Blood Oxygenation Level-dependent fMRI Research Articles

Pharmacological manipulation of neurotransmitter activity induces disparate effects on cerebral blood flow and resting-state fluctuations

Abstract Functional MRI methods can assess aspects of drug-induced brain response. Resting blood oxygenation level dependent (BOLD) fMRI and arterial spin labeling (ASL) perfusion MRI indirectly measure brain function through the coupling of activity to cerebral blood flow (CBF) and oxygenation but their relative sensitivity has not been directly compared. We assessed changes in resting measures of BOLD and ASL MRI in response to two neurotransmitter modulators: citalopram, a selective serotonin reuptake inhibitor, and alprazolam, a positive allosteric modulator of GABA type A receptor. Thirty healthy subjects were imaged in a placebo-controlled study, with N=20 subjects receiving each treatment as part of an incomplete block design. Time-averaged CBF images from ASL and measures of resting-state fluctuations of BOLD and ASL images were assessed for significant effects. Following acute citalopram administration, analysis of the ASL data showed a reduction in time-averaged regional CBF in regions associated with high levels of 5-HT1A receptor density. In contrast, following alprazolam administration, BOLD amplitude of low frequency fluctuations showed a highly significant and cortically widespread increase, consistent with the distribution of GABA-A receptors. Only a marginal decrease in ASL CBF was detected after alprazolam intake. BOLD and ASL are each sensitive to drugs targeting neurotransmitter systems, but appear to reflect different aspects of neural metabolism and the balance between excitatory and inhibitory activity. Accordingly, their combination may best capture the effects of neurotransmitter modulations, and thus be advantageous for pharmacological MRI studies.

Functional Localization of the Human Auditory and Visual Thalamus Using a Thalamic Localizer Functional Magnetic Resonance Imaging Task

Abstract Functional magnetic resonance imaging (fMRI) of the auditory and visual sensory systems of the human brain is an active area of investigation in the study of human health and disease. The medial geniculate nucleus (MGN) and lateral geniculate nucleus (LGN) are key thalamic nuclei involved in the processing and relay of auditory and visual information, respectively, and are the subject of blood-oxygen-level-dependent (BOLD) fMRI studies of neural activation and functional connectivity in human participants. However, localization of BOLD fMRI signal originating from neural activity in MGN and LGN remains a technical challenge, due in part to the poor definition of boundaries of these thalamic nuclei in standard T1-weighted and T2-weighted magnetic resonance imaging sequences. Here, we report the development and evaluation of an auditory and visual sensory thalamic localizer (TL) fMRI task that produces participant-specific functionally-defined regions of interest (fROIs) of both MGN and LGN, using 3 Tesla multiband fMRI and a clustered-sparse temporal acquisition sequence, in less than 16 minutes of scan time. We demonstrate the use of MGN and LGN fROIs obtained from the TL fMRI task in standard resting-state functional connectivity (RSFC) fMRI analyses in the same participants. In RSFC analyses, we validated the specificity of MGN and LGN fROIs for signals obtained from primary auditory and visual cortex, respectively, and benchmark their performance against alternative atlas- and segmentation-based localization methods. The TL fMRI task and analysis code (written in Presentation and MATLAB, respectively) have been made freely available to the wider research community.

Feasibility of submillimeter functional quantitative susceptibility mapping using 3D echo planar imaging at 7 T.

Quantitative susceptibility mapping (QSM) is a tool for mapping tissue susceptibility. Using QSM for functional brain mapping, it is possible to directly quantify blood-oxygen-level-dependent (BOLD) susceptibility changes. This study presents a submillimeter functional QSM (fQSM) approach compared to BOLD fMRI from data acquired with 3D gradient-echo echo planar imaging (EPI) at ultra-high field. Complex EPI data were acquired in nine healthy subjects with varying temporal and spatial resolutions and used for BOLD fMRI and for fQSM. Right-hand finger tapping experiments were performed as well as one measurement with intentional subject movement. Susceptibility maps were computed using 3D path-based unwrapping, the variable-kernel sophisticated harmonic artifact reduction for phase data, and the streaking artifact reduction for QSM algorithm. Functional data analysis included general linear modeling and computation of z-scores. Submillimeter data were denoised using NOise reduction with DIstribution Corrected (NORDIC), which improved z-scores in the motor cortex for fQSM and fMRI. An expected increase in BOLD fMRI signal and corresponding decrease in magnetic susceptibility was observed in sensorimotor areas during active periods. For all experiments, fQSM showed smaller activation regions compared with fMRI. The percentage of high negative t-values localized in the cortex was higher for fQSM (52%) than for positive or negative t-values for fMRI (45%). For the scans with intentional motion, movement exceeded the size of a voxel, but paradigm dependent signal evolution could be recovered using motion correction. In conclusion, this study demonstrates the feasibility of submillimeter whole-brain fQSM with voxel volume of 0.53 μL. In comparison to traditional BOLD fMRI, fQSM provided improved localization of brain activation within the cortex, especially in submillimeter 3D EPI sequences.

Somatosensory migraine auras evoked by bihemispheric cortical spreading depression events in human parietal cortex.

Cortical spreading depression (CSD) is associated with pronounced alterations in cerebral blood flow. These alterations can be captured using high-field functional magnetic resonance imaging (fMRI). While compelling clinical and experimental data suggest that CSD is involved in the pathogenesis of migraine aura, the mechanistic intricacies remain poorly understood. Here, we use visual stimulus-induced blood oxygen level-dependent (BOLD) fMRI responses to characterize spatiotemporal alterations in cerebral blood flow during spontaneous attacks with migraine aura. Six adult participants diagnosed with migraine with aura underwent BOLD fMRI scans with a visual stimulation paradigm, consisting of flickering checkerboard stimulation. Our results revealed that auras with somatosensory symptoms corresponded with bilateral alterations of stimulus-induced BOLD responses in the somatosensory cortex, exhibiting anterior-to-posterior propagation and absence of antecedent occipital abnormalities. These altered stimulus-induced BOLD responses were bilateral, despite a unilateral manifestation of aura symptoms, and had no relationship with positive or negative aura symptoms. The bilateral abnormalities in stimulus-induced BOLD responses completes our current knowledge on migraine aura.

I feel your pain: higher empathy is associated with higher posterior default mode network activity

Abstract Empathy is characterized as the ability to share one's experience and is associated with altruism. Previous work using blood oxygen level–dependent (BOLD) functional MRI (fMRI) has found that empathy is associated with greater activation in brain mechanisms supporting mentalizing (temporoparietal junction), salience (anterior cingulate cortex; insula), and self-reference (medial prefrontal cortex; precuneus). However, BOLD fMRI has some limitations that may not reliably capture the tonic experience of empathy. To address this, the present study used a perfusion-based arterial spin labeling fMRI approach that provides direct a quantifiable measurement of cerebral blood flow (1 mL/100 g tissue/min) and is less susceptible to low-frequency fluctuations and empathy-based “carry-over” effects that may be introduced by BOLD fMRI–based block designs. Twenty-nine healthy females (mean age = 29 years) were administered noxious heat (48°C; left forearm) during arterial spin labeling fMRI. In the next 2 fMRI scans, female volunteers viewed a stranger (laboratory technician) and their romantic partner, respectively, receive pain-evoking heat (48°C; left forearm) in real-time and positioned proximal to the scanner during fMRI acquisition. Visual analog scale (0 = “not unpleasant”; 10 = “most unpleasant sensation imaginable”) empathy ratings were collected after each condition. There was significantly (P = 0.01) higher empathy while viewing a romantic partner in pain and greater cerebral blood flow in the right temporoparietal junction, amygdala, anterior insula, orbitofrontal cortex, and precuneus when compared with the stranger. Higher empathy was associated with greater precuneus and primary visual cortical activation. The present findings indicate that brain mechanisms supporting the embodiment of another's experience is associated with higher empathy.

Graded Intensity Aerobic Exercise to Improve Cerebrovascular Function and Performance in Older Veterans: Protocol for a Randomized Controlled Trial.

Growing health care challenges resulting from a rapidly expanding aging population necessitate examining effective rehabilitation techniques that mitigate age-related comorbidity and improve quality of life. To date, exercise is one of a few proven interventions known to attenuate age-related declines in cognitive and sensorimotor functions critical to sustained independence. This work aims to implement a multimodal imaging approach to better understand the mechanistic underpinnings of the beneficial exercise-induced adaptations to sedentary older adults' brains and behaviors. Due to the complex cerebral and vascular dynamics that encompass neuroplastic change with aging and exercise, we propose an imaging protocol that will model exercise-induced changes to cerebral perfusion, cerebral vascular reactivity (CVR), and cognitive and sensorimotor task-dependent functional magnetic resonance imaging (fMRI) after prescribed exercise. Sedentary older adults (aged 65-80 years) were randomly assigned to either a 12-week aerobic-based interval-based cycling intervention or a 12-week balance and stretching intervention. Assessments of cardiovascular fitness used the YMCA submaximal VO2 test, basal cerebral perfusion using arterial spin labeling (ASL), CVR using hypercapnic fMRI, and cortical activation using fMRI during verbal fluency and motor tapping tasks. A battery of cognitive-executive and motor function tasks outside the scanning environment will be performed before and after the interventions. Our studies and others show that improved cardiovascular fitness in older adults results in improved outcomes related to physical and cognitive health as well as quality of life. A consistent but unexplained finding in many of these studies is a change in cortical activation patterns during task-based fMRI, which corresponds with improved task performance (cognitive-executive and motor). We hypothesize that the 12-week aerobic exercise intervention will increase basal perfusion and improve CVR through a greater magnitude of reactivity in brain areas susceptible to neural and vascular decline (inferior frontal and motor cortices) in previously sedentary older adults. To differentiate between neural and vascular adaptations in these regions, we will map changes in basal perfusion and CVR over the inferior frontal and the motor cortices-regions we have previously shown to be beneficially altered during fMRI BOLD (blood oxygen level dependent), such as verbal fluency and motor tapping, through improved cardiovascular fitness. Exercise is one of the most impactful interventions for improving physical and cognitive health in aging. This study aims to better understand the mechanistic underpinnings of improved health and function of the cerebrovascular system. If our hypothesis of improved perfusion and cerebrovascular reactivity following a 12-week aerobic exercise intervention is supported, it would add critically important insights into the potential of exercise to improve brain health in aging and could inform exercise prescription for older adults at risk for neurodegenerative disease brought on by cerebrovascular dysfunction. ClinicalTrials.gov NCT05932069; https://clinicaltrials.gov/study/NCT05932069. DERR1-10.2196/58316.

Functional MRI study with conductivity signal changes during visual stimulation

BackgroundAlthough blood oxygen level-dependent (BOLD) functional MRI (fMRI) is a standard method, major BOLD signals primarily originate from intravascular sources. Magnetic resonance electrical properties tomography (MREPT)-based fMRI signals may provide additional insights into electrical activity caused by alterations in ion concentrations and mobilities. PurposeThis study aimed to investigate the neuronal response of conductivity during visual stimulation and compare it with BOLD. Materials and methodsA total of 30 young, healthy volunteers participated in two independent experiments using BOLD and MREPT techniques with a visual stimulation paradigm at 3 T MRI. The first set of MREPT fMRI data was obtained using a multi-echo spin-echo (SE) echo planar imaging (EPI) sequence from 14 participants. The second set of MREPT fMRI data was collected from 16 participants using both a single-echo SE-EPI and a single-echo three-dimensional (3D) balanced fast-field-echo (bFFE) sequence. We reconstructed the time-course Larmor frequency conductivity to evaluate hemodynamics. ResultsConductivity values slightly increased during visual stimulation. Activation strengths were consistently stronger with BOLD than with conductivity for both SE-EPI MREPT and bFFE MREPT. Additionally, the activated areas were always larger with BOLD than MREPT. Some participants also exhibited decreased conductivity values during visual stimulations. In Experiment 1, conductivity showed significant differences between the fixation and visual stimulation blocks in the secondary visual cortex (SVC) and cuneus, with conductivity differences of 0.43 % and 0.47 %, respectively. No significant differences in conductivity were found in the cerebrospinal fluid (CSF) areas between the two blocks. In Experiment 2, significant conductivity differences were observed between the two blocks in the SVC, cuneus, and lingual gyrus for SE-EPI MREPT, with differences of 0.90 %, 0.67 %, and 0.24 %, respectively. Again, no significant differences were found in the CSF areas. ConclusionConductivity values increased slightly during visual stimulation in the visual cortex areas but were much weaker than BOLD responses. The conductivity change during visual stimulation was less than 1 % compared to the fixation block. No significant differences in conductivity were observed between the primary visual cortex (PVC)-CSF and SVC-CSF during fixation and visual stimulations, suggesting that the observed conductivity changes may not be related to CSF changes in the visual cortex but rather to diffusion changes. Future research should explore the potential of MREPT to detect neuronal electrical activity and hemodynamic changes, with further optimization of the MREPT technique.

Dynamics of human serotonin synthesis differentially link to reward anticipation and feedback.

Serotonin (5-HT) plays an essential role in reward processing, however, the possibilities to investigate 5-HT action in humans during emotional stimulation are particularly limited. Here we demonstrate the feasibility of assessing reward-specific dynamics in 5-HT synthesis using functional PET (fPET), combining its molecular specificity with the high temporal resolution of blood oxygen level dependent (BOLD) fMRI. Sixteen healthy volunteers underwent simultaneous fPET/fMRI with the radioligand [11C]AMT, a substrate for tryptophan hydroxylase. During the scan, participants completed the monetary incentive delay task and arterial blood samples were acquired for quantifying 5-HT synthesis rates. BOLD fMRI was recorded as a proxy of neuronal activation, allowing differentiation of reward anticipation and feedback. Monetary gain and loss resulted in substantial increases in 5-HT synthesis in the ventral striatum (VStr, +21% from baseline) and the anterior insula (+41%). In the VStr, task-specific 5-HT synthesis was further correlated with BOLD signal changes during reward feedback (ρ = -0.65), but not anticipation. Conversely, 5-HT synthesis in the anterior insula correlated with BOLD reward anticipation (ρ = -0.61), but not feedback. In sum, we provide a robust tool to identify task-induced changes in 5-HT action in humans, linking the dynamics of 5-HT synthesis to distinct phases of reward processing in a regionally specific manner. Given the relevance of altered reward processing in psychiatric disorders such as addiction, depression and schizophrenia, our approach offers a tailored assessment of impaired 5-HT signaling during cognitive and emotional processing.

Leveraging Multi-Echo EPI to Enhance BOLD Sensitivity in Task-based Olfactory fMRI.

Functional magnetic resonance imaging (fMRI) using blood-oxygenation-level-dependent (BOLD) contrast relies on gradient echo echo-planar imaging (GE-EPI) to quantify dynamic susceptibility changes associated with the hemodynamic response to neural activity. However, acquiring BOLD fMRI in human olfactory regions is particularly challenging due to their proximity to the sinuses where large susceptibility gradients induce magnetic field distortions. BOLD fMRI of the human olfactory system is further complicated by respiratory artifacts that are highly correlated with event onsets in olfactory tasks. Multi-echo EPI (ME-EPI) acquires gradient echo data at multiple echo times (TEs) during a single acquisition and can leverage signal evolution over the multiple echo times to enhance BOLD sensitivity and reduce artifactual signal contributions. In the current study, we developed a ME-EPI acquisition protocol for olfactory task-based fMRI and demonstrated significant improvement in BOLD signal sensitivity over conventional single-echo EPI (1E-EPI). The observed improvement arose from both an increase in BOLD signal changes through a T 2 * -weighted echo combination and a reduction in non-BOLD artifacts through the application of the Multi-Echo Independent Components Analysis (ME-ICA) denoising method. This study represents one of the first direct comparisons between 1E-EPI and ME-EPI in high-susceptibility regions and provides compelling evidence in favor of using ME-EPI for future task-based fMRI studies.

Repetitive mild closed-head injury induced synapse loss and increased local BOLD-fMRI signal homogeneity.

Repeated mild head injuries due to sports, or domestic violence and military service are increasingly linked to debilitating symptoms in the long term. Although symptoms may take decades to manifest, potentially treatable neurobiological alterations must begin shortly after injury. Better means to diagnose and treat traumatic brain injuries, requires an improved understanding of the mechanisms underlying progression and means through which they can be measured. Here, we employ a repetitive mild closed-head injury (rmTBI) and chronic variable stress (CVS) mouse model to investigate emergent structural and functional brain abnormalities. Brain imaging is achieved with [18F]SynVesT-1 positron emission tomography, with the synaptic vesicle glycoprotein 2A ligand marking synapse density and BOLD (blood-oxygen-level-dependent) functional magnetic resonance imaging (fMRI). Animals were scanned six weeks after concluding rmTBI/Stress procedures. Injured mice showed widespread decreases in synaptic density coupled with an increase in local BOLD-fMRI synchrony detected as regional homogeneity. Injury-affected regions with higher synapse density showed a greater increase in fMRI regional homogeneity. Taken together, these observations may reflect compensatory mechanisms following injury. Multimodal studies are needed to provide deeper insights into these observations.

Dose-Dependent Target Engagement of a Clinical iTBS Protocol: An Interleaved TMS-fMRI Study in Healthy Subjects

BackgroundIntermittent theta burst stimulation (iTBS) of the dorsolateral prefrontal cortex (DLPFC) is widely applied as a therapeutic intervention in mental health; however, the understanding of its mechanisms is still incomplete. Prior magnetic resonance imaging studies have mainly used offline iTBS or short sequences in concurrent transcranial magnetic stimulation functional magnetic resonance imaging (fMRI). This study investigated a full 600-stimuli iTBS protocol using interleaved transcranial magnetic stimulation fMRI in comparison with 2 control conditions in healthy subjects. MethodsIn a crossover design, 18 participants underwent 3 sessions of interleaved iTBS-fMRI: 1) the left DLPFC at 40% resting motor threshold (rMT) intensity, 2) the left DLPFC at 80% rMT intensity, and 3) the left primary motor cortex (M1) at 80% rMT intensity. We compared immediate blood oxygen level–dependent (BOLD) responses during interleaved iTBS-fMRI across these conditions including correlations between individual fMRI BOLD activation and iTBS-induced electric field strength at the target sites. ResultsWhole-brain analysis showed increased activation in several regions following iTBS. Specifically, the left DLPFC, as well as the bilateral M1, anterior cingulate cortex, and insula, showed increased activation during 80% rMT left DLPFC stimulation. Increased BOLD activity in the left DLPFC was observed with neither 40% rMT left DLPFC stimulation nor left M1 80% rMT iTBS, whereas activation in other regions was found to overlap between conditions. Of note, BOLD activation and electric field intensities were only correlated for M1 stimulation and not for the DLPFC conditions. ConclusionsThe study showed dosage- and target-specific BOLD activation during interleaved transcranial magnetic stimulation fMRI with 600-stimuli iTBS in healthy individuals. Future studies may use our approach for demonstrating target engagement.

BOLD fMRI responses to amplitude-modulated sounds across age in adult listeners

Abstract Age-related alterations in the auditory system have been suggested to affect the processing of temporal envelope amplitude modulations (AM) at different levels of the auditory hierarchy, yet few studies have used functional magnetic resonance imaging (fMRI) to study this noninvasively in humans with high spatial resolution. In this study, we utilized sparse-sampling fMRI at 3 Tesla (3T) to investigate regional blood oxygenation level-dependent (BOLD) responses to AM noise stimuli in 65 individuals ranging in age from 19 to 77 years. We contrasted BOLD responses to AM noise stimuli modulated at 4 Hz or 80 Hz with responses to unmodulated stimuli. This allowed us to derive functional measures of regional neural sensitivity to the imposed AM. Compared with unmodulated noise, slowly varying 4 Hz AM noise stimuli elicited significantly greater BOLD responses in the left and right auditory cortex along the Heschl’s gyrus (HG). BOLD responses to the 80 Hz AM stimuli were significantly greater than responses to unmodulated stimuli in putatively primary auditory cortical regions in the lateral HG. BOLD responses to 4 Hz AM stimuli were significantly greater in magnitude than responses to 80 Hz AM stimuli in auditory cortical regions. We find no discernible effects of age on the functional recruitment of the auditory cortex by AM stimuli. While the results affirm the involvement of the auditory cortex in processing temporal envelope rate information, they provide no support for age-related effects on these measures. We discuss potential caveats in assessing age-related changes in responses to AM stimuli in the auditory pathway.

Functional magnetic resonance imaging of the lumbosacral cord during a lower extremity motor task

Abstract Blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) can be used to map neuronal function in the cervical cord, yet conclusive evidence supporting its applicability in the lumbosacral cord is still lacking. This study aimed to (i) demonstrate the feasibility of BOLD fMRI for indirectly mapping neural activity in the lumbosacral cord during a unilateral lower extremity motor task and (ii) investigate the impact of echo time (TE) on the BOLD effect size. Twelve healthy volunteers underwent BOLD fMRI using four reduced field-of-view single-shot gradient-echo echo planar imaging sequences, all with the same geometry but different TE values ranging from 20 to 42 ms. Each sequence was employed to acquire a single 6-min rest run and two 10-min task runs, which included alternating 15-s blocks of rest and unilateral ankle dorsi- and plantar flexion. We detected lateralized task-related BOLD activity at neurological levels L3-S2, centered at the ipsilateral (right) ventral spinal cord but also extending into the ipsilateral dorsal spinal cord. This pattern of activation is consistent with our current understanding of spinal cord organization, wherein lower motor neurons are located in the ventral gray matter horn, while interneurons neurons of the proprioceptive pathway, activated during the movement, are located in the dorsal horns and the intermediate gray matter. At the subject level, BOLD activity showed considerable variability but was lateralized in all participants. The highest BOLD effect size within the ipsilateral ventral spinal cord, as well as the highest split-half reliability, was observed at a TE of 42 ms. Sequences with a shorter TE (20 and 28 ms) also detected activity in the medioventral part of the spinal cord, likely representing large vein effects. In summary, our results demonstrate the feasibility of detecting task-related BOLD activity in the lumbosacral cord induced by voluntary lower limb movements. BOLD fMRI in the lumbosacral cord has significant implications for assessing motor function and its alterations in disease or after spinal cord injury.

Optimization and validation of multi-echo, multi-contrast SAGE acquisition in fMRI.

The purpose of this study was to optimize and validate a multi-contrast, multi-echo fMRI method using a combined spin- and gradient-echo (SAGE) acquisition. It was hypothesized that SAGE-based blood oxygen level-dependent (BOLD) functional MRI (fMRI) will improve sensitivity and spatial specificity while reducing signal dropout. SAGE-fMRI data were acquired with five echoes (2 gradient-echoes, 2 asymmetric spin-echoes, and 1 spin-echo) across 12 protocols with varying acceleration factors, and temporal SNR (tSNR) was assessed. The optimized protocol was then implemented in working memory and vision tasks in 15 healthy subjects. Task-based analysis was performed using individual echoes, quantitative dynamic relaxation times T2 * and T2, and echo time-dependent weighted combinations of dynamic signals. These methods were compared to determine the optimal analysis method for SAGE-fMRI. Implementation of a multiband factor of 2 and sensitivity encoding (SENSE) factor of 2.5 yielded adequate spatiotemporal resolution while minimizing artifacts and loss in tSNR. Higher BOLD contrast-to-noise ratio (CNR) and tSNR were observed for SAGE-fMRI relative to single-echo fMRI, especially in regions with large susceptibility effects and for T2-dominant analyses. Using a working memory task, the extent of activation was highest with T2 *-weighting, while smaller clusters were observed with quantitative T2 * and T2. SAGE-fMRI couples the high BOLD sensitivity from multi-gradient-echo acquisitions with improved spatial localization from spin-echo acquisitions, providing two contrasts for analysis. SAGE-fMRI provides substantial advantages, including improving CNR and tSNR for more accurate analysis.

Laminar CBV and BOLD response-characteristics over time and space in the human primary somatosensory cortex at 7T.

Uncovering the cortical representation of the body has been at the core of human brain mapping for decades, with special attention given to the digits. In the last decade, advances in functional magnetic resonance imaging (fMRI) technologies have opened the possibility of noninvasively unraveling the 3rd dimension of digit representations in humans along cortical layers. In laminar fMRI it is common to combine the use of the highly sensitive blood oxygen level dependent (BOLD) contrast with cerebral blood volume sensitive measurements, like vascular space occupancy (VASO), that are more specific to the underlying neuronal populations. However, the spatial and temporal VASO response characteristics across cortical depth to passive stimulation of the digits are still unknown. Therefore, we characterized haemodynamic responses to vibrotactile stimulation of individual digit-tips across cortical depth at 0.75 mm in-plane spatial resolution using BOLD and VASO fMRI at 7T. We could identify digit-specific regions of interest (ROIs) in putative Brodmann area 3b, following the known anatomical organization. In the ROIs, the BOLD response increased towards the cortical surface due to the draining vein effect, while the VASO response was more shifted towards middle cortical layers, likely reflecting bottom-up input from the thalamus, as expected. Interestingly, we also found slightly negative BOLD and VASO responses for non-preferred digits in the ROIs, potentially indicating neuronal surround inhibition. Finally, we explored the temporal signal dynamics for BOLD and VASO as a function of distance from activation peaks resulting from stimulation of contralateral digits. With this analysis, we showed a triphasic response consisting of an initial peak and a subsequent negative deflection during stimulation, followed by a positive post-stimulus response in BOLD and to some extent in VASO. While similar responses were reported with invasive methods in animal models, here we demonstrate a potential neuronal excitation-inhibition mechanism in a center-surround architecture across layers in the human somatosensory cortex. Given that, unlike in animals, human experiments do not rely on anesthesia and can readily implement extensive behavioral testing, obtaining this effect in humans is an important step towards further uncovering the functional significance of the different aspects of the triphasic response.

Multimodal identification of the mouse brain using simultaneous Ca 2+ imaging and fMRI.

Individual differences in neuroimaging are of interest to clinical and cognitive neuroscientists based on their potential for guiding the personalized treatment of various heterogeneous neurological conditions and diseases. Despite many advantages, the workhorse in this arena, BOLD (blood-oxygen-level-dependent) functional magnetic resonance imaging (fMRI) suffers from low spatiotemporal resolution and specificity as well as a propensity for noise and spurious signal corruption. To better understand individual differences in BOLD-fMRI data, we can use animal models where fMRI, alongside complementary but more invasive contrasts, can be accessed. Here, we apply simultaneous wide-field fluorescence calcium imaging and BOLD-fMRI in mice to interrogate individual differences using a connectome-based identification framework adopted from the human fMRI literature. This approach yields high spatiotemporal resolution cell-type specific signals (here, from glia, excitatory, as well as inhibitory interneurons) from the whole cortex. We found mouse multimodal connectome- based identification to be successful and explored various features of these data.

A fully synthetic three-dimensional human cerebrovascular model based on histological characteristics to investigate the hemodynamic fingerprint of the layer BOLD fMRI signal formation.

Recent advances in functional magnetic resonance imaging (fMRI) at ultra-high field (≥7 tesla), novel hardware, and data analysis methods have enabled detailed research on neurovascular function, such as cortical layer-specific activity, in both human and nonhuman species. A widely used fMRI technique relies on the blood oxygen level-dependent (BOLD) signal. BOLD fMRI offers insights into brain function by measuring local changes in cerebral blood volume, cerebral blood flow, and oxygen metabolism induced by increased neuronal activity. Despite its potential, interpreting BOLD fMRI data is challenging as it is only an indirect measurement of neuronal activity. Computational modeling can help interpret BOLD data by simulating the BOLD signal formation. Current developments have focused on realistic 3D vascular models based on rodent data to understand the spatial and temporal BOLD characteristics. While such rodent-based vascular models highlight the impact of the angioarchitecture on the BOLD signal amplitude, anatomical differences between the rodent and human vasculature necessitate the development of human-specific models. Therefore, a computational framework integrating human cortical vasculature, hemodynamic changes, and biophysical properties is essential. Here, we present a novel computational approach: a three-dimensional VAscular MOdel based on Statistics (3D VAMOS), enabling the investigation of the hemodynamic fingerprint of the BOLD signal within a model encompassing a fully synthetic human 3D cortical vasculature and hemodynamics. Our algorithm generates microvascular and macrovascular architectures based on morphological and topological features from the literature on human cortical vasculature. By simulating specific oxygen saturation states and biophysical interactions, our framework characterizes the intravascular and extravascular signal contributions across cortical depth and voxel-wise levels for gradient-echo and spin-echo readouts. Thereby, the 3D VAMOS computational framework demonstrates that using human characteristics significantly affects the BOLD fingerprint, making it an essential step in understanding the fundamental underpinnings of layer-specific fMRI experiments.

Test-retest reliability and time-of-day variations of perfusion imaging at rest and during a vigilance task.

Arterial spin-labeled perfusion and blood oxygenation level-dependent functional MRI are indispensable tools for noninvasive human brain imaging in clinical and cognitive neuroscience, yet concerns persist regarding the reliability and reproducibility of functional MRI findings. The circadian rhythm is known to play a significant role in physiological and psychological responses, leading to variability in brain function at different times of the day. Despite this, test-retest reliability of brain function across different times of the day remains poorly understood. This study examined the test-retest reliability of six repeated cerebral blood flow measurements using arterial spin-labeled perfusion imaging both at resting-state and during the psychomotor vigilance test, as well as task-induced cerebral blood flow changes in a cohort of 38 healthy participants over a full day. The results demonstrated excellent test-retest reliability for absolute cerebral blood flow measurements at rest and during the psychomotor vigilance test throughout the day. However, task-induced cerebral blood flow changes exhibited poor reliability across various brain regions and networks. Furthermore, reliability declined over longer time intervals within the day, particularly during nighttime scans compared to daytime scans. These findings highlight the superior reliability of absolute cerebral blood flow compared to task-induced cerebral blood flow changes and emphasize the importance of controlling time-of-day effects to enhance the reliability and reproducibility of future brain imaging studies.

Assessment of Oculomotor Functions as a Biomarker in Mild Traumatic Brain Injury.

Mild traumatic brain injury (mTBI), or concussion, is a major public health problem, and ambiguity still exists regarding its diagnosis. While functional magnetic resonance imaging (fMRI) has been identified as a helpful screening tool for concussion, its limited accessibility in clinical or field settings necessitates a more efficient alternative. Oculomotor function deficit is an often-reported pathology in mTBI. Due to the neuroanatomical overlap between eye-movement circuitry and mTBI pathophysiology, visual deficits are expected. In this study, we investigate the possibility of using an oculomotor assessment tool for finding biomarkers in concussion. We used fMRI with tasks evaluating oculomotor functions: smooth pursuit (SP), saccades, anti-saccades, and optokinetic nystagmus (OKN). Before the scanning, the testing with a system of virtual reality goggles with integrated eye- and head-tracking was used where subjects performed the same tasks as those used in fMRI. Twenty-nine concussed symptomatic adults (CSA) within 1-month postconcussion and 29 age- and sex-matched healthy controls (HCS) were tested to examine blood oxygen level-dependent (BOLD) fMRI alterations associated with performances in oculomotor function after mTBI and evaluate the efficacy of the oculomotor assessment in detecting oculomotor and gaze deficits following mTBI. Comparing CSA with HCS, significant differences were observed in anti-saccades and OKN performance. CSA group exhibited elevated %BOLD signal change on each task compared with HCS: in the superior frontal gyrus during the smooth pursuit, inferior frontal gyrus during the saccades, putamen and dorsolateral prefrontal cortex (DLPFC) during the anti-saccades, and lingual gyrus and IFG during the OKN. Key findings include the following: (1) oculomotor deficits in concussed subjects compared with controls, (2) abnormal activation patterns in areas related to the regulation and control of oculomotor movements, suggesting concussion-induced disruptions, and (3) the potential of oculomotor assessment as a promising approach for mTBI biomarkers, with anti-saccades and OKN identified as the most sensitive tasks.

Shen Shuai II recipe improves renal hypoxia to attenuate renal injury in 5/6 renal ablation/infarction rats and effect evaluation using blood oxygenation level-dependent functional magnetic resonance imaging

Background: Renal hypoxia plays a key role in the progression of chronic kidney disease (CKD). Shen Shuai II Recipe (SSR) has shown good results in the treatment of CKD as a common herbal formula. This study aimed to explore the effect of SSR on renal hypoxia and injury in CKD rats. Methods: Twenty-five Wistar rats underwent 5/6 renal ablation/infarction (A/I) surgery were randomly divided into three groups: 5/6 (A/I), 5/6 (A/I) + losartan (LOS), and 5/6 (A/I) + SSR groups. Another eight normal rats were used as the Sham group. After 8-week corresponding interventions, blood oxygenation level-dependent functional magnetic resonance imaging (BOLD-fMRI) was performed to evaluate renal oxygenation in all rats, and biochemical indicators were used to measure kidney and liver function, hemoglobin, and proteinuria. The expression of fibrosis and hypoxia-related proteins was analyzed using immunoblotting examination. Results: Renal oxygenation, evaluated by BOLD-fMRI as cortical and medullary T2* values (COT2* and MET2*), was decreased in 5/6 (A/I) rats, but increased after SSR treatment. SSR also downregulated the expression of hypoxia-inducible factor-1α (HIF-1α) in 5/6 (A/I) kidneys. With the improvement of renal hypoxia, renal function and fibrosis were improved in 5/6 (A/I) rats, accompanied by reduced proteinuria. Furthermore, the COT2* and MET2* were significantly positively correlated with the levels of creatinine clearance rate (Ccr) and hemoglobin, but negatively associated with the levels of serum creatinine (SCr), blood urea nitrogen (BUN), serum cystatin C (CysC), serum uric acid (UA), 24-h urinary protein (24-h Upr), and urinary albumin:creatinine ratio (UACR). Conclusion: The degree of renal oxygenation reduction is correlated with the severity of renal injury in CKD. SSR can improve renal hypoxia to attenuate renal injury in 5/6 (A/I) rats of CKD.