The impact of correction on MP2RAGE cortical T1 and apparent cortical thickness at 7T

Determination of cortical thickness using MRI has often been criticized due to the presence of various error sources. Specifically, anatomical MRI relying on T₁ contrast may be unreliable due to spatially variable image contrast between gray matter (GM), white matter (WM) and cerebrospinal fluid (CSF). Especially at ultra‐high field (≥ 7T) MRI, transmit and receive B₁‐related image inhomogeneities can hamper correct classification of tissue types. In the current paper, we demonstrate that residual (transmit) inhomogeneities in the T₁‐weighted and quantitative T₁ images using the MP2RAGE sequence at 7T lead to biases in cortical thickness measurements. As expected, post‐hoc correction for the spatially varying profile reduced the apparent T₁ values across the cortex in regions with low , and slightly increased apparent T₁ in regions with high . As a result, improved contrast‐to‐noise ratio both at the GM‐CSF and GM‐WM boundaries can be observed leading to more accurate surface reconstructions and cortical thickness estimates. Overall, the changes in cortical thickness ranged between a 5% decrease to a 70% increase after correction, reducing the variance of cortical thickness values across the brain dramatically and increasing the comparability with normative data. More specifically, the cortical thickness estimates increased in regions characterized by a strong decrease of apparent T₁ after correction in regions with low due to improved detection of the pial surface_. The current results suggest that cortical thickness can be more accurately determined using MP2RAGE data at 7T if inhomogeneities are accounted for.     

In vivo normative atlas of the hippocampal subfields using multi‐echo susceptibility imaging at 7 Tesla

Objectives: To generate a high‐resolution atlas of the hippocampal subfields using images acquired from 7 T, multi‐echo, gradient‐echo MRI for the evaluation of epilepsy and neurodegenerative disorders as well as investigating (apparent transverse relaxation rate) and quantitative volume magnetic susceptibility (QS) of the subfields. Experimental Design: Healthy control subjects (n = 17) were scanned at 7 T using a multi‐echo gradient‐echo sequence and susceptibility‐weighted magnitude images, and QS maps were reconstructed. We defined a hippocampal subfield labeling protocol for the magnitude image produced from the average of all echoes and assessed reproducibility through volume and shape metrics. A group‐wise diffeomorphic registration procedure was used to generate an average atlas of the subfields for the whole subject cohort. The quantitative MRI maps and subfield labels were then warped to the average atlas space and used to measure mean values of and QS characterizing each subfield. Principal Observations: We were able to reliably label hippocampal subfields on the multi‐echo susceptibility images. The group‐averaged atlas accurately aligns these structures to produce a high‐resolution depiction of the subfields, allowing assessment of both quantitative susceptibility and across subjects. Our analysis of variance demonstrates that there are more apparent differences between the subfields on these quantitative maps than the normalized magnitude images. Conclusion: We constructed a high‐resolution atlas of the hippocampal subfields for use in voxel‐based studies and demonstrated in vivo quantification of susceptibility and in the subfields. This work is the first in vivo quantification of susceptibility values within the hippocampal subfields at 7 T. Hum Brain Mapp 35:3588–3601, 2014. © 2013 Wiley Periodicals, Inc.     

Partial volume model for brain MRI scan using MP2RAGE

MP2RAGE is a weighted MRI sequence that estimates a composite image providing much reduction of the receiver bias, has a high intensity dynamic range, and provides an estimate of mapping. It is, therefore, an appealing option for brain morphometry studies. However, previous studies have reported a difference in cortical thickness computed from MP2RAGE compared with widely used Multi‐Echo MPRAGE. In this article, we demonstrated that using standard segmentation and partial volume estimation techniques on MP2RAGE introduces systematic errors, and we proposed a new model to estimate partial volume of the cortical gray matter. We also included in their model a local estimate of tissue intensity to take into account the natural variation of tissue intensity across the brain. A theoretical framework is provided and validated using synthetic and physical phantoms. A repeatability experiment comparing MPRAGE and MP2RAGE confirmed that MP2RAGE using our model could be considered for structural imaging in brain morphology study, with similar cortical thickness estimate than that computed with MPRAGE. Hum Brain Mapp 38:5115–5127, 2017. © 2017 Wiley Periodicals, Inc.     

Augmented cystine–glutamate exchange by pituitary adenylate cyclase‐activating polypeptide signaling via the VPAC1 receptor

In the central nervous system, cystine import in exchange for glutamate through system is critical for the production of the antioxidant glutathione by astrocytes, as well as the maintenance of extracellular glutamate. Therefore, regulation of system activity affects multiple aspects of cellular physiology and may contribute to disease states. Pituitary adenylate cyclase‐activating polypeptide (PACAP) is a neuronally derived peptide that has already been demonstrated to modulate multiple aspects of glutamate signaling suggesting PACAP may also target activity of cystine–glutamate exchange via system . In this study, 24‐h treatment of primary cortical cultures containing neurons and glia with PACAP concentration‐dependently increased system function as measured by radiolabeled cystine uptake. Furthermore, the increase in cystine uptake was completely abolished by the system inhibitor, (S)‐4‐carboxyphenylglycine (CPG), attributing increases in cystine uptake specifically to system activity. Time course and quantitative PCR results indicate that PACAP signaling may increase cystine–glutamate exchange by increasing expression of xCT, the catalytic subunit of system . Furthermore, the potentiation of system activity by PACAP occurs via a PKA‐dependent pathway that is not mediated by the PAC1R, but rather the shared vasoactive intestinal polypeptide receptor VPAC1R. Finally, assessment of neuronal, astrocytic, and microglial‐enriched cultures demonstrated that only astrocyte‐enriched cultures exhibit enhanced cystine uptake following both PACAP and VIP treatment. These data introduce a novel mechanism by which both PACAP and VIP regulate system activity. Synapse 68:604–612, 2014 . © 2014 Wiley Periodicals, Inc.     

Genome‐wide mediation analysis of psychiatric and cognitive traits through imaging phenotypes

Heritability is well documented for psychiatric disorders and cognitive abilities which are, however, complex, involving both genetic and environmental factors. Hence, it remains challenging to discover which and how genetic variations contribute to such complex traits. In this article, they propose to use mediation analysis to bridge this gap, where neuroimaging phenotypes were utilized as intermediate variables. The Philadelphia Neurodevelopmental Cohort was investigated using genome‐wide association studies (GWAS) and mediation analyses. Specifically, 951 participants were included with age ranging from 8 to 21 years. Two hundred and four neuroimaging measures were extracted from structural magnetic resonance imaging scans. GWAS were conducted for each measure to evaluate the SNP‐based heritability. Furthermore, mediation analyses were employed to understand the mechanisms in which genetic variants have influence on pathological behaviors implicitly through neuroimaging phenotypes, and identified SNPs that would not be detected otherwise. Our analyses found that rs10494561, located in the intron region within NMNAT2, was associated with the severity of the prodromal symptoms of psychosis implicitly, mediated through the volume of the left hemisphere of the superior frontal region ( ). The gene NMNAT2 is known to be associated with brainstem degeneration, and produce cytoplasmic enzyme which is mainly expressed in the brain. Another SNP rs2285351 was found in the intron region of gene IFT122 which may be potentially associated with human spatial orientation ability through the area of the left hemisphere of the isthmuscingulate region ( ). Hum Brain Mapp 38:4088–4097, 2017. © 2017 Wiley Periodicals, Inc.     

Involvement of Nax sodium channel in peripheral nerve regeneration via lactate signaling

Na_x, a sodium concentration‐sensitive sodium channel, is expressed in non‐myelinating Schwann cells of the adult peripheral nervous system, but the pathophysiological role remains unclear. We found that functional recovery of the hind paw responses from the sciatic nerve transection was delayed in Na_x knockout ( ) mice. Histological analyses showed a decrease in the number of regenerated myelinated axons in sciatic nerves. The delay in the recovery in mice was improved by lactate and inhibited by a monocarboxylate transporter inhibitor. In vitro experiments using cultured Schwann cells showed that lactate release was enhanced by endothelin (ET)‐1 and blocked by an ET receptor type B antagonist. Here, it is conceivable that Na_x was activated by ET‐1. The amount of lactate release by ET‐1 was lower in mice than in wild‐type mice. These results indicated that Na_x is functionally coupled to ET for lactate release via ET receptor type B and is involved in peripheral nerve regeneration.     

Rats with persistently high exploratory activity have both higher extracellular dopamine levels and higher proportion of D receptors in the striatum

Increases in both striatal dopamine release and the proportion of the D₂ receptors in the high affinity state (D) accompany the behavioral sensitization to psychostimulants, but it is not known whether the physiological substrate of the interindividual differences locomotor and exploratory behavior is similar. Thus, we examined whether persistently high spontaneous exploratory activity is associated with extracellular dopamine as well as the proportion of D in the striatum. Extracellular dopamine levels were found to be significantly higher in rats with high exploratory activity (high explorers, HE) as compared with low explorers (LE) in baseline conditions as well as after administration of amphetamine (0.5 mg/kg, i.p.). Also, the HE animals had significantly higher proportion of striatal D receptors than the LE‐rats (43.8 ± 4.4% and 22.5 ± 1.5%, respectively). Thus, the present findings support the notion that concomitant higher extracellular dopamine levels and the proportion of D receptors in the striatum, whether naturally occurring and persistent or pharmacologically induced, are causally related to high behavioral activity. Synapse 63:443–446, 2009. © 2009 Wiley‐Liss, Inc.     

Opposite in vivo effects of agents that stimulate or inhibit the glutamate/cysteine exchanger system on the inhibition of hippocampal LTP by Aß

Aggregated amyloid ß‐protein (Aß) is pathognomonic of Alzheimer's disease and certain assemblies of Aß are synaptotoxic. Excess glutamate or diminished glutathione reserve are both implicated in mediating or modulating Aß‐induced disruption of synaptic plasticity. The system antiporter promotes Na⁺‐independent exchange of cystine with glutamate thereby providing a major source of extracellular glutamate and intracellular glutathione concentrations. Here we probed the ability of two drugs with opposite effects on system , the inhibitor sulfasalazine and facilitator N‐acetylcysteine, to modulate the ability of Aß1‐42 to inhibit long‐term potentiation (LTP) in the CA1 area of the anaesthetized rat. Whereas acute systemic treatment with sulfasalazine lowered the threshold for Aß to interfere with synaptic plasticity, N‐acetylcysteine prevented the inhibition of LTP by Aß alone or in combination with sulfasalazine. Moreover acute N‐acetylcysteine also prevented the inhibition of LTP by TNFα, a putative mediator of Aß actions, and repeated systemic N‐acetylcysteine treatment for 7 days reversed the delayed deleterious effect of Aß on LTP. Since both of these drugs are widely used clinically, further evaluation of their potential beneficial and deleterious actions in early Alzheimer's disease seems warranted. © 2016 Wiley Periodicals, Inc.     

Supratentorial and infratentorial damage in spinocerebellar ataxia 2: A diffusion‐weighted MRI study

Spinocerebellar ataxia type 2 (SCA2) is an autosomal‐dominant degenerative disorder that is neuropathologically characterized primarily by infratentorial damage, although less severe supratentorial involvement may contribute to the clinical manifestation. Diffusion‐weighted imaging (DWI)–Magnetic Resonance Imaging (MRI) studies of SCA2 have enabled in vivo quantification of neurodegeneration in infratentorial regions, whereas supratentorial regions have been explored less thoroughly. We measured microstructural changes in both infratentorial and supratentorial regions in 13 SCA2 patients (9 men, 4 women; mean age, 50 ± 12 years) and 15 controls (10 men, 5 women; mean age, 49 ± 14 years) using DWI‐MRI and correlated the DWI changes with disease severity and duration. Disease severity was evaluated using the International Cooperative Ataxia Rating Scale and the Inherited Ataxia Clinical Rating Scale. Cerebral diffusion trace ( ) values were generated, and regions of interest (ROIs) and voxel‐based analysis with Statistical Parametric Mapping (SPM) were used for data analysis. In SCA2 patients, ROI analysis and SPM confirmed significant increases in values in the pons, cerebellar white matter (CWM) and middle cerebellar peduncles. Moreover, SPM analysis revealed increased values in the right thalamus, bilateral temporal cortex/white matter, and motor cortex/pyramidal tract regions. Increased diffusivity in the frontal white matter (FWM) and the CWM was significantly correlated with ataxia severity. DWI‐MRI revealed that both infratentorial and supratentorial microstructural changes may characterize SCA2 patients in the course of the disease and might contribute to the severity of the symptoms. © 2013 International Parkinson and Movement Disorder Society     

Increased dopamine D receptors in rats reared in social isolation

Postweaning social isolation in the rat induces lasting alterations that parallel several of the core symptoms seen in human schizophrenics, including hyperreactivity to novel environments, cognitive impairment, and deficits in sensorimotor gating. The current study determined whether these changes are accompanied by any elevation in the proportion of striatal dopamine receptors in the functional high affinity state (D), as observed in other preclinical models of psychosis. Male Lister hooded rats (20–24 days) were housed in groups of three or alone. On Day 36 postweaning locomotor activity was monitored for 60 min in a novel arena, and on Day 37 novel object discrimination was assessed using a 2 h intertrial interval. Three days later striata were collected, homogenized, washed three times to remove endogenous dopamine, and the proportion of D determined by competition between dopamine and 2.27 nM [³H]domperidone. Isolates were significantly more active than group housed controls for both ambulation and rears. Although both groups exhibited comparable levels of familiarization trial object exploration, group housed animals were able to discriminate between novel and familiar objects during the choice trial while isolates were not. Social isolation was associated with a highly significant elevation in the proportion of striatal D, equivalent to a 3.3‐fold increase (group 15.2% ± 1.4%, isolate 49.8% ± 4.8%; P < 0.0001, Student's unpaired t‐test). These findings support both the hypothesis that elevated D is a common feature of multiple animal models of psychosis, and the validity of isolation rearing as a neurodevelopmental model of a “schizophrenia‐like” state. Synapse 63:476–483, 2009. © 2009 Wiley‐Liss, Inc.     

The diffeomorphometry of regional shape change rates and its relevance to cognitive deterioration in mild cognitive impairment and Alzheimer's disease

We proposed a diffeomorphometry‐based statistical pipeline to study the regional shape change rates of the bilateral hippocampus, amygdala, and ventricle in mild cognitive impairment (MCI) and Alzheimer's disease (AD) compared with healthy controls (HC), using sequential magnetic resonance imaging (MRI) scans of 713 subjects (3,123 scans in total). The subgroup shape atrophy rates of the bilateral hippocampus and amygdala, as well as the expansion rates of the bilateral ventricles, for a majority of vertices were found to follow the order of . The bilateral hippocampus and the left amygdala were subsegmented into multiple functionally meaningful subregions with the help of high‐field MRI scans. The largest group differences in localized shape atrophy rates on the hippocampus were found to occur in CA1, followed by subiculum, CA2, and finally CA3/dentate gyrus, which is consistent with the neurofibrillary tangle accumulation trajectory. Highly nonuniform group differences were detected on the amygdala; vertices on the core amygdala (basolateral and lateral nucleus) revealed much larger atrophy rates, whereas those on the noncore amygdala (mainly centromedial) displayed similar or even smaller atrophy rates in AD relative to HC. The temporal horns of the ventricles were observed to have the largest localized ventricular expansion rate differences; with the AD group showing larger localized expansion rates on the anterior horn and the body part of the ventricles as well. Significant correlations were observed between the localized shape change rates of each of these six structures and the cognitive deterioration rates as quantified by the Alzheimer's Disease Assessment Scale‐Cognitive Behavior Section increase rate and the Mini Mental State Examination decrease rate. Hum Brain Mapp 36:2093–2117, 2015. © 2015 Wiley Periodicals, Inc.     

Close temporal coupling of neuronal activity and tissue oxygen responses in rodent whisker barrel cortex

Neuronal activity elicits metabolic and vascular responses, during which oxygen is first consumed and then supplied to the tissue via an increase in cerebral blood flow. Understanding the spatial and temporal dynamics of blood and tissue oxygen () responses following neuronal activity is crucial for understanding the physiological basis of functional neuroimaging signals. However, our knowledge is limited because previous measurements have been made at low temporal resolution (>100 ms). Here we recorded at high temporal resolution (1 ms), simultaneously with co‐localized field potentials, at several cortical depths from the whisker region of the somatosensory cortex in anaesthetized rats and mice. Stimulation of the whiskers produced rapid, laminar‐specific changes in . Positive responses (i.e. increases) were observed in the superficial layers within 50 ms of stimulus onset, faster than previously reported. Negative responses (i.e. decreases) were observed in the deeper layers, with maximal amplitude in layer IV, within 40 ms of stimulus onset. The amplitude of the negative, but not the positive, response correlated with local field potential amplitude. Disruption of neurovascular coupling, via nitric oxide synthase inhibition, abolished positive responses to whisker stimulation in the superficial layers and increased negative responses in all layers. Our data show that responses occur rapidly following neuronal activity and are laminar dependent.     

Functional connectivity predicts gender: Evidence for gender differences in resting brain connectivity

Prevalence of certain forms of psychopathology, such as autism and depression, differs between genders and understanding gender differences of the neurotypical brain may provide insights into risk and protective factors. In recent research, resting state functional magnetic resonance imaging (rfMRI) is widely used to map the inherent functional networks of the brain. Although previous studies have reported gender differences in rfMRI, the robustness of gender differences is not well characterized. In this study, we use a large data set to test whether rfMRI functional connectivity (FC) can be used to predict gender and identify FC features that are most predictive of gender. We utilized rfMRI data from 820 healthy controls from the Human Connectome Project. By applying a predefined functional template and partial least squares regression modeling, we achieved a gender prediction accuracy of 87% when multi‐run rfMRI was used. Permutation tests confirmed that gender prediction was reliable ( ). Effects of motion, age, handedness, blood pressure, weight, and brain volume on gender prediction are discussed. Further, we found that FC features within the default mode (DMN), fronto‐parietal and sensorimotor networks contributed most to gender prediction. In the DMN, right fusiform gyrus and right ventromedial prefrontal cortex were important contributors. The above regions have been previously implicated in aspects of social functioning and this suggests potential gender differences in social cognition mediated by the DMN. Our findings demonstrate that gender can be reliably predicted using rfMRI data and highlight the importance of controlling for gender in brain imaging studies.     

Scale‐free brain dynamics under physical and psychological distress: Pre‐treatment effects in women diagnosed with breast cancer

Stressful life events are related to negative outcomes, including physical and psychological manifestations of distress, and behavioral deficits. Patients diagnosed with breast cancer report impaired attention and working memory prior to adjuvant therapy, which may be induced by distress. In this article, we examine whether brain dynamics show systematic changes due to the distress associated with cancer diagnosis. We hypothesized that impaired working memory is associated with suppression of “long‐memory” neuronal dynamics; we tested this by measuring scale‐free (“fractal”) brain dynamics, quantified by the Hurst exponent (H). Fractal scaling refers to signals that do not occur at a specific time‐scale, possessing a spectral power curve ; they are “long‐memory” processes, with significant autocorrelations. In a BOLD functional magnetic resonance imaging study, we scanned three groups during a working memory task: women scheduled to receive chemotherapy or radiotherapy and aged‐matched controls. Surprisingly, patients' BOLD signal exhibited greater H with increasing intensity of anticipated treatment. However, an analysis of H and functional connectivity against self‐reported measures of psychological distress (Worry, Anxiety, Depression) and physical distress (Fatigue, Sleep problems) revealed significant interactions. The modulation of (Worry, Anxiety) versus (Fatigue, Sleep Problems, Depression) showed the strongest effect, where higher worry and lower fatigue was related to reduced H in regions involved in visuospatial search, attention, and memory processing. This is also linked to decreased functional connectivity in these brain regions. Our results indicate that the distress associated with cancer diagnosis alters BOLD scaling, and H is a sensitive measure of the interaction between psychological versus physical distress. Hum Brain Mapp 36:1077–1092, 2015. © 2014 Wiley Periodicals, Inc.     

A cell population that strongly expresses the CB1 cannabinoid receptor in the ependyma of the rat spinal cord

The cells surrounding the central canal of the spinal cord are a source of stem/precursor cells that may give rise to neurons, astrocytes, or oligodendrocytes. However, they are a heterogeneous population that remains poorly understood. Here we describe a subpopulation characterized by their strong expression of the CB₁ cannabinoid receptor, oval/round soma, apical nucleus, a variable number of cilia (0, 1, or 2), and the presence of a single short and occasionally ramified basal process. These cells are mainly located in the lateral and dorsal central canal throughout the spinal cord. These CB cells are closely related to the basal lamina labyrinths or fractones derived from subependymal microglia. In addition, CB cells express some stem/precursor cell markers, including vimentin, nestin, Sox2, Sox9, and GLAST, but not others such as CD15 or GFAP. In addition, this cell population does not proliferate in the intact adult spinal cord, although up to 50% of these cells express the proliferation marker Ki67 in newly born rats or after a spinal cord contusion. The present findings contribute to our understanding of the spinal cord central canal structure and reveal the targets for endocannabinoids inside this neurogenic niche. J. Comp. Neurol. 521:233–251, 2013. © 2012 Wiley Periodicals, Inc.     

Williams syndrome: a relationship between genetics, brain morphology and behaviour

Background Genetically Williams syndrome (WS) promises to provide essential insight into the pathophysiology of cortical development because its ～28 deleted genes are crucial for cortical neuronal migration and maturation. Phenotypically, WS is one of the most puzzling childhood neurodevelopmental disorders affecting most intellectual deficiencies (i.e. low‐moderate intelligence quotient, visuospatial deficits) yet relatively preserving what is uniquely human (i.e. language and social‐emotional cognition). Therefore, WS provides a privileged setting for investigating the relationship between genes, brain and the consequent complex human behaviour. Methods We used in vivo anatomical magnetic resonance imaging analysing cortical surface‐based morphometry, (i.e. surface area , cortical volume , cortical thickness , gyrification index ) and cortical complexity , which is of particular relevance to the WS genotype–phenotype relationship in 22 children (2.27–14.6 years) to compare whole hemisphere and lobar surface‐based morphometry between WS (n = 10) and gender/age matched normal controls healthy controls (n = 12). Results Compared to healthy controls, WS children had a (1) relatively preserved Cth; (2) significantly reduced SA and CV; (3) significantly increased GI mostly in the parietal lobe; and (4) decreased CC specifically in the frontal and parietal lobes. Conclusion Our findings are then discussed with reference to the Rakic radial‐unit hypothesis of cortical development, arguing that WS gene deletions may spare Cth yet affecting the number of founder cells/columns/radial units, hence decreasing the SA and CV. In essence, cortical brain structure in WS may be shaped by gene‐dosage abnormalities.     

Functional brain segmentation using inter‐subject correlation in fMRI

The human brain continuously processes massive amounts of rich sensory information. To better understand such highly complex brain processes, modern neuroimaging studies are increasingly utilizing experimental setups that better mimic daily‐life situations. A new exploratory data‐analysis approach, functional segmentation inter‐subject correlation analysis (FuSeISC), was proposed to facilitate the analysis of functional magnetic resonance (fMRI) data sets collected in these experiments. The method provides a new type of functional segmentation of brain areas, not only characterizing areas that display similar processing across subjects but also areas in which processing across subjects is highly variable. FuSeISC was tested using fMRI data sets collected during traditional block‐design stimuli (37 subjects) as well as naturalistic auditory narratives (19 subjects). The method identified spatially local and/or bilaterally symmetric clusters in several cortical areas, many of which are known to be processing the types of stimuli used in the experiments. The method is not only useful for spatial exploration of large fMRI data sets obtained using naturalistic stimuli, but also has other potential applications, such as generation of a functional brain atlases including both lower‐ and higher‐order processing areas. Finally, as a part of FuSeISC, a criterion‐based sparsification of the shared nearest‐neighbor graph was proposed for detecting clusters in noisy data. In the tests with synthetic data, this technique was superior to well‐known clustering methods, such as Ward's method, affinity propagation, and K‐means . Hum Brain Mapp 38:2643–2665, 2017. © 2017 Wiley Periodicals, Inc.