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Addiction Biology Jun 2024The association of impaired dopaminergic neurotransmission with the development and maintenance of alcohol use disorder is well known. More specifically, reduced...
Correlation of striatal dopamine D2/3 receptor availability with GABA level in the anterior cingulate cortex in healthy controls but not in alcohol-dependent subjects and individuals at high risk: A multimodal magnetic resonance spectroscopy and positron emission tomography study.
BACKGROUND
The association of impaired dopaminergic neurotransmission with the development and maintenance of alcohol use disorder is well known. More specifically, reduced dopamine D2/3 receptors in the striatum of subjects with alcohol dependence (AD) compared to healthy controls have been found in previous studies. Furthermore, alterations of gamma-aminobutyric acid (GABA) and glutamate (Glu) levels in the anterior cingulate cortex (ACC) of AD subjects have been documented in several studies. However, the interaction between cortical Glu levels and striatal dopamine D2/3 receptors has not been investigated in AD thus far.
METHODS
This study investigated dopamine D2/3 receptor availability via 18F-fallypride positron emission tomography (PET) and GABA as well as Glu levels via magnetic resonance spectroscopy (MRS) in 19 detoxified AD subjects, 18 healthy controls (low risk, LR) controls and 19 individuals at high risk (HR) for developing AD, carefully matched for sex, age and smoking status.
RESULTS
We found a significant negative correlation between GABA levels in the ACC and dopamine D2/3 receptor availability in the associative striatum of LR but not in AD or HR individuals. Contrary to our expectations, we did not observe a correlation between Glu concentrations in the ACC and striatal D2/3 receptor availability.
CONCLUSIONS
The results may reflect potential regulatory cortical mechanisms on mesolimbic dopamine receptors and their disruption in AD and individuals at high risk, mirroring complex neurotransmitter interactions associated with the pathogenesis of addiction. This is the first study combining 18F-fallypride PET and MRS in AD subjects and individuals at high risk.
Topics: Humans; Positron-Emission Tomography; Gyrus Cinguli; Male; Alcoholism; Receptors, Dopamine D2; Adult; Female; Receptors, Dopamine D3; gamma-Aminobutyric Acid; Magnetic Resonance Spectroscopy; Middle Aged; Corpus Striatum; Case-Control Studies; Glutamic Acid; Benzamides
PubMed: 38899357
DOI: 10.1111/adb.13424 -
Kidney International Reports Jun 2024Blood pressure (BP) is a highly heritable trait with over 2000 underlying genomic loci identified to date. Although the kidney plays a key role, little is known about...
INTRODUCTION
Blood pressure (BP) is a highly heritable trait with over 2000 underlying genomic loci identified to date. Although the kidney plays a key role, little is known about specific cell types involved in the genetic regulation of BP.
METHODS
Here, we applied stratified linkage disequilibrium score (LDSC) regression to connect BP genome-wide association studies (GWAS) results to specific cell types of the mature human kidney. We used the largest single-stage BP genome-wide analysis to date, including up to 1,028,980 adults of European ancestry, and single-cell transcriptomic data from 14 mature human kidneys, with mean age of 41 years.
RESULTS
Our analyses prioritized myofibroblasts and endothelial cells, among the total of 33 annotated cell type, as specifically involved in BP regulation ( < 0.05/33, i.e., 0.001515). Enrichment of heritability for systolic BP (SBP) was observed in myofibroblast cells in mature human kidney cortex, and enrichment of heritability for diastolic BP (DBP) was observed in descending vasa recta and peritubular capillary endothelial cells as well as stromal myofibroblast cells. The new finding of myofibroblast, the significant cell type for both BP traits, was consistent in 8 replication efforts using 7 sets of independent data, including in human fetal kidney, in East-Asian (EAS) ancestry, using mouse single-cell RNA sequencing (scRNA-seq) data, and when using another prioritization method.
CONCLUSION
Our findings provide a solid basis for follow-up studies to further identify genes and mechanisms in myofibroblast cells that underlie the regulation of BP.
PubMed: 38899223
DOI: 10.1016/j.ekir.2024.03.001 -
The Journal of Headache and Pain Jun 2024The insula is an important part of the posttraumatic headache (PTH) attributed to mild traumatic brain injury (mTBI) neuropathological activity pattern. It is composed...
Connectivity of the insular subdivisions differentiates posttraumatic headache-associated from nonheadache-associated mild traumatic brain injury: an arterial spin labelling study.
OBJECTIVE
The insula is an important part of the posttraumatic headache (PTH) attributed to mild traumatic brain injury (mTBI) neuropathological activity pattern. It is composed of functionally different subdivisions and each of which plays different role in PTH neuropathology.
METHODS
Ninety-four mTBI patients were included in this study. Based on perfusion imaging data obtained from arterial spin labelling (ASL) perfusion magnetic resonance imaging (MRI), this study evaluated the insular subregion perfusion-based functional connectivity (FC) and its correlation with clinical characteristic parameters in patients with PTH after mTBI and non-headache mTBI patients.
RESULTS
The insular subregions of mTBI + PTH (mTBI patients with PTH) and mTBI-PTH (mTBI patients without PTH) group had positive perfusion-based functional connections with other insular nuclei and adjacent discrete cortical regions. Compared with mTBI-PTH group, significantly increased resting-state perfusion-based FC between the anterior insula (AI) and middle cingulate cortex (MCC)/Rolandic operculum (ROL), between posterior insula (PI) and supplementary motor area (SMA), and decreased perfusion-based FC between PI and thalamus were found in mTBI + PTH group. Changes in the perfusion-based FC of the left posterior insula/dorsal anterior insula with the thalamus/MCC were significant correlated with headache characteristics.
CONCLUSIONS
Our findings provide new ASL-based evidence for changes in the perfusion-based FC of the insular subregion in PTH patients attributed to mTBI and the association with headache features, revealing the possibility of potential neuroplasticity after PTH. These findings may contribute to early diagnosis of the disease and follow-up of disease progression.
Topics: Humans; Male; Female; Adult; Post-Traumatic Headache; Spin Labels; Brain Concussion; Magnetic Resonance Imaging; Middle Aged; Insular Cortex; Young Adult; Cerebral Cortex
PubMed: 38898386
DOI: 10.1186/s10194-024-01809-z -
Communications Biology Jun 2024The inequitable distribution of economic resources and exposure to adversity between racial groups contributes to mental health disparities within the United States....
The inequitable distribution of economic resources and exposure to adversity between racial groups contributes to mental health disparities within the United States. Consideration of the potential neurodevelopmental consequences, however, has been limited particularly for neurocircuitry known to regulate the emotional response to threat. Characterizing the consequences of inequity on threat neurocircuitry is critical for robust and generalizable neurobiological models of psychiatric illness. Here we use data from the Adolescent Brain and Cognitive Development Study 4.0 release to investigate the contributions of individual and neighborhood-level economic resources and exposure to discrimination. We investigate the potential appearance of race-related differences using both standard methods and through population-level normative modeling. We show that, in a sample of white and Black adolescents, racial inequities in socioeconomic factors largely contribute to the appearance of race-related differences in cortical thickness of threat neurocircuitry. The race-related differences are preserved through the use of population-level models and such models also preserve associations between cortical thickness and specific socioeconomic factors. The present findings highlight that such socioeconomic inequities largely underlie race-related differences in brain morphology. The present findings provide important new insight for the generation of generalizable neurobiological models of psychiatric illness.
Topics: Humans; Adolescent; Male; Female; Socioeconomic Factors; United States; White People; Black or African American; Cerebral Cortex
PubMed: 38898062
DOI: 10.1038/s42003-024-06436-7 -
Trends in Neurosciences Jun 2024While many core biological processes are conserved across species, the human brain has evolved with unique capacities. Current understanding of the neurobiological... (Review)
Review
While many core biological processes are conserved across species, the human brain has evolved with unique capacities. Current understanding of the neurobiological mechanisms that endow human traits as well as associated vulnerabilities remains limited. However, emerging data have illuminated species divergence in DNA elements and genome organization, in molecular, morphological, and functional features of conserved neural cell types, as well as temporal differences in brain development. Here, we summarize recent data on unique features of the human brain and their complex implications for the study and treatment of brain diseases. We also consider key outstanding questions in the field and discuss the technologies and foundational knowledge that will be required to accelerate understanding of human neurobiology.
PubMed: 38897852
DOI: 10.1016/j.tins.2024.05.009 -
Cerebral Cortex (New York, N.Y. : 1991) Jun 2024The left and right anterior temporal lobes (ATLs) encode semantic representations. They show graded hemispheric specialization in function, with the left ATL...
The left and right anterior temporal lobes (ATLs) encode semantic representations. They show graded hemispheric specialization in function, with the left ATL contributing preferentially to verbal semantic processing. We investigated the cognitive correlates of this organization, using resting-state functional connectivity as a measure of functional segregation between ATLs. We analyzed two independent resting-state fMRI datasets (n = 86 and n = 642) in which participants' verbal semantic expertise was measured using vocabulary tests. In both datasets, people with more advanced verbal semantic knowledge showed weaker functional connectivity between left and right ventral ATLs. This effect was highly specific. It was not observed for within-hemisphere connections between semantic regions (ventral ATL and inferior frontal gyrus (IFG), though it was found for left-right IFG connectivity in one dataset). Effects were not found for tasks probing semantic control, nonsemantic cognition, or face recognition. Our results suggest that hemispheric specialization in the ATLs is not an innate property but rather emerges as people develop highly detailed verbal semantic representations. We speculate that this effect is a consequence of the left ATL's greater connectivity with left-lateralized written word recognition regions, which causes it to preferentially represent meaning for advanced vocabulary acquired primarily through reading.
Topics: Humans; Temporal Lobe; Male; Female; Magnetic Resonance Imaging; Adult; Semantics; Functional Laterality; Young Adult; Brain Mapping; Neural Pathways
PubMed: 38897815
DOI: 10.1093/cercor/bhae256 -
BMJ Paediatrics Open Jun 2024To determine the dose-dependent associations between antenatal corticosteroids (ANS) exposure and the rates of major morbidities, and the early weight loss percentage...
Association of different doses of antenatal corticosteroids exposure with early major outcomes and early weight loss percentage in extremely preterm infants or extremely low birthweight infants: a multicentre cohort study.
OBJECTIVES
To determine the dose-dependent associations between antenatal corticosteroids (ANS) exposure and the rates of major morbidities, and the early weight loss percentage (EWLP) in hospital among extremely preterm infants (EPI) or extremely low birthweight infants (ELBWI).
METHODS
A multicentre, retrospective cohort study of EPI or ELBWI born between 2017 and 2018 was conducted. Infants were classified into no ANS, partial ANS and complete ANS exposure group; three subgroups were generated by gestational age and birth weight. Multiple logistic regression and multiple linear regression were performed.
RESULTS
There were 725 infants included from 32 centres. Among no ANS, partial ANS and complete ANS exposure, there were significant differences in the proportions of bronchopulmonary dysplasia (BPD) (24.5%, 25.4% and 16.1%), necrotising enterocolitis (NEC) (6.7%, 2.0% and 2.0%) and death (29.6%, 18.5% and 13.5%), and insignificant differences in the proportions of intraventricular haemorrhage (IVH) (12.5%, 13.2% and 12.2%), and extrauterine growth restriction (EUGR) (50.0%, 56.6% and 59.5%). In the logistic regression, compared with no ANS exposure, complete ANS reduced the risk of BPD (OR 0.58, 95% CI 0.37 to 0.91), NEC (OR 0.21, 95% CI 0.08 to 0.57) and death (OR 0.36, 95% CI 0.23 to 0.56), and partial ANS reduced the risk of NEC (OR 0.23, 95% CI 0.07 to 0.72) and death (OR 0.54, 95% CI 0.34 to 0.87). Compared with partial ANS exposure, complete ANS decreased the risk of BPD (OR 0.58, 95% CI 0.37 to 0.91). There were insignificant associations between ANS exposure and IVH, EUGR. In the multiple linear regression, partial and complete ANS exposure increased EWLP only in the ≥28 weeks (w) and <1000 g subgroup (p<0.05).
CONCLUSIONS
Different doses of ANS (dexamethasone) exposure were protectively associated with BPD, NEC, death in hospital, but not EUGR at discharge among EPI or ELBWI. Beneficial dose-dependent associations between ANS (dexamethasone) exposure and BPD existed. ANS exposure increased EWLP only in the ≥28 w and<1000 g subgroup. ANS administration, especially complete ANS, is encouraged before preterm birth.
TRIAL REGISTRATION NUMBER
NCT06082414.
Topics: Humans; Infant, Newborn; Female; Infant, Extremely Low Birth Weight; Retrospective Studies; Infant, Extremely Premature; Male; Pregnancy; Weight Loss; Enterocolitis, Necrotizing; Bronchopulmonary Dysplasia; Dose-Response Relationship, Drug; Adrenal Cortex Hormones; Gestational Age; Infant, Premature, Diseases
PubMed: 38897621
DOI: 10.1136/bmjpo-2024-002506 -
Neurology(R) Neuroimmunology &... Jul 2024A CSF-in gradient in cortical and thalamic gray matter (GM) damage has been found in multiple sclerosis (MS). We concomitantly explored the patterns of cortical,...
BACKGROUND AND OBJECTIVES
A CSF-in gradient in cortical and thalamic gray matter (GM) damage has been found in multiple sclerosis (MS). We concomitantly explored the patterns of cortical, thalamic, and caudate microstructural abnormalities at progressive distances from CSF using a multiparametric MRI approach.
METHODS
For this cross-sectional study, from 3T 3D T1-weighted scans, we sampled cortical layers at 25%-50%-75% depths from pial surface and thalamic and caudate bands at 2-3-4 voxels from the ventricular-GM interface. Using linear mixed models, we tested between-group comparisons of magnetization transfer ratio (MTR) and R2* layer-specific z-scores, CSF-in across-layer z-score changes, and their correlations with clinical (disease duration and disability) and structural (focal lesions, brain, and choroid plexus volume) MRI measures.
RESULTS
We enrolled 52 patients with MS (33 relapsing-remitting [RRMS], 19 progressive [PMS], mean age: 46.4 years, median disease duration: 15.1 years, median: EDSS 2.0) and 70 controls (mean age 41.5 ± 12.8). Compared with controls, RRMS showed lower MTR values in the outer and middle cortical layers (false-discovery rate [FDR]- ≤ 0.025) and lower R2* values in all 3 cortical layers (FDR- ≤ 0.016). PMS had lower MTR values in the outer and middle cortical (FDR- ≤ 0.016) and thalamic (FDR- ≤ 0.048) layers, and in the outer caudate layer (FDR- = 0.024). They showed lower R2* values in the outer cortical layer (FDR- = 0.003) and in the outer thalamic layer (FDR- = 0.046) and higher R2* values in all 3 caudate layers (FDR- ≤ 0.031). Both RRMS and PMS had a gradient of damage, with lower values closer to the CSF, for cortical (FDR- ≤ 0.002) and thalamic (FDR- ≤ 0.042) MTR. PMS showed a gradient of damage for cortical R2* (FDR- = 0.005), thalamic R2* (FDR- = 0.004), and caudate MTR (FDR- ≤ 0.013). Lower MTR and R2* of outer cortical, thalamic, and caudate layers and steeper gradient of damage toward the CSF were significantly associated with older age, higher T2-hyperintense white matter lesion volume, higher thalamic lesion volume, and lower brain volume (β ≥ 0.08, all FDR- ≤ 0.040). Lower MTR of outer caudate layer was associated with more severe disability (β = -0.26, FDR- = 0.040). No correlations with choroid plexus volume were found.
DISCUSSION
CSF-in damage gradients are heterogeneous among different GM regions and through MS course, possibly reflecting different dynamics of demyelination and iron loss/accumulation.
Topics: Humans; Middle Aged; Male; Female; Adult; Cross-Sectional Studies; Gray Matter; Cerebral Cortex; Thalamus; Multiple Sclerosis, Relapsing-Remitting; Multiple Sclerosis, Chronic Progressive; Magnetic Resonance Imaging; Multiparametric Magnetic Resonance Imaging; Multiple Sclerosis; Caudate Nucleus
PubMed: 38896808
DOI: 10.1212/NXI.0000000000200271 -
Animal Models and Experimental Medicine Jun 2024Apolipoprotein E4 (ApoE4) allele is the strongest genetic risk factor for late-onset Alzheimer's disease, and it can aggravate depressive symptoms in non-AD patients....
BACKGROUND
Apolipoprotein E4 (ApoE4) allele is the strongest genetic risk factor for late-onset Alzheimer's disease, and it can aggravate depressive symptoms in non-AD patients. However, the impact of ApoE4 on AD-associated depression-like behaviors and its underlying pathogenic mechanisms remain unclear.
METHODS
This study developed a 5xFAD mouse model overexpressing human ApoE4 (E4FAD). Behavioral assessments and synaptic function tests were conducted to explore the effects of ApoE4 on cognition and depression in 5xFAD mice. Changes in peripheral and central lipid metabolism, as well as the levels of serotonin (5-HT) and γ-aminobutyric acid (GABA) neurotransmitters in the prefrontal cortex, were examined. In addition, the protein levels of 24-dehydrocholesterol reductase/glycogen synthase kinase-3 beta/mammalian target of rapamycin (DHCR24/GSK3β/mTOR) and postsynaptic density protein 95/calmodulin-dependent protein kinase II/brain-derived neurotrophic factor (PSD95/CaMK-II/BDNF) were measured to investigate the molecular mechanism underlying the effects of ApoE4 on AD mice.
RESULTS
Compared with 5xFAD mice, E4FAD mice exhibited more severe depression-like behaviors and cognitive impairments. These mice also exhibited increased amyloid-beta deposition in the hippocampus, increased astrocyte numbers, and decreased expression of depression-related neurotransmitters 5-HT and GABA in the prefrontal cortex. Furthermore, lipid metabolism disorders were observed in E4FAD, manifesting as elevated low-density lipoprotein cholesterol and reduced high-density lipoprotein cholesterol in peripheral blood, decreased cholesterol level in the prefrontal cortex, and reduced expression of key enzymes and proteins related to cholesterol synthesis and homeostasis. Abnormal expression of proteins related to the DHCR24/GSK3β/mTOR and PSD95/CaMK-II/BDNF pathways was also observed.
CONCLUSION
This study found that ApoE4 overexpression exacerbates depression-like behaviors in 5xFAD mice and confirmed that ApoE4 reduces cognitive function in these mice. The mechanism may involve the induction of central and peripheral lipid metabolism disorders. Therefore, modulating ApoE expression or function to restore cellular lipid homeostasis may be a promising therapeutic target for AD comorbid with depression. This study also provided a better animal model for studying AD comorbid with depression.
PubMed: 38895818
DOI: 10.1002/ame2.12446 -
BioRxiv : the Preprint Server For... Jun 2024In school-age children, the myelination of the auditory radiation thalamocortical pathway is associated with the latency of auditory evoked responses, with the...
In school-age children, the myelination of the auditory radiation thalamocortical pathway is associated with the latency of auditory evoked responses, with the myelination of thalamocortical axons facilitating the rapid propagation of acoustic information. Little is known regarding this auditory system function-structure association in infants and toddlers. The present study tested the hypothesis that maturation of auditory radiation white-matter microstructure (e.g., fractional anisotropy (FA); measured using diffusion-weighted MRI) is associated with the latency of the infant auditory response (P2m measured using magnetoencephalography, MEG) in a cross-sectional (2 to 24 months) as well as longitudinal cohort (2 to 29 months) of typically developing infants and toddlers. In the cross-sectional sample, non-linear maturation of P2m latency and auditory radiation diffusion measures were observed. After removing the variance associated with age in both P2m latency and auditory radiation diffusion measures, auditory radiation still accounted for significant variance in P2m latency. In the longitudinal sample, latency and FA associations could be observed at the level of a single child. Findings provide strong support for a contribution of auditory radiation white matter to rapid cortical auditory encoding processes in infants.
PubMed: 38895425
DOI: 10.1101/2024.06.05.597426