TSPO mediated transport of cholesterol into the mitochondrion is a necessary step in steroid synthesis. The rs6971 polymorphism in the TSPO gene causes an amino acid substitution (Ala147Thr) within the transmembrane domain where the cholesterol-binding pocket is located, and has been shown to affect the steroidogenic pathway. We report a nominal association between this TSPO polymorphism and the diagnosis of Bipolar Disorder in both the genome-wide dataset of the Wellcome Trust Case–Control Consortium and the Psychiatric Genome-Wide Association Study Consortium Bipolar Disorder group (OR = 1.11, p = 0.007; OR = 1.10, p = 0.011, respectively). We propose that the amino acid substitution affects hypothalamic–pituitary–adrenal (HPA) regulation, and hence may predispose to Bipolar Disorder. This supports the hypothesis that HPA dysregulation has a causal role in Bipolar Disorder, and is not just a consequence of the disease.
Translocator Protein; Cortisol; HPA; Neurosteroids; rs6971; Genome-wide; WTCCC; Polymorphism; Mitochondria; Bipolar Disorder
Structural magnetic resonance imaging (MRI) has shown great utility in diagnosing soft tissue burden in osteoarthritis (OA), though MRI measures of cartilage integrity have proven more elusive. Sodium MRI can reflect the proteoglycan content of cartilage; however, it requires specialized hardware, acquisition sequences, and long imaging times. This study was designed to assess the potential of a clinically feasible sodium MRI acquisition to detect differences in the knee cartilage of subjects with OA versus healthy controls (HC), and to determine whether longitudinal changes in sodium content are observed at 3 and 6 months. 28 subjects with primary knee OA and 19 HC subjects age and gender matched were enrolled in this ethically-approved study. At baseline, 3 and 6 months subjects underwent structural MRI and a 0.4ms echo time 3D T1-weighted sodium scan as well as the knee injury and osteoarthritis outcome score (KOOS) and knee pain by visual analogue score (VAS). A standing radiograph of the knee was taken for Kellgren-Lawrence (K-L) scoring. A blinded reader outlined the cartilage on the structural images which was used to determine median T1-weighted sodium concentrations in each region of interest on the co-registered sodium scans. VAS, K-L, and KOOS all significantly separated the OA and HC groups. OA subjects had higher T1-weighted sodium concentrations, most strongly observed in the lateral tibial, lateral femoral and medial patella ROIs. There were no significant changes in cartilage volume or sodium concentration over 6 months. This study has shown that a clinically-feasible sodium MRI at a moderate 3T field strength and imaging time with fluid attenuation by T1 weighting significantly separated HCs from OA subjects.
Failure of adaptive plasticity with increasing pathology is suggested to contribute to progression of disability in multiple sclerosis (MS). However, functional impairments can be reduced with practice, suggesting that brain plasticity is preserved even in patients with substantial damage.
Here, functional magnetic resonance imaging (fMRI) was used to probe systems-level mechanisms of brain plasticity associated with improvements in visuomotor performance in MS patients and related to measures of microstructural damage.
23 MS patients and 12 healthy controls underwent brain fMRI during the first practice session of a visuomotor task (short-term practice) and after 2 weeks of daily practice with the same task (longer-term practice). Participants also underwent a structural brain MRI scan.
Patients performed more poorly than controls at baseline. Nonetheless, with practice, patients showed performance improvements similar to controls and independent of the extent of MRI measures of brain pathology. Different relationships between performance improvements and activations were found between groups: greater short-term improvements were associated with lower activation in the sensorimotor, posterior cingulate, and parahippocampal cortices for patients, whereas greater long-term improvements correlated with smaller activation reductions in the visual cortex of controls.
Brain plasticity for visuomotor practice is preserved in MS patients despite a high burden of cerebral pathology. Cognitive systems different from those acting in controls contribute to this plasticity in patients. These findings challenge the notion that increasing pathology is accompanied by an outright failure of adaptive plasticity, supporting a neuroscientific rationale for recovery-oriented strategies even in chronically disabled patients.
People vary in their ability to learn new motor skills. We hypothesize that between-subject variability in brain structure and function can explain differences in learning. We use brain functional and structural MRI methods to characterize such neural correlates of individual variations in motor learning. Healthy subjects applied isometric grip force of varying magnitudes with their right hands cued visually to generate smoothly-varying pressures following a regular pattern. We tested whether individual variations in motor learning were associated with anatomically colocalized variations in magnitude of functional MRI (fMRI) signal or in MRI differences related to white and grey matter microstructure. We found that individual motor learning was correlated with greater functional activation in the prefrontal, premotor, and parietal cortices, as well as in the basal ganglia and cerebellum.
Structural MRI correlates were found in the premotor cortex [for fractional anisotropy (FA)] and in the cerebellum [for both grey matter density and FA]. The cerebellar microstructural differences were anatomically colocalized with fMRI correlates of learning. This study thus suggests that variations across the population in the function and structure of specific brain regions for motor control explain some of the individual differences in skill learning. This strengthens the notion that brain structure determines some limits to cognitive function even in a healthy population. Along with evidence from pathology suggesting a role for these regions in spontaneous motor recovery, our results also highlight potential targets for therapeutic interventions designed to maximize plasticity for recovery of similar visuomotor skills after brain injury.
Several studies have demonstrated benefits of rehabilitation in multiple sclerosis (MS). However, the neuroscientific foundations for rehabilitation in MS are poorly established.
As rehabilitation and motor learning share similar mechanisms of brain plasticity, we test whether the dynamics of skill learning are preserved in MS patients relative to controls.
MS patients and controls learned a repeating sequence of hand movements and were assessed for short-term learning. Long-term learning was tested in another cohort of patients and controls practising the same sequence daily for two weeks.
Despite differences in baseline performance, the dynamics and extent of improvements were comparable between MS and control groups for both the short- and long-term learning. Even the most severely damaged patients were capable of performance improvements of similar magnitude to that seen in controls. After one week of training patients performed as well as the controls at baseline.
Mechanisms for short- and long-term plasticity may compensate for impaired functional connectivity in MS to mediate behavioural improvements. Future studies are needed to define the neurobiological substrates of this plasticity and the extent to which mechanisms of plasticity in patients may be distinct from those used for motor learning in controls.
UK Biobank is a prospective cohort study with 500,000 participants aged 40 to 69. Recently an enhanced imaging study received funding. Cardiovascular magnetic resonance (CMR) will be part of a multi-organ, multi-modality imaging visit in 3–4 dedicated UK Biobank imaging centres that will acquire and store imaging data from 100,000 participants (subject to successful piloting). In each of UK Biobank’s dedicated bespoke imaging centres, it is proposed that 15–20 participants will undergo a 2 to 3 hour visit per day, seven days a week over a period of 5–6 years. The imaging modalities will include brain MRI at 3 Tesla, CMR and abdominal MRI at 1.5 Tesla, carotid ultrasound and DEXA scans using carefully selected protocols. We reviewed the rationale, challenges and proposed approaches for concise phenotyping using CMR on such a large scale. Here, we discuss the benefits of this imaging study and review existing and planned population based cardiovascular imaging in prospective cohort studies. We will evaluate the CMR protocol, feasibility, process optimisation and costs. Procedures for incidental findings, quality control and data processing and analysis are also presented. As is the case for all other data in the UK Biobank resource, this database of images and related information will be made available through UK Biobank’s Access Procedures to researchers (irrespective of their country of origin and whether they are academic or commercial) for health-related research that is in the public interest.
Cardiovascular magnetic resonance; Prospective cohort study; Population-based study; Nested-case control study; Biobank
Gene-gene interactions are proposed as one important component of the genetic architecture of complex diseases, and are just beginning to be evaluated in the context of genome wide association studies (GWAS). In addition to detecting epistasis, a benefit to interaction analysis is that it also increases power to detect weak main effects. We conducted a knowledge-driven interaction analysis of a GWAS of 931 multiple sclerosis trios to discover gene-gene interactions within established biological contexts. We identify heterogeneous signals, including a gene-gene interaction between CHRM3 and MYLK (joint p = 0.0002), an interaction between two phospholipase-β isoforms, PLCβ1 & PLCβ4 (joint p = 0.0098), and a modest interaction between ACTN1 and MYH9 (joint p = 0.0326), all localized to calcium-signaled cytoskeletal regulation. Furthermore, we discover a main effect (joint p = 5.2E-5) previously unidentified by single-locus analysis within another related gene, SCIN, a calcium-binding cytoskeleton regulatory protein. This work illustrates that knowledge-driven interaction analysis of GWAS data is a feasible approach to identify new genetic effects. The results of this study are among the first gene-gene interactions and non-immune susceptibility loci for multiple sclerosis. Further, the implicated genes cluster within inter-related biological mechanisms that suggest a neurodegenerative component to multiple sclerosis.
Impaired attention (‘difficulty concentrating') is a cognitive symptom of nicotine withdrawal that may be an important contributor to smoking relapse. However, the neurobiological basis of this effect and the potentially beneficial effects of nicotine replacement therapy both remain unclear. We used functional MRI with simultaneous electroencephalogram (EEG) recording to define brain activity correlates of cognitive impairment with short-term smoking cessation in habitual smokers and the effects of nicotine replacement. We found that irrespective of treatment (ie nicotine or placebo) EEG α power was negatively correlated with increased activation during performance of a rapid visual information processing (RVIP) task in dorsolateral prefrontal, dorsal anterior cingulate, parietal, and insular cortices, as well as, caudate, and thalamus. Relative to placebo, nicotine replacement further increased the α-correlated activation across these regions. We also found that EEG α power was negatively correlated with RVIP-induced deactivation in regions comprising the ‘default mode' network (ie angular gyrus, cuneus, precuneus, posterior cingulate, and ventromedial prefrontal cortex). These α-correlated deactivations were further reduced by nicotine. These findings confirm that effects of nicotine on cognition during short-term smoking cessation occur with modulation of neuronal sources common to the generation of both the blood oxygen-level-dependent and α EEG signals. Our observations thus demonstrate that nicotine replacement in smokers has direct pharmacological effects on brain neuronal activity modulating cognitive networks.
nicotine; cognitive impairment; smoking; addiction; fMRI; EEG; addiction & substance abuse; cognition; imaging; clinical or preclinical; neuropharmacology; nicotine; fMRI; EEG
Functional magnetic resonance imaging (fMRI) has provided the opportunity to safely investigate the workings of the human brain. This paper focuses on its use in the field of human appetitive behaviour and its impact in obesity research. In the present absence of any safe or effective centrally acting appetite suppressants, a better understanding of how appetite is controlled is vital for the development of new antiobesity pharmacotherapies. Early functional imaging techniques revealed an attenuation of brain reward area activity in response to visual food stimuli when humans are fed—in other words, the physiological state of hunger somehow increases the appeal value of food. Later studies have investigated the action of appetite modulating hormones on the fMRI signal, showing how the attenuation of brain reward region activity that follows feeding can be recreated in the fasted state by the administration of anorectic gut hormones. Furthermore, differences in brain activity between obese and lean individuals have provided clues about the possible aetiology of overeating. The hypothalamus acts as a central gateway modulating homeostatic and nonhomeostatic drives to eat. As fMRI techniques constantly improve, functional data regarding the role of this small but hugely important structure in appetite control is emerging.
Functional magnetic resonance imaging has become a powerful tool to investigate the neuroendocrinology of appetite. In a recent study, we demonstrated that the brain activation pattern seen following the infusion of the anorectic gut hormones PYY3–36 and GLP-17–36 amide to fasted individuals resembles the brain activation pattern seen in the physiological satiated state. This commentary discusses the significance of these findings and compares them with other landmark studies in the field, with specific reference to the brain areas involved in appetite regulation. We highlight the importance of this type of research in order to pave the way for the development of efficacious and safe anti-obesity therapies.
appetite; CNS; fMRI; GLP-1; imaging; obesity; PYY
Obesity is a major public health issue worldwide. Understanding how the brain controls appetite offers promising inroads toward new therapies for obesity. Peptide YY (PYY) and glucagon-like peptide 1 (GLP-1) are coreleased postprandially and reduce appetite and inhibit food intake when administered to humans. However, the effects of GLP-1 and the ways in which PYY and GLP-1 act together to modulate brain activity in humans are unknown. Here, we have used functional MRI to determine these effects in healthy, normal-weight human subjects and compared them to those seen physiologically following a meal. We provide a demonstration that the combined administration of PYY3-36 and GLP-17-36 amide to fasted human subjects leads to similar reductions in subsequent energy intake and brain activity, as observed physiologically following feeding.
► Coadministration of PYY3-36 and GLP-17-36 amide reduces food intake and brain activity ► The reduction in brain activity is notable in areas that control appetitive behavior ► Changes in food intake and brain activity are similar to that observed after a meal
Glutamate is the main excitatory neurotransmitter in the mammalian brain. Appropriate transmission of nerve impulses through glutamatergic synapses is required throughout the brain and forms the basis of many processes including learning and memory. However, abnormally high levels of extracellular brain glutamate can lead to neuroaxonal cell death. We have previously reported elevated glutamate levels in the brains of patients suffering from multiple sclerosis. Here two complementary analyses to assess the extent of genomic control over glutamate levels were used. First, a genome-wide association analysis in 382 patients with multiple sclerosis using brain glutamate concentration as a quantitative trait was conducted. In a second approach, a protein interaction network was used to find associated genes within the same pathway. The top associated marker was rs794185 (P < 6.44 × 10−7), a non-coding single nucleotide polymorphism within the gene sulphatase modifying factor 1. Our pathway approach identified a module composed of 70 genes with high relevance to glutamate biology. Individuals carrying a higher number of associated alleles from genes in this module showed the highest levels of glutamate. These individuals also showed greater decreases in N-acetylaspartate and in brain volume over 1 year of follow-up. Patients were then stratified by the amount of annual brain volume loss and the same approach was performed in the ‘high’ (n = 250) and ‘low’ (n = 132) neurodegeneration groups. The association with rs794185 was highly significant in the group with high neurodegeneration. Further, results from the network-based pathway analysis remained largely unchanged even after stratification. Results from these analyses indicated that variance in the activity of neurochemical pathways implicated in neurodegeneration is explained, at least in part, by the inheritance of common genetic polymorphisms. Spectroscopy-based imaging provides a novel quantitative endophenotype for genetic association studies directed towards identifying new factors that contribute to the heterogeneity of clinical expression of multiple sclerosis.
glutamate receptor; genetics; multiple sclerosis
[11C]PBR28, a radioligand targeting the translocator protein (TSPO), does not produce a specific binding signal in approximately 14% of healthy volunteers. This phenomenon has not been reported for [11C]PK11195, another TSPO radioligand. We measured the specific binding signals with [3H]PK11195 and [3H]PBR28 in brain tissue from 22 donors. Overall, 23% of the samples did not generate a visually detectable specific autoradiographic signal with [3H]PBR28, although all samples showed [3H]PK11195 binding. There was a marked reduction in the affinity of [3H]PBR28 for TSPO in samples with no visible [3H]PBR28 autoradiographic signal (Ki=188±15.6 nmol/L), relative to those showing normal signal (Ki=3.4±0.5 nmol/L, P<0.001). Of this latter group, [3H]PBR28 bound with a two-site fit in 40% of cases, with affinities (Ki) of 4.0±2.4 nmol/L (high-affinity site) and 313±77 nmol/L (low-affinity site). There was no difference in Kd or Bmax for [3H]PK11195 in samples showing no [3H]PBR28 autoradiographic signal relative to those showing normal [3H]PBR28 autoradiographic signal. [3H]PK11195 bound with a single site for all samples. The existence of three different binding patterns with PBR28 (high-affinity binding (46%), low-affinity binding (23%), and two-site binding (31%)) suggests that a reduction in [11C]PBR28 binding may not be interpreted simply as a reduction in TSPO density. The functional significance of differences in binding characteristics warrants further investigation.
PBR; [3H]PBR28; [3H]PK11195; radioligand binding; TSPO
11C-PBR28 PET can detect the 18-kDa translocator protein (TSPO) expressed within macrophages. However, quantitative evaluation of the signal in brain tissue from donors with multiple sclerosis (MS) shows that PBR28 binds the TSPO with high affinity (binding affinity [Ki], ~4 nM), low affinity (Ki, ~200 nM), or mixed affinity (2 sites with Ki, ~4 nM and ~300 nM). Our study tested whether similar binding behavior could be detected in brain tissue from donors with no history of neurologic disease, with TSPO-binding PET ligands other than 11C-PBR28, for TSPO present in peripheral blood, and with human brain PET data acquired in vivo with 11C-PBR28.
The affinity of TSPO ligands was measured in the human brain post-mortem from donors with a history of MS (n = 13), donors without any history of neurologic disease (n = 20), and in platelets from healthy volunteers (n = 13). Binding potential estimates from thirty-five 11C-PBR28 PET scans from an independent sample of healthy volunteers were analyzed using a gaussian mixture model.
Three binding affinity patterns were found in brains from subjects without neurologic disease in similar proportions to those reported previously from studies of MS brains. TSPO ligands showed substantial differences in affinity between subjects classified as high-affinity binders (HABs) and low-affinity binders (LABs). Differences in affinity between HABs and LABs are approximately 50-fold with PBR28, approximately 17-fold with PBR06, and approximately 4-fold with DAA1106, DPA713, and PBR111. Where differences in affinity between HABs and LABs were low (~4-fold), distinct affinities were not resolvable in binding curves for mixed-affinity binders (MABs), which appeared to express 1 class of sites with an affinity approximately equal to the mean of those for HABs and LABs. Mixed-affinity binding was detected in platelets from an independent sample (HAB, 69%; MAB, 31%), although LABs were not detected. Analysis of 11C-PBR28 PET data was not inconsistent with the existence of distinct subpopulations of HABs, MABs, and LABs.
With the exception of 11C-PK11195, all TSPO PET ligands in current clinical application recognize HABs, LABs, and MABs in brain tissue in vitro. Knowledge of subjects’ binding patterns will be required to accurately quantify TSPO expression in vivo using PET.
TSPO; mixed-affinity binding; radioligand binding
Degenerative features such as neuronal, glial, synaptic and axonal loss have been identified in neocortical and other grey matter structures in patients with multiple sclerosis, but mechanisms for neurodegeneration are unclear. Cortical demyelinating lesions are a potential cause of this degeneration but the pathological and clinical significance of these lesions is uncertain, as they remain difficult to identify and study in vivo. In this study we aimed to describe and quantify cellular and subcellular pathology in the cortex of MOG-induced marmoset experimental autoimmune encephalomyelitis using quantitative immunohistochemical methods.
We found evidence of diffuse axonal damage occurring throughout cortical grey matter with evidence for synaptic loss and gliosis and a 13.6% decrease in neuronal size and occurring in deep cortical layers. Evidence of additional axonal damage and a 29.6–36.5% loss of oligodendrocytes was found in demyelinated cortical lesions. Leucocortical lesions also showed neuronal loss of 22.2% and a 15.8% increase in oligodendrocyte size.
The marmoset EAE model therefore shows both focal and generalised neurodegeneration. The generalised changes cannot be directly related to focal lesions, suggesting that they either are a consequence of diffusible inflammatory factors or secondary to remote lesions acting through trans-synaptic or retrograde degeneration.
multiple sclerosis; cortex; inflammation; neurodegeneration; experimental autoimmune encephalomyelitis; marmoset; Callithrix jacchus; immunohistochemistry; demyelination; myelin oligodendrocyte glycoprotein
Marmoset experimental autoimmune encephalomyelitis (EAE) has previously been shown to replicate the essential features of both white matter and grey matter lesions of MS. This study set out to investigate whether cortical atrophy occurs in marmoset EAE and whether cortical thinning is related to the presence of focal, demyelinated cortical lesions.
17 leucocortical lesions and 13 subpial lesions were identified in 6 EAE cases. Cortical thickness surrounding these lesions was recorded and compared with matched cortical areas from 5 control animals.
We found a diffuse13–21% loss of cortical thickness in all areas of EAE cortex compared with control animals but there was no additional loss seen in demyelinated verses myelinated EAE cortex. These findings could not be accounted for by effects of age, sex and disease duration.
These findings confirm the presence of significant cortical atrophy in this model. We conclude that localised cortical demyelination is not responsible for the major part of the atrophy observed and that cortical thinning is largely due to more diffuse or more remote factors. Marmoset EAE is an invaluable tool which can be used to further investigate the cause and the substrate of cortical loss in demyelinating diseases.
multiple sclerosis; experimental autoimmune encephalomyelitis; marmoset; callithrix jacchus; cortical atrophy; cortical lesions
Reduced fecundity, associated with severe mental disorders1, places negative selection pressure on risk alleles and may explain, in part, why common variants have not been found that confer risk of disorders such as autism2 schizophrenia3 and mental retardation4. Thus, rare variants may account for a larger fraction of the overall genetic risk than previously assumed. In contrast to rare single nucleotide mutations, rare copy number variations (CNVs) can be detected using genome-wide single nucleotide polymorphism arrays. This has led to the identification of CNVs associated with mental retardation4,5 and autism2. In a genome-wide search for CNVs associating with schizophrenia, we used a population-based sample to identify de novo CNVs by analysing 9,878 transmissions from parents to offspring. The 66 de novo CNVs identified were tested for association in a sample of 1,433 schizophrenia cases and 33,250 controls. Three deletions at 1q21.1, 15q11.2 and 15q13.3 showing nominal association with schizophrenia in the first sample (phase I) were followed up in a second sample of 3,285 cases and 7,951 controls (phase II). All three deletions significantly associate with schizophrenia and related psychoses in the combined sample. The identification of these rare, recurrent risk variants, having occurred independently in multiple founders and being subject to negative selection, is important in itself. CNV analysis may also point the way to the identification of additional and more prevalent risk variants in genes and pathways involved in schizophrenia.
Genome-wide association studies (GWAS) testing several hundred thousand SNPs have been performed in multiple sclerosis (MS) and other complex diseases. Typically, the number of markers in which the evidence for association exceeds the genome-wide significance threshold is very small, and markers that do not exceed this threshold are generally neglected. Classical statistical analysis of these datasets in MS revealed genes with known immunological functions. However, many of the markers showing modest association may represent false negatives. We hypothesize that certain combinations of genes flagged by these markers can be identified if they belong to a common biological pathway. Here we conduct a pathway-oriented analysis of two GWAS in MS that takes into account all SNPs with nominal evidence of association (P < 0.05). Gene-wise P-values were superimposed on a human protein interaction network and searches were conducted to identify sub-networks containing a higher proportion of genes associated with MS than expected by chance. These sub-networks, and others generated at random as a control, were categorized for membership of biological pathways. GWAS from eight other diseases were analyzed to assess the specificity of the pathways identified. In the MS datasets, we identified sub-networks of genes from several immunological pathways including cell adhesion, communication and signaling. Remarkably, neural pathways, namely axon-guidance and synaptic potentiation, were also over-represented in MS. In addition to the immunological pathways previously identified, we report here for the first time the potential involvement of neural pathways in MS susceptibility.
Category-related brain activations have been reported in the posterior fusiform gyri when people view pictures of tools and animals, but only a single study has observed this pattern when the stimuli were words, rather than pictures. Here we replicate these category effects with words and provide evidence that distinctive patterns of activation are task-specific. The results suggest that category-related activation in the posterior fusiform gyri can be driven either “bottom-up” by visual processing of images or “top-down” by word processing.
category-specificity; written words; visual form processing; posterior fusiform gyri; fMRI
Functional neuroimaging has demonstrated reduced activation correlated with behavioural priming effects, a finding generally interpreted in terms of facilitated retrieval of target items in the context of related primes. Without a neutral prime, however, one cannot separate facilitatory effects of related primes from inhibitory effects of unrelated primes. Here we report an auditory semantic priming paradigm with congruent (“The boy bounced the ball”), neutral (“The next item is ball”), and incongruent (“Pasta is my favourite kind of ball”) sentence trials. As previously reported, reduced LIPC activation was observed for congruent relative to incongruent trials; however, the neutral condition allowed us to show that the effect arose from increased activation in the incongruent condition rather than reduced activation for congruent trials. Our results suggest that LIPC inhibits interference from pre-potent representations in order to select a task-appropriate target, and is consistent with its broader role in behavioural inhibition.
sentence processing; inhibition; facilitation; LIPC; fMRI
Studies of skilled reading (Price & Mechelli, 2005), its acquisition in children (Shaywitz et al., 2002; Turkeltaub, Gareau, Flowers, Zeffiro, & Eden, 2003), and its impairment in patients with pure alexia (Leff et al., 2001), all highlight the importance of the left posterior fusiform cortex in visual word recognition. We used visual masked priming and fMRI to elucidate the specific functional contribution of this region to reading and found that: i) unlike words, repetition of pseudowords (“solst-solst”) did not produce a neural priming effect in this region, ii) orthographically related words such as “corner-corn” did produce a neural priming effect, but iii) this orthographic priming effect was reduced when prime-target pairs were semantically related (“teacher-teach”). These findings conflict with the notion of stored visual word forms and instead suggest that this region acts as an interface between visual form information and higher-order stimulus properties such as its associated sound and meaning. Importantly, this function is not specific to reading, but is also engaged when processing any meaningful visual stimulus.
Reading; fusiform; visual word form area; fMRI; masked priming
Activated microglia are thought to play a major role in cortical gray matter (GM) demyelination in multiple sclerosis (MS). Our objective was to evaluate microglial activation in cortical GM of patients with MS in vivo and to explore its relationship to measures of disability.
Using PET and optimized modeling and segmentation procedures, we investigated cortical 11C-PK11195 (PK11195) binding in patients with relapsing-remitting MS (RRMS), patients with secondary progressive MS (SPMS), and healthy controls. Disability was assessed with the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Impact Scale (MSIS-29).
Patients with MS showed increased cortical GM PK11195 binding relative to controls, which was multifocal and highest in the postcentral, middle frontal, anterior orbital, fusiform, and parahippocampal gyri. Patients with SPMS also showed additional increases in precentral, superior parietal, lingual and anterior superior, medial and inferior temporal gyri. Total cortical GM PK11195 binding correlated with EDSS scores, with a stronger correlation for the subgroup of patients with SPMS. In patients with SPMS, PK11195 binding also correlated with MSIS-29 scores. No correlation with disability measures was seen for PK11195 binding in white matter. Higher EDSS scores correlated with higher levels of GM PK11195 binding in the postcentral gyrus for patients with RRMS and in precentral gyrus for those with SPMS.
Microglial activation in cortical GM of patients with MS can be assessed in vivo. The distribution is not uniform and shows a relationship to clinical disability. We speculate that the increased PK11195 binding corresponds to enhanced microglial activation described in postmortem SPMS cortical GM.