Significant Blood Oxygen Level-dependent Signal Research Articles

Resting-State Brain Variability in Youth With Attention-Deficit/Hyperactivity Disorder.

In this study, we sought to determine the nature of the abnormality in resting-state default mode network (DMN) activation and explore its correlation with functional connectivity in attention-deficit/hyperactivity disorder (ADHD). We obtained resting-state functional magnetic resonance images of youth with ADHD and typically developing counterparts from the publicly available ADHD-200 database. We used data from Peking University (232 scans) and New York University (172 scans); the scan repetition time was 2 s for both data collection sites. We applied generalized estimating equations to estimate the variability of the averaged blood-oxygen-level-dependent (BOLD) time series extracted from the DMN at rest. We performed network-based statistics to determine the association between the observed differences in BOLD signal variability and altered functional connectivity. We analyzed data from 105 youth with ADHD (age: mean 12.17, standard deviation 2.31, median 12.25; 15.2% female, 84.8% male) and 140 typically developing youth (age: mean 11.99, standard deviation 2.28, median 11.85; 47.1% female, 52.9% male), who aged 7–17 years. The imaging data were cross-sectionally collected for each participant at one time point. We observed a greater number of significant BOLD signal changes and higher-order polynomial significant associations in youth with ADHD. Moreover, there were significant between-group differences in BOLD signal change after the first 140 s, which coincided with decreased resting-state functional connectivity within the DMN in youth with ADHD. Increased variability of neural signaling was intermittently observed in the brains of youth with ADHD at rest, thereby indicating their default mode state was more unstable than that of typically developing youth.

Extraction of the cardiac waveform from simultaneous multislice fMRI data using slice sorted averaging and a deep learning reconstruction filter

Cardiac signal contamination has long confounded the analysis of blood-oxygenation-level-dependent (BOLD) functional magnetic resonance imaging (fMRI). Cardiac pulsation results in significant BOLD signal changes, especially in and around blood vessels. Until the advent of simultaneous multislice echo-planar imaging (EPI) acquisition, the time resolution of whole brain EPI was insufficient to avoid cardiac aliasing (and acquisitions with repetition times (TRs) under 400–500 ms are still uncommon). As a result, direct detection and removal of the cardiac signal with spectral filters is generally not possible. Modelling methods have been developed to mitigate cardiac contamination, and recently developed techniques permit the visualization of cardiac signal propagation through the brain in undersampled data (e.g., TRs > 1s), which is useful in its own right for finding blood vessels. However, both of these techniques require data from which to estimate cardiac phase, which is generally not available for the data in many large databases of existing imaging data, and even now is not routinely recorded in many fMRI experiments.Here we present a method to estimate the cardiac waveform directly from a multislice fMRI dataset, without additional physiological measurements, such as plethysmograms. The pervasive spatial extent and temporal structure of the cardiac contamination signal across the brain offers an opportunity to exploit the nature of multislice imaging to extract this signal from the fMRI data itself. While any particular slice is recorded at the TR of the imaging experiment, slices are recorded much more quickly – typically from 10 to 20 Hz - sufficiently fast to fully sample the cardiac signal. Using the fairly permissive assumptions that the cardiac signal is a) pseudoperiodic b) somewhat coherent within any given slice, and c) is similarly shaped throughout the brain, we can extract a good estimate of the cardiac phase as a function of time from fMRI data alone. If we make further assumptions about the shape and consistency of cardiac waveforms, we can develop a deep learning filter to greatly improve our estimate of the cardiac waveform.

Reliability of supraspinal correlates to lower urinary tract stimulation in healthy participants – A fMRI study

Previous functional neuroimaging studies provided evidence for a specific supraspinal network involved in lower urinary tract (LUT) control. However, data on the reliability of blood oxygenation level-dependent (BOLD) signal changes during LUT task-related functional magnetic resonance imaging (fMRI) across separate measurements are lacking. Proof of the latter is crucial to evaluate whether fMRI can be used to assess supraspinal responses to LUT treatments.Therefore, we prospectively assessed task-specific supraspinal responses from 20 healthy participants undergoing two fMRI measurements (test-retest) within 5–8 weeks. The fMRI measurements, conducted in a 3T magnetic resonance (MR) scanner, comprised a block design of repetitive bladder filling and drainage using an automated MR-compatible and MR-synchronized infusion-drainage device. Following transurethral catheterization and bladder pre-filling with body warm saline until participants perceived a persistent desire to void (START condition), fMRI was recorded during repetitive blocks (each 15 s) of INFUSION and WITHDRAWAL of 100 mL body warm saline into respectively from the bladder. BOLD signal changes were calculated for INFUSION minus START. In addition to whole brain analysis, we assessed BOLD signal changes within multiple ‘a priori’ region of interest (ROI), i.e. brain areas known to be involved in the LUT control from previous literature. To evaluate reliability of the fMRI results between visits, we applied different types of analyses: coefficient of variation (CV), intraclass correlation coefficient (ICC), Sørensen-Dice index, Bland-Altman method, and block-wise BOLD signal comparison.All participants completed the study without adverse events. The desire to void was rated significantly higher for INFUSION compared to START or WITHDRAWAL at both measurements without any effect of visit. At whole brain level, significant (p < 0.05, cluster corrected, k ≥ 41 voxels) BOLD signal changes were found for the contrast INFUSION compared to START in several brain areas. Overlap of activation maps from both measurements were observed in the orbitofrontal cortex, insula, ventrolateral prefrontal cortex (VLPFC), and inferior parietal lobe. The two highest ICCs, based on a ROI's mean beta weight, were 0.55 (right insular cortex) and 0.47 (VLPFC). Spatial congruency (Sørensen-Dice index) of all voxels within each ROI between measurements was highest in the insular cortex (left 0.55, right 0.44). In addition, the mean beta weight of the right insula and right VLPFC demonstrated the lowest CV and narrowest Bland and Altman 95% limits of agreement.In conclusion, the right insula and right VLPFC were revealed as the two most reliable task-specific ROIs using our automated, MR-synchronized protocol. Achieving high reliability using a viscero-sensory/interoceptive task such as repetitive bladder filling remains challenging and further endeavour is highly warranted to better understand which factors influence fMRI outcomes and finally to assess LUT treatment effects on the supraspinal level.

A hemodynamic network involving the insula, the cingulate, and the basal forebrain correlates with EEG synchronization phases of sleep instability.

The cyclic alternating pattern (CAP) encompasses the pseudoperiodic appearance of synchronized brain waves and rhythms and is considered a regulator of the nonrapid eye movement (NREM) sleep vigilance level, reflecting sleep instability. To determine the brain regions responsible for this phenomenon, we scored and analyzed sleep functional magnetic resonance imaging data acquired with simultaneous electroencephalography (EEG-fMRI). Group analysis revealed a set of brain areas showing statistically significant blood oxygen-level dependent signal correlated positively with the synchronization phase of the CAP, most prominent being the insula, the middle cingulate gyrus, and the basal forebrain. These areas may form a network acting as a synchronization pacemaker, controlling the level of NREM sleep vigilance and the sleeper's arousability.

Noninvasive tongue stimulation combined with intensive cognitive and physical rehabilitation induces neuroplastic changes in patients with multiple sclerosis: A multimodal neuroimaging study.

BackgroundMultiple sclerosis (MS) patients have central nervous system (CNS) lesions that may impede cognitive and sensorimotor function. Few rehabilitative therapies are available.ObjectivesThe objective of this paper is to study effects of noninvasive tongue stimulation using the Portable Neuromodulation Stimulator (PoNS™) combined with intensive cognitive and physical rehabilitation on working memory, gait, balance and concomitant changes in the brain.MethodsFourteen MS patients, seven each in an active and a sham stimulation group, participated. Participants received intensive physical therapy and working memory training for 14 weeks. Functional magnetic resonance imaging (fMRI) using motor imagery and working-memory tasks were completed prior to and following therapy, as were sensory organization tests (SOT), motor performance measures, and neuropsychological assessment.ResultsOn the SOT, the active group showed significant improvement from baseline. fMRI revealed significant blood oxygen level-dependent signal changes in the left primary motor cortex for the Active Group, while the sham group had increased activity in bilateral premotor cortices. All individuals improved on working-memory tasks, but only the active group showed increased dorsolateral prefrontal cortex activity.ConclusionsIn this cohort of MS patients, the results suggest that PoNS stimulation can enhance motor performance and working memory while also driving neuroplasticity. Further studies are warranted to explore these findings.

A novel infusion-drainage device to assess lower urinary tract function in neuro-imaging.

To evaluate the applicability and precision of a novel infusion-drainage device (IDD) for standardized filling paradigms in neuro-urology and functional magnetic resonance imaging (fMRI) studies of lower urinary tract (LUT) function/dysfunction. The IDD is based on electrohydrostatic actuation which was previously proven feasible in a prototype setup. The current design includes hydraulic cylinders and a motorized slider to provide force and motion. Methodological aspects have been assessed in a technical application laboratory as well as in healthy subjects (n=33) and patients with LUT dysfunction (n=3) undergoing fMRI during bladder stimulation. After catheterization, the bladder was pre-filled until a persistent desire to void was reported by each subject. The scan paradigm comprised automated, repetitive bladder filling and withdrawal of 100 mL body warm (37 °C) saline, interleaved with rest and sensation rating. Neuroimaging data were analysed using Statistical Parametric Mapping version 12 (SMP12). Volume delivery accuracy was between 99.1±1.2% and 99.9±0.2%, for different flow rates and volumes. Magnetic resonance (MR) compatibility was demonstrated by a small decrease in signal-to-noise ratio (SNR), i.e. 1.13% for anatomical and 0.54% for functional scans, and a decrease of 1.76% for time-variant SNR. Automated, repetitive bladder-filling elicited robust (P = 0.05, family-wise error corrected) brain activity in areas previously reported to be involved in supraspinal LUT control. There was a high synchronism between the LUT stimulation and the blood oxygenation level-dependent (BOLD) signal changes in such areas. We were able to develop an MR-compatible and MR-synchronized IDD to routinely stimulate the LUT during fMRI in a standardized manner. The device provides LUT stimulation at high system accuracy resulting in significant supraspinal BOLD signal changes in interoceptive and LUT control areas in synchronicity to the applied stimuli. The IDD is commercially available, portable and multi-configurable. Such a device may help to improve precision and standardization of LUT tasks in neuro-imaging studies on supraspinal LUT control, and may therefore facilitate multi-site studies and comparability between different LUT investigations in the future.

Pre-ictal BOLD alterations: Two cases of patients with focal epilepsy

The pre-ictal state is of interest for better understanding pathophysiological processes leading up to seizures and for identifying potential biomarkers for the prediction of these events. We present two cases of patients with focal epilepsy (occipital, insular) who had seizures during functional magnetic resonance imaging (fMRI) scans. Interictal (>30min pre-seizure) control data was available for one participant. The location and timing of pre-ictal blood oxygenation-level dependent (BOLD) signal alterations were examined along with changes in pre-ictal functional connectivity. BOLD signal increases were seen at/close to the seizure onset zone and in/near a contralateral homologous region for both patients. In one patient, BOLD signal decreases were also observed distant from the seizure onset zone. The BOLD signal changes began 11 to 3min prior to seizure onset. These findings add to a growing number of cases of pre-ictal hemodynamic alterations. The significant BOLD signal increases seen in/near the homologous region contralateral to the seizure onset zone in both patients suggests that this area may play a critical role in the pre-ictal state, perhaps functioning to inhibit the seizure onset zone, or alternatively, to be directly involved in seizure generation. Pre-ictal functional connectivity, using a seed at the presumed seizure onset zone, demonstrated increases in connectivity with regions near the contralateral homologous region prior to seizures. Alterations in connectivity were also observed and characterized in interictal data, highlighting the importance of future research in determining if the observed pre-ictal changes are specific indicators for impending seizures.

The Role of the Subgenual Anterior Cingulate Cortex and Amygdala in Environmental Sensitivity to Infant Crying.

Newborns and infants communicate their needs and physiological states through crying and emotional facial expressions. Little is known about individual differences in responding to infant crying. Several theories suggest that people vary in their environmental sensitivity with some responding generally more and some generally less to environmental stimuli. Such differences in environmental sensitivity have been associated with personality traits, including neuroticism. This study investigated whether neuroticism impacts neuronal, physiological, and emotional responses to infant crying by investigating blood-oxygenation-level dependent (BOLD) responses using functional magnetic resonance imaging (fMRI) in a large sample of healthy women (N = 102) with simultaneous skin conductance recordings. Participants were repeatedly exposed to a video clip that showed crying infants and emotional responses (valence, arousal, and irritation) were assessed after every video clip presentation. Increased BOLD signal during the perception of crying infants was found in brain regions that are associated with emotional responding, the amygdala and anterior insula. Significant BOLD signal decrements (i.e., habituation) were found in the fusiform gyrus, middle temporal gyrus, superior temporal gyrus, Broca’s homologue on the right hemisphere, (laterobasal) amygdala, and hippocampus. Individuals with high neuroticism showed stronger activation in the amygdala and subgenual anterior cingulate cortex (sgACC) when exposed to infant crying compared to individuals with low neuroticism. In contrast to our prediction we found no evidence that neuroticism impacts fMRI-based measures of habituation. Individuals with high neuroticism showed elevated skin conductance responses, experienced more irritation, and perceived infant crying as more unpleasant. The results support the hypothesis that individuals high in neuroticism are more emotionally responsive, experience more negative emotions, and may show enhanced cognitive control during the exposure to infant distress, which may impact infant-directed behavior.

Triptan-induced disruption of trigemino-cortical connectivity.

The 5-HT1B/D agonists (triptans) are specific headache medications that have no effect on pain as such. Although they are routinely used in the treatment of acute migraine attacks, the underlying mechanisms of action are still a matter of debate. Forty-three healthy participants underwent fMRI while receiving trigemino-nociceptive stimulation and control stimuli in a standardized fMRI paradigm. Using a crossover, double-blind, placebo-controlled design, 21 participants (10 women, mean age 26.9, range 20-37 years) received sumatriptan and 22 participants (11 women, mean age 25.5, range 22-32 years) received acetylsalicylic acid (ASA). Administration of medication and saline was randomized between participants of each group resulting in half of the participants receiving saline and the other half receiving the respective medication during the first fMRI data acquisition. While mean pain intensity ratings did not differ significantly between control and medication nor between medications, we found a significant blood oxygen level-dependent signal increase in the trigeminal nuclei and the thalamus after sumatriptan treatment compared with placebo or ASA. In addition, we specifically looked for the pharmacologic modulation of functional coupling between trigeminal nuclei and higher brain areas, i.e., trigemino-cortical pathways, and found a strong coupling during the saline condition, which was altered by sumatriptan but not after ASA administration. These data suggest that a specific functional inhibition of trigemino-cortical projections is one of the reasons that triptans, unlike pain killers, act highly specifically on headache and migraine but not pain as such.

Open label smoking cessation with varenicline is associated with decreased glutamate levels and functional changes in anterior cingulate cortex: preliminary findings.

Rationale: Varenicline, the most effective single agent for smoking cessation, is a partial agonist at α4β2 nicotinic acetylcholine receptors. Increasing evidence implicates glutamate in the pathophysiology of addiction and one of the benefits of treatment for smoking cessation is the ability to regain cognitive control.Objective: To evaluate the effects of 12-week varenicline administration on glutamate levels in the dorsal anterior cingulate cortex (dACC) and functional changes within the cognitive control network.Methods: We used single-voxel proton magnetic resonance spectroscopy (1H-MRS) in the dACC and functional MRI (fMRI) during performance of a Stroop color-naming task before and after smoking cessation with varenicline in 11 healthy smokers (open label design). Using the dACC as a seed region, we evaluated functional connectivity changes using a psychophysiological interaction (PPI) analysis.Results: We observed a significant decrease in dACC glutamate + glutamine (Glx)/Cr levels as well as significant blood oxygen level-dependent signal (BOLD) decreases in the rostral ACC/medial orbitofrontal cortex and precuneus/posterior cingulate cortex. These BOLD changes are suggestive of alterations in default mode network (DMN) function and are further supported by the results of the PPI analysis that revealed changes in connectivity between the dACC and regions of the DMN. Baseline measures of nicotine dependence and craving positively correlated with baseline Glx/Cr levels.Conclusions: These results suggest possible mechanisms of action for varenicline such as reduction in Glx levels in dACC and shifts in BOLD connectivity between large scale brain networks. They also suggest a role for ACC Glx in the modulation of behavior. Due to the preliminary nature of this study (lack of control group and small sample size), future studies are needed to replicate these findings.

Fear across the senses: brain responses to music, vocalizations and facial expressions.

Intrinsic emotional expressions such as those communicated by faces and vocalizations have been shown to engage specific brain regions, such as the amygdala. Although music constitutes another powerful means to express emotions, the neural substrates involved in its processing remain poorly understood. In particular, it is unknown whether brain regions typically associated with processing 'biologically relevant' emotional expressions are also recruited by emotional music. To address this question, we conducted an event-related functional magnetic resonance imaging study in 47 healthy volunteers in which we directly compared responses to basic emotions (fear, sadness and happiness, as well as neutral) expressed through faces, non-linguistic vocalizations and short novel musical excerpts. Our results confirmed the importance of fear in emotional communication, as revealed by significant blood oxygen level-dependent signal increased in a cluster within the posterior amygdala and anterior hippocampus, as well as in the posterior insula across all three domains. Moreover, subject-specific amygdala responses to fearful music and vocalizations were correlated, consistent with the proposal that the brain circuitry involved in the processing of musical emotions might be shared with the one that have evolved for vocalizations. Overall, our results show that processing of fear expressed through music, engages some of the same brain areas known to be crucial for detecting and evaluating threat-related information.

Robust cardiac BOLD MRI using an fMRI‐like approach with repeated stress paradigms

Use repeated stress paradigms and an approach taken from neurological blood oxygen level dependent (BOLD) functional MRI (fMRI) to derive robust cardiac BOLD measurements. Multiple-repetition, single-shot, electrocardiograph-triggered, T2-prepared BOLD balanced steady-state free precession was performed during repeated long breath-holds in 13 volunteers. Nonrigid motion correction was applied to the continuously acquired data and it was analyzed with a general linear model (GLM) taking into account the effects of the breath-hold duration, RR interval, motion, and baseline variations. Both voxel- and region of interest-based analyses were performed. The GLM model was able to isolate the component of the BOLD signal arising from the breath-holds and separate it from the background effects due to the changing heart rate and motion. A significant (P<0.05) BOLD signal increase was observed in the myocardium of healthy volunteers. Using a recent elastic motion correction algorithm and adapted acquisition techniques, it was possible to apply fMRI-like strategies for cardiac BOLD MRI in volunteers and derive robust BOLD measurements. The observed slight but significant oxygenation increase in the myocardium of volunteers might be explained by the vasodilator effect of increased CO2 concentration under apnea. Detection of such small physiological changes in volunteers performing breath-holds demonstrates that the method could have potential in identifying low oxygenation regions in the myocardium of patients during stress tests.

Abstract W P368: Longitudinal Change in fMRI Blood Oxygen Level Dependent Signal in Cerebral Amyloid Angiopathy

Introduction: Previous cross-sectional studies show that cerebral amyloid angiopathy (CAA) is associated with reduced blood oxygen level dependent (BOLD) signal change in response to a visual task, and that this reduction is due to impaired vascular reactivity. However, there are no data on the rate at which the BOLD signal changes over time in CAA. We hypothesized that fMRI activation would decline in CAA, representing progressively impaired vasoreactivity, and this decline would be associated with increased white matter hyperintensity (WMH) volume. Methods: fMRI BOLD amplitude was measured in response to a visual task (alternating checkerboard pattern) at study entry and 1-year follow-up for 18 patients with probable CAA by Boston criteria, and 15 healthy controls. fMRI data were matched to a canonical BOLD signal using a general linear model resulting in z-statistic images with a significance threshold of p&lt;0.05 using FSL. The amplitude of the BOLD signal percent change from baseline was measured in the 200 most active voxels in the primary visual cortex. WMH were identified on fluid attenuated inversion recovery (FLAIR) images and the volume was measured using Quantomo software (Cybertrials Inc, Canada). Results: BOLD amplitude was lower at follow-up than baseline in CAA, but the difference was not significant (mean change -0.14±0.55, p=0.30). Mean BOLD amplitude was similar at baseline and follow-up in controls (mean change 0.20±0.49, p=0.14). The difference in rate of change over time between CAA and controls was borderline significant (p=0.04). fMRI was lower at follow-up than baseline in 11/18 CAA compared to 4/15 controls (p=0.08). In CAA patients, WMH increased over time (median 1.44 mL interquartile range -0.22 to 9.70mL, p=0.01). However, BOLD amplitude change and WMH change were not related (r=-0.01, p=0.96). Discussion: Although we did not see significant fMRI BOLD signal reduction from baseline to 1 year in CAA, we did see a difference in change over time between CAA and controls, consistent with our hypothesis that impaired vasoreactivity is a feature of CAA. Studies with larger numbers of patients, or longer duration of follow-up, are needed to more precisely determine the rate of change over time in reduction of fMRI BOLD amplitude in CAA.

Neural response to visual sexual cues in dopamine treatment-linked hypersexuality in Parkinson’s disease

Hypersexuality with compulsive sexual behaviour is a significant source of morbidity for patients with Parkinson's disease receiving dopamine replacement therapies. We know relatively little about the pathophysiology of hypersexuality in Parkinson's disease, and it is unknown how visual sexual stimuli, similar to the portrayals of sexuality in the mainstream mass media may affect the brain and behaviour in such susceptible individuals. Here, we have studied a group of 12 patients with Parkinson's disease with hypersexuality using a functional magnetic resonance imaging block design exposing participants to both sexual, other reward-related and neutral visual cues. We hypothesized that exposure to visual sexual cues would trigger increased sexual desire in patients with Parkinson's disease with hypersexuality that would correspond to changes in brain activity in regions linked to dopaminergically stimulated sexual motivation. Patients with Parkinson's disease with hypersexuality were scanned ON and OFF dopamine drugs, and their results were compared with a group of 12 Parkinson's disease control patients without hypersexuality or other impulse control disorders. Exposure to sexual cues significantly increased sexual desire and hedonic responses in the Parkinson's disease hypersexuality group compared with the Parkinson's disease control patients. These behavioural changes corresponded to significant blood oxygen level-dependent signal changes in regions within limbic, paralimbic, temporal, occipital, somatosensory and prefrontal cortices that correspond to emotional, cognitive, autonomic, visual and motivational processes. The functional imaging data showed that the hypersexuality patients' increased sexual desire correlated with enhanced activations in the ventral striatum, and cingulate and orbitofrontal cortices. When the patients with Parkinson's disease with hypersexuality were OFF medication, the functional imaging data showed decreases in activation during the presentation of sexual cues relative to rest. These deactivations were not observed when the patients were ON medication, suggesting that dopamine drugs may release inhibition within local neuronal circuits in the cerebral cortex that may contribute to compulsive sexual behaviour. The findings of this study have implications with respect to the potential influence of cue exposure via exposure to mass media in enhancing libido, which in this group of vulnerable patients can lead to devastating social consequences and occasionally, custodial sentences. Stimulation through exposure to sexual visual cues in patients with Parkinson's disease with hypersexuality provides a motivational impetus for seeking this reward behaviour through activations and deactivations of cerebral cortex.

Functional MRI detection of hemodynamic response of repeated median nerve stimulation

Median nerve stimulation is a commonly used technique in the clinical setting to determine areas of neuronal function in the brain. Neuronal activity of repeated median nerve stimulation is well studied. The cerebral hemodynamic response of the stimulation, on the other hand, is not very clear. In this study, we investigate how cerebral hemodynamics behave over time using the same repeated median nerve stimulation. Ten subjects received constant repeated electrical stimulation to the right median nerve. Each subject had functional magnetic resonance imaging scans while receiving said stimulations for seven runs. Our results show that the blood oxygen level-dependent (BOLD) signal significantly decreases across each run. Significant BOLD signal decreases can also be seen within runs. These results are consistent with studies that have studied the hemodynamic habituation effect with other forms of stimulation. However, the results do not completely agree with the findings of studies where evoked potentials were examined. Thus, further inquiry of how evoked potentials and cerebral hemodynamics are coupled when using constant stimulations is needed.

Diffusion modulation of the fMRI signal: Early investigations on the origin of the BOLD signal

The early 1990s was a very special period for functional MRI (fMRI). Many original concepts were formed during that period which helped set up the foundations for modern neuroimaging development. I was fortunate to be in graduate school at the time. I was even more fortunate to be enrolled in one of the pioneer groups in fMRI at the Medical College of Wisconsin, and witnessed some of the early fMRI experiments taking place in the lab. Under the daily influence and steady guidance by the extraordinarily talented researchers there, I also began my own work on the contrast mechanisms of fMRI. In particular, I was developing diffusion weighted strategies to investigate the origin of the functional signal using blood oxygenation level dependent (BOLD) contrast. Our results, that there was significant BOLD signal in large veins and their vicinities at low field strengths (e.g. 1.5T), played an immediate role in moving fMRI applications to higher fields (3T and above) where small vessels (e.g. capillaries) contribute more significantly to improve the neuronal specificity of the BOLD signal. This manuscript gathers some of my own recollections concerning this particular development.

Self-Regulation of Amygdala Activation Using Real-Time fMRI Neurofeedback

Real-time functional magnetic resonance imaging (rtfMRI) with neurofeedback allows investigation of human brain neuroplastic changes that arise as subjects learn to modulate neurophysiological function using real-time feedback regarding their own hemodynamic responses to stimuli. We investigated the feasibility of training healthy humans to self-regulate the hemodynamic activity of the amygdala, which plays major roles in emotional processing. Participants in the experimental group were provided with ongoing information about the blood oxygen level dependent (BOLD) activity in the left amygdala (LA) and were instructed to raise the BOLD rtfMRI signal by contemplating positive autobiographical memories. A control group was assigned the same task but was instead provided with sham feedback from the left horizontal segment of the intraparietal sulcus (HIPS) region. In the LA, we found a significant BOLD signal increase due to rtfMRI neurofeedback training in the experimental group versus the control group. This effect persisted during the Transfer run without neurofeedback. For the individual subjects in the experimental group the training effect on the LA BOLD activity correlated inversely with scores on the Difficulty Identifying Feelings subscale of the Toronto Alexithymia Scale. The whole brain data analysis revealed significant differences for Happy Memories versus Rest condition between the experimental and control groups. Functional connectivity analysis of the amygdala network revealed significant widespread correlations in a fronto-temporo-limbic network. Additionally, we identified six regions — right medial frontal polar cortex, bilateral dorsomedial prefrontal cortex, left anterior cingulate cortex, and bilateral superior frontal gyrus — where the functional connectivity with the LA increased significantly across the rtfMRI neurofeedback runs and the Transfer run. The findings demonstrate that healthy subjects can learn to regulate their amygdala activation using rtfMRI neurofeedback, suggesting possible applications of rtfMRI neurofeedback training in the treatment of patients with neuropsychiatric disorders.

Brain functional magnetic resonance imaging response to glucose and fructose infusions in humans

In animals, intracerebroventricular glucose and fructose have opposing effects on appetite and weight regulation. In humans, functional brain magnetic resonance imaging (fMRI) studies during glucose ingestion or infusion have demonstrated suppression of hypothalamic signalling, but no studies have compared the effects of glucose and fructose. We therefore sought to determine if the brain response differed to glucose vs. fructose in humans independently of the ingestive process. Nine healthy, normal weight subjects underwent blood oxygenation level dependent (BOLD) fMRI measurements during either intravenous (IV) glucose (0.3 mg/kg), fructose (0.3 mg/kg) or saline, administered over 2 min in a randomized, double-blind, crossover study. Blood was sampled every 5 min during a baseline period and following infusion for 60 min in total for glucose, fructose, lactate and insulin levels. No significant brain BOLD signal changes were detected in response to IV saline. BOLD signal in the cortical control areas increased during glucose infusion (p = 0.002), corresponding with increased plasma glucose and insulin levels. In contrast, BOLD signal decreased in the cortical control areas during fructose infusion (p = 0.006), corresponding with increases of plasma fructose and lactate. Neither glucose nor fructose infusions significantly altered BOLD signal in the hypothalamus. In normal weight humans, cortical responses as assessed by BOLD fMRI to infused glucose are opposite to those of fructose. Differential brain responses to these sugars and their metabolites may provide insight into the neurologic basis for dysregulation of food intake during high dietary fructose intake.

Automated real-time behavioral and physiological data acquisition and display integrated with stimulus presentation for fMRI

Functional magnetic resonance imaging (fMRI) is based on correlating blood oxygen-level dependent (BOLD) signal fluctuations in the brain with other time-varying signals. Although the most common reference for correlation is the timing of a behavioral task performed during the scan, many other behavioral and physiological variables can also influence fMRI signals. Variations in cardiac and respiratory functions in particular are known to contribute significant BOLD signal fluctuations. Variables such as skin conduction, eye movements, and other measures that may be relevant to task performance can also be correlated with BOLD signals and can therefore be used in image analysis to differentiate multiple components in complex brain activity signals. Combining real-time recording and data management of multiple behavioral and physiological signals in a way that can be routinely used with any task stimulus paradigm is a non-trivial software design problem. Here we discuss software methods that allow users control of paradigm-specific audio–visual or other task stimuli combined with automated simultaneous recording of multi-channel behavioral and physiological response variables, all synchronized with sub-millisecond temporal accuracy. We also discuss the implementation and importance of real-time display feedback to ensure data quality of all recorded variables. Finally, we discuss standards and formats for storage of temporal covariate data and its integration into fMRI image analysis. These neuroinformatics methods have been adopted for behavioral task control at all sites in the Functional Biomedical Informatics Research Network (FBIRN) multi-center fMRI study.

Pharmacological magnetic resonance imaging of muscarinic acetylcholine receptor activation in rat brain

The central cholinergic system is involved in several cognitive functions such as attention, consciousness, learning and memory. Functional imaging of this neurotransmitter system may provide novel opportunities in the diagnosis and evaluation of cognitive disorders. The aim of this study was to investigate the spatial and temporal activation patterns of muscarinic acetylcholine receptor (mAChR) stimulation in rat brain with pharmacological magnetic resonance imaging (phMRI). We performed blood oxygenation level-dependent (BOLD) MRI and contrast-enhanced cerebral blood volume (CBV)-weighted MRI combined with injection of pilocarpine, a non-selective mAChR agonist. BOLD and CBV responses were assessed after pretreatment with methyl-scopolamine in order to block peripheral muscarinic effects. Region-of-interest analysis in individual animals and group-level independent component analysis failed to show significant BOLD signal changes following pilocarpine injection. However, with contrast-enhanced CBV-weighted MRI, positive CBV responses were detected in the cerebral cortex, thalamus, and hippocampus whereas a negative CBV response was observed in the striatum. Thus, pilocarpine-induced significant activation responses in brain regions that are known to have a high density of muscarinic receptors. Our study demonstrates that phMRI of mAChR stimulation in rats allows functional assessment of the cholinergic system in vivo.