Reduction In Cortical Thickness Research Articles

Cortical thickness correlates of minor neurological signs in patients with first episode psychosis

Neurological soft signs (NSS) are subtle abnormalities of motor and sensory function that are present in the absence of localized brain pathological lesions. In psychoses they have been consistently associated with a distinct pattern of cortical and subcortical brain structural alterations at the level of the heteromodal cortex and basal ganglia. However, a more specific and accurate evaluation of the cytoarchitecture of the cortical mantle could further advance our understanding of the neurobiological substrate of psychosis.We investigated the relationship between brain structure and NSS in a sample of 66 patients at their first episode of psychosis. We used the Neurological Evaluation Scale for neurological assessment and high-resolution MRI and Freesurfer to explore cortical thickness and surface area. Higher rates of NSS were associated with a reduction of cortical thickness in the precentral and postcentral gyri, inferior-parietal, superior temporal, and fusiform gyri. Higher rates of NSS were also associated with smaller surface areas of superior temporal gyrus and frontal regions (including middle frontal, superior and orbito-frontal gyri). Finally, more sensory integration signs were also associated with larger surface area of the latero-occipital region.We conclude that the presence of NSS in psychosis is associated with distinct but widespread changes in cortical thickness and surface area, in areas crucial for sensory-motor integration and for the fluid execution of movement. Studying these morphological correlates with advanced neuroimaging techniques can continue to improve our knowledge on the neurobiological substrate of these important functional correlates of psychosis.

Effects of Sedentary Behavior and Physical Activity on Cognitive Function are Conferred by Cortical Thickness

Physical activity and aerobic fitness may have positive impacts on brain structure and function in older adults. Conversely, sedentary behavior may have negative effects. PURPOSE: To determine associations of sedentary behavior with cerebral cortical thickness and neurocognitive function in older adults in cognitively normal older adults (NC) and patients with mild cognitive impairment (MCI). METHODS: We tested 28 NC and 50 MCI participants matched for age, sex, and education. Participants wore a 3D accelerometer for 1 week to measure daily physical activity levels. Minutes spent in sedentary behavior (<4.0METs) and moderate-to-vigorous physical activity (MVPA) (>5.0METs) were recorded. RESULTS: Sedentary behavior and MVPA were associated with cortical thickness in multiple brain regions within the default mode network. The effects of sedentary behavior on Trails B performance were mediated through left middle temporal gyrus (B=0.0017, SE=0.0010, 0.0002 to 0.0046 95% CI) and right frontal pole (B=0.0027, SE=0.0013, 0.0006 to 0.0058 95%CI) cortical thickness. MVPA (B=-0.011, SE=0.0070, -0.0304 to -0.0006 95%CI) positively impacted Trails B through left middle temporal gyrus thickness. California Verbal Learning Test cued recall was negatively affected by sedentary behavior (B=-0.00026, SE=0.0013, 0.0006 to 0.0058 95%CI), but positively affected by MVPA (B=0.0012, SE=0.0008, 0.0001 to 0.0033 95%CI) through right superior parietal cortical thickness. Cognitive status moderated the association of sedentary behavior with left posterior cingulate thickness (interaction, p=0.02) and MVPA to right supramarginal gyrus thickness (interaction, p=0.04) with greater effects occurring in NC. CONCLUSION: Sedentary behavior is associated with reductions in cerebral cortical thickness which lead to impairment in memory and executive function in older adults. Sedentary behavior may be more detrimental to individuals with normal cognitive function. Supported by the NIH (R01AG033106)

S139. Accelerated Cortical Thinning Within Structural Brain Networks is Associated With Irritability in Youth

Irritability is an important dimension of psychopathology that spans multiple clinical diagnostic categories, yet its relationship to patterns of brain development remains sparsely explored. Here, we examined how transdiagnostic symptoms of irritability relate to the development of structural brain networks. All participants (n = 137, 83 females) completed structural brain imaging with 3 Tesla MRI at two timepoints (mean age at follow-up: 21.1 years, mean inter-scan interval: 5.2 years). Irritability at follow-up was assessed using the Affective Reactivity Index, and cortical thickness was quantified using Advanced Normalization Tools software. Structural covariance networks were delineated using non-negative matrix factorization, a multivariate analysis technique. Both cross-sectional and longitudinal associations with irritability at follow-up were evaluated using generalized additive models with penalized splines. The False Discovery Rate (q < 0.05) was used to correct for multiple comparisons. Cross-sectional analysis of follow-up data revealed that 11 of the 24 covariance networks were associated with irritability, with higher levels of irritability being associated with thinner cortex. Longitudinal analyses further revealed that accelerated cortical thinning within nine networks was related to irritability at follow-up. Effects were particularly prominent in brain regions implicated in emotion regulation, including the orbitofrontal, lateral temporal, and medial temporal cortex. Collectively, these findings suggest that irritability is associated with widespread reductions in cortical thickness and accelerated cortical thinning, particularly within the frontal and temporal cortex. Aberrant structural maturation of regions important for emotional regulation may in part underlie symptoms of irritability.

Loss of Wnt9a and Wnt4 causes degenerative joint alterations

Purpose: Both induced and reduced Wnt-signaling has been shown in literature to contribute to osteoarthritis. The Wnt-ligands Wnt9a and Wnt4 are of special interest since they are expressed in cells of the joint forming region and are positive regulators of chondrocyte maturation. More specifically, Wnt9a regulates the pace of chondrocyte proliferation and maturation, while Wnt4 regulates chondrocyte maturation at the transition from prehypertrophic to hypertrophic chondrocytes and misexpression accelerates chondrocyte maturation. Wnt9a downregulation has been shown in OA patients, and knockout or inhibition of β-catenin leads to the destruction of articular cartilage in mice. In addition, Wnt-antagonists Dkk-1 and Frzb-1 are expressed by articular chondrocytes, suggesting that canonical Wnt-signaling in articular chondrocytes has to be tightly controlled. Methods: Here, we investigate the effects of loss of Wnt9a and the combined loss of Wnt9a and Wnt4 with respect to joint maintenance in aged mice. To circumvent the postnatal lethality of loss of Wnt9a and Wnt4, the genes for both Wnt ligands were either conditionally deleted in the limb mesenchyme (Prx1-Cre), or in the case of Wnt9a in the superficial zone of the articular cartilage (Prg4-Cre). The resulting skeletal phenotype was analyzed at the ages of 6, 9 and 12 months by μCT and histology. To investigate expression changes in chondrocytes and synovial fibroblasts upon deletion of Wnt9a and Wnt4, we isolated superficial zone cells and deeper layered chondrocytes from femoral condyles and tibial plateaus of the knee and synovial fibroblasts from paws of 8-day-old Wnt9afl/fl and Wnt4fl/fl mice. Cultured cells were either infected with a lentivirus expressing or non-expressing Cre and alterations in gene expression levels were measured via qPCR. Results: The limb specific Wnt9a knockout mice show a joint phenotype at the age of 9 months. The onset of the phenotypic changes in the joints is accelerated by the additional loss of Wnt4. Phenotypically, the articular cartilage shows loss of proteoglycans, erosion, reduction of subchondral cortical thickness, and formation of ectopic calcifications and osteophytes at the knee joint. These alterations are progressively worsening with the age of the mice. Concomitant with the reduction of subchondral cortical thickness, an enriched TRAP-positive cell population can be found in the subchondral compartment. Mice with a conditional loss of Wnt9a in the superficial articular zone show degenerative changes of the articular cartilage at an age of 12 months. In the in vitro chondrocyte culture experiments a downregulation of Prg4 and an upregulation of Tnfsf11 (encoding RANKL) was observed upon the combined knockdown of Wnt9a and Wnt4 while an upregulation of Il-6 was noted upon deletion of Wnt9a alone. In fibroblast cultures an upregulation of Cd34 and metalloproteases Mmp9, Adamts-4 and Adamts-5 and can be detected in Wnt9a single and combined Wnt9a and Wnt4 knowdowns. Conclusions: Taken together, our results further support the notion that imbalanced Wnt-signaling can cause degenerative joint alterations. Furthermore, we show that Wnt9a and Wnt4 signaling are critical for maintenance of the joint. Yet, the underlying mechanisms remain to be elucidated in the future.

S182. CHANGE IN CORTICAL MORPHOMETRY IN INDIVIDUALS WITH PERSISTING PSYCHOTIC EXPERIENCES: A LONGITUDINAL PILOT STUDY

BackgroundThere is an increasing interest in the presence of psychotic symptoms in the general population that do not meet the threshold for psychotic disorder. Such psychotic experiences (PEs) are more prevalent than conditions such as schizophrenia and often manifest during childhood and adolescence. PEs are a risk factor for psychotic disorders and a range of adverse psychosocial outcomes. PEs can become abnormally persistent with a corresponding increase in psychiatric morbidity. Previous research has highlighted subtle deviations in brain structure associated with the presence and persistence of PEs, but longitudinal assessments are needed to gauge if these deviations continue, perhaps as part of an atypical neurodevelopmental trajectory.MethodsLongitudinal imaging data, taken at ages 20 and 25, were available for 25 young adults who were part an MRI nested case control study within the Avon Longitudinal Study of Parents and Children. They were selected originally on the basis of presence or absence of PEs. Cortical surface data were analysed using Freesurfer. Presence of PEs was assessed at ages 18, 20, and 25 and we defined persistence as endorsing PEs at multiple time-points. Average cortical volume and thickness were extracted from each brain parcellation. We additionally calculated fractal dimensionality (FD) of each parcellation using a box-count algorithm to capture shape complexity. We compared the rate of change between healthy controls (HC) and those with persistent PEs in each parcellation and used permutation testing to control for multiple comparisons.ResultsBoth HC and PEs showed the expected age-related net loss in brain volume; an increase in white matter volume offset by a greater reduction in grey matter. We identified greater volume loss in PEs in the left parietal lobe and further examination of local volume highlighted additional changes. PEs were associated with a greater rate of volume loss in the anterior cingulate, postcentral, and lingual gyrus in the left hemisphere and in the right inferior parietal lobule and pars orbitalis. Thinning of the left inferior parietal lobule was greater in those with PEs. There was further converging evidence of focal abnormalities in the left postcentral gyrus in terms of reductions in cortical thickness and FD in PEs. Similarly, we found reduced FD relative to HC in the left rostral anterior cingulate. There was additional evidence for reductions in FD in the left hemisphere in the cuneus, isthmus cingulate, and middle frontal gyrus.DiscussionOur findings highlight a deviation from typical age-related changes in brain volume in individuals with persisting manifestations of PEs. Though these changes could reflect an acceleration of the typical volume loss that is seen with aging, there are several points of evidence against this. We found no differences in global volume changes and only the left parietal lobule was found to show a greater volume loss in PEs. On a local scale, findings seemed to mostly converge on parietal and cingulate regions in the left hemisphere with some evidence of aberrations in frontal regions. These pilot data are, uniquely, unconfounded by illness and treatment related factors and highlight the continued need for longitudinal assessments of brain structure in relation to PEs; there is an increasing risk of transitioning to a psychotic disorder with persistence of PEs and our findings may reflect the neuroanatomical basis for an anomalous developmental trajectory related to psychotic disorders.

F28. PROGRESSIVE POST-ONSET REORGANISATION OF MRI-DERIVED CORTICAL THICKNESS IN ADOLESCENTS WITH SCHIZOPHRENIA

BackgroundCortical thickness changes continuously throughout healthy adolescence reflecting ongoing maturation. In schizophrenia, distributed abnormalities in cortical maturation are suspected. To study if these distributed changes are a result of a co-ordinated process, we investigated the structural covariance among the longitudinal post-onset thickness changes that occur across various brain regions in adolescent-onset schizophrenia.Methods19 healthy adolescents and 18 age-matched patients with early-onset schizophrenia were scanned twice (~2 years’ interval). The rate of change in cortical thickness was estimated both at lobar and sulcogyral level. Group level structural covariance was studied using a graph theoretical framework.ResultsAt baseline, patients had distributed reduction in cortical thickness compared to controls, though this deviation was abolished over the next 2 years. Occipital cortex had a significantly deviant rate of change in patients (0.8% increase per year) compared to controls (2.5% thinning/year). Patients had a significant increase in covariance of right anterior insula and calcarine sulcus with rest of the brain.DiscussionPost-onset structural changes in EOS are not a result of random, mutually independent processes. A spatially interconnected reorganization process, distinct from normal maturational events may underlie these distributed changes.

S184. MACHINE LEARNING REVEALS DEVIANCE IN NEUROANATOMICAL MATURITY PREDICTIVE OF FUTURE PSYCHOSIS IN YOUTH AT CLINICAL HIGH RISK

BackgroundBoth early (pre- and perinatal) and late (adolescent) neurodevelopmental disturbances are hypothesized to contribute to the pathophysiology of schizophrenia. Disturbances originating earlier in life (e.g., resulting from the interplay of genetic factors and obstetric complications) would be expected to affect brain integrity from birth onwards and could therefore help to explain cases with subtle deficits in premorbid functioning during childhood and earlier ages at onset of full psychosis (i.e., early to mid-teens). In contrast, disturbances that emerge during late adolescence and early adulthood (e.g., via abnormal neuromaturational events and/or environmental factors) could help to explain cases with normal premorbid psychological health and a more acute onset of psychotic symptoms and functional impairment in the late teens and early twenties. However, it is yet unclear whether neuroanatomical data among individuals at clinical high risk (CHR) for psychosis can be modeled to detect early versus late neurodevelopmental influences that is predictive of future psychosis onset. Therefore, in this study, we investigated whether the timing of the appearance or course of the deviation from normal brain maturation, as determined using a machine learning algorithm trained on structural MRI data to estimate age, is potentially relevant to the early versus late neurodevelopmental framework among CHR individuals.MethodsA neuroanatomical-based age prediction model was trained using a supervised machine learning technique with T1 MRI scans from 953 typically developing healthy controls (HC) from the Pediatric Imaging, Neurocognition, and Genetics study (PING) study. The trained model was then applied to 109 HCs and 275 CHR, including 39 converters (CHR-C), from the North American Prodrome Longitudinal Study (NAPLS2) and 14 cases of first episode psychosis patients (FE) for external validation and clinical application. Discrepancy between neuroanatomical-based estimated age and chronological age was computed for each individual (i.e., brain age gap) and compared across clinical groups.ResultsThe PING-derived model for estimating age accurately predicted NAPLS HC subjects’ chronological ages, explaining 51% of the variance (P < 0.001) in chronological age, with a mean absolute error of 1.41 years, providing evidence of independent external validation. CHR subjects and FE adolescents showed a significantly greater overestimated gap between model-predicted age and chronological age compared with HC (Ps < 0.01). This effect was significantly moderated by chronological age, with neuroanatomical-based estimated age systematically overestimating CHR cases aged 12–17 years, but not among those aged 18–21 years. In the ROC analysis, brain age gap was a significant predictor of conversion to psychosis with an area under the curve of 0.63 (P < 0.05) among younger adolescents. In addition, increased deviation of brain age gap predicted pattern of stably low functioning over time (P < 0.05) among CHR individuals. In contrast, previously reported evidence of an accelerated reduction in cortical thickness among CHR-C was found to apply only to those cases who were 18 years or older.DiscussionThese results are consistent with the view that both early and later neurodevelopmental disturbances contribute to the onset and course of schizophrenia, with the two sets of influences having differing implications for the intercepts and trajectories in structural brain parameters as a function of age. The results also suggest that baseline neuroanatomical measures are likely to be useful in prediction of psychosis especially (or only) among CHR cases who are below 18 years of age at the time of ascertainment.

T166. SPATIAL INCOHERENCE OF LARGE-SCALE CORTICAL NETWORKS RELATES TO FORMAL THOUGHT DISORDER IN SCHIZOPHRENIA: A 7T MRI-BASED THICKNESS STUDY

BackgroundThe thickness of cerebral cortex varies across individuals as well as across different regions within an individual. Shared trophic or plastic influences such as repeated task-related recruitment of extant brain regions results in morphological covariance within large-scale brain networks. Pathological processes disrupting functional co-activation can result in higher than expected degree of variability within large-scale networks in an individual level, resulting in spatial incoherence. We studied spatial incoherence of cortical thickness in 17 cortical networks identified on the basis of well-known patterns of intrinsic connectivity, to identify the spatially incoherent networks and relate them to differences in severity of thought disorder among patients with schizophrenia.MethodsUltra-high field 7T anatomical MRI scans (MPRAGE) were obtained from 20 subjects in a clinically stable, medicated early stage of schizophrenia, and 19 sex, parental socioeconomic-status and age matched healthy controls. Cortical thickness was estimated using Freesurfer v5.0, across 17 networks based on the parcellation scheme of Yeo et al. We computed within-network coefficient of variation in thickness (CVT) across vertices that constitute each network. Higher CVT of a network in a subject indicates higher spatial incoherence within the network for that individual. Independent 2-tailed t-tests were used to compare CVT of 17 networks between the 2 groups with FDR-corrected p=0.05 considered as statistically significant. We related CVT of affected networks to the scores of positive and negative Formal Thought Disorder measured using Thought and Language Index in patients.ResultsSalience Network (aka Ventral Attention Network as per Yeo atlas), Default Mode Network and Central Executive Network (aka dorsal Attention Network in Yeo atlas) showed most significant reduction in MRI-derived cortical thickness (networks #8, #12, #15 as well as #16 of Yeo atlas). Only the Salience and Executive Networks (network #8 and #12) showed higher coefficient of variation in patients compared to controls, indicating either a failure of coordinated maturation or co-ordinated function. Higher spatial incoherence of Salience Network related to reduced mean thickness of Central Executive Network in patients with schizophrenia; this relationship was not seen in healthy controls (Fisher’s z test, p=0.02). Both higher coefficient of variation in Salience Network and lower mean thickness in Central Executive Network predicted the severity of positive but not negative thought disorder scores.DiscussionOur results indicate that (1) large-scale cortical networks involved in information processing (Salience and Executive Networks) show spatial incoherence in schizophrenia (2) the degree of spatial incoherence relates to the severity of disorganisation of thoughts and language in patients. Spatial incoherence may be the result of a dysmaturational or functional dysplastic effect reflecting inefficient cortical recruitment in schizophrenia. Within-subject morphological variability carries useful information that can potentially explain the elusive neural basis of complex symptoms such as formal thought disorder.

Inducible Wnt16 inactivation: WNT16 regulates cortical bone thickness in adult mice.

Substantial progress has been made in the therapeutic reduction of vertebral fracture risk in patients with osteoporosis, but non-vertebral fracture risk has been improved only marginally. Human genetic studies demonstrate that the WNT16 locus is a major determinant of cortical bone thickness and non-vertebral fracture risk and mouse models with life-long Wnt16 inactivation revealed that WNT16 is a key regulator of cortical thickness. These studies, however, could not exclude that the effect of Wnt16 inactivation on cortical thickness might be caused by early developmental and/or growth effects. To determine the effect of WNT16 specifically on adult cortical bone homeostasis, Wnt16 was conditionally ablated in young adult and old mice through tamoxifen-inducible Cre-mediated recombination using CAG-Cre-ER; Wnt16flox/flox (Cre-Wnt16flox/flox) mice. First, 10-week-old Cre-Wnt16flox/flox and Wnt16flox/flox littermate control mice were treated with tamoxifen. Four weeks later, Wnt16 mRNA levels in cortical bone were reduced and cortical thickness in femur was decreased in Cre-Wnt16flox/flox mice compared to Wnt16flox/flox mice. Then, inactivation of Wnt16 in 47-week-old mice (evaluated four weeks later) resulted in a reduction of Wnt16 mRNA levels, cortical thickness and cortical bone strength with no effect on trabecular bone volume fraction. Mechanistic studies demonstrated that the reduced cortical bone thickness was caused by a combination of increased bone resorption and reduced periosteal bone formation. In conclusion, WNT16 is a crucial regulator of cortical bone thickness in young adult and old mice. We propose that new treatment strategies targeting the adult regulation of WNT16 might be useful to reduce fracture risk at cortical bone sites.

Verbal Memory Performance and Reduced Cortical Thickness of Brain Regions Along the Uncinate Fasciculus in Young Adult Cannabis Users.

Introduction: Memory impairment is one of the most commonly reported effects of cannabis use, especially among those who initiate use earlier, perhaps due to the effects of delta-9- tetrahydrocannabinol on cannabinoid (CB1) receptors in the brain. Studies have increasingly investigated whether cannabis use is associated with impairments in verbal memory, and with alterations in brain structures underlying verbal memory. The uncinate fasciculus (UF), a long-range white matter tract, connects regions with densely localized CB1 receptors that are important in verbal memory. This study investigated the impact of cannabis use on UF structures and its association with memory performance in young adult cannabis users (CU) and non-using controls (CON).Materials and Methods: Nineteen CU and 22 CON completed a verbal memory task and a neuroimaging protocol, in which diffusion tensor imaging and structural scans were collected. We compared memory performance, diffusion and tractography measures of the UF, and cortical thickness of regions connected by the UF, between CU and CON. In regions showing a significant group effect, we also examined associations between verbal memory performance, cortical thickness, and age of onset of cannabis use.Results: Compared to non-users, CU had worse memory performance, decreased fiber bundle length in the UF, and decreased cortical thickness of brain regions along the UF such as the entorhinal cortex and fusiform gyrus. Verbal memory performance was significantly associated with age of onset of cannabis use, indicating that those who initiated cannabis use at an earlier age performed worse. Cortical thickness of the entorhinal cortex was significantly correlated with age of first use and memory performance.Conclusion: This study provides evidence that cannabis use, especially when initiated at a young age, may be associated with worse verbal memory and altered neural development along the UF. Reductions in cortical thickness in regions implicated in memory processes may underlie weaknesses in verbal memory performance.

P.3.025 - Reduced thickness of the cingulate cortex in adolescents at ultra-high risk for psychosis

Introduction Identification of individuals at ultra-high risk for psychosis (UHR) has the potential to help prevent or delay the onset of disease [1]. Structural MRI studies have revealed that UHR are characterized by cortical thickness (CTH) reductions in temporal, frontal and cingulate cortices in both cross-sectional and longitudinal comparisons [2,3]. However, studies so far have focused on adult samples, with few exceptions [4]. Aim To provide evidence regarding how onset of prodromal symptoms during adolescence impacts on changes in CTH, and how CTH relates with clinical features. Methods Multicentre cross-sectional case-control study, including adolescents aged 10-17 years, recruited from child and adolescent mental health services of two independent Hospitals in Barcelona. UHR individuals were identified using the Structured Interview for Prodromal Syndromes criteria with some modifications. Healthy controls (HC) were recruited from the same geographical area. Exclusion criteria for all participants comprised personal history of psychotic symptoms, IQ High-resolution magnetic resonance structural images were acquired on a 3Tesla and 1.5Tesla scanners. An inter-site compatibility study (conducted with healthy controls) revealed high inter-site correlation coefficients (r>.6) for CTH measures. Images were pre-processed employing automated procedures implemented in FreeSurfer 5.3.0, cortical parcellation employed the Desikan-Killiany brain atlas. Analyses: First, mean global and lobar (frontal, parietal, temporal, occipital, insula and cingulate) CTH measurements were computed. Then, within lobes showing group effects, CTH was measured for each parcellation. Between-group analyses were conducted with the general linear model in SPSS 22.0, including gender, age, total intracranial volume and site as covariates. Finally, pearson correlations were performed to test associations between CTH measures and symptom severity (Scale of Prodromal Symptoms). Significance was set at p Results 122 subjects were included (77 UHR vs. 45 HC, mean ages: 15.1(SD=1.8) vs. 15.8(SD=1.5), t=1.9, p=0.055; gender (%female): 61.0% vs 69.9%, χ2=0.76, p=0.38). There were no significant differences in case-control proportion between centres: χ2=1.3, p=0.25. No significant differences in global CTH in UHR (2.57mm, SD=0.10) relative to HC (2.59mm, SD=0.14) were found. Between-group analyses showed a significantly lower CTH in the right cingulate in UHR compared to HC (F=12.2, pFDR=0.01). Within the right cingulate, CTH in the posterior cingulate (F=11.5, pFDR=0.004), isthmus cingulate (F=8.2, pFDR=0.01) and caudal anterior cingulate (F=5.4, pFDR=0.03) was smaller in UHR compared to HC. Pearson correlation showed a significant inverse association between symptom severity and CTH in right posterior cingulate (p=0.01) and isthmus cingulate (p=0.04) uncorrected. Discussion UHR showed significant cortical thinning in several regions of the right cingulate, which correlated with symptom severity. These findings add support to the notion that structural alterations in the cingulate cortex may be present in children and adolescents prior to onset of psychosis and may be associated with attenuated psychotic symptoms. Longitudinal follow-up of this sample will inform on which of these cross-sectional changes are related to transition.

Migraine improvement correlates with posterior cingulate cortical thickness reduction.

Objective The main goal of this study was to correlate migraine improvement, after prophylactic therapy, with cortical thickness changes. Methods Cortical thickness maps were obtained with magnetic resonance imaging (MRI) from 19 patients with migraine before (first scan) and after (second scan) prophylactic treatment, and these were compared with controls using the FreeSurfer MRI tool. Cortical changes were correlated with the headache index (HI). Results Anincrease incortical thickness was found in the right cuneus and precuneus, somatosensory and superior parietal cortices in both patient scans, compared with the controls. No changes were observed in the left hemisphere. Following correction for multiple comparisons, no areas changed from the first to the second scan. Regression analysis showed a significant negative correlation between the HI improvement and cortical thickness changes in the left posterior cingulate, a region involved with nociception and, possibly, the development of chronic pain. Conclusion There were changes in cortical thickness in patients with migraine relative to controls in areas involved with vision and pain processing. Left posterior cingulate cortical changes correlated with headache frequency and intensity.

Effects of HIV Infection, methamphetamine dependence and age on cortical thickness, area and volume.

ObjectiveThis study examined the effects of HIV infection, methamphetamine dependence and their interaction on cortical thickness, area and volume, as well as the potential interactive effects on cortical morphometry of HIV and methamphetamine with age.MethodT1-weighted structural images were obtained on a 3.0T General Electric MR750 scanner. Freesurfer v5.3.0 was used to derive cortical thickness, area and volume measures in thirty-four regions based on Desikan-Killiany atlas labels.ResultsFollowing correction for multiple statistical tests, HIV diagnosis was not significantly related to cortical thickness or area in any ROI, although smaller global cortical area and volume were seen in those with lower nadir CD4 count. HIV diagnosis, nevertheless, was associated with smaller mean cortical volumes in rostral middle frontal gyrus and in the inferior and superior parietal lobes. Methamphetamine dependence was significantly associated with thinner cortex especially in posterior cingulate gyrus, but was not associated with cortical area or volume following correction for multiple statistical tests. We found little evidence that methamphetamine dependence moderated differences in cortical area, volume or thickness for any ROI in the HIV seropositive group. Interactions with age revealed that HIV diagnosis attenuated the degree of age-related cortical thinning seen in non-infected individuals; intercepts indicated that young HIV seropositive individuals had thinner cortex than non-infected peers.ConclusionsMethamphetamine dependence does not appear to potentiate a reduction of cortical area, volume or thickness in HIV seropositive individuals. The finding of thinner cortex in young HIV seropositive individuals and the association between CD4 nadir and global cortical area and volume argue for prioritizing early antiretroviral treatment.

Structural and functional abnormalities of the insular cortex in trigeminal neuralgia: a multimodal magnetic resonance imaging analysis.

Trigeminal neuralgia (TN) is a chronic neuropathic pain disorder characterized by intense, lancinating attacks of facial pain. Increasing evidence suggests that TN is accompanied by abnormalities in brain morphology, white matter microstructure, and function. However, whether these abnormalities are linked or reflect independent etiologies remains unknown. Using multimodal magnetic resonance imaging data of 20 patients with TN and 21 healthy controls, we investigated cortical gyrification abnormalities, their relationships with abnormalities of the underlying white matter microstructure and gray matter morphology, as well as their functional significance in TN. Compared with controls, patients with TN showed significant local gyrification index (LGI) reductions predominantly in the left insular cortex, which were negatively correlated with pain intensity. In this cluster, patients with TN had concurrent cortical thickness reductions but unaltered cortical surface area. Meanwhile, LGI of this cluster was not correlated with overlying cortical thickness or surface area but was positively correlated with the fractional anisotropy of 2 nearby white matter clusters, suggesting that insular LGI reductions may be primarily driven by microstructural abnormalities of the underlying white matter tracts, rather than by abnormalities in cortical thickness and surface area. In addition, patients with TN exhibited increased insula functional connectivity to the left posterior cingulate cortex and thalamus, which was positively correlated with disease duration. These findings provide new evidence for the involvement of insular abnormalities in the pathophysiology of TN.

Kit W-sh Mutation Prevents Cancellous Bone Loss during Calcium Deprivation.

Calcium is essential for normal bone growth and development. Inadequate calcium intake increases the risk of osteoporosis and fractures. Kit ligand/c-Kit signaling plays an important role in regulating bone homeostasis. Mice with c-Kit mutations are osteopenic. The present study aimed to investigate whether impairment of or reduction in c-Kit signaling affects bone turnover during calcium deprivation. Three-week-old male WBB6F1/J-Kit W /Kit W-v /J (W/W v ) mice with c-Kit point mutation, Kit W-sh /HNihrJaeBsmJ (W sh /W sh ) mice with an inversion mutation in the regulatory elements upstream of the c-Kit promoter region, and their wild-type controls (WT) were fed either a normal (0.6% calcium) or a low calcium diet (0.02% calcium) for 3weeks. μCT analysis indicated that both mutants fed normal calcium diet had significantly decreased cortical thickness and cancellous bone volume compared to WT. The low calcium diet resulted in a comparable reduction in cortical bone volume and cortical thickness in the W/W v and W sh /W sh mice, and their corresponding controls. As expected, the low calcium diet induced cancellous bone loss in the W/W v mice. In contrast, W sh /W sh cancellous bone did not respond to this diet. This c-Kit mutation prevented cancellous bone loss by antagonizing the low calcium diet-induced increase in osteoblast and osteoclast numbers in the W sh /W sh mice. Gene expression profiling showed that calcium deficiency increased Osx, Ocn, Alp, type I collagen, c-Fms, M-CSF, and RANKL/OPG mRNA expression in controls; however, the W sh mutation suppressed these effects. Our findings indicate that although calcium restriction increased bone turnover, leading to osteopenia, the decreased c-Kit expression levels in the W sh /W sh mice prevented the low calcium diet-induced increase in cancellous bone turnover and bone loss but not the cortical bone loss.

Preserved cortical asymmetry despite thinner cortex in children and adolescents with prenatal alcohol exposure and associated conditions.

Prenatal alcohol exposure (PAE) is associated with reduced overall brain volume. Although this has been reported consistently across studies, the status of cortical thickness after PAE is more variable. The cortex is asymmetric in typical controls, but it is unclear whether the left and right counter parts of the cortical gray matter are unevenly influenced in postpartum brain development after PAE. Brain MRI was acquired in a newly recruited sample of 157 participants (PAE: N = 78, 5.5-18.9 years, 40 females and controls: N = 79, 5.8-18.5 years, 44 females) across four Canadian sites in the NeuroDevNet project. The PAE group had other confounds such as psychiatric co-morbidity, different living environment, and so on, not present in the control group. In agreement with previous studies, the volumes of all brain structures were reduced in PAE compared to controls, including gray and white matter of cerebrum and cerebellum, and all deep gray matter including the hippocampus, amygdala, thalamus, caudate, putamen, and pallidum. The PAE group showed reductions in global and regional cortical thickness, while the pattern and degree of cortical thickness asymmetry were preserved in PAE participants with the greatest rightward asymmetry in the lateral parietal lobe and the greatest leftward asymmetry in the lateral frontal cortex. This persistent asymmetry reflects that the homologous left and right cortical regions followed typical relative developmental patterns in the PAE group despite being thinner bilaterally than controls. Hum Brain Mapp 39:72-88, 2018. © 2017 Wiley Periodicals, Inc.

Age-related brain structural alterations as an intermediate phenotype of psychosis.

There is only limited agreement with respect to location, directionality and functional implications of brain structural alterations observed in patients with schizophrenia. Additionally, their link to occurrence of psychotic symptoms remains unclear. A viable way of addressing these questions is to examine populations in an at-risk mental state (ARMS) before the transition to psychosis. We tested for structural brain alterations in individuals in an ARMS compared with healthy controls and patients with first-episode psychosis (FEP) using voxel-based morphometry and measures of cortical thickness. Furthermore, we evaluated if these alterations were modified by age and whether they were linked to the observed clinical symptoms. Our sample included 59 individuals with ARMS, 26 healthy controls and 59 patients with FEP. We found increased grey matter volume and cortical thickness in individuals with ARMS and a similar pattern of structural alterations in patients with FEP. We further found stronger age-related reductions in grey matter volume and cortical thickness in both patients with FEP and individuals with ARMS, linking these alterations to observed clinical symptoms. The ARMS group comprised subgroups with heterogeneous levels of psychosis risk and medication status. Furthermore, the cross-sectional nature of our study and the reduced number of older patients limit conclusions with respect to observed interactions with age. Our findings on consistent structural alterations in individuals with ARMS and patients with FEP and their link to clinical symptoms have major implications for understanding their time of occurrence and relevance to psychotic symptoms. Interactions with age found for these alterations may explain the heterogeneity of findings reported in the literature.

Reduction of prefrontal thickness in military police officers with post-traumatic stress disorder

Abstract Background Brain-imaging studies in post-traumatic stress disorder (PTSD) have consistently revealed alterations in brain structure and function and this is correlated to symptomatology. However, few studies have investigated the role of biomarkers in PTSD some specific groups, as police officers. Objective To evaluate prefrontal and limbic volumes, and cortical thickness of police officers exposed to trauma during work who developed post-traumatic stress disorder, resilient matched controls (without PTSD), and compared to healthy civilians. Methods Prefrontal and limbic volumes, and cortical thickness of 12 police officers with PTSD, 12 resilient police officers, and 12 healthy civilians who underwent brain MRI were analyzed. Results Differences in limbic structures volume were not significative after Bonferroni correction. A significant reduction in cortical thickness on right rostral cingulate, right and left middle frontal gyrus, left superior frontal, left lingual, calcarine and cuneus were observed in PTSD group in comparison to controls was observed. Discussion Although preliminary, our results suggested not only the association between cortical thickness and PTSD, but also indicated that patients and controls have anatomical differences.

Structural Brain Correlations of Visuospatial and Visuoperceptual Tests in Parkinson's Disease.

Diagnosis of mild cognitive impairment in Parkinson's disease (PD) is relevant because it is a marker for evolution to dementia. However, the selection of suitable tests to evaluate separate cognitive domains in mild cognitive impairment related to PD remains an open question. The current work aims to investigate the neuroanatomical correlates of several visuospatial/visuoperceptual tests using the same sample and a multimodal MRI approach. The study included 36 PD patients and 20 healthy subjects matched for age, sex, and education. The visuospatial/visuoperceptual tests selected were: Pentagon Copying Test (PCT), Judgment of Line Orientation Test (JLOT), Visual Form Discrimination Test (VFDT), Facial Recognition Test (FRT), Symbol Digit Modalities Test (SMDT), and clock copying task (CLOX2). FreeSurfer was used to assess cortical thickness, and tract-based spatial statistics was used for fractional anisotropy analysis. Lower performance in the PCT, JLOT, and SDMT was associated with extensive cortical thickness reductions in lateral parietal and temporal regions. VFDT and CLOX2 did not show this common pattern and correlated with more limited medial occipito-temporal and occipito-parietal regions. Performance in all visuospatial/visuoperceptual tests correlated with fractional anisotropy in the corpus callosum. Our findings show that JLOT, SDMT, and PCT, in addition to differentiating patients from controls, are suitable visuospatial/visuoperceptual tests to reflect cortical thinning in lateral temporo-parietal regions in PD patients. We did not observe the dissociation between dorsal and ventral streams that was expected according to the neuropsychological classification of visuospatial and visuoperceptual tests. (JINS, 2018, 24, 33-44).

Sirtuin-3 Promotes Adipogenesis, Osteoclastogenesis, and Bone Loss in Aging Male Mice.

Sirtuin-3 (Sirt3) is an essential metabolic regulatory enzyme that plays an important role in mitochondrial metabolism, but its role in bone marrow and skeletal homeostasis remains largely unknown. In this study, we hypothesize that increased expression of Sirt3 plays a role in skeletal aging. Using mice that overexpress Sirt3 [i.e., Sirt3 transgenic (Sirt3Tg)], we show that Sirt3 is a positive regulator of adipogenesis and osteoclastogenesis and a negative regulator of skeletal homeostasis. Sirt3Tg mice exhibited more adipocytes in the tibia compared with control mice. Bone marrow stromal cells (BMSCs) from Sirt3Tg mice displayed an enhanced ability to differentiate into adipocytes compared with control BMSCs. We found a 2.5-fold increase in the number of osteoclasts on the bone surface in Sirt3Tg mice compared with control mice (P < 0.03), and increased osteoclastogenesis in vitro. Importantly, Sirt3 activates the mechanistic target of rapamycin (mTOR) pathway to regulate osteoclastogenesis. Sirt3Tg male mice exhibited a significant reduction in cortical thickness at the tibiofibular junction (P < 0.05). In summary, Sirt3 activity in bone marrow cells is associated with increased adipogenesis, increased osteoclastogenesis through activation of mTOR signaling, and reduced bone mass. Interestingly, Sirt3 expression in bone marrow cells increases during aging, suggesting that Sirt3 promotes age-related adipogenesis and osteoclastogenesis associated with bone loss. These findings identify Sirt3 as an important regulator of adipogenesis and skeletal homeostasis in vivo and identify Sirt3 as a potential target for the treatment of osteoporosis.