We tested the hypothesis that epigenetic mechanisms in the brain and the immune system are associated with chronic pain. Genome-wide DNA methylation assessed in 9 months post nerve-injury (SNI) and Sham rats, in the prefrontal cortex (PFC) as well as in T cells revealed a vast difference in the DNA methylation landscape in the brain between the groups and a remarkable overlap (72%) between differentially methylated probes in T cells and prefrontal cortex. DNA methylation states in the PFC showed robust correlation with pain score of animals in several genes involved in pain. Finally, only 11 differentially methylated probes in T cells were sufficient to distinguish SNI or Sham individual rats. This study supports the plausibility of DNA methylation involvement in chronic pain and demonstrates the potential feasibility of DNA methylation markers in T cells as noninvasive biomarkers of chronic pain susceptibility.

The primary motor cortex (M1) plays an essential role in the control of hand movements in primates and is part of a complex cortical sensorimotor network involving multiple premotor and parietal areas. In a previous study in squirrel monkeys, we found that the ventral premotor cortex (PMv) projected mainly to 3 regions within the M1 forearm representation [rostro-medial (RM), rostro-lateral (RL), and caudo-lateral (CL)] with very few caudo-medial (CM) projections. These results suggest that projections from premotor areas to M1 are not uniform, but rather segregated into subregions. The goal of the present work was to study how inputs from diverse areas of the ipsilateral cortical network are organized within the M1 hand representation. In Cebus apella, different retrograde neuroanatomical tracers were injected in 4 subregions of the hand area of M1 (RM, RL, CM, and CL). We found a different pattern of input to each subregion of M1. RM receives inputs predominantly from dorsal premotor cortex, RL from PMv, CM from area 5, and CL from area 2. These results support that the M1 hand representation is composed of several subregions, each part of a unique cortical network.

Recently, much attention has been focused on the definition and structure of the hippocampus and its subfields, while the projections from the hippocampus have been relatively understudied. Here, we derive a reliable protocol for manual segmentation of hippocampal white matter regions (alveus, fimbria, and fornix) using high-resolution magnetic resonance images that are complementary to our previous definitions of the hippocampal subfields, both of which are freely available at https://github.com/cobralab/atlases. Our segmentation methods demonstrated high inter- and intra-rater reliability, were validated as inputs in automated segmentation, and were used to analyze the trajectory of these regions in both healthy aging (OASIS), and Alzheimer's disease (AD) and mild cognitive impairment (MCI; using ADNI). We observed significant bilateral decreases in the fornix in healthy aging while the alveus and cornu ammonis (CA) 1 were well preserved (all p's<0.006). MCI and AD demonstrated significant decreases in fimbriae and fornices. Many hippocampal subfields exhibited decreased volume in both MCI and AD, yet no significant differences were found between MCI and AD cohorts themselves. Our results suggest a neuroprotective or compensatory role for the alveus and CA1 in healthy aging and suggest that an improved understanding of the volumetric trajectories of these structures is required.

Hippocampal interneurons release the inhibitory transmitter GABA to regulate excitation, rhythm generation and synaptic plasticity. A subpopulation of GABAergic basket cells co-expresses the GABA/glycine vesicular transporters (VIAAT) and the atypical type III vesicular glutamate transporter (VGLUT3); therefore, these cells have the ability to signal with both GABA and glutamate. GABAergic transmission by basket cells has been extensively characterized but nothing is known about the functional implications of VGLUT3-dependent glutamate released by these cells. Here, using VGLUT3-null mice we observed that the loss of VGLUT3 results in a metaplastic shift in synaptic plasticity at Shaeffer's collaterals - CA1 synapses and an altered theta oscillation. These changes were paralleled by the loss of a VGLUT3-dependent inhibition of GABAergic current in CA1 pyramidal layer. Therefore presynaptic type III metabotropic could be activated by glutamate released from VGLUT3-positive interneurons. This putative presynaptic heterologous feedback mechanism inhibits local GABAergic tone and regulates the hippocampal neuronal network.

The cerebellum is implicated in social cognition and is likely to be involved in the pathophysiology of autism spectrum disorder (ASD). The goal of our study was to explore cerebellar morphology in adults with ASD and its relationship to eye contact, as measured by fixation time allocated on the eye region using an eye-tracking device. Two-hundred ninety-four subjects with ASD and controls were included in our study and underwent a structural magnetic resonance imaging scan. Global segmentation and cortical parcellation of the cerebellum were performed. A sub-sample of 59 subjects underwent an eye tracking protocol in order to measure the fixation time allocated to the eye region. We did not observe any difference in global cerebellar volumes between ASD patients and controls; however, regional analyses found a decrease of the volume of the right anterior cerebellum in subjects with ASD compared to controls. There were significant correlations between fixation time on eyes and the volumes of the vermis and Crus I. Our results suggest that cerebellar morphology may be related to eye avoidance and reduced social attention. Eye tracking may be a promising neuro-anatomically based stratifying biomarker of ASD.

Animal and human studies suggest that prenatal exposure to stress is associated with adverse health outcomes such as type 2 diabetes. Epigenetic modification, such as DNA methylation, is considered one possible underlying mechanism. The 1998 Quebec ice storm provides a unique opportunity to study an independent prenatal stressor on child outcomes. C-peptide is the best measure of endogenous insulin secretion and is widely used in the clinical management of patients with diabetes. The objectives of this study are to determine 1) the extent to which prenatal exposure to disaster-related stress (maternal objective hardship and maternal cognitive appraisal) influences children's C-peptide secretion, and 2) whether DNA methylation of diabetes-related genes mediates the effects of prenatal stress on C-peptide secretion. Children's (n = 30) C-peptide secretion in response to an oral glucose tolerance test were assessed in blood at 13½ years. DNA methylation levels of selected type 1 and 2 diabetes-related genes were chosen based upon the genes associated with prenatal maternal objective hardship and/or cognitive appraisal levels. Bootstrapping analyses were performed to determine the mediation effect of DNA methylation. We found that children whose mothers experienced higher objective hardship exhibited higher C-peptide secretion. Cognitive appraisal was not directly associated with C-peptide secretion. DNA methylation of diabetes-related genes had a positive mediation effect of objective hardship on C-peptide secretion: higher objective hardship predicted higher C-peptide secretion through DNA methylation. Negative mediation effects of cognitive appraisal were observed: negative cognitive appraisal predicted higher C-peptide secretion through DNA methylation. However, only one gene, LTA, remained a significant mediator of cognitive appraisal on C-peptide secretion after the conservative Bonferroni multiple corrections. Our findings suggest that DNA methylation could act as an intervening variable between prenatal stress and metabolic outcomes, highlighting the importance of epigenetic mechanisms in response to environmental factors.

The rate of progress in human neurosciences is limited by the inability to easily apply a wide range of analysis methods to the plethora of different datasets acquired in labs around the world. In this work, we introduce a framework for creating, testing, versioning and archiving portable applications for analyzing neuroimaging data organized and described in compliance with the Brain Imaging Data Structure (BIDS). The portability of these applications (BIDS Apps) is achieved by using container technologies that encapsulate all binary and other dependencies in one convenient package. BIDS Apps run on all three major operating systems with no need for complex setup and configuration and thanks to the comprehensiveness of the BIDS standard they require little manual user input. Previous containerized data processing solutions were limited to single user environments and not compatible with most multi-tenant High Performance Computing systems. BIDS Apps overcome this limitation by taking advantage of the Singularity container technology. As a proof of concept, this work is accompanied by 22 ready to use BIDS Apps, packaging a diverse set of commonly used neuroimaging algorithms.

The European Huntington's Disease Network (EHDN) commissioned an international task force to provide global evidence-based recommendations for everyday clinical practice for treatment of Huntington's disease (HD). The objectives of such guidelines are to standardize pharmacological, surgical and non-pharmacological treatment regimen and improve care and quality of life of patients. A formalized consensus method, adapted from the French Health Authority recommendations was used. First, national committees (French and English Experts) reviewed all studies published between 1965 and 2015 included dealing with HD symptoms classified in motor, cognitive, psychiatric, and somatic categories. Quality grades were attributed to these studies based on levels of scientific evidence. Provisional recommendations were formulated based on the strength and the accumulation of scientific evidence available. When evidence was not available, recommendations were framed based on professional agreement. A European Steering committee supervised the writing of the final recommendations through a consensus process involving two rounds of online questionnaire completion with international multidisciplinary HD health professionals. Patients' associations were invited to review the guidelines including the HD symptoms. Two hundred and nineteen statements were retained in the final guidelines. We suggest to use this adapted method associating evidence base-medicine and expert consensus to other rare diseases.

Maternal nutritional programming by caloric exposure during pregnancy and lactation results in long-term behavioral modification in the offspring. Here, we characterized the effect of maternal caloric exposure on synaptic and brain morphological organization and its effects on depression-like behavior susceptibility in rats' offspring. Female Wistar rats were exposed to chow or cafeteria (CAF) diet for 9 weeks (pre-pregnancy, pregnancy, and lactation) and then switched to chow diet after weaning. By postnatal day 60, the male Wistar rat offspring were tested for depressive-like behavior using operational conditioning, novelty suppressed feeding, sucrose preference, and open-field test. Brain macro and microstructural morphology were analyzed using magnetic resonance imaging deformation-based morphometry (DBM) and western blot, immunohistochemistry for NMDA and AMPA receptor, synaptophysin and myelin, respectively. We found that the offspring of mothers exposed to CAF diet displayed deficient motivation showing decrease in the operant conditioning, sucrose preference, and suppressed feeding test. Macrostructural DBM analysis showed reduction in the frontomesocorticolimbic circuit volume including the nucleus accumbens (NAc), hippocampus, and prefrontal cortex. Microstructural analysis revealed reduced synaptic terminals in hippocampus and NAc, whereas increased glial fibrillary acidic protein in hippocampus and lateral hypothalamus, as well as a decrease in the hippocampal cell number and myelin reduction in the dentate gyrus and hilus, respectively. Also, offspring exhibited increase of the GluR1 and GLUR2 subunits of AMPA receptor, whereas a decrease in the mGluR2 expression in hippocampus. Our findings reveal that maternal programming might prime depression-like behavior in the offspring by modulating macro and micro brain organization of the frontomesocorticolimbic circuit.

The study of the hippocampus across the healthy adult lifespan has rendered inconsistent findings. While volumetric measurements have often been a popular technique for analysis, more advanced morphometric techniques have demonstrated compelling results that highlight the importance and improved specificity of shape-based measures. Here, the MAGeT Brain algorithm was applied on 134 healthy individuals aged 18-81 years old to extract hippocampal subfield volumes and hippocampal shape measurements, namely: local surface area (SA) and displacement. We used linear-, second- or third-order natural splines to examine the relationships between hippocampal measures and age. In addition, partial least squares analyses were performed to relate volume and shape measurements with cognitive and demographic information. Volumetric results indicated a relative preservation of the right cornus ammonis 1 with age and a global volume reduction linked with older age, female sex, lower levels of education and cognitive performance. Vertex-wise analysis demonstrated an SA preservation in the anterior hippocampus with a peak during the sixth decade, while the posterior hippocampal SA gradually decreased across lifespan. Overall, SA decrease was linked to older age, female sex and, to a lesser extent lower levels of education and cognitive performance. Outward displacement in the lateral hippocampus and inward displacement in the medial hippocampus were enlarged with older age, lower levels of cognition and education, indicating an accentuation of the hippocampal "C" shape with age. Taken together, our findings suggest that vertex-wise analyses have higher spatial specifity and that sex, education, and cognition are implicated in the differential impact of age on hippocampal subregions throughout its anteroposterior and medial-lateral axes. This article is part of the Virtual Special Issue titled COGNITIVE NEU- ROSCIENCE OF HEALTHY AND PATHOLOGICAL AGING. The full issue can be found on ScienceDirect at https://www.sciencedirect.com/journal/neurobiology-of-aging/special-issue/105379XPWJP.

In rats, forelimb movements are evoked from two cortical regions, the caudal and rostral forelimb areas (CFA and RFA, respectively). These areas are densely interconnected and RFA induces complex and powerful modulations of CFA outputs. CFA and RFA also have interhemispheric connections, and these areas from both hemispheres send projections to common targets along the motor axis, providing multiple potential sites of interactions for movement production. Our objective was to characterize how CFA and RFA in one hemisphere can modulate motor outputs of the opposite hemisphere. To do so, we used paired-pulse protocols with intracortical microstimulation techniques (ICMS), while recording electromyographic (EMG) activity of forelimb muscles in sedated rats. A subthreshold conditioning stimulation was applied in either CFA or RFA in one hemisphere simultaneously or before a suprathreshold test stimulation in either CFA or RFA in the opposite hemisphere. Both CFA and RFA tended to facilitate motor outputs with short (0-2.5 ms) or long (20-35 ms) delays between the conditioning and test stimuli. In contrast, they tended to inhibit motor outputs with intermediate delays, in particular 10 ms. When comparing the two areas, we found that facilitatory effects from RFA were more frequent and powerful than the ones from CFA. In contrast, inhibitory effects from CFA on its homolog were more frequent and powerful than the ones from RFA. Our results demonstrate that interhemispheric modulations from CFA and RFA share some similarities but also have clear differences that could sustain specific functions these cortical areas carry for the generation of forelimb movements.NEW & NOTEWORTHY We show that caudal and rostral forelimb areas (CFA and RFA) have distinct effects on motor outputs from the opposite hemisphere, supporting that they are distinct nodes in the motor network of rats. However, the pattern of interhemispheric modulations from RFA has no clear equivalent among premotor areas in nonhuman primates, suggesting they contribute differently to the generation of ipsilateral hand movements. Understanding these interspecies differences is important given the common use of rodent models in motor control and recovery studies.

Gender dysphoria (GD) is characterized by distress due to an incongruence between experienced gender and sex assigned at birth. Sex-differentiated brain regions are hypothesized to reflect the experienced gender in GD and may play a role in sexual orientation development. Magnetic resonance brain images were acquired from 16 GD adolescents assigned female at birth (AFAB) not receiving hormone therapy, 17 cisgender girls, and 14 cisgender boys (ages 12-17 years) to examine three morphological and microstructural gray matter features in 76 brain regions: surface area (SA), cortical thickness (CT), and T1 relaxation time. Sexual orientation was represented by degree of androphilia-gynephilia and sexual attraction strength. Multivariate analyses found that cisgender boys had larger SA than cisgender girls and GD AFAB. Shorter T1, reflecting denser, macromolecule-rich tissue, correlated with older age and stronger gynephilia in cisgender boys and GD AFAB, and with stronger attractions in cisgender boys. Thus, cortical morphometry (mainly SA) was related to sex assigned at birth, but not experienced gender. Effects of experienced gender were found as similarities in correlation patterns in GD AFAB and cisgender boys in age and sexual orientation (mainly T1), indicating the need to consider developmental trajectories and sexual orientation in brain studies of GD.

Efficient cognitive tasks sensitive to longitudinal deterioration in small cohorts of Huntington's disease (HD) patients are lacking in HD research. We thus developed and assessed the digitized arithmetic task (DAT), which combines inner language and executive functions in approximately 4 minutes.

Many magnetic resonance imaging (MRI) measures are being studied longitudinally to explore topics such as biomarker detection and clinical staging. A pertinent concern to longitudinal work is MRI scanner upgrades. When upgrades occur during the course of a longitudinal MRI neuroimaging investigation, there may be an impact on the compatibility of pre- and post-upgrade measures. Similarly, subject motion is another issue that may be detrimental to MRI work and embedding volumetric navigators (vNavs) within acquisition sequences has emerged as a technique that allows for prospective motion correction. Our research group recently underwent an upgrade from a Siemens MAGNETOM 3T Tim Trio system to a Siemens MAGNETOM 3T Prisma Fit system. The goals of the current work were to: 1) investigate the impact of this upgrade on commonly used structural imaging measures and proton magnetic resonance spectroscopy indices ("Prisma Upgrade protocol") and 2) examine structural imaging measures in a sequence with vNavs alongside a standard acquisition sequence ("vNav protocol"). While high reliability was observed for most of the investigated MRI outputs, suboptimal reliability was observed for certain indices. Across the scanner upgrade, increases in frontal, temporal, and cingulate cortical thickness (CT) and thalamus volume, along with decreases in parietal CT and amygdala, globus pallidus, hippocampus, and striatum volumes, were observed. No significant impact of the upgrade was found in 1H-MRS analyses. Further, CT estimates were found to be larger in MPRAGE acquisitions compared to vNav-MPRAGE acquisitions mainly within temporal areas, while the opposite was found mostly in parietal brain regions. The results from this work should be considered in longitudinal study designs and comparable prospective motion correction investigations are warranted in cases of marked head movement.

Exposure to maternal immune activation (MIA) in utero is a risk factor for neurodevelopmental disorders later in life. The impact of the gestational timing of MIA exposure on downstream development remains unclear.

Obesity is recognized as a significant risk factor for Alzheimer's disease (AD). Studies have supported that obesity accelerates AD-related pathophysiology and memory impairment in mouse models of AD. However, the nature of the brain structure-behaviour relationship mediating this acceleration remains unclear. In this manuscript we evaluated the impact of adolescent obesity on the brain morphology of the triple transgenic mouse model of AD (3xTg) and a non-transgenic control model of the same background strain (B6129s) using longitudinally acquired structural magnetic resonance imaging (MRI). At 8 weeks of age, animals were placed on a high-fat diet (HFD) or an ingredient-equivalent control diet (CD). Structural images were acquired at 8, 16, and 24 weeks. At 25 weeks, animals underwent the novel object recognition (NOR) task and the Morris water maze (MWM) to assess short-term non-associative memory and spatial memory, respectively. All analyses were carried out across four groups: B6129s-CD and -HFD and 3xTg-CD and -HFD. Neuroanatomical changes in MRI-derived brain morphology were assessed using volumetric and deformation-based analyses. HFD-induced obesity during adolescence exacerbated brain volume alterations by adult life in the 3xTg mouse model in comparison to control-fed mice and mediated volumetric alterations of select brain regions, such as the hippocampus. Further, HFD-induced obesity aggravated memory in all mice, lowering certain memory measures of B6129s control mice to the level of 3xTg mice maintained on a CD. Moreover, decline in the volumetric trajectories of hippocampal regions for all mice were associated with the degree of spatial memory impairments on the MWM. Our results suggest that obesity may interact with the brain changes associated with AD-related pathology in the 3xTg mouse model to aggravate brain atrophy and memory impairments and similarly impair brain structural integrity and memory capacity of non-transgenic mice. Further insight into this process may have significant implications in the development of lifestyle interventions for treatment of AD.

Prenatal maternal stress (PNMS) is an important programming factor of postnatal immunity. We tested here the hypothesis that DNA methylation of genes in the NF-κB signaling pathway in T cells mediates the effect of objective PNMS on Th1 and Th2 cytokine production in blood from 13½ year olds who were exposed in utero to the 1998 Quebec ice storm.

Neuroanatomical alterations are well established in patients suffering from schizophrenia, however the extent to which these changes are attributable to illness, antipsychotic drugs (APDs), or their interaction is unclear. APDs have been extremely effective for treatment of positive symptoms in major psychotic disorders. Their therapeutic effects are mediated, in part, through blockade of D2-like dopamine (DA) receptors, i.e. the D2, D3 and D4 dopamine receptors. Furthermore, the dependency of neuroanatomical change on DA system function and D2-like receptors has yet to be explored.

Increasing evidence shows that the semantic variant of primary progressive aphasia (svPPA) is characterized by hippocampal atrophy. However, less is known about disease-related morphological hippocampal changes. The goal of the present study is to conduct a detailed characterization of the impact of svPPA on global hippocampus volume and morphology compared with control subjects and patients with Alzheimer's disease (AD).

Exposure to maternal immune activation (MIA) in utero is a risk factor for neurodevelopmental and psychiatric disorders. MIA-induced deficits in adolescent and adult offspring have been well characterized; however, less is known about the effects of MIA exposure on embryo development. To address this gap, we performed high-resolution ex vivo MRI to investigate the effects of early (gestational day [GD]9) and late (GD17) MIA exposure on embryo (GD18) brain structure. We identify striking neuroanatomical changes in the embryo brain, particularly in the late-exposed offspring. We further examined the putative neuroanatomical underpinnings of MIA timing in the hippocampus using electron microscopy and identified differential effects due to MIA timing. An increase in apoptotic cell density was observed in the GD9-exposed offspring, while an increase in the density of neurons and glia with ultrastructural features reflective of increased neuroinflammation and oxidative stress was observed in GD17-exposed offspring, particularly in females. Overall, our findings integrate imaging techniques across different scales to identify differential impact of MIA timing on the earliest stages of neurodevelopment.