Blood Oxygen Level-dependent Signal Research Articles

An open-access dataset of naturalistic viewing using simultaneous EEG-fMRI

In this work, we present a dataset that combines functional magnetic imaging (fMRI) and electroencephalography (EEG) to use as a resource for understanding human brain function in these two imaging modalities. The dataset can also be used for optimizing preprocessing methods for simultaneously collected imaging data. The dataset includes simultaneously collected recordings from 22 individuals (ages: 23–51) across various visual and naturalistic stimuli. In addition, physiological, eye tracking, electrocardiography, and cognitive and behavioral data were collected along with this neuroimaging data. Visual tasks include a flickering checkerboard collected outside and inside the MRI scanner (EEG-only) and simultaneous EEG-fMRI recordings. Simultaneous recordings include rest, the visual paradigm Inscapes, and several short video movies representing naturalistic stimuli. Raw and preprocessed data are openly available to download. We present this dataset as part of an effort to provide open-access data to increase the opportunity for discoveries and understanding of the human brain and evaluate the correlation between electrical brain activity and blood oxygen level-dependent (BOLD) signals.

Surface-based integration approach for fNIRS-fMRI reliability assessment

IntroductionStudies integrating functional near-infrared spectroscopy (fNIRS) with functional MRI (fMRI) employ heterogeneous methods in defining common regions of interest in which similarities are assessed. Therefore, spatial agreement and temporal correlation may not be reproducible across studies. In the present work, we address this issue by proposing a novel method for integration and analysis of fNIRS and fMRI over the cortical surface. Materials and methodsEighteen healthy volunteers (age mean±SD 30.55 ± 4.7, 7 males) performed a motor task during non-simultaneous fMRI and fNIRS acquisitions. First, fNIRS and fMRI data were integrated by projecting subject- and group-level source maps over the cortical surface mesh to define anatomically constrained functional ROIs (acfROI). Next, spatial agreement and temporal correlation were quantified as Dice Coefficient (DC) and Pearson’s correlation coefficient between fNIRS-fMRI in the acfROIs. ResultsSubject-level results revealed moderate to substantial spatial agreement (DC range 0.43 – 0.64), confirmed at the group-level only for blood oxygenation level-dependent (BOLD) signal vs. HbO2 (0.44 – 0.69), while lack of agreement was found for BOLD vs. HbR in some instances (0.05 – 0.49). Subject-level temporal correlation was moderate to strong (0.79 – 0.85 for BOLD vs. HbO2 and −0.62 to −0.72 for BOLD vs. HbR), while an overall strong correlation was found for group-level results (0.95 – 0.98 for BOLD vs. HbO2 and −0.91 to −0.94 for BOLD vs. HbR). ConclusionThe proposed method directly compares fNIRS and fMRI by projecting individual source maps to the cortical surface. Our results indicate spatial and temporal correspondence between fNIRS and fMRI, and promotes the use of fNIRS when more ecological acquision settings are required, such as longitudinal monitoring of brain activity before and after rehabilitation.

Abnormal voxel-mirrored homotopic connectivity in first-episode, drug-naïve patients with obsessive-compulsive disorder.

Prior studies suggest that obsessive-compulsive disorder (OCD) can cause both anatomical and functional variations in the brain, but to date, altered functional synchronization between two functional hemispheres remains unclear in OCD patients. Voxel-mirrored homotopic connectivity (VMHC) is defined as the temporal correlation of spontaneous low-frequency blood oxygenation level-dependent signal fluctuations across mirror regions of hemisphere revealing the homotopic connectivity between each voxel in one hemisphere and its mirrored counterpart in the contralateral hemisphere. To investigate the alterations of brain regional function and VMHC in patients with OCD, the current study enrolled 103 OCD patients and 118 healthy controls, undergoing resting-state functional magnetic resonance imaging. Compared to healthy controls (HCs), patients had decreased VMHC in bilateral cerebellum, lingual and fusiform gyrus; bilateral paracentral lobule, pre and postcentral gyrus; and bilateral superior and middle temporal gyrus, putamen and bilateral precuneus without global signal regression. And we found mostly similar results after regressing global signals; apart from the regions mentioned above, decreased in bilateral cuneus and calcarine was also showed. Furthermore, the mean VMHC values of the left cerebellum were negatively correlated with the obsession scores (ρ = -.204, π = .039). The decreased values in right fusiform and putamen were negatively correlated with duration of disease (ρ = -.205, π = .038; ρ = -.196, π = .047). We confirmed a significant VMHC reduction in OCD patients in broad areas. Our findings suggest that the patients tend to disconnect information exchange across hemispheres.

Effects of ulotaront on brain circuits of reward, working memory, and emotion processing in healthy volunteers with high or low schizotypy

Ulotaront, a trace amine-associated receptor 1 (TAAR1) and serotonin 5-HT1A receptor agonist without antagonist activity at dopamine D2 or the serotonin 5-HT2A receptors, has demonstrated efficacy in the treatment of schizophrenia. Here we report the phase 1 translational studies that profiled the effect of ulotaront on brain responses to reward, working memory, and resting state connectivity (RSC) in individuals with low or high schizotypy (LS or HS). Participants were randomized to placebo (n = 32), ulotaront (50 mg; n = 30), or the D2 receptor antagonist amisulpride (400 mg; n = 34) 2 h prior to functional magnetic resonance imaging (fMRI) of blood oxygen level-dependent (BOLD) responses to task performance. Ulotaront increased subjective drowsiness, but reaction times were impaired by less than 10% and did not correlate with BOLD responses. In the Monetary Incentive Delay task (reward processing), ulotaront significantly modulated striatal responses to incentive cues, induced medial orbitofrontal responses, and prevented insula activation seen in HS subjects. In the N-Back working memory task, ulotaront modulated BOLD signals in brain regions associated with cognitive impairment in schizophrenia. Ulotaront did not show antidepressant-like biases in an emotion processing task. HS had significantly reduced connectivity in default, salience, and executive networks compared to LS participants and both drugs reduced this difference. Although performance impairment may have weakened or contributed to the fMRI findings, the profile of ulotaront on BOLD activations elicited by reward, memory, and resting state is compatible with an indirect modulation of dopaminergic function as indicated by preclinical studies. This phase 1 study supported the subsequent clinical proof of concept trial in people with schizophrenia.Clinical trial registration: Registry# and URL: ClinicalTrials.gov NCT01972711, https://clinicaltrials.gov/ct2/show/NCT01972711

Connectivity of the Brain in the Light of Chemogenetic Modulation of Neuronal Activity.

Connectivity is the coordinated activity of the neuronal networks responsible for brain functions; it is detected based on functional magnetic resonance imaging signals that depend on the oxygen level in the blood (blood oxygen level-dependent (BOLD) signals) supplying the brain. The BOLD signal is only indirectly related to the underlying neuronal activity; therefore, it remains an open question whether connectivity and changes in it are only manifestations of normal and pathological states of the brain or they are, to some extent, the causes of these states. The creation of chemogenetic receptors activated by synthetic drugs (designer receptors exclusively activated by designer drugs, DREADDs), which, depending on the receptor type, either facilitate or, on the contrary, inhibit the neuronal response to received physiological stimuli, makes it possible to assess brain connectivity in the light of controlled neuronal activity. Evidence suggests that connectivity is based on neuronal activity and is a manifestation of connections between brain regions that integrate sensory, cognitive, and motor functions. Chemogenetic modulation of the activity of various groups and types of neurons changes the connectivity of the brain and its complex functions. Chemogenetics can be useful in reconfiguring the pathological mechanisms of nervous and mental diseases. The initiated integration, based on the whole-brain connectome from molecular-cellular, neuronal, and synaptic processes to higher nervous activity and behavior, has the potential to significantly increase the fundamental and applied value of this branch of neuroscience.

Functional Network of Neurocognitive Development in Correlations of BOLD Signals

Blood Oxygen Level Dependent (BOLD) fMRI is widely used for non-invasive brain mapping and neuroimaging. Despite the challenges, significant advancements have been made in empirically explaining several (BOLD) signal features. Before applying functional connectivity measures to assess the (BOLD) signal, preprocessing is required. Different stimuli produced by a regular periodic oscillation pulse and propagation loops were applied to generate the (BOLD) signal. The fundamentals of the brain and cognitive development are being highlighted through functional connectivity in a unique approach. In this work, we present an approach that analyzes variations in (BOLD) connectivity over time. Our approach emphasizes the temporal or spatial aspects however, simultaneous co-activation events may trigger (BOLD). Our findings show the measures to assess Functional Connectivity (FC) through Pearson’s correlation to describe FC. (BOLD) responses are used in a voxel-wise linear model with an estimation of the maximum likelihood to get the regressors’ correlated components.

Modeling venous bias in resting state functional MRI metrics.

Resting-state (rs) functional magnetic resonance imaging (fMRI) is used to detect low-frequency fluctuations in the blood oxygen-level dependent (BOLD) signal across brain regions. Correlations between temporal BOLD signal fluctuations are commonly used to infer functional connectivity. However, because BOLD is based on the dilution of deoxyhemoglobin, it is sensitive to veins of all sizes, and its amplitude is biased by draining veins. These biases affect local BOLD signal location and amplitude, and may also influence BOLD-derived connectivity measures, but the magnitude of this venous bias and its relation to vein size and proximity is unknown. Here, veins were identified using high-resolution quantitative susceptibility maps and utilized in a biophysical model to investigate systematic venous biases on common local rsfMRI-derived measures. Specifically, we studied the impact of vein diameter and distance to veins on the amplitude of low-frequency fluctuations (ALFF), fractional ALFF (fALFF), Hurst exponent (HE), regional homogeneity (ReHo), and eigenvector centrality values in the grey matter. Values were higher across all distances in smaller veins, and decreased with increasing vein diameter. Additionally, rsfMRI values associated with larger veins decrease with increasing distance from the veins. ALFF and ReHo were the most biased by veins, while HE and fALFF exhibited the smallest bias. Across all metrics, the amplitude of the bias was limited in voxel-wise data, confirming that venous structure is not the dominant source of contrast in these rsfMRI metrics. Finally, the models presented can be used to correct this venous bias in rsfMRI metrics.

Non-invasive estimation of arterial blood pressure fluctuations using a peripheral photoplethysmograph inside the MRI scanner.

The blood-oxygen-level-dependent (BOLD) signal measured by functional magnetic resonance imaging (fMRI) is modulated by neural activity through the neurovascular coupling effect, as well as non-neural factors of physiological origin such as heart rate, respiration, and arterial blood pressure (ABP). While the former two effects have been previously characterized, the modulation of the BOLD signal by ABP fluctuations is still poorly understood. This is largely due to the difficulty of obtaining reliable ABP measurements in the MRI environment. Here, we propose a combined experimental and mathematical modeling framework to estimate ABP fluctuations inside the MRI scanner using photoplethysmography (PPG). Specifically, we used concurrent PPG and ABP measurements obtained outside the scanner to train the mathematical model and applied it to PPG measurements obtained inside the MRI scanner. Our results suggest good agreement between the model-predicted and experimentally measured ABP fluctuations and region specific correlations with the BOLD fluctuations.

The Role of Blood Oxygen Level Dependent Signal Variability in Pediatric Neuroscience: A Systematic Review.

As pediatric BOLD Signal Variability (SV) analysis is relatively novel, there is a need to provide a foundational framework that gives researchers an entry point into engaging with the topic. This begins with clarifying the definition of BOLD signal variability by identifying and categorizing the various metrics utilized to measure BOLD SV. A systematic review of the literature was conducted. Inclusion criteria were restricted to studies utilizing any metric of BOLD SV and with individuals younger than 18 in the study population. The definition of BOLD SV was any measure of intra-individual variability in the BOLD signal. Five databases were searched: Psychinfo, Healthstar, MEDLINE, Embase, and Scopus. A total of 17 observational studies, including male (n = 1796) and female (n = 1324) pediatric participants were included. Eight studies quantified variability as the amount of deviation from the average BOLD signal, seven used complexity-based metrics, three used correlation measures of variability, and one used the structure of the hemodynamic response function. In this study, 10 methods of quantifying signal variability were identified. Associations and trends in BOLD SV were commonly found with age, factors specific to mental and/or neurological disorders such as attention deficit disorder, epilepsy, psychotic symptoms, and performance on psychological and behavioral tasks. BOLD SV is a potential biomarker of neurodevelopmental and neurological conditions and symptom severity in mental disorders for defined pediatric populations. Studies that establish clinical trends and identify the mechanisms underlying BOLD SV with a low risk of bias are needed before clinical applications can be utilized by physicians.

Neural variability in three major psychiatric disorders.

Across the major psychiatric disorders (MPDs), a shared disruption in brain physiology is suspected. Here we investigate the neural variability at rest, a well-established behavior-relevant marker of brain function, and probe its basis in gene expression and neurotransmitter receptor profiles across the MPDs. We recruited 219 healthy controls and 279 patients with schizophrenia, major depressive disorder, or bipolar disorders (manic or depressive state). The standard deviation of blood oxygenation level-dependent signal (SDBOLD) obtained from resting-state fMRI was used to characterize neural variability. Transdiagnostic disruptions in SDBOLD patterns and their relationships with clinical symptoms and cognitive functions were tested by partial least-squares correlation. Moving beyond the clinical sample, spatial correlations between the observed patterns of SDBOLD disruption and postmortem gene expressions, Neurosynth meta-analytic cognitive functions, and neurotransmitter receptor profiles were estimated. Two transdiagnostic patterns of disrupted SDBOLD were discovered. Pattern 1 is exhibited in all diagnostic groups and is most pronounced in schizophrenia, characterized by higher SDBOLD in the language/auditory networks but lower SDBOLD in the default mode/sensorimotor networks. In comparison, pattern 2 is only exhibited in unipolar and bipolar depression, characterized by higher SDBOLD in the default mode/salience networks but lower SDBOLD in the sensorimotor network. The expression of pattern 1 related to the severity of clinical symptoms and cognitive deficits across MPDs. The two disrupted patterns had distinct spatial correlations with gene expressions (e.g., neuronal projections/cellular processes), meta-analytic cognitive functions (e.g., language/memory), and neurotransmitter receptor expression profiles (e.g., D2/serotonin/opioid receptors). In conclusion, neural variability is a potential transdiagnostic biomarker of MPDs with a substantial amount of its spatial distribution explained by gene expressions and neurotransmitter receptor profiles. The pathophysiology of MPDs can be traced through the measures of neural variability at rest, with varying clinical-cognitive profiles arising from differential spatial patterns of aberrant variability.

Potential biomarker of brain response to opioid antagonism in adolescents with eating disorders: a pilot study.

Eating Disorders (ED) affect up to 5% of youth and are associated with reward system alterations and compulsive behaviors. Naltrexone, an opioid antagonist, is used to treat ED behaviors such as binge eating and/or purging. The presumed mechanism of action is blockade of reward activation; however, not all patients respond, and the optimal dose is unknown. Developing a tool to detect objective drug response in the brain will facilitate drug development and therapeutic optimization. This pilot study evaluated neuroimaging as a pharmacodynamic biomarker of opioid antagonism in adolescents with ED. Youth aged 13-21 with binge/purge ED completed functional magnetic resonance imaging (fMRI) pre- and post-oral naltrexone. fMRI detected blood oxygenation-level dependent (BOLD) signal at rest and during two reward probes (monetary incentive delay, MID, and passive food view, PFV) in predefined regions of interest associated with reward and inhibitory control. Effect sizes for Δ%BOLD (post-naltrexone vs. baseline) were estimated using linear mixed effects modeling. In 12 youth (16-21 years, 92% female), BOLD signal changes were detected following naltrexone in the nucleus accumbens during PFV (Δ%BOLD -0.08 ± 0.03; Cohen's d -1.06, p = 0.048) and anterior cingulate cortex during MID (Δ%BOLD 0.06 ± 0.03; Cohen's d 1.25, p = 0.086). fMRI detected acute reward pathway modulation in this small sample of adolescents with binge/purge ED. If validated in future, larger trials, task-based Δ%BOLD detected by fMRI may serve as a pharmacodynamic biomarker of opioid antagonism to facilitate the development of novel therapeutics targeting the reward pathway, enable quantitative pharmacology trials, and inform drug dosing. https://clinicaltrials.gov/ct2/show/NCT04935931, NCT#04935931.

Left or right ear? A neuroimaging study using combined taVNS/fMRI to understand the interaction between ear stimulation target and lesion location in chronic stroke

BackgroundImplanted vagus nerve stimulation (VNS) and transcutaneous auricular VNS (taVNS) have been primarily administered clinically to the unilateral-left vagus nerve. This left-only convention has proved clinically beneficial in brain disorders. However, in stroke survivors, the presence of a lesion in the brain may complicate VNS-mediated signaling, and it is important to understand the laterality effects of VNS in stroke survivors to optimize the intervention. ObjectiveTo understand whether taVNS delivered to different ear targets relative to the lesion (ipsilesional vs contralesional vs bilateral vs sham) impacts blood oxygenation level dependent (BOLD) signal propagation in stroke survivors. MethodsWe enrolled 20 adults with a prior history of stroke. Each participant underwent a single visit, during which taVNS was delivered concurrently during functional magnetic resonance imaging (fMRI) acquisition. Each participant received three discrete active stimulation conditions (ipsilesional, contralesional, bilateral) and one sham condition in a randomized order. Stimulation-related BOLD signal changes in the active conditions were compared to sham conditions to understand the interaction taVNS and laterality effects. ResultsAll active taVNS conditions deactivated the contralesional default mode network related regions compared to sham, however only ipsilesional taVNS enhanced the activations in the ipsilesional visuomotor and secondary visual cortex. Furthermore, we reveal an interaction in task activations between taVNS and cortical visuomotor areas, where ipsilesional taVNS significantly increased ipsilesional visuomotor activity and decreased contralesional visuomotor activity compared to sham. ConclusionLaterality of taVNS relative to the lesion is a critical factor in optimizing taVNS in a stroke population, with ipsilesional stimulation providing largest direct brain activation and should be explored further when designing taVNS studies in neurorehabilitation.

Comparative study of preoperative functional imaging combined with tractography for prediction of iatrogenic motor deficits.

Robust preoperative imaging can improve the extent of resection in patients with brain tumors while minimizing postoperative neurological morbidity. Both structural and functional imaging techniques can provide helpful preoperative information. A recent study found that transcranial magnetic stimulation (TMS) tractography has significant predictive value for permanent deficits. The present study directly compares the predictive value of TMS tractography and task-based functional MRI (fMRI) tractography in the same cohort of glioma patients. Clinical outcome data were collected from charts of patients with motor eloquent glioma and preoperative fMRI and TMS studies. The primary outcome was a new or worsened motor deficit present at the 3-month postoperative follow-up, which was termed a "permanent deficit." Postoperative MR images were overlaid onto preoperative plans to determine which imaging features were resected. Multiple fractional anisotropic thresholds (FATs) were screened for both TMS and fMRI tractography. The predictive value of the various thresholds was modeled using receiver operating characteristic curve analysis. Forty patients were included in this study. Six patients (15%) sustained permanent postoperative motor deficits. A significantly greater predictive value was found for TMS tractography than for fMRI tractography regardless of the FAT. Despite 35% of patients showing clinically relevant neuroplasticity captured by TMS, only 2.5% of patients showed a blood oxygen level-dependent signal displaced from the precentral gyrus. Comparing the best-performing FAT for both modalities, TMS seeded tractography showed superior predictive value across all metrics: sensitivity, specificity, positive predictive value, and negative predictive value. The results from this study indicate that the prediction of permanent deficits with TMS tractography is superior to that with fMRI tractography, possibly because TMS tractography captures clinically relevant neuroplasticity. However, future large-scale prospective studies are needed to fully illuminate the proper role of each modality in comprehensive presurgical workups for patients with motor-eloquent tumors.

Assessing blood oxygen level-dependent signal variability as a biomarker of brain injury in sport-related concussion.

Mild traumatic brain injury is a complex neurological disorder of significant concern among athletes who play contact sports. Athletes who sustain sport-related concussion typically undergo physical examination and neurocognitive evaluation to determine injury severity and return-to-play status. However, traumatic disruption to neurometabolic processes can occur with minimal detectable anatomic pathology or neurocognitive alteration, increasing the risk that athletes may be cleared for return-to-play during a vulnerable period and receive a repetitive injury. This underscores the need for sensitive functional neuroimaging methods to detect altered cerebral physiology in concussed athletes. The present study compared the efficacy of Immediate Post-concussion Assessment and Cognitive Testing composite scores and whole-brain measures of blood oxygen level-dependent signal variability for classifying concussion status and predicting concussion symptomatology in healthy, concussed and repetitively concussed athletes, assessing blood oxygen level-dependent signal variability as a potential diagnostic tool for characterizing functional alterations to cerebral physiology and assisting in the detection of sport-related concussion. We observed significant differences in regional blood oxygen level-dependent signal variability measures for concussed athletes but did not observe significant differences in Immediate Post-concussion Assessment and Cognitive Testing scores of concussed athletes. We further demonstrate that incorporating measures of functional brain alteration alongside Immediate Post-concussion Assessment and Cognitive Testing scores enhances the sensitivity and specificity of supervised random forest machine learning methods when classifying and predicting concussion status and post-concussion symptoms, suggesting that alterations to cerebrovascular status characterize unique variance that may aid in the detection of sport-related concussion and repetitive mild traumatic brain injury. These results indicate that altered blood oxygen level-dependent variability holds promise as a novel neurobiological marker for detecting alterations in cerebral perfusion and neuronal functioning in sport-related concussion, motivating future research to establish and validate clinical assessment protocols that can incorporate advanced neuroimaging methods to characterize altered cerebral physiology following mild traumatic brain injury.

Changes in white matter functional networks across late adulthood.

The aging brain is characterized by decreases in not only neuronal density but also reductions in myelinated white matter (WM) fibers that provide the essential foundation for communication between cortical regions. Age-related degeneration of WM has been previously characterized by histopathology as well as T2 FLAIR and diffusion MRI. Recent studies have consistently shown that BOLD (blood oxygenation level dependent) effects in WM are robustly detectable, are modulated by neural activities, and thus represent a complementary window into the functional organization of the brain. However, there have been no previous systematic studies of whether or how WM BOLD signals vary with normal aging. We therefore performed a comprehensive quantification of WM BOLD signals across scales to evaluate their potential as indicators of functional changes that arise with aging. By using spatial independent component analysis (ICA) of BOLD signals acquired in a resting state, WM voxels were grouped into spatially distinct functional units. The functional connectivities (FCs) within and among those units were measured and their relationships with aging were assessed. On a larger spatial scale, a graph was reconstructed based on the pair-wise connectivities among units, modeling the WM as a complex network and producing a set of graph-theoretical metrics. The spectral powers that reflect the intensities of BOLD signals were found to be significantly affected by aging across more than half of the WM units. The functional connectivities (FCs) within and among those units were found to decrease significantly with aging. We observed a widespread reduction of graph-theoretical metrics, suggesting a decrease in the ability to exchange information between remote WM regions with aging. Our findings converge to support the notion that WM BOLD signals in specific regions, and their interactions with other regions, have the potential to serve as imaging markers of aging.

Electroacupuncture protective effects after cerebral ischemia are mediated through miR-219a inhibition

BackgroundElectroacupuncture (EA) is a complementary and alternative therapy which has shown protective effects on vascular cognitive impairment (VCI). However, the underlying mechanisms are not entirely understood.MethodsRat models of VCI were established with cerebral ischemia using occlusion of the middle cerebral artery or bilateral common carotid artery. The brain structure and function imaging were measured through animal MRI. miRNA expression was detected by chip and qPCR. Synaptic functional plasticity was detected using electrophysiological techniques.ResultsThis study demonstrated the enhancement of Regional Homogeneity (ReHo) activity of blood oxygen level-dependent (BOLD) signal in the entorhinal cortical (EC) and hippocampus (HIP) in response to EA treatment. miR-219a was selected and confirmed to be elevated in HIP and EC in VCI but decreased after EA. N-methyl-D-aspartic acid receptor1 (NMDAR1) was identified as the target gene of miR-219a. miR-219a regulated NMDAR-mediated autaptic currents, spontaneous excitatory postsynaptic currents (sEPSC), and long-term potentiation (LTP) of the EC-HIP CA1 circuit influencing synaptic plasticity. EA was able to inhibit miR-219a, enhancing synaptic plasticity of the EC-HIP CA1 circuit and increasing expression of NMDAR1 while promoting the phosphorylation of downstream calcium/calmodulin-dependent protein kinase II (CaMKII), improving overall learning and memory in VCI rat models.ConclusionInhibition of miR-219a ameliorates VCI by regulating NMDAR-mediated synaptic plasticity in animal models of cerebral ischemia.

Chinese character unitization enhances recollection-based associative recognition: Evidence from fMRI.

Previous research has suggested that familiarity can enhance associative memory after unitization, but the cognitive mechanisms underlying unitization remain debated. To explore the neural mechanisms of associative memory after unitization in the absence of semantic relations, we used Chinese characters as stimuli and recorded participants' blood oxygen level-dependent signals during recognition. Behavioral results showed that after Chinese character unitization, not only the associative performance of recognition (Pr, hit rate minus false alarm rate) and general Pr but also the hit rate and correct rejection rate increased. Neuroimaging results revealed activation of the hippocampus and parahippocampal gyrus during associative recognition in both the unitized and the non-unitized condition, and hippocampal activation increased after unitization. However, activation of the perirhinal cortex was not observed in either condition. These findings, in contrast to those from previous studies on unitization, suggest that Chinese character unitization enhances recollection-based, rather than familiarity-based, associative recognition. This suggests that the encoding of semantic relations during unitization is critical for subsequent familiarity-based associative recognition.

1534-P: Nasal-Insulin–Induced Change of Functional MRI Signal at the Level of Hypothalamic Nuclei in the Patients with Type 2 Diabetes Mellitus

Insulin resistance in the hypothalamus is related to both increased appetite and systemic metabolic deterioration and may be an essential cause of metabolic diseases. In human studies, hypothalamic activity after intranasal insulin administration (INIA) has been measured by functional MRI (fMRI). However, to date, the resolution of fMRI has not been high enough to assess which neuronal nuclei in the hypothalamus are responsible for insulin. The purpose of this study was to investigate whether we can assess hypothalamic reaction after INIA at the nuclear level using high-resolution fMRI and if so, to examine its association with clinical parameters. Here, we studied 20 men with type 2 diabetes (T2DM) and 20 non-obese men without diabetes (CON). All subjects underwent fMRI with INIA (160 IU human insulin). The average of the cleaned blood oxygenation level-dependent (BOLD) signal from -15 min to 0 min was used as the baseline value in each subject. The signal change compared to the baseline value was calculated at every 5 min after INIA. The mean ages of subjects were both around 50 years and HbA1c levels were 6.88±1.13% in T2DM and 5.24±0.25% in CON (p<0.001). There were significant differences in the BOLD signal changes after INIA in the posterior nucleus (PH) at 5 min and posterior lateral hypothalamic area (LHAp) at 5 and 10 min between T2DM and CON. In other hypothalamic nuclei, there were no significant differences between T2DM and CON in the rate of change of the BOLD signal up to 30 min after INIA. Multiple regression analysis revealed that fasting plasma glucose (FPG) was a significant independent variable for activity change of the PH at 5 min and LHAp at 5 and 10 min, while BMI and HOMA-IR were not. In summary, we successfully detected nasal-insulin-induced change of fMRI signal at the level of hypothalamic nuclei. We found the differences in neural activity in the PH and LHAp early after INIA between those with and without diabetes, which were associated with FPG. Disclosure M.Kiya: None. Y.Tamura: None. H.Kaga: None. N.Ito: None. T.Tajima: None. H.Naito: None. M.Sato: None. S.Kadowaki: None. S.Kakehi: None. H.Watada: Research Support; Boehringer Ingelheim Japan, Inc., Mitsubishi Tanabe Pharma Corporation, LifeScan Diabetes Institute, Eli Lilly Japan K.K., Sun Pharmaceutical Industries Ltd., Teijin Pharma Limited, Taisho Pharmaceutical Holdings Co., Ltd., Ono Pharmaceutical Co., Ltd., Kowa Company, Ltd., Merck Sharp & Dohme Corp., Sanwa Kagaku Kenkyusho, Speaker's Bureau; Mitsubishi Tanabe Pharma Corporation, Taiho Pharmaceutical Co. Ltd., Novo Nordisk, Abbott Japan Co., Ltd., Astellas Pharma Inc., Merck Sharp & Dohme Corp., Kissei Pharmaceutical Co., Ltd., AstraZeneca, Ono Pharmaceutical Co., Ltd., Boehringer Ingelheim Japan, Inc., Sanofi, Sun Pharmaceutical Industries Ltd., Eli Lilly Japan K.K. Funding Japan Society for the Promotion of Science (21H03380, 22K17835); Ministry of Education, Culture, Sports, Science and Technology of Japan; Suzuken Memorial Foundation

Examining temporal features of BOLD-based cerebrovascular reactivity in clinical populations.

Conventional cerebrovascular reactivity (CVR) estimation has demonstrated that many brain diseases and/or conditions are associated with altered CVR. Despite the clinical potential of CVR, characterization of temporal features of a CVR challenge remains uncommon. This work is motivated by the need to develop CVR parameters that characterize individual temporal features of a CVR challenge. Data were collected from 54 adults and recruited based on these criteria: (1) Alzheimer's disease diagnosis or subcortical Vascular Cognitive Impairment, (2) sleep apnea, and (3) subjective cognitive impairment concerns. We investigated signal changes in blood oxygenation level dependent (BOLD) contrast images with respect to hypercapnic and normocapnic CVR transition periods during a gas manipulation paradigm. We developed a model-free, non-parametric CVR metric after considering a range of responses through simulations to characterize BOLD signal changes that occur when transitioning from normocapnia to hypercapnia. The non-parametric CVR measure was used to examine regional differences across the insula, hippocampus, thalamus, and centrum semiovale. We also examined the BOLD signal transition from hypercapnia back to normocapnia. We found a linear association between isolated temporal features of successive CO2 challenges. Our study concluded that the transition rate from hypercapnia to normocapnia was significantly associated with the second CVR response across all regions of interest (p < 0.001), and this association was highest in the hippocampus (R2 = 0.57, p < 0.0125). This study demonstrates that it is feasible to examine individual responses associated with normocapnic and hypercapnic transition periods of a BOLD-based CVR experiment. Studying these features can provide insight on between-subject differences in CVR.

Altered neurovascular coupling in the children with attention-deficit/hyperactivity disorder: a comprehensive fMRI analysis.

The coupling between resting-state cerebral blood flow (CBF) and blood oxygenation level-dependent (BOLD) signals reflects the mechanism of neurovascular coupling (NVC), which have not been illustrated in attention-deficit/hyperactivity disorder (ADHD). Fifty ADHD and 42 age- and gender-matched typically developing controls (TDs) were enrolled. The NVC imaging metrics were investigated by exploring the Pearson correlation coefficients between CBF and BOLD-derived quantitative maps (ALFF, fALFF, DCP maps). Three types of NVC metrics (CBF-ALFF, CBF-fALFF, CBF-DCP coupling) were compared between ADHD and TDs group, and the inner association between altered NVC metrics and clinical variables in ADHD group was further analyzed. Compared to TDs, ADHD showed significantly reduced whole-brain CBF-ALFF coupling (P < 0.001). Among regional level (all PFDR < 0.05), ADHD showed significantly lower CBF-ALFF coupling in bilateral thalamus, default-mode network (DMN) involving left anterior cingulate (ACG.L) and right parahippocampal gyrus (PHG.R), execution control network (ECN) involving right middle orbital frontal gyrus (ORBmid.R) and right inferior frontal triangular gyrus (IFGtriang.R), and increased CBF-ALFF coupling in attention network (AN)-related left superior temporal gyrus (STG.L) and somatosensory network (SSN))-related left rolandic operculum (ROL.L). Furthermore, increased CBF-fALFF coupling was found in the visual network (VN)-related left cuneus and negatively correlated with the concentration index of ADHD (R = - 0.299, PFDR = 0.035). Abnormal regional NVC metrics were at widespread neural networks in ADHD, mainly involved in DMN, ECN, SSN, AN, VN and bilateral thalamus. Notably, this study reinforced the insights into the neural basis and pathophysiological mechanism underlying ADHD.