Voxel-based Analysis Research Articles

Preventive treatment effects on brain structures and functions in patients with chronic migraine: A multimodel magnetic resonance imaging study.

Patients with chronic migraine (CM) often exhibit structural and functional alterations in pain-matrix regions, but it remains unclear how preventive treatment affects these changes. Therefore, this study aimed to investigate the structural and functional changes in pain-matrix regions in CM patients after 6-month treatment. A total of 24 patients with CM and 15 healthy controls were recruited for this study. Patients were divided into responder group (N = 9) and non-responder group (N = 15). After completing the Migraine Disability Assessment (MIDAS) questionnaire, all patients underwent whole-brain high-resolution T1-weighted images, diffusion-weighted imaging, and resting-state functional magnetic resonance imaging at baseline and 6-month follow-up. Whole brain gray matter volume and white matter diffusion indices were analyzed using voxel-based analysis. Structural and functional connectivity analyses were performed to understand brain changes in patients after 6-month preventive treatment. The responder group exhibited significantly higher MIDAS scores than the non-responder group at baseline, but no significant difference between the two groups at follow-up. No significant interval change was noted in gray matter volume, white matter diffusion indices, and structural connectivity in CM patients after 6-month treatment. Nonetheless, the functional connectivity was significantly increased between occipital, temporal lobes and cerebellum, and was significantly decreased between parietal and temporal lobes after 6-month preventive treatment. We concluded that resting-state functional connectivity was suitable for investigating the preventive treatment effect on CM patients.

A Macrocyclic Hybrid PET/MRI Probe for Quantitative Perfusion Imaging In Vivo.

Perfusion dynamics play a vital role in delivering essential nutrients and oxygen to tissues while removing metabolic waste products. Imaging techniques such as magnetic resonance imaging (MRI), computed tomography (CT), and positron emission tomography (PET) use contrast agents to visualize perfusion and clearance patterns; however, each technique has specific limitations. Hybrid PET/MRI combines the quantitative power and sensitivity of PET with the high functional and anatomical detail of MRI and holds great promise for precision in molecular imaging. However, the development of dual PET/MRI probes has been hampered by challenging synthesis and radiolabeling. Here, we present a novel PET/MRI probe, [18F][Gd(FL1)], which exhibits excellent stability comparable to macrocyclic MRI contrast agents used in clinical practice. The unique molecular design of [18F][Gd(FL1)] allows selective and expeditious radiolabeling of the gadolinium chelate in the final synthetic step. Leveraging the strengths of MRI and PET signals, the probe enables quantitative in vivo mapping of perfusion and excretion dynamics through an innovative voxel-based analysis. The diagnostic capabilities of [18F][Gd(FL1)] were demonstrated in a pilot study on healthy mice, successfully detecting early cases of unilateral renal dysfunction, a condition that is typically challenging to diagnose. This study introduces a new approach for PET/MRI and emphasizes a streamlined probe design for practical synthesis and improved diagnostic accuracy.

Comparisons of MR and EM inferred tissue microstructure properties using a human autopsy corpus callosum sample

Degeneration of white matter (WM) microstructure in the central nervous system is characteristic of many neurodegenerative conditions. Previous research indicates that axonal degeneration visible in ex vivo electron microscopy (EM) photomicrographs precede the onset of clinical symptoms. Measuring WM microstructural features, such as axon diameter and packing fraction, currently require these highly invasive methods of analysis and it is therefore of great importance to develop methods for in vivo measurements. Diffusion weighted Magnetic Resonance Imaging (MRI) is a non-invasive method which can be used in conjunction with temporal diffusion spectroscopy (TDS) and an oscillating gradient spin echo (OGSE) pulse sequence to probe micron-scale structures within neural tissue. The current experiment aims to compare axon diameter measurements, mean effective axon diameter (AxD¯), and packing fractions calculated from EM histopathological analysis and inferred values from MR images. Mathematical models of axon diameters used for analysis include the ActiveAx Frequency-Dependent Extra-Axonal Diffusion (AAD) model and the AxCaliber Frequency-Dependent Extra-Axonal Diffusion (ACD) model using ROI (Region of Interest) based analysis (RBA) and voxel-based analysis (VBA), respectively. Overall, it was observed that MRI inferred WM microstructural parameters overestimate those calculated from EM. This may be attributable to tissue shrinkage during EM dehydration, the sensitivity of MR pulse sequences to larger diameter axons, and/or inaccurate model assumptions. The results of the current study provide a means to characterize the precision and accuracy of RBA-ACD and VBA-AAD OGSE-TDS and highlight the need for further research investigating the relationship between ex vivo MRI and EM, with the goal of reaching in vivo MRI.

Oxygen Extraction Fraction Mapping on Admission Magnetic Resonance Imaging May Predict Recovery of Hyperacute Ischemic Brain Lesions After Successful Thrombectomy: A Retrospective Observational Study.

In acute stroke, diffusion-weighted imaging (DWI) is used to assess the ischemic core. Dynamic-susceptibility contrast perfusion magnetic resonance imaging allows an estimation of the oxygen extraction fraction (OEF), but the outcome of DWI lesions with increased OEF postrecanalization is unclear. This study investigated the impact of OEF on the fate of DWI lesions in patients achieving recanalization after thrombectomy. This was a retrospective analysis of the HIBISCUS-STROKE cohort (Cohort of Patients to Identify Biological and Imaging Markers of Cardiovascular Outcomes in Stroke; NCT: 03149705), a single-center observational study that prospectively enrolled patients who underwent magnetic resonance imaging triage for thrombectomy and a day-6 T2-fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging. Automated postprocessing of admission dynamic-susceptibility contrast perfusion magnetic resonance imaging generated OEF maps. At visual analysis, the OEF status within DWI lesions was assessed in comparison to the contralateral side and correlated with volume changes (difference of ischemic lesion between admission DWI and registered day-6 T2-FLAIR). At voxel-based analysis, recovered DWI regions (lesions present on the admission DWI but absent on the registered day-6 T2-FLAIR) and nonrecovered regions were segmented to extract semiquantitative OEF values. Of the participants enrolled from 2016 to 2022, 134 of 321 (41.7%) were included (median age, 71.0 years; 58.2% male; median baseline National Institutes of Health Scale score, 15.0). At visual analysis, 46 of 134 (34.3%) patients had increased OEF within DWI lesions. These patients were more likely to show a reduction in ischemic lesion volumes compared with those without increased OEF (median change, -4.0 versus 4.8 mL; P<0.0001). Multivariable analysis indicated that increased OEF within DWI lesions was associated with a reduction in ischemic lesion volumes from admission DWI to day-6 T2-FLAIR (odds ratio, 0.68 [95% CI, 0.49-0.87]; P=0.008). At voxel-based analysis, recovered DWI regions had increased OEF, while nonrecovered regions had decreased OEF (median, 126.9% versus -27.0%; P<0.0001). Increased OEF within hyperacute DWI lesions was associated with ischemic lesion recovery between admission DWI and day-6 T2-FLAIR in patients achieving recanalization after thrombectomy. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03149705.

Diffusion and functional MRI reveal microstructural and network connectivity impairment in adult-onset neuronal intranuclear inclusion disease.

Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disorder lacking reliable neuroimaging biomarkers. This study aimed to evaluate microstructural and functional connectivity alterations using diffusion kurtosis imaging (DKI) and resting-state fMRI (rs-fMRI), and to investigate their diagnostic potential as biomarkers. Twenty-three patients with NIID and 40 matched healthy controls (HCs) were recruited. Firstly, gray matter (GM) and white matter (WM) changes were assessed by voxel-based analysis (VBA) and tract-based spatial statistics (TBSS). Then we explored modifications in brain functional networks connectivity by independent component analysis. And the relationship between the altered DKI parameters and neuropsychological evaluation was analyzed. Finally, a receiver operating characteristic (ROC) curve was used to evaluate the diagnostic performance of different gray matter and white matter parameters. Compared with the HCs, NIID patients showed reduced mean kurtosis (MK), radial kurtosis (RK), axial kurtosis (AK), and kurtosis fractional anisotropy (KFA) values in deep gray matter regions. Significantly decreased MK, RK, AK, KFA and fractional anisotropy (FA), and increased mean diffusivity (MD) values were observed in extensive white matter fiber tracts. Notable alterations in functional connectivity were also detected. Among all DKI parameters, the diagnostic efficiency of AK in GM and FA in WM regions was the highest. Adult-onset NIID patients exhibited altered microstructure and functional network connectivity. Our findings suggest that DKI parameters may serve as potential imaging biomarkers for diagnosing adult-onset NIID.

Graph theory network analysis reveals widespread white matter damage in brains of patients with classic ALS.

Objective: Amyotrophic lateral sclerosis (ALS) exhibits several different presentations and clinical phenotypes. Of these, classic ALS (ALS-Cl), which is the most common phenotype, presents with relatively equal amounts of upper motor neuron and lower motor neuron signs. Magnetic resonance imaging (MRI) provides a noninvasive way to assess central nervous system damage in these patients. To our knowledge no study is available where exploratory whole brain grey matter (GM) and white matter (WM) network analysis is performed considering only the ALS-Cl subgroup of ALS patients. Methods: GM voxel-based morphometry analysis and WM network analysis using graph theory was performed in the MRI dataset of 14 neurologic controls and 25 ALS-Cl patients. Results and Conclusions: No significant GM differences were observed between ALS-Cl and neurologic controls. WM network revealed significant (p < 0.05) reduction and increase in degree measure in several extramotor brain regions of ALS-Cl patients. Both global and local graph metrics revealed significant abnormal values in ALS-Cl patients when compared to neurologic controls. Significant WM changes in ALS-Cl patients with no significant GM changes suggest that neurodegeneration may onset as an "axonopathy" in this ALS subtype.

Associations between antagonistic SNPs for neuropsychiatric disorders and human brain structure

A previously published genome-wide association study (GWAS) meta-analysis across eight neuropsychiatric disorders identified antagonistic single-nucleotide polymorphisms (SNPs) at eleven genomic loci where the same allele was protective against one neuropsychiatric disorder and increased the risk for another. Until now, these antagonistic SNPs have not been further investigated regarding their link to brain structural phenotypes. Here, we explored their associations with cortical surface area and cortical thickness (in 34 brain regions and one global measure each) as well as the volumes of eight subcortical structures using summary statistics of large-scale GWAS of brain structural phenotypes. We assessed if significantly associated brain structural phenotypes were previously reported to be associated with major neuropsychiatric disorders in large-scale case-control imaging studies by the ENIGMA consortium. We further characterized the effects of the antagonistic SNPs on gene expression in brain tissue and their association with additional cognitive and behavioral phenotypes, and performed an exploratory voxel-based whole-brain analysis in the FOR2107 study (n = 754 patients with major depressive disorder and n = 847 controls). We found that eight antagonistic SNPs were significantly associated with brain structural phenotypes in regions such as anterior parts of the cingulate cortex, the insula, and the superior temporal gyrus. Case-control differences in implicated brain structural phenotypes have previously been reported for bipolar disorder, major depressive disorder, and schizophrenia. In addition, antagonistic SNPs were associated with gene expression changes in brain tissue and linked to several cognitive-behavioral traits. In our exploratory whole-brain analysis, we observed significant associations of gray matter volume in the left superior temporal pole and left superior parietal region with the variants rs301805 and rs1933802, respectively. Our results suggest that multiple antagonistic SNPs for neuropsychiatric disorders are linked to brain structural phenotypes. However, to further elucidate these findings, future case-control genomic imaging studies are required.

Neural correlates of pain acceptance and the role of the cerebellum: Functional connectivity and anatomical differences in individuals with headaches versus matched controls.

Despite functional connectivity network dysfunction among individuals with headaches, no studies have examined functional connectivity neural correlates and anatomical differences in coping with headaches. This study investigated inter-individual variability in whole-brain functional connectivity and anatomical differences among 37 individuals with primary headaches and 24 age- and gender-matched controls, and neural correlates of psychological flexibility (PF) that was previously found to contribute to headache adjustment. Participants (84% women; M headache severity = 4/10; M age = 43 years) underwent functional magnetic resonance imaging scans and completed questionnaires to examine global and subnetwork brain areas, and their relations with PF components, controlling for age, gender, education, and head-motion. Seed and voxel-based contrast analyses between groups showed atypical functional connectivity of regions involved in pain matrix and core resting-state networks. Pain acceptance was the sole PF component that correlated with the cerebellum (x, y, z: 28, -72, -34, p-false discovery rate <0.001), where individuals with headaches showed higher grey matter density compared to controls. The cerebellum, recently implicated in modulating emotional and cognitive processes, was indicated to process information resembling what individuals do when practicing pain acceptance. Our findings establish for the first time this connection of the cerebellum and its role in pain acceptance. We propose that pain acceptance might be a behavioural biomarker target that could modulate problematic headache perceptions and brain networks abnormalities. This study highlights the potential use of emerging behavioural biomarkers in headache management, such as pain acceptance, and their role in modifying the headache experience. Notably, grey matter reorganization in the cerebellum and other known brain pain networks, could indicate brain networks that can be modified from targeted behavioural interventions to help decode the nociplastic mechanisms that predominates in headaches.

Correlations of gray matter volume with peripheral cytokines in Parkinson's disease

IntroductionPeripheral cytokine levels may affect specific brain volumes. Few studies have examined this possible relationship. ObjectiveIn a case–control study, we used magnetic resonance imaging (MRI) voxel-based morphological analysis techniques to examine the relationship between gray matter volume changes and cognitive, motor and emotional dysfunction as well as between gray matter volume changes and peripheral blood cytokine levels. MethodA total of 134 subjects, comprising 66 PD patients and 68 healthy controls, were recruited. Peripheral venous blood was collected to measure the concentrations of 12 cytokines, including IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17, IFN-α, IFN-γ, and TNF-α. All the subjects also underwent MRI, where 3D-T1-weighted MR images were used for the analysis. In addition, the Montreal Cognitive Assessment (MoCA), Mini-Mental Status Examination (MMSE), Unified Parkinson's disease Rating Scale (UPDRS), Hamilton Anxiety Scale (HAMA), and Hamilton Depression Scale (HAMD) scores were assessed in PD patients. Statistical parameter mapping 12 software was used for the statistical analysis of the images. ResultCompared with control patients, PD patients presented decreased gray matter volume (GMV) in the bilateral frontal lobe, temporal lobe, parietal lobe, occipital lobe, insula, and right cerebellar lobule VIII. Regional GMV in the temporal lobe, parietal lobe, and cerebellum was correlated with MoCA, MMSE, UPDRS, HAMA, and HAMD scores in PDs. In addition, the regional GMV in PDs was correlated with the concentrations of cytokines, including IL-4, IL-6, IFN-γ, and TNF-α. The IL-6 concentration was negatively correlated with the UPDRS-IV score. ConclusionPD patients exhibit gray matter atrophy in a wide range of brain regions, which are symmetrically distributed and mainly concentrated in the frontal and temporal lobes, and these changes may be linked to motor disorders and neuropsychiatric manifestations. Cytokine concentrations in peripheral blood are correlated with regional gray matter volume in PDs, and the IL-6 level affects gray matter volume in the left precentral gyrus and the manifestation of motor complications.

History of Peripartum Depression Moderates the Association Between Estradiol Polygenic Risk Scores and Basal Ganglia Volumes in Major Depressive Disorder

The neurobiological differences between women who have experienced a peripartum episode and those who have only had episodes outside of this period are not well understood. 64 parous female patients with major depressive disorder that have either a positive (n=30) or negative (n=34) history of peripartum depression (PPD) underwent MRI acquisition to obtain structural brain images. An independent two-sample t-test comparing patients with and without a history of PPD was performed using voxel-based morphometry analysis (VBM). Additionally, polygenic risk scores (PRSs) for estradiol were calculated and a moderation analysis was conducted between 3 estradiol PRSs and PPD history status on extracted cluster volumes using IBM SPSS PROCESS macro. The VBM analysis identified larger grey matter volumes in bilateral clusters encompassing the putamen, pallidum, caudate, and thalamus in patients with PPD history compared to patients without a history. The moderation analysis identified a significant interaction of 2 estradiol PRSs and PPD history on grey matter cluster volumes with a positive effect in PPD women and a negative effect in women with no history of PPD. Our findings demonstrate that women who have experienced a peripartum episode are neurobiologically distinct from women who have no history of PPD in a cluster within the basal ganglia, an area important for motivation, decision-making, and emotional processing. Furthermore, we show that the genetic load for estradiol has a differing effect in this area based on PPD status which supports the claim that PPD is associated with sensitivity to sex steroid hormones.

Fitness, Gray Matter Volume, and Executive Function in Cognitively Normal Older Adults: Cross-Sectional Findings From the AGUEDA Trial.

The aim of the study is to investigate the association of cardiorespiratory fitness (CRF) and muscular strength indicators with gray matter volume (GMV) and to study whether fitness-related regions of GMV are associated to executive function (EF) in cognitively normal older adults. Ninety-one cognitively normal older adults (71.69 ± 3.91 years; 57.14% females) participated in this study from the AGUEDA trial. CRF was measured by a 2-km walking test and a 6-min walking test. Muscular strength was measured by handgrip, biceps curl, squats, and isokinetic strength tests. T1-weigthed images were obtained through a magnetic resonance scan. GMV was determined by voxel-based morphometric analysis. Standardized EF tests were performed. CRF did not show any positive association with GMV. Handgrip strength was positively associated with GMV (p < 0.001) in nine regions (β from 0.6 to 0.8 and k from 106 to 1927) and knee extension strength in three regions (β from 0.4 to 0.5 and k from 76 to 2776). Squats strength was negatively associated with GMV (p < 0.001) in two regions (β = -0.3, k = 1102 and k = 152) and the 2-km walking test in one region (β = -0.4, k = 99). Only handgrip strength-related GMV was associated with cognitive flexibility (p = 0.039, β = 0.215) and spatial working memory (p < 0.03, β 0.247-0.317), but not with EF score (p > 0.05). Muscular strength, but no CRF, may be positively related to GMV in cortical and subcortical regions, with implications for specific cognitive domains rather than the overall EF score. Specifically, handgrip strength was the indicator most associated with higher GMV, while squats strength and CRF were negatively related to GMV. ClinicalTrials.gov identifier: NCT05186090.

Crossover evaluation of time-of-flight-based attenuation correction in brain 18F-FDG and 18F-flutemetamol PET.

Brain-dedicated positron emission tomography (PET) systems offer high spatial resolution and sensitivity for accurate clinical assessments. Attenuation correction (AC) is important in PET imaging, particularly in brain studies. This study assessed the reproducibility of attenuation maps (µ-maps) generated by a specialized time-of-flight (TOF) brain-dedicated PET system for imaging using different PET tracers. Twelve subjects underwent both 18F-fluorodeoxyglucose (FDG)-PET and 18F-flutemetamol (FMM) amyloid-PET scans. Images were reconstructed with µ-maps obtained by a maximum likelihood-based AC method. Voxel-based and region-based analyses were used to compare µ-maps obtained with FDG-PET versus FMM-PET; FDG-PET images reconstructed using an FDG-PET µ-map (FDG × FDG) versus those reconstructed with an FMM-PET µ-map (FDG × FMM); and FMM-PET images reconstructed using an FDG-PET µ-map (FMM × FDG) versus those reconstructed with an FMM-PET µ-map (FMM × FMM). Small but significant differences in µ-maps were observed between tracers, primarily in bone regions. In the comparison between the µ-maps obtained with FDG-PET and FMM-PET, the µ-maps obtained with FDG-PET had higher µ-values than those obtained with FMM-PET in the parietal regions of the head and skull, in a portion of the cerebellar dentate nucleus and on the surface of the frontal lobe. The comparison between FDG and FDG × FMM values in different regions yielded findings similar to those of the µ-maps comparison. FDG × FMM values were significantly higher than FDG values in the bilateral temporal bones and a small part of the temporal lobe. Similarly, FMM values were significantly higher than FMM × FDG values in the bilateral temporal bones. FMM × FDG values were significantly higher than FMM values in a small area of the right cerebellar hemisphere. However, the relative errors in these µ-maps were within ± 4%, suggesting that they are clinically insignificant. In PET images reconstructed with the original and swapped µ-maps, the relative errors were within ± 7% and the quality was nearly equivalent. These findings suggest the clinical reliability of the AC method without an external radiation source in TOF brain-dedicated PET systems.

Structural neuroanatomy of human facial behaviors.

The human face plays a central role in emotions and social communication. The emotional and somatic motor networks generate facial behaviors, but whether facial behaviors have representations in the structural anatomy of the human brain is unknown. We coded 16 facial behaviors in 55 healthy older adults who viewed five videos that elicited emotions and examined whether individual differences in facial behavior were related to regional variation in gray matter volume. Voxel-based morphometry analyses revealed that greater emotional facial behavior during the disgust trial (i.e. greater brow furrowing and eye tightening as well as nose wrinkling and upper lip raising) and the amusement trial (i.e. greater smiling and eye tightening) was associated with larger gray matter volume in midcingulate cortex, supplementary motor area, and precentral gyrus, areas spanning both the emotional and somatic motor networks. When measured across trials, however, these facial behaviors (and others) only related to gray matter volume in the precentral gyrus, a somatic motor network hub. These findings suggest that the emotional and somatic motor networks store structural representations of facial behavior and that the midcingulate cortex is critical for generating the predictable movements in the face that arise during emotions.

Whole brain causal functional connectivity analysis of noise-induced deafness based on resting state-functional magnetic resonance imaging

Objective: To investigate the changes of directional connections of auditory and non-auditory in patients with noise-induced deafness (NID) by degree centrality (DC) and Granger causality analysis (GCA), and to explore the mode of brain function remodeling after NID. Methods: In October 2023, a total of 58 patients diagnosed with NID by the Occupational Diseases Department of Yantaishan Hospital of Yantai from 2014 to 2022 were collected as case group (NID group), and 42 healthy volunteers matched by gender, age and education level were selected as the control group (HC group). Resting state-functional magnetic resonance imaging (Rs-fMRI) was perfomed and PC analysis was performed. The brain regions with statistically significant differences in DC values between groups and the bilateral Heschl regions were extracted as regions of interest (ROI) for voxel-based whole brain GCA and correlation analysis. Results: Compared with HC group, the SOG.L DC value of NID group was lower, the connectivity values of SFGdor.L to SOG.L was increased, the connectivity value of PCL.L to SOG.L was decreased, the connectivity values of ORBmid.L, PCG.R and CUN. L/R to HES.L were increased, the connectivity value of SFGdor.L to HES.L was decreased, the connectivity value of HES.L to PCUN.L was decreased, the connectivity values of ORBsup.L and PCG.R to HES.R were increased, the connectivity value of HES.R to CUN.L was decreased (P voxel level<0.01, P cluster level<0.05). The connectivity value of PCL.L to SOG.L was negatively correlated with the weighted value of the better whisper frequency (P<0.05) . Conclusion: The NID patients have abnormal directional connectivity activity in multiple brain regions, such as auditory vision, executive control, somatosensory movement, and default mode network. It is suggested that hearing loss may cause complex neural remodeling between auditory and non-auditory centers.

Neural basis of false recognition in Alzheimer's disease and dementia with lewy bodies.

In Alzheimer's disease (AD), reports on the association between false recognition and brain structure have been inconsistent. In dementia with Lewy bodies (DLB), no such association has been reported. This study aimed to identify brain regions associated with false recognition in AD and DLB by analyzing regional gray matter volume (rGMV). We included 184 patients with AD and 60 patients with DLB. The number of false recognitions was assessed using the Alzheimer's Disease Assessment Scale' word recognition task. Brain regions associated with the number of false recognitions were examined by voxel-based morphometry analysis. The number of false recognitions significantly negatively correlated with rGMV in the bilateral hippocampus, left parahippocampal gyrus, bilateral amygdala, and bilateral entorhinal cortex in patients with AD (p < 0.05, family-wise error [FEW] corrected) and in the bilateral hippocampus, left parahippocampal gyrus, right inferior frontal gyrus, right middle frontal gyrus, right basal forebrain, right insula, left medial and lateral orbital gyri, and left fusiform in those with DLB (p < 0.05, FWE corrected). Bilateral hippocampus and left parahippocampal gyrus were associated with false recognition in both diseases. However, we found there were regions where the association between false recognition and rGMV differed from disease to disease.

Limbic Network Derangement Mediates Unawareness of Apathy in Mild Cognitive Impairment due to Alzheimer's Disease: Clues from [18F]FDG PET Voxel-Wise Analysis.

Discrepancy between caregiver and patient assessments of apathy in mild cognitive impairment (MCI) is considered an index of apathy unawareness, independently predicting progression to AD dementia. However, its neural underpinning are uninvestigated. To explore the [18F]FDG PET-based metabolic correlates of apathy unawareness measured through the discrepancy between caregiver and patient self-report, in patients diagnosed with MCI. We retrospectively studied 28 patients with an intermediate or high likelihood of MCI-AD, progressed to dementia over an average of two years, whose degree of apathy was evaluated by means of the Apathy Evaluation Scale (AES) for both patients (PT-AES) and caregivers (CG-AES). Voxel-based analysis at baseline was used to obtain distinct volumes of interest (VOIs) correlated with PT-AES, CG-AES, or their absolute difference (DISCR-AES). The resulting DISCR-AES VOI count densities were used as covariates in an inter-regional correlation analysis (IRCA) in MCI-AD patients and a group of matched healthy controls (HC). DISCR-AES negatively correlated with metabolism in bilateral parahippocampal gyrus, posterior cingulate cortex, and thalamus, PT-AES score with frontal and anterior cingulate areas, while there was no significant correlation between CG-AES and brain metabolism. IRCA revealed that MCI-AD patients exhibited reduced metabolic/functional correlations of the DISCR-AES VOI with the right cingulate gyrus and its anterior projections compared to HC. Apathy unawareness entails early disruption of the limbic circuitry rather than the classical frontal-subcortical pathways typically associated with apathy. This reaffirms apathy unawareness as an early and independent measure in MCI-AD, marked by distinct pathophysiological alterations.

Associations between differential connectivity patterns of executive control networks and APOE ɛ4 in the Alzheimer continuum

The APOE ɛ4 allele and age are risk factors for Alzheimer’s disease (AD) and contribute to decreased executive function. However, the influence of APOE ɛ4 on the executive control network (ECN) in the AD continuum is still unclear. This study included 269 participants aged between 50 and 95 years old, based on ADNI data, including 104 cognitively normal (CN) individuals, 72 individuals with early mild cognitive impairment (EMCI), 55 individuals with late mild cognitive impairment (LMCI), and 38 AD patients. Within each disease group, participants were subdivided into APOE ɛ4 carriers and non-carriers. We explored brain regions within the ECN affected by the interactions between genes and disease states by resting-state functional magnetic resonance imaging (fMRI) and voxel-based two-way analysis of variance (ANOVA). Subsequently, functional connectivity (FC) between seeds and peak clusters were extracted and correlated with the cognitive performance. We found that the damages of carrying APOE ɛ4 in ECNs mainly distributed in the fronto-parietal and parietal-temporal systems. Functional network intergroup differences indicated increased intrafrontal and fronto-parietal connectivity at the early stage of AD and increased connectivity between the parietal lobe and related regions at late disease in these APOE ɛ4 carriers. Our conclusion is that the functional connectivity in the ECN exhibits different distinguishably patterns of impairment in the AD continuum under the influence of the APOE ɛ4 allele. Patients with different genotypes showed heterogeneity in functional network changes in the early stages of disease, which may be a potential biomarker for early AD.

Cortical and subcortical substrates of working memory in the right hemisphere: A connectome-based lesion-symptom mapping study

Working Memory (WM) is a cognitive system whose crucial role is to temporarily hold and manipulate information. Early studies suggest that verbal WM is typically associated with left hemisphere (LH) brain regions, while the processing of visuospatial information in WM more specifically depends on the right hemisphere (RH). However, recent evidence suggests a more complex network involving both hemispheres' prefrontal and posterior parietal cortices in these processes. Unfortunately, previous lesion studies often examined only one modality (either verbal, or visuospatial) or one hemisphere, which limits the possible conclusions regarding non-lateralized hemispheric involvement. Using connectome-based lesion-symptom mapping on a large sample of patients with left (LBD) and right (RBD) focal brain damage, we examined whether gray matter damage and white matter disconnections predict deficits of WM updating in an N-back task. Patients were examined with two WM tasks that differed regarding modality (verbal, spatial) and cognitive load (1-back, 2-back). Behavioral outcomes indicated that RBD patients showed significant deficits in WM updating, regardless of task modality or load. This observation was supported by whole-brain voxel-based analysis, revealing associations between WM deficits and gray matter clusters in the RH. Specifically, damage to the right lateral frontal cortex including the brain region homologous to Broca's area was associated with verbal WM deficits, while damage to the right inferior parietal lobe and posterior temporal cortex predicted spatial WM deficits. Additionally, white matter analyses identified severely impacted tracts in the RH, predicting deficits in both verbal and spatial WM. Our findings suggest that the mental manipulation of both verbal and visuospatial information in WM updating relies on the integrity of the RH, irrespective of the specific type of information held in mind.

Progressive gray matter atrophy in parkinsonian variant of multiple system atrophy assessed by using causal structural covariance network.

Multiple system atrophy (MSA), a rare neurodegenerative disease, is usually accompanied by brain morphological alterations. However, the causal relationships between progressive gray matter atrophy in MSA parkinsonian (MSA-P) subtype remain unknown. In total, thirty-five MSA-P patients and thirty-five healthy controls (HC) underwent three-dimensional high-resolution T1-weighted structural imaging and voxel-based morphometry analysis. The causal structural covariance network (CaSCN) of gray matter was assessed to explore the causal relationships in MSA-P. With greater illness duration, the reduction of gray matter was originated from right cerebellum and progressed to bilateral cerebellum, fusiform gyrus, insula, putamen, caudate nucleus, frontal lobe, right angular gyrus, right precuneus, left middle occipital lobe and left inferior temporal lobe, then expanded to midbrain, bilateral para-hippocampus, thalamus, temporal lobe, inferior parietal lobule (IPL), precentral gyrus, postcentral gyrus and middle cingulate cortex. The right cerebellum was revealed to be the core node of the directional network and projected positive causal effects to bilateral cerebellum, caudate nucleus and left IPL. MSA-P patients showed progression of gray matter atrophy over time, with the right cerebellum probably as a primary hub. Furthermore, the early structural vulnerability of cerebellum in MSA-P may play a pivotal role in the modulation of motor and non-motor circuits at the structural level.

Structural covariance network activity in the medial prefrontal cortex is modulated by childhood abuse in adolescents with depression

Aberrant structural covariance (SC) in the medial prefrontal cortex (mPFC) is believed to play a crucial role in adolescent-onset major depressive disorder (AO-MDD). However, the effect of childhood abuse (CA) on SC in AO-MDD patients is still unknown. Here, we measured anomalous SC in the mPFC of AO-MDD patients and assessed the potential modulation of this feature by CA. We acquired T1-weighted structural images of AO-MDD patients (n = 93) and healthy controls (HCs, n = 81). Using voxel-based morphometry analysis, we calculated gray matter volumes for each subject. Subsequently, we classified abnormal SC in the mPFC into three subtypes according to overall CA. Compared with HCs, AO-MDD patients showed alterations in the structural covariance network of the mPFC, which is a central region in the default mode network (DMN). We also found an anterior-posterior dissociation in the structural covariance connectivity of the DMN. A history of CA modulated bilateral mPFC SC. These changes were primarily focused on the SC between the mPFC and the limbic system, indicating a gap in the rate of neural maturation between these regions. In summary, the DMN and frontal-limbic system, which are involved in emotional processing, appear to play a significant role in the development of AO-MDD. These findings highlight the crucial effects of CA on neurophysiological alterations in individuals with AO-MDD.