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The Journal of Neuroscience : the... Jan 2023Hexanucleotide repeat expansion (HRE) within is the most common genetic cause of frontotemporal dementia (FTD). Thalamic atrophy occurs in both sporadic and familial...
Hexanucleotide repeat expansion (HRE) within is the most common genetic cause of frontotemporal dementia (FTD). Thalamic atrophy occurs in both sporadic and familial FTD but is thought to distinctly affect HRE carriers. Separately, emerging evidence suggests widespread derepression of transposable elements (TEs) in the brain in several neurodegenerative diseases, including HRE-mediated FTD (C9-FTD). Whether TE activation can be measured in peripheral blood and how the reduction in peripheral expression observed in HRE carriers relates to atrophy and clinical impairment remain unknown. We used FreeSurfer software to assess the effects of HRE and clinical diagnosis ( = 78 individuals, male and female) on atrophy of thalamic nuclei. We also generated a novel, human, whole-blood RNA-sequencing dataset to determine the relationships among peripheral expression, TE activation, thalamic atrophy, and clinical severity ( = 114 individuals, male and female). We confirmed global thalamic atrophy and reduced expression in HRE carriers. Moreover, we identified disproportionate atrophy of the right mediodorsal lateral nucleus in HRE carriers and showed that expression associated with clinical severity, independent of thalamic atrophy. Strikingly, we found global peripheral activation of TEs, including the human endogenous LINE-1 element levels were associated with atrophy of multiple pulvinar nuclei, a thalamic region implicated in C9-FTD. Integration of peripheral transcriptomic and neuroimaging data from human HRE carriers revealed atrophy of specific thalamic nuclei, demonstrated that levels relate to clinical severity, and identified marked derepression of TEs, including , which predicted atrophy of FTD-relevant thalamic nuclei. Pathogenic repeat expansion in is the most frequent genetic cause of FTD and amyotrophic lateral sclerosis (ALS; C9-FTD/ALS). The clinical, neuroimaging, and pathologic features of C9-FTD/ALS are well characterized, whereas the intersections of transcriptomic dysregulation and brain structure remain largely unexplored. Herein, we used a novel radiogenomic approach to examine the relationship between peripheral blood transcriptomics and thalamic atrophy, a neuroimaging feature disproportionately impacted in C9-FTD/ALS. We confirmed reduction of in blood and found broad dysregulation of transposable elements-genetic elements typically repressed in the human genome-in symptomatic expansion carriers, which associated with atrophy of thalamic nuclei relevant to FTD. expression was also associated with clinical severity, suggesting that peripheral levels capture disease-relevant information.
Topics: Humans; Male; Female; Amyotrophic Lateral Sclerosis; Frontotemporal Dementia; C9orf72 Protein; DNA Transposable Elements; Atrophy
PubMed: 36446586
DOI: 10.1523/JNEUROSCI.1448-22.2022 -
Brain Sciences Nov 2022Fatigue is a debilitating and prevalent symptom of multiple sclerosis (MS). The thalamus is atrophied at an earlier stage of MS and although the role of the thalamus in...
Fatigue is a debilitating and prevalent symptom of multiple sclerosis (MS). The thalamus is atrophied at an earlier stage of MS and although the role of the thalamus in the pathophysiology of MS-related fatigue has been reported, there have been few studies on intra-thalamic changes. We investigated the alterations of thalamic nuclei volumes and the intrinsic thalamic network in people with MS presenting fatigue (F-MS). The network metrics comprised the clustering coefficient (Cp), characteristic path length (Lp), small-world index (σ), local efficiency (Eloc), global efficiency (Eglob), and nodal metrics. Volumetric analysis revealed that the right anteroventral, right central lateral, right lateral geniculate, right pulvinar anterior, left pulvinar medial, and left pulvinar inferior nuclei were atrophied only in the F-MS group. Furthermore, the F-MS group had significantly increased Lp compared to people with MS not presenting fatigue (NF-MS) (2.9674 vs. 2.4411, PAUC = 0.038). The F-MS group had significantly decreased nodal efficiency and betweenness centrality of the right mediodorsal medial magnocellular nucleus than the NF-MS group (false discovery rate corrected p < 0.05). The F-MS patients exhibited more atrophied thalamic nuclei, poorer network global functional integration, and disrupted right mediodorsal medial magnocellular nuclei interconnectivity with other nuclei. These findings might aid the elucidation of the underlying pathogenesis of MS-related fatigue.
PubMed: 36421863
DOI: 10.3390/brainsci12111538 -
Phylogenetic view of the compensatory mechanisms in motor and sensory systems after neuronal injury.Current Research in Neurobiology 2022Through phylogeny, novel neural circuits are added on top of ancient circuits. Upon injury of a novel circuit which enabled fine control, the ancient circuits can... (Review)
Review
Through phylogeny, novel neural circuits are added on top of ancient circuits. Upon injury of a novel circuit which enabled fine control, the ancient circuits can sometimes take over its function for recovery; however, the recovered function is limited according to the capacity of the ancient circuits. In this review, we discuss two examples of functional recovery after neural injury in nonhuman primate models. The first is the recovery of dexterous hand movements following damage to the corticospinal tract. The second is the recovery of visual function after injury to the primary visual cortex (V1). In the former case, the functions of the direct cortico-motoneuronal pathway, which specifically developed in higher primates for the control of fractionated digit movements, can be partly compensated for by other descending motor pathways mediated by rubrospinal, reticulospinal, and propriospinal neurons. However, the extent of recovery depends on the location of the damage and which motor systems take over its function. In the latter case, after damage to V1, which is highly developed in primates, either the direct pathway from the lateral geniculate nucleus to extrastriate visual cortices or that from the midbrain superior colliculus-pulvinar-extrastriate/parietal cortices partly takes over the function of V1. However, the state of visual awareness is no longer the same as in the intact state, which might reflect the limited capacity of the compensatory pathways in visual recognition. Such information is valuable for determining the targets of neuromodulatory therapies and setting treatment goals after brain and spinal cord injuries.
PubMed: 36304591
DOI: 10.1016/j.crneur.2022.100058 -
Brain Sciences Sep 2022Although subjective conscious experience and introspection have long been considered unscientific and banned from psychology, they are indispensable in scientific... (Review)
Review
Although subjective conscious experience and introspection have long been considered unscientific and banned from psychology, they are indispensable in scientific practice. These terms are used in scientific contexts today; however, their meaning remains vague, and earlier objections to the distinction between conscious experience and unconscious processing, remain valid. This also applies to the distinction between conscious visual perception and unconscious visual processing. Damage to the geniculo-striate pathway or the visual cortex results in a perimetrically blind visual hemifield contralateral to the damaged hemisphere. In some cases, cerebral blindness is not absolute. Patients may still be able to guess the presence, location, shape or direction of movement of a stimulus even though they report no conscious visual experience. This "unconscious" ability was termed "blindsight". The present paper demonstrates how the term conscious visual experience can be introduced in a logically precise and methodologically correct way and becomes amenable to scientific examination. The distinction between conscious experience and unconscious processing is demonstrated in the cases of conscious vision and blindsight. The literature on "blindsight" and its neurobiological basis is reviewed. It is shown that blindsight can be caused by residual functions of neural networks of the visual cortex that have survived cerebral damage, and may also be due to an extrastriate pathway via the midbrain to cortical areas such as areas V4 and MT/V5.
PubMed: 36291239
DOI: 10.3390/brainsci12101305 -
European Radiology Mar 2023The clinical impact of brain microstructural abnormalities in multiple sclerosis (MS) remains elusive. We aimed to characterize the topography of longitudinal relaxation...
OBJECTIVES
The clinical impact of brain microstructural abnormalities in multiple sclerosis (MS) remains elusive. We aimed to characterize the topography of longitudinal relaxation rate (R1) and quantitative susceptibility (χ) changes, as indices of iron and myelin, together with brain atrophy, and to clarify their contribution to cognitive and motor disability in MS.
METHODS
In this cross-sectional study, voxel-based morphometry, and voxel-based quantification analyses of R1 and χ maps were conducted in gray matter (GM) and white matter (WM) of 117 MS patients and 53 healthy controls. Voxel-wise between-group differences were assessed with nonparametric permutation tests, while correlations between MRI metrics and clinical variables (global disability, cognitive and motor performance) were assessed both globally and voxel-wise within clusters emerging from the between-group comparisons.
RESULTS
MS patients showed widespread R1 decrease associated with more limited modifications of χ, with atrophy mainly involving deep GM, posterior and infratentorial regions (p < 0.02). While R1 and χ showed a parallel reduction in several WM tracts (p < 0.001), reduced GM R1 values (p < 0.001) were associated with decreased thalamic χ (p < 0.001) and small clusters of increased χ in the caudate nucleus and prefrontal cortex (p < 0.02). In addition to the atrophy, χ values in the cingulum and corona radiata correlated with global disability and motor performance, while focal demyelination correlated with cognitive performance (p < 0.04).
CONCLUSIONS
We confirmed the presence of widespread R1 changes, involving both GM and WM, and atrophy in MS, with less extensive modifications of tissue χ. While atrophy and χ changes are related to global and motor disability, R1 changes are meaningful correlates of cognition.
KEY POINTS
• Compared to healthy controls, multiple sclerosis patients showed R1 and χ changes suggestive of iron increase within the basal ganglia and reduced iron and myelin content within (subnuclei of) the thalamus. • Thalamic volume and χ changes significantly predicted clinical disability, as well as pulvinar R1 and χ changes, independently from atrophy. • Atrophy-independent R1 and χ changes, suggestive of thalamic iron and myelin depletion, may represent a sensitive marker of subclinical inflammation.
Topics: Humans; Multiple Sclerosis; Myelin Sheath; Cross-Sectional Studies; Iron; Disabled Persons; Motor Disorders; Brain; Gray Matter; Magnetic Resonance Imaging; Brain Diseases; Atrophy
PubMed: 36241917
DOI: 10.1007/s00330-022-09154-y -
Journal of Neural Transmission (Vienna,... Dec 2022Prior studies indicate more severe brainstem cholinergic deficits in Progressive Supranuclear Palsy (PSP) compared to Parkinson's disease (PD), but the extent and...
Prior studies indicate more severe brainstem cholinergic deficits in Progressive Supranuclear Palsy (PSP) compared to Parkinson's disease (PD), but the extent and topography of subcortical deficits remains poorly understood. The objective of this study is to investigate differential cholinergic systems changes in progressive supranuclear palsy (PSP, n = 8) versus Parkinson's disease (PD, n = 107) and older controls (n = 19) using vesicular acetylcholine transporter [F]-fluoroethoxybenzovesamicol (FEOBV) positron emission tomography (PET). A whole-brain voxel-based PET analysis using Statistical Parametric Mapping (SPM) software (SPM12) for inter-group comparisons using parametric [F]-FEOBV DVR images. Voxel-based analyses showed lower FEOBV binding in the tectum, metathalamus, epithalamus, pulvinar, bilateral frontal opercula, anterior insulae, superior temporal pole, anterior cingulum, some striatal subregions, lower brainstem, and cerebellum in PSP versus PD (p < 0.05; false discovery rate-corrected). More severe and diffuse reductions were present in PSP vs controls. Higher frequency of midbrain cholinergic losses was seen in PSP compared to the PD participants using 5th percentile normative cut-off values (χ = 4.12, p < 0.05). When compared to PD, these findings suggested disease-specific cholinergic vulnerability in the tectum, striatal cholinergic interneurons, and projections from the pedunculopontine nucleus, medial vestibular nucleus, and the cholinergic forebrain in PSP.
Topics: Humans; Supranuclear Palsy, Progressive; Parkinson Disease; Positron-Emission Tomography; Pedunculopontine Tegmental Nucleus; Cholinergic Agents
PubMed: 36222971
DOI: 10.1007/s00702-022-02547-9 -
Frontiers in Neuroscience 2022An increasing number of studies have shown that the functional interactions between the thalamus and cerebral cortices play an important role in cognitive function and...
An increasing number of studies have shown that the functional interactions between the thalamus and cerebral cortices play an important role in cognitive function and are influenced by age. Previous studies have revealed age-related changes in the thalamo-cortical system within individuals, while neglecting differences between individuals. Here, we characterized inter-subject functional correlation (ISFC) between the thalamus and several cortical brain networks in 500 healthy participants aged 18-87 years old from the Cambridge Centre for Aging and Neuroscience (Cam-CAN) cohort using movie-watching state fMRI data. General linear models (GLM) were performed to assess age-related changes in ISFC of thalamo-cortical networks and the relationship between ISFC and fluid intelligence. We found significant age-related decreases in ISFC between the posterior thalamus (e.g., ventral posterior nucleus and pulvinar) and the attentional network, sensorimotor network, and visual network (FDR correction with < 0.05). Meanwhile, the ISFC between the thalamus (mainly the mediodorsal nucleus and ventral thalamic nuclei) and higher-order cortical networks, including the default mode network, salience network and control network, showed complex changes with age. Furthermore, the altered ISFC of thalamo-cortical networks was positively correlated with decreased fluid intelligence (FDR correction with < 0.05). Overall, our results provide further evidence that alterations in the functional integrity of the thalamo-cortical system might play an important role in cognitive decline during aging.
PubMed: 36213738
DOI: 10.3389/fnins.2022.984571 -
NeuroImage. Clinical 2022The thalamus seems to be important in the development of postoperative delirium (POD) as previously revealed by volumetric and diffusion magnetic resonance imaging. In... (Observational Study)
Observational Study
BACKGROUND
The thalamus seems to be important in the development of postoperative delirium (POD) as previously revealed by volumetric and diffusion magnetic resonance imaging. In this observational cohort study, we aimed to further investigate the impact of the microstructural integrity of the thalamus and thalamic nuclei on the incidence of POD by applying diffusion kurtosis imaging (DKI).
METHODS
Older patients without dementia (≥65 years) who were scheduled for major elective surgery received preoperative DKI at two study centres. The DKI metrics fractional anisotropy (FA), mean diffusivity (MD), mean kurtosis (MK) and free water (FW) were calculated for the thalamus and - as secondary outcome - for eight predefined thalamic nuclei and regions. Low FA and MK and, conversely, high MD and FW, indicate aspects of microstructural abnormality. To assess patients' POD status, the Nursing Delirium Screening Scale (Nu-DESC), Richmond Agitation Sedation Scale (RASS), Confusion Assessment Method (CAM) and Confusion Assessment Method for the Intensive Care Unit score (CAM-ICU) and chart review were applied twice a day after surgery for the duration of seven days or until discharge. For each metric and each nucleus, logistic regression was performed to assess the risk of POD.
RESULTS
This analysis included the diffusion scans of 325 patients, of whom 53 (16.3 %) developed POD. Independently of age, sex and study centre, thalamic MD was statistically significantly associated with POD [OR 1.65 per SD increment (95 %CI 1.17 - 2.34) p = 0.004]. FA (p = 0.84), MK (p = 0.41) and FW (p = 0.06) were not significantly associated with POD in the examined sample. Exploration of thalamic nuclei also indicated that only the MD in certain areas of the thalamus was associated with POD. MD was increased in bilateral hemispheres, pulvinar nuclei, mediodorsal nuclei and the left anterior nucleus.
CONCLUSIONS
Microstructural abnormalities of the thalamus and thalamic nuclei, as reflected by increased MD, appear to predispose to POD. These findings affirm the thalamus as a region of interest in POD research.
Topics: Humans; Aged; Emergence Delirium; Cohort Studies; Prospective Studies; Diffusion Tensor Imaging; Thalamic Nuclei; Thalamus
PubMed: 36201951
DOI: 10.1016/j.nicl.2022.103208 -
Human Brain Mapping Feb 2023Specific thalamic nuclei are implicated in healthy aging and age-related neurodegenerative diseases. However, few methods are available for robust automated segmentation...
Specific thalamic nuclei are implicated in healthy aging and age-related neurodegenerative diseases. However, few methods are available for robust automated segmentation of thalamic nuclei. The threefold aims of this study were to validate the use of a modified thalamic nuclei segmentation method on standard T1 MRI data, to apply this method to quantify age-related volume declines, and to test functional meaningfulness by predicting performance on motor testing. A modified version of THalamus Optimized Multi-Atlas Segmentation (THOMAS) generated 22 unilateral thalamic nuclei. For validation, we compared nuclear volumes obtained from THOMAS parcellation of white-matter-nulled (WMn) MRI data to T1 MRI data in 45 participants. To examine the effects of age/sex on thalamic nuclear volumes, T1 MRI available from a second data set of 121 men and 117 women, ages 20-86 years, were segmented using THOMAS. To test for functional ramifications, composite regions and constituent nuclei were correlated with Grooved Pegboard test scores. THOMAS on standard T1 data showed significant quantitative agreement with THOMAS from WMn data, especially for larger nuclei. Sex differences revealing larger volumes in men than women were accounted for by adjustment with supratentorial intracranial volume (sICV). Significant sICV-adjusted correlations between age and thalamic nuclear volumes were detected in 20 of the 22 unilateral nuclei and whole thalamus. Composite Posterior and Ventral regions and Ventral Anterior/Pulvinar nuclei correlated selectively with higher scores from the eye-hand coordination task. These results support the use of THOMAS for standard T1-weighted data as adequately robust for thalamic nuclear parcellation.
Topics: Humans; Male; Female; Young Adult; Adult; Middle Aged; Aged; Aged, 80 and over; Thalamic Nuclei; Thalamus; Aging; White Matter; Magnetic Resonance Imaging
PubMed: 36181510
DOI: 10.1002/hbm.26088 -
Frontiers in Pain Research (Lausanne,... 2022Chronic neuropathic pain refractory to medical management can be debilitating and can seriously affect one's quality of life. The interest of ablative surgery for the... (Review)
Review
Chronic neuropathic pain refractory to medical management can be debilitating and can seriously affect one's quality of life. The interest of ablative surgery for the treatment or palliation of chronic neuropathic pain, cancer-related or chemotherapy-induced, has grown. Numerous regions along the nociceptive pathways have been prominent targets including the various nuclei of the thalamus. Traditional targets include the medial pulvinar, central median, and posterior complex thalamic nuclei. However, there has been little research regarding the role of the central lateral nucleus. In this paper, we aim to summarize the anatomy, pathophysiology, and patient experiences of the central lateral thalamotomy.
PubMed: 36176711
DOI: 10.3389/fpain.2022.999891