Quantitative MRI at 7-Tesla reveals novel frontocortical myeloarchitecture anomalies in major depressive disorder.

Whereas meta-analytical data highlight abnormal frontocortical macrostructure (thickness/surface area/volume) in Major Depressive Disorder (MDD), the underlying microstructural processes remain uncharted, due to the use of conventional MRI scanners and acquisition techniques. We uniquely combined Ultra-High Field MRI at 7.0 Tesla with Quantitative Imaging to map intracortical myelin (proxied by longitudinal relaxation time T1) and iron concentration (proxied by transverse relaxation time T2*), microstructural processes deemed particularly germane to cortical macrostructure. Informed by meta-analytical evidence, we focused specifically on orbitofrontal and rostral anterior cingulate cortices among adult MDD patients (N = 48) and matched healthy controls (HC; N = 10). Analyses probed the association of MDD diagnosis and clinical profile (severity, medication use, comorbid anxiety disorders, childhood trauma) with aforementioned microstructural properties. MDD diagnosis (p's < 0.05, Cohen's D = 0.55-0.66) and symptom severity (p's < 0.01, r = 0.271-0.267) both related to decreased intracortical myelination (higher T1 values) within the lateral orbitofrontal cortex, a region tightly coupled to processing negative affect and feelings of sadness in MDD. No relations were found with local iron concentrations. These findings allow uniquely fine-grained insights on frontocortical microstructure in MDD, and cautiously point to intracortical demyelination as a possible driver of macroscale cortical disintegrity in MDD.

Computational model links normalization to chemoarchitecture in the human visual system.

A goal of cognitive neuroscience is to provide computational accounts of brain function. Canonical computations-mathematical operations used by the brain in many contexts-fulfill broad information-processing needs by varying their algorithmic parameters. A key question concerns the identification of biological substrates for these computations and their algorithms. Chemoarchitecture-the spatial distribution of neurotransmitter receptor densities-shapes brain function. Here, we propose that local variations in specific receptor densities implement algorithmic modulations of canonical computations. To test this hypothesis, we combine mathematical modeling of brain responses with chemoarchitecture data. We compare parameters of divisive normalization obtained from 7-tesla functional magnetic resonance imaging with receptor density maps obtained from positron emission tomography. We find evidence that serotonin and γ-aminobutyric acid receptor densities are the biological substrate for algorithmic modulations of divisive normalization in the human visual system. Our model links computational and biological levels of vision, explaining how canonical computations allow the brain to fulfill broad information-processing needs.

A selection and targeting framework of cortical locations for line-scanning fMRI.

Depth-resolved functional magnetic resonance imaging (fMRI) is an emerging field growing in popularity given the potential of separating signals from different computational processes in cerebral cortex. Conventional acquisition schemes suffer from low spatial and temporal resolutions. Line-scanning methods allow depth-resolved fMRI by sacrificing spatial coverage to sample blood oxygenated level-dependent (BOLD) responses at ultra-high temporal and spatial resolution. For neuroscience applications, it is critical to be able to place the line accurately to (1) sample the right neural population and (2) target that neural population with tailored stimuli or tasks. To this end, we devised a multi-session framework where a target cortical location is selected based on anatomical and functional properties. The line is then positioned according to this information in a separate second session, and we tailor the experiment to focus on the target location. Anatomically, the precision of the line placement was confirmed by projecting a nominal representation of the acquired line back onto the surface. Functional estimates of neural selectivities in the line, as quantified by a visual population-receptive field model, resembled the target selectivities well for most subjects. This functional precision was quantified in detail by estimating the distance between the visual field location of the targeted vertex and the location in visual cortex (V1) that most closely resembled the line-scanning estimates; this distance was on average ~5.5 mm. Given the dimensions of the line, differences in acquisition, session, and stimulus design, this validates that line-scanning can be used to probe local neural sensitivities across sessions. In summary, we present an accurate framework for line-scanning MRI; we believe such a framework is required to harness the full potential of line-scanning and maximize its utility. Furthermore, this approach bridges canonical fMRI experiments with electrophysiological experiments, which in turn allows novel avenues for studying human physiology non-invasively.

Towards functional spin-echo BOLD line-scanning in humans at 7T.

OBJECTIVE: Neurons cluster into sub-millimeter spatial structures and neural activity occurs at millisecond resolutions; hence, ultimately, high spatial and high temporal resolutions are required for functional MRI. In this work, we implemented a spin-echo line-scanning (SELINE) sequence to use in high spatial and temporal resolution fMRI. MATERIALS AND METHODS: A line is formed by simply rotating the spin-echo refocusing gradient to a plane perpendicular to the excited slice and by removing the phase-encoding gradient. This technique promises a combination of high spatial and temporal resolution (250 µm, 500 ms) and microvascular specificity of functional responses. We compared SELINE data to a corresponding gradient-echo version (GELINE). RESULTS: We demonstrate that SELINE showed much-improved line selection (i.e. a sharper line profile) compared to GELINE, albeit at the cost of a significant drop in functional sensitivity. DISCUSSION: This low functional sensitivity needs to be addressed before SELINE can be applied for neuroscientific purposes.

Robust high spatio-temporal line-scanning fMRI in humans at 7T using multi-echo readouts, denoising and prospective motion correction.

BACKGROUND: Functional magnetic resonance imaging (fMRI), typically using blood oxygenation level-dependent (BOLD) contrast weighted imaging, allows the study of brain function with millimeter spatial resolution and temporal resolution of one to a few seconds. At a mesoscopic scale, neurons in the human brain are spatially organized in structures with dimensions of hundreds of micrometers, while they communicate at the millisecond timescale. For this reason, it is important to develop an fMRI method with simultaneous high spatial and temporal resolution. Line-scanning promises to reach this goal at the cost of volume coverage. NEW METHOD: Here, we release a comprehensive update to human line-scanning fMRI. First, we investigated multi-echo line-scanning with five different protocols varying the number of echoes and readout bandwidth while keeping the TR constant. In these, we compared different echo combination approaches in terms of BOLD activation (sensitivity) and temporal signal-to-noise ratio. Second, we implemented an adaptation of NOise reduction with DIstribution Corrected principal component analysis (NORDIC) thermal noise removal for line-scanning fMRI data. Finally, we tested three image-based navigators for motion correction and investigated different ways of performing fMRI analysis on the timecourses which were influenced by the insertion of the navigators themselves. RESULTS: The presented improvements are relatively straightforward to implement; multi-echo readout and NORDIC denoising together, significantly improve data quality in terms of tSNR and t-statistical values, while motion correction makes line-scanning fMRI more robust. COMPARISON WITH EXISTING METHODS: Multi-echo acquisitions and denoising have previously been applied in 3D magnetic resonance imaging. Their combination and application to 1D line-scanning is novel. The current proposed method greatly outperforms the previous line-scanning acquisitions with single-echo acquisition, in terms of tSNR (4.0 for single-echo line-scanning and 36.2 for NORDIC-denoised multi-echo) and t-statistical values (3.8 for single-echo line-scanning and 25.1 for NORDIC-denoised multi-echo line-scanning). CONCLUSIONS: Line-scanning fMRI was advanced compared to its previous implementation in order to improve sensitivity and reliability. The improved line-scanning acquisition could be used, in the future, for neuroscientific and clinical applications.

Visual Working Memory Adapts to the Nature of Anticipated Interference.

Visual working memory has been proven to be relatively robust against interference. However, little is known on whether such robust coding is obligatory, or can be flexibly recruited depending on its expected usefulness. To address this, participants remembered both the color and orientation of a grating. During the maintenance, we inserted a secondary color/orientation memory task, interfering with the primary task. Crucially, we varied the expectations of the type of interference by varying the probability of the two types of intervening task. Behavioral data indicate that to-be-remembered features for which interference is expected are bolstered, whereas to-be-remembered features for which no interference is expected are left vulnerable. This was further supported by fMRI data obtained from visual cortex. In conclusion, the flexibility of visual working memory allows it to strengthen memories for which it anticipates the highest risk of interference.

Visuospatial coding as ubiquitous scaffolding for human cognition.

For more than 100 years we have known that the visual field is mapped onto the surface of visual cortex, imposing an inherently spatial reference frame on visual information processing. Recent studies highlight visuospatial coding not only throughout visual cortex, but also brain areas not typically considered visual. Such widespread access to visuospatial coding raises important questions about its role in wider cognitive functioning. Here, we synthesise these recent developments and propose that visuospatial coding scaffolds human cognition by providing a reference frame through which neural computations interface with environmental statistics and task demands via perception-action loops.

Divisive normalization unifies disparate response signatures throughout the human visual hierarchy.

Neural processing is hypothesized to apply the same mathematical operations in a variety of contexts, implementing so-called canonical neural computations. Divisive normalization (DN) is considered a prime candidate for a canonical computation. Here, we propose a population receptive field (pRF) model based on DN and evaluate it using ultra-high-field functional MRI (fMRI). The DN model parsimoniously captures seemingly disparate response signatures with a single computation, superseding existing pRF models in both performance and biological plausibility. We observe systematic variations in specific DN model parameters across the visual hierarchy and show how they relate to differences in response modulation and visuospatial information integration. The DN model delivers a unifying framework for visuospatial responses throughout the human visual hierarchy and provides insights into its underlying information-encoding computations. These findings extend the role of DN as a canonical computation to neuronal populations throughout the human visual hierarchy.

A line through the brain: implementation of human line-scanning at 7T for ultra-high spatiotemporal resolution fMRI.

Functional magnetic resonance imaging (fMRI) is a widely used tool in neuroscience to detect neurally evoked responses, e.g. the blood oxygenation level-dependent (BOLD) signal. Typically, BOLD fMRI has millimeter spatial resolution and temporal resolution of one to few seconds. To study the sub-millimeter structures and activity of the cortical gray matter, the field needs an fMRI method with high spatial and temporal resolution. Line-scanning fMRI achieves very high spatial resolution and high sampling rate, at the cost of a sacrifice in volume coverage. Here, we present a human line-scanning implementation on a 7T MRI system. First, we investigate the quality of the saturation pulses that suppress MR signal outside the line. Second, we established the best coil combination for reconstruction. Finally, we applied the line-scanning method in the occipital lobe during a visual stimulation task, showing BOLD responses along cortical depth, every 250 µm with a 200 ms repetition time (TR). We found a good correspondence of t-statistics values with 2D gradient-echo echo planar imaging (GE-EPI) BOLD fMRI data with the same temporal resolution and voxel volume (R = 0.6 ± 0.2). In summary, we demonstrate the feasibility of line-scanning in humans and this opens line-scanning fMRI for applications in cognitive and clinical neuroscience.

Separable pupillary signatures of perception and action during perceptual multistability.

The pupil provides a rich, non-invasive measure of the neural bases of perception and cognition and has been of particular value in uncovering the role of arousal-linked neuromodulation, which alters both cortical processing and pupil size. But pupil size is subject to a multitude of influences, which complicates unique interpretation. We measured pupils of observers experiencing perceptual multistability-an ever-changing subjective percept in the face of unchanging but inconclusive sensory input. In separate conditions, the endogenously generated perceptual changes were either task-relevant or not, allowing a separation between perception-related and task-related pupil signals. Perceptual changes were marked by a complex pupil response that could be decomposed into two components: a dilation tied to task execution and plausibly indicative of an arousal-linked noradrenaline surge, and an overlapping constriction tied to the perceptual transient and plausibly a marker of altered visual cortical representation. Constriction, but not dilation, amplitude systematically depended on the time interval between perceptual changes, possibly providing an overt index of neural adaptation. These results show that the pupil provides a simultaneous reading on interacting but dissociable neural processes during perceptual multistability, and suggest that arousal-linked neuromodulator release shapes action but not perception in these circumstances.

Representation of Contralateral Visual Space in the Human Hippocampus.

The initial encoding of visual information primarily from the contralateral visual field is a fundamental organizing principle of the primate visual system. Recently, the presence of such retinotopic sensitivity has been shown to extend well beyond early visual cortex to regions not historically considered retinotopically sensitive. In particular, human scene-selective regions in parahippocampal and medial parietal cortex exhibit prominent biases for the contralateral visual field. Here, we used fMRI to test the hypothesis that the human hippocampus, which is thought to be anatomically connected with these scene-selective regions, would also exhibit a biased representation of contralateral visual space. First, population receptive field (pRF) mapping with scene stimuli revealed strong biases for the contralateral visual field in bilateral hippocampus. Second, the distribution of retinotopic sensitivity suggested a more prominent representation in anterior medial portions of the hippocampus. Finally, the contralateral bias was confirmed in independent data taken from the Human Connectome Project (HCP) initiative. The presence of contralateral biases in the hippocampus, a structure considered by many as the apex of the visual hierarchy, highlights the truly pervasive influence of retinotopy. Moreover, this finding has important implications for understanding how visual information relates to the allocentric global spatial representations known to be encoded therein.SIGNIFICANCE STATEMENT Retinotopic encoding of visual information is an organizing principle of visual cortex. Recent work demonstrates this sensitivity in structures far beyond early visual cortex, including those anatomically connected to the hippocampus. Here, using population receptive field (pRF) modeling in two independent sets of data we demonstrate a consistent bias for the contralateral visual field in bilateral hippocampus. Such a bias highlights the truly pervasive influence of retinotopy, with important implications for understanding how the presence of retinotopy relates to more allocentric spatial representations.

Ultra-high field fMRI reveals origins of feedforward and feedback activity within laminae of human ocular dominance columns.

Ultra-high field MRI can functionally image the cerebral cortex of human subjects at the submillimeter scale of cortical columns and laminae. Here, we investigate both in concert, by imaging ocular dominance columns (ODCs) in primary visual cortex (V1) across different cortical depths. We ensured that putative ODC patterns in V1 (a) are stable across runs, sessions, and scanners located in different continents, (b) have a width (~1.3 mm) expected from post-mortem and animal work and (c) are absent at the retinotopic location of the blind spot. We then dissociated the effects of bottom-up thalamo-cortical input and attentional feedback processes on activity in V1 across cortical depth. Importantly, the separation of bottom-up information flows into ODCs allowed us to validly compare attentional conditions while keeping the stimulus identical throughout the experiment. We find that, when correcting for draining vein effects and using both model-based and model-free approaches, the effect of monocular stimulation is largest at deep and middle cortical depths. Conversely, spatial attention influences BOLD activity exclusively near the pial surface. Our findings show that simultaneous interrogation of columnar and laminar dimensions of the cortical fold can dissociate thalamocortical inputs from top-down processing, and allow the investigation of their interactions without any stimulus manipulation.

Topographic connectivity reveals task-dependent retinotopic processing throughout the human brain.

The human visual system is organized as a hierarchy of maps that share the topography of the retina. Known retinotopic maps have been identified using simple visual stimuli under strict fixation, conditions different from everyday vision which is active, dynamic, and complex. This means that it remains unknown how much of the brain is truly visually organized. Here I demonstrate widespread stable visual organization beyond the traditional visual system, in default-mode network and hippocampus. Detailed topographic connectivity with primary visual cortex during movie-watching, resting-state, and retinotopic-mapping experiments revealed that visual-spatial representations throughout the brain are warped by cognitive state. Specifically, traditionally visual regions alternate with default-mode network and hippocampus in preferentially representing the center of the visual field. This visual role of default-mode network and hippocampus would allow these regions to interface between abstract memories and concrete sensory impressions. Together, these results indicate that visual-spatial organization is a fundamental coding principle that structures the communication between distant brain regions.

Intracranial Recordings Reveal Unique Shape and Timing of Responses in Human Visual Cortex during Illusory Visual Events.

During binocular rivalry, perception spontaneously changes without any alteration to the visual stimulus. What neural events bring about this illusion that a constant stimulus is changing? We recorded from intracranial electrodes placed on the occipital and posterior temporal cortex of two patients with epilepsy while they experienced illusory changes of a face-house binocular-rivalry stimulus or observed a control stimulus that physically changed. We performed within-patient comparisons of broadband high-frequency responses, focusing on single epochs recorded along the ventral processing stream. We found transient face- and house-selective responses localized to the same electrodes for illusory and physical changes, but the temporal characteristics of these responses markedly differed. In comparison with physical changes, responses to illusory changes were longer lasting, in particular exhibiting a characteristic slow rise. Furthermore, the temporal order of responses across the visual hierarchy was reversed for illusory as compared to physical changes: for illusory changes, higher order fusiform and parahippocampal regions responded before lower order occipital regions. Our tentative interpretation of these findings is that two stages underlie the initiation of illusory changes: a destabilization stage in which activity associated with the impending change gradually accumulates across the visual hierarchy, ultimately graduating in a top-down cascade of activity that may stabilize the new perceptual interpretation of the stimulus.

Visual Organization of the Default Network.

The default network (DN) is a brain network with correlated activities spanning frontal, parietal, and temporal cortical lobes. The DN activates for high-level cognition tasks and deactivates when subjects are actively engaged in perceptual tasks. Despite numerous observations, the role of DN deactivation remains unclear. Using computational neuroimaging applied to a large dataset of the Human Connectome Project (HCP) and to two individual subjects scanned over many repeated runs, we demonstrate that the DN selectively deactivates as a function of the position of a visual stimulus. That is, we show that spatial vision is encoded within the DN by means of deactivation relative to baseline. Our results suggest that the DN functions as a set of high-level visual regions, opening up the possibility of using vision-science tools to understand its putative function in cognition and perception.

Learning in Visual Regions as Support for the Bias in Future Value-Driven Choice.

Reinforcement learning can bias decision-making toward the option with the highest expected outcome. Cognitive learning theories associate this bias with the constant tracking of stimulus values and the evaluation of choice outcomes in the striatum and prefrontal cortex. Decisions however first require processing of sensory input, and to date, we know far less about the interplay between learning and perception. This functional magnetic resonance imaging study (N = 43) relates visual blood oxygen level-dependent (BOLD) responses to value beliefs during choice and signed prediction errors after outcomes. To understand these relationships, which co-occurred in the striatum, we sought relevance by evaluating the prediction of future value-based decisions in a separate transfer phase where learning was already established. We decoded choice outcomes with a 70% accuracy with a supervised machine learning algorithm that was given trial-by-trial BOLD from visual regions alongside more traditional motor, prefrontal, and striatal regions. Importantly, this decoding of future value-driven choice outcomes again highlighted an important role for visual activity. These results raise the intriguing possibility that the tracking of value in visual cortex is supportive for the striatal bias toward the more valued option in future choice.

Dopaminergic medication reduces striatal sensitivity to negative outcomes in Parkinson's disease.

Reduced levels of dopamine in Parkinson's disease contribute to changes in learning, resulting from the loss of midbrain neurons that transmit a dopaminergic teaching signal to the striatum. Dopamine medication used by patients with Parkinson's disease has previously been linked to behavioural changes during learning as well as to adjustments in value-based decision-making after learning. To date, however, little is known about the specific relationship between dopaminergic medication-driven differences during learning and subsequent changes in approach/avoidance tendencies in individual patients. Twenty-four Parkinson's disease patients ON and OFF dopaminergic medication and 24 healthy controls subjects underwent functional MRI while performing a probabilistic reinforcement learning experiment. During learning, dopaminergic medication reduced an overemphasis on negative outcomes. Medication reduced negative (but not positive) outcome learning rates, while concurrent striatal blood oxygen level-dependent responses showed reduced prediction error sensitivity. Medication-induced shifts in negative learning rates were predictive of changes in approach/avoidance choice patterns after learning, and these changes were accompanied by systematic striatal blood oxygen level-dependent response alterations. These findings elucidate the role of dopamine-driven learning differences in Parkinson's disease, and show how these changes during learning impact subsequent value-based decision-making.

Correction: How pupil responses track value-based decision-making during and after reinforcement learning.

[This corrects the article DOI: 10.1371/journal.pcbi.1006632.].

Topographic Maps of Visual Space in the Human Cerebellum.

The purported role of the cerebellum has shifted from one that is exclusively sensorimotor related to one that encompasses a wide range of cognitive and associative functions [1-5]. Within sensorimotor areas of the cerebellum, functional organization is characterized by ipsilateral representations of the body [6]. Yet, in the remaining cerebellar cognitive and associative networks, functional organization remains less well understood. Regions of cerebral cortex [7-9] and subcortex [10] important for visual perception and cognition are organized topographically: neural organization mirrors the retina. Recently, it was shown that known retinotopic areas in cerebral cortex are functionally connected to nodes in the cerebellum [2, 11, 12]. In fact, this revealed signals with visuospatial selectivity in the cerebellum [13]. Here, we analyzed the highly powered Human Connectome Project (HCP) retinotopy dataset [14] to create a comprehensive and detailed overview of visuospatial organization in the cerebellum. This revealed 5 ipsilateral topographic maps in 3 cerebellar clusters (oculomotor vermis [OMV]-lobule VIIb-lobule VIIIb), of which we quantified visual field coverage and topography. These quantifications dovetail with the known roles of these areas in eye movements (OMV) [5, 15], attention (OMV-VIIb) [5, 13], working memory (VIIb) [13], and the integration of visuomotor information with respect to effector movements (VIIIb) [5]. To aid future research on visual perception in the cerebellum, we provide an online atlas of the visuospatial maps in Montreal Neurological Institute (MNI) space. Our findings demonstrate that the cerebellum is abundant with visuospatial information and, moreover, that it is organized according to known retinotopic properties.

Implicit and explicit learning in reactive and voluntary saccade adaptation.

Saccades can either be elicited automatically by salient peripheral stimuli or can additionally depend on explicit cognitive goals. Similarly, it is thought that motor adaptation is driven by the combination of a more automatic, implicit process and a more explicit, cognitive process. However, the degree to which such implicit and explicit learning contribute to the adaptation of more reactive and voluntary saccades remains elusive. To study this question, we employed a global saccadic adaptation paradigm with both increasing and decreasing saccade amplitudes. We assessed the resulting adaptation using a dual state model of motor adaptation. This model decomposes learning into a fast and slow process, which are thought to constitute explicit and implicit learning, respectively. Our results show that adaptation of reactive saccades is equally driven by fast and slow learning, while fast learning is nearly absent when adapting voluntary (i.e. scanning) saccades. This pattern of results was present both when saccade gain was increased or decreased. Our results suggest that the increased cognitive demands associated with voluntary compared to reactive saccade planning interfere specifically with explicit learning.