Quantification of cerebral blood volume changes caused by visual stimulation at 3 T using DANTE-prepared dual-echo EPI.

PURPOSE: We investigate the influence of moving blood-attenuation effects when using "delay alternating with nutation for tailored excitation" (DANTE) pulses in conjunction with blood oxygen level dependent (BOLD) of functional MRI (fMRI) at 3 T. Based on the effects of including DANTE pulses, we propose quantification of cerebral blood volume (CBV) changes following functional stimulation. METHODS: Eighteen volunteers in total underwent fMRI scans at 3 T. Seven volunteers were scanned to investigate the effects of DANTE pulses on the fMRI signal. CBV changes in response to visual stimulation were quantified in 11 volunteers using a DANTE-prepared dual-echo EPI sequence. RESULTS: The inflow effects from flowing blood in arteries and draining vein effects from flowing blood in large veins can be suppressed by use of a DANTE preparation module. Using DANTE-prepared dual-echo EPI, we quantitatively measured intravascular-weighted microvascular CBV changes of 25.4%, 29.8%, and 32.6% evoked by 1, 5, and 10 Hz visual stimulation, respectively. The extravascular fraction (∆S/S)extra at TE = 30 ms in total BOLD signal was determined to be 64.8 ± 3.4%, which is in line with previous extravascular component estimation at 3 T. Results show that the microvascular CBV changes are linearly dependent on total BOLD changes at TE = 30 ms with a slope of 0.113, and this relation is independent of stimulation frequency and subject. CONCLUSION: The DANTE preparation pulses can be incorporated into a standard EPI fMRI sequence for the purpose of minimizing inflow effects and reducing draining veins effects in large vessels. Additionally, the DANTE-prepared dual-echo EPI sequence is a promising fast imaging tool for quantification of intravascular-weighted CBV change in the microvascular space at 3 T.

Sub-millimeter fMRI reveals multiple topographical digit representations that form action maps in human motor cortex.

The human brain coordinates a wide variety of motor activities. On a large scale, the cortical motor system is topographically organized such that neighboring body parts are represented by neighboring brain areas. This homunculus-like somatotopic organization along the central sulcus has been observed using neuroimaging for large body parts such as the face, hands and feet. However, on a finer scale, invasive electrical stimulation studies show deviations from this somatotopic organization that suggest an organizing principle based on motor actions rather than body part moved. It has not been clear how the action-map organization principle of the motor cortex in the mesoscopic (sub-millimeter) regime integrates into a body map organization principle on a macroscopic scale (cm). Here we developed and applied advanced mesoscopic (sub-millimeter) fMRI and analysis methodology to non-invasively investigate the functional organization topography across columnar and laminar structures in humans. Compared to previous methods, in this study, we could capture locally specific blood volume changes across entire brain regions along the cortical curvature. We find that individual fingers have multiple mirrored representations in the primary motor cortex depending on the movements they are involved in. We find that individual digits have cortical representations up to 3 â€‹mm apart from each other arranged in a column-like fashion. These representations are differentially engaged depending on whether the digits' muscles are used for different motor actions such as flexion movements, like grasping a ball or retraction movements like releasing a ball. This research provides a starting point for non-invasive investigation of mesoscale topography across layers and columns of the human cortex and bridges the gap between invasive electrophysiological investigations and large coverage non-invasive neuroimaging.

Visual temporal frequency preference shows a distinct cortical architecture using fMRI.

Studies of visual temporal frequency preference typically examine frequencies under 20 Hz and measure local activity to evaluate the sensitivity of different cortical areas to variations in temporal frequencies. Most of these studies have not attempted to map preferred temporal frequency within and across visual areas, nor have they explored in detail, stimuli at gamma frequency, which recent research suggests may have potential clinical utility. In this study, we address this gap by using functional magnetic resonance imaging (fMRI) to measure response to flickering visual stimuli varying in frequency from 1 to 40 Hz. We apply stimulation in both a block design to examine task response and a steady-state design to examine functional connectivity. We observed distinct activation patterns between 1 Hz and 40 Hz stimuli. We also found that the correlation between medial thalamus and visual cortex was modulated by the temporal frequency. The modulation functions and tuned frequencies are different for the visual activity and thalamo-visual correlations. Using both fMRI activity and connectivity measurements, we show evidence for a temporal frequency specific organization across the human visual system.

Techniques for blood volume fMRI with VASO: From low-resolution mapping towards sub-millimeter layer-dependent applications.

Quantitative cerebral blood volume (CBV) fMRI has the potential to overcome several specific limitations of BOLD fMRI. It provides direct physiological interpretability and promises superior localization specificity in applications of sub-millimeter resolution fMRI applications at ultra-high magnetic fields (7T and higher). Non-invasive CBV fMRI using VASO (vascular space occupancy), however, is inherently limited with respect to its data acquisition efficiency, restricting its imaging coverage and achievable spatial and temporal resolution. This limitation may be reduced with recent advanced acceleration and reconstruction strategies that allow two-dimensional acceleration, such as in simultaneous multi-slice (SMS) 2D-EPI or 3D-EPI in combination with CAIPIRINHA field-of-view shifting. In this study, we sought to determine the functional sensitivity and specificity of these readout strategies with VASO over a broad range of spatial resolutions; spanning from low spatial resolution (3mm) whole-cortex to sub-millimeter (0.75mm) slab-of-cortex (for cortical layer-dependent applications). In the thermal-noise-dominated regime of sub-millimeter resolutions, 3D-EPI-VASO provides higher temporal stability and sensitivity to detect changes in CBV compared to 2D-EPI-VASO. In this regime, 3D-EPI-VASO unveils task activation located in the cortical laminae with little contamination from surface veins, in contrast to the cortical surface weighting of GE-BOLD fMRI. In the physiological-noise-dominated regime of lower resolutions, however, 2D-SMS-VASO shows superior performance compared to 3D-EPI-VASO. Due to its superior sensitivity at a layer-dependent level, 3D-EPI VASO promises to play an important role in future neuroscientific applications of layer-dependent fMRI.

The neural systems that mediate human perceptual decision making.

Perceptual decision making is the act of choosing one option or course of action from a set of alternatives on the basis of available sensory evidence. Thus, when we make such decisions, sensory information must be interpreted and translated into behaviour. Neurophysiological work in monkeys performing sensory discriminations, combined with computational modelling, has paved the way for neuroimaging studies that are aimed at understanding decision-related processes in the human brain. Here we review findings from human neuroimaging studies in conjunction with data analysis methods that can directly link decisions and signals in the human brain on a trial-by-trial basis. This leads to a new view about the neural basis of human perceptual decision-making processes.

Topographical and laminar distribution of audiovisual processing within human planum temporale.

The brain is capable of integrating signals from multiple sensory modalities. Such multisensory integration can occur in areas that are commonly considered unisensory, such as planum temporale (PT) representing the auditory association cortex. However, the roles of different afferents (feedforward vs. feedback) to PT in multisensory processing are not well understood. Our study aims to understand that by examining laminar activity patterns in different topographical subfields of human PT under unimodal and multisensory stimuli. To this end, we adopted an advanced mesoscopic (sub-millimeter) fMRI methodology at 7 T by acquiring BOLD (blood-oxygen-level-dependent contrast, which has higher sensitivity) and VAPER (integrated blood volume and perfusion contrast, which has superior laminar specificity) signal concurrently, and performed all analyses in native fMRI space benefiting from an identical acquisition between functional and anatomical images. We found a division of function between visual and auditory processing in PT and distinct feedback mechanisms in different subareas. Specifically, anterior PT was activated more by auditory inputs and received feedback modulation in superficial layers. This feedback depended on task performance and likely arose from top-down influences from higher-order multimodal areas. In contrast, posterior PT was preferentially activated by visual inputs and received visual feedback in both superficial and deep layers, which is likely projected directly from the early visual cortex. Together, these findings provide novel insights into the mechanism of multisensory interaction in human PT at the mesoscopic spatial scale.

Layer-dependent functional connectivity methods.

Recent methodological advances in fMRI contrast and readout strategies have allowed researchers to approach the mesoscopic spatial regime of cortical layers. This has revolutionized the ability to map cortical information processing within and across brain systems. However, until recently, most layer-fMRI studies have been confined to primary cortices using basic block-design tasks and macro-vascular-contaminated sequence contrasts. To become an established method for user-friendly applicability in neuroscience practice, layer-fMRI acquisition and analysis methods need to be extended to more flexible connectivity-based experiment designs; they must be able to capture subtle changes in brain networks of higher-order cognitive areas, and they should not be spatially biased with unwanted vein signals. In this article, we review the most pressing challenges of layer-dependent fMRI for large-scale neuroscientific applicability and describe recently developed acquisition methodologies that can resolve them. In doing so, we review technical tradeoffs and capabilities of modern MR-sequence approaches to achieve measurements that are free of locally unspecific vein signal, with whole-brain coverage, sub-second sampling, high resolutions, and with a combination of those capabilities. The presented approaches provide whole-brain layer-dependent connectivity data that open a new window to investigate brain network connections. We exemplify this by reviewing a number of candidate tools for connectivity analyses that will allow future studies to address new questions in network neuroscience. The considered network analysis tools include: hierarchy mapping, directional connectomics, source-specific connectivity mapping, and network sub-compartmentalization. We conclude: Whole-brain layer-fMRI without large-vessel contamination is applicable for human neuroscience and opens the door to investigate biological mechanisms behind any number of psychological and psychiatric phenomena, such as selective attention, hallucinations and delusions, and even conscious perception.

Amygdala volume in depressed patients with bipolar disorder assessed using high resolution 3T MRI: the impact of medication.

MRI-based reports of both abnormally increased and decreased amygdala volume in bipolar disorder (BD) have surfaced in the literature. Two major methodological weaknesses characterizing extant studies are treatment with medication and inaccurate segmentation of the amygdala due to limitations in spatial and tissue contrast resolution. Here, we acquired high-resolution images (voxel size=0.55 x 0.55 x 0.60 mm) using a GE 3T MRI scanner, and a pulse sequence optimized for tissue contrast resolution. The amygdala was manually segmented by one rater blind to diagnosis, using coronal images. Eighteen unmedicated (mean medication-free period 11+/-10 months) BD subjects were age and gender matched with 18 healthy controls, and 17 medicated (lithium or divalproex) subjects were matched to 17 different controls. The unmedicated BD patients displayed smaller left and right amygdala volumes than their matched control group (p<0.01). Conversely, the BD subjects undergoing medication treatment showed a trend towards greater amygdala volumes than their matched HC sample (p=0.051). Right and left amygdala volumes were larger (p<0.05) or trended larger, respectively, in the medicated BD sample compared with the unmedicated BD sample. The two control groups did not differ from each other in either left or right amygdala volume. BD patients treated with lithium have displayed increased gray matter volume of the cortex and hippocampus relative to untreated BD subjects in previous studies. Here we extend these results to the amygdala. We raise the possibility that neuroplastic changes in the amygdala associated with BD are moderated by some mood stabilizing medications.

Functional but not structural changes associated with learning: an exploration of longitudinal voxel-based morphometry (VBM).

Voxel-Based Morphometry (VBM) has been used for several years to study differences in brain structure between populations. Recently, a longitudinal version of VBM has been used to show changes in gray matter associated with relatively short periods of training. In the present study we use fMRI and three different standard implementations of longitudinal VBM: SPM2, FSL, and SPM5 to assess functional and structural changes associated with a simple learning task. Behavioral and fMRI data clearly showed a significant learning effect. However, initially positive VBM results were found to be inconsistent across minor perturbations of the analysis technique and ultimately proved to be artifactual. When alignment biases were controlled for and recommended statistical procedures were used, no significant changes in grey matter density were found. This work, initially intended to show structural and functional changes with learning, rather demonstrates some of the potential pitfalls of existing longitudinal VBM methods and prescribes that these tools be applied and interpreted with extreme caution.

Crowdsourced MRI quality metrics and expert quality annotations for training of humans and machines.

The neuroimaging community is steering towards increasingly large sample sizes, which are highly heterogeneous because they can only be acquired by multi-site consortia. The visual assessment of every imaging scan is a necessary quality control step, yet arduous and time-consuming. A sizeable body of evidence shows that images of low quality are a source of variability that may be comparable to the effect size under study. We present the MRIQC Web-API, an open crowdsourced database that collects image quality metrics extracted from MR images and corresponding manual assessments by experts. The database is rapidly growing, and currently contains over 100,000 records of image quality metrics of functional and anatomical MRIs of the human brain, and over 200 expert ratings. The resource is designed for researchers to share image quality metrics and annotations that can readily be reused in training human experts and machine learning algorithms. The ultimate goal of the database is to allow the development of fully automated quality control tools that outperform expert ratings in identifying subpar images.

Activations in visual and attention-related areas predict and correlate with the degree of perceptual learning.

Repeated experience with a visual stimulus can result in improved perception of the stimulus, i.e., perceptual learning. To understand the underlying neural mechanisms of this process, we used functional magnetic resonance imaging to track brain activations during the course of training on a contrast discrimination task. Based on their ability to improve on the task within a single scan session, subjects were separated into two groups: "learners" and "nonlearners." As learning progressed, learners showed progressively reduced activation in both visual cortex, including Brodmann's areas 18 and 19 and the fusiform gyrus, and several cortical regions associated with the attentional network, namely, the intraparietal sulcus (IPS), frontal eye field (FEF), and supplementary eye field. Among learners, the decrease in brain activations in these regions was highly correlated with the magnitude of performance improvement. Unlike learners, nonlearners showed no changes in brain activations during training. Learners showed stronger activation than nonlearners during the initial period of training in all these brain regions, indicating that one could predict from the initial activation level who would learn and who would not. In addition, over the course of training, the functional connectivity between IPS and FEF in the right hemisphere with early visual areas was stronger for learners than nonlearners. We speculate that sharpened tuning of neuronal representations may cause reduced activation in visual cortex during perceptual learning and that attention may facilitate this process through an interaction of attention-related and visual cortical regions.

High-Resolution CBV-fMRI Allows Mapping of Laminar Activity and Connectivity of Cortical Input and Output in Human M1.

Layer-dependent fMRI allows measurements of information flow in cortical circuits, as afferent and efferent connections terminate in different cortical layers. However, it is unknown to what level human fMRI is specific and sensitive enough to reveal directional functional activity across layers. To answer this question, we developed acquisition and analysis methods for blood-oxygen-level-dependent (BOLD) and cerebral-blood-volume (CBV)-based laminar fMRI and used these to discriminate four different tasks in the human motor cortex (M1). In agreement with anatomical data from animal studies, we found evidence for somatosensory and premotor input in superficial layers of M1 and for cortico-spinal motor output in deep layers. Laminar resting-state fMRI showed directional functional connectivity of M1 with somatosensory and premotor areas. Our findings demonstrate that CBV-fMRI can be used to investigate cortical activity in humans with unprecedented detail, allowing investigations of information flow between brain regions and outperforming conventional BOLD results that are often buried under vascular biases.

Oxidative and nonoxidative metabolism of excited neurons and astrocytes.

There is evidence that the metabolic responses to afferent and efferent nervous activity are dissociated at sites of neuronal excitation in brain. Whether efferent activity follows afferent activity depends on the responsiveness of postsynaptic neurons, which in turn depends on the summation of excitatory and inhibitory postsynaptic potentials. The afferent activity excites the presynaptic terminals and astrocytes, whereas the efferent activity arises from excitation of the dendrites of projection neurons. Measurements in vivo indicate that primary stimulation, elicited by simple stimuli, gives rise to limited increases of energy metabolism associated with afferent activity. Reports show that a major consequence of afferent activity, in addition to the release of excitatory neurotransmitters from presynaptic terminals and the import of glutamate by astrocytes, is the establishment of rates of blood flow commensurate with increased rates of oxidative energy metabolism associated with efferent activity projecting from the site of activation. Increased flow rates overcome the inherent diffusion limitation of oxygen delivery, while increased rates of glycolysis elevate tissue pyruvate contents, to which oxygen consumption rates are matched. In vivo, neurons in the baseline condition sustain no net import of pyruvate or lactate, and the reported changes of metabolism subserving afferent and efferent activity are additive rather than linked by significant additional transfer of pyruvate or lactate from astrocytes. The dissociation of blood flow changes from efferent activity weakens the identification of functional states by changes of blood flow alone. It raises the possibility that uncoupling of flow from oxidative metabolism occurs at sites of low efferent activity, such that dissociations of flow and glycolysis from oxygen consumption signify imbalances of afferent and efferent activity.

Habenula volume in bipolar disorder and major depressive disorder: a high-resolution magnetic resonance imaging study.

BACKGROUND: Increased activity of the habenula has been implicated in the etiology of major depressive disorder (MDD), in which reductions in habenula volume are present after death. We conducted the first magnetic resonance imaging analysis of habenula volume in MDD and bipolar disorder (BD). METHODS: High-resolution images (resolution approximately .4 mm(3)) were acquired with a 3T scanner, and a pulse sequence was optimized for tissue contrast resolution. The habenula was manually segmented by one rater blind to diagnosis. Seventy-four healthy control subjects (HC) were compared with both medicated (lithium/divalproex, n = 15) and unmedicated, depressed BD (n = 22) patients; unmedicated, depressed MDD patients (n = 28); and unmedicated MDD patients in remission (n = 32). RESULTS: The unmedicated BD patients displayed significantly smaller absolute (p < .01) and normalized (p < .05) habenula volumes than the HC subjects. In post hoc assessments analyzing men and women separately, the currently-depressed women with MDD had smaller absolute (p < .05) habenula volumes than the HC women. None of the other psychiatric groups differed significantly from the HC group. CONCLUSIONS: We provide further evidence for the involvement of the habenula in affective illness but suggest that a reduction in volume might be more pronounced in unmedicated, depressed BD subjects and female currently depressed MDD subjects. The habenula plays major roles in the long-term modification of monoamine transmission and behavioral responses to stress and in the suppression of dopamine cell activity after the absence of an expected reward. A reduction in habenula volume might thus have functional consequences that contribute to the risk for developing affective disease.

Complementary roles of systems representing sensory evidence and systems detecting task difficulty during perceptual decision making.

Perceptual decision making is a multi-stage process where incoming sensory information is used to select one option from several alternatives. Researchers typically have adopted one of two conceptual frameworks to define the criteria for determining whether a brain region is involved in decision computations. One framework, building on single-unit recordings in monkeys, posits that activity in a region involved in decision making reflects the accumulation of evidence toward a decision threshold, thus showing the lowest level of BOLD signal during the hardest decisions. The other framework instead posits that activity in a decision-making region reflects the difficulty of a decision, thus showing the highest level of BOLD signal during the hardest decisions. We had subjects perform a face detection task on degraded face images while we simultaneously recorded BOLD activity. We searched for brain regions where changes in BOLD activity during this task supported either of these frameworks by calculating the correlation of BOLD activity with reaction time - a measure of task difficulty. We found that the right supplementary eye field, right frontal eye field, and right inferior frontal gyrus had increased activity relative to baseline that positively correlated with reaction time, while the left superior frontal sulcus and left middle temporal gyrus had decreased activity relative to baseline that negatively correlated with reaction time. We propose that a simple mechanism that scales a region's activity based on task demands can explain our results.

Cortical abnormalities in bipolar disorder investigated with MRI and voxel-based morphometry.

Bipolar disorder (BD) has been associated with abnormalities of brain structure. Specifically, in vivo volumetric MRI and/or post mortem studies of BD have reported abnormalities of gray matter (GM) volume in the medial prefrontal cortex (PFC), amygdala, hippocampal subiculum and ventral striatum. These structures share anatomical connections with each other and form part of a "visceromotor" network modulating emotional behavior. Areas of the lateral orbital, superior temporal and posterior cingulate cortices project to this network, but morphometric abnormalities in these areas have not been established in BD. The current study assessed tissue volumes within these areas in BD using MRI and voxel-based morphometry (VBM). MRI images were obtained from 36 BD subjects and 65 healthy controls. To account for possible neurotrophic and neuroprotective effects of psychotropic medications, BD subjects were divided into medicated and unmedicated groups. Images were segmented into tissue compartments, which were examined on a voxel-wise basis to determine the location and extent of morphometric changes. The GM was reduced in the posterior cingulate/retrosplenial cortex and superior temporal gyrus of unmedicated BD subjects relative to medicated BD subjects and in the lateral orbital cortex of medicated BD subjects relative to controls. White matter (WM) was increased in the orbital and posterior cingulate cortices, which most likely reflected alterations in gyral morphology resulting from the reductions in the associated GM. The morphometric abnormalities in the posterior cingulate, superior temporal and lateral orbital cortices in BD support the hypothesis that the extended network of neuroanatomical structures subserving visceromotor regulation contains structural alterations in BD. Additionally, localization of morphometric abnormalities to areas known to exhibit increased metabolism in depression supports the hypothesis that repeated stress and elevated glucocorticoid secretion may result in neuroplastic changes in BD.

Imaging cortical anatomy by high-resolution MR at 3.0T: detection of the stripe of Gennari in visual area 17.

The brain can be parcellated into numerous anatomical and functional subunits. The classic work by Brodmann (Vergleichende Lokalisationslehre der Grosshirnrinde in ihren Prinzipien dargestellt auf Grund des Zellenbaues. Leipzig: Barth; 1909) identified areas of the cerebral cortex based on histological differences. An alternative to his cytoarchitectonic approach is the myeloarchitectonic approach. MRI has excellent white/gray matter contrast in the brain due to the presence of myelin, and thus seems uniquely suited for in vivo studies of cortical myeloarchitecture. Here it is demonstrated that the stripe or stria of Gennari can be consistently detected in human occipital cortex. T(1)-weighted images obtained at 3T from six of 10 normal volunteers, with resolutions of 350 x 350 x 600 mu clearly demonstrate this myelin-rich intracortical layer. It is concluded that the striate cortex (area 17 of Brodmann) of the human brain can be delineated in vivo on T(1)-weighted images, potentially enabling detection of specific cortical boundaries within individual brains.