Whole-brain, gray, and white matter time-locked functional signal changes with simple tasks and model-free analysis.

Recent studies have revealed the production of time-locked blood oxygenation level-dependent (BOLD) functional MRI (fMRI) signals throughout the entire brain in response to tasks, challenging the existence of sparse and localized brain functions and highlighting the pervasiveness of potential false negative fMRI findings. "Whole-brain" actually refers to gray matter, the only tissue traditionally studied with fMRI. However, several reports have demonstrated reliable detection of BOLD signals in white matter, which have previously been largely ignored. Using simple tasks and analyses, we demonstrate BOLD signal changes across the whole brain, in both white and gray matters, in similar manner to previous reports of whole brain studies. We investigated whether white matter displays time-locked BOLD signals across multiple structural pathways in response to a stimulus in a similar manner to the cortex. We find that both white and gray matter show time-locked activations across the whole brain, with a majority of both tissue types showing statistically significant signal changes for all task stimuli investigated. We observed a wide range of signal responses to tasks, with different regions showing different BOLD signal changes to the same task. Moreover, we find that each region may display different BOLD responses to different stimuli. Overall, we present compelling evidence that, just like all gray matter, essentially all white matter in the brain shows time-locked BOLD signal changes in response to multiple stimuli, challenging the idea of sparse functional localization and the prevailing wisdom of treating white matter BOLD signals as artifacts to be removed.

Intracranial electrophysiological and structural basis of BOLD functional connectivity in human brain white matter.

While functional MRI (fMRI) studies have mainly focused on gray matter, recent studies have consistently found that blood-oxygenation-level-dependent (BOLD) signals can be reliably detected in white matter, and functional connectivity (FC) has been organized into distributed networks in white matter. Nevertheless, it remains unclear whether this white matter FC reflects underlying electrophysiological synchronization. To address this question, we employ intracranial stereotactic-electroencephalography (SEEG) and resting-state fMRI data from a group of 16 patients with drug-resistant epilepsy. We find that BOLD FC is correlated with SEEG FC in white matter, and this result is consistent across a wide range of frequency bands for each participant. By including diffusion spectrum imaging data, we also find that white matter FC from both SEEG and fMRI are correlated with white matter structural connectivity, suggesting that anatomical fiber tracts underlie the functional synchronization in white matter. These results provide evidence for the electrophysiological and structural basis of white matter BOLD FC, which could be a potential biomarker for psychiatric and neurological disorders.

Hippocampal and motor regions contribute to memory benefits after enacted encoding: cross-sectional and longitudinal evidence.

The neurobiological underpinnings of action-related episodic memory and how enactment contributes to efficient memory encoding are not well understood. We examine whether individual differences in level (n = 338) and 5-year change (n = 248) in the ability to benefit from motor involvement during memory encoding are related to gray matter (GM) volume, white matter (WM) integrity, and dopamine-regulating genes in a population-based cohort (age range = 25-80 years). A latent profile analysis identified 2 groups with similar performance on verbal encoding but with marked differences in the ability to benefit from motor involvement during memory encoding. Impaired ability to benefit from enactment was paired with smaller HC, parahippocampal, and putamen volume along with lower WM microstructure in the fornix. Individuals with reduced ability to benefit from encoding enactment over 5 years were characterized by reduced HC and motor cortex GM volume along with reduced WM microstructure in several WM tracts. Moreover, the proportion of catechol-O-methyltransferase-Val-carriers differed significantly between classes identified from the latent-profile analysis. These results provide converging evidence that individuals with low or declining ability to benefit from motor involvement during memory encoding are characterized by low and reduced GM volume in regions critical for memory and motor functions along with altered WM microstructure.

Modelling the differential effects of age on transcranial magnetic stimulation induced electric fields.

Objective. The therapeutic application of noninvasive brain stimulation modalities such as transcranial magnetic stimulation (TMS) has expanded in terms of indications and patient populations. Often neurodevelopmental and neurodegenerative changes are not considered in research studies and clinical applications. This study sought to examine TMS dosing across time points in the life cycle.Approach. TMS induced electric fields with a figure-of-eight coil was simulated at left dorsolateral prefrontal cortex regions and taken in vertex as a control region. Realistic magnetic resonance imaging-based head models (N= 48) were concurrently examined in a cross-sectional study of three different age groups (children, adults, and elderlies).Main results. Age had a negative correlation with electric field peaks in white matter, grey matter and cerebrospinal fluid (P< 0.001). Notably, the electric field map in children displayed the widest cortical surface spread of TMS induced electric fields.Significance. Age-related anatomical geometry beneath the coil stimulation site had a significant impact on the TMS induced electric fields for different age groups. Safety considerations for TMS applications and protocols in children are warranted based on the present electric field findings.

The functional connectivity between left insula and left medial superior frontal gyrus underlying the relationship between rumination and procrastination.

Procrastination is regarded as a prevalent problematic behavior that impairs people's physical and mental health. Although previous studies have indicated that trait rumination is robustly positively correlated with procrastination, it remains unknown about the neural substrates underlying the relationship between trait rumination and procrastination. To address this issue, we used voxel-based morphometry (VBM) and resting-state functional connectivity (RSFC) approaches to explore the neural basis of the relationship between trait rumination and procrastination. Our behavior results found that trait rumination was significantly positively correlated to procrastination, while the VBM analysis showed that trait rumination was negatively correlated with gray matter volume of the insula. Furthermore, the RSFC results revealed a negative association of the left insula-lmSFG (left medial superior frontal gyrus) functional connectivity with trait rumination. More importantly, the mediation analysis showed that trait rumination could completely mediate the relationship between left insula-lmSFG functional connectivity and procrastination. These results suggest that the left insula-lmSFG functional connectivity involved in emotion regulation modulates the association between trait rumination and procrastination, which provides neural evidence for the relationship between trait rumination and procrastination.

Detection of functional activity in brain white matter using fiber architecture informed synchrony mapping.

A general linear model is widely used for analyzing fMRI data, in which the blood oxygenation-level dependent (BOLD) signals in gray matter (GM) evoked in response to neural stimulation are modeled by convolving the time course of the expected neural activity with a canonical hemodynamic response function (HRF) obtained a priori. The maps of brain activity produced reflect the magnitude of local BOLD responses. However, detecting BOLD signals in white matter (WM) is more challenging as the BOLD signals are weaker and the HRF is different, and may vary more across the brain. Here we propose a model-free approach to detect changes in BOLD signals in WM by measuring task-evoked increases of BOLD signal synchrony in WM fibers. The proposed approach relies on a simple assumption that, in response to a functional task, BOLD signals in relevant fibers are modulated by stimulus-evoked neural activity and thereby show greater synchrony than when measured in a resting state, even if their magnitudes do not change substantially. This approach is implemented in two technical stages. First, for each voxel a fiber-architecture-informed spatial window is created with orientation distribution functions constructed from diffusion imaging data. This provides the basis for defining neighborhoods in WM that share similar local fiber architectures. Second, a modified principal component analysis (PCA) is used to estimate the synchrony of BOLD signals in each spatial window. The proposed approach is validated using a 3T fMRI dataset from the Human Connectome Project (HCP) at a group level. The results demonstrate that neural activity can be reliably detected as increases in fMRI signal synchrony within WM fibers that are engaged in a task with high sensitivities and reproducibility.

Cerebellum anatomy predicts individual risk-taking behavior and risk tolerance.

Human risk tolerance is highly idiosyncratic and individuals often show distinctive preferences when faced with similar risky situations. However, the neural underpinnings of individual differences in risk-taking remain unclear. Here we combined structural and perfusion MRI and examined the associations between brain anatomy and individual risk-taking behavior/risk tolerance in a sample of 115 healthy participants during the Balloon Analogue Risk Task, a well-established sequential risky decision paradigm. Both whole brain and region-of-interest analyses showed that the left cerebellum gray matter volume (GMV) has a strong association with individual risk-taking behavior and risk tolerance, outperforming the previously reported associations with the amygdala and right posterior parietal cortex (PPC) GMV. Left cerebellum GMV also accounted for risk tolerance and risk-taking behavior changes with aging. However, regional cerebral blood flow (CBF) provided no additional predictive power. These findings suggest a novel cerebellar anatomical contribution to individual differences in risk tolerance. Further studies are necessary to elucidate the underestimated important role of cerebellum in risk-taking.

The temporal dedifferentiation of global brain signal fluctuations during human brain ageing.

The variation of brain functions as healthy ageing has been discussed widely using resting-state brain imaging. Previous conclusions may be misinterpreted without considering the effects of global signal (GS) on local brain activities. Up to now, the variation of GS with ageing has not been estimated. To fill this gap, we defined the GS as the mean signal of all voxels in the gray matter and systematically investigated correlations between age and indices of GS fluctuations. What's more, these tests were replicated with data after hemodynamic response function (HRF) de-convolution and data without noise regression as well as head motion data to verify effects of non-neural information on age. The results indicated that GS fluctuations varied as ageing in three ways. First, GS fluctuations were reduced with age. Second, the GS power transferred from lower frequencies to higher frequencies with age. Third, the GS power was more evenly distributed across frequencies in ageing brain. These trends were partly influenced by HRF and physiological noise, indicating that the age effects of GS fluctuations are associated with a variety of physiological activities. These results may indicate the temporal dedifferentiation hypothesis of brain ageing from the global perspective.

Estimated gray matter volume rapidly changes after a short motor task.

Skill learning induces changes in estimates of gray matter volume (GMV) in the human brain, commonly detectable with magnetic resonance imaging (MRI). Rapid changes in GMV estimates while executing tasks may however confound between- and within-subject differences. Fluctuations in arterial blood flow are proposed to underlie this apparent task-related tissue plasticity. To test this hypothesis, we acquired multiple repetitions of structural T1-weighted and functional blood-oxygen level-dependent (BOLD) MRI measurements from 51 subjects performing a finger-tapping task (FTT; á 2 min) repeatedly for 30-60 min. Estimated GMV was decreased in motor regions during FTT compared with rest. Motor-related BOLD signal changes did not overlap nor correlate with GMV changes. Nearly simultaneous BOLD signals cannot fully explain task-induced changes in T1-weighted images. These sensitive and behavior-related GMV changes pose serious questions to reproducibility across studies, and morphological investigations during skill learning can also open new avenues on how to study rapid brain plasticity.

Cortical signature related to psychometric properties of pain vigilance in healthy individuals: A voxel-based morphometric study.

The Pain Vigilance and Awareness Questionnaire (PVAQ) is a questionnaire for non-clinical and clinical cases of patients, such as those suffering from chronic pain. Moreover, it is used for evaluation of two aspects of habitual attention to pain: attention to pain and attention to changes in pain. As the PVAQ assesses two different aspects of attention function, different neural basis may present. However, it remains unclear which brain regions are involved. Here, we performed voxel-based morphometry (VBM) in 30 healthy participants to determine the regional morphology associated with the two attention states. Multiple regression analysis was conducted between each score and the regional grey matter (GM) volume, which revealed that a decreased GM volume in the left anterior insular cortex (AIC) was associated with a higher attention to pain score. In contrast, no brain region was correlated with the attention to changes in pain score. Our VBM results demonstrate that attention to pain scores assessed by PVAQ are associated with morphological features of the left AIC. Moreover, they may contribute to the elucidation of the complex psychological and neurophysiological characteristics of patients with chronic pain.

Differences in regional gray matter volume predict the extent to which openness influences judgments of beauty and pleasantness of interior architectural spaces.

Hedonic evaluation of sensory objects varies from person to person. While this variability has been linked to differences in experience, little is known about why stimuli lead to different evaluations in different people. We used linear mixed-effects models to determine the extent to which the openness, contour, and ceiling height of interior spaces influenced the beauty and pleasantness ratings of 18 participants. Then, by analyzing structural brain images acquired for the same group of participants, we asked if any regional gray matter volume (rGMV) covaried with these differences in the extent to which the three features influence beauty and pleasantness ratings. Voxel-based morphometry analysis revealed that the influence of openness on pleasantness ratings correlated with rGMV in the anterior prefrontal cortex (Brodmann area (BA)-10), and the influence of openness on beauty ratings correlated with rGMV in the temporal pole (BA38) and cluster, including the posterior cingulate cortex (BA31) and paracentral lobule (BA5/6). There were no significant correlations involving contour or ceiling height. Our results suggest that regional variance in gray matter volume may play a role in the computation of hedonic valuation and account for differences in the way people weigh certain attributes of interior architectural spaces.

Myelin: A gatekeeper of activity-dependent circuit plasticity?

The brain is responsive to an ever-changing environment, enabling the organism to learn and change behavior accordingly. Efforts to understand the underpinnings of this plasticity have almost exclusively focused on the functional and underlying structural changes that neurons undergo at neurochemical synapses. What has received comparatively little attention is the involvement of activity-dependent myelination in such plasticity and the functional output of circuits controlling behavior. The traditionally held view of myelin as a passive insulator of axons is changing to one of lifelong changes in myelin, modulated by neuronal activity and experience. We review the nascent evidence of the functional role of myelin plasticity in strengthening circuit functions that underlie learning and behavior.

Estimating the effect of a scanner upgrade on measures of grey matter structure for longitudinal designs.

Longitudinal imaging studies are crucial for advancing the understanding of brain development over the lifespan. Thus, more and more studies acquire imaging data at multiple time points or with long follow-up intervals. In these studies changes to magnetic resonance imaging (MRI) scanners often become inevitable which may decrease the reliability of the MRI assessments and introduce biases. We therefore investigated the difference between MRI scanners with subsequent versions (3 Tesla Siemens Verio vs. Skyra) on the cortical and subcortical measures of grey matter in 116 healthy, young adults using the well-established longitudinal FreeSurfer stream for T1-weighted brain images. We found excellent between-scanner reliability for cortical and subcortical measures of grey matter structure (intra-class correlation coefficient > 0.8). Yet, paired t-tests revealed statistically significant differences in at least 67% of the regions, with percent differences around 2 to 4%, depending on the outcome measure. Offline correction for gradient distortions only slightly reduced these biases. Further, T1-imaging based quality measures reflecting gray-white matter contrast systematically differed between scanners. We conclude that scanner upgrades during a longitudinal study introduce bias in measures of cortical and subcortical grey matter structure. Therefore, before upgrading a MRI scanner during an ongoing study, researchers should prepare to implement an appropriate correction method for these effects.

Investigation of the Compressive Viscoelastic Properties of Brain Tissue Under Time and Frequency Dependent Loading Conditions.

The mechanical characterization of brain tissue has been generally analyzed in the frequency and time domain. It is crucial to understand the mechanics of the brain under realistic, dynamic conditions and convert it to enable mathematical modelling in a time domain. In this study, the compressive viscoelastic properties of brain tissue were investigated under time and frequency domains with the same physical conditions and the theory of viscoelasticity was applied to estimate the prediction of viscoelastic response in the time domain based on frequency-dependent mechanical moduli through Finite Element models. Storage and loss modulus were obtained from white and grey matter, of bovine brains, using dynamic mechanical analysis and time domain material functions were derived based on a Prony series representation. The material models were evaluated using brain testing data from stress relaxation and hysteresis in the time dependent analysis. The Finite Element models were able to represent the trend of viscoelastic characterization of brain tissue under both testing domains. The outcomes of this study contribute to a better understanding of brain tissue mechanical behaviour and demonstrate the feasibility of deriving time-domain viscoelastic parameters from frequency-dependent compressive data for biological tissue, as validated by comparing experimental tests with computational simulations.

Differences in the gray-to-white matter ratio according to different computed tomography scanners for outcome prediction in post-cardiac arrest patients receiving target temperature management.

The gray-to-white matter ratio (GWR) has been used to identify brain damage in comatose patients after cardiac arrest. However, Hounsfield units (HUs), the measurement of brain density on computed tomography (CT) images, may vary depending on the machine type or parameter. Therefore, differences in CT scanners may affect the GWR in post-cardiac arrest patients. We performed a retrospective study on comatose post-cardiac arrest patients who visited the hospital from 2007 to 2017. Two CT, Lightspeed and SOMATOM, scanners were used. Two observers independently measured the HUs of the caudate nucleus, putamen, posterior internal capsule, and corpus callosum using regions of interest. We compared the GWR calculated from the HUs measured at different CT scanners. The analysis of different scanners showed statistically significant differences in the measured HUs and GWR. The HUs and GWR of Lightspeed were measured lower than SOMATOM. The difference between the two CT scanners was also evident in groups divided by neurological prognosis. The area under the curve of the receiver operating characteristic curve to predict poor outcomes of Lightspeed was 0.798, and the cut-off value for 100% specificity was 1.172. The SOMATOM was 0.855, and the cut-off value was 1.269. The difference in scanners affects measurements and performance characteristics of the GWR in post-cardiac arrest patients. Therefore, when applying the results of the GWR study to clinical practice, reference values for each device should be presented, and an integrated plan should be prepared.

Speeding-up while growing-up: Synchronous functional development of motor and non-motor processes across childhood and adolescence.

Describing the maturation of information processing in children is fundamental for developmental science. Although non-linear changes in reaction times have been well-documented, direct measurement of the development of the different processing components is lacking. In this study, electromyography was used to quantify the maturation of premotor and motor processes on a sample of 114 children (6-14 years-old) and 15 adults. Using a model-based approach, we show that the development of these two components is well-described by an exponential decrease in duration, with the decay rate being equal for the two components. These findings provide the first unbiased evidence in favour of the common developmental rate of nonmotor and motor processes by directly confronting rates of development of different processing components within the same task. This common developmental rate contrasts with the differential physical maturation of region-specific cerebral gray and white matter. Tentative paths of interpretation are proposed in the discussion.

Gray areas: Neuropeptide circuits linking the Edinger-Westphal and Dorsal Raphe nuclei in addiction.

The circuitry of addiction comprises several neural networks including the midbrain - an expansive region critically involved in the control of motivated behaviors. Midbrain nuclei like the Edinger-Westphal (EW) and dorsal raphe (DR) contain unique populations of neurons that synthesize many understudied neuroactive molecules and are encircled by the periaqueductal gray (PAG). Despite the proximity of these special neuron classes to the ventral midbrain complex and surrounding PAG, functions of the EW and DR remain substantially underinvestigated by comparison. Spanning approximately -3.0 to -5.2 mm posterior from bregma in the mouse, these various cell groups form a continuum of neurons that we refer to collectively as the subaqueductal paramedian zone. Defining how these pathways modulate affective behavioral states presents a difficult, yet conquerable challenge for today's technological advances in neuroscience. In this review, we cover the known contributions of different neuronal subtypes of the subaqueductal paramedian zone. We catalogue these cell types based on their spatial, molecular, connectivity, and functional properties and integrate this information with the existing data on the EW and DR in addiction. We next discuss evidence that links the EW and DR anatomically and functionally, highlighting the potential contributions of an EW-DR circuit to addiction-related behaviors. Overall, we aim to derive an integrated framework that emphasizes the contributions of EW and DR nuclei to addictive states and describes how these cell groups function in individuals suffering from substance use disorders. This article is part of the special Issue on 'Neurocircuitry Modulating Drug and Alcohol Abuse'.

Gray matter correlates of reading fluency deficits: SES matters, IQ does not.

Brain correlates of reading ability have been intensely investigated. Most studies have focused on single-word reading and phonological processing, but the brain basis of reading fluency remains poorly explored to date. Here, in a voxel-based morphometry study with 8-year-old children, we compared fluent readers (n = 18; seven boys) with dysfluent readers with normal IQ (n = 18; six boys) and with low IQ (n = 18; ten boys). Relative to dysfluent readers, fluent readers had larger gray matter volume in the right superior temporal gyrus and the two subgroups of dysfluent readers did not differ from each other, as shown in frequentist and Bayesian analyses. Pairwise comparisons showed that dysfluent readers of normal and low IQ did not differ in core reading regions and that both subgroups had less gray matter volume than fluent readers in occipito-temporal, parieto-temporal and fusiform areas. We also examined gray matter volume in matched subgroups of dysfluent readers differing only in socioeconomic status (SES): lower-SES (n = 14; seven boys) vs. higher-SES (n = 14; seven boys). Higher-SES dysfluent readers had larger gray matter volume in the right angular gyrus than their lower-SES peers, and the volume of this cluster correlated positively with lexico-semantic fluency. Age, sex, IQ, and gray matter volume of the right angular cluster explained 68% of the variance in the reading fluency of higher-SES dysfluent readers. In sum, this study shows that gray matter correlates of dysfluent reading are independent of IQ, and suggests that SES modulates areas sub-serving lexico-semantic processes in dysfluent readers-two findings that may be useful to inform language/reading remediation programs.

Can 7T MPRAGE match MP2RAGE for gray-white matter contrast?

Ultra-High Field (UHF) MRI provides a significant increase in Signal-to-Noise Ratio (SNR) and gains in contrast weighting in several functional and structural acquisitions. Unfortunately, an increase in field strength also induces non-uniformities in the transmit field (B1+) that can compromise image contrast non-uniformly. The MPRAGE is one of the most common T1 weighted (T1w) image acquisitions for structural imaging. It provides excellent contrast between gray and white matter and is widely used for brain segmentation. At 7T, the signal non-uniformities tend to complicate this and therefore, the self-bias-field corrected MP2RAGE is often used there. In both MPRAGE and MP2RAGE, more homogeneous image contrast can be achieved with adiabatic pulses, like the TR-FOCI inversion pulse, or special pulse design on parallel transmission systems, like Universal Pulses (UP). In the present study, we investigate different strategies to improve the bias-field for MPRAGE at 7T, comparing the contrast and GM/WM segmentability against MP2RAGE. The higher temporal efficiency of MPRAGE combined with the potential of the user-friendly UPs was the primary motivation for this MPRAGE-MP2RAGE comparison. We acquired MPRAGE data in six volunteers, adding a k-space shutter to reduce scan time, a kt-point UP approach for homogeneous signal excitation, and a TR-FOCI pulse for homogeneous inversion. Our results show remarkable signal contrast improvement throughout the brain, including regions of low B1+ such as the cerebellum. The improvements in the MPRAGE were largest following the introduction of the UPs. In addition to the CNR, both SNR and GM/WM segmentability were also assessed. Among the MPRAGEs, the combined strategy (UP + TR-FOCI) yielded highest SNR and showed highest spatial similarity between GM segments to the MP2RAGE. Interestingly, the distance between gray and white matter peaks in the intensity histograms did not increase, as better pulses and higher SNR especially benefitted the (cerebellar) gray matter. Overall, the gray-white matter contrast from MP2RAGE is higher, with higher CNR and higher intensity peak distances, even when scaled to scan time. Hence, the extra acquisition time for MP2RAGE is justified by the improved segmentability.

Structural correlates of trauma-induced hyperarousal in mice.

Post-traumatic stress disorder (PTSD) is a chronic disease caused by traumatic incidents. Numerous studies have revealed grey matter volume differences in affected individuals. The nature of the disease renders it difficult to distinguish between a priori versus a posteriori changes. To overcome this difficulty, we studied the consequences of a traumatic event on brain morphology in mice before and 4 weeks after exposure to brief foot shocks (or sham treatment), and correlated morphology with symptoms of hyperarousal. In the latter context, we assessed hyperarousal upon confrontation with acoustic, visual, or composite (acoustic/visual/tactile) threats and integrated the individual readouts into a single Hyperarousal Score using logistic regression analysis. MRI scans with subsequent whole-brain deformation-based morphometry (DBM) analysis revealed a volume decrease of the dorsal hippocampus and an increase of the reticular nucleus in shocked mice when compared to non-shocked controls. Using the Hyperarousal Score as regressor for the post-exposure MRI measurement, we observed negative correlations with several brain structures including the dorsal hippocampus. If the development of changes with respect to the basal MRI was considered, reduction in globus pallidus volume reflected hyperarousal severity. Our findings demonstrate that a brief traumatic incident can cause volume changes in defined brain structures and suggest the globus pallidus as an important hub for the control of fear responses to threatening stimuli of different sensory modalities.