Thalamic Atrophy Research Articles

Thalamohippocampal atrophy in focal epilepsy of unknown cause at the time of diagnosis.

Patients with chronic focal epilepsy may have atrophy of brain structures important for the generation and maintenance of seizures. However, little research has been conducted in patients with newly diagnosed focal epilepsy (NDfE), despite it being a crucial point in time for understanding the underlying biology of the disorder. We aimed to determine whether patients with NDfE show evidence of volumetric abnormalities of subcortical structures. Eighty-two patients with NDfE and 40 healthy controls underwent magnetic resonance imaging scanning using a standard clinical protocol. Volume estimation of the left and right hippocampus, thalamus, caudate nucleus, putamen and cerebral hemisphere was performed for all participants and normalised to whole brain volume. Volumes lower than two standard deviations below the control mean were considered abnormal. Volumes were analysed with respect to patient clinical characteristics, including treatment outcome 12months after diagnosis. Volume of the left hippocampus (p(FDR-corr) =0.04) and left (p(FDR-corr) =0.002) and right (p(FDR-corr) =0.04) thalamus was significantly smaller in patients relative to controls. Relative to the normal volume limits in controls, 11% patients had left hippocampal atrophy, 17% had left thalamic atrophy and 9% had right thalamic atrophy. We did not find evidence of a relationship between volumes and future seizure control or with other clinical characteristics of epilepsy. Volumetric abnormalities of structures known to be important for the generation and maintenance of focal seizures are established at the time of epilepsy diagnosis and are not necessarily a result of the chronicity of the disorder.

Thalamic Atrophy Plays a Crucial Role in the Effect of Asymptomatic Carotid Stenosis on Cognitive Impairment.

PurposeOur objectives were to assess the abnormalities of subcortical nuclei by combining volume and shape analyses and potential association with cognitive impairment.Patients and MethodsTwenty-nine patients with severe ACS of the unilateral internal carotid artery and 31 controls were enrolled between January 2017 to August 2018. All participants underwent a comprehensive neuropsychological evaluation, blood lipid biochemical measurements, and structural magnetic resonance imaging (MRI) to measure subcortical volumes and sub-regional shape deformations. Basic statistics, correction for multiple comparisons. Seventeen ACS patients underwent carotid endarterectomy (CEA) within one week after baseline measurements, cognitive assessments and MRI scans were repeated 6 months after CEA.ResultsThe ACS patients had higher apolipoprotein B/apolipoprotein A1 (ApoB/ApoA1) ratio and worse performance in all cognitive domains than controls. Moreover, the ACS patients showed more profound thalamic atrophy assessed by shape and volume analysis, especially in the medial dorsal thalamus. No significant differences were found in other subcortical nuclei after multiple comparisons correction. At baseline, thalamic atrophy correlated with cognitive impairment and ApoB/ApoA1 ratio. Furthermore, mediation analysis at baseline showed that the association of carotid intima-media thickness with executive functioning was mediated by thalamic volume. After CEA, cognitive improvement and increase in the bilateral medial dorsal thalamic volume were observed.ConclusionOur study identified the distinct atrophy of subcortical nuclei and their association with cognition in patients with ACS. Assessments of the thalamus by volumetric and shape analysis may provide an early marker for cerebral ischemia and reperfusion after CEA.

Phenylalanine Effects on Brain Function in Adult Phenylketonuria

To evaluate the relationship between circulating phenylalanine and brain function as well as neuropsychiatric symptoms in adults with phenylketonuria. In this prospective cross-sectional study, early-treated patients with phenylketonuria older than 30 years and age- and sex-matched controls were included. Extensive neurologic evaluation, neuropsychological and behavioral testing, sensory and motor evoked potentials, and MRI were performed. CSF concentrations of neurodegenerative markers were evaluated in addition in a subset of 10 patients. Nineteen patients with phenylketonuria (median age 41 years) with different phenylalanine levels (median 873 μmol/L) entered the study. They showed higher prevalence of neurologic symptoms, cognitive and behavioral abnormalities, autonomic dysfunction, alterations in neurophysiologic measures, and atrophy in putamen and right thalamus compared to controls. In CSF, patients with phenylketonuria exhibited higher β-amyloid 1-42 (p = 0.003), total tau (p < 0.001), and phosphorylated tau (p = 0.032) levels compared to controls. Plasma phenylalanine levels highly correlated with the number of failed neuropsychological tests (r = 0.64, p = 0.003), neuropsychiatric symptoms (r = 0.73, p < 001), motor evoked potential latency (r = 0.48, p = 0.030), and parietal lobe atrophy. Our study provides strong evidence for a correlation between phenylalanine levels and clinical, neuropsychological, neurophysiologic, biochemical, and imaging alterations in adult patients with phenylketonuria.

The significance of thalamic nuclei degeneration in relapsing-remitting and secondary progressive multiple sclerosis: results of neuropsychological and morphometry studies

Introduction. The thalamus is a 'transmitting organ' that is involved in a wide range of neurological functions. Its functional uniqueness and high sensitivity to damage during the earliest stages of multiple sclerosis (MS) make the thalamus a kind of barometer of diffuse brain damage in MS. The aim of the study was to examine the structural and functional changes in the thalamus and its subregions using magnetic resonance morphometry and to determine their clinical significance in different types of MS. Materials and methods. We examined 68 patients with relapsing-remitting (n = 40) and secondary progressive (n = 28) MS. The control group consisted of 10 healthy people matched for age and gender. The Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Severity Score (MSSS) were used to assess the patients' neurological status. The cognitive and mental domains were tested using the MMSE, FAB, MoCA, SDMT, Beck's test, and HADS. All patients underwent a brain MRI and morphometric evaluation of the obtained data using the FreeSurfer 6.0 software. Results. The size of the thalamic pulvinar in relapsing-remitting MS was reduced on the left (M (anterior : posterior) = 186.6 : 149.4 mm 3 ) compared with the controls (229.5 : 187.5 mm 3 ) and on the right (219.5 : 187.1 mm 3 ) compared with the controls (261.6 : 240.5 mm 3 ; p < 0.05). The size of the left thalamic nuclei was significantly reduced in secondary progressive MS when compared with relapsing-remitting MS and the controls. EDSS was correlated with a decrease in the dimensions of the geniculate nucleus on the left (r = –0.48) and the pulvinar nuclei on the left (r = 0.46–0.54). Standard neuropsychological scales correlated with the size of the medial dorsal nucleus (r (MMSE:FAB:MoCA) = 0.51; 0.45; 0.59). The greatest correlation was between the SDMT test (written section) and the left ventral anterior nucleus (r = 0.71). Conclusion. The obtained data indicate that thalamic nuclei atrophy plays a significant role in the progression of disability and cognitive disorders in MS. Mag- netic resonance morphometry of the thalamic nuclei can be considered an important marker and predictor of MS progression.

MRI data confirm the selective involvement of thalamic and amygdalar nuclei in amyotrophic lateral sclerosis and primary lateral sclerosis.

A standardised imaging protocol was implemented to evaluate disease burden in specific thalamic and amygdalar nuclei in 133 carefully phenotyped and genotyped motor neuron disease patients. “Switchboard malfunction in motor neuron diseases: selective pathology of thalamic nuclei in amyotrophic lateral sclerosis and primary lateral sclerosis” [1] “Amygdala pathology in amyotrophic lateral sclerosis and primary lateral sclerosis” [2] Raw volumetric data, group comparisons, effect sizes and percentage change are presented. Both ALS and PLS patients exhibited focal thalamus atrophy in ventral lateral and ventral anterior regions revealing extrapyramidal motor degeneration. Reduced accessory basal nucleus and cortical nucleus volumes were noted in the amygdala of C9orf72 negative ALS patients compared to healthy controls. ALS patients carrying the GGGGCC hexanucleotide repeats in C9orf72 exhibited preferential pathology in the mediodorsal-paratenial-reuniens thalamic nuclei and in the lateral nucleus and cortico-amygdaloid transition area of the amygdala. Considerable thalamic atrophy was observed in the sensory nuclei and lateral geniculate region of PLS patients. Our data demonstrate genotype-specific patterns of thalamus and amygdala involvement in ALS and a distinct disease-burden pattern in PLS. The dataset may be utilised for validation purposes, meta-analyses and the interpretation of thalamic and amygdalar profiles from other ALS genotypes.

Automated thalamic nuclei segmentation using multi-planar cascaded convolutional neural networks

PurposeTo develop a fast and accurate convolutional neural network based method for segmentation of thalamic nuclei. MethodsA cascaded multi-planar scheme with a modified residual U-Net architecture was used to segment thalamic nuclei on conventional and white-matter-nulled (WMn) magnetization prepared rapid gradient echo (MPRAGE) data. A single network was optimized to work with images from healthy controls and patients with multiple sclerosis (MS) and essential tremor (ET), acquired at both 3 T and 7 T field strengths. WMn-MPRAGE images were manually delineated by a trained neuroradiologist using the Morel histological atlas as a guide to generate reference ground truth labels. Dice similarity coefficient and volume similarity index (VSI) were used to evaluate performance. Clinical utility was demonstrated by applying this method to study the effect of MS on thalamic nuclei atrophy. ResultsSegmentation of each thalamus into twelve nuclei was achieved in under a minute. For 7 T WMn-MPRAGE, the proposed method outperforms current state-of-the-art on patients with ET with statistically significant improvements in Dice for five nuclei (increase in the range of 0.05–0.18) and VSI for four nuclei (increase in the range of 0.05–0.19), while performing comparably for healthy and MS subjects. Dice and VSI achieved using 7 T WMn-MPRAGE data are comparable to those using 3 T WMn-MPRAGE data. For conventional MPRAGE, the proposed method shows a statistically significant Dice improvement in the range of 0.14–0.63 over FreeSurfer for all nuclei and disease types. Effect of noise on network performance shows robustness to images with SNR as low as half the baseline SNR. Atrophy of four thalamic nuclei and whole thalamus was observed for MS patients compared to healthy control subjects, after controlling for the effect of parallel imaging, intracranial volume, gender, and age (p < 0.004). ConclusionThe proposed segmentation method is fast, accurate, performs well across disease types and field strengths, and shows great potential for improving our understanding of thalamic nuclei involvement in neurological diseases.

Dynamic Regional Brain Atrophy Rates in the First Year After Ischemic Stroke.

Brain atrophy can be regarded as an end-organ effect of cumulative cardiovascular risk factors. Accelerated brain atrophy is described following ischemic stroke, but it is not known whether atrophy rates vary over the poststroke period. Examining rates of brain atrophy allows the identification of potential therapeutic windows for interventions to prevent poststroke brain atrophy. We charted total and regional brain volume and cortical thickness trajectories, comparing atrophy rates over 2 time periods in the first year after ischemic stroke: within 3 months (early period) and between 3 and 12 months (later period). Patients with first-ever or recurrent ischemic stroke were recruited from 3 Melbourne hospitals at 1 of 2 poststroke time points: within 6 weeks (baseline) or 3 months. Whole-brain 3T magnetic resonance imaging was performed at 3 time points: baseline, 3 months, and 12 months. Eighty-six stroke participants completed testing at baseline; 125 at 3 months (76 baseline follow-up plus 49 delayed recruitment); and 113 participants at 12 months. Their data were compared with 40 healthy control participants with identical testing. We examined 5 brain measures: hippocampal volume, thalamic volume, total brain and hemispheric brain volume, and cortical thickness. We tested whether brain atrophy rates differed between time points and groups. A linear mixed-effect model was used to compare brain structural changes, including age, sex, years of education, a composite cerebrovascular risk factor score, and total intracranial volume as covariates. Atrophy rates were greater in stroke than control participants. Ipsilesional hemispheric, hippocampal, and thalamic atrophy rates were 2 to 4 times greater in the early versus later period. Regional atrophy rates vary over the first year after stroke. Rapid brain volume loss in the first 3 months after stroke may represent a potential window for intervention. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02205424.

Neuronal Ceroid Lipofuscinosis: Clinical and Laboratory Profile in Children from Tertiary Care Centre in South India.

Neuronal ceroid Lipofuscinosis (NCL), inherited disorders of lysosomal storage disorders, constitute the most common progressive encephalopathies with an incidence of 1.3 to 7 in 100,000 live births. We reported clinical, electrophysiological, radiological, ultrastructural, and molecular genetic features of NCL. This is a retrospective review, in a tertiary care center from January 2016 to December 2019. All children with clinical features of NCL and confirmed by pathogenic mutation and/or enzyme assay were included. A total of 60 children (male:female = 3:1) were studied. The commonest type was CLN 2 (41.7%). Neuroregression, seizures, and ataxia were present in all cases. Retinal arterial attenuation was seen in 38.33% cases. Magnetic resonance imaging (MRI) brain was abnormal in all patients, thalamic and caudate nucleus atrophy common in CLN1 (62%). Electroencephalography was abnormal in all children, but photoparoxysmal response at low intermittent photic stimulation frequencies was seen in four children of CLN2. Electron microscopy done in 43 children revealed abnormal inclusions in 20 (46.52%) children. Enzyme study showed low levels in 36 (78%) out of 46 cases. Of these, 21 had low tripeptidyl peptidase and 15 had low palmitoyl protein thioesterase levels. Molecular testing done in 26 cases showed pathogenic variant in 23 (88%) cases. Infantile onset with thalamic atrophy on MRI is common in CLN1 and refractory epilepsy, visual impairment and specific EEG changes are common in CLN2. These features are helpful in selecting enzyme assay for CLN1 versus CLN2. Electron microscopy helped in the diagnosis and genetic testing in subtyping. Thus, a multimode approach played a role in the diagnosis of NCL.

Thalamic Atrophy Predicts 5-Year Disability Progression in Multiple Sclerosis.

Purpose: Thalamus is among the first brain regions to become atrophic in multiple sclerosis (MS). We studied whether thalamic atrophy predicts disability progression at 5 years in a cohort of Finnish MS patients.Methods: Global and regional brain volumes were measured from 24 newly diagnosed relapsing MS (RMS) patients 6 months after initiation of therapy and from 36 secondary progressive MS (SPMS) patients. The patients were divided into groups based on baseline whole brain parenchymal (BP) and thalamic atrophy. Standard scores (z scores) were computed by comparing individual brain volumes with healthy controls. A z score cutoff of −1.96 was applied to separate atrophic from normal brain volumes. The Expanded Disability Status Scale (EDSS), brain magnetic resonance imaging (MRI) findings, and relapses were assessed at baseline and at 2 years and EDSS progression at 5 years.Results: Baseline thalamus volume predicted disability in 5 years in a logistic regression model (p = 0.031). At 5 years, EDSS was same or better in 12 of 18 patients with no brain atrophy at baseline but only in 5 of 18 patients with isolated thalamic atrophy [odds ratio (OR) (95% CI) = 5.2 (1.25, 21.57)]. The patients with isolated thalamic atrophy had more escalations of disease-modifying therapies during follow-up.Conclusion: Patients with thalamic atrophy at baseline were at a higher risk for 5-year EDSS increase than patients with no identified brain atrophy. Brain volume measurement at a single time point could help predict disability progression in MS and complement clinical and routine MRI evaluation in therapeutic decision-making.

Regional White Matter Atrophy Correlates with Spike Activity in Encephalopathy Related to Status Epilepticus During Slow Sleep (ESES) After Early Thalamic Lesions.

Encephalopathy related to Status Epilepticus during slow Sleep (ESES) is an age-related, epileptic syndrome, which associates cognitive/behavioral disturbances with a peculiar pattern of spike activity. One promising line of research is the study of ESES in cases of early thalamic lesions. We studied 7 ESES patients with unilateral thalamic lesions using magnetic resonance imaging to assess regional white matter (WM) and thalamic nuclei volume differences, and long-term electroencephalogram recordings to localize the epileptogenic cortex. N170 event-related potentials were used to demonstrate the dysfunctional character of the WM abnormalities. Diffusion-weighted images in a subset of 4 patients were used to parcellate the thalamus and evaluate volume asymmetries, based on cortical connectivity. Large WM regional atrophy in the hemisphere with the thalamic lesion was associated with both cortical dysfunction and epileptic activity. A correlation was demonstrated between lesions in the pulvinar and the mediodorsal thalamic nuclei and WM atrophy of the corresponding cortical projection areas. We propose that these abnormalities are due to the widespread structural disconnection produced by the thalamic lesions associated to a yet unknown age-dependent factor. Further exploration of WM regional atrophy association with the spike activity in other etiologies could lend support to the cortical disconnection role in ESES genesis.

Thalamic atrophy correlates with dysfunctional impulsivity in multiple sclerosis

BackgroundRecent studies highlight the central role of thalamic atrophy in Multiple Sclerosis (MS) related disorders. Behavioural aspects of (MS) are rarely explored but their investigation is of high interest. Dickman's Impulsiveness Inventory (DII) allows distinguishing functional impulsivity (FI) which is the ability to react fast and properly when necessary, from dysfunctional impulsivity (DI) which is a behavioural symptom corresponding to the tendency to miss forethought before acting. ObjectiveThis paper aims to explore whether MS patients show significantly high and pathological DI, and to evaluate the impulsivity frequency in the different forms of MS including at the early stage of the Clinically Isolated Syndrome. Furthermore, this study focused on the factors that may induce abnormal impulsivity, and the link between thalamic atrophy and dysfunctional impulsivity in patients with MS. Methods95 patients with demyelinating diseases including 21 Clinically Isolated Syndrome (CIS), 30 Relapsing-Remitting MS (RRMS), 23 Secondary Progressive MS (SPMS) and 21 Primary Progressive MS (PPMS) were prospectively recruited, and covered by extensive cognitive evaluation including the BCCogSEP (French version of the Brief Repeatable Battery for Neurological disease), the CSCT (Computerized Speed Cognitive Test) for processing speed of information (PSI), the DII to measure FI and DI, the Fast BDI to evaluate depression, and the EMIF-SEP scale to study physical, cognitive and social fatigues. 3D T2-FLAIR and 3D T1-weighted MRI were analyzed using automatic segmentation tools to quantify the T2 lesion load and to measure the whole and regional brain atrophy. Results7% showed a pathologically high DI. The level of DI tended to differ significantly depending on the MS phenotype. There was no significant difference between RRMS, SPMS and PPMS, but RRMS showed significantly higher DI than CIS patients. Cognitive fatigue (r:-0.27, p<.01), depression (r:-0.21, p=.04) but mainly PSI (r:.33, p<.001) showed a significant correlation with DI. Among the brain regions of interest, the strongest significant correlation with DI was with thalamic atrophy (r:.33, p<.001). ConclusionSome MS patients show a pathologically high DI, mainly RRMS compared to CIS. Previous study highlighted impulsive traits in MS patients only in relation with the presence of depression. The present study demonstrates that depression tends to correlate with DI, but that cognitive fatigue, and mainly slowing of PSI, which is the most early and severe cognitive impairment in MS, have a stronger impact on the rise of pathological impulsive behaviour. DI in MS is linked to frontal regions but even more strongly to thalamus atrophy. This is in line with the hypothesis of a disconnection syndrome in MS that causes cognitive impairment to trigger and could have the same impact on behaviour. Hence, impulsive behaviour should be evaluated and taken into account in the care of patients with MS.

The TOTEM RRMS (Testosterone Treatment on neuroprotection and Myelin Repair in Relapsing Remitting Multiple Sclerosis) trial: study protocol for a randomized, double-blind, placebo-controlled trial

BackgroundCentral nervous system damage in multiple sclerosis (MS) is responsible for serious deficiencies. Current therapies are focused on the treatment of inflammation; however, there is an urgent need for innovative therapies promoting neuroregeneration, particularly myelin repair.It is demonstrated that testosterone can act through neural androgen receptors and several clinical observations stimulated an interest in the potential protective effects of testosterone treatment for MS. Here, we sought to demonstrate the effects of a testosterone supplementation in testosterone-deficient men with relapsing-remitting MS.Methods/designThis report presents the rationale and methodology of TOTEM RRMS, a French, phase 2, multicenter, randomized, placebo-controlled, and double-blind trial, which aims to prevent the progression of MS in men with low testosterone levels by administration of testosterone undecanoate, who were kept under natalizumab (Tysabri®) to overcome the anti-inflammatory effect of testosterone. Forty patients will be randomized into two groups receiving either a testosterone treatment (Nebido®) or a matching placebo. The intervention period for each group will last 66 weeks (treatment will be injected at baseline, week 6, and then every 12 weeks). The main objective is to determine the neuroprotective and remyelinating effects of testosterone using tensor diffusion imaging techniques and thalamic atrophy analyses. As secondary objectives, impacts of the testosterone supplementation will be studied using other conventional and unconventional MRI parameters and with clinical outcomes.DiscussionThe action of testosterone is observed in different experimental autoimmune encephalomyelitis models and epidemiological studies in humans. However, despite several preclinical data and some small clinical trials in MS, clear evidence for a therapeutic effect of hormone therapy is still missing. Therefore, our goal is to demonstrate the effects of testosterone therapies in MS. As there is no effective treatment currently available on fatigue in MS, careful attention should also be paid to secondary endpoints: fatigue, cognitive functions, and other symptoms that may improve life quality.Assuming a positive outcome of the trial, this treatment could be considered as a new neuroprotective and remyelinating therapy in relapsing-remitting MS and could be applicable to other demyelinating diseases.Trial registrationClinicalTrials.gov NCT03910738. Registered on 10 April 2019.

Characterization of thalamic lesions and their correlates in multiple sclerosis by ultra-high-field MRI

Background: Thalamic pathology is a marker for neurodegeneration and multiple sclerosis (MS) disease progression. Objective: To characterize (1) the morphology of thalamic lesions, (2) their relation to cortical and white matter (WM) lesions, and (3) clinical measures, and to assess (4) the imaging correlates of thalamic atrophy. Methods: A total of 90 MS patients and 44 healthy controls underwent acquisition of 7 Tesla images for lesion segmentation and 3 Tesla scans for atrophy evaluation. Thalamic lesions were classified according to the shape and the presence of a central venule. Regression analysis identified the predictors of (1) thalamic atrophy, (2) neurological disability, and (3) information processing speed. Results: Thalamic lesions were mostly ovoid than periventricular, and for the great majority (78%) displayed a central venule. Lesion volume in the thalamus, cortex, and WM did not correlate with each other. Thalamic atrophy was only associated with WM lesion volume (p = 0.002); subpial and WM lesion volumes were associated with neurological disability (p = 0.016; p < 0.001); and WM and thalamic lesion volumes were related with cognitive impairment (p < 0.001; p = 0.03). Conclusion: Thalamic lesions are unrelated to those in the cortex and WM, suggesting that they may not share common pathogenic mechanisms and do not contribute to thalamic atrophy. Combined WM, subpial, and thalamic lesion volumes at 7 Tesla contribute to the disease severity.

Automated MRI-based volumetry of basal ganglia and thalamus at the chronic phase of cortical stroke

PurposeWe aimed at assessing the potential of automated MR morphometry to assess individual basal ganglia and thalamus volumetric changes at the chronic phase after cortical stroke.MethodsNinety-six patients (mean age: 65 ± 18 years, male 55) with cortical stroke at the chronic phase were retrospectively included. Patients were scanned at 1.5 T or 3 T using a T1-MPRAGE sequence. Resulting 3D images were processed with the MorphoBox prototype software to automatically segment basal ganglia and thalamus structures, and to obtain Z scores considering the confounding effects of age and sex. Stroke volume was estimated by manual delineation on T2-SE imaging. Z scores were compared between ipsi- and contralateral stroke side and according to the vascular territory. Potential relationship between Z scores and stroke volume was assessed using the Spearman correlation coefficient.ResultsBasal ganglia and thalamus volume Z scores were lower ipsilaterally to MCA territory stroke (p values < 0.034) while they were not different between ipsi- and contralateral stroke sides in non-MCA territory stroke (p values > 0.37). In MCA territory stroke, ipsilateral caudate nucleus (rho = − 0.34, p = 0.007), putamen (rho = − 0.50, p < 0.001), pallidum (rho = − 0.44, p < 0.001), and thalamus (rho = − 0.48, p < 0.001) volume Z scores negatively correlated with the cortical stroke volume. This relation was not influenced by cardiovascular risk factors or time since stroke.ConclusionAutomated MR morphometry demonstrated atrophy of ipsilateral basal ganglia and thalamus at the chronic phase after cortical stroke in the MCA territory. The atrophy was related to stroke volume. These results confirm the potential role for automated MRI morphometry to assess remote changes after stroke.

Evidence for a novel subcortical mechanism for posterior cingulate cortex atrophy in HIV peripheral neuropathy.

We previously reported that neuropathic pain was associated with smaller posterior cingulate cortical (PCC) volumes, suggesting that a smaller/dysfunctional PCC may contribute to development of pain via impaired mind wandering. A gap in our previous report was lack of evidence for a mechanism for the genesis of PCC atrophy in HIV peripheral neuropathy. Here we investigate if volumetric differences in the subcortex for those with neuropathic paresthesia may contribute to smaller PCC volumes, potentially through deafferentation of ascending white matter tracts resulting from peripheral nerve damage in HIV neuropathy. Since neuropathic pain and paresthesia are highly correlated, statistical decomposition was used to separate pain and paresthesia symptoms to determine which regions of brain atrophy are associated with both pain and paresthesia and which are associated separately with pain or paresthesia. HIV+ individuals (N = 233) with and without paresthesia in a multisite study underwent structural brain magnetic resonance imaging. Voxel-based morphometry and a segmentation/registration tool were used to investigate regional brain volume changes associated with paresthesia. Analysis of decomposed variables found that smaller midbrain and thalamus volumes were associated with paresthesia rather than pain. However, atrophy in the PCC was related to both pain and paresthesia. Peak thalamic atrophy (p = 0.004; MNI x = - 14, y = - 24, z = - 2) for more severe paresthesia was in a region with reciprocal connections with the PCC. This provides initial evidence that smaller PCC volumes in HIV peripheral neuropathy are related to ascending white matter deafferentation caused by small fiber damage observed in HIV peripheral neuropathy.

Intrinsic and Extrinsic Mechanisms of Thalamic Pathology in Multiple Sclerosis.

Thalamic atrophy is among the earliest brain changes detected in patients with multiple sclerosis (MS) and the degree of thalamic atrophy is a strong predictor of disability progression. The causes of thalamic atrophy are not fully understood. Here, we investigate the contributions of thalamic demyelinated lesions, thalamic neuronal loss, and cerebral white matter (WM) lesions to thalamic volume. We used postmortem in situ magnetic resonance imaging (MRI) scans of 95 subjects with MS to correlate thalamic lesion volumes with global MRI metrics. We histologically characterized thalamic demyelination patterns and compared neuronal loss and neuritic pathology in the thalami with the extremes of volume. Grossly apparent thalamic discolorations in cm-thick brain slices were T2/fluid-attenuated inversion recovery (FLAIR) hyperintense, T1-hypointense, and appeared as perivascular demyelinated lesions with dystrophic neurons/axons. Subependymal demyelinated lesions with axonal loss and microglial/macrophage activation were also observed. The 12 subjects with the least thalamic volume had a 17.6% reduction of median neuronal density in the dorsomedial/ventrolateral and pulvinar nuclei compared with the 14 subjects with the greatest thalamic volume (p = 0.03). After correcting for age, disease duration, sex, and T2 lesion volume, the total (p = 0.20), ovoid (p = 0.31), or subependymal (p = 0.44) MRI thalamic lesion volumes correlated with thalamic volume. Thalamic volume correlated with cerebral T2 lesion volume (Spearman's rho = -0.65, p < 0.001; p < 0.0001 after correcting for age, disease duration, and sex). Our findings suggest the degeneration of efferent/afferent thalamic projections and/or a neurodegenerative process as greater contributors to thalamic atrophy than thalamic demyelinating lesions. ANN NEUROL 2020 ANN NEUROL 2020;88:81-92.

The Impact of Intracortical Lesions on Volumes of Subcortical Structures in Multiple Sclerosis.

Recent studies showed thalamic atrophy in the early stages of MS. We investigated the impact of intracortical lesions on the volumes of subcortical structures (especially the thalamus) compared with other lesions in MS. Seventy-one patients with MS were included. The volumes of intracortical lesions and white matter lesions were identified on double inversion recovery and FLAIR, respectively, by using 3D Slicer. Volumes of white matter T1 hypointensities and subcortical gray matter, thalamus, caudate, putamen, and pallidum volumes were calculated using FreeSurfer. Age, MS duration, and the Expanded Disability Status Scale score were assessed. Patients with intracortical lesions were older (P = .003), had longer disease duration (P < .001), and higher Expanded Disability Status Scale scores (P = .02). The presence of intracortical lesions was associated with a significant decrease of subcortical gray matter volume (P = .02). In our multiple regression model, intracortical lesion volume was the only predictor of thalamic volume (R 2 = 0.4, b* = -0.28, P = .03) independent of white matter lesion volume and T1 hypointensity volume. White matter lesion volume showed an impact on subcortical gray matter volume in patients with relapsing-remitting MS (P = .04) and those with disease duration of <5 years (P = .04) and on thalamic volume in patients with Expanded Disability Status Scale scores of <4.0 (P = .01). By contrast, intracortical lesion volume showed an impact on subcortical gray matter and thalamic volumes in the secondary-progressive MS subgroup (P = .02 and P < .001) in patients with a long-standing disease course (P < .001 and P = .001) and more profound disability (P < .001 and P < .001). Thalamic atrophy was explained better by intracortical lesions than by white matter lesion and T1 hypointensity volumes, especially in patients with more profound disability.

Cognitive impairment in early MS: contribution of white matter lesions, deep grey matter atrophy, and cortical atrophy

BackgroundCognitive impairment (CI) is a frequent and debilitating symptom in MS. To better understand the neural bases of CI in MS, this magnetic resonance imaging (MRI) study aimed to identify and quantify related structural brain changes and to investigate their relation to each other.MethodsWe studied 51 patients with CI and 391 patients with cognitive preservation (CP). We analyzed three-dimensional T1-weighted and FLAIR scans at 3 Tesla. We determined mean cortical thickness as well as volumes of cortical grey matter (GM), deep GM including thalamus, cerebellar cortex, white matter, corpus callosum, and white matter lesions (WML). We also analyzed GM across the whole brain by voxel-wise and surface-based techniques.ResultsMean disease duration was 5 years. Comparing MS patients with CI and CP, we found higher volumes of WML, lower volumes of deep and cortical GM structures, and lower volumes of the corpus callosum (all corrected p values < 0.05). Effect sizes were largest for WML and thalamic volume (standardized ß values 0.25 and − 0.25). By logistic regression analysis including both WML and thalamic volume, we found a significant effect only for WML volume. Inclusion of the interaction term of WML and thalamic volume increased the model fit and revealed a highly significant interaction of WML and thalamic volume. Moreover, voxel-wise and surface-based comparisons of MS patients with CI and CP showed regional atrophy of both deep and cortical GM independent of WML volume and overall disability, but effect sizes were lower.ConclusionAlthough several mechanisms contribute to CI already in the early stage of MS, WML seem to be the main driver with thalamic atrophy primarily intensifying this effect.

Variability Between Direct and Indirect Targeting of the Anterior Nucleus of the Thalamus

Preoperative thalamic targeting methods have historically relied on indirect targeting techniques that do not fully account for variances in anatomy or for thalamic atrophy in epilepsy. We aimed to address variability noted between traditional indirect targeting and direct targeting methods for the anterior nucleus of the thalamus (ANT). Fifteen consecutive patients undergoing ANT deep brain stimulator placement were evaluated (30 thalamic nuclei). Direct ANT targeting was performed using a fast gray matter acquisition T1 inversion recovery sequence and compared with standard stereotactic coordinates. Thalamic volumes were calculated for each patient, and degree of thalamic volume loss was assessed compared with matched control subjects. Vertex analysis was performed to assess shape changes in the thalamus compared with age- and sex-matched subjects. There was significant variation between direct and indirect targets in the y-axis and z-axis on both sides. On the left, the direct target was located at y= 2 ±1.3 mm and z= 9.3 ± 1.8 mm (both P= 0.02). On the right, the direct target was located at y= 2.9 ± 1.8 mm and z= 9.2 ± 2 mm (both P ≤ 0.0003). There was no significant difference in the x-coordinate on either side (P > 0.5). Additionally, there was a correlation between thalamic volume and difference between direct and indirect targets in the y-axis and the z-axis. We showed a significant difference in direct and indirect targeting in the y-axis and z-axis when targeting the ANT for deep brain stimulation for epilepsy. This difference is correlated to thalamic volume, with a larger difference noted in patients with thalamic atrophy.

Effect of Ocrelizumab on Thalamic Atrophy in Patients with Relapsing and Primary Progressive Multiple Sclerosis (1286)

Effect of Ocrelizumab on Thalamic Atrophy in Patients with Relapsing and Primary Progressive Multiple Sclerosis (1286)