Quantifying differences in fMRI preprocessing pipelines via OGRE (One-step General Registration and Extraction).

Volumetric preprocessing methods continue to enjoy great popularity in the analysis of functional MRI (fMRI) data. Among these methods, the software packages FSL (FMRIB, Oxford, UK) and FreeSurfer (LCN, Charlestown, MA) are omnipresent throughout the field. However, it remains unknown what advantages an integrated FSL+FreeSurfer preprocessing approach might provide over FSL alone. Here we developed the One-step General Registration and Extraction (OGRE) pipeline to combine FreeSurfer and FSL tools for brain extraction and registration, for FSL volumetric analysis of fMRI data. We compared preprocessing approaches in a dataset wherein adult human volunteers (N=26) performed a precision drawing task during fMRI scanning. OGRE's preprocessing, compared to traditional FSL preprocessing, led to lower inter-individual variability across the brain, more precise brain extraction, and greater detected activation in sensorimotor areas contralateral to movement. This demonstrates that the introduction of FreeSurfer tools via OGRE preprocessing can improve fMRI data analysis, in the context of FSL's volumetric analysis approach. The OGRE pipeline provides a turnkey method to integrate FreeSurfer-based brain extraction and registration with FSL analysis of task fMRI data.

Brain aerobic glycolysis and resilience in Alzheimer disease.

The distribution of brain aerobic glycolysis (AG) in normal young adults correlates spatially with amyloid-beta (Aß) deposition in individuals with symptomatic and preclinical Alzheimer disease (AD). Brain AG decreases with age, but the functional significance of this decrease with regard to the development of AD symptomatology is poorly understood. Using PET measurements of regional blood flow, oxygen consumption, and glucose utilization-from which we derive AG-we find that cognitive impairment is strongly associated with loss of the typical youthful pattern of AG. In contrast, amyloid positivity without cognitive impairment was associated with preservation of youthful brain AG, which was even higher than that seen in cognitively unimpaired, amyloid negative adults. Similar findings were not seen for blood flow nor oxygen consumption. Finally, in cognitively unimpaired adults, white matter hyperintensity burden was found to be specifically associated with decreased youthful brain AG. Our results suggest that AG may have a role in the resilience and/or response to early stages of amyloid pathology and that age-related white matter disease may impair this process.

Interhemispheric Parietal-Frontal Connectivity Predicts the Ability to Acquire a Nondominant Hand Skill.

Introduction: After chronic impairment of the right dominant hand, some individuals are able to compensate with increased performance with the intact left nondominant hand. This process may depend on the nondominant (right) hemisphere's ability to access dominant (left) hemisphere mechanisms. To predict or modulate patients' ability to compensate with the left hand, we must understand the neural mechanisms and connections that underpin this process. Methods: We studied 17 right-handed healthy adults who underwent resting-state functional connectivity (FC) magnetic resonance imaging scans before 10 days of training on a left-hand precision drawing task. We sought to identify right-hemisphere areas where FC from left-hemisphere seeds (primary motor cortex, intraparietal sulcus [IPS], inferior parietal lobule) would predict left-hand skill learning or magnitude. Results: Left-hand skill learning was predicted by convergent FC from left primary motor cortex and left IPS onto the same small region (0.31 cm3) in the right superior parietal lobule (SPL). Discussion: For patients who must compensate with the left hand, the right SPL may play a key role in integrating left-hemisphere mechanisms that typically control the right hand. Our study provides the first model of how interhemispheric functional connections in the human brain may support compensation after chronic injury to the right hand.

Human non-REM sleep and the mean global BOLD signal.

A hallmark of non-rapid eye movement (REM) sleep is the decreased brain activity as measured by global reductions in cerebral blood flow, oxygen metabolism, and glucose metabolism. It is unknown whether the blood oxygen level dependent (BOLD) signal undergoes similar changes. Here we show that, in contrast to the decreases in blood flow and metabolism, the mean global BOLD signal increases with sleep depth in a regionally non-uniform manner throughout gray matter. We relate our findings to the circulatory and metabolic processes influencing the BOLD signal and conclude that because oxygen consumption decreases proportionately more than blood flow in sleep, the resulting decrease in paramagnetic deoxyhemoglobin accounts for the increase in mean global BOLD signal.

Mapping visual dominance in human sleep.

Sleep is a universal behavior, essential for humans and animals alike to survive. Its importance to a person's physical and mental health cannot be overstated. Although lateralization of function is well established in the lesion, split-brain and task based neuroimaging literature, and more recently in functional imaging studies of spontaneous fluctuations of the fMRI BOLD signal during wakeful rest, it is unknown if these asymmetries are present during sleep. We investigated hemispheric asymmetries in the global brain signal during non-REM sleep. Here we show that increasing sleep depth is accompanied by an increasing rightward asymmetry of regions in visual cortex including primary bilaterally and in the right hemisphere along the lingual gyrus and middle temporal cortex. In addition, left hemisphere language regions largely maintained their leftward asymmetry during sleep. Right hemisphere attention related regions expressed a more complicated relation with some regions maintaining a rightward asymmetry while this was lost in others. These results suggest that asymmetries in the human brain are state dependent.

Differential white matter involvement associated with distinct visuospatial deficits after right hemisphere stroke.

Visuospatial attention depends on the integration of multiple processes, and people with right hemisphere lesions after a stroke may exhibit severe or no visuospatial deficits. The anatomy of core components of visuospatial attention is an area of intense interest. Here we examine the relationship between the disruption of core components of attention and lesion distribution in a heterogeneous group (N = 70) of patients with right hemisphere strokes regardless of the presence of clinical neglect. Deficits of lateralized spatial orienting, measured as the difference in reaction times for responding to visual targets in the contralesional or ipsilesional visual field, and deficits in re-orienting attention, as measured by the difference in reaction times for invalidly versus validly cued targets, were measured using a computerized spatial orienting task. Both measures were related through logistic regression and a novel ridge regression method to anatomical damage measured with magnetic resonance imaging. While many regions were common to both deficit maps, a deficit in lateralized spatial orienting was more associated with lesions in the white matter underlying the posterior parietal cortex, and middle and inferior frontal gyri. A deficit in re-orienting of attention toward unattended locations was associated with lesions in the white matter of the posterior parietal cortex, insular cortex and less so with white matter involvement of the anterior frontal lobe. An hodological analysis also supports this partial dissociation between the white matter tracts that are damaged in lateralized spatial biases versus impaired re-orienting. Our results underscore that the integrity of fronto-parietal white matter tracts is crucial for visuospatial attention and that different attention components are mediated by partially distinct neuronal substrates.

Adaptive smoothing based on Gaussian processes regression increases the sensitivity and specificity of fMRI data.

Temporal and spatial filtering of fMRI data is often used to improve statistical power. However, conventional methods, such as smoothing with fixed-width Gaussian filters, remove fine-scale structure in the data, necessitating a tradeoff between sensitivity and specificity. Specifically, smoothing may increase sensitivity (reduce noise and increase statistical power) but at the cost loss of specificity in that fine-scale structure in neural activity patterns is lost. Here, we propose an alternative smoothing method based on Gaussian processes (GP) regression for single subjects fMRI experiments. This method adapts the level of smoothing on a voxel by voxel basis according to the characteristics of the local neural activity patterns. GP-based fMRI analysis has been heretofore impractical owing to computational demands. Here, we demonstrate a new implementation of GP that makes it possible to handle the massive data dimensionality of the typical fMRI experiment. We demonstrate how GP can be used as a drop-in replacement to conventional preprocessing steps for temporal and spatial smoothing in a standard fMRI pipeline. We present simulated and experimental results that show the increased sensitivity and specificity compared to conventional smoothing strategies. Hum Brain Mapp 38:1438-1459, 2017. © 2016 Wiley Periodicals, Inc.

Unmasking Language Lateralization in Human Brain Intrinsic Activity.

Lateralization of function is a fundamental feature of the human brain as exemplified by the left hemisphere dominance of language. Despite the prominence of lateralization in the lesion, split-brain and task-based fMRI literature, surprisingly little asymmetry has been revealed in the increasingly popular functional imaging studies of spontaneous fluctuations in the fMRI BOLD signal (so-called resting-state fMRI). Here, we show the global signal, an often discarded component of the BOLD signal in resting-state studies, reveals a leftward asymmetry that maps onto regions preferential for semantic processing in left frontal and temporal cortex and the right cerebellum and a rightward asymmetry that maps onto putative attention-related regions in right frontal, temporoparietal, and parietal cortex. Hemispheric asymmetries in the global signal resulted from amplitude modulation of the spontaneous fluctuations. To confirm these findings obtained from normal, healthy, right-handed subjects in the resting-state, we had them perform 2 semantic processing tasks: synonym and numerical magnitude judgment and sentence comprehension. In addition to establishing a new technique for studying lateralization through functional imaging of the resting-state, our findings shed new light on the physiology of the global brain signal.

Eye position modulates retinotopic responses in early visual areas: a bias for the straight-ahead direction.

Even though the eyes constantly change position, the location of a stimulus can be accurately represented by a population of neurons with retinotopic receptive fields modulated by eye position gain fields. Recent electrophysiological studies, however, indicate that eye position gain fields may serve an additional function since they have a non-uniform spatial distribution that increases the neural response to stimuli in the straight-ahead direction. We used functional magnetic resonance imaging and a wide-field stimulus display to determine whether gaze modulations in early human visual cortex enhance the blood-oxygenation-level dependent (BOLD) response to stimuli that are straight-ahead. Subjects viewed rotating polar angle wedge stimuli centered straight-ahead or vertically displaced by ± 20° eccentricity. Gaze position did not affect the topography of polar phase-angle maps, confirming that coding was retinotopic, but did affect the amplitude of the BOLD response, consistent with a gain field. In agreement with recent electrophysiological studies, BOLD responses in V1 and V2 to a wedge stimulus at a fixed retinal locus decreased when the wedge location in head-centered coordinates was farther from the straight-ahead direction. We conclude that stimulus-evoked BOLD signals are modulated by a systematic, non-uniform distribution of eye-position gain fields.

Early life stress and trauma and enhanced limbic activation to emotionally valenced faces in depressed and healthy children.

OBJECTIVE: Previous studies have examined the relationships between structural brain characteristics and early life stress in adults. However, there is limited evidence for functional brain variation associated with early life stress in children. We hypothesized that early life stress and trauma would be associated with increased functional brain activation response to negative emotional faces in children with and without a history of depression. METHOD: Psychiatric diagnosis and life events in children (starting at age 3-5 years) were assessed in a longitudinal study. A follow-up magnetic resonance imaging (MRI) study acquired data (N = 115 at ages 7-12, 51% girls) on functional brain response to fearful, sad, and happy faces relative to neutral faces. We used a region-of-interest mask within cortico-limbic areas and conducted regression analyses and repeated-measures analysis of covariance. RESULTS: Greater activation responses to fearful, sad, and happy faces in the amygdala and its neighboring regions were found in children with greater life stress. Moreover, an association between life stress and left hippocampal and globus pallidus activity depended on children's diagnostic status. Finally, all children with greater life trauma showed greater bilateral amygdala and cingulate activity specific to sad faces but not the other emotional faces, although right amygdala activity was moderated by psychiatric status. CONCLUSIONS: These findings suggest that limbic hyperactivity may be a biomarker of early life stress and trauma in children and may have implications in the risk trajectory for depression and other stress-related disorders. However, this pattern varied based on emotion type and history of psychopathology.

Memory accumulation mechanisms in human cortex are independent of motor intentions.

Previous studies on perceptual decision-making have often emphasized a tight link between decisions and motor intentions. Human decisions, however, also depend on memories or experiences that are not closely tied to specific motor responses. Recent neuroimaging findings have suggested that, during episodic retrieval, parietal activity reflects the accumulation of evidence for memory decisions. It is currently unknown, however, whether these evidence accumulation signals are functionally linked to signals for motor intentions coded in frontoparietal regions and whether activity in the putative memory accumulator tracks the amount of evidence for only previous experience, as reflected in "old" reports, or for both old and new decisions, as reflected in the accuracy of memory judgments. Here, human participants used saccadic-eye and hand-pointing movements to report recognition judgments on pictures defined by different degrees of evidence for old or new decisions. A set of cortical regions, including the middle intraparietal sulcus, showed a monotonic variation of the fMRI BOLD signal that scaled with perceived memory strength (older > newer), compatible with an asymmetrical memory accumulator. Another set, including the hippocampus and the angular gyrus, showed a nonmonotonic response profile tracking memory accuracy (higher > lower evidence), compatible with a symmetrical accumulator. In contrast, eye and hand effector-specific regions in frontoparietal cortex tracked motor intentions but were not modulated by the amount of evidence for the effector outcome. We conclude that item recognition decisions are supported by a combination of symmetrical and asymmetrical accumulation signals largely segregated from motor intentions.

Distinct representations for shifts of spatial attention and changes of reward contingencies in the human brain.

Success in a dynamically changing world requires both rapid shifts of attention to the location of important objects and the detection of changes in motivational contingencies that may alter future behavior. Here we addressed the relationship between these two processes by measuring the blood-oxygenation-level-dependent (BOLD) signal during a visual search task in which the location and the color of a salient cue respectively indicated where a rewarded target would appear and the monetary gain (large or small) associated with its detection. While cues that either shifted or maintained attention were presented every 4 to 8 sec, the reward magnitude indicated by the cue changed roughly every 30 sec, allowing us to distinguish a change in expected reward magnitude from a maintained state of expected reward magnitude. Posterior cingulate cortex was modulated by cues signaling an increase in expected reward magnitude, but not by cues for shifting versus maintaining spatial attention. Dorsal fronto-parietal regions in precuneus and frontal eye field (FEF) also showed increased BOLD activity for changes in expected reward magnitude from low to high, but in addition showed large independent modulations for shifting versus maintaining attention. In particular, the differential activation for shifting versus maintaining attention was not affected by expected reward magnitude. These results indicate that BOLD activations for shifts of attention and increases in expected reward magnitude are largely separate. Finally, visual cortex showed sustained spatially selective signals that were significantly enhanced when greater reward magnitude was expected, but this reward-related modulation was not observed in spatially selective regions of dorsal fronto-parietal cortex.

Dissociated mean and functional connectivity BOLD signals in visual cortex during eyes closed and fixation.

We investigated the effects of resting state type on blood oxygen level-dependent (BOLD) signal and functional connectivity in two paradigms: participants either alternated between fixation and eyes closed or maintained fixation or eyes closed throughout each scan. The BOLD signal and functional connectivity of lower and higher tiers of the visual cortical hierarchy were found to be differentially modulated during eyes closed versus fixation. Fixation was associated with greater mean BOLD signals in primary visual cortex and lower mean BOLD signals in extrastriate visual areas than periods of eyes closed. In addition, analysis of thalamocortical functional connectivity during scans in which participants maintained fixation showed synchronized BOLD fluctuations between those thalamic nuclei whose mean BOLD signal was systematically modulated during alternating epochs of eyes closed and fixation, primary visual cortex and the attention network, while during eyes closed negatively correlated fluctuations were seen between the same thalamic nuclei and extrastriate visual areas. Finally, in all visual areas the amplitude of spontaneous BOLD fluctuations was greater during eyes closed than during fixation. The dissociation between early and late tiers of visual cortex, which characterizes both mean and functionally connected components of the BOLD signal, may depend on the reorganization of thalamocortical networks. Since dissociated changes in local blood flow also characterize transitions between different stages of sleep and wakefulness (Braun AR, Balkin TJ, Wesenten NJ, Gwadry F, Carson RE, Varga M, Baldwin P, Belenky G, Herscovitch P. Science 279: 91-95, 1998), our results suggest that dissociated endogenous neural activity in primary and extrastriate cortex may represent a general aspect of brain function.

Right hemisphere dominance during spatial selective attention and target detection occurs outside the dorsal frontoparietal network.

Spatial selective attention is widely considered to be right hemisphere dominant. Previous functional magnetic resonance imaging studies, however, have reported bilateral blood-oxygenation-level-dependent responses in dorsal frontoparietal regions during anticipatory shifts of attention to a location (Kastner et al., 1999; Corbetta et al., 2000; Hopfinger et al., 2000). Right-lateralized activity has mainly been reported in ventral frontoparietal regions for shifts of attention to an unattended target stimulus (Arrington et al., 2000; Corbetta et al., 2000). However, clear conclusions cannot be drawn from these studies because hemispheric asymmetries were not assessed using direct voxelwise comparisons of activity in left and right hemispheres. Here, we used this technique to measure hemispheric asymmetries during shifts of spatial attention evoked by a peripheral cue stimulus and during target detection at the cued location. Stimulus-driven shifts of spatial attention in both visual fields evoked right-hemisphere dominant activity in temporoparietal junction (TPJ). Target detection at the attended location produced a more widespread right hemisphere dominance in frontal, parietal, and temporal cortex, including the TPJ region asymmetrically activated during shifts of spatial attention. However, hemispheric asymmetries were not observed during either shifts of attention or target detection in the dorsal frontoparietal regions (anterior precuneus, medial intraparietal sulcus, frontal eye fields) that showed the most robust activations for shifts of attention. Therefore, right hemisphere dominance during stimulus-driven shifts of spatial attention and target detection reflects asymmetries in cortical regions that are largely distinct from the dorsal frontoparietal network involved in the control of selective attention.

Interaction of stimulus-driven reorienting and expectation in ventral and dorsal frontoparietal and basal ganglia-cortical networks.

Shifts of attention to unattended stimuli (stimulus-driven reorienting) are often studied by measuring responses to unexpected stimuli, confounding reorienting and expectation. We separately measured the blood-oxygenation-level-dependent signal for both factors by manipulating the probability of salient visual cues that either shifted attention away from or maintained attention on a stream of visual stimuli. The results distinguished three networks recruited by reorienting. Right temporoparietal junction (TPJ), the posterior core of a ventral frontoparietal network, was activated more by cues for shifting than maintaining attention independently of cue location and probability, acting as a switch. TPJ was separately modulated by low probability cues, which signaled a breach of spatial expectation, independently of whether they shifted attention. Under resting conditions, TPJ activity was correlated [resting-state functional connectivity magnetic resonance imaging, (rs-fcMRI)] with right inferior frontal gyrus (IFG), an anterior component of the ventral network. Nevertheless, IFG was activated only by unexpected shifts of attention, dissociating its function from TPJ. Basal ganglia and frontal/insula regions also were activated only when reorienting was unexpected but showed strong rs-fcMRI among themselves, not with TPJ/IFG, defining a distinct network that may retrieve/activate commands for shifting attention. Within dorsal frontoparietal regions, shifting attention produced sustained spatially selective modulations in intraparietal sulcus (IPS) and frontal-eye field (FEF), and transient less selective modulations in precuneus and FEF. Modulations were observed even when reorienting was likely, but increased when reorienting was unexpected. The latter result may partly reflect interactions with lateral prefrontal components of the basal-ganglia/frontal/insula network that showed significant rs-fcMRI with the dorsal network.

Pictures of a thousand words: investigating the neural mechanisms of reading with extremely rapid event-related fMRI.

Reading is one of the most important skills human beings can acquire, but has proven difficult to study naturalistically using functional magnetic resonance imaging (fMRI). We introduce a novel Event-Related Reading (ERR) fMRI approach that enables reliable estimation of the neural correlates of single-word processing during reading of rapidly presented narrative text (200-300 ms/word). Application to an fMRI experiment in which subjects read coherent narratives and made no overt responses revealed widespread effects of orthographic, phonological, contextual, and semantic variables on brain activation. Word-level variables predicted activity in classical language areas as well as the inferotemporal visual word form area, specifically supporting a role for the latter in mapping visual forms onto articulatory or acoustic representations. Additional analyses demonstrated that ERR results replicate across experiments and predict reading comprehension. The ERR approach represents a powerful and extremely flexible new approach for studying reading and language behavior with fMRI.

Resting states affect spontaneous BOLD oscillations in sensory and paralimbic cortex.

The brain exhibits spontaneous neural activity that depends on the behavioral state of the organism. We asked whether the blood oxygenation level-dependent (BOLD) signal reflects these modulations. BOLD was measured under three steady-state conditions: while subjects kept their eyes closed, kept their eyes open, or while fixating. The BOLD spectral density was calculated across brain voxels and subjects. Visual, sensory-motor, auditory, and retrosplenial cortex showed modulations of the BOLD spectral density by resting state type. All modulated regions showed greater spontaneous BOLD oscillations in the eyes closed than the eyes open or fixation conditions, suggesting that the differences were endogenously driven. Next, we examined the pattern of correlations between regions whose ongoing BOLD signal was modulated by resting state type. Regional neuronal correlations were estimated using an analytic procedure from the comparison of BOLD-BOLD covariances in the fixation and eyes closed conditions. Most regions were highly correlated with one another, with the exception of the primary visual cortices, which showed low correlations with the other regions. In conclusion, changes in resting state were associated with synchronous modulations of spontaneous BOLD oscillations in cortical sensory areas driven by two spatially overlapping, but temporally uncorrelated signals.

Right TPJ deactivation during visual search: functional significance and support for a filter hypothesis.

Behavioral performance depends on attending to important objects in the environment rather than irrelevant objects. Regions in the right temporal-parietal junction (TPJ) are thought to be involved in redirecting attention to new objects that are behaviorally relevant. When subjects monitor a stream of distracter objects for a target, TPJ deactivates until the target is detected. We have proposed that the deactivation reflects the filtering of irrelevant inputs from TPJ, preventing unimportant objects from being attended. This hypothesis predicts that the mean deactivation to distracters should be larger when the subsequent target is detected than missed, reflecting more efficient filtering. An analysis of the blood oxygenation level-dependent (BOLD) task-evoked signals from 20 subjects during 2 monitoring tasks confirmed this prediction for regions in right supramarginal gyrus (SMG). Because the deactivation preceded the target, this mean BOLD-detection relationship did not reflect feedback from target detection or postdetection processes. The SMG regions showing this relationship overlapped or neighbored some regions associated with a "default" mode of brain function, suggesting the functional significance of deactivations in some default regions during task performance.

Separate modulations of human V1 associated with spatial attention and task structure.

Functional magnetic resonance imaging (fMRI) was used while normal human volunteers engaged in simple detection and discrimination tasks, revealing separable modulations of early visual cortex associated with spatial attention and task structure. Both modulations occur even when there is no change in sensory stimulation. The modulation due to spatial attention is present throughout the early visual areas V1, V2, V3, and VP, and varies with the attended location. The task structure activations are strongest in V1 and are greater in regions that represent more peripheral parts of the visual field. Control experiments demonstrate that the task structure activations cannot be attributed to visual, auditory, or somatosensory processing, the motor response for the detection/discrimination judgment, or oculomotor responses such as blinks or saccades. These findings demonstrate that early visual areas are modulated by at least two types of endogenous signals, each with distinct cortical distributions.

Visual motion and the neural correlates of event perception.

People perceive ongoing activity in terms of discrete temporal events. Distinctive changes in the movement of objects or actors may contribute to the perception that one event has ended and another has begun. However, little is known about the quantitative contribution of movement information to the processing of events. This study investigated how movement features are related to the neural processing of events by performing functional magnetic resonance imaging while participants viewed simple animations of moving objects. After the imaging session, participants watched the animations again and segmented them into meaningful events. Movement features were systematically related to viewers' perceptual segmentation and to cortical activity throughout visual processing areas. Activity in the MT complex, which is known to be specialized for processing motion, increased with increases in the objects' speed. The perception of an event boundary was associated with transient changes in the MT complex and in a nearby region in the superior temporal sulcus associated with processing biological motion. Other movement features were associated with changes in activity in occipital, parietal, and frontal cortex. These results indicate a role for movement features in the perceptual processing of meaningful events, and in the neural basis of that processing.