Thalamic Volume Loss Research Articles

Volume loss in the deep gray matter and thalamic subnuclei: a longitudinal study on disability progression in multiple sclerosis.

Volume loss in the deep gray matter (DGM) has been reported in patients with multiple sclerosis (MS) already at early stages of the disease and is thought to progress throughout the disease course. To investigate the impact and predictive value of volume loss in DGM and thalamic subnuclei on disability worsening in patients MS over a 6-year follow-up period. Hundred and seventy-nine patients with RRMS (132 women; median Expanded Disability Status Scale, EDSS: 2.5) and 50 with SPMS (27 women; median EDSS: 4.5) were included in the study. Patients underwent annual EDSS assessments and annual MRI at 1.5T. DGM/thalamic subnuclei volumes were identified on high-resolution T1-weighted. A hierarchical linear mixed model for each anatomical DGM area and each thalamic subnucleus was performed to investigate the associations with disability scores. Cox regression was used to estimate the predictive properties of volume loss in DGM and thalamic subnuclei on disease worsening. In the whole sample and in RRMS, volumes of the thalamus and the striatum were associated with the EDSS; however, only thalamic volume loss was associated with EDSS change at follow-up. Regarding thalamic subnuclei, volume loss in the anterior nucleus, the pulvinar and the ventral anterior nucleus was associated with EDSS change in the whole cohort. A trend was observed for the ventral lateral nucleus. Volume loss in the anterior and ventral anterior nuclei was associated with EDSS change over time in patients with RRMS. Moreover, MS phenotype and annual rates of volume loss in the thalamus and ventral lateral nucleus were predictive of disability worsening. These results highlight the relevance of volume loss in the thalamus as a key metric for predicting disability worsening as assessed by EDSS (in RRMS). Moreover, the volume loss in specific nuclei such as the ventral lateral nucleus seems to play a role in disability worsening.

Age-dependent cut-offs for pathological deep gray matter and thalamic volume loss using Jacobian integration

IntroductionSeveral recent studies indicate that deep gray matter or thalamic volume loss (VL) might be promising surrogate markers of disease activity in multiple sclerosis (MS) patients. To allow applying these markers to individual MS patients in clinical routine, age-dependent cut-offs distinguishing physiological from pathological VL and an estimation of the measurement error, which provides the confidence of the result, are to be defined. MethodsLongitudinal MRI scans of the following cohorts were analyzed in this study: 189 healthy controls (HC) (mean age 54 years, 22% female), 98 MS patients from Zurich university hospital (mean age 34 years, 62% female), 33 MS patients from Dresden university hospital (mean age 38 years, 60% female), and publicly available reliability data sets consisting of 162 short-term MRI scan-rescan pairs with scan intervals of days or few weeks. Percentage annualized whole brain volume loss (BVL), gray matter (GM) volume loss (GMVL), deep gray matter volume loss (deep GMVL), and thalamic volume loss (ThalaVL) were computed deploying the Jacobian integration (JI) method. BVL was additionally computed using Siena, an established method used in many Phase III drug trials. A linear mixed effect model was used to estimate the measurement error as the standard deviation (SD) of model residuals of all 162 scan-rescan pairs For estimation of age-dependent cut-offs, a quadratic regression function between age and the corresponding annualized VL values of the HC was computed. The 5th percentile was defined as the threshold for pathological VL per year since 95% of HC subjects exhibit a less pronounced VL for a given age. For the MS patients BVL, GMVL, deep GMVL, and ThalaVL were mutually compared and a paired t-test was used to test whether there are systematic differences in VL between these brain regions. ResultsSiena and JI showed a high agreement for BVL measures, with a median absolute difference of 0.1% and a correlation coefficient of r = 0.78. Siena and GMVL showed a similar standard deviation (SD) of the scan-rescan error of 0.28% and 0.29%, respectively. For deep GMVL, ThalaVL the SD of the scan-rescan error was slightly higher (0.43% and 0.5%, respectively). Among the HC the thalamus showed the highest mean VL (−0.16%, −0.39%, and −0.59% at ages 35, 55, and 75, respectively). Corresponding cut-offs for a pathological VL/year were −0.68%, −0.91%, and −1.11%. The MS cohorts did not differ in BVL and GMVL. However, both MS cohorts showed a significantly (p = 0.05) stronger deep GMVL than BVL per year. ConclusionIt might be methodologically feasible to assess deep GMVL using JI in individual MS patients. However, age and the measurement error need to be taken into account. Furthermore, deep GMVL may be used as a complementary marker to BVL since MS patients exhibit a significantly stronger deep GMVL than BVL.

Stereological Investigation of Regional Brain Volumes after Acute and Chronic Cuprizone-Induced Demyelination.

Brain volume measurement is one of the most frequently used biomarkers to establish neuroprotective effects during pre-clinical multiple sclerosis (MS) studies. Furthermore, whole-brain atrophy estimates in MS correlate more robustly with clinical disability than traditional, lesion-based metrics. However, the underlying mechanisms leading to brain atrophy are poorly understood, partly due to the lack of appropriate animal models to study this aspect of the disease. The purpose of this study was to assess brain volumes and neuro-axonal degeneration after acute and chronic cuprizone-induced demyelination. C57BL/6 male mice were intoxicated with cuprizone for up to 12 weeks. Brain volume, as well as total numbers and densities of neurons, were determined using design-based stereology. After five weeks of cuprizone intoxication, despite severe demyelination, brain volumes were not altered at this time point. After 12 weeks of cuprizone intoxication, a significant volume reduction was found in the corpus callosum and diverse subcortical areas, particularly the internal capsule and the thalamus. Thalamic volume loss was accompanied by glucose hypermetabolism, analyzed by [18F]-fluoro-2-deoxy-d-glucose (18F-FDG) positron-emission tomography. This study demonstrates region-specific brain atrophy of different subcortical brain regions after chronic cuprizone-induced demyelination. The chronic cuprizone demyelination model in male mice is, thus, a useful tool to study the underlying mechanisms of subcortical brain atrophy and to investigate the effectiveness of therapeutic interventions.

Thalamic volume loss as an early sign of amnestic mild cognitive impairment

The aim of this study was to compare brain volume reduction in patients with Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI) with age-related changes in age- and gender-matched healthy individuals.Sixty-six patients were divided in three groups based on medical history, neurological and neurocognitive assessment: 26 patients with AD, 20 patients with aMCI and 20 healthy controls. All participants underwent high-resolution magnetic resonance (MR) imaging on 3 T unit. MR volumetry of cerebral cortex, white matter and lateral ventricles volumes, as well as volumes of subcortical nuclei (hippocampus, amygdala, thalamus) was performed.Global cerebral and grey matter volumes were lower in AD patients compared to aMCI (p = 0.023 and p = 0.001, respectively) and controls (p < 0.001 and p < 0.001, respectively). Volume of lateral ventricles was significantly higher in AD patients compared to controls (right p = 0.007, left p = 0.007). Volumes of thalamus were lower in AD patients (right p < 0.001, left p < 0.001), and in aMCI patients (right p = 0.004, left p = 0.015), compared to controls. Hippocampal volume was lower in AD patients compared to both aMCI patients (right p = 0.047, left p = 0.003) and controls (right p < 0.001, left p < 0.001). In aMCI patients, hippocampal volume was lower than in controls (right p = 0.004, left p = 0.007). Volumes of amygdala were lower in AD patients compared to controls (righ p = 0.003, left p = 0.001).Our results show that thalamic volume loss could be an early sign associated with poorercognitiveperformance in aMCI, preceeding the atrophy of amygdala, global grey and white matter volume loss, and cerebrospinal fluid spaces dilatation.

Gray matter atrophy in multiple sclerosis despite clinical and lesion stability during natalizumab treatment.

BackgroundBrain volume loss is an important surrogate marker for assessing disability in MS; however, contribution of gray and white matter to the whole brain volume loss needs further examination in the context of specific MS treatment.ObjectivesTo examine whole and segmented gray, white, thalamic, and corpus callosum volume loss in stable patients receiving natalizumab for 2–5 years.MethodsThis was a retrospective study of 20 patients undergoing treatment with natalizumab for 24–68 months. Whole brain volume loss was determined with SIENA. Gray and white matter segmentation was done using FAST. Thalamic and corpus callosum volumes were determined using Freesurfer. T1 relaxation values of chronic hypointense lesions (black holes) were determined using a quantitative, in-house developed method to assess lesion evolution.ResultsOver a mean of 36.6 months, median percent brain volume change (PBVC) was -2.0% (IQR 0.99–2.99). There was decline in gray (p = 0.001) but not white matter (p = 0.6), and thalamic (p = 0.01) but not corpus callosum volume (p = 0.09). Gray matter loss correlated with PBVC (Spearman’s r = 0.64, p = 0.003) but not white matter (Spearman’s r = 0.42, p = 0.07). Age significantly influenced whole brain volume loss (p = 0.010, multivariate regression), but disease duration and baseline T2 lesion volume did not. There was no change in T1 relaxation values of lesions or T2 lesion volume over time. All patients remained clinically stable.ConclusionsThese results demonstrate that brain volume loss in MS is primarily driven by gray matter changes and may be independent of clinically effective treatment.

Immune Cell Neurotrophin Production Is Associated with Subcortical Brain Atrophy in Neuropsychiatric Systemic Lupus Erythematosus Patients

Objective: Central nervous system (CNS) involvement in systemic lupus erythematosus (SLE) remains poorly understood. Damage within the CNS is driven by the autoimmune response; however, immunopathophysiology of neuropsychiatric (NP) SLE is multifactorial. Immune cell neurotrophin production could be neuroprotective against autoimmunity-driven CNS damage, as has been shown in multiple sclerosis. The aim of this study was to establish whether immune cell neurotrophin production is associated with damage severity in NPSLE. Methods: Selected neurotrophins (BDNF, NGF, NT-3, and NT-4/5) were measured with ELISA within peripheral blood mononuclear cells (PBMCs) isolated from 38 NPSLE patients matched with 39 healthy controls. Subcortical and cortical structure volumes were segmented with the Freesurfer 5.3 pipeline on T1-weighted isotropic images acquired on a 1.5-T MRI scanner. Results: BDNF and NGF levels in PBMCs were reduced in NPSLE compared to the healthy population. The PBMC BDNF level was associated with reduced thalamus, caudate, and putamen volumes. The NGF level correlated with lateral ventricles enlargement and thalamic volume loss. Conclusions: In NPSLE, immune cell BDNF and NGF levels are linked with subcortical atrophy. Higher BDNF levels are associated with higher midsagittal atrophy, which may reflect compensatory mechanisms, upregulating BDNF when neuroprotection is needed. These data require further confirmation.

Thalamic atrophy in multiple sclerosis: A magnetic resonance imaging marker of neurodegeneration throughout disease.

Thalamic volume is a candidate magnetic resonance imaging (MRI)-based marker associated with neurodegeneration to hasten development of neuroprotective treatments. Our objective is to describe the longitudinal evolution of thalamic atrophy in MS and normal aging, and to estimate sample sizes for study design. Six hundred one subjects (2,632 MRI scans) were analyzed. Five hundred twenty subjects with relapse-onset MS (clinically isolated syndrome, n = 90; relapsing-remitting MS, n = 392; secondary progressive MS, n = 38) underwent annual standardized 3T MRI scans for an average of 4.1 years, including a 1mm3 3-dimensional T1-weighted sequence (3DT1; 2,485 MRI scans). Eighty-one healthy controls (HC) were scanned longitudinally on the same scanner using the same protocol (147 MRI scans). 3DT1s were processed using FreeSurfer's longitudinal pipeline after lesion inpainting. Rates of normalized thalamic volume loss in MS and HC were compared in linear mixed effects models. Simulation-based sample size calculations were performed incorporating the rate of atrophy in HC. Thalamic volume declined significantly faster in MS subjects compared to HC, with an estimated decline of -0.71% per year (95% confidence interval [CI] = -0.77% to -0.64%) in MS subjects and -0.28% per year (95% CI = -0.58% to 0.02%) in HC (p for difference = 0.007). The rate of decline was consistent throughout the MS disease duration and across MS clinical subtypes. Eighty or 100 subjects per arm (α = 0.1 or 0.05, respectively) would be needed to detect the maximal effect size with 80% power in a 24-month study. Thalamic atrophy occurs early and consistently throughout MS. Preliminary sample size calculations appear feasible, adding to its appeal as an MRI marker associated with neurodegeneration. Ann Neurol 2018;83:223-234.

Early Procedural Pain Is Associated with Regionally-Specific Alterations in Thalamic Development in Preterm Neonates.

Very preterm human neonates are exposed to numerous invasive procedures as part of life-saving care. Evidence suggests that repetitive neonatal procedural pain precedes long-term alterations in brain development. However, to date the link between pain and brain development has limited temporal and anatomic specificity. We hypothesized that early exposure to painful stimuli during a period of rapid brain development, before pain modulatory systems reach maturity, will predict pronounced changes in thalamic development, and thereby cognitive and motor function. In a prospective cohort study, 155 very preterm neonates (82 males, 73 females) born 24-32 weeks' gestation underwent two MRIs at median postmenstrual ages 32 and 40 weeks that included structural, metabolic, and diffusion imaging. Detailed day-by-day clinical data were collected. Cognitive and motor abilities were assessed at 3 years, corrected age. The association of early (skin breaks, birth-Scan 1) and late pain (skin breaks, Scans 1-2) with thalamic volumes and N-acetylaspartate (NAA)/choline (Cho), and fractional anisotropy of white-matter pathways was assessed. Early pain was associated with slower thalamic macrostructural growth, most pronounced in extremely premature neonates. Deformation-based morphometry analyses confirmed early pain-related volume losses were localized to somatosensory regions. In extremely preterm neonates early pain was associated with decreased thalamic NAA/Cho and microstructural alterations in thalamocortical pathways. Thalamic growth was in turn related to cognitive and motor outcomes. We observed regionally-specific alterations in the lateral thalamus and thalamocortical pathways in extremely preterm neonates exposed to more procedural pain. Findings suggest a sensitive period leading to lasting alterations in somatosensory-system development.SIGNIFICANCE STATEMENT Early exposure to repetitive procedural pain in very preterm neonates may disrupt the development of regions involved in somatosensory processing, leading to poor functional outcomes. We demonstrate that early pain is associated with thalamic volume loss in the territory of the somatosensory thalamus and is accompanied by disruptions thalamic metabolic growth and thalamocortical pathway maturation, particularly in extremely preterm neonates. Thalamic growth was associated with cognitive and motor outcome at 3 years corrected age. Findings provide evidence for a developmentally sensitive period whereby subcortical structures in young neonates may be most vulnerable to procedural pain. Furthermore, results suggest that the thalamus may play a key role underlying the association between neonatal pain and poor neurodevelopmental outcomes in these high-risk neonates.

Pathological cut-offs of global and regional brain volume loss in multiple sclerosis

Background: Volumetric MRI surrogate markers of disease progression are lacking. Objective: To establish cut-off values of brain volume loss able to discriminate between healthy controls and MS patients. Methods: In total, 386 patients after first demyelinating event suggestive of MS (CIS), 964 relapsing-remitting MS (RRMS) patients, 63 secondary-progressive MS (SPMS) patients and 58 healthy controls were included in this longitudinal study. A total of 11,438 MRI scans performed on the same MRI scanner with the same protocol were analysed. Annualised percentage changes of whole brain, grey matter, thalamus and corpus callosum volumes were estimated. We investigated cut-offs able to discriminate between healthy controls and MS patients. Results: At a predefined specificity of 90%, the annualised percentage change cut-off of corpus callosum volume (−0.57%) was able to distinguish between healthy controls and patients with the highest sensitivity (51% in CIS, 48% in RRMS and 42% in SPMS patients). Lower sensitivities (22%−49%) were found for cut-offs of whole brain, grey matter and thalamic volume loss. Among CIS and RRMS patients, cut-offs were associated with greater accumulation of disability. Conclusion: We identified cut-offs of annualised global and regional brain volume loss rates able to discriminate between healthy controls and MS patients.

Age-Dependent Effects of ALK5 Inhibition and Mechanism of Neuroprotection in Neonatal Hypoxic-Ischemic Brain Injury

Neonatal encephalopathy due to hypoxic-ischemic (HI) brain injury triggers a wave of neuroinflammatory events attributed to causing the progressive degeneration and functional deficits seen weeks after the initial insult. In a recent set of studies, we evaluated the therapeutic efficacy of a small molecule antagonist for ALK5 (activin-like kinase 5 ), TGF-β receptor in a rat model of moderate perinatal HI and found significant improvements in neurologic outcomes. Here, we have extended those studies to evaluate the efficacy of delayed TGF-β receptor antagonism on postnatal day (P) 6 and P9 HI rat pups with and without hypothermia. The ALK5 receptor antagonist SB505124 was administered systemically by osmotic pump beginning 3 days following HI. Extending our earlier data set that showed protection of the hippocampus in P6 pups treated with SB505124, these animals sustained less damage to their hippocampi and had improved performance on the Morris water maze (MWM) when tested on P60 versus vehicle-treated HI animals. By contrast, SB505124 did not improve sensorimotor deficits and exacerbated hippocampal and thalamic volume loss when administered 3 days after HI to P9 pups. SB505124-treated rats injured on P9 tended to perform worse than their vehicle-treated counterparts on MWM, and SB505124 treatment did not preserve hippocampal or thalamic neurons in P9 pups when combined with hypothermia. To elucidate the mechanism whereby ALK5 inhibition reduced neuronal death in the P6 HI model, we assessed levels of autophagy markers in neurons of the neocortex, hippocampus, and thalamus, and in the subcortical white matter, and found that SB505124 increased numbers of autophagosomes and levels of lipidated LC3 (light chain 3), a key protein known to mediate autophagy. Altogether, our results demonstrate that there is a dynamic switch in the CNS response to TGF-β₁ that occurs around P9 in rats where TGF-β signaling inhibition worsens functional outcomes. This response is similar to the outcome of antagonizing TGF-β signaling in adult stroke and other CNS disease models. We conclude that attenuating TGF-β₁ signaling will likely be an effective treatment for HI-related encephalopathy in moderately preterm infants, offering protection of the neocortex, hippocampus, and thalamus with enhanced cerebral autophagy contributing to the decrease in the extent of progressive neuronal cell death.

Natalizumab stabilizes physical, cognitive, MRI, and OCT markers of disease activity: A prospective, non-randomized pilot study.

Natalizumab is an effective therapy for multiple sclerosis (MS). Its effectiveness has been demonstrated in several clinical and imaging studies. The objective of this study was to further demonstrate the efficacy of natalizumab using a comprehensive battery of clinical and imaging markers in the same cohort of patients followed longitudinally, hence capturing the multi-faceted nature of the MS disease process. A prospective, open-label, pilot study of 20 MS patients treated with natalizumab was conducted. High resolution MRI, Symbol-Digit Modalities Test (SDMT), and Optical Coherence Tomography (OCT) scans were obtained at baseline, 48, and 96 weeks. 15 patients completed the study. Natalizumab treatment decreased Expanded Disability Status Scale score (EDSS) and no change in SDMT, Brain Parenchymal Fraction (BPF), or any of the OCT markers of retinal degeneration was observed. Thalamic and whole brain volume as assessed by Percentage Brain Volume Change (PBVC) showed continuous deterioration. Higher baseline T2 lesion load correlated with increased rate of PBVC at 96-weeks (r = 0.566, R2 = 0.320, p = 0.035) and thalamic volume loss (r = -0.586, R2 = 0.344, p = 0.027). Most patients, 93%, achieved no evidence of disease activity (NEDA) at 2 years, likely due to early disease duration and lower initial baseline lesion load. This study further demonstrates stabilization of clinical and imaging markers of disease activity during natalizumab treatment.

90. Targeted Cognitive Training is Neuroprotective Against Thalamic Volume Loss in Early Schizophrenia

90. Targeted Cognitive Training is Neuroprotective Against Thalamic Volume Loss in Early Schizophrenia

Thalamo-Cortical Disruption Contributes to Short-Term Memory Deficits in Patients with Medial Temporal Lobe Damage.

Short-term (STM) and long-term memory (LTM) have largely been considered as separate brain systems reflecting fronto-parietal and medial temporal lobe (MTL) functions, respectively. This functional dichotomy has been called into question by evidence of deficits on aspects of working memory in patients with MTL damage, suggesting a potentially direct hippocampal contribution to STM. As the hippocampus has direct anatomical connections with the thalamus, we tested the hypothesis that damage to thalamic nuclei regulating cortico-cortical interactions may contribute to STM deficits in patients with hippocampal dysfunction. We used diffusion-weighted magnetic resonance imaging-based tractography to identify anatomical subdivisions in patients with MTL epilepsy. From these, we measured resting-state functional connectivity with detailed cortical divisions of the frontal, temporal, and parietal lobes. Whereas thalamo-temporal functional connectivity reflected LTM performance, thalamo-prefrontal functional connectivity specifically predicted STM performance. Notably, patients with hippocampal volume loss showed thalamic volume loss, most prominent in the pulvinar region, not detected in patients with normal hippocampal volumes. Aberrant thalamo-cortical connectivity in the epileptic hemisphere was mirrored in a loss of behavioral association with STM performance specifically in patients with hippocampal atrophy. These findings identify thalamo-cortical disruption as a potential mechanism contributing to STM deficits in the context of MTL damage.

Early CNS neurodegeneration in radiologically isolated syndrome.

Objective:Increasing evidence indicates that the thalamus may be a location of early neurodegeneration in multiple sclerosis (MS). Our objective was to identify the presence of gray matter volume loss and thinning in patients with radiologically isolated syndrome (RIS).Methods:Sixty-three participants were included in this case-control study. Twenty-one patients with RIS were age- and sex-matched to 42 healthy controls in a 1:2 ratio. All participants underwent brain MRIs on a single 3T scanner. After lesion segmentation and inpainting, 1 mm3-isometric T1-weighted images were submitted to FreeSurfer (v5.2). Normalized cortical and deep gray matter volumes were compared between patients with RIS and controls using t tests, and thalamic volumes were correlated with white matter lesion volumes using Pearson correlation. Exploratory cortical thickness maps were created.Results:Although traditional normalized total gray and white matter volumes were not statistically different between patients with RIS and controls, normalized left (0.0046 ± 0.0005 vs 0.0049 ± 0.0004, p = 0.006), right (0.0045 ± 0.0005 vs 0.0048 ± 0.0004, p = 0.008), and mean (0.0045 ± 0.0005 vs 0.0049 ± 0.0004, p = 0.004) thalamic volumes were significantly lower in patients with RIS (n = 21, mean age 41.9 ± 12.7 years) than in controls (n = 42, mean age 41.4 ± 11.2 years). Thalamic volumes correlated modestly with white matter lesion volumes (range: r = −0.35 to −0.47).Conclusion:Our data provide novel evidence of thalamic atrophy in RIS and are consistent with previous reports in early MS stages. Thalamic volume loss is present early in CNS demyelinating disease and should be further investigated as a metric associated with neurodegeneration.

Volume Estimation of the Thalamus Using Freesurfer and Stereology: Consistency between Methods

Freely available automated MR image analysis techniques are being increasingly used to investigate neuroanatomical abnormalities in patients with neurological disorders. It is important to assess the specificity and validity of automated measurements of structure volumes with respect to reliable manual methods that rely on human anatomical expertise. The thalamus is widely investigated in many neurological and neuropsychiatric disorders using MRI, but thalamic volumes are notoriously difficult to quantify given the poor between-tissue contrast at the thalamic gray-white matter interface. In the present study we investigated the reliability of automatically determined thalamic volume measurements obtained using FreeSurfer software with respect to a manual stereological technique on 3D T1-weighted MR images obtained from a 3 T MR system. Further to demonstrating impressive consistency between stereological and FreeSurfer volume estimates of the thalamus in healthy subjects and neurological patients, we demonstrate that the extent of agreeability between stereology and FreeSurfer is equal to the agreeability between two human anatomists estimating thalamic volume using stereological methods. Using patients with juvenile myoclonic epilepsy as a model for thalamic atrophy, we also show that both automated and manual methods provide very similar ratios of thalamic volume loss in patients. This work promotes the use of FreeSurfer for reliable estimation of global volume in healthy and diseased thalami.

Multimodal Quantitative Magnetic Resonance Imaging of Thalamic Development and Aging across the Human Lifespan: Implications to Neurodegeneration in Multiple Sclerosis

The human brain thalami play essential roles in integrating cognitive, sensory, and motor functions. In multiple sclerosis (MS), quantitative magnetic resonance imaging (qMRI) measurements of the thalami provide important biomarkers of disease progression, but late development and aging confound the interpretation of data collected from patients over a wide age range. Thalamic tissue volume loss due to natural aging and its interplay with lesion-driven pathology has not been investigated previously. In this work, we used standardized thalamic volumetry combined with diffusion tensor imaging, T2 relaxometry, and lesion mapping on large cohorts of controls (N = 255, age range = 6.2-69.1 years) and MS patients (N = 109, age range = 20.8-68.5 years) to demonstrate early age- and lesion-independent thalamic neurodegeneration.

Impact of cannabis use on thalamic volume in people at familial high risk of schizophrenia

No longitudinal study has yet examined the association between substance use and brain volume changes in a population at high risk of schizophrenia. To examine the effects of cannabis on longitudinal thalamus and amygdala-hippocampal complex volumes within a population at high risk of schizophrenia. Magnetic resonance imaging scans were obtained from individuals at high genetic risk of schizophrenia at the point of entry to the Edinburgh High-Risk Study (EHRS) and approximately 2 years later. Differential thalamic and amygdala-hippocampal complex volume change in high-risk individuals exposed (n = 25) and not exposed (n = 32) to cannabis in the intervening period was investigated using repeated-measures analysis of variance. Cannabis exposure was associated with bilateral thalamic volume loss. This effect was significant on the left (F = 4.47, P = 0.04) and highly significant on the right (F= 7.66, P= 0.008). These results remained significant when individuals using other illicit drugs were removed from the analysis. These are the first longitudinal data to demonstrate an association between thalamic volume loss and exposure to cannabis in currently unaffected people at familial high risk of developing schizophrenia. This observation may be important in understanding the link between cannabis exposure and the subsequent development of schizophrenia.

Different Pain, Different Brain: Thalamic Anatomy in Neuropathic and Non-Neuropathic Chronic Pain Syndromes

Trigeminal neuropathic pain (TNP) and temporomandibular disorders (TMD) are thought to have fundamentally different etiologies. It has been proposed that TNP arises through damage to, or pressure on, somatosensory afferents in the trigeminal nerve, whereas TMD results primarily from peripheral nociceptor activation. Because some reports suggest that neuropathic pain is associated with changes in brain anatomy, it is possible that TNP is maintained by changes in higher brain structures, whereas TMD is not. The aim of this investigation is to determine whether changes in regional brain anatomy and biochemistry occur in both conditions. Twenty-one TNP subjects, 20 TMD subjects, and 36 healthy controls were recruited. Voxel-based morphometry of T1-weighted anatomical images revealed no significant regional gray matter volume change in TMD patients. In contrast, gray matter volume of TNP patients was reduced in the primary somatosensory cortex, anterior insula, putamen, nucleus accumbens, and the thalamus, whereas gray matter volume was increased in the posterior insula. The thalamic volume decrease was only seen in the TNP patients classified as having trigeminal neuropathy but not those with trigeminal neuralgia. Furthermore, in trigeminal neuropathy patients, magnetic resonance spectroscopy revealed a significant reduction in the N-acetylaspartate/creatine ratio, a biochemical marker of neural viability, in the region of thalamic volume loss. The data suggest that the pathogenesis underlying neuropathic and non-neuropathic pain conditions are fundamentally different and that neuropathic pain conditions that result from peripheral injuries may be generated and/or maintained by structural changes in regions such as the thalamus.

Thalamofrontal neurodevelopment in new-onset pediatric idiopathic generalized epilepsy

Quantitative MRI techniques have demonstrated thalamocortical abnormalities in idiopathic generalized epilepsy (IGE). However, there are few studies examining IGE early in its course and the neurodevelopmental course of this region is not adequately defined. We examined the 2-year developmental course of the thalamus and frontal lobes in pediatric new-onset IGE (i.e., within 12 months of diagnosis). We performed whole-brain MRI in 22 patients with new-onset IGE and 36 age-matched healthy controls. MRI was repeated 24 months after baseline MRI. Quantitative volumetrics were used to examine thalamic and frontal lobe volumes. The IGE group showed significant differences in thalamic volume within 1 year of seizure onset (baseline) and went on to show thalamic volume loss at a significantly faster rate than healthy control children over the 2-year interval. The control group also showed a significantly greater increase in frontal white matter expansion than the IGE group. In contrast, frontal lobe gray matter volume differences were moderate at baseline and persisted over time, indicating similar developmental trajectories with differences early in the disease process that are maintained. Brain tissue abnormalities in thalamic and frontal regions can be identified very early in the course of IGE and an abnormal trajectory of growth continues over a 2-year interval.

Involvement of the thalamocortical network in TLE with and without mesiotemporal sclerosis

The thalamus plays an important role in seizure propagation in temporal lobe epilepsy (TLE). This study investigated how structural abnormalities in the focus, ipsilateral thalamus and extrafocal cortical structures relate to each other in TLE with mesiotemporal sclerosis (TLE-MTS) and without hippocampal sclerosis (TLE-no). T₁ and high-resolution T₂ images were acquired on a 4T magnet in 29 controls, 15 TLE-MTS cases, and 14 TLE-no. Thalamus volumes were obtained by warping a labeled atlas onto each subject's brain. Deformation-based morphometry was used to identify regions of thalamic volume loss and FreeSurfer for cortical thickness measurements. CA1 volumes were obtained from high-resolution T₂ images. Multiple regression analysis and correlation analyses for voxel- and vertex-based analyses were performed in SPM2 and FreeSurfer. TLE-MTS had bilateral volume loss in the anterior thalamus, which was correlated with CA1 volume and cortical thinning in the mesiotemporal lobe. TLE-no had less severe volume loss in the dorsal lateral nucleus, which was correlated with thinning in the mesiotemporal region but not with extratemporal thinning. The findings suggest that seizure propagation from the presumed epileptogenic focus or regions close to it into the thalamus occurs in TLE-MTS and TLE-no and results in circumscribed neuronal loss in the thalamus. However, seizure spread beyond the thalamus seems not to be responsible for the extensive extratemporal cortical abnormalities in TLE.