A multicenter, single-arm, phase II clinical trial of adrenomedullin in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common form of hereditary cerebral small vessel disease (SVD), currently lacks disease-modifying treatments. Adrenomedullin (AM), a vasoactive peptide with angiogenic, vasodilatory, anti-inflammatory, and anti-oxidative properties, shows potential effects on the neuro-glial-vascular unit. Objective: The AdrenoMedullin for CADASIL (AMCAD) study aims to assess the efficacy and safety of AM in patients with CADASIL. Sample size: Overall, 60 patients will be recruited. Methods: The AMCAD is a multicenter, investigator-initiated, single-arm phase II trial. Patients with a confirmed CADASIL diagnosis, based on NOTCH3 genetic testing, will receive an 8-h AM treatment (15 ng/kg/min) for 14 days following a baseline assessment (from day 1 to day 14). Follow-up evaluations will be performed on days 15, 28, 90, and 180. Study outcomes: The primary endpoint is the cerebral blood flow change rate in the frontal cortex, evaluated using arterial spin labeling magnetic resonance imaging, from baseline to day 28. Summary statistics, 95% confidence intervals, and a one-sample t-test will be used for analysis. Conclusion: The AMCAD study aims to represent the therapeutic potential of AM in patients with CADASIL, addressing an unmet medical need in this challenging condition. Clinical Trial Registration: jRCT 2,051,210,117 (https://jrct.niph.go.jp/en-latest-detail/jRCT2051210117).

Associations of conservatism and jumping to conclusions biases with aberrant salience and default mode network.

AIM: While conservatism bias refers to the human need for more evidence for decision-making than rational thinking expects, the jumping to conclusions (JTC) bias refers to the need for less evidence among individuals with schizophrenia/delusion compared to healthy people. Although the hippocampus-midbrain-striatal aberrant salience system and the salience, default mode (DMN), and frontoparietal networks ("triple networks") are implicated in delusion/schizophrenia pathophysiology, the associations between conservatism/JTC and these systems/networks are unclear. METHODS: Thirty-seven patients with schizophrenia and 33 healthy controls performed the beads task, with large and small numbers of bead draws to decision (DTD) indicating conservatism and JTC, respectively. We performed independent component analysis (ICA) of resting functional magnetic resonance imaging (fMRI) data. For systems/networks above, we investigated interactions between diagnosis and DTD, and main effects of DTD. We similarly applied ICA to structural and diffusion MRI to explore the associations between DTD and gray/white matter. RESULTS: We identified a significant main effect of DTD with functional connectivity between the striatum and DMN, which was negatively correlated with delusion severity in patients, indicating that the greater the anti-correlation between these networks, the stronger the JTC and delusion. We further observed the main effects of DTD on a gray matter network resembling the DMN, and a white matter network connecting the functional and gray matter networks (all P < 0.05, family-wise error [FWE] correction). Function and gray/white matter showed no significant interactions. CONCLUSION: Our results support the novel association of conservatism and JTC biases with aberrant salience and default brain mode.

Efficacy and Safety of Cilostazol in Mild Cognitive Impairment: A Randomized Clinical Trial.

Importance: Recent evidence indicates the efficacy of ß-amyloid immunotherapy for the treatment of Alzheimer disease, highlighting the need to promote ß-amyloid removal from the brain. Cilostazol, a selective type 3 phosphodiesterase inhibitor, promotes such clearance by facilitating intramural periarterial drainage. Objective: To determine the safety and efficacy of cilostazol in mild cognitive impairment. Design, Setting, and Participants: The COMCID trial (A Trial of Cilostazol for Prevention of Conversion from Mild Cognitive Impairment to Dementia) was an investigator-initiated, double-blind, phase 2 randomized clinical trial. Adult participants were registered between May 25, 2015, and March 31, 2018, and received placebo or cilostazol for up to 96 weeks. Participants were treated in the National Cerebral and Cardiovascular Center and 14 other regional core hospitals in Japan. Patients with mild cognitive impairment with Mini-Mental State Examination (MMSE) scores of 22 to 28 points (on a scale of 0 to 30, with lower scores indicating greater cognitive impairment) and Clinical Dementia Rating scores of 0.5 points (on a scale of 0, 0.5, 1, 2, and 3, with higher scores indicating more severe dementia) were enrolled. The data were analyzed from May 1, 2020, to December 1, 2020. Interventions: The participants were treated with placebo, 1 tablet twice daily, or cilostazol, 50 mg twice daily, for up to 96 weeks. Main Outcomes and Measures: The primary end point was the change in the total MMSE score from baseline to the final observation. Safety analyses included all adverse events. Results: The full analysis set included 159 patients (66 [41.5%] male; mean [SD] age, 75.6 [5.2] years) who received placebo or cilostazol at least once. There was no statistically significant difference between the placebo and cilostazol groups for the primary outcome. The least-squares mean (SE) changes in the MMSE scores among patients receiving placebo were -0.1 (0.3) at the 24-week visit, -0.8 (0.3) at 48 weeks, -1.2 (0.4) at 72 weeks, and -1.3 (0.4) at 96 weeks. Among those receiving cilostazol, the least-squares mean (SE) changes in MMSE scores were -0.6 (0.3) at 24 weeks, -1.0 (0.3) at 48 weeks, -1.1 (0.4) at 72 weeks, and -1.8 (0.4) at 96 weeks. Two patients (2.5%) in the placebo group and 3 patients (3.8%) in the cilostazol group withdrew owing to adverse effects. There was 1 case of subdural hematoma in the cilostazol group, which may have been related to the cilostazol treatment; the patient was successfully treated surgically. Conclusions and Relevance: In this randomized clinical trial, cilostazol was well tolerated, although it did not prevent cognitive decline. The efficacy of cilostazol should be tested in future trials. Trial Registration: ClinicalTrials.gov Identifier: NCT02491268.

Identifying and reverting the adverse effects of white matter hyperintensities on cortical surface analyses.

The Human Connectome Project (HCP)-style surface-based brain MRI analysis is a powerful technique that allows precise mapping of the cerebral cortex. However, the strength of its surface-based analysis has not yet been tested in the older population that often presents with white matter hyperintensities (WMHs) on T2-weighted (T2w) MRI (hypointensities on T1w MRI). We investigated T1-weighted (T1w) and T2w structural MRI in 43 healthy middle-aged to old participants. Juxtacortical WMHs were often misclassified by the default HCP pipeline as parts of the gray matter in T1w MRI, leading to incorrect estimation of the cortical surfaces and cortical metrics. To revert the adverse effects of juxtacortical WMHs, we incorporated the Brain Intensity AbNormality Classification Algorithm into the HCP pipeline (proposed pipeline). Blinded radiologists performed stereological quality control (QC) and found a decrease in the estimation errors in the proposed pipeline. The superior performance of the proposed pipeline was confirmed using an originally-developed automated surface QC based on a large database. Here we showed the detrimental effects of juxtacortical WMHs for estimating cortical surfaces and related metrics and proposed a possible solution for this problem. The present knowledge and methodology should help researchers identify adequate cortical surface biomarkers for aging and age-related neuropsychiatric disorders.

Neural correlates of a mindfulness-based intervention in anorexia nervosa.

We examined the neural underpinnings of the effects of mindfulness on anxiety in anorexia nervosa using functional magnetic resonance imaging in 21 anorexia patients. We used a functional magnetic resonance imaging task designed to induce weight-related anxiety and asked participants to regulate their anxiety either using or not using an acceptance strategy. Our results showed reduced activity in the amygdala, anterior cingulate cortex, putamen, caudate, orbital gyrus, middle frontal gyrus, posterior cingulate cortex and precuneus following a mindfulness-based intervention. The present study provides new insight regarding the neural mechanisms underlying the effect of mindfulness-based intervention in ameliorating anorexia nervosa.

A model for estimating the brainstem volume in normal healthy individuals and its application to diffuse axonal injury patients.

Diffuse axonal injury (DAI) is a subtype of traumatic brain injury that causes acute-phase consciousness disorders and widespread chronic-phase brain atrophy. Considering the importance of brainstem damage in DAI, a valid method for evaluating brainstem volume is required. We obtained volume measurements from 182 healthy adults by analyzing T1-weighted magnetic resonance images, and created an age-/sex-/intracranial volume-based quantitative model to estimate the normal healthy volume of the brainstem and cerebrum. We then applied this model to the volume measurements of 22 DAI patients, most of whom were in the long-term chronic phase and had no gross focal injury, to estimate the percentage difference in volume from the expected normal healthy volume in different brain regions, and investigated its association with the duration of posttraumatic amnesia (which is an early marker of injury severity). The average loss of the whole brainstem was 13.9%. Moreover, the percentage loss of the whole brainstem, and particularly of the pons and midbrain, was significantly negatively correlated with the duration of posttraumatic amnesia. Our findings suggest that injury severity, as denoted by the duration of posttraumatic amnesia, is among the factors affecting the chronic-phase brainstem volume in patients with DAI.

Combining Multiple Indices of Diffusion Tensor Imaging Can Better Differentiate Patients with Traumatic Brain Injury from Healthy Subjects.

Aim: Diffuse axonal injury (DAI) is one of the most common pathological features of traumatic brain injury (TBI). Diffusion tensor imaging (DTI) indices can be used to identify and quantify white matter microstructural changes following DAI. Recently, many studies have used DTI with various machine learning approaches to predict white matter microstructural changes following TBI. The current study sought to examine whether our classification approach using multiple DTI indices in conjunction with machine learning is a useful tool for diagnosing/classifying TBI patients and healthy controls. Methods: Participants were adult patients with chronic TBI (n = 26) with DAI pathology, and age- and sex-matched healthy controls (n = 26). DTI images were obtained from all participants. Tract-based spatial statistics analyses were applied to DTI images. Classification models were built using principal component analysis and support vector machines. Receiver operator characteristic curve analysis and area under the curve were used to assess the classification performance of the different classifiers. Results: Tract-based spatial statistics revealed significantly decreased fractional anisotropy, as well as increased mean diffusivity, axial diffusivity, and radial diffusivity in patients with TBI compared with healthy controls (all p-values < 0.01). The principal component analysis and support vector machine-based machine learning classification using combined DTI indices classified patients with TBI and healthy controls with an accuracy of 90.5% with an area under the curve of 93 ± 0.09. Conclusion: These results highlight the potential of our approach combining multiple DTI measures to identify patients with TBI.

The relationship between attention and avoidance coping in anorexia nervosa: functional magnetic resonance imaging study.

BACKGROUND: Numerous studies have demonstrated attentional control difficulties and high avoidance coping in patients with anorexia nervosa. Attention is a critical coping resource because it enables individuals to demonstrate self-control and complete goal-directed behaviours. AIMS: We aimed to examine whether attentional control difficulty is related to high avoidance coping, and investigate the neural underpinnings of attentional control difficulties in individuals with anorexia nervosa. METHOD: Twenty-three patients with anorexia nervosa and 17 healthy controls completed questionnaires that assessed attention and coping, and underwent functional magnetic resonance imaging while performing a go/no-go task. RESULTS: Patients with anorexia nervosa showed weaker attentional control, higher omission error rates and higher avoidance coping compared with healthy controls. Attentional control difficulty was associated with higher avoidance coping in both groups. Functional magnetic resonance imaging analysis showed less deactivation in regions representing internal mental processing, such as the praecuneus, cuneus and left lingual gyrus, during the no-go condition. Moreover, weakened deactivation of the left lingual gyrus was associated with higher commission error rate in the anorexia nervosa group. CONCLUSIONS: Our results suggest that patients with anorexia nervosa may have difficulty in maintaining attention to external ongoing events because of disturbance from internal self-related thought, and support the notion that attentional control difficulties underlie the frequent use of avoidance coping in anorexia nervosa.

Brain/MINDS beyond human brain MRI project: A protocol for multi-level harmonization across brain disorders throughout the lifespan.

Psychiatric and neurological disorders are afflictions of the brain that can affect individuals throughout their lifespan. Many brain magnetic resonance imaging (MRI) studies have been conducted; however, imaging-based biomarkers are not yet well established for diagnostic and therapeutic use. This article describes an outline of the planned study, the Brain/MINDS Beyond human brain MRI project (BMB-HBM, FY2018 ~ FY2023), which aims to establish clinically-relevant imaging biomarkers with multi-site harmonization by collecting data from healthy traveling subjects (TS) at 13 research sites. Collection of data in psychiatric and neurological disorders across the lifespan is also scheduled at 13 sites, whereas designing measurement procedures, developing and analyzing neuroimaging protocols, and databasing are done at three research sites. A high-quality scanning protocol, Harmonization Protocol (HARP), was established for five high-quality 3 T scanners to obtain multimodal brain images including T1 and T2-weighted, resting-state and task functional and diffusion-weighted MRI. Data are preprocessed and analyzed using approaches developed by the Human Connectome Project. Preliminary results in 30 TS demonstrated cortical thickness, myelin, functional connectivity measures are comparable across 5 scanners, suggesting sensitivity to subject-specific connectome. A total of 75 TS and more than two thousand patients with various psychiatric and neurological disorders are scheduled to participate in the project, allowing a mixed model statistical harmonization. The HARP protocols are publicly available online, and all the imaging, demographic and clinical information, harmonizing database will also be made available by 2024. To the best of our knowledge, this is the first project to implement a prospective, multi-level harmonization protocol with multi-site TS data. It explores intractable brain disorders across the lifespan and may help to identify the disease-specific pathophysiology and imaging biomarkers for clinical practice.

Spatial Patterns of Amyloid Deposition in Patients with Chronic Focal or Diffuse Traumatic Brain Injury Using 18F-FPYBF-2 PET.

AIM: Amyloid-ß (Aß) accumulation, accelerated by traumatic brain injury (TBI), may play a crucial role in neurodegeneration in chronic-stage TBI. The injury type could influence Aß dynamics because of TBI's complex, heterogeneous nature. We, therefore, investigated spatial patterns of amyloid deposition according to injury type after TBI using 5-(5-(2-(2-(2-[F]-fluoroethoxy)ethoxy)ethoxy)benzofuran-2-yl)-N-methylpyridin-2-amine (18F-FPYBF-2) positron emission tomography (PET). METHODS: Altogether, 20 patients with chronic TBI [12 with focal injury, 8 with diffuse axonal injury (DAI)] underwent 18F-FPYBF-2 PET, structural magnetic resonance imaging (MRI), and neuropsychological examination. Additionally, 50 healthy controls underwent either 18F-FPYBF-2 PET (n=30) or structural MRI (n=20). RESULTS: Standardized uptake value ratio (SUVR) on PET images and regional brain volumes were measured in four cortical (frontal, parietal, occipital, temporal) and subcortical (combined caudate, putamen, pallidum, thalamus) regions. Patients with DAI showed significantly increased (compared with controls) SUVR in occipital and temporal cortices and decreased brain volume in occipital cortex (corrected p < 0.05). Although patients with focal injury showed decreased SUVR in all regions except occipital cortex, there were no significant differences (compared with controls) in the SUVR in any regions. There were no significant correlations between increased SUVR and neuropsychological impairments in patients with DAI. CONCLUSION: Varying spatial patterns of amyloid deposition suggest amyloid pathology diversity depending on the injury type in chronic-TBI patients.

Early and late effects of electroconvulsive therapy associated with different temporal lobe structures.

Recent studies examining electroconvulsive therapy (ECT) have reported that early sessions can induce rapid antidepressant and antipsychotic effects, and the early termination of ECT was reported to increase the risk of relapse. We hypothesized that different neural mechanisms associated with the therapeutic effects of ECT may be involved in the different responses observed during the early and late periods of ECT treatment. We investigated whether these antidepressant and antipsychotic effects were associated with temporally and spatially different regional gray matter volume (GMV) changes during ECT. Fourteen patients with major depressive disorder, with or without psychotic features, underwent 3-Tesla structural magnetic resonance imaging scans before (time point [Tp] 1), after the fifth or sixth ECT session (Tp2), and after ECT completion (Tp3). We investigated the regions in which GMV changed between Tp1 and Tp2, Tp2 and Tp3, and Tp1 and Tp3 using voxel-based morphometry. In addition, we investigated the association between regional GMV changes and improvement in depressive or psychotic symptoms. GMV increase in the left superior and inferior temporal gyrus during Tp1-Tp2 was associated with improvement in psychotic symptoms (P < 0.025). GMV increase in the left hippocampus was associated with improvement of depressive symptoms in Tp2-Tp3 (P < 0.05). Our findings suggest that different temporal lobe structures are associated with early antipsychotic and late antidepressant effects of ECT.

Hyperactive sensorimotor cortex during voice perception in spasmodic dysphonia.

Spasmodic dysphonia (SD) is characterized by an involuntary laryngeal muscle spasm during vocalization. Previous studies measured brain activation during voice production and suggested that SD arises from abnormal sensorimotor integration involving the sensorimotor cortex. However, it remains unclear whether this abnormal sensorimotor activation merely reflects neural activation produced by abnormal vocalization. To identify the specific neural correlates of SD, we used a sound discrimination task without overt vocalization to compare neural activation between 11 patients with SD and healthy participants. Participants underwent functional MRI during a two-alternative judgment task for auditory stimuli, which could be modal or falsetto voice. Since vocalization in falsetto is intact in SD, we predicted that neural activation during speech perception would differ between the two groups only for modal voice and not for falsetto voice. Group-by-stimulus interaction was observed in the left sensorimotor cortex and thalamus, suggesting that voice perception activates different neural systems between the two groups. Moreover, the sensorimotor signals positively correlated with disease severity of SD, and classified the two groups with 73% accuracy in linear discriminant analysis. Thus, the sensorimotor cortex and thalamus play a central role in SD pathophysiology and sensorimotor signals can be a new biomarker for SD diagnosis.

Enhanced carbonyl stress and disrupted white matter integrity in schizophrenia.

Carbonyl stress is a state caused by an increase in rich reactive carbonyl compounds (RCOs); RCOs facilitate the formation of advanced glycation end products (AGEs), which are associated with various age-related illnesses. Recently, enhanced carbonyl stress and lower levels of pyridoxal, a kind of vitamin B6 that scavenges RCOs, have been shown to be associated with schizophrenia. Meanwhile, lower levels of pyridoxal have been reported to decrease myelination through the biochemical process of carbonyl stress. Despite a number of reports on white matter disruption in schizophrenia, it is unclear whether this disruption is related to enhanced carbonyl stress. Therefore, we investigated the relationship between carbonyl stress and white matter integrity in schizophrenia using diffusion tensor imaging. A total of 53 patients with schizophrenia and 83 age- and gender-matched healthy controls were recruited. We used plasma pentosidine, an AGE, and serum pyridoxal as carbonyl stress markers. Between-group differences in these carbonyl stress markers and their relationships with white matter integrity were investigated using Tract-Based Spatial Statistics. In the schizophrenia group, plasma pentosidine level was significantly higher and serum pyridoxal level was lower than those of controls. There was a significant negative correlation between plasma pentosidine and white matter integrity in the schizophrenia group, but not in the control group. Our findings suggest that enhanced carbonyl stress is a possible underlying mechanism of white matter microstructural disruption in schizophrenia.

Atypical spatial frequency dependence of visual metacognition among schizophrenia patients.

Although altered early stages of visual processing have been reported among schizophrenia patients, how such atypical visual processing may affect higher-level cognition remains largely unknown. Here we tested the hypothesis that metacognitive performance may be atypically modulated by spatial frequency (SF) of visual stimuli among individuals with schizophrenia, given their altered magnocellular function. To study the effect of SF on metacognitive performance, we asked patients and controls to perform a visual detection task on gratings with different SFs and report confidence, and analyzed the data using the signal detection theoretic measure meta-d'. Control subjects showed better metacognitive performance after yes- (stimulus presence) than after no- (stimulus absence) responses ('yes-response advantage') for high SF (HSF) stimuli but not for low SF (LSF) stimuli. The patients, to the contrary, showed a 'yes-response advantage' not only for HSF but also for LSF stimuli, indicating atypical SF dependency of metacognition. An fMRI experiment using the same task revealed that the dorsolateral prefrontal cortex (DLPFC), known to be crucial for metacognition, shows activity mirroring the behavioral results: decoding accuracy of perceptual confidence in DLPFC was significantly higher for HSF than for LSF stimuli in controls, whereas this decoding accuracy was independent of SF in patients. Additionally, the functional connectivity of DLPFC with parietal and visual areas was modulated by SF and response type (yes/no) in a different manner between controls and patients. While individuals without schizophrenia may flexibly adapt metacognitive computations across SF ranges, patients may employ a different mechanism that is independent of SF. Because visual stimuli of low SF have been linked to predictive top-down processing, this may reflect atypical functioning in these processes in schizophrenia.

A venous mechanism of ventriculomegaly shared between traumatic brain injury and normal ageing.

Recently, age-related timing dissociation between the superficial and deep venous systems has been observed; this was particularly pronounced in patients with normal pressure hydrocephalus, suggesting a common mechanism of ventriculomegaly. Establishing the relationship between venous drainage and ventricular enlargement would be clinically relevant and could provide insight into the mechanisms underlying brain ageing. To investigate a possible link between venous drainage and ventriculomegaly in both normal ageing and pathological conditions, we compared 225 healthy subjects (137 males and 88 females) and 71 traumatic brain injury patients of varying ages (53 males and 18 females) using MRI-based volumetry and a novel perfusion-timing analysis. Volumetry, focusing on the CSF space, revealed that the sulcal space and ventricular size presented different lifespan profiles with age; the latter presented a quadratic, rather than linear, pattern of increase. The venous timing shift slightly preceded this change, supporting a role for venous drainage in ventriculomegaly. In traumatic brain injury, a small but significant disease effect, similar to idiopathic normal pressure hydrocephalus, was found in venous timing, but it tended to decrease with age at injury, suggesting an overlapping mechanism with normal ageing. Structural bias due to, or a direct causative role of ventriculomegaly was unlikely to play a dominant role, because of the low correlation between venous timing and ventricular size after adjustment for age in both patients and controls. Since post-traumatic hydrocephalus can be asymptomatic and occasionally overlooked, the observation suggested a link between venous drainage and CSF accumulation. Thus, hydrocephalus, involving venous insufficiency, may be a part of normal ageing, can be detected non-invasively, and is potentially treatable. Further investigation into the clinical application of this new marker of venous function is therefore warranted.

Connectivity Gradient in the Human Left Inferior Frontal Gyrus: Intraoperative Cortico-Cortical Evoked Potential Study.

In the dual-stream model of language processing, the exact connectivity of the ventral stream to the anterior temporal lobe remains elusive. To investigate the connectivity between the inferior frontal gyrus (IFG) and the lateral part of the temporal and parietal lobes, we integrated spatiotemporal profiles of cortico-cortical evoked potentials (CCEPs) recorded intraoperatively in 14 patients who had undergone surgical resection for a brain tumor or epileptic focus. Four-dimensional visualization of the combined CCEP data showed that the pars opercularis (Broca's area) is connected to the posterior temporal cortices and the supramarginal gyrus, whereas the pars orbitalis is connected to the anterior lateral temporal cortices and angular gyrus. Quantitative topographical analysis of CCEP connectivity confirmed an anterior-posterior gradient of connectivity from IFG stimulus sites to the temporal response sites. Reciprocality analysis indicated that the anterior part of the IFG is bidirectionally connected to the temporal or parietal area. This study shows that each IFG subdivision has different connectivity to the temporal lobe with an anterior-posterior gradient and supports the classical connectivity concept of Dejerine; that is, the frontal lobe is connected to the temporal lobe through the arcuate fasciculus and also a double fan-shaped structure anchored at the limen insulae.

A positive shift in resting-state functional connectivity between the insula and default mode network regions reflects the duration of illness in gambling disorder patients without lifetime substance abuse.

The insula is considered an important structure involved in addiction and in the context of dynamic activity switching between large-scale brain networks, such as the default mode network (DMN) and the central executive network. Although insular-DMN resting-state functional connectivity (rsFC), which could affect such switching, has been examined in substance addiction populations, the results have been inconsistent, partly because of the confounding neural effects of the abused substances. To investigate this subject, using MRI, we examined insular-DMN rsFC in gambling disorder (GD) patients without a history of substance use. We examined rsFC between insular seeds and DMN regions of interest during rest in 23 GD patients and 27 age-, sex-, handedness-, and high education rate-matched healthy control (HC) subjects. We found a positive shift in insular-DMN rsFC in GD patients compared with HC subjects. Furthermore, the connectivity strength between insular seed regions and DMN regions was positively correlated with illness duration in GD patients. This alteration might affect switching between large-scale brain networks, potentially leading to a preoccupation with gambling as well as various types of cognitive impairments. Our results could clarify the controversial findings regarding substance addiction and enhance the system-level understanding of addiction.

Correction: Axial variation of deoxyhemoglobin density as a source of the low-frequency time lag structure in blood oxygenation level-dependent signals.

[This corrects the article DOI: 10.1371/journal.pone.0222787.].

Axial variation of deoxyhemoglobin density as a source of the low-frequency time lag structure in blood oxygenation level-dependent signals.

Perfusion-related information is reportedly embedded in the low-frequency component of a blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) signal. The blood-propagation pattern through the cerebral vascular tree is detected as an interregional lag variation of spontaneous low-frequency oscillations (sLFOs). Mapping of this lag, or phase, has been implicitly treated as a projection of the vascular tree structure onto real space. While accumulating evidence supports the biological significance of this signal component, the physiological basis of the "perfusion lag structure," a requirement for an integrative resting-state fMRI-signal model, is lacking. In this study, we conducted analyses furthering the hypothesis that the sLFO is not only largely of systemic origin, but also essentially intrinsic to blood, and hence behaves as a virtual tracer. By summing the small fluctuations of instantaneous phase differences between adjacent vascular regions, a velocity response to respiratory challenges was detected. Regarding the relationship to neurovascular coupling, the removal of the whole lag structure, which can be considered as an optimized global-signal regression, resulted in a reduction of inter-individual variance while preserving the fMRI response. Examination of the T2* and S0, or non-BOLD, components of the fMRI signal revealed that the lag structure is deoxyhemoglobin dependent, while paradoxically presenting a signal-magnitude reduction in the venous side of the cerebral vasculature. These findings provide insight into the origin of BOLD sLFOs, suggesting that they are highly intrinsic to the circulating blood.