not control) cues was associated with significantly greater activation in brain areas involved in introspection. Further, this activation was related to significantly better treatment outcomes for youth.

Integrating brain and behavior: evaluating adolescents' response to a cannabis intervention.

Given the link between depression, anxiety, and cannabis abuse, a serotonin receptor (rs6311) and transporter polymorphism (rs2020936) were examined as moderators of neural response as measured by functional magnetic resonance imaging following a psychosocial treatment for cannabis use disorders (CUDs). While the proposed hypotheses were unsupported, we found that the rs6311 C allele was significantly related to brain activation (medial frontal gyrus, precuneus), indicating the role of this serotonin receptor in adolescent treatment response.

A preliminary examination of how serotonergic polymorphisms influence brain response following an adolescent cannabis intervention.

To examine the potential benefits of life-long aerobic exercise on brain health, in particular cerebrovascular function.

Life-long aerobic exercise preserved baseline cerebral blood flow but reduced vascular reactivity to CO2.

Loss of control is a prominent feature of cannabis use disorders (CUD) and involves orchestrated activity from several brain inhibitory control networks.

Functional connectivity in inhibitory control networks and severity of cannabis use disorder.

Motivational interviewing (MI) is a promising treatment for heavy drinking. Client change talk (CT), a critical component of MI, has been associated with differential brain activation. The goal of this study was to begin to deconstruct how and why CT may affect the brain. Specifically, we sought to determine whether simply repeating statements in favor of change would cause differential brain activation, or whether client statements must be spontaneously generated within a therapeutic milieu in order to influence brain activation. We therefore examined blood oxygenation level dependent (BOLD) response following two types of client language (CT; and sustain talk, ST) across two conditions: (1) Self-Generated: CT and ST were elicited during an MI session vs. (2) Experimenter-Selected: a pre-established list of CT and ST was provided to the individual in the absence of an MI session. Across both conditions, participants' CT and ST were visually and aurally presented during fMRI. We enrolled 39 recent binge drinkers (41% male; M age=19.9; n=18 in Self-Generated group; n=21 in Experimenter-Selected group). We found that both types of client language (CT and ST) elicited greater BOLD activation in the Self-Generated vs. the Experimenter-Selected group in the left inferior frontal gyrus/anterior insula and superior temporal gyri (p≤0.001). These findings indicate that the nature of client language matters. It appears that it is not just the words themselves, but the origin (naturally generated within a therapeutic session) that influences brain-based effects.

Uma Yezhuvath

Advanced Imaging Research Center

University of Texas Southwestern Medical Center

MRI Mapping of Cerebrovascular Reactivity via Gas Inhalation Challenges

Uma Yezhuvath

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Advanced Imaging Research Center

University of Texas Southwestern Medical Center

MRI Mapping of Cerebrovascular Reactivity via Gas Inhalation Challenges

Advanced Imaging Research Center