The mouse motor system contains multiple premotor areas and partially follows human organizational principles.

While humans are known to have several premotor cortical areas, secondary motor cortex (M2) is often considered to be the only higher-order motor area of the mouse brain and is thought to combine properties of various human premotor cortices. Here, we show that axonal tracer, functional connectivity, myelin mapping, gene expression, and optogenetics data contradict this notion. Our analyses reveal three premotor areas in the mouse, anterior-lateral motor cortex (ALM), anterior-lateral M2 (aM2), and posterior-medial M2 (pM2), with distinct structural, functional, and behavioral properties. By using the same techniques across mice and humans, we show that ALM has strikingly similar functional and microstructural properties to human anterior ventral premotor areas and that aM2 and pM2 amalgamate properties of human pre-SMA and cingulate cortex. These results provide evidence for the existence of multiple premotor areas in the mouse and chart a comparative map between the motor systems of humans and mice.

Lasting dynamic effects of the psychedelic 2,5-dimethoxy-4-iodoamphetamine ((±)-DOI) on cognitive flexibility.

Psychedelic drugs can aid fast and lasting remission from various neuropsychiatric disorders, though the underlying mechanisms remain unclear. Preclinical studies suggest serotonergic psychedelics enhance neuronal plasticity, but whether neuroplastic changes can also be seen at cognitive and behavioural levels is unexplored. Here we show that a single dose of the psychedelic 2,5-dimethoxy-4-iodoamphetamine ((±)-DOI) affects structural brain plasticity and cognitive flexibility in young adult mice beyond the acute drug experience. Using ex vivo magnetic resonance imaging, we show increased volumes of several sensory and association areas one day after systemic administration of 2 mgkg-1 (±)-DOI. We then demonstrate lasting effects of (±)-DOI on cognitive flexibility in a two-step probabilistic reversal learning task where 2 mgkg-1 (±)-DOI improved the rate of adaptation to a novel reversal in task structure occurring one-week post-treatment. Strikingly, (±)-DOI-treated mice started learning from reward omissions, a unique strategy not typically seen in mice in this task, suggesting heightened sensitivity to previously overlooked cues. Crucially, further experiments revealed that (±)-DOI's effects on cognitive flexibility were contingent on the timing between drug treatment and the novel reversal, as well as on the nature of the intervening experience. (±)-DOI's facilitation of both cognitive adaptation and novel thinking strategies may contribute to the clinical benefits of psychedelic-assisted therapy, particularly in cases of perseverative behaviours and a resistance to change seen in depression, anxiety, or addiction. Furthermore, our findings highlight the crucial role of time-dependent neuroplasticity and the influence of experiential factors in shaping the therapeutic potential of psychedelic interventions for impaired cognitive flexibility.

7,8-dihydroxyflavone enhances long-term spatial memory and alters brain volume in wildtype mice.

Introduction: 7,8-dihydroxyflavone (7,8-DHF) is a low molecular weight compound that can cross the blood brain barrier and has been implicated in numerous functions and behaviours. It is thought to have neuroprotective capability and has been shown to alleviate symptoms in a wide range of diseases. Methods: 7,8-DHF was administered systemically to wildtype mice during Morris water maze training. Long-term spatial memory was assessed 28 days later. Ex-vivo T2-weighted (T2w) imaging was undertaken on a subset of these mice to assess brain-wide changes in volume. Results: We found that systemic 7,8-DHF administration during the training period enhanced spatial memory 28 days later. Volumetric changes were observed in numerous brain regions associated with a broad range of functions including cognition, sensory, and motor processing. Discussion: Our findings give the first whole brain overview of long-term anatomical changes following 7,8-DHF administration providing valuable information for assessing and understanding the widespread effects this drug has been shown to have in behaviour and disease.

A consensus protocol for functional connectivity analysis in the rat brain.

Task-free functional connectivity in animal models provides an experimental framework to examine connectivity phenomena under controlled conditions and allows for comparisons with data modalities collected under invasive or terminal procedures. Currently, animal acquisitions are performed with varying protocols and analyses that hamper result comparison and integration. Here we introduce StandardRat, a consensus rat functional magnetic resonance imaging acquisition protocol tested across 20 centers. To develop this protocol with optimized acquisition and processing parameters, we initially aggregated 65 functional imaging datasets acquired from rats across 46 centers. We developed a reproducible pipeline for analyzing rat data acquired with diverse protocols and determined experimental and processing parameters associated with the robust detection of functional connectivity across centers. We show that the standardized protocol enhances biologically plausible functional connectivity patterns relative to previous acquisitions. The protocol and processing pipeline described here is openly shared with the neuroimaging community to promote interoperability and cooperation toward tackling the most important challenges in neuroscience.

Individual differences in slow wave sleep architecture relate to variation in white matter microstructure across adulthood.

Sleep plays a key role in supporting brain function and resilience to brain decline. It is well known that sleep changes substantially with aging and that aging is associated with deterioration of brain structure. In this study, we sought to characterize the relationship between slow wave slope (SWslope)-a key marker of sleep architecture and an indirect proxy of sleep quality-and microstructure of white matter pathways in healthy adults with no sleep complaints. Participants were 12 young (24-27 years) and 12 older (50-79 years) adults. Sleep was assessed with nocturnal electroencephalography (EEG) and the Pittsburgh Sleep Quality Index (PSQI). White matter integrity was assessed using tract-based spatial statistics (TBSS) on tensor-based metrics such as Fractional Anisotropy (FA) and Mean Diffusivity (MD). Global PSQI score did not differ between younger (n = 11) and older (n = 11) adults (U = 50, p = 0.505), but EEG revealed that younger adults had a steeper SWslope at both frontal electrode sites (F3: U = 2, p < 0.001, F4: U = 4, p < 0.001, n = 12 younger, 10 older). There were widespread correlations between various diffusion tensor-based metrics of white matter integrity and sleep SWslope, over and above effects of age (n = 11 younger, 9 older). This was particularly evident for the corpus callosum, corona radiata, superior longitudinal fasciculus, internal and external capsule. This indicates that reduced sleep slow waves may be associated with widespread white matter deterioration. Future studies should investigate whether interventions targeted at improving sleep architecture also impact on decline in white matter microstructure in older adults.

qMRI-BIDS: An extension to the brain imaging data structure for quantitative magnetic resonance imaging data.

The Brain Imaging Data Structure (BIDS) established community consensus on the organization of data and metadata for several neuroimaging modalities. Traditionally, BIDS had a strong focus on functional magnetic resonance imaging (MRI) datasets and lacked guidance on how to store multimodal structural MRI datasets. Here, we present and describe the BIDS Extension Proposal 001 (BEP001), which adds a range of quantitative MRI (qMRI) applications to the BIDS. In general, the aim of qMRI is to characterize brain microstructure by quantifying the physical MR parameters of the tissue via computational, biophysical models. By proposing this new standard, we envision standardization of qMRI through multicenter dissemination of interoperable datasets. This way, BIDS can act as a catalyst of convergence between qMRI methods development and application-driven neuroimaging studies that can help develop quantitative biomarkers for neural tissue characterization. In conclusion, this BIDS extension offers a common ground for developers to exchange novel imaging data and tools, reducing the entrance barrier for qMRI in the field of neuroimaging.

A macroscopic link between interhemispheric tract myelination and cortico-cortical interactions during action reprogramming.

Myelination has been increasingly implicated in the function and dysfunction of the adult human brain. Although it is known that axon myelination shapes axon physiology in animal models, it is unclear whether a similar principle applies in the living human brain, and at the level of whole axon bundles in white matter tracts. Here, we hypothesised that in humans, cortico-cortical interactions between two brain areas may be shaped by the amount of myelin in the white matter tract connecting them. As a test bed for this hypothesis, we use a well-defined interhemispheric premotor-to-motor circuit. We combined TMS-derived physiological measures of cortico-cortical interactions during action reprogramming with multimodal myelin markers (MT, R1, R2* and FA), in a large cohort of healthy subjects. We found that physiological metrics of premotor-to-motor interaction are broadly associated with multiple myelin markers, suggesting interindividual differences in tract myelination may play a role in motor network physiology. Moreover, we also demonstrate that myelination metrics link indirectly to action switching by influencing local primary motor cortex dynamics. These findings suggest that myelination levels in white matter tracts may influence millisecond-level cortico-cortical interactions during tasks. They also unveil a link between the physiology of the motor network and the myelination of tracts connecting its components, and provide a putative mechanism mediating the relationship between brain myelination and human behaviour.

Hebbian activity-dependent plasticity in white matter.

Synaptic plasticity is required for learning and follows Hebb's rule, the computational principle underpinning associative learning. In recent years, a complementary type of brain plasticity has been identified in myelinated axons, which make up the majority of brain's white matter. Like synaptic plasticity, myelin plasticity is required for learning, but it is unclear whether it is Hebbian or whether it follows different rules. Here, we provide evidence that white matter plasticity operates following Hebb's rule in humans. Across two experiments, we find that co-stimulating cortical areas to induce Hebbian plasticity leads to relative increases in cortical excitability and associated increases in a myelin marker within the stimulated fiber bundle. We conclude that Hebbian plasticity extends beyond synaptic changes and can be observed in human white matter fibers.

Microscopy-BIDS: An Extension to the Brain Imaging Data Structure for Microscopy Data.

The Brain Imaging Data Structure (BIDS) is a specification for organizing, sharing, and archiving neuroimaging data and metadata in a reusable way. First developed for magnetic resonance imaging (MRI) datasets, the community-led specification evolved rapidly to include other modalities such as magnetoencephalography, positron emission tomography, and quantitative MRI (qMRI). In this work, we present an extension to BIDS for microscopy imaging data, along with example datasets. Microscopy-BIDS supports common imaging methods, including 2D/3D, ex/in vivo, micro-CT, and optical and electron microscopy. Microscopy-BIDS also includes comprehensible metadata definitions for hardware, image acquisition, and sample properties. This extension will facilitate future harmonization efforts in the context of multi-modal, multi-scale imaging such as the characterization of tissue microstructure with qMRI.

Reassessing associations between white matter and behaviour with multimodal microstructural imaging.

Several studies have established specific relationships between White Matter (WM) and behaviour. However, these studies have typically focussed on fractional anisotropy (FA), a neuroimaging metric that is sensitive to multiple tissue properties, making it difficult to identify what biological aspects of WM may drive such relationships. Here, we carry out a pre-registered assessment of WM-behaviour relationships in 50 healthy individuals across multiple behavioural and anatomical domains, and complementing FA with myelin-sensitive quantitative MR modalities (MT, R1, R2∗). Surprisingly, we only find support for predicted relationships between FA and behaviour in one of three pre-registered tests. For one behavioural domain, where we failed to detect an FA-behaviour correlation, we instead find evidence for a correlation between behaviour and R1. This hints that multimodal approaches are able to identify a wider range of WM-behaviour relationships than focusing on FA alone. To test whether a common biological substrate such as myelin underlies WM-behaviour relationships, we then ran joint multimodal analyses, combining across all MRI parameters considered. No significant multimodal signatures were found and power analyses suggested that sample sizes of 40-200 may be required to detect such joint multimodal effects, depending on the task being considered. These results demonstrate that FA-behaviour relationships from the literature can be replicated, but may not be easily generalisable across domains. Instead, multimodal microstructural imaging may be best placed to detect a wider range of WM-behaviour relationships, as different MRI modalities provide distinct biological sensitivities. Our findings highlight a broad heterogeneity in WM's relationship with behaviour, suggesting that variable biological effects may be shaping their interaction.

Frequency modulation of entorhinal cortex neuronal activity drives distinct frequency-dependent states of brain-wide dynamics.

Human neuroimaging studies have shown that, during cognitive processing, the brain undergoes dynamic transitions between multiple, frequency-tuned states of activity. Although different states may emerge from distinct sources of neural activity, it remains unclear whether single-area neuronal spiking can also drive multiple dynamic states. In mice, we ask whether frequency modulation of the entorhinal cortex activity causes dynamic states to emerge and whether these states respond to distinct stimulation frequencies. Using hidden Markov modeling, we perform unsupervised detection of transient states in mouse brain-wide fMRI fluctuations induced via optogenetic frequency modulation of excitatory neurons. We unveil the existence of multiple, frequency-dependent dynamic states, invisible through standard static fMRI analyses. These states are linked to different anatomical circuits and disrupted in a frequency-dependent fashion in a transgenic model of cognitive disease directly related to entorhinal cortex dysfunction. These findings provide cross-scale insight into basic neuronal mechanisms that may underpin flexibility in brain-wide dynamics.

Identification and disruption of a neural mechanism for accumulating prospective metacognitive information prior to decision-making.

More than one type of probability must be considered when making decisions. It is as necessary to know one's chance of performing choices correctly as it is to know the chances that desired outcomes will follow choices. We refer to these two choice contingencies as internal and external probability. Neural activity across many frontal and parietal areas reflected internal and external probabilities in a similar manner during decision-making. However, neural recording and manipulation approaches suggest that one area, the anterior lateral prefrontal cortex (alPFC), is highly specialized for making prospective, metacognitive judgments on the basis of internal probability; it is essential for knowing which decisions to tackle, given its assessment of how well they will be performed. Its activity predicted prospective metacognitive judgments, and individual variation in activity predicted individual variation in metacognitive judgments. Its disruption altered metacognitive judgments, leading participants to tackle perceptual decisions they were likely to fail.

Can MRI measure myelin? Systematic review, qualitative assessment, and meta-analysis of studies validating microstructural imaging with myelin histology.

Recent years have seen an increased understanding of the importance of myelination in healthy brain function and neuropsychiatric diseases. Non-invasive microstructural magnetic resonance imaging (MRI) holds the potential to expand and translate these insights to basic and clinical human research, but the sensitivity and specificity of different MR markers to myelination is a subject of debate. To consolidate current knowledge on the topic, we perform a systematic review and meta-analysis of studies that validate microstructural imaging by combining it with myelin histology. We find meta-analytic evidence for correlations between various myelin histology metrics and markers from different MRI modalities, including fractional anisotropy, radial diffusivity, macromolecular pool, magnetization transfer ratio, susceptibility and longitudinal relaxation rate, but not mean diffusivity. Meta-analytic correlation effect sizes range widely, between R2 = 0.26 and R2 = 0.82. However, formal comparisons between MRI-based myelin markers are limited by methodological variability, inconsistent reporting and potential for publication bias, thus preventing the establishment of a single most sensitive strategy to measure myelin with MRI. To facilitate further progress, we provide a detailed characterisation of the evaluated studies as an online resource. We also share a set of 12 recommendations for future studies validating putative MR-based myelin markers and deploying them in vivo in humans.

Fronto-parietal involvement in chronic stroke motor performance when corticospinal tract integrity is compromised.

BACKGROUND: Preserved integrity of the corticospinal tract (CST) is a marker of good upper-limb behavior and recovery following stroke. However, there is less understanding of neural mechanisms that might help facilitate upper-limb motor recovery in stroke survivors with extensive CST damage. OBJECTIVE: The purpose of this study was to investigate resting state functional connectivity in chronic stroke survivors with different levels of CST damage and to explore neural correlates of greater upper-limb motor performance in stroke survivors with compromised ipsilesional CST integrity. METHODS: Thirty chronic stroke survivors (24 males, aged 64.7 ± 10.8 years) participated in this study. Three experimental sessions were conducted to: 1) obtain anatomical (T1, T2) structural (diffusion) and functional (resting state) MRI sequences, 2) determine CST integrity with transcranial magnetic stimulation (TMS) and conduct assessments of upper-limb behavior, and 3) reconfirm CST integrity status. Participants were divided into groups according to the extent of CST damage. Those in the extensive CST damage group did not show TMS evoked responses and had significantly lower ipsilesional fractional anisotropy. RESULTS: Of the 30 chronic stroke survivors, 12 were categorized as having extensive CST damage. Stroke survivors with extensive CST damage had weaker functional connectivity in the ipsilesional sensorimotor network and greater functional connectivity in the ipsilesional fronto-parietal network compared to those with preserved CST integrity. For participants with extensive CST damage, improved motor performance was associated with greater functional connectivity of the ipsilesional fronto-parietal network and higher fractional anisotropy of the ipsilesional rostral superior longitudinal fasciculus. CONCLUSIONS: Stroke survivors with extensive CST damage have greater resting state functional connectivity of an ipsilesional fronto-parietal network that appears to be a behaviorally relevant neural mechanism that improves upper-limb motor performance.

Experience-related reductions of myelin and axon diameter in adulthood.

The production of new myelin has been highlighted as an underappreciated mechanism of brain plasticity, but whether plastic decreases in myelin also happen in the adult brain has been largely unexplored. Recently, Sinclair et al. (Sinclair JS, Fischl MJ, Alexandrova O, Heß M, Grothe B, Leibold C, and Kopp-Scheinpflug C. J Neurosci 37: 8239-8255, 2017) have shown that auditory deprivation can lead to decrease in myelination and axon caliber even in healthy adulthood. These findings show that activity-regulated myelination is more complex than previously thought and expand our knowledge of how adult brain plasticity could operate on a cellular level.

Myelin plasticity and behaviour-connecting the dots.

Myelin sheaths in the vertebrate nervous system enable faster impulse propagation, while myelinating glia provide vital support to axons. Once considered a static insulator, converging evidence now suggests that myelin in the central nervous system can be dynamically regulated by neuronal activity and continues to participate in nervous system plasticity beyond development. While the link between experience and myelination gains increased recognition, it is still unclear what role such adaptive myelination plays in facilitating and shaping behaviour. Additionally, fundamental mechanisms and principles underlying myelin remodelling remain poorly understood. In this review, we will discuss new insights into the link between myelin plasticity and behaviour, as well as mechanistic aspects of myelin remodelling that may help to elucidate this intriguing process.