Threshold-free Cluster Enhancement Research Articles

Dynamic Feedback Between Antidepressant Placebo Expectancies and Mood

Despite high antidepressant placebo response rates, the mechanisms underlying the persistence of antidepressant placebo effects are still poorly understood. To investigate the neurobehavioral mechanisms underlying the evolution of antidepressant placebo effects using a reinforcement learning (RL) framework. In this acute within-patient cross-sectional study of antidepressant placebos, patients aged 18 to 55 years not receiving medication for major depressive disorder (MDD) were recruited at the University of Pittsburgh between February 21, 2017, to March 1, 2021. The antidepressant placebo functional magnetic resonance imaging task manipulates placebo-associated expectancies using visually cued fast-acting antidepressant infusions and controls their reinforcement with sham visual neurofeedback while assessing expected and experienced mood improvement. The trial-by-trial evolution of expectancies and mood was examined using multilevel modeling and RL, relating model-predicted signals to spatiotemporal dynamics of blood oxygenation level-dependent (BOLD) response. A bayesian RL model comparison in 60 individuals (mean [SE] age, 24.5 [0.8] years; 51 females [85%]) with MDD revealed that antidepressant placebo trial-wise expectancies were updated by composite learning signals multiplexing sensory evidence (neurofeedback) and trial-wise mood (bayesian omnibus risk <0.001; exceedance probability = 97%). Placebo expectancy, neurofeedback manipulations, and composite learning signals modulated the visual cortex and dorsal attention network (threshold-free cluster enhancement [TFCE] = 1 - P >.95). As participants anticipated antidepressant infusions, learned placebo expectancies modulated the salience network (SN, TFCE = 1 - P >.95), positively scaling with depression severity. Results of this cross-sectional study suggest that on a timescale of minutes, antidepressant placebo effects were maintained by positive feedback loops between expectancies and mood improvement. During learning, representations of placebos and their perceived effects were enhanced in primary and secondary sensory cortices. Latent learned placebo expectancies were encoded in the SN.

Sex-specific differences in resting-state functional brain activity in pediatric concussion

Pediatric concussion has a rising incidence and can lead to long-term symptoms in nearly 30% of children. Resting state functional magnetic resonance imaging (rs-fMRI) disturbances are a common pathological feature of pediatric concussion, though no studies have explicitly examined sex-differences with respect to this outcome, precluding a sex-specific understanding of the functional neuropathology of pediatric concussion. Therefore, we performed a secondary data analysis of rs-fMRI data collected on children with concussion (n = 29) recruited from in a pediatric hospital setting, with greater than 12:1 matched control data accessed from the open-source ABIDE-II database. Seed-based and region of interest (ROI) analyses were used to examine sex-based rs-fMRI differences; threshold-free cluster enhancement (TFCE) and a family-wise error (FWE) corrected p-values were used to identify significantly different clusters. In comparing females with concussion to healthy females, groupwise differences were observed irrespective of seed selected. Notably, we observed (in order of largest effect) hypo-connectivity between the anterior cingulate cortex of the salience network and the thalamus and precuneus (TFCE = 1473.5, p-FWE < 0.001) and the cingulate gyrus (TFCE = 769.3, p-FWE = 0.009), and the seed (posterior cingulate cortex (PCC)) of the default mode network and the paracingulate gyrus (TFCE = 1275.7, p-FWE < 0.001), occipital pole right (TFCE = 1045.0, p-FWE = 0.001), and sub-callosal cortex (TFCE = 844.9, p-FWE = 0.005). Hyper-connectivity was observed between the salience network seed and the cerebellum (TFCE = 1719.3, p-FWE < 0.001) and the PCC and the thalamus (TFCE = 1198.3, p-FWE < 0.001), cuneal cortex (1070.9, p-FWE = 0.001), and lateral occipital cortex left (TFCE = 832.8, p-FWE = 0.006). ROI analyses showed 10 and 5 significant clusters of hypo- and hyper-connectivity in females, respectively. Only one cluster of difference was found between males with concussion and healthy males on seed-based analyses, and 3 clusters on ROI analyses. There are alterations in rs-fMRI in females with concussion at one-month post-injury that are minimally present in males, which provides further evidence that recovery timelines in pediatric concussion may differ by sex.

Independent and additive contribution of white matter hyperintensities and Alzheimer’s disease pathology to basal forebrain cholinergic system degeneration

ObjectivesDegeneration of the cholinergic basal forebrain nuclei (CBFN) system has been studied extensively in Alzheimer's disease (AD). White matter hyperintensities are a hallmark of aging as well as a common co-morbidity of AD, but their contribution to CBFN degeneration has remained unclear. Therefore, we explored the influence of white matter hyperintensities within cholinergic subcortical-cortical projection pathways on CBFN volumes and regional gray matter volumes in AD and age- and gender-matched controls. MethodsWe analyzed magnetic resonance images (MRI) from 42 patients with AD and 87 age- and gender-matched control subjects. We assessed the white matter hyperintensity burden within the cholinergic projection pathways using the Cholinergic Pathways Hyperintensities Scale (CHIPS), and applied probabilistic anatomical maps for the analysis of CBFN volumes, i.e. the Ch1-3 compartment and the Ch4 cell group (nucleus basalis of Meynert), by diffeomorphic anatomical registration using exponentiated lie algebra analysis of voxel-based morphometry. Using multiple linear regression analyses, we explored correlations between regional gray matter volumes and the extent of white matter hyperintensities or CBFN volumes in both groups. ResultsIn AD, all CBFN volumes were significantly smaller than in controls, and white matter hyperintensity burden within the cholinergic projection pathways was not correlated with CBFN volume. In controls, white matter hyperintensity burden within the cholinergic projection pathways was inversely correlated with CBFN volume when corrected for sex and total intracranial volume, but this correlation was no longer significant after correction for age. Voxel-wise multiple linear regression analyses using threshold-free cluster enhancement revealed that in controls, cholinergic pathway hyperintensities correlated with gray matter loss in perisylvian areas, whereas the were no effects in AD. Moreover, we found that CBFN volumes correlated with distinct regional cortical atrophy patterns in both groups. ConclusionOur results indicate that white matter hyperintensities and AD pathology contribute independently but additively to the degeneration of cholinergic basal forebrain structures. Whereas AD is primarily associated with CBFN volume loss, cholinergic degeneration associated with white matter hyperintensities appears to involve disruption of cholinergic cortical projection fibers with less pronounced effects on CBFN volumes.

Evaluating whole-brain tissue-property changes in MRI-negative pharmacoresistant focal epilepsies using MR fingerprinting.

We aim to quantify whole-brain tissue-property changes in patients with magnetic resonance imaging (MRI)-negative pharmacoresistant focal epilepsy by three-dimensional (3D) magnetic resonance fingerprinting (MRF). We included 30 patients with pharmacoresistant focal epilepsy and negative MRI by official radiology report, as well as 40 age- and gender-matched healthy controls (HCs). MRF scans were obtained with 1 mm3 isotropic resolution. Quantitative T1 and T2 relaxometry maps were reconstructed from MRF and registered to the Montreal Neurological Institute (MNI) space. A two-sample t test was performed in Functional Magnetic Resonance Imaging of the Brain (FMRIB) Software Library (FSL) to evaluate significant abnormalities in patients comparing to HCs, with correction by the threshold-free cluster enhancement (TFCE) method. Subgroups analyses were performed for extra-temporal epilepsy/temporal epilepsy (ETLE/TLE), and for those with/without subtle abnormalities detected by morphometric analysis program (MAP), to investigate each subgroup's pattern of MRF changes. Correlation analyses were performed between the mean MRF values in each significant cluster and seizure-related clinical variables. Compared to HCs, patients exhibited significant group-level T1 increase ipsilateral to the epileptic origin, in the mesial temporal gray matter (GM) and white matter (WM), temporal pole GM, orbitofrontal GM, hippocampus, and amygdala, with scattered clusters in the neocortical temporal and insular GM. No significant T2 changes were detected. The ETLE subgroup showed a T1-increase pattern similar to the overall cohort, with additional involvement of the ipsilateral anterior cingulate GM. The subgroup of MAP+ patients also showed a T1-increase pattern similar to the overall cohort, with additional cluster in the ipsilateral lateral orbitofrontal GM. Higher T1 was associated with younger seizure-onset age, longer epilepsy duration, and higher seizure frequency. MRF revealed group-level T1 increase in limbic/paralimbic structures ipsilateral to the epileptic origin, in patients with pharmacoresistant focal epilepsy and no apparent lesions on MRI, suggesting that these regions may be commonly affected by seizures in the epileptic brain. The significant association between T1 increase and higher seizure burden may reflect progressive tissue damage.

Is There Reduced Hemodynamic Brain Activation in Multiple Sclerosis Even with Undisturbed Cognition?

Cognitive impairments related to changes in deep gray matter and other brain regions occur in up to 70% of people with multiple sclerosis. But do such brain changes also occur in patients without significant cognitive impairment? Eighteen participants with relapsing-remitting multiple sclerosis (RRMS) and fifteen healthy controls participated in this study. Cognitive status, depression, and fatigue were assessed using the Multiple Sclerosis Inventory of Cognition (MUSIC), Beck's Depression Inventory (BDI-II), and the Fatigue Severity Scale (FSS). fMRI was recorded while a participant performed the modified attention network test (ANT). The effects of ANT executive attention network on hemodynamic activation of a priori defined regions of interest, including the hippocampus, anterior cingulate cortex (ACC), thalamus, caudate nucleus, pallidum, and putamen were studied. The individual lesion load was estimated. For fMRI data analysis a general linear model with randomization statistics including threshold-free cluster enhancement as implemented in the FSL software was used. Participants with RRMS showed reduced activation of the executive attention network in the hippocampus, pallidum, and ACC. The thalamus was involved in both group activations but did not differ between groups. In summary, functional changes in the brain can also be demonstrated in RRMS patients without cognitive deficits. The affected brain regions can best be assigned to the attention network for executive control. This association could likely serve as a biological indicator of susceptibility to imminent cognitive impairment in MS.

Differential effects of age and sex on medial temporal lobe networks revealed by longitudinal analyses across the adult lifespan

AbstractBackgroundThe medial temporal lobe (MTL) is extensively connected to the rest of the brain through two specific networks which are particularly affected in Alzheimer’s disease (AD): the anterior‐temporal (AT) and posterior‐medial (PM) systems. As the specific and respective effects of age and sex on the functional integrity of these networks are still largely unknown, we sought to fill this gap using longitudinal data spanning the entire adult life.MethodLongitudinal data from 215 cognitively unimpaired adults (aged 19‐85, including 113 females, followed‐up up to 47 months, 419 scans) were analysed. Seed‐based analyses were applied to resting‐state functional magnetic resonance imaging to generate connectivity maps (seeds: the perirhinal cortex for AT and the parahippocampal cortex for PM). The AT and PM networks were defined by comparing baseline maps from adults younger than 40 using a paired permutation t‐test with threshold‐free cluster enhancement (TFCE) and familywise error (FWE) correction (p&lt;.05) (Figure 1). These masks were then used to extract the mean functional connectivity (FC) for each participant. The interaction effects between network, age and sex were investigated using linear mixed models.ResultThere was a significant interaction between age and networks (p&lt;.001), with a decrease of FC with age in PM and an increase in AT (Figure 2). Sex differences were also observed within these two systems (p&lt;.001), with males exhibiting higher FC than females in AT but lower FC in PM (Figure 3). Age‐related trajectories were not modulated by sex differences (p&gt;.05) and were best described by a linear relationship according to model comparison testing different polynomials.ConclusionBy encompassing the entire adult lifespan and assessing longitudinal changes, our study provides strong support that the two MTL networks display differential alterations in the context of aging, as well as sex differences. Since MTL connectivity has been described as particularly affected in the early stages of AD, and age and sex are risk factors, these findings may be helpful to enhance the clinical utility of such biomarkers for the early detection of AD‐related changes.

Differential effects of age and sex on medial temporal lobe networks revealed by longitudinal analyses across the adult lifespan

AbstractBackgroundThe medial temporal lobe (MTL) is extensively connected to the rest of the brain through two specific networks which are particularly affected in Alzheimer’s disease (AD): the anterior‐temporal (AT) and posterior‐medial (PM) systems. As the specific and respective effects of age and sex on the functional integrity of these networks are still largely unknown, we sought to fill this gap using longitudinal data spanning the entire adult life.MethodLongitudinal data from 215 cognitively unimpaired adults (aged 19‐85, including 113 females, followed‐up up to 47 months, 419 scans) were analysed. Seed‐based analyses were applied to resting‐state functional magnetic resonance imaging to generate connectivity maps (seeds: the perirhinal cortex for AT and the parahippocampal cortex for PM). The AT and PM networks were defined by comparing baseline maps from adults younger than 40 using a paired permutation t‐test with threshold‐free cluster enhancement (TFCE) and familywise error (FWE) correction (p&lt;.05) (Figure 1). These masks were then used to extract the mean functional connectivity (FC) for each participant. The interaction effects between network, age and sex were investigated using linear mixed models.ResultThere was a significant interaction between age and networks (p&lt;.001), with a decrease of FC with age in PM and an increase in AT (Figure 2). Sex differences were also observed within these two systems (p&lt;.001), with males exhibiting higher FC than females in AT but lower FC in PM (Figure 3). Age‐related trajectories were not modulated by sex differences (p&gt;.05) and were best described by a linear relationship according to model comparison testing different polynomials.ConclusionBy encompassing the entire adult lifespan and assessing longitudinal changes, our study provides strong support that the two MTL networks display differential alterations in the context of aging, as well as sex differences. Since MTL connectivity has been described as particularly affected in the early stages of AD, and age and sex are risk factors, these findings may be helpful to enhance the clinical utility of such biomarkers for the early detection of AD‐related changes.

Neural substrates underlying effortful control deficit in autism spectrum disorder: a meta-analysis of fMRI studies

Effortful control comprises attentional control, inhibitory control, and cognitive flexibility subprocesses. Effortful control is impaired in individuals with autism spectrum disorder, yet its neural underpinnings remain elusive. By conducting a coordinate-based meta-analysis, this study compared the brain activation patterns between autism and typically developing individuals and examined the effect of age on brain activation in each effortful control subprocesses. Meta-analytic results from 22 studies revealed that, individuals with autism showed hypoactivation in the default mode network for tasks tapping inhibitory control functioning (threshold-free cluster enhancement p < 0.001). When these individuals perform tasks tapping attentional control and cognitive flexibility, they exhibited aberrant activation in various brain networks including default mode network, dorsal attention, frontoparietal, visual and somatomotor networks (uncorrected ps < 0.005). Meta-regression analyses revealed that brain regions within the default mode network showed a significant decreasing trend in activation with increasing age (uncorrected p < 0.05). In summary, individuals with autism showed aberrant activation patterns across multiple brain functional networks during all cognitive tasks supporting effortful control, with some regions showing a decrease in activation with increasing age.

Brain White Matter Structural Alteration in Hemifacial Spasm: A Diffusion Tensor Imaging Study

To analyze the changes in the white matter structure of the whole brain in hemifacial spasm (HFS) patients by using the tract-based spatial statistics (TBSS) method. 29 HFS patients without anxiety and depression and 29 healthy controls with matching age, sex, and education were selected. All subjects received a 3.0T magnetic resonance (MR) brain diffusion tensor imaging scan. Tract-based spatial statistics method was used to analyze the changes in white matter structure in the whole brain and obtained the cerebral white matter fibrous areas exhibiting significant intergroup differences. The fractional anisotropy (FA), mean diffusivity, axial diffusivity, and radial diffusivity of these areas were abstracted. Analyzed the correlation between these diffusion metrics and clinical variables (disease duration, spasm severity). Compared with the healthy controls group, the HFS group exhibited significantly lower FA in the forceps minor, bilateral anterior thalamic radiation, and right superior longitudinal fasciculus ( P <0.05, threshold-free cluster enhancement corrected). Cohen grading scale of HFS patients was negatively correlated with FA of forceps minor. Based on TBSS analysis, the injury of white matter fiber tracts in HFS patients was found, including forceps minor, bilateral anterior thalamic radiation, and right superior longitudinal fasciculus. The changes of FA values in forceps minor were negatively correlated with the Cohen grading scale, suggesting that the alteration of white matter fiber in the genu-of-corpus-callosum-cortex circuit plays an important role in the neuro-pathological mechanism of HFS. Combined with previous research, it is also necessary to further explore the change of the superior longitudinal fasciculus in the future.

Insulin resistance disrupts white matter microstructure and amplitude of functional spontaneous activity in bipolar disorder.

Bipolar disorder (BD) is linked to several structural and functional brain alterations. In addition, BD patients have a three-fold increased risk of developing insulin resistance, which is associated with neural changes and poorer BD outcomes. Therefore, we investigated the effects of insulin and two derived measures (insulin resistance and sensitivity) on white matter (WM) microstructure, resting-state (rs) functional connectivity (FC), and fractional amplitude of low-frequency fluctuation (fALFF). BD patients (n= 92) underwent DTI acquisition, and a subsample (n=22) underwent rs-fMRI. Blood samples were collected to determine insulin and glucose levels. The Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI) were computed. DTI data were analyzed via tract-based spatial statistics and threshold-free cluster enhancement. From rs-fMRI data, both ROI-to-ROI FC matrices and fALFF maps were extracted. Insulin showed a widespread negative association with fractional anisotropy (FA) and a positive effect on radial diffusivity (RD) and mean diffusivity (MD). HOMA-IR exerted a significant effect on RD in the right superior longitudinal fasciculus, whereas QUICKI was positively associated with FA and negatively with RD and MD in the left superior longitudinal fasciculus, left anterior corona radiata, and forceps minor. fALFF was negatively modulated by insulin and HOMA-IR and positively associated with QUICKI in the precuneus. No significant results were found in the ROI-to-ROI analysis. Our findings suggest that WM microstructure and functional alterations might underlie the effect of IR on BD pathophysiology, even if the causal mechanisms need to be further investigated.

Sex differences in regional gray matter density in pre-adolescent binge eating disorder: a voxel-based morphometry study.

Binge eating disorder (BED) is a pernicious psychiatric disorder which is linked with broad medical and psychiatric morbidity, and obesity. While BED may be characterized by altered cortical morphometry, no evidence to date examined possible sex-differences in regional gray matter characteristics among those with BED. This is especially important to consider in children, where BED symptoms often emerge coincident with rapid gray matter maturation. Pre-adolescent, 9-10-year old boys (N = 38) and girls (N = 33) with BED were extracted from the 3.0 baseline (Year 0) release of the Adolescent Brain Cognitive Development Study. We investigated sex differences in gray matter density (GMD) via voxel-based morphometry. Control sex differences were also assessed in age and body mass index and developmentally matched control children (boys N = 36; girls N = 38). Among children with BED, we additionally assessed the association between dorsolateral prefrontal (dlPFC) GMD and parent-reported behavioral approach and inhibition tendencies. Girls with BED uniquely demonstrate diffuse clusters of greater GMD (p < 0.05, Threshold Free Cluster Enhancement corrected) in the (i) left dlPFC (p = 0.003), (ii) bilateral dmPFC (p = 0.004), (iii) bilateral primary motor and somatosensory cortex (p = 0.0003) and (iv) bilateral precuneus (p = 0.007). Brain-behavioral associations suggest a unique negative correlation between GMD in the left dlPFC and behavioral approach tendencies among girls with BED. Early-onset BED may be characterized by regional sex differences in terms of its underlying gray matter morphometry.

Alteration of default mode network: association with executive dysfunction in frontal glioma patients.

Patients with frontal gliomas often experience executive dysfunction (EF-D) before surgery, and the changes in brain plasticity underlying this effect remain obscure. In this study, the authors aimed to assess whole-brain structural and functional alterations by using structural MRI and resting-state functional MRI (rs-fMRI) in frontal glioma patients with or without EF-D. Fifty-seven patients with frontal gliomas were admitted prospectively to the authors' institution and assigned to one of two groups: 1) the normal executive function (EF-N) group and 2) the EF-D group, based on patient results for the Trail Making Test, Part B and Stroop Color-Word Test, Part C. Twenty-nine baseline-matched healthy controls were also recruited. All participants underwent multimodal MRI examination. Cortical surface thickness, surface-based resting-state activity (fractional amplitude of low-frequency fluctuation [fALFF] and regional homogeneity [ReHo]), and edge-based network functional connectivity (FC) were measured with FreeSurfer and fMRIPrep. The correlation between altered MRI parameters and executive function (EF) was assessed using Pearson correlation and receiver operating characteristic (ROC) analysis. Demographic characteristics (sex, age, and education level) and clinical characteristics (location, volume, grade of tumor, and preoperative epilepsy) were not significantly different between the groups, but the Karnofsky Performance Scale score was worse in the EF-D group. There was no significant difference in cortical surface thickness between the EF-D and EF-N groups. In both low-grade and high-grade glioma patients the fALFF value (permutation test + threshold-free cluster enhancement, p value after family-wise error correction < 0.05) and ReHo value (t-test, p < 0.001) of the left precuneus cortex in the EF-D group were greater than those in the EF-N group, which were negatively correlated with EF (p < 0.05) and enabled prediction of EF (area under the ROC curve 0.826 for fALFF and 0.855 for ReHo, p < 0.001). Compared with the EF-N group, the FCs between the default mode network (DMN) from DMN node to DMN node (DMN-DMN) and from the DMN to the central executive network (DMN-CEN) in the EF-D group were increased significantly (network-based statistics corrected p < 0.05) and negatively correlated with EF (Pearson correlation, p < 0.05). Apart from local disruption, the abnormally activated DMN in the resting state is related to EF-D in frontal glioma patients. DMN activity should be considered during preoperative planning and postoperative neurorehabilitation for frontal glioma patients to preserve EF. Clinical trial registration no.: NCT03087838 (ClinicalTrials.gov).

Neurite Orientation Dispersion Density Imaging Indicates Positive Associations Between Physical Activity And White Matter Structure

Human and animal studies have shown that exercise training increases hippocampal volume and improves cognitive function, but whether exercise influences white matter (WM) microstructure in healthy women is not fully understood. PURPOSE: To compare cerebral WM microstructure between high and low active women. METHODS: Forty-eight healthy women (ages 25-40) who reported either greater than 300 minutes per week of moderate-vigorous physical activity (MVPA) from exercise training, designated as high active (HA; n = 31)) or less than 30 minutes of MVPA, designated as low active (LA; n = 17), were enrolled. Physical activity was measured over 14 days using accelerometry. WM integrity was assessed using diffusion-weighted Magnetic Resonance Imaging that included Diffusion Tensor Imaging (DTI) and Neurite Orientation Dispersion and Density Imaging (NODDI). A multiple b-value diffusion weighted EPI sequence was used to acquire a total of 126 diffusion weighted images, plus 10 images without additional diffusion weighting. This included 18 images with b = 350 s/mm2, 36 with b = 800 s/mm2, and 72 with b = 2000 s/mm2. Tract-based Spatial Statistics were used to estimate WM DTI and NODDI metrics over the whole brain corrected using a threshold-free cluster enhancement and a family-wise error correction for multiple comparisons at the p < 0.05 level with 5000 permutations. Analysis of Covariance was used to compare groups on each DTI variable of interest covarying for age. Multiple linear regression was used to test the associations between sedentary time, DTI, and NODDI measures. RESULTS: HA women had higher fractional anisotropy (FA), lower radial diffusivity (RD), and lower orientation dispersion index (p ≤ 0.05) in the corpus callosum – consistent with higher WM integrity. For the whole sample, higher levels of sedentary behavior were negatively associated with FA and neurite density index and positively associated with RD across extensive white matter areas (p ≤ 0.05) – consistent with lower WM integrity. CONCLUSION: Performing high levels of physical activity and spending less time in sedentary behavior may benefit white matter microstructure in tracts involved in a diverse array of cognitive, emotional, motor, and perceptual functions. Supported by a grant from the Virginia Horne-Henry Foundation.

Reduced cortical cerebral blood flow in antipsychotic-free first-episode psychosis and relationship to treatment response.

Altered cerebral blood flow (CBF) has been found in people at risk for psychosis, with first-episode psychosis (FEP) and with chronic schizophrenia (SCZ). Studies using arterial spin labelling (ASL) have shown reduction of cortical CBF and increased subcortical CBF in SCZ. Previous studies have investigated CBF using ASL in FEP, reporting increased CBF in striatum and reduced CBF in frontal cortex. However, as these people were taking antipsychotics, it is unclear whether these changes are related to the disorder or antipsychotic treatment and how they relate to treatment response. We examined CBF in FEP free from antipsychotic medication (N = 21), compared to healthy controls (N = 22). Both absolute and relative-to-global CBF were assessed. We also investigated the association between baseline CBF and treatment response in a partially nested follow-up study (N = 14). There was significantly lower absolute CBF in frontal cortex (Cohen's d = 0.84, p = 0.009) and no differences in striatum or hippocampus. Whole brain voxel-wise analysis revealed widespread cortical reductions in absolute CBF in large cortical clusters that encompassed occipital, parietal and frontal cortices (Threshold-Free Cluster Enhancement (TFCE)-corrected <0.05). No differences were found in relative-to-global CBF in the selected region of interests and in voxel-wise analysis. Relative-to-global frontal CBF was correlated with percentage change in total Positive and Negative Syndrome Scale after antipsychotic treatment (r = 0.67, p = 0.008). These results show lower cortical absolute perfusion in FEP prior to starting antipsychotic treatment and suggest relative-to-global frontal CBF as assessed with magnetic resonance imaging could potentially serve as a biomarker for antipsychotic response.

Microstructural Differences of the Cerebellum-Thalamus-Basal Ganglia-Limbic Cortex in Patients with Somatic Symptom Disorders: a Diffusion Kurtosis Imaging Study.

Somatic symp tom disorders (SSDs) are a group of psychiatric disorders characterized by persistent disproportionate concern and obsessive behaviors regarding physical conditions. Currently, SSDs lack effective treatments and their pathophysiology is unclear. In this paper, we aimed to examine microstructural abnormalities in the brains of patients with SSD using diffusion kurtosis imaging (DKI) and to investigate the correlation between these abnormalities and clinical indicators. Diffusion kurtosis images were acquired from 30 patients with SSD and 30 healthy controls (HCs). Whole-brain maps of multiple diffusion measures, including fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), mean diffusivity (MD), mean kurtosis (MK), radial kurtosis (RK), and axial kurtosis (AK), were calculated. To analyze differences between the two groups, nonparametric permutation testing with 10,000 randomized permutations and threshold-free cluster enhancement was used with family-wise error-corrected p values < 0.05 as the threshold for statistical significance. Then, the correlations between significant changes in these diffusion measures and clinical factors were examined. Compared to HCs, patients with SSD had significantly higher FA, MK, and RK and significantly lower MD and RD in the cerebellum, thalamus, basal ganglia, and limbic cortex. The FA in the left caudate and the pontine crossing tract were negatively correlated with disease duration; the MD and the RD in the genu of the corpus callosum were positively correlated with disease duration. Our findings highlight the role of the cerebellum-thalamus-basal ganglia-limbic cortex pathway, especially the cerebellum, in SSDs and enhance our understanding of the pathogenesis of SSDs.

Alterations in resting-state functional activity and connectivity for major depressive disorder appetite and weight disturbance phenotypes.

Major depressive disorder (MDD) is often accompanied by changes in appetite and weight. Prior task-based functional magnetic resonance imaging (fMRI) findings suggest these MDD phenotypes are associated with altered reward and interoceptive processing. Using resting-state fMRI data, we compared the fractional amplitude of low-frequency fluctuations (fALFF) and seed-based connectivity (SBC) among hyperphagic (n = 77), hypophagic (n = 66), and euphagic (n = 42) MDD groups and a healthy comparison group (n = 38). We examined fALFF and SBC in a mask restricted to reward [nucleus accumbens (NAcc), putamen, caudate, ventral pallidum, and orbitofrontal cortex (OFC)] and interoceptive (anterior insula and hypothalamus) regions and also performed exploratory whole-brain analyses. SBC analyses included as seeds the NAcc and also regions demonstrating group differences in fALFF (i.e. right lateral OFC and right anterior insula). All analyses used threshold-free cluster enhancement. Mask-restricted analyses revealed stronger fALFF in the right lateral OFC, and weaker fALFF in the right anterior insula, for hyperphagic MDD v. healthy comparison. We also found weaker SBC between the right lateral OFC and left anterior insula for hyperphagic MDD v. healthy comparison. Whole-brain analyses revealed weaker fALFF in the right anterior insula, and stronger SBC between the right lateral OFC and left precentral gyrus, for hyperphagic MDD v. healthy comparison. Findings were no longer significant after controlling for body mass index, which was higher for hyperphagic MDD. Our results suggest hyperphagic MDD may be associated with altered activity in and connectivity between interoceptive and reward regions.

Brain Structural Changes During Juvenile Fibromyalgia: Relationships With Pain, Fatigue, and Functional Disability.

ObjectiveJuvenile fibromyalgia (FM) is a prevalent chronic pain condition affecting children and adolescents worldwide during a critical period of brain development. To date, no published studies have addressed the pathophysiology of juvenile FM. This study was undertaken to characterize gray matter volume (GMV) alterations in juvenile FM patients for the first time, and to investigate their functional and clinical relevance.MethodsThirty‐four female adolescents with juvenile FM and 38 healthy adolescents underwent a structural magnetic resonance imaging examination and completed questionnaires assessing core juvenile FM symptoms. Using voxel‐based morphometry, we assessed between‐group GMV differences and associations between GMV and functional disability, fatigue, and pain interference in juvenile FM. We also studied whether validated brain patterns predicting pain, cognitive control, or negative emotion were amplified/attenuated in juvenile FM patients and whether structural alterations reported in adult FM were replicated in adolescents with juvenile FM.ResultsCompared to controls, juvenile FM patients showed GMV reductions in the anterior midcingulate cortex (aMCC) region (family‐wise error corrected P [P FWE‐corr] = 0.04; estimated with threshold‐free cluster enhancement [TFCE]; n = 72) associated with pain. Within the juvenile FM group, patients reporting higher functional disability had larger GMV in inferior frontal regions (P FWE‐corr = 0.006; TFCE estimated; n = 34) linked to affective, self‐referential, and language‐related processes. Last, GMV reductions in juvenile FM showed partial overlap with findings in adult FM, specifically for the anterior/posterior cingulate cortices (P = 0.02 and P = 0.03, respectively; n = 72).ConclusionPain‐related aMCC reductions may be a structural hallmark of juvenile FM, whereas alterations in regions involved in emotional, self‐referential, and language‐related processes may predict disease impact on patients’ well‐being. The partial overlap between juvenile and adult FM findings strengthens the importance of early symptom identification and intervention to prevent the transition to adult forms of the disease.

Structural imaging studies of patients with chronic pain: an anatomical likelihood estimate meta-analysis.

Neuroimaging is a powerful tool to investigate potential associations between chronic pain and brain structure. However, the proliferation of studies across diverse chronic pain syndromes and heterogeneous results challenges data integration and interpretation. We conducted a preregistered anatomical likelihood estimate meta-analysis on structural magnetic imaging studies comparing patients with chronic pain and healthy controls. Specifically, we investigated a broad range of measures of brain structure as well as specific alterations in gray matter and cortical thickness. A total of 7849 abstracts of experiments published between January 1, 1990, and April 26, 2021, were identified from 8 databases and evaluated by 2 independent reviewers. Overall, 103 experiments with a total of 5075 participants met the preregistered inclusion criteria. After correction for multiple comparisons using the gold-standard family-wise error correction ( P < 0.05), no significant differences associated with chronic pain were found. However, exploratory analyses using threshold-free cluster enhancement revealed several spatially distributed clusters showing structural alterations in chronic pain. Most of the clusters coincided with regions implicated in nociceptive processing including the amygdala, thalamus, hippocampus, insula, anterior cingulate cortex, and inferior frontal gyrus. Taken together, these results suggest that chronic pain is associated with subtle, spatially distributed alterations of brain structure.

Evaluation of thresholding methods for activation likelihood estimation meta-analysis via large-scale simulations.

In recent neuroimaging studies, threshold‐free cluster enhancement (TFCE) gained popularity as a sophisticated thresholding method for statistical inference. It was shown to feature higher sensitivity than the frequently used approach of controlling the cluster‐level family‐wise error (cFWE) and it does not require setting a cluster‐forming threshold at voxel level. Here, we examined the applicability of TFCE to a widely used method for coordinate‐based neuroimaging meta‐analysis, Activation Likelihood Estimation (ALE), by means of large‐scale simulations. We created over 200,000 artificial meta‐analysis datasets by independently varying the total number of experiments included and the amount of spatial convergence across experiments. Next, we applied ALE to all datasets and compared the performance of TFCE to both voxel‐level and cluster‐level FWE correction approaches. All three multiple‐comparison correction methods yielded valid results, with only about 5% of the significant clusters being based on spurious convergence, which corresponds to the nominal level the methods were controlling for. On average, TFCE's sensitivity was comparable to that of cFWE correction, but it was slightly worse for a subset of parameter combinations, even after TFCE parameter optimization. cFWE yielded the largest significant clusters, closely followed by TFCE, while voxel‐level FWE correction yielded substantially smaller clusters, showcasing its high spatial specificity. Given that TFCE does not outperform the standard cFWE correction but is computationally much more expensive, we conclude that employing TFCE for ALE cannot be recommended to the general user.

Microstructural Gray Matter Integrity Deteriorates After an Ischemic Stroke and Is Associated with Processing Speed.

Microstructural changes after an ischemic stroke (IS) have mainly been described in white matter. Data evaluating microstructural changes in gray matter (GM) remain scarce. The aim of the present study was to evaluate the integrity of GM on longitudinal data using mean diffusivity (MD), and its influence on post-IS cognitive performances. A prospective study was conducted, including supra-tentorial IS patients without pre-stroke disability. A cognitive assessment was performed at baseline and 1year, including a Montreal Cognitive Assessment, an Isaacs set test, and a Zazzo cancelation task (ZCT): completion time and number of errors. A 3-T brain MRI was performed at the same two time-points, including diffusion tensor imaging for the assessment of GM MD. GM volume was also computed, and changes in GM volume and GM MD were evaluated, followed by the assessment of the relationship between these structural changes and changes in cognitive performances. One hundred and four patients were included (age 68.5 ± 21.5, 38.5% female). While no GM volume loss was observed, GM MD increased between baseline and 1year. The increase of GM MD in left fronto-temporal regions (dorsolateral prefrontal cortex, superior and medial temporal gyrus, p < 0.05, Threshold-Free Cluster Enhancement, 5000 permutations) was associated with an increase time to complete ZCT, regardless of demographic confounders, IS volume and location, GM, and white matter hyperintensity volume. GM integrity deterioration was thus associated with processing speed slowdown, and appears to be a biomarker of cognitive frailty. This broadens the knowledge of post-IS cognitive impairment mechanisms.