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Chemogenetic techniques, such as designer receptors exclusively activated by designer drugs (DREADDs), enable transient, reversible, and minimally invasive manipulation of neural activity in vivo. Their development in nonhuman primates is essential for uncovering neural circuits contributing to cognitive functions and their translation to humans. One key issue that has delayed the development of chemogenetic techniques in primates is the lack of an accessible drug-screening method. Here, we use resting-state fMRI, a noninvasive neuroimaging tool, to assess the impact of deschloroclozapine (DCZ) on brainwide resting-state functional connectivity in 7 rhesus macaques (6 males and 1 female) without DREADDs. We found that systemic administration of 0.1 mg/kg DCZ did not alter the resting-state functional connectivity. Conversely, 0.3 mg/kg of DCZ was associated with a prominent increase in functional connectivity that was mainly confined to the connections of frontal regions. Additional behavioral tests confirmed a negligible impact of 0.1 mg/kg DCZ on socio-emotional behaviors as well as on reaction time in a probabilistic learning task; 0.3 mg/kg DCZ did, however, slow responses in the probabilistic learning task, suggesting attentional or motivational deficits associated with hyperconnectivity in fronto-temporo-parietal networks. Our study highlights both the excellent selectivity of DCZ as a DREADD actuator, and the side effects of its excess dosage. The results demonstrate the translational value of resting-state fMRI as a drug-screening tool to accelerate the development of chemogenetics in primates. SIGNIFICANCE STATEMENT Chemogenetics, such as designer receptors exclusively activated by designer drugs (DREADDs), can afford control over neural activity with unprecedented spatiotemporal resolution. Accelerating the translation of chemogenetic neuromodulation from rodents to primates requires an approach to screen novel DREADD actuators in vivo. Here, we assessed brainwide activity in response to a DREADD actuator deschloroclozapine (DCZ) using resting-state fMRI in macaque monkeys. We demonstrated that low-dose DCZ (0.1 mg/kg) did not change whole-brain functional connectivity or affective behaviors, while a higher dose (0.3 mg/kg) altered frontal functional connectivity and slowed response in a learning task. Our study highlights the excellent selectivity of DCZ at proper dosing, and demonstrates the utility of resting-state fMRI to screen novel chemogenetic actuators in primates.

Obsessive–compulsive disorder (OCD) is highly heterogeneous. While obsessions often involve fear of harm, many patients report uncomfortable sensations and/or urges that drive repetitive behaviors in the absence of a specific fear. Prior work suggests that urges in OCD may be similar to everyday “urges‐for‐action” (UFA) such as the urge to blink, swallow, or scratch, but very little work has investigated the pathophysiology underlying urges in OCD. In the current study, we used an urge‐to‐blink approach to model sensory‐based urges that could be experimentally elicited and compared across patients and controls using the same task stimuli. OCD patients and controls suppressed eye blinking over a period of 60 s, alternating with free blinking blocks, while brain activity was measured using functional magnetic resonance imaging. OCD patients showed significantly increased activation in several regions during the early phase of eyeblink suppression (first 30 s), including mid‐cingulate, insula, striatum, parietal cortex, and occipital cortex, with lingering group differences in parietal and occipital regions during late eyeblink suppression (last 30 s). There were no differences in brain activation during free blinking blocks, and no conditions where OCD patients showed reduced activation compared to controls. In an exploratory analysis of blink counts performed in a subset of subjects, OCD patients were less successful than controls in suppressing blinks. These data indicate that OCD patients exhibit altered brain function and behavior when experiencing and suppressing the urge to blink, raising the possibility that the disorder is associated with a general abnormality in the UFA system that could ultimately be targeted by future treatments.

Magnetic Resonance Elastography (MRE) is a developing imaging technique that enables non-invasive estimation of tissue mechanical properties through the combination of induced mechanical displacements in the tissue and Magnetic Resonance Imaging (MRI). The mechanical drivers necessary to produce shear waves in the tissue have been a focus of engineering effort in the development and refinement of MRE. The potential targeting of smaller and stiffer tissues calls for increases in actuation frequency and refinement of mechanical driver positioning. Furthermore, the anisotropic nature of soft tissues results in driver position related changes in observed displacement wave patterns. These challenges motivate the investigation and development of the concept of active MRE driver positioning through visual servoing under MR imaging.This work demonstrates the initial prototype of an MRE driver positioning system, allowing capture of displacement wave patterns from various mechanical vibration loading angles under different vibration frequencies through MR imaging.Three different configurations of the MRE driver positioning robot are tested with an intervertebral disc (IVD) shaped gel phantom.Both the octahedral shear stress signal to noise ratio (OSS-SNR) and estimated stiffness show statistically significant dependence on driver configuration in each of the three phantom IVD regions.This dependence demonstrates that driver configuration is a critical factor in MRE, and that the developed robot is capable of producing a range of configurations.This work presents the first demonstration of an active, imaging guided MRE driver positioning system, with significance for the future application of MRE to a wider range of human tissues.

Sensory phenomena (SP) are aversive or uncomfortable sensations that accompany and/or drive repetitive behaviors in obsessive-compulsive disorder (OCD). Although SP are associated with significant distress and may respond less well to standard treatments than harm-related obsessions, little is known about their underlying neurobiology. The present study used functional magnetic resonance imaging (fMRI) to measure brain functioning related to severity of SP during a “body-focused” videos task designed to elicit activation in sensorimotor brain regions. Regression analysis examined the relationship between severity of SP and activation during task using permutation analysis with threshold-free cluster enhancement, corrected for multiple comparisons (family-wise error rate p

ObjectiveIn this observational study, we explored cortical structure as function of cortical depth through a laminar analysis of the T1/T2-weighted (T1w/T2w) ratio, which has been related to dendrite density in ex vivo brain tissue specimens of patients with MS.MethodsIn 39 patients (22 relapsing-remitting, 13 female, age 41.1 ± 10.6 years; 17 progressive, 11 female, age 54.1 ± 9.9 years) and 21 healthy controls (8 female, , age 41.6 ± 10.6 years), we performed a voxel-wise analysis of T1w/T2w ratio maps from high-resolution 7T images from the subpial surface to the gray matter/white matter boundary. Six layers were sampled to ensure accuracy based on mean cortical thickness and image resolution.ResultsAt the voxel-wise comparison (p < 0.05, family wise error rate corrected), the whole MS group showed lower T1w/T2w ratio values than controls, both when considering the entire cortex and each individual layer, with peaks occurring in the fusiform, temporo-occipital, and superior and middle frontal cortex. In relapsing-remitting patients, differences in the T1w/T2w ratio were only identified in the subpial layer, with the peak occurring in the fusiform cortex, whereas results obtained in progressive patients mirrored the widespread damage found in the whole group.ConclusionsLaminar analysis of T1w/T2w ratio mapping confirms the presence of cortical damage in MS and shows a variable expression of intracortical damage according to the disease phenotype. Although in the relapsing-remitting stage, only the subpial layer appears susceptible to damage, in progressive patients, widespread cortical abnormalities can be observed, not only, as described before, with regard to myelin/iron concentration but, possibly, to other microstructural features.

Background and purpose A wide range of strategies have been developed to mitigate motion, as a major source of image quality degradation in clinical MRI. We aimed to assess the efficiency of a commercially available prospective motion correction (PMC) system in reducing motion in acquiring high-resolution 3D magnetization-prepared rapid gradient-echo (MPRAGE). Methods A total of 100 patients who referred for brain MRI studies were prospectively imaged using a 3.0T scanner. 3D MPRAGE acquisition was obtained with and without application of PMC. The motion tracking system (KinetiCor Inc.) consisted of a quad camera apparatus, which tracks a specific marker on patient's head by evaluating the marker's optical pattern. The patient's head motion in 6 degrees of freedom throughout the acquisition was then incorporated into the MRI sequence, updating the image acquisition in real time based on the most recent head pose data. MPRAGE images with and without motion correction were assessed independently by two board-certified neuroradiologists using a 5-point Likert scale. Statistical analysis included kappa and Wilcoxon Rank-Sum tests. Results Observers 1 and 2 identified nondiagnostic studies in 17.2% and 20.7% of patients (K = .78, 95% CI .70-.86) without motion correction and in 5.7% and 8% of the studies with motion correction (K = .84, 95% CI .76-.92). The number of nondiagnostic studies was significantly (P = .001) reduced from 19.5% to 5.7% after motion correction in consensus read analysis. Conclusion The described motion tracking system can be used effectively in clinical practice reducing motion artifact and improving image quality of 3D MPRAGE sequence.

The aim of this study was to determine the feasibility of diffusion basis spectrum imaging in multiple sclerosis at 7 T and to investigate the pathological substrates of tissue damage in lesions and normal-appearing white matter. To this end, 43 patients with multiple sclerosis (24 relapsing-remitting, 19 progressive), and 21 healthy control subjects were enrolled. White matter lesions were classified in T1-isointense, T1-hypointense and black holes. Mean values of diffusion basis spectrum imaging metrics (fibres, restricted and non-restricted fractions, axial and radial diffusivities and fractional anisotropy) were measured from whole brain white matter lesions and from both lesions and normal appearing white matter of the corpus callosum. Significant differences were found between T1-isointense and black holes (P ranging from 0.005 to

Contains fulltext : 217200.pdf (Publisher’s version ) (Closed access) Nonhuman primate neuroimaging is on the cusp of a transformation, much in the same way its human counterpart was in 2010, when the Human Connectome Project was launched to accelerate progress. Inspired by an open data-sharing initiative, the global community recently met and, in this article, breaks through obstacles to define its ambitions. 4 p.

Several psychiatric disorders involve abnormalities of interoception and associated neural circuitry centered on the insula. The development of interventions modulating interoceptive circuits could lead to novel treatment approaches for these disorders. The 5-HT3 receptor antagonist ondansetron is a good candidate for the modulation of interoceptive circuits, as 5-HT3 receptors are located abundantly on sensory pathways and ondansetron has shown some clinical utility in disorders characterized by sensory and interoceptive abnormalities. The present study tested the ability of three different doses of ondansetron to engage neural regions involved in interoception to determine the drug’s utility as a therapeutic agent to target circuit abnormalities in patients. Fifty-three healthy subjects were randomized to receive a single 8-mg (n = 18), 16-mg (n = 17), or 24-mg (n = 18) dose of ondansetron and placebo before MRI scanning on separate days. Subjects performed an fMRI task previously shown to engage interoceptive circuitry in which they viewed videos depicting body movements/sensation and control videos. The results revealed a highly significant relationship between dosage and activation in bilateral insula, somatosensory and premotor regions, cingulate cortex, and temporal cortex for control but not body-focused videos. These effects were driven by a robust reduction in activation for ondansetron compared to placebo for the 24-mg group, with weaker effects for the 16-mg and 8-mg groups. In conclusion, high-dose ondansetron reduces activation of several areas important for interoception, including insula and sensorimotor cortical regions. This study reveals the potential utility of this drug in modulating hyperactivity in these regions in patients.

HIV-associated neurocognitive disorders (HAND) occur in ~50% of HIV infected individuals despite combined antiretroviral therapy. Transmigration into the CNS of CD14(+)CD16(+) monocytes, particularly those that are HIV infected and express increased surface chemokine receptor CCR2, contributes to neuroinflammation and HAND. To examine whether in HIV infected individuals CCR2 on CD14(+)CD16(+) monocytes serves as a potential peripheral blood biomarker of HAND, we examined a cohort of 45 HIV infected people. We correlated CCR2 on CD14(+)CD16(+) monocytes with cognitive status, proton magnetic resonance spectroscopy ((1)H-MRS) measured neurometabolite levels, and peripheral blood mononuclear cell (PBMC) HIV DNA copies. We determined that CCR2 was increased specifically on CD14(+)CD16(+) monocytes from people with HAND (median [interquartile range (IQR)]) (63.3 [51.6, 79.0]), compared to those who were not cognitively impaired (38.8 [26.7, 56.4]) or those with neuropsychological impairment due to causes other than HIV (39.8 [30.2, 46.5]). CCR2 was associated with neuronal damage, based on the inverse correlation of CCR2 on CD14(+)CD16(+) monocytes with total N-Acetyl Aspartate (tNAA)/total Creatine (tCr) (r(2) = 0.348, p = 0.01) and Glutamine-Glutamate (Glx)/tCr (r(2) = 0.356, p = 0.01) in the right and left caudate nucleus, respectively. CCR2 on CD14(+)CD16(+) monocytes also correlated with PBMC HIV DNA copies (ρ = 0.618, p = 0.02) that has previously been associated with HAND. These findings suggest that CCR2 on CD14(+)CD16(+) monocytes may be a peripheral blood biomarker of HAND, indicative of increased HIV infected CD14(+)CD16(+) monocyte entry into the CNS that possibly increases the macrophage viral reservoir and contributes to HAND.

Little is known about the neural correlates of lower limbs position sense, despite the impact that proprioceptive deficits have on everyday life activities, such as posture and gait control. We used fMRI to investigate in 30 healthy right‐handed and right‐footed subjects the regional distribution of brain activity during position matching tasks performed with the right dominant and the left nondominant foot. Along with the brain activation, we assessed the performance during both ipsilateral and contralateral matching tasks. Subjects had lower errors when matching was performed by the left nondominant foot. The fMRI analysis suggested that the significant regions responsible for position sense are in the right parietal and frontal cortex, providing a first characterization of the neural correlates of foot position matching.

The aim of this study was to evaluate the capability of sequences acquired on a 7-T MRI scanner, within times and anatomical coverage appropriate for clinical studies, to identify cortical lesions (CLs) in patients with Multiple Sclerosis (MS). Furthermore, we aimed to confirm the clinical significance of CL, testing the correlations between gray matter (GM) lesions and clinical scores. A 7-T MRI protocol included 3D-T1-weighted and T2*-weighted sequences. Images were evaluated independently by three readers of different experience, and the number of CLs was recorded. Between-rater concordance was assessed calculating the intraclass correlation coefficient (ICC). Lin’s concordance correlation coefficient was used to compare CL detection between sequences, while partial correlations and multivariable regression models were used to study the relationship between CL and clinical data. Forty MS patients (M/F, 17/23; 44.7 ± 12.6 years) were enrolled in this study, and CLs were identified in 35/40 subjects (87.5%). CL detection rate on 3D-T1-weighted images was significantly correlated with the detection rate on T2*-weighted images (r = 0.99; p

Graph theory and network modelling have been previously applied to characterize motor network structural topology in multiple sclerosis (MS). However, between‐group differences disclosed by graph analysis might be primarily driven by discrepancy in density, which is likely to be reduced in pathologic conditions as a consequence of macroscopic damage and fibre loss that may result in less streamlines properly traced. In this work, we employed the convex optimization modelling for microstructure informed tractography (COMMIT) framework, which, given a tractogram, estimates the actual contribution (or weight) of each streamline in order to optimally explain the diffusion magnetic resonance imaging signal, filtering out those that are implausible or not necessary. Then, we analysed the topology of this ‘COMMIT‐weighted sensory‐motor network’ in MS accounting for network density. By comparing with standard connectivity analysis, we also tested if abnormalities in network topology are still identifiable when focusing on more ‘quantitative’ network properties. We found that topology differences identified with standard tractography in MS seem to be mainly driven by density, which, in turn, is strongly influenced by the presence of lesions. We were able to identify a significant difference in density but also in network global and local properties when accounting for density discrepancy. Therefore, we believe that COMMIT may help characterize the structural organization in pathological conditions, allowing a fair comparison of connectomes which considers discrepancies in network density. Moreover, discrepancy‐corrected network properties are clinically meaningful and may help guide prognosis assessment and treatment choice.

Background and purpose Although interhemispheric disconnection significantly contributes to disability in multiple sclerosis (MS), the topography, timeline and relationship of callosal damage accrual with hemispheric damage are still unclear. Methods Streamline density and the presence of focal lesions in five callosal subregions were computed in 55 people with MS [13 relapsing-remitting (RRMS), 20 secondary progressive (SPMS), 22 primary progressive (PPMS)] and 24 healthy controls. Results Streamline density decrease was identified in SPMS in all corpus callosum (CC) subregions, in PPMS in the posterior CC and mid-posterior CC and in RRMS in the posterior CC. CC density was independently predicted by CC lesion volume and hemispheric lesion volume and independently predicted visuospatial memory, Expanded Disability Status Scale, manual dexterity and ambulation. Conclusions The reduction in CC density across phenotypes suggests an earlier involvement of the posterior regions, followed only at a later stage by involvement of the anterior portions of the CC. Such interhemispheric disconnection seems to develop as a consequence of white matter macroscopic damage and exerts a relevant impact on motor and, to a lesser extent, cognitive disability.

Background and purpose The advent of high and ultra-high-field MRI has significantly improved the investigation of infratentorial structures by providing high-resolution images. However, none of the publicly available methods for cerebellar image analysis has been optimized for high-resolution images yet. Methods We present the implementation of an automated algorithm-SUITer (spatially unbiased infratentorial for enhanced resolution) method for cerebellar lobules parcellation on high-resolution MR images acquired at both 3 and 7T MRI. SUITer was validated on five manually segmented data and compared with SUIT, FreeSurfer, and convolutional neural networks (CNN). SUITer was then applied to 3 and 7T MR images from 10 multiple sclerosis (MS) patients and 10 healthy controls (HCs). Results The difference in volumes estimation for the cerebellar grey matter (GM), between the manual segmentation (ground truth), SUIT, CNN, and SUITer was reduced when computed by SUITer compared to SUIT (5.56 vs. 29.23 mL) and CNN (5.56 vs. 9.43 mL). FreeSurfer showed low volumes difference (3.56 mL). SUITer segmentations showed a high correlation (R2 = .91) and a high overlap with manual segmentations for cerebellar GM (83.46%). SUITer also showed low volumes difference (7.29 mL), high correlation (R2 = .99), and a high overlap (87.44%) for cerebellar GM segmentations across magnetic fields. SUITer showed similar cerebellar GM volume differences between MS patients and HC at both 3T and 7T (7.69 and 7.76 mL, respectively). Conclusions SUITer provides accurate segmentations of infratentorial structures across different resolutions and MR fields.

In subjects with multiple sclerosis (MS), pathology is more frequent near the inner and outer surfaces of the brain. Here, we sought to explore if in subjects with primary progressive MS (PPMS) cortical lesion load is selectively associated with the severity of periventricular normal appearing white matter (NAWM) damage, as assessed with diffusion weighted imaging. To this aim, twenty-four subjects with PPMS and twenty healthy controls were included in the study. Using diffusion data, skeletonized mean diffusivity (MD) NAWM maps were computed excluding WM lesions and a 2 mm-thick peri-lesional rim. The supra-tentorial voxels between 2 and 6 mm of distance from the lateral ventricles were included in the periventricular NAWM mask while the voxels between 6 and 10 mm from the lateral ventricles were included in the deep NAWM mask; mean MD values were then computed separately for these two masks. Lastly, cortical lesions were assessed on phase-sensitive inversion recovery (PSIR) images and cortical thickness was quantified on volumetric T1 images. Our main result was the observation in the PPMS group of a significant correlation between periventricular NAWM MD values and cortical lesion load, with a greater cortical lesion burden being associated with more abnormal periventricular NAWM MD. Conversely, there was no correlation between cortical lesion load and deep NAWM MD values or periventricular WM lesions. Our data thus suggest that a common – and relatively selective - factor plays a role in the development of both cortical lesion and periventricular NAWM abnormalities in PPMS., Highlights • In PPMS, pathology is more frequent near the inner and outer brain surfaces. • We evaluated the association between cortical lesions and periventricular damage. • Cortical lesion load directly correlated with periventricular NAWM damage severity. • Cortical lesion load did not correlate with periventricular lesions. • A common factor seems to modulate cortical lesions and periventricular NAWM damage.

Background: Cortical gray matter (GM) demyelination is frequent and clinically relevant in multiple sclerosis (MS). Quantitative magnetic resonance imaging (qMRI) sequences such as magnetization transfer ratio (MTR) and quantitative R2* (qR2*) can capture pathological subtleties missed by conventional magnetic resonance imaging (MRI) sequences. Although differences in MTR and qR2* have been reported between lesional and non-lesional tissue, differences between lesion types or lesion types and myelin density matched normal-appearing gray matter (NAGM) have not been found or investigated. Objective: Identify quantitative differences in histopathologically verified GM lesion types and matched NAGM at ultra-high field strength. Methods: Using 7T post-mortem MRI, MRI lesions were marked on T2 images and co-registered to the calculated MTR and qR2* maps for further evaluation. In all, 15 brain slices were collected, containing a total of 74 cortical GM lesions and 45 areas of NAGM. Results: Intracortical lesions had lower MTR and qR2* values compared to NAGM. Type I lesions showed lower MTR than type III lesions. Type III lesions showed lower MTR than matched NAGM, and type I and IV lesions showed lower qR2* than matched NAGM. Conclusion: qMRI at 7T can provide additional information on extent of cortical pathology, especially concerning subpial lesions. This may be relevant for monitoring disease progression and potential treatment effects.

Background: Using diffusion tensor imaging (DTI), it was previously found that demyelinated gray matter (GM) lesions have increased fractional anisotropy (FA) when compared to normal-appearing gray matter (NAGM) in multiple sclerosis (MS). The biological substrate underlying this FA change is so far unclear; both neurodegenerative changes and microglial activation have been proposed as causal contributors. Objective: To test the proposed hypothesis that microglia activation is responsible for increased FA in cortical GM lesions. Methods: We investigated post-mortem cortical DTI changes in hemispheric, coronally cut sections and investigated the underlying histopathology using immunohistochemistry. Results: Overall, there were few activated microglia/macrophages, and no difference between GM lesions and NAGM was observed. However, cell density was increased in GM lesions compared to NAGM (309.67 ± standard deviation (SD) 124.44 vs 249.95 ± SD 56.75, p = 0.002). Conclusion: FA increase was not due to lesional and non-lesional differences in microglia activation and/or proliferation. We found an increase in general cellular density without a notable difference in cellular size, that is, tissue compaction, as a possible alternative explanation.

Our aim was to characterize the nature and extent of pathological changes in the normal-appearing white matter (NAWM) of patients with multiple sclerosis (MS) using novel diffusion kurtosis imaging-derived white matter tract integrity (WMTI) metrics and to investigate the association between these WMTI metrics and clinical parameters. Thirty-two patients with relapsing–remitting MS and 19 age- and gender-matched healthy controls underwent MRI and neurological examination. Maps of mean diffusivity, fractional anisotropy and WMTI metrics (intra-axonal diffusivity, axonal water fraction, tortuosity and axial and radial extra-axonal diffusivity) were created. Tract-based spatial statistics analysis was performed to assess for differences in the NAWM between patients and controls. A region of interest analysis of the corpus callosum was also performed to assess for group differences and to evaluate correlations between WMTI metrics and measures of disease severity. Mean diffusivity and radial extra-axonal diffusivity were significantly increased while fractional anisotropy, axonal water fraction, intra-axonal diffusivity and tortuosity were decreased in MS patients compared with controls (p values ranging from

Background Large-scale functional abnormalities and decreased synchronization between functionally connected regions within brain networks were reported in progressive multiple sclerosis (P-MS) patients. Low concentration of gamma-aminobutyric acid (GABA) was observed in the sensorimotor cortex (SMC) of these patients and was associated with reduced motor functions of limbs. Yet, the role of GABA in modulating functional connectivity (FC) has not been investigated in MS patients. Objectives To determine the relationship between GABA concentration in the SMC and short-term FC changes within the sensorimotor network (SMN) in P-MS patients. Methods Combining magnetic resonance spectroscopy (MRS) and resting-state functional MRI (rs-fMRI), we investigated the relationship between baseline GABA concentration in the left SMC and FC within SMN in P-MS patients compared to healthy controls (HCs). Additionally, we assessed the relationship between baseline GABA concentration and FC changes over a 1-year follow-up period in the patients’ group only. Results At baseline, lower GABA levels, and decreased FC levels in regions within the SMN were observed in MS patients compared to healthy controls (HCs). Overtime, an increase in FC was observed in regions within the SMN in the MS group. This increase correlated inversely with motor performance scores. Conclusions We postulate that in P-MS patients, lower levels of GABA in the SMC contribute to decreased inhibition, and as a result, to a reactive increase of FC in inter-connected sensorimotor brain regions, thus minimizing clinical worsening.

The brain displays a remarkable ability to adapt following injury by altering its connections through neural plasticity. Many of the biological mechanisms that underlie plasticity are known, but there is little knowledge as to when, or where in the brain plasticity will occur following injury. This knowledge could guide plasticity-promoting interventions and create a more accurate roadmap of the recovery process following injury. We causally investigated the time-course of plasticity after hippocampal lesions using multi-modal MRI in monkeys. We show that post-injury plasticity is highly dynamic, but also largely predictable on the basis of the functional connectivity of the lesioned region, gradients of cell densities across the cortex and the pre-lesion network structure of the brain. The ability to predict which brain areas will plastically adapt their functional connectivity following injury may allow us to decipher why some brain lesions lead to permanent loss of cognitive function, while others do not., eLife digest The brain has the ability to adapt after injury, a process known as plasticity. When one area sustains damage, for example following a car accident or stroke, other areas change their activity and structure to compensate. Understanding how this happens is critical to helping people recover from brain injuries. Certain factors may affect how well the brain can repair itself. These include how much the damaged area interacts with other areas, and which cell types different areas of the brain contain. Froudist-Walsh et al. set out to determine how these factors influence recovery from brain injury in monkeys, whose brains are similar to our own. The monkeys had damage to a structure called the hippocampus. This part of the brain has a key role in memory, which is often impaired in patients with brain injuries. The hippocampus cannot repair itself because the brain has only a limited capacity to grow new neurons. Instead, the brain attempts to compensate for disruption to the hippocampus via changes in other, undamaged areas. Using brain imaging, Froudist-Walsh et al. show that the types of changes that occur depend on how much time has passed since the injury. In the first three months, many areas of the brain change how much they coordinate their activity with other areas. Highly connected areas reduce their communication with other areas the most. In the long-term, the responses of brain areas depend more on which cell types they contain. Areas with more support cells known as “glia” – which supply nutrients and energy to neurons – are better able to adapt their connectivity up to a year after the injury. These findings may ultimately benefit people who have suffered brain injuries after accidents or stroke. They suggest that stimulating intact brain areas may be helpful in the months immediately after an injury. By contrast, long-term therapy may need to focus more on structural repair. Future studies must build on these results to discover the best ways to induce successful recovery from brain injury.

BACKGROUND AND PURPOSE: At 7T MR imaging, T2*-weighted gradient echo has been shown to provide high-resolution anatomic images of gray matter lesions. However, few studies have verified T2*WI lesions histopathologically or compared them with more standard techniques at ultra-high-field strength. This study aimed to determine the sensitivity of T2WI and T2*WI sequences for detecting cortical GM lesions in MS. MATERIALS AND METHODS: At 7T, 2D multiecho spin-echo T2WI and 3D gradient-echo T2*WI were acquired from 27 formalin-fixed coronal hemispheric brain sections of 15 patients and 4 healthy controls. Proteolipid-stained tissue sections (8 μm) were matched to the corresponding MR images, and lesions were manually scored on both MR imaging sequences (blinded to histopathology) and tissue sections (blinded to MR imaging). The sensitivity of MR imaging sequences for GM lesion types and white matter lesions was calculated. An unblinded retrospective scoring was also performed. RESULTS: If all cortical GM lesions were taken into account, the T2WI sequence detected slightly more lesions than the T2*WI sequence: 28% and 16%, respectively ( P = .054). This difference disappeared when only intracortical lesions were considered. When histopathologic information (type, location) was revealed to the reader, the sensitivity went up to 84% (T2WI) and 85% (T2*WI) (not significant). Furthermore, the false-positive rate was 8.6% for the T2WI and 10.5% for the T2*WI sequence. CONCLUSIONS: There is no strong advantage of the T2*WI sequence compared with a conventional T2WI sequence in the detection of cortical lesions at 7T. Retrospectively, a high percentage of lesions could be detected with both sequences. However, many lesions are still missed prospectively. This could possibly be minimized with better a priori observer training.

OBJECTIVE: Individuals with eating disorders are theorized to have basic impairments in affective appraisal and social-emotional processing that contribute to pathogenesis of the disease. We aimed to determine if facial electromyography could be used to discriminate between happy and disgust emotions during simultaneous acquisition of an fMRI BOLD sequence in efforts to establish a novel tool for investigating emotion-driven hypotheses about eating pathology. In line with standards for rigor and reproducibility, we provide detailed protocols and code to support each step of this project. METHOD: Sixteen adolescents with low-weight eating disorders viewed emotional faces (Happy or Disgust) and were asked to mimic their facial expression during simultaneous BOLD and EMG (Corrugator supercilli, Lavator lavii, Zygomaticus major) acquisition. Trials were repeated with the scanner off and again with scanner on (i.e., Fatigue). RESULTS: The Levator and Zygomaticus activation patterns discriminated disgust and happy faces successfully. The pattern held between scanner on and off conditions, but muscle activation attenuated in the Fatigue condition, especially for the Zygomaticus. DISCUSSION: Simultaneous fMRI-EMG is a new tool capable of discriminating specific emotions based on muscle activation patterns and can be leveraged to answer emotion-driven hypotheses about clinical populations characterized by difficulty labeling or processing emotions.

OBJECTIVE: Multiple sclerosis (MS) is less prevalent in African Americans (AAs) than Caucasians (CAs) but in the former the disease course tends to be more severe. In order to clarify the MRI correlates of disease severity in AAs, we performed a multimodal brain MRI study to comprehensively assess the extent of grey matter (GM) damage and the degree of functional adaptation to structural damage in AAs with MS. METHODS: In this cross-sectional study, we characterized GM damage in terms of focal lesions and volume loss and functional adaptation during the execution of a simple motor task on a sample of 20 AAs and 20 CAs with MS and 20 healthy controls (CTRLs). RESULTS: In AAs, we observed a wider range of EDSS scores than CAs, with multisystem involvement being more likely in AAs (p

Interoception has been defined as the sensing of the physiological condition of the body, with interoceptive sensibility (IS) characterizing an individual's self-reported awareness of internal sensation. IS is a multidimensional construct including not only the tendency to be aware of sensation but also how sensations are interpreted, regulated, and used to inform behavior, with different dimensions relating to different aspects of health and disease. Here we investigated neural mechanisms of interoception when healthy individuals attended to their heartbeat and skin temperature, and examined the relationship between neural activity during interoception and individual differences in self-reported IS using the Multidimensional Scale of Interoceptive Awareness (MAIA). Consistent with prior work, interoception activated a network involving insula and sensorimotor regions but also including occipital, temporal, and prefrontal cortex. Differences based on interoceptive focus (heartbeat vs skin temperature) were found in insula, sensorimotor regions, occipital cortex, and limbic areas. Factor analysis of MAIA dimensions revealed 3 dissociable components of IS in our dataset, only one of which was related to neural activity during interoception. Reduced scores on the third factor, which reflected reduced ability to control attention to body sensation and increased tendency to distract from and worry about aversive sensations, was associated with greater activation in many of the same regions as those involved in interoception, including insula, sensorimotor, anterior cingulate, and temporal cortex. These data suggest that self-rated interoceptive sensibility is related to altered activation in regions involved in monitoring body state, which has implications for disorders associated with abnormality of interoception. Hum Brain Mapp 38:6068-6082, 2017. © 2017 Wiley Periodicals, Inc.

Spasmodic dysphonia is a focal dystonia characterized by involuntary spasms in the laryngeal muscles that occur selectively during speaking. Although hereditary trends have been reported in up to 16% of patients, the causative etiology of spasmodic dysphonia is unclear, and the influences of various phenotypes and genotypes on disorder pathophysiology are poorly understood. In this study, we examined structural alterations in cortical gray matter and white matter integrity in relationship to different phenotypes and putative genotypes of spasmodic dysphonia to elucidate the structural component of its complex pathophysiology.Eighty-nine patients with spasmodic dysphonia underwent high-resolution magnetic resonance imaging and diffusion-weighted imaging to examine cortical thickness and white matter fractional anisotropy in adductor versus abductor forms (distinct phenotypes) and in sporadic versus familial cases (distinct genotypes).Phenotype-specific abnormalities were localized in the left sensorimotor cortex and angular gyrus and the white matter bundle of the right superior corona radiata. Genotype-specific alterations were found in the left superior temporal gyrus, supplementary motor area, and the arcuate portion of the left superior longitudinal fasciculus.Our findings suggest that phenotypic differences in spasmodic dysphonia arise at the level of the primary and associative areas of motor control, whereas genotype-related pathophysiological mechanisms may be associated with dysfunction of regions regulating phonological and sensory processing. Identification of structural alterations specific to disorder phenotype and putative genotype provides an important step toward future delineation of imaging markers and potential targets for novel therapeutic interventions for spasmodic dysphonia. © 2017 International Parkinson and Movement Disorder Society.

Noncontrast techniques for peripheral MR angiography are receiving renewed interest because of safety concerns about the use of gadolinium in patients with renal insufficiency. One class of techniques involves subtraction of dark-blood images acquired during fast systolic flow from bright-blood images obtained during slow diastolic flow. The goal of this work was to determine whether the inherent sparsity of the difference images could be exploited to achieve greater acceleration without loss of image quality in the context of generalized autocalibrating partially parallel acquisition (GRAPPA). It is shown that noise amplification at high acceleration factors can be reduced by performing subtraction on the raw data, before calculation of the GRAPPA weights, rather than on the final magnitude images. Use of the difference data to calculate the GRAPPA weights decreases the geometry factor (g-factor), because the difference data represent a sparse image set. This demonstrates an inherent property of GRAPPA and does not require the use of compressed sensing. Application of this approach to highly accelerated data from healthy volunteers resulted in similar depiction of large arteries to that obtained with low acceleration and standard reconstruction. However, visualization of very small vessels and arterial branches was compromised. Magn Reson Med, 2012. © 2011 Wiley Periodicals, Inc.

Although recent studies indicate that use of a single global transverse relaxation time, T(2), per metabolite is sufficient for better than +/-10% quantification precision at intermediate and short echo-time spectroscopy in young adults, the age-dependence of this finding is unknown. Consequently, the age effect on regional brain choline (Cho), creatine (Cr), and N-acetylaspartate (NAA) T(2)s was examined in four age groups using 3D (four slices, 80 voxels 1 cm(3) each) proton MR spectroscopy in an optimized two-point protocol. Metabolite T(2)s were estimated in each voxel and in 10 gray and white matter (GM, WM) structures in 20 healthy subjects: four adolescents (13 +/- 1 years old), eight young adults (26 +/- 1); two middle-aged (51 +/- 6), and six elderly (74 +/- 3). The results reveal that T(2)s in GM (average +/- standard error of the mean) of adolescents (NAA: 301 +/- 30, Cr: 162 +/- 7, Cho: 263 +/- 7 ms), young adults (NAA: 269 +/- 7, Cr: 156 +/- 7, Cho: 226 +/- 9 ms), and elderly (NAA: 259 +/- 13, Cr: 154 +/- 8, Cho: 229 +/- 14 ms), were 30%, 16%, and 10% shorter than in WM, yielding mean global T(2)s of NAA: 343, Cr: 172, and Cho: 248 ms. The elderly NAA, Cr, and Cho T(2)s were 12%, 6%, and 10% shorter than the adolescents, a change of under 1 ms/year assuming a linear decline with age. Formulae for T(2) age-correction for higher quantification precision are provided.

Intra-axonal accumulation of sodium ions is one of the key mechanisms of delayed neuro-axonal degeneration that contributes to disability accrual in multiple sclerosis. In vivo sodium magnetic resonance imaging studies have demonstrated an increase of brain total sodium concentration in patients with multiple sclerosis, especially in patients with greater disability. However, total sodium concentration is a weighted average of intra- and extra-cellular sodium concentration whose changes reflect different tissue pathophysiological processes. The in vivo , non-invasive measurement of intracellular sodium concentration is quite challenging and the few applications in patients with neurological diseases are limited to case reports and qualitative assessments. In the present study we provide first evidence of the feasibility of triple quantum filtered 23 Na magnetic resonance imaging at 7 T, and provide in vivo quantification of global and regional brain intra- and extra-cellular sodium concentration in 19 relapsing-remitting multiple sclerosis patients and 17 heathy controls. Global grey matter and white matter total sodium concentration (respectively P < 0.05 and P < 0.01), and intracellular sodium concentration (both P < 0.001) were higher while grey matter and white matter intracellular sodium volume fraction (indirect measure of extracellular sodium concentration) were lower (respectively P = 0.62 and P < 0.001) in patients compared with healthy controls. At a brain regional level, clusters of increased total sodium concentration and intracellular sodium concentration and decreased intracellular sodium volume fraction were found in several cortical, subcortical and white matter regions when patients were compared with healthy controls ( P < 0.05 family-wise error corrected for total sodium concentration, P < 0.05 uncorrected for multiple comparisons for intracellular sodium concentration and intracellular sodium volume fraction). Measures of total sodium concentration and intracellular sodium volume fraction, but not measures of intracellular sodium concentration were correlated with T 2 -weighted and T 1 -weighted lesion volumes (0.05 < P < 0.01) and with Expanded Disability Status Scale ( P < 0.05). Thus, suggesting that while intracellular sodium volume fraction decrease could reflect expansion of extracellular space due to tissue loss, intracellular sodium concentration increase could reflect neuro-axonal metabolic dysfunction.

Multiple sclerosis (MS) is the most common cause of non-traumatic disability in young adults. The mechanisms underlying neurodegeneration and disease progression are poorly understood, in part as a result of the lack of non-invasive methods to measure and monitor neurodegeneration in vivo. Sodium MRI is a topic of increasing interest in MS research as it allows the metabolic characterization of brain tissue in vivo, and integration with the structural information provided by (1)H MRI, helping in the exploration of pathogenetic mechanisms and possibly offering insights into disease progression and monitoring of treatment outcomes. We present an up-to-date review of the sodium MRI application in MS organized into four main sections: (i) biological and pathogenetic role of sodium; (ii) brief overview of sodium imaging techniques; (iii) results of sodium MRI application in clinical studies; and (iv) future perspectives.

Background and purpose Spasmodic dysphonia (SD), or laryngeal dystonia, is a task-specific isolated focal dystonia of unknown causes and pathophysiology. Although functional and structural abnormalities have been described in this disorder, the influence of its different clinical phenotypes and genotypes remains scant, making it difficult to explain SD pathophysiology and to identify potential biomarkers. Methods We used a combination of independent component analysis and linear discriminant analysis of resting-state functional magnetic resonance imaging data to investigate brain organization in different SD phenotypes (abductor versus adductor type) and putative genotypes (familial versus sporadic cases) and to characterize neural markers for genotype/phenotype categorization. Results We found abnormal functional connectivity within sensorimotor and frontoparietal networks in patients with SD compared with healthy individuals as well as phenotype- and genotype-distinct alterations of these networks, involving primary somatosensory, premotor and parietal cortices. The linear discriminant analysis achieved 71% accuracy classifying SD and healthy individuals using connectivity measures in the left inferior parietal and sensorimotor cortices. When categorizing between different forms of SD, the combination of measures from the left inferior parietal, premotor and right sensorimotor cortices achieved 81% discriminatory power between familial and sporadic SD cases, whereas the combination of measures from the right superior parietal, primary somatosensory and premotor cortices led to 71% accuracy in the classification of adductor and abductor SD forms. Conclusions Our findings present the first effort to identify and categorize isolated focal dystonia based on its brain functional connectivity profile, which may have a potential impact on the future development of biomarkers for this rare disorder.

Neuroimaging studies support the involvement of the cerebello-cortical and striato-cortical motor loops in motor sequence learning. Here, we investigated whether the gain of motor sequence learning could depend on a-priori resting-state functional connectivity (rsFC) between motor areas and structures belonging to these circuits. Fourteen healthy subjects underwent a resting-state functional magnetic resonance imaging session. Afterward, they were asked to reproduce a verbally-learned sequence of finger opposition movements as fast and as accurately as possible. All subjects increased their movement rate with practice, by reducing the touch duration and/or intertapping interval. The rsFC analysis showed that, at rest, the left and right primary motor cortex (M1) and left and right supplementary motor area (SMA) were mainly connected with other motor areas. The covariate analysis taking into account the different kinematic parameters indicated that the subjects achieving greater movement rate increase were those showing stronger rsFC of the left M1 and SMA with the right lobule VIII of the cerebellum. Notably, the subjects with greater intertapping interval reduction showed stronger rsFC of the left M1 and SMA with the association nuclei of the thalamus. Conversely, the regression analysis with the right M1 and SMA seeds showed only a few significant clusters for the different covariates not located in the cerebellum and thalamus. No common clusters were found between the right M1 and SMA. All of these findings indicated important functional connections at rest of those neural circuits responsible for motor learning improvement, involving the motor areas related to the hemisphere directly controlling the finger movements, the thalamus and cerebellum.

In vivo sodium magnetic resonance imaging (MRI) measures tissue sodium content in living human brain but current methods do not allow noninvasive quantitative assessment of intracellular sodium concentration (ISC) - the most useful marker of tissue viability. In this study, we report the first noninvasive quantitative in vivo measurement of ISC and intracellular sodium volume fraction (ISVF) in healthy human brain, made possible by measuring tissue sodium concentration (TSC) and intracellular sodium molar fraction (ISMF) at ultra-high field MRI. The method uses single-quantum (SQ) and triple-quantum filtered (TQF) imaging at 7 Tesla to separate intra- and extracellular sodium signals and provide quantification of ISMF, ISC and ISVF. This novel method allows noninvasive quantitative measurement of ISC and ISVF, opening many possibilities for structural and functional metabolic studies in healthy and diseased brains.

The evidence suggesting a role of extensive cortical demyelization and atrophy in progressive multiple sclerosis is rapidly increasing. Although conventional magnetic resonance imaging has had a huge impact on multiple sclerosis by enabling an earlier diagnosis, and by providing surrogate markers for monitoring disease response to anti-inflammatory/immunomodulatory treatments, it is limited by the low pathological specificity and the low sensitivity to both diffuse damage in normal-appearing white matter and focal and diffuse damage in gray matter. Advanced magnetic resonance imaging techniques can partially overcome these limitations by providing markers more specific to the underlying pathologic substrates and more sensitive to the structural and functional "occult" brain tissue damage in patients with multiple sclerosis. This review describes brain and spinal cord imaging studies of multiple sclerosis with particular emphasis on gray matter imaging in both secondary progressive and primary progressive multiple sclerosis, discusses the clinical implications of gray matter damage, and outlines current magnetic resonance imaging developments at high and ultrahigh magnetic field strength.

Localized tissue transverse relaxation time ( T 2 ) is obtained by fitting a decaying exponential to the signals from several spin-echo experiments at different echo times (TE). Unfortunately, time constraints in magnetic resonance spectroscopy (MRS) often mandate in vivo acquisition schemes at short repetition times (TR), that is, comparable with the longitudinal relaxation constant ( T 1 ). This leads to different T 1 -weighting of the signals at each TE. Unaccounted for, this varying weighting causes systematic underestimation of the T 2 's, sometimes by as mush as 30%. In this article, we (i) analyze the phenomenon for common MRS spin-echo T 2 acquisition schemes; (ii) propose a general post hoc T 1 -bias correction for any (TR, TE) combination; (iii) show that approximate knowledge of T 1 is sufficient, since a 20% uncertainty in T 1 leads to under 3% bias in T 2 ; and consequently, (iv) efficient, precision-optimized short TR spin-echo T 2 measurement protocols can be designed and used without risk of accuracy loss. Tables of correction for single-refocusing (conventional) spin-echo and double refocusing, such as, PRESS acquisitions, are provided.

While the inherent low sensitivity of in vivo MR spectroscopy motivated a trend towards higher magnetic fields, B(0), it has since become apparent that this increase does not seem to translate into the anticipated improvement in spectral resolution. This is attributed to the decrease of the transverse relaxation time, T(2)*, in vivo due to macro- and mesoscopic tissue susceptibility. Using spectral contrast-to-noise ratio (SCNR) arguments, we show that if in biological systems the linewidth (on the frequency scale) increases linearly with the field, the spectral resolution (in parts per million) improves approximately as the fifth-root of B(0) for chemically shifted lines and decreases as about B(0)(4/5) (in hertz) for a structure of J-coupled multiplets. It is also shown that for any given B(0) there is a unique voxel size that is optimal in spectral resolution, linking the spectral and spatial resolutions. Since in practical applications the spatial resolution may be dictated by the target anatomy, nomograms to determine the B(0) required to achieve the desired spectral resolution at that voxel size are presented. More generally, the scaling of the nomograms to determine the achievable spectral and spatial resolutions at any given field is described.

Although most mild traumatic brain injury (mTBI) patients suffer any of several post-concussion symptoms suggestive of thalamic involvement, they rarely present with any MRI-visible pathology. The aim here, therefore, is to characterize their thalamic metabolite levels with proton MR spectroscopy (1H-MRS) compared with healthy controls.T1-weighted MRI and multi-voxel 1H-MRS were acquired at 3 Tesla from 20 mTBI (Glasgow Coma Scale score of 15-13) patients, 19-59 years old, 0-7 years post-injury; and from 17 age and gender matched healthy controls. Mixed model regression was used to compare patients and controls with respect to the mean absolute N-acetylaspartate (NAA), choline (Cho) and creatine (Cr) levels within each thalamus.The mTBI-induced thalamic metabolite concentration changes were under +/- 13.0% for NAA, +/- 13.5% for Cr and +/- 18.8% for Cho relative to their corresponding concentrations in the controls: NAA: 10.08 +/- 0.30 (mean +/- standard error), Cr: 5.62 +/- 0.18 and Cho: 2.08 +/- 0.09 mM. These limits represent the minimal detectable differences between the two cohorts.The change in metabolic levels in the thalamus of patients who sustained clinically defined mTBI could be an instrumental characteristic of 'mildness'. 1H-MRS could, therefore, serve as an objective laboratory indicator for differentiating 'mild' from more severe categories of head-trauma, regardless of the presence or lack of current clinical symptoms.

Fast, high-resolution, longitudinal relaxation time (T1) mapping is invaluable in clinical and research applications. It has been shown that two spoiled gradient recalled echo (SPGR) images acquired in steady state with variable flip angles is an attractive alternative to the multi-image sets previously acquired with inversion or saturation recovery. The known sensitivity of the two-point method to transmit radiofrequency field (B1) inhomogeneity exacerbated at 3 T and above, however, mandates its combination with an additional, time-consuming and possibly specific-absorption-rate-intensive B1 measurement, preventing direct migration of the method to these fields. To address this, we introduce a method designed to be free of systematic errors caused by B1 inhomogeneity in which the value of T1 is extracted from three SPGR images acquired with echo planar imaging (EPI) readout. The precision of the T1 maps produced is found to be comparable to the two-point method, while the accuracy is greatly improved in the same time and spatial resolution. A welcome byproduct of the method is a map of B1 that can be used to correct other acquisitions in the same session. Tables of the optimal acquisition protocols are provided for several total imaging times.

The transverse relaxation times, T(2), of N-acetylaspartate (NAA), total choline (Cho), and creatine (Cr) obtained at 3T in several human brain regions of eight healthy volunteers are reported. They were obtained simultaneously in 320 voxels with three-dimensional (3D) proton MR spectroscopy ((1)H-MRS) at 1 cm(3) spatial resolution. A two-point protocol, optimized for the least error per given time by adjusting both the echo delay (TE(i)) and number of averages, N(i), at each point, was used. Eight healthy subjects (four males and four females, age = 26 +/- 2 years) underwent the hour-long procedure of four 15-min, 3D acquisitions (TE(1) = 35 ms, N(1) = 1; and TE(2) = 285 ms, N(2) = 3). The results reveal that across all subjects the NAA and Cr T(2)s in gray matter (GM) structures (226 +/- 17 and 137 +/- 12 ms, respectively) were 13-17% shorter than the corresponding T(2)s in white matter (WM; 264 +/- 10 and 155 +/- 7 ms, respectively). The T(2)s of Cho did not differ between GM and WM (207 +/- 17 and 202 +/- 8, respectively). For the purpose of metabolic quantification, these values justify to within +/-10% the previous use of one T(2) per metabolite for 1) the entire brain and 2) all subjects. These T(2) values (which to our knowledge were obtained for the first time at this field, spatial resolution, coverage, and precision) are essential for reliable absolute metabolic quantification.