Blood Oxygenation Level-dependent Changes Research Articles

On the interplay between state-dependent reconfigurations of global signal correlation and BOLD fluctuations: An fMRI study

BackgroundThe dynamics of global, state-dependent reconfigurations in brain connectivity are yet unclear. We aimed at assessing reconfigurations of the global signal correlation coefficient (GSCORR), a measure of the connectivity between each voxel timeseries and the global signal, from resting-state to a stop-signal task. The secondary aim was to assess the relationship between GSCORR and blood-oxygen-level-dependent (BOLD) activations or deactivation across three different trial-conditions (GO, STOP-correct, and STOP-incorrect). MethodsAs primary analysis we computed whole-brain, voxel-wise GSCORR during resting-state (GSCORR-rest) and stop-signal task (GSCORR-task) in 107 healthy subjects aged 21–50, deriving GSCORR-shift as GSCORR-task minus GSCORR-rest. GSCORR-tr and trGSCORR-shift were also computed on the task residual time series to quantify the impact of the task-related activity during the trials. To test the secondary aim, brain regions were firstly divided in one cluster showing significant task-related activation and one showing significant deactivation across the three trial conditions. Then, correlations between GSCORR-rest/task/shift and activation/deactivation in the two clusters were computed. As sensitivity analysis, GSCORR-shift was computed on the same sample after performing a global signal regression and GSCORR-rest/task/shift were correlated with the task performance. ResultsSensory and temporo-parietal regions exhibited a negative GSCORR-shift. Conversely, associative regions (ie. left lingual gyrus, bilateral dorsal posterior cingulate gyrus, cerebellum areas, thalamus, posterolateral parietal cortex) displayed a positive GSCORR-shift (FDR-corrected p < 0.05). GSCORR-shift showed similar patterns to trGSCORR-shift (magnitude increased) and after global signal regression (magnitude decreased). Concerning BOLD changes, Brodmann area 6 and inferior parietal lobule showed activation, while posterior parietal lobule, cuneus, precuneus, middle frontal gyrus showed deactivation (FDR-corrected p < 0.05). No correlations were found between GSCORR-rest/task/shift and beta-coefficients in the activation cluster, although negative correlations were observed between GSCORR-task and GO/STOP-correct deactivation (Pearson rho=-0.299/-0.273; Bonferroni-p < 0.05). Weak associations between GSCORR and task performance were observed (uncorrected p < 0.05). ConclusionGSCORR state-dependent reconfiguration indicates a reallocation of functional resources to associative areas during stop-signal task. GSCORR, activation and deactivation may represent distinct proxies of brain states with specific neurofunctional relevance.

Functional brain networks involved in the Raven's standard progressive matrices task and their relation to theories of fluid intelligence

A dimensionality reduction method was used to determine the task-timing-related functional brain networks underlying the Raven's Standard Progressive Matrices (RSPM), a non-verbal estimate of fluid intelligence (Gf). We identified five macro-scale task-based blood‑oxygen-level-dependent (BOLD)-signal brain networks and interpreted their network-level task-induced BOLD changes to provide functional interpretations separately for each network. This led to new observations about the brain networks underlying the RSPM: (1) the multiple demand network (MDN) for solution searching peaked early in the trial (∼9 s peak), followed by response (RESP) for response selection (∼12 s), and re-evaluation (RE-EV) for solution checking (∼18 s peak), (2) high activity in the MDN was correlated with high activity in the later-peaking RE-EV network, proposed to underpin cooperative solution searching (MDN) and checking (RE-EV) processes, and (3) high activity in the MDN in all conditions was associated with low accuracy in the hard RSPM condition, suggesting that those with lower performance on hard problems allocate more resources into solution-searching across all conditions. These findings corroborate the MDN's significance in Gf solution searching, and add the RE-EV network as playing an important checking role, providing overlap with the proposed abstraction/elaboration and hypothesis testing phases of the Parieto-Frontal Integration Theory (P-FIT). Therefore, this set of results not only supports past theoretical work on the brain networks underlying Gf and the RSPM task, but extends it by providing more complete anatomical, temporal, and functional information based on a set of brain task-based networks which replicate over many tasks.

Shape-aware Segmentation of the Placenta in BOLD Fetal MRI Time Series

Blood oxygen level dependent (BOLD) MRI time series with maternal hyperoxia can assess placental oxygenation and function. Measuring precise BOLD changes in the placenta requires accurate temporal placental segmentation and is confounded by fetal and maternal motion, contractions, and hyperoxia-induced intensity changes. Current BOLD placenta segmentation methods warp a manually annotated subject-specific template to the entire time series. However, as the placenta is a thin, elongated, and highly non-rigid organ subject to large deformations and obfuscated edges, existing work cannot accurately segment the placental shape, especially near boundaries. In this work, we propose a machine learning segmentation framework for placental BOLD MRI and apply it to segmenting each volume in a time series. We use a placental-boundary weighted loss formulation and perform a comprehensive evaluation across several popular segmentation objectives. Our model is trained and tested on a cohort of (91) subjects containing healthy fetuses, fetuses with fetal growth restriction, and mothers with high BMI. Biomedically, our model performs reliably in segmenting volumes in both normoxic and hyperoxic points in the BOLD time series. We further find that boundary-weighting increases placental segmentation performance by 8.3% and 6.0% Dice coefficient for the cross-entropy and Signed Distance Transform objectives, respectively.

Neurovascular Coupling in Hypertensive COVID‐19 Survivors Medicated With Different Classes of RAS Inhibitors: A Pilot Study

AbstractBackgroundHypertension poses an increased risk of Alzheimer’s disease (AD). Coronavirus disease 2019 (COVID‐19) may exacerbate this risk by affecting the Renin‐Angiotensin system (RAS), which contributes to the regulation of neurovascular coupling (NVC). NVC is a mechanism that optimizes cerebral blood flow (CBF) to meet the metabolic and waste‐removal needs of the brain. Disrupted NVC may predispose individuals to AD through hypoxia‐related protein changes and suboptimal protein‐waste removal from the brain. Several studies reported reduced CBF in long‐haul COVID‐19 patients. Among antihypertensive medicines that target the RAS, angiotensin receptor blockers (ARBs), but not angiotensin‐converting enzyme inhibitors (ACEIs), were previously found to regulate CBF. Therefore, we hypothesized that, if taken during and after a COVID‐19 episode, ARBs rather than ACEIs would be protective against long‐term CBF dysregulation.MethodWe quantified NVC through a novel analysis paradigm that takes advantage of simultaneous resting‐state electroencephalography (EEG) and functional magnetic resonance imaging (fMRI). We obtained scans from older adult participants (aged 55‐80), including healthy controls and hypertensive COVID‐19 survivors medicated with ARBs or ACEIs during their COVID‐19 infection (occurring 3‐27 months before scanning). Hidden Markov modeling on source‐localized EEG was used to detect transient electrophysiological activity in distinct neural networks. A rapid event‐related fMRI analysis deconvolved the blood oxygenation level‐dependent (BOLD) changes evoked by the network‐specific electrophysiological activations. NVC was measured as the slope of vascular BOLD changes over the time‐locked electrophysiological neural changes.ResultIn this pilot study, the default mode network (DMN) showed differences in NVC between the hypertensive COVID‐19 survivors and the healthy control group. Crucially, the ARB‐medicated subgroup, like the control group, showed the BOLD response in the DMN regions time‐locked to the DMN electrophysiological activations; NVC differences between the ARB‐medicated and control groups did not reach significance. In contrast, the ACEI‐medicated subgroup showed a reduced NVC in the DMN relative to the control group.ConclusionThe DMN, which is linked to memory dysfunction in AD, may be vulnerable to NVC disruptions, given its high metabolic demands. Hypertension management with ARBs may reduce COVID‐19’s effects on cerebrovascular regulation, preventing ischemic stroke, vascular dementia, and AD. Results replication is warranted.

Estimation of fMRI responses related to epileptic discharges using Bayesian hierarchical modeling.

Simultaneous electroencephalography-functional MRI (EEG-fMRI) is a unique and noninvasive method for epilepsy presurgical evaluation. When selecting voxels by null-hypothesis tests, the conventional analysis may overestimate fMRI response amplitudes related to interictal epileptic discharges (IEDs), especially when IEDs are rare. We aimed to estimate fMRI response amplitudes represented by blood oxygen level dependent (BOLD) percentage changes related to IEDs using a hierarchical model. It involves the local and distributed hemodynamic response homogeneity to regularize estimations. Bayesian inference was applied to fit the model. Eighty-two epilepsy patients who underwent EEG-fMRI and subsequent surgery were included in this study. A conventional voxel-wise general linear model was compared to the hierarchical model on estimated fMRI response amplitudes and on the concordance between the highest response cluster and the surgical cavity. The voxel-wise model overestimated fMRI responses compared to the hierarchical model, evidenced by a practically and statistically significant difference between the estimated BOLD percentage changes. Only the hierarchical model differentiated brief and long-lasting IEDs with significantly different BOLD percentage changes. Overall, the hierarchical model outperformed the voxel-wise model on presurgical evaluation, measured by higher prediction performance. When compared with a previous study, the hierarchical model showed higher performance metric values, but the same or lower sensitivity. Our results demonstrated the capability of the hierarchical model of providing more physiologically reasonable and more accurate estimations of fMRI response amplitudes induced by IEDs. To enhance the sensitivity of EEG-fMRI for presurgical evaluation, it may be necessary to incorporate more appropriate spatial priors and bespoke decision strategies.

Feature-based Attentional Amplitude Modulations of the Steady-state Visual Evoked Potentials Reflect Blood Oxygen Level Dependent Changes in Feature-sensitive Visual Areas.

Recent EEG studies have investigated basic principles of feature-based attention by means of frequency-tagged random dot kinematograms in which different colors are simultaneously presented at different temporal frequencies to elicit steady-state visual evoked potentials (SSVEPs). These experiments consistently showed global facilitation of the to-be-attended random dot kinematogram-a basic principle of feature-based attention. SSVEP source estimation suggested that posterior visual cortex from V1 to area hMT+/V5 is broadly activated by frequency-tagged stimuli. What is presently unknown is whether the feature-based attentional facilitation of SSVEPs is a rather unspecific neural response including all visual areas that follow the "on/off," or whether SSVEP feature-based amplitude enhancements are driven by activity in visual areas most sensitive to a specific feature, such as V4v in the case of color. Here, we leverage multimodal SSVEP-fMRI recordings in human participants and a multidimensional feature-based attention paradigm to investigate this question. Attending to shape produced significantly greater SSVEP-BOLD covariation in primary visual cortex compared with color. SSVEP-BOLD covariation during color selection increased along the visual hierarchy, with greatest values in areas V3 and V4. Importantly, in area hMT+/V5, we found no differences between shape and color selection. Results suggest that SSVEP amplitude enhancements in feature-based attention is not an unspecific enhancement of neural activity in all visual areas following the "on/off." These findings open new avenues to investigating neural dynamics of competitive interactions in specific visual areas sensitive to a certain feature in a more economical way and better temporal resolution compared with fMRI.

Spectral peak areas do not vary according to spectral averaging scheme used in functional MRS experiments at 3 T with interleaved visual stimulation

Abstract Brain response to visual stimulation can be probed quantitatively using functional magnetic resonance spectroscopy (fMRS), which relies on the blood oxygenation level dependent (BOLD) contrast mechanism. BOLD effect in fMRS is associated with changes in the areas, widths, and heights of the MR spectra. This study investigated the effect of spectral averaging scheme (NEX value) on BOLD changes in the spectra. Using a visual stimulus at 8 Hz in single and interleaved stimulation paradigms, the BOLD effects in spectra acquired from the occipital brain region of three healthy volunteers (mean age ± SD = 32.7 ± 3.5 years) were compared for two fMRS data sets acquired with two NEX values (“2” and “8”) available on a 3 T MR scanner. BOLD signal changes were estimated as percentage changes in spectral areas, heights, and widths of six cerebral metabolites and water using the SAGE software package (version 7). There was a general trend of lower BOLD effects with NEX = 8 in both stimulation paradigms. In the single stimulation paradigm, NEX = 8 was associated with significantly lower N-acetyl aspartate (NAA) spectral height (p = 0.03), creatine (p = 0.04) and choline (p = 0.02) spectral widths, and NAA (p = 0.03), water (p &lt; 0.01), and glutamate (p = 0.02) spectral areas. In the interleaved stimulation paradigm, NEX = 8 was associated with significantly lower glutamate spectral height (p = 0.02), water (p = 0.03), and glutamine (p = 0.03) spectral widths, but there was no significant difference in all spectral areas between the two NEX values. Even though the two NEX values offered some differences in observable BOLD effects, their spectral areas were not significantly different in the interleaved visual stimulation experiments.

Brain BOLD and NIRS response to hyperoxic challenge in sickle cell disease and chronic anemias

PurposeCongenital anemias, including sickle cell anemia and thalassemia, are associated with cerebral tissue hypoxia and heightened stroke risks. Recent works in sickle cell disease mouse models have suggested that hyperoxia respiratory challenges can identify regions of the brain having chronic tissue hypoxia. Therefore, this work investigated differences in hyperoxic response and regional cerebral oxygenation between anemic and healthy subjects. MethodsA cohort of 38 sickle cell disease subjects (age 22 ± 8 years, female 39%), 25 non-sickle anemic subjects (age 25 ± 11 years, female 52%), and 31 healthy controls (age 25 ± 10 years, female 68%) were examined. A hyperoxic gas challenge was performed with concurrent acquisition of blood oxygen level-dependent (BOLD) MRI and near-infrared spectroscopy (NIRS). In addition to hyperoxia-induced changes in BOLD and NIRS, global measurements of cerebral blood flow, oxygen delivery, and cerebral metabolic rate of oxygen were obtained and compared between the three groups. ResultsRegional BOLD changes were not able to identify brain regions of flow limitation in chronically anemic patients. Higher blood oxygen content and tissue oxygenation were observed during hyperoxia gas challenge. Both control and anemic groups demonstrated lower blood flow, oxygen delivery, and metabolic rate compared to baseline, but the oxygen metabolism in anemic subjects were abnormally low during hyperoxic exposure. ConclusionThese results indicated that hyperoxic respiratory challenge could not be used to identify chronically ischemic brain. Furthermore, the low hyperoxia-induced metabolic rate suggested potential negative effects of prolonged oxygen therapy and required further studies to evaluate the risk for hyperoxia-induced oxygen toxicity and cerebral dysfunction.

Grant Report on the Transcranial near Infrared Radiation and Cerebral Blood Flow in Depression (TRIADE) Study

We report on the rationale and design of an ongoing National Institute of Mental Health (NIMH) sponsored R61-R33 project in major depressive disorder (MDD). Current treatments for MDD have significant limitations in efficacy and side effect burden. There is a critical need for device-based treatments in MDD that are efficacious, well-tolerated, and easy to use. This project focuses on the adjunctive use of the transcranial photobiomodulation (tPBM) with near-infrared (NIR) light for the treatment of MDD. tPBM with NIR light penetrates robustly into the cerebral cortex, stimulating the mitochondrial respiratory chain, and also significantly increases cerebral blood flow (CBF). In the R61 phase, we will conduct target engagement studies to demonstrate dose-dependent effects of tPBM on the prefrontal cortex (PFC) CBF, using the increase in fMRI blood-oxygenation-level-dependent (BOLD) signal levels as our Go/No-go target engagement biomarker. In the R33 phase, we will conduct a randomized clinical trial of tPBM vs. sham in MDD to establish the target engagement and evaluate the association between changes in the biomarker (BOLD signal) and changes in clinical symptoms, while also collecting important information on antidepressant effects, safety, and tolerability. The study will be done in parallel at New York University/the Nathan Kline Institute (NYU/NKI) and at Massachusetts General Hospital (MGH). The importance of this study is threefold: 1. it targets MDD, a leading cause of disability worldwide, which lacks adequate treatments; 2. it evaluates tPBM, which has a well-established safety profile and has the potential to be safe in at-home administration; and 3. it uses fMRI BOLD changes as a target engagement biomarker. If effects are confirmed, the present study will both support short-term clinical development of an easy to scale device for the treatment of MDD, while also validating a biomarker for the development of future, novel modulation strategies.

Multi-echo investigations of positive and negative CBF and concomitant BOLD changes

Unlike the positive blood oxygenation level-dependent (BOLD) response (PBR), commonly taken as an indication of an ‘activated’ brain region, the physiological origin of negative BOLD signal changes (i.e. a negative BOLD response, NBR), also referred to as ‘deactivation’ is still being debated. In this work, an attempt was made to gain a better understanding of the underlying mechanism by obtaining a comprehensive measure of the contributing cerebral blood flow (CBF) and its relationship to the NBR in the human visual cortex, in comparison to a simultaneously induced PBR in surrounding visual regions. To overcome the low signal-to-noise ratio (SNR) of CBF measurements, a newly developed multi-echo version of a center-out echo planar-imaging (EPI) readout was employed with pseudo-continuous arterial spin labeling (pCASL). It achieved very short echo and inter-echo times and facilitated a simultaneous detection of functional CBF and BOLD changes at 3 T with improved sensitivity. Evaluations of the absolute and relative changes of CBF and the effective transverse relaxation rate, R2*, the coupling ratios, and their dependence on CBF at rest, CBFrest, indicated differences between activated and deactivated regions. Analysis of the shape of the respective functional responses also revealed faster negative responses with more pronounced post-stimulus transients. Resulting differences in the flow-metabolism coupling ratios were further examined for potential distinctions in the underlying neuronal contributions.

Decreased BOLD signals elicited by 40-Hz auditory stimulation of the right primary auditory cortex in bipolar disorder: An fMRI study.

BackgroundA number studies have been conducted on abnormalities in the cortical circuitry of gamma oscillations, including deficit in auditory steady-state response (ASSR) to gamma-frequency (≧ 30-Hz) stimulation, in patients with bipolar disorder (BD). In the current study, we investigated neural responses during click stimulation by blood oxygen level-dependent (BOLD) signals. We focused on Broadman 41 and 42, the main sources of ASSR.Materials and methodsWe acquired BOLD responses elicited by click trains of 80-, 40-, 30- and 20-Hz frequencies from 25 patients with BD to 27 healthy controls (HC) with normal hearing between 22 and 59 years of age assessed via a standard general linear-model-based analysis. We extracted contrast values by identifying the primary auditory cortex and Brodmann areas 41 and 42 as regions of interest (ROI)s.ResultsBD group showed significantly decreased ASSR-BOLD signals in response to 40-Hz stimuli compared to the HC group in the right Brodmann areas 41 and 42. We found significant negative correlations between the BOLD change in the right Brodmann areas 41 and 42 and Structured Interview Guide for the Hamilton Depression Rating Scale (SIGH-D) scores, also the BOLD change in the right Brodmann areas 41 and 42 and the Positive and Negative Syndrome Scale (PANSS)-Negative scores.ConclusionThe observed decrease in BOLD signal patterns in the right primary auditory cortex during 40-Hz ASSR may be a potential biomarker option for bipolar disorder.

Neural correlates of repeated retrieval of emotional autobiographical events

Understanding the neural correlates of repetitive retrieval of emotional events is critical in addressing pathological emotional processing, as repeated processing is central for a number of different therapeutic interventions. In the current study, single-trial functional brain activity was assessed in key regions implicated in episodic retrieval, including the medial prefrontal cortex (mPFC), anterior hippocampus, posterior hippocampus, and the posteromedial parietal cortex (i.e., posterior cingulate cortex and the precuneus) following repeated retrieval of pleasant and unpleasant autobiographical events. Replicating previous studies, repetition prompted reduced blood-oxygen-level-dependent (BOLD) amplitude in the anterior hippocampus and the mPFC, but not in the posterior hippocampus, due to no functional activity during mental imagery, or in the posteromedial parietal cortex, due to enhanced activation that was sustained across repetitions. Neural activation during pleasant and unpleasant autobiographical retrieval did not differ as a function of repetition, indicating similar processing effects regardless of motivational relevance. Taken together, the hedonic valence of retrieved memories does not affect functional activity associated with repeated retrieval of episodic events, in which the pattern of BOLD amplitude change suggests a dissociation between the hippocampal-prefrontal circuit, which shows repetition suppression, and the posteromedial parietal cortex, which shows sustained activation.

Temporal Lobe Spikes Affect Distant Intrinsic Connectivity Networks.

Objective: To evaluate local and distant blood oxygen level dependent (BOLD) signal changes related to interictal epileptiform discharges (IED) in drug-resistant temporal lobe epilepsy (TLE).Methods: Thirty-three TLE patients undergoing EEG–functional Magnetic Resonance Imaging (fMRI) as part of the presurgical workup were consecutively enrolled. First, a single-subject spike-related analysis was performed: (a) to verify the BOLD concordance with the presumed Epileptogenic Zone (EZ); and (b) to investigate the Intrinsic Connectivity Networks (ICN) involvement. Then, a group analysis was performed to search for common BOLD changes in TLE.Results: Interictal epileptiform discharges were recorded in 25 patients and in 19 (58%), a BOLD response was obtained at the single-subject level. In 42% of the cases, BOLD changes were observed in the temporal lobe, although only one patient had a pure concordant finding, with a single fMRI cluster overlapping (and limited to) the EZ identified by anatomo-electro-clinical correlations. In the remaining 58% of the cases, BOLD responses were localized outside the temporal lobe and the presumed EZ. In every patient, with a spike-related fMRI map, at least one ICN appeared to be involved. Four main ICNs were preferentially involved, namely, motor, visual, auditory/motor speech, and the default mode network. At the single-subject level, EEG–fMRI proved to have high specificity (above 65%) in detecting engagement of an ICN and the corresponding ictal/postictal symptom, and good positive predictive value (above 67%) in all networks except the visual one. Finally, in the group analysis of BOLD changes related to IED revealed common activations at the right precentral gyrus, supplementary motor area, and middle cingulate gyrus.Significance: Interictal temporal spikes affect several distant extra-temporal areas, and specifically the motor/premotor cortex. EEG–fMRI in patients with TLE eligible for surgery is recommended not for strictly localizing purposes rather it might be useful to investigate ICNs alterations at the single-subject level.

Quantification of cerebral blood volume changes caused by visual stimulation at 3 T using DANTE-prepared dual-echo EPI.

We investigate the influence of moving blood-attenuation effects when using "delay alternating with nutation for tailored excitation" (DANTE) pulses in conjunction with blood oxygen level dependent (BOLD) of functional MRI (fMRI) at 3 T. Based on the effects of including DANTE pulses, we propose quantification of cerebral blood volume (CBV) changes following functional stimulation. Eighteen volunteers in total underwent fMRI scans at 3 T. Seven volunteers were scanned to investigate the effects of DANTE pulses on the fMRI signal. CBV changes in response to visual stimulation were quantified in 11 volunteers using a DANTE-prepared dual-echo EPI sequence. The inflow effects from flowing blood in arteries and draining vein effects from flowing blood in large veins can be suppressed by use of a DANTE preparation module. Using DANTE-prepared dual-echo EPI, we quantitatively measured intravascular-weighted microvascular CBV changes of 25.4%, 29.8%, and 32.6% evoked by 1, 5, and 10 Hz visual stimulation, respectively. The extravascular fraction (∆S/S)extra at TE = 30 ms in total BOLD signal was determined to be 64.8 ± 3.4%, which is in line with previous extravascular component estimation at 3 T. Results show that the microvascular CBV changes are linearly dependent on total BOLD changes at TE = 30 ms with a slope of 0.113, and this relation is independent of stimulation frequency and subject. The DANTE preparation pulses can be incorporated into a standard EPI fMRI sequence for the purpose of minimizing inflow effects and reducing draining veins effects in large vessels. Additionally, the DANTE-prepared dual-echo EPI sequence is a promising fast imaging tool for quantification of intravascular-weighted CBV change in the microvascular space at 3 T.

Mapping Epileptic Networks Using Simultaneous Intracranial EEG-fMRI.

Background: Potentially curative epilepsy surgery can be offered if a single, discrete epileptogenic zone (EZ) can be identified. For individuals in whom there is no clear concordance between clinical localization, scalp EEG, and imaging data, intracranial EEG (icEEG) may be needed to confirm a predefined hypothesis regarding irritative zone (IZ), seizure onset zone (SOZ), and EZ prior to surgery. However, icEEG has limited spatial sampling and may fail to reveal the full extent of epileptogenic network if predefined hypothesis is not correct. Simultaneous icEEG-fMRI has been safely acquired in humans and allows exploration of neuronal activity at the whole-brain level related to interictal epileptiform discharges (IED) captured intracranially.Methods: We report icEEG-fMRI in eight patients with refractory focal epilepsy who had resective surgery and good postsurgical outcome. Surgical resection volume in seizure-free patients post-surgically reflects confirmed identification of the EZ. IEDs on icEEG were classified according to their topographic distribution and localization (Focal, Regional, Widespread, and Non-contiguous). We also divided IEDs by their location within the surgical resection volume [primary IZ (IZ1) IED] or outside [secondary IZ (IZ2) IED]. The distribution of fMRI blood oxygen level-dependent (BOLD) changes associated with individual IED classes were assessed over the whole brain using a general linear model. The concordance of resulting BOLD map was evaluated by comparing localization of BOLD clusters with surgical resection volume. Additionally, we compared the concordance of BOLD maps and presence of BOLD clusters in remote brain areas: precuneus, cuneus, cingulate, medial frontal, and thalamus for different IED classes.Results: A total of 38 different topographic IED classes were identified across the 8 patients: Focal (22) and non-focal (16, Regional = 9, Widespread = 2, Non-contiguous = 5). Twenty-nine IEDs originated from IZ1 and 9 from IZ2. All IED classes were associated with BOLD changes. BOLD maps were concordant with the surgical resection volume for 27/38 (71%) IED classes, showing statistical global maximum BOLD cluster or another cluster in the surgical resection volume. The concordance of BOLD maps with surgical resection volume was greater (p < 0.05) for non-focal (87.5%, 14/16) as compared to Focal (59%, 13/22) IED classes. Additionally, BOLD clusters in remote cortical and deep brain areas were present in 84% (32/38) of BOLD maps, more commonly (15/16; 93%) for non-focal IED-related BOLD maps.Conclusions: Simultaneous icEEG-fMRI can reveal BOLD changes at the whole-brain level for a wide range of IEDs on icEEG. BOLD clusters within surgical resection volume and remote brain areas were more commonly seen for non-focal IED classes, suggesting that a wider hemodynamic network is at play.

Elucidating the neural correlates of emotion recognition in children with sub-clinical anxiety

BackgroundThe pervasiveness of subclinical anxiety in children, highlights the need to identify its neurobiological underpinnings to better inform interventions. Given the now well-established link between aberrant emotion processing and anxiety disorders and yet limited neurobiologically-informed research in this area, this study examined the neural correlates of emotion recognition (ER) in children with sub-clinical anxiety. MethodNinety children (aged 9–11 years) with sub-clinical anxiety, completed an emotion recognition task whilst undergoing functional magnetic resonance imaging. The ER task required participants to match shapes and match emotional faces in the context of shape distractors. Participants also completed the Spence Children's Anxiety Scale (SCAS). ResultsGreater blood oxygenation level dependent (BOLD) changes associated with ER were observed in the lateral occipital cortex, middle frontal gyrus, superior middle frontal gyrus, inferior frontal gyrus, superior parietal lobule, inferior parietal lobule, superior temporal gyrus, and middle temporal gyrus symmetrically. The clusters also included posterior cingulate cortex, insula, hippocampus, amygdala and cerebellum during matching emotions than those matching shapes. Females showed greater BOLD changes associated with ER than males in the right middle frontal gyrus. The BOLD changes associated with ER in the right middle frontal gyrus and right insula were greater in children with SCAS subscale (physical injury fear) scores in the normal range than those with elevated scores. DiscussionThe findings in this study implicate the right middle frontal gyrus and insula as key regions in the neurobiological underpinnings of sub-clinical anxiety as they relate to attention impairments in anxious children. ConclusionThe results of this study indicate there are gender differences in young participants during emotion processing and provides a neurobiological target for attention impairments in anxious children.

The longitudinal relationship between BOLD signal variability changes and white matter maturation during early childhood

Intra-individual transient temporal fluctuations in brain signal, as measured by fMRI blood oxygenation level dependent (BOLD) variability, is increasingly considered an important signal rather than measurement noise. Evidence from computational and cognitive neuroscience suggests that signal variability is a good proxy-measure of brain functional integrity and information processing capacity. Here, we sought to explore across-participant and longitudinal relationships between BOLD variability, age, and white matter structure in early childhood. We measured standard deviation of BOLD signal, total white matter volume, global fractional anisotropy (FA) and mean diffusivity (MD) during passive movie viewing in a sample of healthy children (aged 2–8 years; N = 83). We investigated how age and white matter development related to changes in BOLD variability both across- and within-participants. Our across-participant analyses using behavioural partial least squares (bPLS) revealed that the influence of age and white matter maturation on BOLD variability was highly interrelated. BOLD variability increased in widespread frontal, temporal and parietal regions, and decreased in the hippocampus and parahippocampal gyrus with age and white matter development. Our longitudinal analyses using linear mixed effects modelling revealed significant associations between BOLD variability, age and white matter microstructure. Analyses using artificial neural networks demonstrated that BOLD variability and white matter micro and macro-structure at earlier ages were strong predictors of BOLD variability at later ages. By characterizing the across-participant and longitudinal features of the association between BOLD variability and white matter micro- and macrostructure in early childhood, our results provide a novel perspective to understand structure-function relationships in the developing brain.

Distinct Neurophysiological Correlates of the fMRI BOLD Signal in the Hippocampus and Neocortex.

Functional magnetic resonance imaging (fMRI) is among the foremost methods for mapping human brain function but provides only an indirect measure of underlying neural activity. Recent findings suggest that the neurophysiological correlates of the fMRI blood oxygenation level-dependent (BOLD) signal might be regionally specific. We examined the neurophysiological correlates of the fMRI BOLD signal in the hippocampus and neocortex, where differences in neural architecture might result in a different relationship between the respective signals. Fifteen human neurosurgical patients (10 female, 5 male) implanted with depth electrodes performed a verbal free recall task while electrophysiological activity was recorded simultaneously from hippocampal and neocortical sites. The same patients subsequently performed a similar version of the task during a later fMRI session. Subsequent memory effects (SMEs) were computed for both imaging modalities as patterns of encoding-related brain activity predictive of later free recall. Linear mixed-effects modeling revealed that the relationship between BOLD and gamma-band SMEs was moderated by the lobar location of the recording site. BOLD and high gamma (70-150 Hz) SMEs positively covaried across much of the neocortex. This relationship was reversed in the hippocampus, where a negative correlation between BOLD and high gamma SMEs was evident. We also observed a negative relationship between BOLD and low gamma (30-70 Hz) SMEs in the medial temporal lobe more broadly. These results suggest that the neurophysiological correlates of the BOLD signal in the hippocampus differ from those observed in the neocortex.SIGNIFICANCE STATEMENT The BOLD signal forms the basis of fMRI but provides only an indirect measure of neural activity. Task-related modulation of BOLD signals are typically equated with changes in gamma-band activity; however, relevant empirical evidence comes largely from the neocortex. We examined neurophysiological correlates of the BOLD signal in the hippocampus, where the differing neural architecture might result in a different relationship between the respective signals. We identified a positive relationship between encoding-related changes in BOLD and gamma-band activity in the frontal and parietal cortices. This effect was reversed in the hippocampus, where BOLD and gamma-band effects negatively covaried. These results suggest regional variability in the transfer function between neural activity and the BOLD signal in the hippocampus and neocortex.

The Reproducibility of Cerebrovascular Reactivity Across MRI Scanners.

Cerebrovascular reactivity (CVR) is defined as the ratio of the cerebral blood flow (CBF) response to an increase in a vasoactive stimulus. We used changes in blood oxygenation level-dependent (BOLD) MRI as surrogates for changes of CBF, and standardized quantitative changes in arterial partial pressure of carbon dioxide as the stimulus. Despite uniform stimulus and test conditions, differences in voxel-wise BOLD changes between testing sites may remain, attributable to physiologic and machine variability. We generated a reference atlas of normal CVR metrics (voxel-wise mean and SD) for each of two sites. We hypothesized that there would be no significant differences in CVR between the two atlases enabling each atlas to be used at any site. A total of 69 healthy subjects were tested to create site-specific atlases, with 20 of those individuals tested at both sites. 38 subjects were scanned at Site 1 (17F, 37.5 ± 16.8 y) and 51 subjects were tested at Site 2 (22F, 40.9 ± 17.4 y). MRI platforms were: Site 1, 3T Magnetom Skyra Siemens scanner with 20-channel head and neck coil; and Site 2, 3T HDx Signa GE scanner with 8-channel head coil. To construct the atlases, test results of individual subjects were co-registered into a standard space and voxel-wise mean and SD CVR metrics were calculated. Map comparisons of z scores found no significant differences between white matter or gray matter in the 20 subjects scanned at both sites when analyzed with either atlas. We conclude that individual CVR testing, and atlas generation are compatible across sites provided that standardized respiratory stimuli and BOLD MRI scan parameters are used. This enables the use of a single atlas to score the normality of CVR metrics across multiple sites.

A single dose of escitalopram blunts the neural response in the thalamus and caudate during monetary loss.

Background:Selective serotonin reuptake inhibitors (SSRIs) show acute effects on the neural processes associated with negative affective bias in healthy people and people with depression. However, whether and how SSRIs also affect reward and punishment processing on a similarly rapid time scale remains unclear.Methods:We investigated the effects of an acute and clinically relevant dose (20 mg) of the SSRI escitalopram on brain response during reward and punishment processing in 19 healthy participants. In a double-blind, placebo-controlled study using functional MRI, participants performed a well-established monetary reward task at 3 time points: at baseline; after receiving placebo or escitalopram; and after receiving placebo or escitalopram following an 8-week washout period.Results:Acute escitalopram administration reduced blood-oxygen-level-dependent (BOLD) response during punishment feedback in the right thalamus (family-wise error corrected [FWE] p = 0.013 at peak level) and the right caudate head (pFWE = 0.011 at peak level) compared to placebo. We did not detect any significant BOLD changes during reward feedback.Limitations:We included only healthy participants, so interpretation of findings are limited to the healthy human brain and require future testing in patient populations. The paradigm we used was based on monetary stimuli, and results may not be generalizable to other forms of reward.Conclusion:Our findings extend theories of rapid SSRI action on the neural processing of rewarding and aversive stimuli and suggest a specific and acute effect of escitalopram in the punishment neurocircuitry.