Closed-loop fMRI at the mesoscopic scale of columns and layers: Can we do it and why would we want to?

Technological advances in fMRI including ultra-high magnetic fields (≥ 7T) and acquisition methods that increase spatial specificity have paved the way for studies ofthe human cortex at the scale of layers and columns. This mesoscopic scale promises an improved mechanistic understanding of human cortical function so far only accessible to invasive animal neurophysiology. In recent years an increasing number of studies have applied such methods to better understand the cortical function in perception and cognition. This Future Perspective article asks whether closed-loop fMRI studies could equally benefit from these methods to achieve layer and columnar specificity. We outline potential applications and discuss the conceptual and concrete challenges, including data acquisition and volitional control of mesoscopic brain activity. We anticipate an important role of fMRI with mesoscopic resolution for closed-loop fMRI and neurofeedback, yielding new insights into brain function and potentially clinical applications

Spatial specificity of the functional gradient echo and spin echo BOLD signal across cortical depth at 7 T

Functional magnetic resonance imaging (fMRI) at high magnetic field strengths (≥ 7 T) is a promising technique to study the functioning of the human brain at the spatial scale of cortical columns and layers. However, measurements most often rely on the blood oxygenation level dependent (BOLD) response sampled with a gradient echo (GE) sequence, which is known to be most sensitive to macrovascular contributions that limit their effective spatial resolution. Alternatively, a spin echo (SE) sequence can be used to increase the weighting toward the microvasculature and, therefore, the location of neural activation. In addition, due to the heterogeneous structure of the cortical cerebrovascular system, the effective spatial resolution can change across cortical depth. For high-resolution fMRI applications, it is hence important to know how much the effective spatial resolution varies across cortical depth. In this study, we used flickering rotating wedge stimuli to induce traveling waves with varying spatial frequencies in the retinotopically organized primary visual cortex (V1), which allowed us to infer the modulation transfer function (MTF) of the BOLD response that characterizes the spatial specificity of the measured signal. We acquired GE- and SE-BOLD data at 7 T and compared the MTF between acquisition techniques at different cortical depths. Our results show a small but consistent increase in spatial specificity when using SE-BOLD. But across cortical depth, both acquisition techniques generally show a similar decrease of specificity toward the pial surface demonstrating the dependence on macrovascular contributions, which needs to be carefully considered when interpreting the results of high-resolution fMRI studies

Decoding of columnar-level organization across cortical depth using BOLD- and CBV-fMRI at 7 T

Multivariate pattern analysis (MVPA) methods are a versatile tool to retrieve information from neurophysiological data obtained with functional magnetic resonance imaging (fMRI) techniques. Since fMRI is based on measuring the hemodynamic response following neural activation, the spatial specificity of the fMRI signal is inherently limited by contributions of macrovascular compartments that drain the signal from the actual location of neural activation, making it challenging to image cortical structures at the spatial scale of cortical columns and layers. By relying on information from multiple voxels, MVPA has shown promising results in retrieving information encoded in fine-grained spatial patterns. We examined the spatial specificity of the signal exploited by MVPA. Over multiple sessions, we measured ocular dominance columns (ODCs) in human primary visual cortex (V1) with different acquisition techniques at 7 T. For measurements with blood oxygenation level dependent (BOLD) contrast, we included both gradient echo- (GE-BOLD) and spin echo-based (SE-BOLD) sequences. Furthermore, we acquired data using the vascular-space-occupancy (VASO) fMRI technique, which is sensitive to cerebral blood volume (CBV) changes. We used the data to decode eye-of-origin from signals across cortical layers. While ocularity information can be decoded with all imaging techniques, laminar profiles reveal that macrovascular contributions affect all acquisition methods, limiting their specificity across cortical depth. Therefore, although MVPA is a promising approach for investigating the mesoscopic circuitry of the human cerebral cortex, careful consideration of macrovascular contributions is needed that render the spatial specificity of the extracted signal

Challenges in replicating layer-specificity of working memory processes in human dlPFC

Although working memory reliably activates the dorsolateral prefrontal cortex (dlPFC), the functional significance of its distinct cytoarchitectonic layers is not well understood in humans. A recent functional magnetic resonance (fMRI) study at 7T demonstrated for the first time layer-specific responses in the human dlPFC during working memory. Superficial layers were more active during the delay period when working memory items needed to be manipulated compared to mere maintenance. In contrast, deeper layers were more active during the motor response to a probe compared to non-action. Like many current layer fMRI studies, this study relied on several manual and semi-manual processing steps, including the selection of regions of interest. To test the replicability of these findings, we conducted a pre-registered replication of this study in 21 subjects using a fully automated and reproducible analysis pipeline. Our results do not show the same layer-specific effects. Although we observed higher activity in the superficial layers in response to working memory manipulation during the delay period, we did not find any evidence for stronger deep layer involvement during motor response in the probe period. We argue that our results are biologically plausible in light of previous research as well as methodological considerations inherent in layer fMRI acquisition and analysis. Consequently, we conclude that the evidence regarding the functional role of different layers within the human dlPFC during working memory remains inconclusive. A focus on replicability, reproducibility, and a better understanding of the influence of methodological choices will help layer fMRI become a more routine tool in cognitive neuroscience

Laminar dissociation of feedforward and feedback in high-level ventral visual cortex during imagery and perception

Visual imagery and perception share neural machinery, but rely on different information flow. While perception is driven by the integration of sensory feedforward and internally-generated feedback information, imagery relies on feedback only. This suggests that although imagery and perception may activate overlapping brain regions, they do so in informationally distinctive ways. Using lamina-resolved MRI at 7T, we measured the neural activity during imagery and perception of faces and scenes in high-level ventral visual cortex at the mesoscale of laminar organization that distinguish feedforward from feedback signals. We found distinctive laminar profiles for imagery and perception of scenes and faces in the parahippocampal place area and the fusiform face area, respectively. Our findings provide insight into the neural basis of the phenomenology of visual imagery versus perception, and shed new light into the mesoscale organization of feedforward and feedback information flow in high-level ventral visual cortex

Connectivity at fine scale: Mapping structural connective fields by tractography of short association fibres in vivo

The extraordinary number of short association fibres (SAF) connecting neighbouring cortical areas is a prominent feature of the large gyrified human brain. The contribution of SAF to the human connectome is largely unknown because of methodological challenges in mapping them. We present a method to characterise cortico–cortical connectivity mediated by SAF in topologically organised cortical areas. We introduce the ‘structural connective fields’ (sCF) metric which specifically quantifies neuronal signal propagation and integration mediated by SAF. This new metric complements functional connective field metrics integrating across contributions from short- and long-range white matter and intracortical fibres. Applying the method in the human early visual processing stream, we show that SAF preserve cortical functional topology. Retinotopic maps of V2 and V3 could be predicted from retinotopy in V1 and SAF connectivity. The sCF sizes increased along the cortical hierarchy and were smaller than their functional counterparts, in line with the latter being additionally broadened by long-range and intracortical connections. In vivo sCF mapping provides insights into short-range cortico– cortical connectivity in humans comparable to tract tracing studies in animal research and is an essential step towards creating a complete human connectome

Dynamic layer-specific processing in the prefrontal cortex during working memory

The dorsolateral prefrontal cortex (dlPFC) is reliably engaged in working memory (WM) and comprises different cytoarchitectonic layers, yet their functional role in human WM is unclear. Here, participants completed a delayed-match-to-sample task while undergoing functional magnetic resonance imaging (fMRI) at ultra-high resolution. We examine layer-specific activity to manipulations in WM load and motor response. Superficial layers exhibit a preferential response to WM load during the delay and retrieval periods of a WM task, indicating a lamina-specific activation of the frontoparietal network. Multivariate patterns encoding WM load in the superficial layer dynamically change across the three periods of the task. Last, superficial and deep layers are non-differentially involved in the motor response, challenging earlier findings of a preferential deep layer activation. Taken together, our results provide new insights into the functional laminar circuitry of the dlPFC during WM and support a dynamic account of dlPFC coding

Short association fibres form topographic sheets in the human V1–V2 processing stream

Despite the importance of short association fibres (SAF) for human brain function, their structures remain understudied. It is not known how SAF are organised across the brain, and how consistent their geometries and locations are across individuals. To address this gap, we mapped the precise structures of SAF in the primary (V1) and secondary (V2) visual cortex in a group of participants in vivo and a post mortem specimen. We assessed the consistency of SAF geometries and their expected structural and functional topography using probabilistic tractography on sub-millimetre-resolution diffusion-weighted MRI combined with functional MRI retinotopic maps in vivo. We found that dense SAF connected V1 and V2, forming sheet structures with retinotopic topography and bearing consistent geometries that resembled the local V1–V2 cortical folding. In vivo findings were corroborated by the robust and fine-grained post mortem reference. Our in vivo approach provides important insights into SAF organisation and could be applied to studies across species on cortical and SAF reorganisation and support neuronavigation

Short association fibres form topographic sheets in the human V1-V2 processing stream

Despite the importance of short association fibres (SAF) for human brain function their structures remain understudied. It is not known how SAF are organised across the brain, and how consistent their geometries and locations are across individuals. To address this gap, we mapped the precise structures of SAF in the primary (V1) and secondary (V2) visual cortex in a group of participants in vivo and a post mortem specimen. We assessed the consistency of SAF geometries and their expected structural and functional topography using probabilistic tractography on sub-millimetre resolution diffusion-weighted MRI combined with functional MRI retinotopic maps in vivo. We found that dense SAF connected V1 and V2, forming sheet structures with retinotopic topography and bearing consistent geometries that resembled the local V1–V2 cortical folding. In vivo findings were corroborated by the robust and fine-grained post mortem reference. Our in vivo approach provides important insights into SAF organisation and could be applied to studies across species on cortical and SAF reorganisation and support neuronavigation