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1.
Brain Behav ; 13(12): e3296, 2023 12.
Article in English | MEDLINE | ID: mdl-37904336

ABSTRACT

Extensive research has demonstrated the critical role of selenium (Se) and selenoproteins in brain function and cognition. However, the impact of Se on brain cortical structure remains enigmatic. Therefore, this study used Mendelian randomization (MR) analysis to investigate the causal effect between Se levels and brain cortical structure. METHODS: This study utilizes 11 genetic variants associated with Se level variations, extracted from a large-scale genome-wide association study (GWAS) encompassed circulating Se levels (n = 5477) and toenail Se levels (n = 4162) in the European population. Outcome data were sourced from the summary statistics of the ENIGMA Consortium, comprising GWAS data from 51,666 individuals. The variables include cortical surface area (SA), thickness (TH) at the global level, and 34 functional cortical regions evaluated by magnetic resonance imaging. The inverse-variance-weighted method was used as the primary estimate. Additionally, sensitivity analyses were conducted to detect potential violations of assumptions underlying MR. RESULTS: At the global level, Se levels were not correlated with SA but showed a significant negative correlation with TH (ß = -0.00485 mm, SE = 0.00192, p = .0115). Heterogeneity was observed across different brain regions, with positive correlations found between Se levels and the TH of the parahippocampal gyrus, superior frontal gyrus, and frontal pole, whereas negative correlations were found with the TH of the inferior parietal lobe and middle temporal lobe. Regarding SA, Se levels exhibit positive correlations with the pars triangularis, caudal anterior cingulate, inferior parietal lobe, and banks of the superior temporal sulcus. Conversely, negative correlations were observed with the medial orbitofrontal cortex, posterior cingulate gyrus, insula, and the middle, superior, and transverse gyrus of the temporal lobe. No pleiotropy was detected. RESULTS: This MR study indicated that Se levels causally influence the brain cortical structure.


Subject(s)
Selenium , Humans , Genome-Wide Association Study , Mendelian Randomization Analysis , Cerebral Cortex/diagnostic imaging , Cerebral Cortex/pathology , Brain/diagnostic imaging , Brain/pathology
2.
Neurology ; 100(5): e485-e496, 2023 01 31.
Article in English | MEDLINE | ID: mdl-36302664

ABSTRACT

BACKGROUND AND OBJECTIVE: Theories assume that thalamic stroke may cause aphasia because of dysfunction in connected cortical networks. This takes into account that brain functions are organized in distributed networks, and in turn, localized damage may result in a network disorder such as thalamic aphasia. With this study, we investigate whether the integration of the thalamus into specific thalamocortical networks underlies symptoms after thalamic stroke. We hypothesize that thalamic lesions in patients with language impairments are functionally connected to cortical networks for language and cognition. METHODS: We combined nonparametric lesion mapping methods in a retrospective cohort of patients with acute or subacute first-ever thalamic stroke. A relationship between lesion location and language impairments was assessed using nonparametric voxel-based lesion-symptom mapping. This method reveals regions more frequently damaged in patients with compared with those without a symptom of interest. To test whether these symptoms are linked to a common thalamocortical network, we additionally performed lesion-network-symptom mapping. This method uses normative connectome data from resting-state fMRI of healthy participants (n = 65) for functional connectivity analyses, with lesion sites serving as seeds. Resulting lesion-dependent network connectivity of patients with language impairments was compared with those with motor and sensory deficits as baseline. RESULTS: A total of 101 patients (mean [SD] age 64.1 [14.6] years, 57 left, 42 right, and 2 bilateral lesions) were included in the study. Voxel-based lesion-symptom mapping showed an association of language impairments with damage to left mediodorsal thalamic nucleus lesions. Lesion-network-symptom mapping revealed that language compared with sensory deficits were associated with higher normative lesion-dependent network connectivity to left frontotemporal language networks and bilateral prefrontal, insulo-opercular, midline cingular, and parietal domain-general networks. Lesions related to motor and sensory deficits showed higher lesion-dependent network connectivity within the sensorimotor network spanning prefrontal, precentral, and postcentral cortices. DISCUSSION: Thalamic aphasia relates to lesions in the left mediodorsal thalamic nucleus and to functionally connected left cortical language and bilateral cortical networks for cognitive control. This suggests that dysfunction in thalamocortical networks contributes to thalamic aphasia. We propose that inefficient integration between otherwise undamaged domain-general and language networks may cause thalamic aphasia.


Subject(s)
Aphasia , Language Disorders , Stroke , Humans , Middle Aged , Retrospective Studies , Aphasia/etiology , Aphasia/complications , Stroke/complications , Stroke/diagnostic imaging , Stroke/pathology , Cerebral Cortex/pathology , Thalamus , Language Disorders/diagnostic imaging , Language Disorders/etiology , Magnetic Resonance Imaging/methods , Brain Mapping
3.
Neurobiol Dis ; 174: 105878, 2022 Nov.
Article in English | MEDLINE | ID: mdl-36183947

ABSTRACT

The striatum receives abundant glutamatergic afferents from the cortex and thalamus. These inputs play a major role in the functions of the striatal neurons in normal conditions, and are significantly altered in pathological states, such as Parkinson's disease. This review summarizes the current knowledge of the connectivity of the corticostriatal and thalamostriatal pathways, with emphasis on the most recent advances in the field. We also discuss novel findings regarding structural changes in cortico- and thalamostriatal connections that occur in these connections as a consequence of striatal loss of dopamine in parkinsonism.


Subject(s)
Parkinson Disease , Thalamus , Humans , Thalamus/pathology , Corpus Striatum/pathology , Cerebral Cortex/pathology , Neurons/pathology , Parkinson Disease/pathology , Neural Pathways/pathology
4.
Nat Commun ; 13(1): 5069, 2022 08 29.
Article in English | MEDLINE | ID: mdl-36038566

ABSTRACT

The mechanisms controlling dynamical patterns in spontaneous brain activity are poorly understood. Here, we provide evidence that cortical dynamics in the ultra-slow frequency range (<0.01-0.1 Hz) requires intact cortical-subcortical communication. Using functional magnetic resonance imaging (fMRI) at rest, we identify Dynamic Functional States (DFSs), transient but recurrent clusters of cortical and subcortical regions synchronizing at ultra-slow frequencies. We observe that shifts in cortical clusters are temporally coincident with shifts in subcortical clusters, with cortical regions flexibly synchronizing with either limbic regions (hippocampus/amygdala), or subcortical nuclei (thalamus/basal ganglia). Focal lesions induced by stroke, especially those damaging white matter connections between basal ganglia/thalamus and cortex, provoke anomalies in the fraction times, dwell times, and transitions between DFSs, causing a bias toward abnormal network integration. Dynamical anomalies observed 2 weeks after stroke recover in time and contribute to explaining neurological impairment and long-term outcome.


Subject(s)
Cerebral Cortex , Stroke , Basal Ganglia/pathology , Brain/diagnostic imaging , Cerebral Cortex/pathology , Humans , Magnetic Resonance Imaging/methods , Thalamus
5.
Sci Rep ; 11(1): 23323, 2021 12 02.
Article in English | MEDLINE | ID: mdl-34857797

ABSTRACT

Dysfunctional thalamocortical interactions have been suggested as putative mechanisms of ineffective pain modulation and also suggested as possible pathophysiology of fibromyalgia (FM). However, it remains unclear which specific thalamocortical networks are altered and whether it is related to abnormal pain perception in people with FM. Here, we conducted combined vertex-wise subcortical shape, cortical thickness, structural covariance, and resting-state functional connectivity analyses to address these questions. FM group exhibited a regional shape deflation of the left posterior thalamus encompassing the ventral posterior lateral and pulvinar nuclei. The structural covariance analysis showed that the extent of regional deflation of the left posterior thalamus was negatively covaried with the left inferior parietal cortical thickness in the FM group, whereas those two regions were positively covaried in the healthy controls. In functional connectivity analysis with the left posterior thalamus as a seed, FM group had less connectivity with the periaqueductal gray compared with healthy controls, but enhanced connectivity between the posterior thalamus and bilateral inferior parietal regions, associated with a lower electrical pain threshold at the hand dorsum (pain-free point). Overall, our findings showed the structural thalamic alteration interacts with the cortical regions in a functionally maladaptive direction, leading the FM brain more responsive to external stimuli and potentially contributing to pain amplification.


Subject(s)
Cerebral Cortex/pathology , Fibromyalgia/physiopathology , Nerve Net/pathology , Pain/pathology , Thalamus/pathology , Adult , Brain/physiopathology , Case-Control Studies , Female , Humans , Middle Aged , Neural Pathways , Neuroimaging , Pain Perception
6.
Article in English | MEDLINE | ID: mdl-34465616

ABSTRACT

BACKGROUND AND OBJECTIVES: To determine the relative importance of global or regional MRI and blood markers of neurodegeneration and neuroaxonal injury in predicting cognitive performance for recently diagnosed patients with multiple sclerosis (MS). METHODS: Thirty-five newly diagnosed patients with relapsing-remitting MS (RRMS) and 23 healthy controls (HCs) simultaneously completed a full clinical and neuropsychological assessment, structural brain MRI, and serum neurofilament light chain (sNfL) level test. Linear regression analyses were performed to determine which global or regional measures of gray matter (GM) atrophy and cortical thickness (CT), in combination with sNfL levels and clinical scores, are most strongly related to neuropsychological impairment. RESULTS: Compared with HCs, patients with MS showed bilateral thalamic GM atrophy (left, p = 0.033; right, p = 0.047) and diminished CT, particularly in the right superior and transverse temporal gyri (p = 0.045; p = 0.037). Regional atrophy failed to add predictive variance, whereas anxiety symptoms, sNfL, and global CT were the best predictors (R2 = 0.404; p < 0.001) of cognitive outcomes, with temporal thickness accounting for greater variance in cognitive deficits than global CT. DISCUSSION: Thalamic GM atrophy and thinning in temporal regions represent a distinctive MRI trait in the early stages of MS. Although sNfL levels alone do not clearly differentiate HCs and patients with RRMS, in combination with global and regional CT, sNfL levels can better explain the presence of underlying cognitive deficits. Hence, cortical thinning and sNfL increases can be considered 2 parallel neurodegenerative markers in the pathogenesis of progression in newly diagnosed patients with MS.


Subject(s)
Cerebral Cortex/pathology , Cognitive Dysfunction , Multiple Sclerosis, Relapsing-Remitting , Neurofilament Proteins/blood , Thalamus/pathology , Adolescent , Adult , Cerebral Cortex/diagnostic imaging , Cognitive Dysfunction/blood , Cognitive Dysfunction/etiology , Cognitive Dysfunction/pathology , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Multiple Sclerosis, Relapsing-Remitting/blood , Multiple Sclerosis, Relapsing-Remitting/complications , Multiple Sclerosis, Relapsing-Remitting/diagnosis , Multiple Sclerosis, Relapsing-Remitting/pathology , Thalamus/diagnostic imaging , Young Adult
7.
Int J Mol Med ; 48(5)2021 11.
Article in English | MEDLINE | ID: mdl-34515324

ABSTRACT

Telomeres, the protective caps of chromosomes, shorten with age, as telomerase, the enzyme responsible for the compensation of telomere erosion, is inactive in the majority of cells. Telomere shortening and subsequent cell senescence lead to tissue aging and age­related diseases. Neurodegenerative disorders, characterized by the progressive loss of neurons among other hallmarks of aged tissue, and poor cognitive function, have been associated with a short telomere length. Thus, telomerase activity has emerged as a therapeutic target, with novel agents being under investigation. The present study aimed to examine the effects of a novel natural telomerase activator, 'Reverse™', containing Centella asiatica extract, vitamin C, zinc and vitamin D3 on the brains of 18­month­old rats. The administration of the 'Reverse™' supplement for 3 months restored telomerase reverse transcriptase (TERT) expression in the brains of rats, as revealed by ELISA and immunohistochemistry. In addition, the findings from PCR­ELISA demonstrated an enhanced telomerase activity in the cerebellum and cortex cells in the brains of rats treated with the 'Reverse™' supplement. The histopathological findings confirmed a structural reversibility effect close to the differentiation observed in the young control group of rats treated with two capsules/kg body weight of the 'Reverse™' supplement. On the whole, the findings of the present study provide a strong indication that an increased telomerase activity and TERT expression may be achieved not only in the postnatal or embryonic period, but also in the brains of middle­aged rats through nutraceutical supplementation. The use of the 'Reverse™' supplement may thus contribute to the potential alleviation of a number of central nervous system diseases.


Subject(s)
Aging/pathology , Brain/pathology , Dietary Supplements , Telomerase/antagonists & inhibitors , Animals , Cerebral Cortex/pathology , Male , Rats, Sprague-Dawley , Telomerase/metabolism
8.
Brain Res ; 1769: 147591, 2021 10 15.
Article in English | MEDLINE | ID: mdl-34324877

ABSTRACT

Traumatic brain injury (TBI) is a significant cause of disability and death worldwide. Accumulating evidence suggests that endoplasmic reticulum (ER) stress would be an important component in the pathogenesis of TBI. Although the neuroprotective effects of naringenin, a natural flavonoid isolated from citrus plants, have been confirmed in several neurological diseases, its mechanism of action in TBI needs further investigation. In ICR mice, we found that TBI induced elevated expression of ER stress marker proteins, including 78-kDa glucose-regulated protein (GRP78) and C/EBP homologous protein (CHOP) in the perilesional cortex, which peaked at 7 days and 3 days after TBI, respectively. The induction of ER stress-related proteins partly coincided with ER architectural changes at 3 days post-TBI, indicating ER stress activation in our TBI model. Our results also revealed that continuous naringenin administration ameliorated neurological dysfunction, cerebral edema, plasmalemma permeability, and neuron cell loss at day 3 after TBI. Further, Naringenin suppressed TBI-induced activation of the ER stress pathway (p-eIF2α, ATF4, and CHOP), oxidative stress and apoptosis on day 3 after TBI. In summary, our data suggest that naringenin could ameliorate TBI-induced secondary brain injury by pleiotropic effects, including ER stress attenuation.


Subject(s)
Apoptosis/drug effects , Brain Injuries, Traumatic/drug therapy , Brain Injuries, Traumatic/pathology , Endoplasmic Reticulum Stress/drug effects , Flavanones/therapeutic use , Neuroprotective Agents/therapeutic use , Recovery of Function/drug effects , Animals , Cerebral Cortex/injuries , Cerebral Cortex/pathology , Endoplasmic Reticulum/metabolism , Endoplasmic Reticulum/pathology , Endoplasmic Reticulum Chaperone BiP/metabolism , Flavanones/pharmacology , Male , Mice , Mice, Inbred ICR , Neuroprotective Agents/pharmacology , Signal Transduction/drug effects , Transcription Factor CHOP/metabolism
9.
Brain ; 144(10): 3142-3158, 2021 11 29.
Article in English | MEDLINE | ID: mdl-34086871

ABSTRACT

Traumatic brain injury (TBI) leads to major brain anatomopathological damages underlined by neuroinflammation, oxidative stress and progressive neurodegeneration, ultimately leading to motor and cognitive deterioration. The multiple pathological events resulting from TBI can be addressed not by a single therapeutic approach, but rather by a synergistic biotherapy capable of activating a complementary set of signalling pathways and providing synergistic neuroprotective, anti-inflammatory, antioxidative, and neurorestorative activities. Human platelet lysate might fulfil these requirements as it is composed of a plethora of biomolecules readily accessible as a TBI biotherapy. In the present study, we tested the therapeutic potential of human platelet lysate using in vitro and in vivo models of TBI. We first prepared and characterized platelet lysate from clinical-grade human platelet concentrates. Platelets were pelletized, lysed by three freeze-thaw cycles, and centrifuged. The supernatant was purified by 56°C 30 min heat treatment and spun to obtain the heat-treated platelet pellet lysate that was characterized by ELISA and proteomic analyses. Two mouse models were used to investigate platelet lysate neuroprotective potential. The injury was induced by an in-house manual controlled scratching of the animals' cortex or by controlled cortical impact injury. The platelet lysate treatment was performed by topical application of 60 µl in the lesioned area, followed by daily 60 µl intranasal administration from Day 1 to 6 post-injury. Platelet lysate proteomics identified over 1000 proteins including growth factors, neurotrophins, and antioxidants. ELISA detected several neurotrophic and angiogenic factors at ∼1-50 ng/ml levels. We demonstrate, using two mouse models of TBI, that topical application and intranasal platelet lysate consistently improved mouse motor function in the beam and rotarod tests, mitigated cortical neuroinflammation, and oxidative stress in the injury area, as revealed by downregulation of pro-inflammatory genes and the reduction in reactive oxygen species levels. Moreover, platelet lysate treatment reduced the loss of cortical synaptic proteins. Unbiased proteomic analyses revealed that heat-treated platelet pellet lysate reversed several pathways promoted by both controlled cortical impact and cortical brain scratch and related to transport, postsynaptic density, mitochondria or lipid metabolism. The present data strongly support, for the first time, that human platelet lysate is a reliable and effective therapeutic source of neurorestorative factors. Therefore, brain administration of platelet lysate is a therapeutical strategy that deserves serious and urgent consideration for universal brain trauma treatment.


Subject(s)
Biological Therapy/methods , Blood Platelets/metabolism , Brain Injuries, Traumatic/metabolism , Brain Injuries, Traumatic/therapy , Administration, Intranasal , Animals , Brain Injuries, Traumatic/pathology , Cell Line, Tumor , Cerebral Cortex/metabolism , Cerebral Cortex/pathology , Humans , Male , Mice , Mice, Inbred C57BL
10.
Neurochem Res ; 46(9): 2317-2332, 2021 Sep.
Article in English | MEDLINE | ID: mdl-34097239

ABSTRACT

Besides motor disorder, cognitive dysfunction is also common in Parkinson's disease (PD). Essentially no causal therapy for cognitive dysfunction of PD exists at present. In this study, a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD was used to analyze the neuroprotective potential of orally administered silibinin, a proverbial hepatoprotective flavonoid derived from the herb milk thistle (Silybum marianum). Results demonstrated that silibinin administration significantly attenuated MPTP-induced cognitive impairment in behavioral tests. Nissl staining results showed that MPTP injection significantly increases the loss of neurons in the hippocampus. However, these mice were protected by oral administration of silibinin, accompanying reduction in the cell apoptosis in the hippocampus. The hippocampal aggregates of α-synuclein (α-syn) appeared in MPTP-injected mice, but were significantly decreased by silibinin treatment. MPTP injection induced oxidative stress, as evidenced by increased malondialdehyde (MDA) and decreased superoxide dismutase (SOD). The oxidative stress was alleviated by silibinin treatment. Mitochondrial disorder including the decline of mitochondrial membrane potential (MMP) was another signature in the hippocampus of MPTP-treated mice, accompanying increased mitochondrial fission and decreased fusion. Silibinin administration restored these mitochondrial disorders, as expected for the protection against MPTP injury. These findings suggest that silibinin has a potential to be further developed as a therapeutic candidate for cognitive dysfunction in PD.


Subject(s)
Mitochondria/drug effects , Mitochondrial Diseases/drug therapy , Neuroprotective Agents/therapeutic use , Parkinsonian Disorders/drug therapy , Silybin/therapeutic use , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine , Administration, Oral , Animals , Apoptosis/drug effects , Cerebral Cortex/drug effects , Cerebral Cortex/pathology , Cognitive Dysfunction/chemically induced , Cognitive Dysfunction/drug therapy , Cognitive Dysfunction/metabolism , Cognitive Dysfunction/pathology , Hippocampus/drug effects , Hippocampus/metabolism , Hippocampus/pathology , Male , Memantine/therapeutic use , Mice, Inbred C57BL , Mitochondrial Diseases/chemically induced , Mitochondrial Diseases/pathology , Morris Water Maze Test/drug effects , Neurons/drug effects , Neuroprotective Agents/administration & dosage , Open Field Test/drug effects , Oxidative Stress/drug effects , Parkinsonian Disorders/chemically induced , Parkinsonian Disorders/metabolism , Parkinsonian Disorders/pathology , Silybin/administration & dosage , alpha-Synuclein/metabolism
11.
Proc Natl Acad Sci U S A ; 118(21)2021 05 25.
Article in English | MEDLINE | ID: mdl-34011608

ABSTRACT

Loss-of-function mutations in chromatin remodeler gene ARID1A are a cause of Coffin-Siris syndrome, a developmental disorder characterized by dysgenesis of corpus callosum. Here, we characterize Arid1a function during cortical development and find unexpectedly selective roles for Arid1a in subplate neurons (SPNs). SPNs, strategically positioned at the interface of cortical gray and white matter, orchestrate multiple developmental processes indispensable for neural circuit wiring. We find that pancortical deletion of Arid1a leads to extensive mistargeting of intracortical axons and agenesis of corpus callosum. Sparse Arid1a deletion, however, does not autonomously misroute callosal axons, implicating noncell-autonomous Arid1a functions in axon guidance. Supporting this possibility, the ascending axons of thalamocortical neurons, which are not autonomously affected by cortical Arid1a deletion, are also disrupted in their pathfinding into cortex and innervation of whisker barrels. Coincident with these miswiring phenotypes, which are reminiscent of subplate ablation, we unbiasedly find a selective loss of SPN gene expression following Arid1a deletion. In addition, multiple characteristics of SPNs crucial to their wiring functions, including subplate organization, subplate axon-thalamocortical axon cofasciculation ("handshake"), and extracellular matrix, are severely disrupted. To empirically test Arid1a sufficiency in subplate, we generate a cortical plate deletion of Arid1a that spares SPNs. In this model, subplate Arid1a expression is sufficient for subplate organization, subplate axon-thalamocortical axon cofasciculation, and subplate extracellular matrix. Consistent with these wiring functions, subplate Arid1a sufficiently enables normal callosum formation, thalamocortical axon targeting, and whisker barrel development. Thus, Arid1a is a multifunctional regulator of subplate-dependent guidance mechanisms essential to cortical circuit wiring.


Subject(s)
Cerebral Cortex/metabolism , Chromatin/chemistry , Corpus Callosum/metabolism , DNA-Binding Proteins/genetics , Loss of Function Mutation , Thalamus/metabolism , Transcription Factors/genetics , Abnormalities, Multiple/genetics , Abnormalities, Multiple/metabolism , Abnormalities, Multiple/pathology , Animals , Cerebral Cortex/pathology , Chromatin/metabolism , Connectome , Corpus Callosum/pathology , DNA-Binding Proteins/deficiency , Face/abnormalities , Face/pathology , Gene Deletion , Gene Expression Regulation , Gray Matter/metabolism , Gray Matter/pathology , Hand Deformities, Congenital/genetics , Hand Deformities, Congenital/metabolism , Hand Deformities, Congenital/pathology , Humans , Intellectual Disability/genetics , Intellectual Disability/metabolism , Intellectual Disability/pathology , Mice , Mice, Transgenic , Micrognathism/genetics , Micrognathism/metabolism , Micrognathism/pathology , Neck/abnormalities , Neck/pathology , Neural Pathways/metabolism , Neural Pathways/pathology , Neurons/metabolism , Neurons/pathology , Thalamus/pathology , Transcription Factors/deficiency , Vibrissae/metabolism , Vibrissae/pathology , White Matter/metabolism , White Matter/pathology
12.
Hum Brain Mapp ; 42(10): 3202-3215, 2021 07.
Article in English | MEDLINE | ID: mdl-33955088

ABSTRACT

A major challenge in the cognitive training field is inducing broad, far-transfer training effects. Thus far, little is known about the neural mechanisms underlying broad training effects. Here, we tested a set of competitive hypotheses regarding the role of brain integration versus segregation underlying the broad training effect. We retrospectively analyzed data from a randomized controlled trial comparing neurocognitive effects of vision-based speed of processing training (VSOP) and an active control consisting of mental leisure activities (MLA) in older adults with MCI. We classified a subset of participants in the VSOP as learners, who showed improvement in executive function and episodic memory. The other participants in the VSOP (i.e., VSOP non-learners) and a subset of participants in the MLA (i.e., MLA non-learners) served as controls. Structural brain networks were constructed from diffusion tensor imaging. Clustering coefficients (CCs) and characteristic path lengths were computed as measures of segregation and integration, respectively. Learners showed significantly greater global CCs after intervention than controls. Nodal CCs were selectively enhanced in cingulate cortex, parietal regions, striatum, and thalamus. Among VSOP learners, those with more severe baseline neurodegeneration had greater improvement in segregation after training. Our findings suggest broad training effects are related to enhanced segregation in selective brain networks, providing insight into cognitive training related neuroplasticity.


Subject(s)
Amnesia , Cerebral Cortex/pathology , Cognitive Dysfunction , Cognitive Remediation , Nerve Net/pathology , Thalamus/pathology , Aged , Aged, 80 and over , Amnesia/diagnostic imaging , Amnesia/pathology , Amnesia/physiopathology , Amnesia/therapy , Cerebral Cortex/diagnostic imaging , Cognitive Dysfunction/diagnostic imaging , Cognitive Dysfunction/pathology , Cognitive Dysfunction/physiopathology , Cognitive Dysfunction/therapy , Corpus Striatum , Diffusion Tensor Imaging , Female , Humans , Male , Middle Aged , Nerve Net/diagnostic imaging , Neuronal Plasticity/physiology , Psychomotor Performance/physiology , Retrospective Studies , Thalamus/diagnostic imaging
13.
Hum Brain Mapp ; 42(12): 3950-3962, 2021 08 15.
Article in English | MEDLINE | ID: mdl-33978292

ABSTRACT

The structural covariance network (SCN) has provided a perspective on the large-scale brain organization impairment in the Alzheimer's Disease (AD) continuum. However, the successive structural impairment across brain regions, which may underlie the disrupted SCN in the AD continuum, is not well understood. In the current study, we enrolled 446 subjects with AD, mild cognitive impairment (MCI) or normal aging (NA) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The SCN as well as a casual SCN (CaSCN) based on Granger causality analysis were applied to the T1-weighted structural magnetic resonance images of the subjects. Compared with that of the NAs, the SCN was disrupted in the MCI and AD subjects, with the hippocampus and left middle temporal lobe being the most impaired nodes, which is in line with previous studies. In contrast, according to the 194 subjects with records on CSF amyloid and Tau, the CaSCN revealed that during AD progression, the CaSCN was enhanced. Specifically, the hippocampus, thalamus, and precuneus/posterior cingulate cortex (PCC) were identified as the core regions in which atrophy originated and could predict atrophy in other brain regions. Taken together, these findings provide a comprehensive view of brain atrophy in the AD continuum and the relationships among the brain atrophy in different regions, which may provide novel insight into the progression of AD.


Subject(s)
Aging/pathology , Alzheimer Disease/pathology , Cerebral Cortex/pathology , Cognitive Dysfunction/pathology , Disease Progression , Thalamus/pathology , Aged , Aged, 80 and over , Alzheimer Disease/diagnostic imaging , Atrophy/pathology , Cerebral Cortex/diagnostic imaging , Cognitive Dysfunction/diagnostic imaging , Female , Hippocampus/diagnostic imaging , Hippocampus/pathology , Humans , Magnetic Resonance Imaging , Male , Thalamus/diagnostic imaging
14.
Ann Clin Transl Neurol ; 8(6): 1183-1199, 2021 06.
Article in English | MEDLINE | ID: mdl-33949799

ABSTRACT

OBJECTIVE: Identification of brain regions susceptible to quantifiable atrophy in sporadic Creutzfeldt-Jakob disease (sCJD) should allow for improved understanding of disease pathophysiology and development of structural biomarkers that might be useful in future treatment trials. Although brain atrophy is not usually present by visual assessment of MRIs in sCJD, we assessed whether using voxel-based morphometry (VBM) can detect group-wise brain atrophy in sCJD. METHODS: 3T brain MRI data were analyzed with VBM in 22 sCJD participants and 26 age-matched controls. Analyses included relationships of regional brain volumes with major clinical variables and dichotomization of the cohort according to expected disease duration based on prion molecular classification (i.e., short-duration/Fast-progressors (MM1, MV1, and VV2) vs. long-duration/Slow-progressors (MV2, VV1, and MM2)). Structural equation modeling (SEM) was used to assess network-level interactions of atrophy between specific brain regions. RESULTS: sCJD showed selective atrophy in cortical and subcortical regions overlapping with all but one region of the default mode network (DMN) and the insulae, thalami, and right occipital lobe. SEM showed that the effective connectivity model fit in sCJD but not controls. The presence of visual hallucinations correlated with right fusiform, bilateral thalami, and medial orbitofrontal atrophy. Interestingly, brain atrophy was present in both Fast- and Slow-progressors. Worse cognition was associated with bilateral mesial frontal, insular, temporal pole, thalamus, and cerebellum atrophy. INTERPRETATION: Brain atrophy in sCJD preferentially affects specific cortical and subcortical regions, with an effective connectivity model showing strength and directionality between regions. Brain atrophy is present in Fast- and Slow-progressors, correlates with clinical findings, and is a potential biomarker in sCJD.


Subject(s)
Cerebellum/pathology , Cerebral Cortex/pathology , Creutzfeldt-Jakob Syndrome/pathology , Default Mode Network/pathology , Disease Progression , Nerve Net/pathology , Thalamus/pathology , Adult , Aged , Aged, 80 and over , Atrophy/pathology , Cerebellum/diagnostic imaging , Cerebral Cortex/diagnostic imaging , Cohort Studies , Creutzfeldt-Jakob Syndrome/diagnostic imaging , Creutzfeldt-Jakob Syndrome/physiopathology , Default Mode Network/diagnostic imaging , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Nerve Net/diagnostic imaging , Thalamus/diagnostic imaging
15.
J Neuroimaging ; 31(3): 524-531, 2021 05.
Article in English | MEDLINE | ID: mdl-33565204

ABSTRACT

BACKGROUND AND PURPOSE: Patients with pulmonary arterial hypertension (PAH) frequently present with anxiety, depression, autonomic, and cognitive deterioration, which may indicate brain changes in regions that control these functions. However, the precise regional brain-injury in sites that regulate cognitive, autonomic, and mood functions in PAH remains unclear. We examined the shifts in regional gray matter (GM) volume, using high-resolution T1-weighted images, and brain tissue alterations, using T2-relaxometry procedures, in PAH compared to healthy subjects. METHODS: We collected two high-resolution T1-weighted series, and proton-density and T2-weighted images using a 3.0-Tesla magnetic resonance imaging scanner from 9 PAH and 19 healthy subjects. Both high-resolution T1-weighted images were realigned and averaged, partitioned to GM tissue type, normalized to a common space, and smoothed. Using proton-density and T2-weighted images, T2-relaxation maps were calculated, normalized to a common space, and smoothed. Whole-brain GM volume and T2-relaxation maps were compared between PAH and controls using analysis of covariance (covariates, age, sex, and total-brain-volume; false discover rate corrections). RESULTS: Significantly decreased GM volumes, indicating tissue injury, emerged in multiple brain regions, including the hippocampus, insula, cerebellum, parahippocampus, temporal, frontal, and occipital gyri, cingulate, amygdala, and thalamus. Higher T2-relaxation values, suggesting tissue damage, appeared in the cerebellum, hippocampus, parahippocampus, frontal, lingual, and temporal and occipital gyri, and cingulate areas in PAH compared to healthy subjects. CONCLUSIONS: PAH patients showed significant GM injury and brain tissue changes in sites that regulate cognition, autonomic, and mood functions. These findings indicate a brain structural basis for functional deficits in PAH patients.


Subject(s)
Brain Injuries/pathology , Brain Mapping/methods , Brain/diagnostic imaging , Brain/pathology , Magnetic Resonance Imaging/methods , Pulmonary Arterial Hypertension/pathology , Adult , Amygdala/diagnostic imaging , Amygdala/pathology , Brain Injuries/diagnostic imaging , Cerebellum/diagnostic imaging , Cerebellum/pathology , Cerebral Cortex/diagnostic imaging , Cerebral Cortex/pathology , Cognition/physiology , Female , Gray Matter/pathology , Hippocampus/diagnostic imaging , Hippocampus/pathology , Humans , Male , Middle Aged , Pulmonary Arterial Hypertension/diagnostic imaging , Thalamus/diagnostic imaging , Thalamus/pathology
16.
Stroke ; 52(2): 687-698, 2021 01.
Article in English | MEDLINE | ID: mdl-33412903

ABSTRACT

BACKGROUND AND PURPOSE: Stroke disrupts neuronal functions in both local and remotely connected regions, leading to network-wide deficits that can hinder recovery. The thalamus is particularly affected, with progressive development of neurodegeneration accompanied by inflammatory responses. However, the complexity of the involved inflammatory responses is poorly understood. Herein we investigated the spatiotemporal changes in the secondary degenerative thalamus after cortical stroke, using targeted transcriptome approach in conjunction with histology and flow cytometry. METHODS: Cortical ischemic stroke was generated by permanent occlusion of the left middle cerebral artery in male C57BL6J mice. Neurodegeneration, neuroinflammatory responses, and microglial activation were examined in naive and stroke mice at from poststroke days (PD) 1 to 84, in both ipsilesional somatosensory cortex and ipsilesional thalamus. NanoString neuropathology panel (780 genes) was used to examine transcriptome changes at PD7 and PD28. Fluorescence activated cell sorting was used to collect CD11c+ microglia from ipsilesional thalamus, and gene expressions were validated by quantitative real-time polymerase chain reaction. RESULTS: Neurodegeneration in the thalamus was detected at PD7 and progressively worsened by PD28. This was accompanied by rapid microglial activation detected as early as PD1, which preceded the neurodegenerative changes. Transcriptome analysis showed higher number of differentially expressed genes in ipsilesional thalamus at PD28. Notably, neuroinflammation was the top activated pathway, and microglia was the most enriched cell type. Itgax (CD11c) was the most significantly increased gene, and its expression was highly detected in microglia. Flow-sorted CD11c+ microglia from degenerative thalamus indicated molecular signatures similar to neurodegenerative disease-associated microglia; these included downregulated Tmem119 and CX3CR1 and upregulated ApoE, Axl, LpL, CSF1, and Cst7. CONCLUSIONS: Our findings demonstrate the dynamic changes of microglia after stroke and highlight the importance of investigating stroke network-wide deficits. Importantly, we report the existence of a unique subtype of microglia (CD11c+) with neurodegenerative disease-associated microglia features in the degenerative thalamus after stroke.


Subject(s)
Cerebral Cortex/pathology , Microglia/pathology , Neurodegenerative Diseases/pathology , Stroke/complications , Stroke/pathology , Thalamic Diseases/etiology , Thalamic Diseases/pathology , Animals , CD11 Antigens/chemistry , Cerebrovascular Circulation , Encephalitis/pathology , Gene Expression Regulation , Male , Mice , Mice, Inbred C57BL , Somatosensory Cortex/pathology , Thalamus/pathology , Transcriptome
17.
Neuron ; 109(5): 788-804.e8, 2021 03 03.
Article in English | MEDLINE | ID: mdl-33497602

ABSTRACT

Gene Ontology analyses of autism spectrum disorders (ASD) risk genes have repeatedly highlighted synaptic function and transcriptional regulation as key points of convergence. However, these analyses rely on incomplete knowledge of gene function across brain development. Here we leverage Xenopus tropicalis to study in vivo ten genes with the strongest statistical evidence for association with ASD. All genes are expressed in developing telencephalon at time points mapping to human mid-prenatal development, and mutations lead to an increase in the ratio of neural progenitor cells to maturing neurons, supporting previous in silico systems biological findings implicating cortical neurons in ASD vulnerability, but expanding the range of convergent functions to include neurogenesis. Systematic chemical screening identifies that estrogen, via Sonic hedgehog signaling, rescues this convergent phenotype in Xenopus and human models of brain development, suggesting a resilience factor that may mitigate a range of ASD genetic risks.


Subject(s)
Autism Spectrum Disorder/genetics , Autism Spectrum Disorder/physiopathology , Cerebral Cortex/growth & development , Estrogens/physiology , Neurogenesis , Animals , Autism Spectrum Disorder/pathology , Cerebral Cortex/drug effects , Cerebral Cortex/pathology , Drug Evaluation, Preclinical , Estrogens/administration & dosage , Female , Gene Expression Regulation, Developmental , Humans , Male , Risk Factors , Signal Transduction , Xenopus
18.
Hum Brain Mapp ; 42(3): 753-765, 2021 02 15.
Article in English | MEDLINE | ID: mdl-33098363

ABSTRACT

This study aimed to explore brain structural and white matter microstructural reorganization in the early stage of tinnitus and identify brain alterations that contribute to its relief after 6 months of sound therapy. We studied 64 patients with idiopathic tinnitus, including 29 patients who were categorized into an effective group (EG) and 35 who were categorized into an ineffective group (IG) according to the 6-month follow-up improvement of the Tinnitus Handicap Inventory score, along with 63 healthy controls (HCs). All participants underwent structural and diffusion tensor imaging scanning on a 3-T magnetic resonance system. Differences in brain gray/white matter volume and white matter microstructure were evaluated using voxel-based morphometry analysis and tract-based spatial statistics among the three groups. Associations between brain reorganization and the improvement of tinnitus symptoms were also investigated. Compared with EG patients, IG patients experienced a significant gray matter volume decrease in the right middle frontal gyrus (MFG)/right precentral gyrus (PreCG). Meanwhile, both EG and IG patients showed significant changes (decrease or increase) in brain white matter integrity in the auditory-related or nonauditory-related white matter fiber tracts compared with HCs, while EG patients showed decreased axial diffusivity in the bilateral middle cerebellar peduncle (MCP) compared with IG patients. We combined the gray matter change of the MFG/PreCG and the white matter integrity of the bilateral MCP as an imaging indicator to evaluate the patient's prognosis and screen patients before treatment; this approach reached a sensitivity of 77.1% and a specificity of 82.8%. Our study suggests that there was a close relationship between brain reorganization and tinnitus improvement. The right MFG/PreCG and bilateral MCP may be indicators that can be used to predict prognoses in patients with idiopathic tinnitus and may be used to screen patients before sound therapy. These findings may provide new useful information that can lead to a better understanding of the tinnitus mechanism.


Subject(s)
Cerebral Cortex/pathology , Gray Matter/pathology , Middle Cerebellar Peduncle/pathology , Neuroimaging/standards , Outcome Assessment, Health Care , Tinnitus/pathology , Tinnitus/therapy , White Matter/pathology , Acoustic Stimulation , Adult , Cerebral Cortex/diagnostic imaging , Diffusion Tensor Imaging , Female , Follow-Up Studies , Gray Matter/diagnostic imaging , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Middle Cerebellar Peduncle/diagnostic imaging , Sensitivity and Specificity , Tinnitus/diagnostic imaging , White Matter/diagnostic imaging
19.
Int J Radiat Biol ; 97(3): 348-355, 2021.
Article in English | MEDLINE | ID: mdl-33320758

ABSTRACT

PURPOSE: The present study aims to investigate the radioprotective effect of melatonin (MEL) against early period brain damage caused by different dose rate beams in the experimental rat model. MATERIALS AND METHODS: Forty-eight Sprague Dawley rats were randomly divided into six groups; the control, only melatonin, low dose rate-radiotherapy (LDR-RT), high dose rate-radiotherapy (HDR-RT) groups and (LDR-RT) + MEL and (HDR-RT) + MEL radiotherapy plus melatonin groups. Each rat administered melatonin was given a dose of 10 mg/kg through intraperitoneal injection, 15 minutes before radiation exposure. The head and neck region of each rat in only radiotherapy and radiotherapy plus melatonin groups was irradiated with a single dose of 16 Gy in LDR-RT and HDR-RT beams. Rats in all groups were examined for histopathology and biochemistry analysis 10 days after radiotherapy. RESULTS: Comparing the findings for LDR-RT and HDR-RT only radiotherapy groups and the control group, there was a statistically significant difference in histopathological and biochemical parameters, however, melatonin administered in radiotherapy plus melatonin groups contributed improving these parameters (p < .05). There was no statistically significant difference between LDR-RT and HDR-RT beams (p > .05). CONCLUSIONS: It was concluded that melatonin applied before LDR-RT and HDR-RT radiotherapy protected early period radiotherapy-induced brain damage. The effects of clinically low and high dose beams on the cerebral cortex and cerebellum were investigated histopathologically for the first time. HDR beams can be safely applied in brain radiotherapy. However, more experimental rat and clinical studies are needed to explain the radiobiological uncertainties about the clinic dose rate on different cancerous and healthy tissues.


Subject(s)
Cerebellum/radiation effects , Cerebral Cortex/radiation effects , Melatonin/pharmacology , Radiation-Protective Agents/pharmacology , Radiotherapy/adverse effects , Animals , Cerebellum/pathology , Cerebral Cortex/pathology , Female , Radiotherapy Dosage , Rats , Rats, Sprague-Dawley
20.
Hum Brain Mapp ; 42(4): 1102-1115, 2021 03.
Article in English | MEDLINE | ID: mdl-33372704

ABSTRACT

Generalized tonic-clonic seizures (GTCS) are the severest and most remarkable clinical expressions of human epilepsy. Cortical, subcortical, and cerebellar structures, organized with different network patterns, underlying the pathophysiological substrates of genetic associated epilepsy with GTCS (GE-GTCS) and focal epilepsy associated with focal to bilateral tonic-clonic seizure (FE-FBTS). Structural covariance analysis can delineate the features of epilepsy network related with long-term effects from seizure. Morphometric MRI data of 111 patients with GE-GTCS, 111 patients with FE-FBTS and 111 healthy controls were studied. Cortico-striato-thalao-cerebellar networks of structural covariance within the gray matter were constructed using a Winner-take-all strategy with five cortical parcellations. Comparisons of structural covariance networks were conducted using permutation tests, and module effects of disease duration on networks were conducted using GLM model. Both patient groups showed increased connectivity of structural covariance relative to controls, mainly within the striatum and thalamus, and mostly correlated with the frontal, motor, and somatosensory cortices. Connectivity changes increased as a function of epilepsy durations. FE-FBTS showed more intensive and extensive gray matter changes with volumetric loss and connectivity increment than GE-GTCS. Our findings implicated cortico-striato-thalamo-cerebellar network changes at a large temporal scale in GTCS, with FE-FBTS showing more severe network disruption. The study contributed novel imaging evidence for understanding the different epilepsy syndromes associated with generalized seizures.


Subject(s)
Cerebellum , Cerebral Cortex , Corpus Striatum , Epilepsy, Tonic-Clonic , Epileptic Syndromes , Gray Matter , Nerve Net , Thalamus , Adult , Cerebellum/diagnostic imaging , Cerebellum/pathology , Cerebellum/physiopathology , Cerebral Cortex/diagnostic imaging , Cerebral Cortex/pathology , Cerebral Cortex/physiopathology , Connectome , Corpus Striatum/diagnostic imaging , Corpus Striatum/pathology , Corpus Striatum/physiopathology , Epilepsy, Tonic-Clonic/diagnostic imaging , Epilepsy, Tonic-Clonic/pathology , Epilepsy, Tonic-Clonic/physiopathology , Epileptic Syndromes/diagnostic imaging , Epileptic Syndromes/pathology , Epileptic Syndromes/physiopathology , Female , Gray Matter/diagnostic imaging , Gray Matter/pathology , Gray Matter/physiopathology , Humans , Magnetic Resonance Imaging , Male , Nerve Net/diagnostic imaging , Nerve Net/pathology , Nerve Net/physiopathology , Thalamus/diagnostic imaging , Thalamus/pathology , Thalamus/physiopathology , Young Adult
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