Mitigating the effects of COVID-19 pandemic on controlling vascular risk factors among participants in a carotid stenosis trial.

INTRODUCTION: The COVID-19 pandemic has presented challenges to managing vascular risk factors with in-person follow-up of patients with asymptomatic carotid stenosis enrolled in the CREST2 trial. CREST2 is comparing intensive medical management alone versus intensive medical management plus revascularization with endarterectomy or stenting. We performed a study to evaluate the feasibility of a home-based program for testing blood pressure (BP) and low-density lipoprotein (LDL) in CREST2. METHODS: This study involved 45 patients at 10 sites in the CREST2 trial. The initial patients were identified by the Medical Management Core (MMC) as high-risk patients defined by stage 2 hypertension, LDL > 90 mg/dl, or both. If a patient at the site declined participation, another was substituted. All patients who agreed to participate were sent a BP monitoring device and a commercially available at-home lipid test kit that uses a self-performed finger-stick blood sample that was resulted to the patient. Training on the use of the equipment and obtaining the risk factor results was done by the study coordinator by telephone. RESULTS: Ten of the 130 currently active CREST2 sites participated, 8 in the LDL portion and 5 in the BP portion (3 sites did both). Twenty-six BP devices and 23 lipid tests were sent to patients. Of the 26 patients who obtained BP readings with the devices, 9 were out of the study target and adjustments in BP medications were made in 3. Of the 23 patients sent LDL tests, 13 were able to perform the test showing 7 were out of target, leading to adjustments in lipid medications in 4. CONCLUSION: This study established the feasibility of at-home monitoring of BP and LDL in a clinical trial and identified implementation challenges prior to widespread use in the trial. (ClinicalTrials.gov number NCT02089217).

Rationale, Design, and Implementation of Intensive Risk Factor Treatment in the CREST2 Trial.

BACKGROUND AND PURPOSE: The CREST2 trial (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis) is comparing intensive medical management (IMM) alone to IMM plus revascularization with carotid endarterectomy or transfemoral carotid artery stenting for preventing stroke or death within 44 days after randomization or ipsilateral ischemic stroke thereafter. There are extensive clinical trial data on outcomes after revascularization of asymptomatic carotid stenosis, but not for IMM. As such, the experimental treatment in CREST2 is IMM, which is described in this article. METHODS: IMM consists of aspirin 325 mg/day and intensive risk factor management, primarily targeting systolic blood pressure <130 mm Hg (initially systolic blood pressure <140 mm Hg) and LDL (low-density lipoprotein) cholesterol <70 mg/dL. Secondary risk factor targets focus on tobacco smoking, non-HDL (high-density lipoprotein), HbA1c (hemoglobin A1c), physical activity, and weight. Risk factor management is performed by site personnel and a lifestyle coaching program delivered by telephone. We report interim risk factor data on 1618 patients at baseline and last follow-up through 24 months. RESULTS: The mean baseline LDL of 80.5 mg/dL improved to 66.7 mg/dL. The mean baseline systolic blood pressure of 139.7 mm Hg improved to 130.3 mm Hg. The proportion of patients in-target improved from 43% to 61% for systolic blood pressure <130 mm Hg and from 45% to 67% for LDL<70 mg/dL (both changes P<0.001). CONCLUSIONS: The rigorous multimodal approach to intensive stroke risk factor management in CREST2 has resulted in significant improvements in risk factor control that will enable a comparison of cutting-edge medical care to revascularization in patients with asymptomatic carotid stenosis. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02089217.

Development of a high resolution MRI intracranial atherosclerosis imaging phantom.

BACKGROUND AND PURPOSE: Currently, there is neither a standard protocol for vessel wall MR imaging of intracranial atherosclerotic disease (ICAD) nor a gold standard phantom to compare MR sequences. In this study, a plaque phantom is developed and characterized that provides a platform for establishing a uniform imaging approach for ICAD. MATERIALS AND METHODS: A patient specific injection mold was 3D printed to construct a geometrically accurate ICAD phantom. Polyvinyl alcohol hydrogel was infused into the core shell mold to form the stenotic artery. The ICAD phantom incorporated materials mimicking a stenotic vessel and plaque components, including fibrous cap and lipid core. Two phantoms were scanned using high resolution cone beam CT and compared with four different 3 T MRI systems across eight different sites over a period of 18 months. Inter-phantom variability was assessed by lumen dimensions and contrast to noise ratio (CNR). RESULTS: Quantitative evaluation of the minimum lumen radius in the stenosis showed that the radius was on average 0.80 mm (95% CI 0.77 to 0.82 mm) in model 1 and 0.77 mm (95% CI 0.74 to 0.81 mm) in model 2. The highest CNRs were observed for comparisons between lipid and vessel wall. To evaluate manufacturing reproducibility, the CNR variability between the two models had an average absolute difference of 4.31 (95% CI 3.82 to 5.78). Variation in CNR between the images from the same scanner separated by 7 months was 2.5-6.2, showing reproducible phantom durability. CONCLUSIONS: A plaque phantom composed of a stenotic vessel wall and plaque components was successfully constructed for multicenter high resolution MRI standardization.

Individualized real-time fMRI neurofeedback to attenuate craving in nicotine-dependent smokers.

BACKGROUND: Cue-induced craving plays an important role in relapse, and the neural correlates of cue-induced craving have been elucidated using fMRI. This study examined the utility of real-time fMRI (rtfMRI) neurofeedback to strengthen self-regulation of craving-related neural activation and cue-reactivity in cigarette smokers. METHODS: Nicotine-dependent smokers were randomized to rtfMRI neurofeedback or to a no-feedback control group. Participants completed 3 neuroimaging visits. Within each visit, an initial run during which smoking-related cues were used to provoke craving, an individualized craving-related region of interest (ROI) in the prefrontal cortex or anterior cingulate cortex was identified. In the rtfMRI group, activity from the ROI was fed back via a visual display during 3 subsequent runs while participants were instructed to reduce craving during cue exposure. The control group had an identical experience with no feedback provided. RESULTS: Forty-four nicotine-dependent smokers were recruited to participate in our study; data from the 33 participants who completed a 1-week follow-up visit were included in the analysis. Subjective craving ratings and cue-induced brain activation were lower in the rtfMRI group than in the control group. LIMITATIONS: As participants were not seeking treatment, clinical outcomes are lacking. CONCLUSION: Nicotine-dependent smokers receiving rtfMRI feedback from an individualized ROI attenuated smoking cue-elicited neural activation and craving, relative to a control group. Further studies are needed in treatment-seeking smokers to determine if this intervention can translate into a clinically meaningful treatment modality.

The fMRI BOLD response to unisensory and multisensory smoking cues in nicotine-dependent adults.

Given that the vast majority of functional magnetic resonance imaging (fMRI) studies of drug cue reactivity use unisensory visual cues, but that multisensory cues may elicit greater craving-related brain responses, the current study sought to compare the fMRI BOLD response to unisensory visual and multisensory, visual plus odor, smoking cues in 17 nicotine-dependent adult cigarette smokers. Brain activation to smoking-related, compared to neutral, pictures was assessed under cigarette smoke and odorless odor conditions. While smoking pictures elicited a pattern of activation consistent with the addiction literature, the multisensory (odor+picture) smoking cues elicited significantly greater and more widespread activation in mainly frontal and temporal regions. BOLD signal elicited by the multisensory, but not unisensory cues, was significantly related to participants' level of control over craving as well. Results demonstrated that the co-presentation of cigarette smoke odor with smoking-related visual cues, compared to the visual cues alone, elicited greater levels of craving-related brain activation in key regions implicated in reward. These preliminary findings support future research aimed at a better understanding of multisensory integration of drug cues and craving.

Characterization of intracranial atherosclerotic stenosis using high-resolution MRI study--rationale and design.

BACKGROUND: Intracranial atherosclerosis is a leading cause of stroke, but little is known about the composition of the intracranial atherosclerotic lesion and how intracranial plaque morphology is related to the risk of stroke. High-resolution magnetic resonance imaging (HR MRI) has been used in patients with extracranial carotid atherosclerosis as an in vivo tool to identify, with high-interrater agreement, histologically defined plaque components (i.e., intraplaque hemorrhage, fibrous cap, and lipid core), which have been shown to be predictors of recurrent stroke. With careful imaging the components of atherosclerotic plaque can be visualized in the intracranial arteries using HR MRI, but there are no reports of reproducibility or interrater reliability. METHODS/STUDY DESIGN: The Characterization of intracranial atherosclerotic stenosis using high-resolution MRI (CHIASM) study is a single-center NIH-funded prospective observational study, to (1) demonstrate high -interrater agreement for identifying intracranial plaque components on HR MRI, (2) determine the frequency of these components in symptomatic versus asymptomatic plaques, and (3) estimate the 1-year rate of stroke in the territory of high-risk plaque components. CHIASM will recruit 90 patients with 50-99% intracranial atherosclerosis to undergo HRMRI of the intracranial artery plaque at enrollment and 1-year follow-up. Both symptomatic and asymptomatic subjects will be recruited. CONCLUSION: Determination of good interrater reliability is an important first step in the development of HR MRI as a tool to predict risk in patients with intracranial atherosclerosis. This study will inform the design of future multicenter studies to determine the prevalence and prognosis of intracranial atherosclerotic plaque components. Such studies could lead to new understanding of the pathophysiological mechanisms of cerebral ischemia in patients with atherosclerotic intracranial stenosis, improvements in risk stratification, and potentially to new treatments of this common and serious disease.

Right anterior insula connectivity is important for cue-induced craving in nicotine-dependent smokers.

The insula has been implicated in cue-induced craving and relapse in nicotine-dependent tobacco cigarette smokers. The aims of the present study were to identify brain regions that exhibit greater functional connectivity with the right anterior insula in response to smoking cues than to neutral cues and the role of functional connectivity between these regions in mediating cue-induced craving in healthy (free of axis I psychiatric disorders) nicotine-dependent tobacco cigarette smokers. Functional magnetic resonance imaging data were collected from 63 healthy nicotine-dependent smokers viewing blocks of smoking and neutral cues. Craving ratings were obtained after each block. A psychophysiologic interaction approach was used to identify regions that exhibited significantly greater functional connectivity with the right anterior insula (seed) during the smoking cues than during the neutral (corrected cluster thresholding, Z > 2.3, P = 0.05). Parameter estimates of the interaction effects from each region were regressed against the mean cue-induced craving scores. Significant task by seed interactions were observed in two clusters centered in the bilateral precuneus and left angular gyrus. The strength of connectivity between the right anterior insula and the precuneus, which is involved interoceptive processing and self-awareness, was positively correlated with the magnitude of the craving response to the smoking cues (r(2) = 0.15; P < 0.01). These data suggest that among smokers, cue-induced craving may be a function of connectivity between two regions involved in interoception and self-awareness. Moreover, treatment strategies that incorporate mindful attention may be effective in attenuating cue-induced craving and relapse in nicotine-dependent smokers.

Sustained reduction of nicotine craving with real-time neurofeedback: exploring the role of severity of dependence.

BACKGROUND: Neurofeedback delivered via real-time functional magnetic resonance imaging (rtfMRI) is a promising therapeutic technique being explored to facilitate self-regulation of craving in nicotine-dependent cigarette smokers. The current study examined the role of nicotine-dependence severity and the efficacy of multiple visits of neurofeedback from a single region of interest (ROI) in the anterior cingulate cortex (ACC) on craving reduction. METHODS: Nine nicotine-dependent cigarette smokers participated in three rtfMRI visits that examined cue-induced craving and brain activation. Severity of nicotine dependence was assessed with the Fagerström Test for Nicotine Dependence. When viewing smoking-related images with instructions to "crave," patient-tailored ROIs were generated in the vicinity of the ACC. Activity levels from the ROI were fed back while participants viewed smoking cues with the instruction to reduce craving. RESULTS: Neurofeedback from a single ROI in the ACC led to consistent decreases in self-reported craving and activation in the ACC across the three visits. Dependence severity predicted response to neurofeedback at Visit 3. CONCLUSIONS: This study builds upon previous rtfMRI studies on the regulation of nicotine craving in demonstrating that feedback from the ACC can reduce activation to smoking cues across three separate visits. Individuals with lower nicotine-dependence severity were more successful in reducing ACC activation over time. These data highlight the need to consider dependence severity in developing more individualized neurofeedback methods.

Reduction of cue-induced craving through realtime neurofeedback in nicotine users: the role of region of interest selection and multiple visits.

This multi-visit, real-time functional magnetic resonance imaging feedback study demonstrates that treatment-seeking smokers can effectively modulate their behavioral and brain responses to smoking cues. They are more effective at decreasing activity in functionally defined regions involved in "craving" (e.g. ventral anterior cingulate cortex (vACC)) rather than increasing activity in regions involved in "resisting" (e.g. dorsal medial prefrontal cortex (dmPFC)).

Repetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex reduces nicotine cue craving.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) can noninvasively stimulate the brain and transiently amplify or block behaviors mediated through a region. We hypothesized that a single high-frequency rTMS session over the left dorsolateral prefrontal cortex (DLPFC) would reduce cue craving for cigarettes compared with a sham TMS session. METHODS: Sixteen non-treatment-seeking, nicotine-dependent participants were randomized to receive either real high-frequency rTMS (10 Hz, 100% resting motor threshold, 5-sec on, 10-sec off for 15 min; 3000 pulses) or active sham (eSham) TMS over the DLPFC in two visits with 1 week between visits. The participants received cue exposure before and after rTMS and rated their craving after each block of cue presentation. RESULTS: Stimulation of the left DLFPC with real, but not sham, rTMS reduced craving significantly from baseline (64.1±5.9 vs. 45.7±6.4, t = 2.69, p = .018). When compared with neutral cue craving, the effect of real TMS on cue craving was significantly greater than the effect of sham TMS (12.5±10.4 vs. -9.1±10.4; t = 2.07, p = .049). More decreases in subjective craving induced by TMS correlated positively with higher Fagerström Test for Nicotine Dependence score (r = .58, p = .031) and more cigarettes smoked per day (r = .57, p = .035). CONCLUSIONS: One session of high-frequency rTMS (10 Hz) of the left DLPFC significantly reduced subjective craving induced by smoking cues in nicotine-dependent participants. Additional studies are needed to explore rTMS as an aid to smoking cessation.

Resisting the urge to smoke and craving during a smoking quit attempt on varenicline: results from a pilot fMRI study.

BACKGROUND: Varenicline has been shown to reduce cigarette craving during a quit attempt. OBJECTIVES: Use BOLD fMRI to explore differences in smoking cue reactivity at baseline and after five weeks of varenicline smoking cessation treatment. METHODS: Treatment-seeking nicotine-dependent adult smokers underwent BOLD fMRI scans with block presentation of visual smoking, neutral, and rest cues under two conditions: craving or resisting the urge to smoke at baseline and following 5 weeks of standard varenicline therapy. Data were analyzed using FMRI Expert Analysis Tool, version 5.98 of Functional Magnetic Imaging of the Brain Software Library focused on the smoking vs. neutral cue contrast at the individual and group level, Z>2.3 with cluster threshold p=0.05. RESULTS: Twenty-one participants were scanned at baseline and 16 completed the study; 10 were abstinent at the 2(nd) session, confirmed with urinary cotinine. In the Crave Condition no significant differences were found between the abstinent and non-abstinent groups at either time point. During the baseline Resist Condition, the abstinent group compared to the non-abstinent group demonstrated activation in a distributed network involved in alertness, learning and memory. Additionally, within the abstinent group, increased activation of the superior frontal gyrus was found at baseline compared to week 5. CONCLUSION: Successful smoking cessation with varenicline is associated with increased activation, prior to a quit attempt, in brain areas related to attentiveness and memory while resisting the urge to smoke Scientific Significance: Varenicline may exert effects by both reducing craving and enhancing resistance to smoking urges during cue-elicited craving.

Volitional reduction of anterior cingulate cortex activity produces decreased cue craving in smoking cessation: a preliminary real-time fMRI study.

Numerous research groups are now using analysis of blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) results and relaying back information about regional activity in their brains to participants in the scanner in 'real time'. In this study, we explored the feasibility of self-regulation of frontal cortical activation using real-time fMRI (rtfMRI) neurofeedback in nicotine-dependent cigarette smokers during exposure to smoking cues. Ten cigarette smokers were shown smoking-related visual cues in a 3 Tesla MRI scanner to induce their nicotine craving. Participants were instructed to modify their craving using rtfMRI feedback with two different approaches. In a 'reduce craving' paradigm, participants were instructed to 'reduce' their craving, and decrease the anterior cingulate cortex (ACC) activity. In a separate 'increase resistance' paradigm, participants were asked to increase their resistance to craving and to increase middle prefrontal cortex (mPFC) activity. We found that participants were able to significantly reduce the BOLD signal in the ACC during the 'reduce craving' task (P=0.028). There was a significant correlation between decreased ACC activation and reduced craving ratings during the 'reduce craving' session (P=0.011). In contrast, there was no modulation of the BOLD signal in mPFC during the 'increase resistance' session. These preliminary results suggest that some smokers may be able to use neurofeedback via rtfMRI to voluntarily regulate ACC activation and temporarily reduce smoking cue-induced craving. Further research is needed to determine the optimal parameters of neurofeedback rtfMRI, and whether it might eventually become a therapeutic tool for nicotine dependence.

Intermittent "real-time" fMRI feedback is superior to continuous presentation for a motor imagery task: a pilot study.

BACKGROUND: Real-time functional MRI feedback (RTfMRIf) is a developing technique, with unanswered methodological questions. Given a delay of seconds between neural activity and the measurable hemodynamic response, one issue is the optimal method for presentation of neurofeedback to subjects. The primary objective of this preliminary study was to compare the methods of continuous and intermittent presentation of neural feedback on targeted brain activity. METHODS: Thirteen participants performed a motor imagery task and were instructed to increase activation in an individually defined region of left premotor cortex using RTfMRIf. The fMRI signal change was compared between real and false feedback for scans with either continuous or intermittent feedback presentation. RESULTS: More individuals were able to increase their fMRI signal with intermittent feedback, while some individuals had decreased signal with continuous feedback. The evaluation of feedback itself activated an extensive amount of brain regions, and false feedback resulted in brain activation outside of the individually defined region of interest. CONCLUSIONS: As implemented in this study, intermittent presentation of feedback is more effective than continuous presentation in promoting self-modulation of brain activity. Furthermore, it appears that the process of evaluating feedback involves many brain regions that can be isolated using intermittent presentation.

Neural correlates of craving and resisting craving for tobacco in nicotine dependent smokers.

Craving is a significant factor which can lead to relapse during smoking quit attempts. Attempts to resist urges to smoke during cue-elicited craving have been shown to activate regions in the brain associated with decision-making, anxiety regulation and visual processing. In this study, 32 treatment-seeking, nicotine-dependent smokers viewed blocks of smoking and neutral cues alternating with rest periods during magnetic resonance imaging scanning in a 3T Siemens scanner (Siemens AG, Erlangen, Bavaria, Germany). While viewing cues or control images, participants were instructed either to 'allow yourself to crave' or 'resist craving.' Data were analyzed with FSL 4.1.5, focused on the smoking cues versus neutral cues contrast, using cluster thresholding (Z > 2.3 and corrected cluster threshold of P = 0.05) at the individual and group levels. During the Crave condition, activation was seen on the left anterior cingulated cortex (LACC), medial prefrontal cortex, left middle cingulate gyrus, bilateral posterior cingulated gyrus and bilateral precuneus, areas associated with attention, decision-making and episodic memory. The LACC and areas of the prefrontal cortex associated with higher executive functioning were activated during the Resist condition. No clear distinctions between group crave and resist analyses as a whole were seen without taking into account specific strategies used to resist the urge to smoke, supporting the idea that craving is associated with some degree of resisting the urge to smoke, and trying to resist is almost always accompanied by some degree of craving. Different strategies for resisting, such as distraction, activated different regions. Understanding the underlying neurobiology of resisting craving to smoke may identify new foci for treatments.