fMRI Metrics Research Articles

The Mindful Brain: A Systematic Review of the Neural Correlates of Trait Mindfulness.

Trait self-report mindfulness scales measure one's disposition to pay nonjudgmental attention to the present moment. Concerns have been raised about the validity of trait mindfulness scales. Despite this, there is extensive literature correlating mindfulness scales with objective brain measures, with the goal of providing insight into mechanisms of mindfulness, and insight into associated positive mental health outcomes. Here, we systematically examined the neural correlates of trait mindfulness. We assessed 68 correlational studies across structural magnetic resonance imaging, task-based fMRI, resting-state fMRI, and EEG. Several consistent findings were identified, associating greater trait mindfulness with decreased amygdala reactivity to emotional stimuli, increased cortical thickness in frontal regions and insular cortex regions, and decreased connectivity within the default-mode network. These findings converged with results from intervention studies and those that included mindfulness experts. On the other hand, the connections between trait mindfulness and EEG metrics remain inconclusive, as do the associations between trait mindfulness and between-network resting-state fMRI metrics. ERP measures from EEG used to measure attentional or emotional processing may not show reliable individual variation. Research on body awareness and self-relevant processing is scarce. For a more robust correlational neuroscience of trait mindfulness, we recommend larger sample sizes, data-driven, multivariate approaches to self-report and brain measures, and careful consideration of test-retest reliability. In addition, we should leave behind simplistic explanations of mindfulness, as there are many ways to be mindful, and leave behind simplistic explanations of the brain, as distributed networks of brain areas support mindfulness.

Altered regional neural activity and functional connectivity in patients with non-communicating hydrocephalus: a resting-state functional magnetic resonance imaging study.

Cognitive impairment is a frequent clinical symptom of non-communicating hydrocephalus (NCH) involving multiple domains, including executive function, working memory, visual-spatial function, language, and attention. Functional magnetic resonance imaging (fMRI) can be used to obtain information on functional activity in local brain areas and functional connectivity (FC) across multiple brain regions. However, studies on the associated cognitive impairment are limited; further, the pathophysiological mechanisms of NCH with cognitive impairment remain unclear. Here, we aimed to explore alterations in regional neural activity and FC, as well as the mechanisms of cognitive impairment, in patients with NCH. Overall, 16 patients with NCH and 25 demographically matched healthy controls (HCs) were assessed using the Mini-Mental State Examination (MMSE) and fMRI. Changes in regional homogeneity (ReHo), degree centrality (DC), and region of interest-based FC were analyzed in both groups. The relationship between fMRI metrics (ReHo, DC, and FC) and MMSE scores in patients with NCH was also investigated. Compared with the HC group, the NCH group exhibited significantly lower ReHo values in the left precentral and postcentral gyri, and significantly higher ReHo values in the left medial prefrontal cortex (MPFC). The NCH group also showed significantly higher DC values in the bilateral MPFC compared with the HC group. Regarding seed-based FC, the MPFC showed reduced FC values in the right superior parietal and postcentral gyrus in the NCH group compared with those in the HC group. Moreover, within the NCH group, MMSE scores were significantly negatively correlated with the ReHo value in the left MPFC and the DC value in the bilateral MPFC, whereas MMSE scores were significantly positively correlated with FC values. To conclude, regional neural activity and FC are altered in patients with NCH and are correlated with cognitive impairment. These results advance our understanding of the pathophysiological mechanisms underlying the association between NCH and cognitive impairment.

A preliminary investigation of sex differences in cognitive and fMRI changes following 28 days of cannabis abstinence

BackgroundPrevious studies have investigated the influence of cannabis on cognition among people with MS (pwMS), yet the influence of sex in the context of cannabis use remains unexplored. We aim to fill this gap by investigating cannabis-sex related differences in verbal learning, memory and processing speed in association with fMRI (resting state, and task-based) metrics. MethodOur sample consisted of 19 long-term, frequent cannabis users (8 males, 11 females). Assessments were conducted at baseline and after 28 days of cannabis abstinence. The tests included measures of verbal memory (Selective Reminding Test (SRT)), working memory (n-back), information processing speed (Symbol Digit Modalities Test (SDMT)) and the resting state DMN. To evaluate the effects of cannabis abstinence, we performed a group x time interaction analysis using repeated measures ANCOVA. This analysis controlled for several covariates, including the level of disability (EDSS), baseline cannabis THC metabolite levels, and cannabis withdrawal symptoms. By controlling for these variables, we aimed to isolate the impact of cannabis abstinence on cognitive performance over time. Statistical significance was set at p < 0.05. ResultsThere were no baseline cognitive differences between the sexes. After 28 days of cannabis abstinence, females performed better on the Selective Reminding Test (SRT) (p = 0.04), with a large effect size (η² = 0.286). The mean correct response improved over time for females, but there was no statistically significant group x time interaction on the Symbol Digit Modalities Test (SDMT) and the n-back task. Resting state default mode network data showed overall increased activation in females relative to males at day 28, which meshed with lower brain activation during task-based fMRI paradigms. ConclusionCannabis negated sex-based cognitive differences. Functional MRI task-based paradigms revealed less cerebral activation in females compared to males, which was associated with comparable or better cognitive performance in females, particularly after cannabis abstinence.

Local and global effects of sedation in resting-state fMRI: a randomized, placebo-controlled comparison between etifoxine and alprazolam

TSPO ligands are promising alternatives to benzodiazepines in the treatment of anxiety, as they display less pronounced side effects such as sedation, cognitive impairment, tolerance development and abuse potential. In a randomized double-blind repeated-measures study we compare a benzodiazepine (alprazolam) to a TSPO ligand (etifoxine) by assessing side effects and acquiring resting-state fMRI data from 34 healthy participants after 5 days of taking alprazolam, etifoxine or a placebo. To study the effects of the pharmacological interventions in fMRI in detail and across different scales, we combine in our study complementary analysis strategies related to whole-brain functional network connectivity, local connectivity analysis expressed in regional homogeneity, fluctuations in low-frequency BOLD amplitudes and coherency of independent resting-state networks. Participants reported considerable adverse effects such as fatigue, sleepiness and concentration impairments, related to the administration of alprazolam compared to placebo. In resting-state fMRI we found a significant decrease in functional connection density, network efficiency and a decrease in the networks rich-club coefficient related to alprazolam. While observing a general decrease in regional homogeneity in high-level brain networks in the alprazolam condition, we simultaneously could detect an increase in regional homogeneity and resting-state network coherence in low-level sensory regions. Further we found a general increase in the low-frequency compartment of the BOLD signal. In the etifoxine condition, participants did not report any significant side effects compared to the placebo, and we did not observe any corresponding modulations in our fMRI metrics. Our results are consistent with the idea that sedation globally disconnects low-level functional networks, but simultaneously increases their within-connectivity. Further, our results point towards the potential of TSPO ligands in the treatment of anxiety and depression.

Utilizing fMRI to Guide TMS Targets: the Reliability and Sensitivity of fMRI Metrics at 3T and 1.5T.

US Food and Drug Administration (FDA) cleared a Transcranial Magnetic Stimulation (TMS) system with functional Magnetic Resonance Imaging-guided (fMRI) individualized treatment protocol for major depressive disorder, which employs resting state-fMRI (RS-fMRI) functional connectivity (FC) to pinpoint the target individually to increase the accuracy and effeteness of the stimulation. Furthermore, task activation-guided TMS, as well as the use of RS-fMRI local metrics for targeted the specific abnormal brain regions, are considered a precise scheme for TMS targeting. Since 1.5T MRI is more available in hospitals, systematic evaluation of the test-retest reliability and sensitivity of fMRI metrics on 1.5T and 3T MRI may provide reference for the application of fMRI-guided individualized-precise TMS stimulation. Twenty participants underwent three RS-fMRI scans and one scan of finger-tapping task fMRI with self-initiated (SI) and visual-guided (VG) conditions at both 3T and 1.5T. Then the location reliability derived by FC (with three seed regions) and peak activation were assessed by intra-individual distance. The test-retest reliability and sensitivity of five RS-fMRI local metrics were evaluated using intra-class correlation and effect size, separately. The intra-individual distance of peak activation location between 1.5T and 3T was 15.8mm and 19mm for two conditions, respectively. The intra-individual distance for the FC derived targets at 1.5T was 9.6-31.2mm, compared to that of 3T (7.6-31.1mm). The test-retest reliability and sensitivity of RS-fMRI local metrics showed similar trends on 1.5T and 3T. These findings hasten the application of fMRI-guided individualized TMS treatment in clinical practice.

Systematic investigation of cerebellar functional alterations and their association with surgical outcomes in patients with degenerative cervical myelopathy: a resting-state fMRI study.

The aim of this study was to systematically investigate the changes in cerebellar neural activity and cerebellar-cortical functional connectivity (FC) in patients with degenerative cervical myelopathy (DCM) using resting-state functional magnetic resonance imaging (fMRI). In this study, we collected clinical data and resting-state fMRI data from 54 DCM patients and 50 healthy controls (HCs). We analyzed voxel-wise regional fMRI metrics, including amplitude of low frequency fluctuation(ALFF), fractional ALFF, regional homogeneity, functional connectivity density, and voxel-mirrored homotopic connectivity. In analysis 1, we examined the differences in regional fMRI metrics within the cerebellum between the DCM patient group and the healthy control group, as well as their correlation with preoperative neurological status and prognosis. In analysis 2, we investigated cerebellar-cortical functional connectivity differences between the two groups and their correlation with preoperative neurological status and prognosis. Lastly, in analysis 3, we explored the internetwork connectivity between the 'cerebellar-SMN' (sensorimotornetwork) system, examined the between-group differences, and investigated its correlation with preoperative neurological status and prognosis. (1) Relative to HCs, DCM patients exhibited functional alterations in wide-spread cerebellar regions; (2) DCM patients exhibited altered cerebellar-cortical FC which was associated with the preoperative neurological status and prognosis; (3) DCM patients exhibited altered internetwork connectivity between 'cerebellar-SMN' system which was associated with duration of symptom. Wide-spread cerebellar functional alterations occur in DCM pathogenesis and the deficits in cerebellar-SMN functional connectivity may be beneficial in future studies for predicting surgical outcomes in patients with DCM.

Examining the role of dopamine in methylphenidate's effects on resting brain function.

The amplitude of low-frequency fluctuations (ALFF) and global functional connectivity density (gFCD) are fMRI (Functional MRI) metrics widely used to assess resting brain function. However, their differential sensitivity to stimulant-induced dopamine (DA) increases, including the rate of DA rise and the relationship between them, have not been investigated. Here we used, simultaneous PET-fMRI to examine the association between dynamic changes in striatal DA and brain activity as assessed by ALFF and gFCD, following placebo, intravenous (IV), or oral methylphenidate (MP) administration, using a within-subject double-blind placebo-controlled design. In putamen, MP significantly reduced D2/3 receptor availability and strongly reduced ALFF and increased gFCD in the brain for IV-MP (Cohen's d > 1.6) but less so for oral-MP (Cohen's d < 0.6). Enhanced gFCD was associated with both the level and the rate of striatal DA increases, whereas decreased ALFF was only associated with the level of DA increases. These findings suggest distinct representations of neurovascular activation with ALFF and gFCD by stimulant-induced DA increases with differential sensitivity to the rate and the level of DA increases. We also observed an inverse association between gFCD and ALFF that was markedly enhanced during IV-MP, which could reflect an increased contribution from MP's vasoactive properties.

Human brain effects of DMT assessed via EEG-fMRI

Psychedelics have attracted medical interest, but their effects on human brain function are incompletely understood. In a comprehensive, within-subjects, placebo-controlled design, we acquired multimodal neuroimaging [i.e., EEG-fMRI(electroencephalography-functional MRI)] data to assess the effects of intravenous (IV) N,N-Dimethyltryptamine (DMT) on brain function in 20 healthy volunteers. Simultaneous EEG-fMRI was acquired prior to, during, and after a bolus IV administration of 20 mg DMT, and, separately, placebo. At dosages consistent with the present study, DMT, a serotonin 2A receptor (5-HT2AR) agonist, induces a deeply immersive and radically altered state of consciousness. DMT is thus a useful research tool for probing the neural correlates of conscious experience. Here, fMRI results revealed robust increases in global functional connectivity (GFC), network disintegration and desegregation, and a compression of the principal cortical gradient under DMT. GFC × subjective intensity maps correlated with independent positron emission tomography (PET)-derived 5-HT2AR maps, and both overlapped with meta-analytical data implying human-specific psychological functions. Changes in major EEG-measured neurophysiological properties correlated with specific changes in various fMRI metrics, enriching our understanding of the neural basis of DMT's effects. The present findings advance on previous work by confirming a predominant action of DMT-and likely other 5-HT2AR agonist psychedelics-on the brain's transmodal association pole, i.e., the neurodevelopmentally and evolutionarily recent cortex that is associated with species-specific psychological advancements, and high expression of 5-HT2A receptors.

Abnormal Spontaneous Blood Oxygenation Level Dependent Fluctuations in Children with Focal Cortical Dysplasias: Initial Findings in Surgically Confirmed Cases.

Focal cortical dysplasias (FCD) are a frequent cause of drug-resistant epilepsy in children but are often undetected on structural magnetic resonance imaging (MRI). We aimed to measure and validate the variation of resting state functional MRI (rs-fMRI) blood oxygenation level dependent (BOLD) metrics in surgically proven FCDs in children, to assess the potential yield for detecting and understanding these lesions. We prospectively included pediatric patients with surgically proven FCD with inconclusive structural MRI and healthy controls, who underwent a ten-minute rs-fMRI acquired at 3T. Rs-fMRI data was pre-processed and maps of values of regional homogeneity (ReHo), degree centrality (DC), amplitude of low frequency fluctuations (ALFF) and fractional ALFF (fALFF) were calculated. The variations of BOLD metrics within the to-be-resected areas were analyzed visually, and quantitatively using lateralization indices. BOLD metrics variations were also analyzed in fluorodeoxyglucose-positron emission tomography (FDG-PET) hypometabolic areas. We included 7 patients (range: 3-15 years) and 6 aged-matched controls (range: 6-17 years). ReHo lateralization indices were positive in the to-be-resected areas in 4/7 patients, and in 6/7 patients in the additional PET hypometabolic areas. These indices were significantly higher compared to controls in 3/7 and 4/7 patients, respectively. Visual analysis revealed a good spatial correlation between high ReHo areas and MRI structural abnormalities (when present) or PET hypometabolic areas. No consistent variation was seen using DC, ALFF, or fALFF. Resting-state fMRI metrics, noticeably increase in ReHo, may have potential to help detect MRI-negative FCDs in combination with other morphological and functional techniques, used in clinical practice and epilepsy-surgery screening.

Comparing the test-retest reliability of resting-state functional magnetic resonance imaging metrics across single band and multiband acquisitions in the context of healthy aging.

The identification of meaningful functional magnetic resonance imaging (fMRI) biomarkers requires measures that reliably capture brain performance across different subjects and over multiple scanning sessions. Recent developments in fMRI acquisition, such as the introduction of multiband (MB) protocols and in-plane acceleration, allow for increased scanning speed and improved temporal resolution. However, they may also lead to reduced temporal signal to noise ratio and increased signal leakage between simultaneously excited slices. These methods have been adopted in several scanning modalities including diffusion weighted imaging and fMRI. To our knowledge, no study has formally compared the reliability of the same resting-state fMRI (rs-fMRI) metrics (amplitude of low-frequency fluctuations; seed-to-voxel and region of interest [ROI]-to-ROI connectivity) across conventional single-band fMRI and different MB acquisitions, with and without in-plane acceleration, across three sessions. In this study, 24 healthy older adults were scanned over three visits, on weeks 0, 1, and 4, and, on each occasion, underwent a conventional single band rs-fMRI scan and three different rs-fMRI scans with MB factors 4 and 6, with and without in-plane acceleration. Across all three rs-fMRI metrics, the reliability scores were highest with MB factor 4 with no in-plane acceleration for cortical areas and with conventional single band for subcortical areas. Recommendations for future research studies are discussed.

Reliability and sensitivity to altered hemodynamics measured with resting-state fMRI metrics: Comparison with 123I-IMP SPECT

Blood oxygenation level-dependent (BOLD) contrast is sensitive to local hemodynamic changes and thus is applicable to imaging perfusion or vascular reactivity. However, knowledge about its measurement characteristics compared to reference standard perfusion imaging is limited. This study longitudinally evaluated perfusion in patients with steno-occlusive disease using resting-state functional MRI (rsfMRI) acquired before and within nine days of anterior circulation revascularization in patients with large cerebral artery steno-occlusive diseases. The reliability and sensitivity to longitudinal changes of rsfMRI temporal correlation (Rc) and time delay (TDc) relative to the cerebellar signal were examined voxel-wise in comparison with single-photon emission CT (SPECT) cerebral blood flow (CBF) using the within-subject standard deviation (Sw) and intraclass correlation coefficients (ICCs). For statistical comparisons, the standard deviation (SD) of longitudinal changes within the cerebellum, the number of voxels with significant changes in the left middle cerebral artery territory ipsilateral to surgery, and their average changes relative to the cerebellar SD were evaluated. The test-retest reliability of the fMRI metrics was also similarly evaluated using the human connectome project (HCP) healthy young adult dataset. The test-retest time interval was 31 ± 18 days. Test-retest reliability was significantly higher for SPECT (cerebellar SD: −2.59 ± 0.20) than for fMRI metrics (cerebellar SD: Rc, −2.34 ± 0.24, p = 0.04; TDc, −2.19 ± 0.21, p = 0.003). Sensitivity to postoperative changes, which was evaluated as the number of voxels, was significantly higher for fMRI TDc (8.78 ± 0.72) than for Rc (7.42 ± 1.48, p = 0.03) or SPECT CBF (6.88 ± 0.67, p < 0.001). The ratio between the average Rc, TDc, and SPECT CBF changes within the left MCA target region and cerebellar SD was also significantly higher for fMRI TDc (1.21 ± 0.79) than Rc (0.48 ± 0.94, p = 0.006) or SPECT CBF (0.23 ± 0.57, p = 0.001). The measurement variability of time delay was also larger than that of temporal correlation in HCP data within the cerebellum (t = −8.7, p < 0.001) or in the whole-brain (t = −27.4, p < 0.001) gray matter. These data suggest that fMRI time delay is more sensitive to the hemodynamic changes than SPECT CBF, although the reliability is lower. The implication for fMRI connectivity studies is that temporal correlation can be significantly decreased due to altered hemodynamics, even in cases with normal CBF.

Enhanced clinical task-based fMRI metrics through locally low-rank denoising of complex-valued data.

This study investigates a locally low-rank (LLR) denoising algorithm applied to source images from a clinical task-based functional MRI (fMRI) exam before post-processing for improving statistical confidence of task-based activation maps. Task-based motor and language fMRI was obtained in eleven healthy volunteers under an IRB approved protocol. LLR denoising was then applied to raw complex-valued image data before fMRI processing. Activation maps generated from conventional non-denoised (control) data were compared with maps derived from LLR-denoised image data. Four board-certified neuroradiologists completed consensus assessment of activation maps; region-specific and aggregate motor and language consensus thresholds were then compared with nonparametric statistical tests. Additional evaluation included retrospective truncation of exam data without and with LLR denoising; a ROI-based analysis tracked t-statistics and temporal SNR (tSNR) as scan durations decreased. A test-retest assessment was performed; retest data were matched with initial test data and compared for one subject. fMRI activation maps generated from LLR-denoised data predominantly exhibited statistically significant (p = 4.88×10-4 to p = 0.042; one p = 0.062) increases in consensus t-statistic thresholds for motor and language activation maps. Following data truncation, LLR data showed task-specific increases in t-statistics and tSNR respectively exceeding 20 and 50% compared to control. LLR denoising enabled truncation of exam durations while preserving cluster volumes at fixed thresholds. Test-retest showed variable activation with LLR data thresholded higher in matching initial test data. LLR denoising affords robust increases in t-statistics on fMRI activation maps compared to routine processing, and offers potential for reduced scan duration while preserving map quality.

The effect of general anesthesia on the test-retest reliability of resting-state fMRI metrics and optimization of scan length.

Resting-state functional magnetic resonance imaging (rs-fMRI) has been known as a powerful tool in neuroscience. However, exploring the test–retest reliability of the metrics derived from the rs-fMRI BOLD signal is essential, particularly in the studies of patients with neurological disorders. Here, two factors, namely, the effect of anesthesia and scan length, have been estimated on the reliability of rs-fMRI measurements. A total of nine patients with drug-resistant epilepsy (DRE) requiring interstitial thermal therapy (LITT) were scanned in two states. The first scan was performed in an awake state before surgery on the same patient. The second scan was performed 2 weeks later under general anesthesia necessary for LITT surgery. At each state, two rs-fMRI sessions were obtained that each one lasted 15 min, and the effect of scan length was evaluated. Voxel-wise rs-fMRI metrics, including the amplitude of low-frequency fluctuation (ALFF), the fractional amplitude of low-frequency fluctuation (fALFF), functional connectivity (FC), and regional homogeneity (ReHo), were measured. Intraclass correlation coefficient (ICC) was calculated to estimate the reliability of the measurements in two states of awake and under anesthesia. Overall, it appeared that the reliability of rs-fMRI metrics improved under anesthesia. From the 15-min data, we found mean ICC values in awake state including 0.81, 0.51, 0.65, and 0.84 for ALFF, fALFF, FC, and ReHo, respectively, as well as 0.80, 0.59, 0.83, and 0.88 for ALFF, fALFF, FC, and ReHo, respectively, under anesthesia. Additionally, our findings revealed that reliability increases as the function of scan length. We showed that the optimized scan length to achieve less variability of rs-fMRI measurements was 3.1–7.5 min shorter in an anesthetized, compared to a wakeful state.

Integrated Positron Emission Tomography/Magnetic Resonance Imaging for Resting-State Functional and Metabolic Imaging in Human Brain: What Is Correlated and What Is Impacted.

Integrated positron emission tomography (PET)/magnetic resonance imaging (MRI) could simultaneously obtain both functional MRI (fMRI) and 18F-fluorodeoxyglucose (FDG) PET and thus provide multiparametric information for the analysis of brain metabolism. In this study, we aimed to, for the first time, investigate the interplay of simultaneous fMRI and FDG PET scan using a randomized self-control protocol. In total, 24 healthy volunteers underwent PET/MRI scan for 30–40 min after the injection of FDG. A 22-min brain scan was separated into MRI-off mode (without fMRI pulsing) and MRI-on mode (with fMRI pulsing), with each one lasting for 11 min. We calculated the voxel-wise fMRI metrics (regional homogeneity, amplitude of low-frequency fluctuations, fractional amplitude of low-frequency fluctuations, and degree centrality), resting networks, relative standardized uptake value ratios (SUVr), SUVr slope, and regional cerebral metabolic rate of glucose (rCMRGlu) maps. Paired two-sample t-tests were applied to assess the statistical differences between SUVr, SUVr slope, correlation coefficients of fMRI metrics, and rCMRGlu between MRI-off and MRI-on modes, respectively. The voxel-wise whole-brain SUVr revealed no statistical difference (P > 0.05), while the SUVr slope was significantly elevated in sensorimotor, dorsal attention, ventral attention, control, default, and auditory networks (P < 0.05) during fMRI scan. The task-based group independent-component analysis revealed that the most active network components derived from the combined MRI-off and MRI-on static PET images were frontal pole, superior frontal gyrus, middle temporal gyrus, and occipital pole. High correlation coefficients were found among fMRI metrics with rCMRGlu in both MRI-off and MRI-on mode (P < 0.05). Our results systematically evaluated the impact of simultaneous fMRI scan on the quantification of human brain metabolism from an integrated PET/MRI system.

Cortical reinstatement in the visual associative memory network is compromised by early tau in normal older adults

AbstractBackgroundThe structure and computations associated with specific hippocampal subfields decline in aging and are also initial sites of Alzheimer’s disease pathology. The degree to which age‐associated changes in hippocampal‐dependent memory are driven by early AD pathology among older normal adults remains unclear.MethodWe enrolled one hundred ninety‐nine clinically unimpaired (CU) older individuals into the Stanford Aging and Memory Study (SAMS, 117 Female, mean age= 68.9±6.2). Participants completed a lumbar puncture to collect cerebrospinal fluid (CSF), high‐resolution fMRI (at 3T) during a visual associative memory paradigm, and ultra high‐resolution structural MRI (at 7T) to assess MTL subregion integrity, as well as extensive cognitive assessment. Data collection is complete, and analysis of fMRI and 7T structural data of the 199 participants is currently underway. To examine neuronal computations underlying hippocampal dependent memory, we focused on fMRI metrics in a subset of 78 participants that quantify cortical reinstatement (the degree to which voxelwise patterns of activation during retrieval match activation patterns during encoding) in two a priori regions known to be important for visual associative memory (ventral temporal cortex, VTC; and angular gyrus, ANG). Additionally, we extracted univariate fMRI signal from the hippocampus during successful retrieval. Finally, hippocampal thickness from CA1 in a subset of 77 participants was manually delineated on 7T scans, and CSF was processed with Lumipulse to measure Ab42:Ab40 ratio and p‐tau181.ResultElevated p‐tau181 was associated with worse performance on the fMRI‐scanned visual associative memory task (Figure A), reduced cortical reinstatement strength in both VTC (r = ‐0.25, p = .027, Figure B) and ANG (r = ‐0.22, p = .048), as well as reduced CA1‐SRLM thickness (r = ‐0.32, p = .004, Figure C). Although Ab42:Ab40 ratios were related to p‐tau181, they were not independently associated with neuronal indices of hippocampal‐dependent memory.ConclusionCU with evidence of early tau abnormalities show worse hippocampal‐dependent memory and differences in fMRI and structural measurements in regions critical for successful associative memory. Initial consequences of AD pathology target specific hippocampal‐cortical circuits, and this is measurable using advanced MRI techniques.

Interpreting null models of resting-state functional MRI dynamics: not throwing the model out with the hypothesis

Null models are useful for assessing whether a dataset exhibits a non-trivial property of interest. These models have recently gained interest in the neuroimaging community as means to explore dynamic properties of functional Magnetic Resonance Imaging (fMRI) time series. Interpretation of null-model testing in this context may not be straightforward because (i) null hypotheses associated to different null models are sometimes unclear and (ii) fMRI metrics might be ‘trivial’, i.e. preserved under the null hypothesis, and still be useful in neuroimaging applications. In this commentary, we review several commonly used null models of fMRI time series and discuss the interpretation of the corresponding tests. We argue that, while null-model testing allows for a better characterization of the statistical properties of fMRI time series and associated metrics, it should not be considered as a mandatory validation step to assess their relevance in representing brain functional dynamics.

Towards robust and replicable sex differences in the intrinsic brain function of autism

BackgroundMarked sex differences in autism prevalence accentuate the need to understand the role of biological sex-related factors in autism. Efforts to unravel sex differences in the brain organization of autism have, however, been challenged by the limited availability of female data.MethodsWe addressed this gap by using a large sample of males and females with autism and neurotypical (NT) control individuals (ABIDE; Autism: 362 males, 82 females; NT: 409 males, 166 females; 7–18 years). Discovery analyses examined main effects of diagnosis, sex and their interaction across five resting-state fMRI (R-fMRI) metrics (voxel-level Z > 3.1, cluster-level P < 0.01, gaussian random field corrected). Secondary analyses assessed the robustness of the results to different pre-processing approaches and their replicability in two independent samples: the EU-AIMS Longitudinal European Autism Project (LEAP) and the Gender Explorations of Neurogenetics and Development to Advance Autism Research.ResultsDiscovery analyses in ABIDE revealed significant main effects of diagnosis and sex across the intrinsic functional connectivity of the posterior cingulate cortex, regional homogeneity and voxel-mirrored homotopic connectivity (VMHC) in several cortical regions, largely converging in the default network midline. Sex-by-diagnosis interactions were confined to the dorsolateral occipital cortex, with reduced VMHC in females with autism. All findings were robust to different pre-processing steps. Replicability in independent samples varied by R-fMRI measures and effects with the targeted sex-by-diagnosis interaction being replicated in the larger of the two replication samples—EU-AIMS LEAP.LimitationsGiven the lack of a priori harmonization among the discovery and replication datasets available to date, sample-related variation remained and may have affected replicability.ConclusionsAtypical cross-hemispheric interactions are neurobiologically relevant to autism. They likely result from the combination of sex-dependent and sex-independent factors with a differential effect across functional cortical networks. Systematic assessments of the factors contributing to replicability are needed and necessitate coordinated large-scale data collection across studies.

The Relationship Among Glucose Metabolism, Cerebral Blood Flow, and Functional Activity: a Hybrid PET/fMRI Study.

18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) estimate brain activities from different aspects, including regional glucose uptake (rGU) by 18FDG-PET, regional cerebral blood flow (rCBF) by arterial spin labeling, and dynamic changes of deoxyhemoglobin by blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI). However, the relationships between them remain incompletely understood. In the current study, twenty-four subjects (14 males, 10 females) were recruited and investigated the correlation among rGU, rCBF, and BOLD fMRI-derived metrics reflecting the neural activity, including amplitude of low-frequency fluctuation (ALFF), regional homogeneity (ReHo), and degree centrality (DC) by hybrid PET/fMRI. Correlation analyses were performed across subject and across space at both voxel level and region level, considering partial volume effects by adjusting for gray matter volume. Each pair of metrics showed significant across-space correlations. rGU against ReHo showed the highest mean correlation coefficients. rGU had higher correlations with three resting-state (RS) fMRI metrics than did ASL-rCBF. However, the across-subject correlations were not significant among functional modalities (rGU, rCBF, and RS-fMRI BOLD data) at either voxel level or region level even with a liberal threshold, except for significant across-subject correlation between RS-fMRI metrics (ALFF, ReHo, and DC). These comprehensive findings from hybrid PET/MR might provide complementary information to reveal the underlying mechanisms of the brain activity and open new perspective to interpret pathologic conditions.

FMRI hemodynamic response function (HRF) as a novel marker of brain function: applications for understanding obsessive-compulsive disorder pathology and treatment response.

The hemodynamic response function (HRF) represents the transfer function linking neural activity with the functional MRI (fMRI) signal, modeling neurovascular coupling. Since HRF is influenced by non-neural factors, to date it has largely been considered as a confound or has been ignored in many analyses. However, underlying biophysics suggests that the HRF may contain meaningful correlates of neural activity, which might be unavailable through conventional fMRI metrics. Here, we estimated the HRF by performing deconvolution on resting-state fMRI data from a longitudinal sample of 25 healthy controls scanned twice and 44 adults with obsessive-compulsive disorder (OCD) before and after 4-weeks of intensive cognitive-behavioral therapy (CBT). HRF response height, time-to-peak and full-width at half-maximum (FWHM) in OCD were abnormal before treatment and normalized after treatment in regions including the caudate. Pre-treatment HRF predicted treatment outcome (OCD symptom reduction) with 86.4% accuracy, using machine learning. Pre-treatment HRF response height in the caudate head and time-to-peak in the caudate tail were top-predictors of treatment response. Time-to-peak in the caudate tail, a region not typically identified in OCD studies using conventional fMRI activation or connectivity measures, may carry novel importance. Additionally, pre-treatmentresponse height in caudate head predicted post-treatment OCD severity (R = -0.48, P = 0.001), and was associated with treatment-related OCD severity changes (R = -0.44, P = 0.0028), underscoring its relevance. With HRF being a reliable marker sensitive to brain function, OCD pathology, and intervention-related changes, these results could guide future studies towards novel discoveries not possible through conventional fMRI approaches like standard BOLD activation or connectivity.

Association of Intrinsic Brain Architecture With Changes in Attentional and Mood Symptoms During Development

Understanding the neurodevelopmental trajectory of psychiatric symptoms is important for improving early identification, intervention, and prevention of mental disorders. To test whether the strength of the coupling of activation between specific brain regions, as measured by resting-state functional magnetic resonance imaging (fMRI), predicted individual children's developmental trajectories in terms of attentional problems characteristic of attention-deficit/hyperactivity disorder and internalizing problems characteristics of major depressive disorder (MDD). A community cohort of 94 children was recruited from Vanderbilt University between 2010 and 2013. They were followed up longitudinally for 4 years and the data were analyzed from 2016 to 2019. Based on preregistered hypotheses and an analytic plan, we examined whether specific brain connectivity patterns would be associated with longitudinal changes in scores on the Child Behavior Checklist (CBCL), a parental-report assessment used to screen for emotional, behavioral, and social problems and to predict psychiatric illnesses. We used the strength of resting-state fMRI connectivity at age 7 years to predict subsequent changes in CBCL measures 4 years later and investigated the mechanisms of change by associating brain connectivity changes with changes in the CBCL. We analyzed data from a longitudinal brain development study involving children assessed at age 7 years (n = 94; 41 girls [43.6%]) and 11 years (n = 54; 32 girls [59.3%]). As predicted, less positive coupling at age 7 years between the medial prefrontal cortex and dorsolateral prefrontal cortex (DLPFC) was associated with a decrease in attentional symptoms by age 11 years (t49 = 2.38; P = .01; β = 0.32). By contrast, a less positive coupling between a region implicated in mood, the subgenual anterior cingulate cortex (sgACC), and DLPFC at age 7 years was associated with an increase in internalizing (eg, anxiety/depression) behaviors by age 11 years (t49 = -2.4; P = .01; β = -0.30). Logistic regression analyses revealed that sgACC-DLPFC connectivity was a more accurate predictor than baseline CBCL measures for progression to a subclinical score on internalization (t50 = -2.61; P = .01; β = -0.29). We then replicated and extended the sgACC-DLPFC result in an independent sample of children with (n = 25) or without (n = 18) familial risk for MDD. These resting-state fMRI metrics are promising biomarkers for the early identification of children at risk of developing MDD or attention-deficit/hyperactivity disorder.