fMRI BOLD responses to film stimuli and their association with exhaled nitric oxide in asthma and health.

Little is known about central nervous system (CNS) responses to emotional stimuli in asthma. Nitric oxide in exhaled breath (FENO) is elevated in asthma due to allergic immune processes, but endogenous nitric oxide is also known to modulate CNS activity. We measured fMRI blood oxygen-dependent (BOLD) brain activation to negative (blood-injection-injury themes) and neutral films in 31 participants (15 with asthma). Regions-of-interest analysis was performed on key areas relevant to central adaptive control, threat processing, or salience networks, with dorsolateral prefrontal cortex (PFC), anterior insula, dorsal anterior cingulate cortex (dACC), amygdala, ventral striatum, ventral tegmentum, and periaqueductal gray, as well as top-down modulation of emotion, with ventrolateral and ventromedial PFC. Both groups showed less BOLD deactivation from fixation cross-baseline in the left anterior insula and bilateral ventromedial PFC for negative than neutral films, and for an additional number of areas, including the fusiform gyrus, for film versus recovery phases. Less deactivation during films followed by less recovery from deactivation was found in asthma compared to healthy controls. Changes in PCO2 did not explain these findings. FENO was positively related to BOLD activation in general, but more pronounced in healthy controls and more likely in neutral film processing. Thus, asthma is associated with altered processing of film stimuli across brain regions not limited to central adaptive control, threat processing, or salience networks. Higher levels of NO appear to facilitate CNS activity, but only in healthy controls, possibly due to allergy's masking effects on FENO.

Neural substrates of emotional conflict with anxiety in major depressive disorder: Findings from the Establishing Moderators and biosignatures of Antidepressant Response in Clinical Care (EMBARC) randomized controlled trial.

BACKGROUND: The brain circuitry of depression and anxiety/fear is well-established, involving regions such as the limbic system and prefrontal cortex. We expand prior literature by examining the extent to which four discrete factors of anxiety (immediate state anxiety, physiological/panic, neuroticism/worry, and agitation/restlessness) among depressed outpatients are associated with differential responses during reactivity to and regulation of emotional conflict. METHODS: A total of 172 subjects diagnosed with major depressive disorder underwent functional magnetic resonance imaging while performing an Emotional Stroop Task. Two main contrasts were examined using whole brain voxel wise analyses: emotional reactivity and emotion regulation. We also evaluated the association of these contrasts with the four aforementioned anxiety factors. RESULTS: During emotional reactivity, participants with higher immediate state anxiety showed potentiated activation in the rolandic operculum and insula, while individuals with higher levels of physiological/panic demonstrated decreased activation in the posterior cingulate. No significant results emerged for any of the four factors on emotion regulation. When re-analyzing these statistically-significant brain regions through analyses of a subsample with (n = 92) and without (n = 80) a current anxiety disorder, no significant associations occurred among those without an anxiety disorder. Among those with an anxiety disorder, results were similar to the full sample, except the posterior cingulate was associated with the neuroticism/worry factor. CONCLUSIONS: Divergent patterns of task-related brain activation across four discrete anxiety factors could be used to inform treatment decisions and target specific aspects of anxiety that involve intrinsic processing to attenuate overactive responses to emotional stimuli.

Central nervous system signatures of affect in asthma: associations with emotion-induced bronchoconstriction, airway inflammation, and asthma control.

The effects of asthma on affect have been noted for some time, but little is known about associated brain processes. We therefore examined whether emotion-induced bronchoconstriction, airway inflammation, and asthma control are related to specific patterns of brain activity during processing negative affective stimuli. Fifteen adults with asthma viewed alternating blocks of distressing film clips (negative condition), affectively neutral film clips (neutral condition), and a crosshair image (baseline condition) while undergoing blood oxygenation level-dependent (BOLD) functional MRI (fMRI). Block-design fMRI analysis evaluated the BOLD response to "negative-baseline" and "neutral-baseline" contrasts. Airway response to these film clips was also assessed with impulse oscillometry in a separate session. Measures of airway inflammation [fractional exhaled nitric oxide (FENO)] and asthma control [Asthma Control Questionnaire (ACQ)] were additionally obtained. A whole brain voxel-based regression analysis of contrast maps was performed against respiratory resistance increase during negative and neutral films, FENO, and ACQ. Peak airway obstruction to negative affective stimulation was associated with stronger activation of the anterior and middle cingulate gyrus, including the dorsal anterior cingulate cortex (dACC). Stronger airway inflammation and lower asthma control were associated with reduced activation to negative stimuli in the superior frontal gyrus, middle cingulate gyrus, and supplementary motor area. Activation of the dACC in negative-affect-induced airway obstruction could be part of an integrated defensive response to critical environmental change. In addition, reduced frontal and limbic activation during processing of negative affect may reflect consequences of pathophysiological processes for CNS functioning. NEW & NOTEWORTHY This functional magnetic resonance imaging study shows, for the first time, that the degree of airway constriction due to negative affective stimuli in asthma is associated with stronger response to these stimuli in the dorsal anterior and middle cingulate cortex. Asthma patients with stronger airway inflammation and reduced asthma control also show reduced activation in a number of cortical and subcortical areas relevant for affective processing and breathing control.

Higher-order cognitive training effects on processing speed-related neural activity: a randomized trial.

Higher-order cognitive training has shown to enhance performance in older adults, but the neural mechanisms underlying performance enhancement have yet to be fully disambiguated. This randomized trial examined changes in processing speed and processing speed-related neural activity in older participants (57-71 years of age) who underwent cognitive training (CT, N = 12) compared with wait-listed (WLC, N = 15) or exercise-training active (AC, N = 14) controls. The cognitive training taught cognitive control functions of strategic attention, integrative reasoning, and innovation over 12 weeks. All 3 groups worked through a functional magnetic resonance imaging processing speed task during 3 sessions (baseline, mid-training, and post-training). Although all groups showed faster reaction times (RTs) across sessions, the CT group showed a significant increase, and the WLC and AC groups showed significant decreases across sessions in the association between RT and BOLD signal change within the left prefrontal cortex (PFC). Thus, cognitive training led to a change in processing speed-related neural activity where faster processing speed was associated with reduced PFC activation, fitting previously identified neural efficiency profiles.

A multimodal study of impulsivity and body weight: Integrating behavioral, cognitive, and neuroimaging approaches.

OBJECTIVE: Dimensions of impulsivity are related to obesity. Accordingly, characterization of impulsivity in individuals with overweight and obesity holds promise for more targeted and effective intervention. METHODS: Forty-five individuals (13 males, mean age = 32.6, mean body mass index [BMI] = 30.7) were recruited to determine the role of impulsivity in elevated body weight by evaluating: (1) trait impulsivity via impulsive sensation-seeking scale (ImpSS), (2) state impulsivity via continuous performance test, and (3) activation and integration of brain cognitive control regions via functional magnetic resonance imaging during a response inhibition task (i.e., stop signal task). RESULTS: Positive correlations were found between BMI and trait (ImpSS) as well as state impulsivity (continuous performance test, ß). BMI was negatively correlated with regional activation in the temporal lobe and insula during successful response inhibition. Further, there was a positive association between BMI and functional connectivity between the right inferior frontal gyrus and right middle frontal gyrus during successful response inhibition. Mediation analyses revealed that ImpSS mediated the relationship between BMI and neural response in the right inferior frontal gyrus. CONCLUSIONS: This multimodal study provides concordant evidence for behavioral, cognitive, and neural markers of impulsivity and elevated BMI, highlighting the need to address inhibitory control mechanisms for more effective weight management programs.

The impact of therapists' words on the adolescent brain: In the context of addiction treatment.

At this time, we still do not know how therapist behaviors influence adolescent brain response and related treatment outcomes. Therefore, we examined this question with 17 binge drinking youth (mean age=16.62 years; 64.3% female; 42.9% Hispanic; 28.6% bi-/multi-racial). In this within-subjects design, all youth completed a baseline assessment, two therapy sessions, an fMRI scan, and were re-evaluated for behavior change at one-month post-treatment. During the fMRI session, youth were presented with two types of responses from their treating therapist: higher-skill statements prescribed in an empirically-supported addiction treatment (complex reflections) vs. language standard within addiction treatment more broadly (closed questions). In terms of behavior change, at the one-month follow-up, youth showed significant reductions in number of drinking days and binge drinking days. Further, we found main effects for complex reflections and closed questions across the superior middle temporal gyrus and middle temporal gyrus (FWE-corrected, p<.05). Greater brain response was observed for complex reflections versus closed questions within the bilateral anterior cingulate gyrus. Greater BOLD response in the parietal lobe during closed questions was significantly associated with less post-treatment drinking. Lower BOLD response during complex reflections and closed questions in the precuneus were associated with greater post-treatment ratings of importance of changing. This study represents a first step in understanding how therapist behaviors influence the developing adolescent brain and how that neural response may be associated with youth treatment outcomes.

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. Therefore, the ability of the blood vessels to dilate or constrict, known as Cerebral-Vascular-Reactivity (CVR), represents an important domain of vascular function. An imaging marker representing this dynamic property will provide new information of cerebral vessels under normal and diseased conditions such as stroke, dementia, atherosclerosis, small vessel diseases, brain tumor, traumatic brain injury, and multiple sclerosis. In order to perform this type of measurement in humans, it is necessary to deliver a vasoactive stimulus such as CO2 and/or O2 gas mixture while quantitative brain magnetic resonance images (MRI) are being collected. In this work, we presented a MR compatible gas-delivery system and the associated protocol that allow the delivery of special gas mixtures (e.g., O2, CO2, N2, and their combinations) while the subject is lying inside the MRI scanner. This system is relatively simple, economical, and easy to use, and the experimental protocol allows accurate mapping of CVR in both healthy volunteers and patients with neurological disorders. This approach has the potential to be used in broad clinical applications and in better understanding of brain vascular pathophysiology. In the video, we demonstrate how to set up the system inside an MRI suite and how to perform a complete experiment on a human participant.

Brain-based origins of change language: a beginning.

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.

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

BACKGROUND: Loss of control is a prominent feature of cannabis use disorders (CUD) and involves orchestrated activity from several brain inhibitory control networks. OBJECTIVES: In this study, we determined the associations between inhibitory control network activation and connectivity and CUD severity. METHODS: To that end, we compared cannabis-dependent (N = 44) vs. nondependent (N = 30) users during a Stop Signal Task. First, we compared differences in neural response during response inhibition via general linear model analysis within a priori regions of interest. Second, we examined functional connectivity via psychophysiological interaction (PPI) analysis between the right frontal control network (seed region) and inhibitory control networks. RESULTS: There was no significant difference in network activation between cannabis-dependent and nondependent users in any of the inhibitory control networks. However, preliminary findings using the PPI analysis showed that during successful response inhibition, cannabis-dependent users had greater connectivity between right frontal control network and substantia nigra/subthalamic nucleus (STN) network compared to nondependent users (small volume correction, FWE-corrected p < 0.05). Further, multiple regression analyses on the PPI maps showed modulatory effects of age of onset and quantity of cannabis use in the nondependent users. CONCLUSIONS: Taken together, these findings suggest that functional connectivity between frontal control and substantia nigra/STN networks during response inhibition is sensitive to the effects of CUD severity unlike behavioral task performance and neural activation in inhibitory control networks. Further, modulators of this connectivity, such as onset and quantity of cannabis use, show attenuated effects with progression of CUD.

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

PURPOSE: To examine the potential benefits of life-long aerobic exercise on brain health, in particular cerebrovascular function. MATERIALS AND METHODS: Ten Masters athletes (MA) (seven males, three females; 74.5 ± 5.8 years) and 10 sedentary elderly individuals (SE) (eight males, two females; 75.4 ± 5.6 years) were recruited and baseline cerebral blood flow (CBF) and cerebral vascular reactivity (CVR) to CO2 were measured on a 3T MRI scanner. Nine sedentary young subjects were also recruited to serve as a control group to verify the age effect. RESULTS: When compared to the SE group, MA showed higher CBF in posterior cingulate cortex/precuneus, which are key regions of the default-mode-network and are known to be highly sensitive to age and dementia. CVR in the MA brains were paradoxically lower than that in SE. This effect was present throughout the brain. Within the MA group, individuals with higher VO2max had an even lower CVR, suggesting a dose-response relationship. CONCLUSION: Life-long aerobic exercise preserved blood supply in the brain's default-mode-network against age-related degradation. On the other hand, its impact on the cerebral vascular system seems to be characterized by a dampening of CO2 reactivity, possibly because of desensitization effects due to a higher lifetime exposure.

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

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.

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

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

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.

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

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.

In vivo vascular hallmarks of diffuse leukoaraiosis.

PURPOSE: To characterize multiple patterns of vascular changes in leukoaraiosis using in vivo magnetic resonance imaging (MRI) techniques. MATERIALS AND METHODS: We measured cerebral blood flow (CBF), cerebrovascular reactivity (CVR), and blood-brain-barrier (BBB) leakage in a group of 33 elderly subjects (age: 72.3 +/- 6.8 years, 17 males, 16 females). Leukoaraiosis brain regions were identified in each subject using fluid-attenuated inversion-recovery (FLAIR) MRI. Vascular parameters in the leukoaraiosis regions were compared to those in the normal-appearing white matter (NAWM) regions. Vascular changes in leukoaraiosis were also compared to structural damage as assessed by diffusion tensor imaging. RESULTS: CBF and CVR in leukoaraiosis regions were found to be 39.7 +/- 5.2% (P < 0.001) and 52.5 +/- 11.6% (P = 0.005), respectively, of those in NAWM. In subjects who did not have significant leukoaraiosis, CBF and CVR in regions with high risk for leukoaraiosis showed a slight reduction compared to the other white matter regions. Significant BBB leakage was also detected (P = 0.003) in leukoaraiosis and the extent of BBB leakage was positively correlated with mean diffusivity. In addition, CVR in NAWM was lower than that in white matter of subjects without significant leukoaraiosis. CONCLUSION: Leukoaraiosis was characterized by reduced CBF, CVR, and a leakage in the BBB.

Estimation of labeling efficiency in pseudocontinuous arterial spin labeling.

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.

Improving fMRI sensitivity by normalization of basal physiologic state.

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.

On the assessment of cerebrovascular reactivity using hypercapnia BOLD MRI.

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.