On the stability of canonical correlation analysis and partial least squares with application to brain-behavior associations.

Associations between datasets can be discovered through multivariate methods like Canonical Correlation Analysis (CCA) or Partial Least Squares (PLS). A requisite property for interpretability and generalizability of CCA/PLS associations is stability of their feature patterns. However, stability of CCA/PLS in high-dimensional datasets is questionable, as found in empirical characterizations. To study these issues systematically, we developed a generative modeling framework to simulate synthetic datasets. We found that when sample size is relatively small, but comparable to typical studies, CCA/PLS associations are highly unstable and inaccurate; both in their magnitude and importantly in the feature pattern underlying the association. We confirmed these trends across two neuroimaging modalities and in independent datasets with n ≈ 1000 and n = 20,000, and found that only the latter comprised sufficient observations for stable mappings between imaging-derived and behavioral features. We further developed a power calculator to provide sample sizes required for stability and reliability of multivariate analyses. Collectively, we characterize how to limit detrimental effects of overfitting on CCA/PLS stability, and provide recommendations for future studies.

Generalising XTRACT tractography protocols across common macaque brain templates.

Non-human primates are extensively used in neuroscience research as models of the human brain, with the rhesus macaque being a prominent example. We have previously introduced a set of tractography protocols (XTRACT) for reconstructing 42 corresponding white matter (WM) bundles in the human and the macaque brain and have shown cross-species comparisons using such bundles as WM landmarks. Our original XTRACT protocols were developed using the F99 macaque brain template. However, additional macaque template brains are becoming increasingly common. Here, we generalise the XTRACT tractography protocol definitions across five macaque brain templates, including the F99, D99, INIA, Yerkes and NMT. We demonstrate equivalence of such protocols in two ways: (a) Firstly by comparing the bodies of the tracts derived using protocols defined across the different templates considered, (b) Secondly by comparing the projection patterns of the reconstructed tracts across the different templates in two cross-species (human-macaque) comparison tasks. The results confirm similarity of all predictions regardless of the macaque brain template used, providing direct evidence for the generalisability of these tractography protocols across the five considered templates.

The spatial extent of anatomical connections within the thalamus varies across the cortical hierarchy in humans and macaques.

Each cortical area has a distinct pattern of anatomical connections within the thalamus, a central subcortical structure composed of functionally and structurally distinct nuclei. Previous studies have suggested that certain cortical areas may have more extensive anatomical connections that target multiple thalamic nuclei, which potentially allows them to modulate distributed information flow. However, there is a lack of quantitative investigations into anatomical connectivity patterns within the thalamus. Consequently, it remains unknown if cortical areas exhibit systematic differences in the extent of their anatomical connections within the thalamus. To address this knowledge gap, we used diffusion magnetic resonance imaging (dMRI) to perform brain-wide probabilistic tractography for 828 healthy adults from the Human Connectome Project. We then developed a framework to quantify the spatial extent of each cortical area's anatomical connections within the thalamus. Additionally, we leveraged resting-state functional MRI, cortical myelin, and human neural gene expression data to test if the extent of anatomical connections within the thalamus varied along the cortical hierarchy. Our results revealed two distinct corticothalamic tractography motifs: 1) a sensorimotor cortical motif characterized by focal thalamic connections targeting posterolateral thalamus, associated with fast, feed-forward information flow; and 2) an associative cortical motif characterized by diffuse thalamic connections targeting anteromedial thalamus, associated with slow, feed-back information flow. These findings were consistent across human subjects and were also observed in macaques, indicating cross-species generalizability. Overall, our study demonstrates that sensorimotor and association cortical areas exhibit differences in the spatial extent of their anatomical connections within the thalamus, which may support functionally-distinct cortico-thalamic information flow.

DENOISING DIFFUSION MRI: CONSIDERATIONS AND IMPLICATIONS FOR ANALYSIS.

Development of diffusion MRI (dMRI) denoising approaches has experienced considerable growth over the last years. As noise can inherently reduce accuracy and precision in measurements, its effects have been well characterised both in terms of uncertainty increase in dMRI-derived features and in terms of biases caused by the noise floor, the smallest measurable signal given the noise level. However, gaps in our knowledge still exist in objectively characterising dMRI denoising approaches in terms of both of these effects and assessing their efficacy. In this work, we reconsider what a denoising method should and should not do and we accordingly define criteria to characterise the performance. We propose a comprehensive set of evaluations, including i) benefits in improving signal quality and reducing noise variance, ii) gains in reducing biases and the noise floor and improving, iii) preservation of spatial resolution, iv) agreement of denoised data against a gold standard, v) gains in downstream parameter estimation (precision and accuracy), vi) efficacy in enabling noise-prone applications, such as ultra-high-resolution imaging. We further provide newly acquired complex datasets (magnitude and phase) with multiple repeats that sample different SNR regimes to highlight performance differences under different scenarios. Without loss of generality, we subsequently apply a number of exemplar patch-based denoising algorithms to these datasets, including Non-Local Means, Marchenko-Pastur PCA (MPPCA) in the magnitude and complex domain and NORDIC, and compare them with respect to the above criteria and against a gold standard complex average of multiple repeats. We demonstrate that all tested denoising approaches reduce noise-related variance, but not always biases from the elevated noise floor. They all induce a spatial resolution penalty, but its extent can vary depending on the method and the implementation. Some denoising approaches agree with the gold standard more than others and we demonstrate challenges in even defining such a standard. Overall, we show that dMRI denoising performed in the complex domain is advantageous to magnitude domain denoising with respect to all the above criteria.

Automated detection of cerebral microbleeds on MR images using knowledge distillation framework.

Introduction: Cerebral microbleeds (CMBs) are associated with white matter damage, and various neurodegenerative and cerebrovascular diseases. CMBs occur as small, circular hypointense lesions on T2*-weighted gradient recalled echo (GRE) and susceptibility-weighted imaging (SWI) images, and hyperintense on quantitative susceptibility mapping (QSM) images due to their paramagnetic nature. Accurate automated detection of CMBs would help to determine quantitative imaging biomarkers (e.g., CMB count) on large datasets. In this work, we propose a fully automated, deep learning-based, 3-step algorithm, using structural and anatomical properties of CMBs from any single input image modality (e.g., GRE/SWI/QSM) for their accurate detections. Methods: In our method, the first step consists of an initial candidate detection step that detects CMBs with high sensitivity. In the second step, candidate discrimination step is performed using a knowledge distillation framework, with a multi-tasking teacher network that guides the student network to classify CMB and non-CMB instances in an offline manner. Finally, a morphological clean-up step further reduces false positives using anatomical constraints. We used four datasets consisting of different modalities specified above, acquired using various protocols and with a variety of pathological and demographic characteristics. Results: On cross-validation within datasets, our method achieved a cluster-wise true positive rate (TPR) of over 90% with an average of <2 false positives per subject. The knowledge distillation framework improves the cluster-wise TPR of the student model by 15%. Our method is flexible in terms of the input modality and provides comparable cluster-wise TPR and better cluster-wise precision compared to existing state-of-the-art methods. When evaluating across different datasets, our method showed good generalizability with a cluster-wise TPR >80 % with different modalities. The python implementation of the proposed method is openly available.

Non-reversibility outperforms functional connectivity in characterisation of brain states in MEG data.

Characterising brain states during tasks is common practice for many neuroscientific experiments using electrophysiological modalities such as electroencephalography (EEG) and magnetoencephalography (MEG). Brain states are often described in terms of oscillatory power and correlated brain activity, i.e. functional connectivity. It is, however, not unusual to observe weak task induced functional connectivity alterations in the presence of strong task induced power modulations using classical time-frequency representation of the data. Here, we propose that non-reversibility, or the temporal asymmetry in functional interactions, may be more sensitive to characterise task induced brain states than functional connectivity. As a second step, we explore causal mechanisms of non-reversibility in MEG data using whole brain computational models. We include working memory, motor, language tasks and resting-state data from participants of the Human Connectome Project (HCP). Non-reversibility is derived from the lagged amplitude envelope correlation (LAEC), and is based on asymmetry of the forward and reversed cross-correlations of the amplitude envelopes. Using random forests, we find that non-reversibility outperforms functional connectivity in the identification of task induced brain states. Non-reversibility shows especially better sensitivity to capture bottom-up gamma induced brain states across all tasks, but also alpha band associated brain states. Using whole brain computational models we find that asymmetry in the effective connectivity and axonal conduction delays play a major role in shaping non-reversibility across the brain. Our work paves the way for better sensitivity in characterising brain states during both bottom-up as well as top-down modulation in future neuroscientific experiments.

QuNex-An integrative platform for reproducible neuroimaging analytics.

Introduction: Neuroimaging technology has experienced explosive growth and transformed the study of neural mechanisms across health and disease. However, given the diversity of sophisticated tools for handling neuroimaging data, the field faces challenges in method integration, particularly across multiple modalities and species. Specifically, researchers often have to rely on siloed approaches which limit reproducibility, with idiosyncratic data organization and limited software interoperability. Methods: To address these challenges, we have developed Quantitative Neuroimaging Environment & Toolbox (QuNex), a platform for consistent end-to-end processing and analytics. QuNex provides several novel functionalities for neuroimaging analyses, including a "turnkey" command for the reproducible deployment of custom workflows, from onboarding raw data to generating analytic features. Results: The platform enables interoperable integration of multi-modal, community-developed neuroimaging software through an extension framework with a software development kit (SDK) for seamless integration of community tools. Critically, it supports high-throughput, parallel processing in high-performance compute environments, either locally or in the cloud. Notably, QuNex has successfully processed over 10,000 scans across neuroimaging consortia, including multiple clinical datasets. Moreover, QuNex enables integration of human and non-human workflows via a cohesive translational platform. Discussion: Collectively, this effort stands to significantly impact neuroimaging method integration across acquisition approaches, pipelines, datasets, computational environments, and species. Building on this platform will enable more rapid, scalable, and reproducible impact of neuroimaging technology across health and disease.

Mapping brain endophenotypes associated with idiopathic pulmonary fibrosis genetic risk.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a serious disease of the lung parenchyma. It has a known polygenetic risk, with at least seventeen regions of the genome implicated to date. Growing evidence suggests linked multimorbidity of IPF with neurodegenerative or affective disorders. However, no study so far has explicitly explored links between IPF, associated genetic risk profiles, and specific brain features. METHODS: We exploited imaging and genetic data from more than 32,000 participants available through the UK Biobank population-level resource to explore links between IPF genetic risk and imaging-derived brain endophenotypes. We performed a brain-wide imaging-genetics association study between the presence of 17 known IPF risk variants and 1248 multi-modal imaging-derived features, which characterise brain structure and function. FINDINGS: We identified strong associations between cortical morphological features, white matter microstructure and IPF risk loci in chromosomes 17 (17q21.31) and 8 (DEPTOR). Through co-localisation analysis, we confirmed that cortical thickness in the anterior cingulate and more widespread white matter microstructure changes share a single causal variant with IPF at the chromosome 8 locus. Post-hoc preliminary analysis suggested that forced vital capacity may partially mediate the association between the DEPTOR variant and white matter microstructure, but not between the DEPTOR risk variant and cortical thickness. INTERPRETATION: Our results reveal the associations between IPF genetic risk and differences in brain structure, for both cortex and white matter. Differences in tissue-specific imaging signatures suggest distinct underlying mechanisms with focal cortical thinning in regions with known high DEPTOR expression, unrelated to lung function, and more widespread microstructural white matter changes consistent with hypoxia or neuroinflammation with potential mediation by lung function. FUNDING: This study was supported by the NIHR Nottingham Biomedical Research Centre and the UK Medical Research Council.

Concurrent mapping of brain ontogeny and phylogeny within a common space: Standardized tractography and applications.

Developmental and evolutionary effects on brain organization are complex, yet linked, as evidenced by the correspondence in cortical area expansion across these vastly different time scales. However, it is still not possible to study concurrently the ontogeny and phylogeny of cortical areal connections, which is arguably more relevant to brain function than allometric measurements. Here, we propose a novel framework that allows the integration of structural connectivity maps from humans (adults and neonates) and nonhuman primates (macaques) onto a common space. We use white matter bundles to anchor the common space and use the uniqueness of cortical connection patterns to these bundles to probe area specialization. This enabled us to quantitatively study divergences and similarities in connectivity over evolutionary and developmental scales, to reveal brain maturation trajectories, including the effect of premature birth, and to translate cortical atlases between diverse brains. Our findings open new avenues for an integrative approach to imaging neuroanatomy.

Predicting time-resolved electrophysiological brain networks from structural eigenmodes.

How temporal modulations in functional interactions are shaped by the underlying anatomical connections remains an open question. Here, we analyse the role of structural eigenmodes, in the formation and dissolution of temporally evolving functional brain networks using resting-state magnetoencephalography and diffusion magnetic resonance imaging data at the individual subject level. Our results show that even at short timescales, phase and amplitude connectivity can partly be expressed by structural eigenmodes, but hardly by direct structural connections. Albeit a stronger relationship was found between structural eigenmodes and time-resolved amplitude connectivity. Time-resolved connectivity for both phase and amplitude was mostly characterised by a stationary process, superimposed with very brief periods that showed deviations from this stationary process. For these brief periods, dynamic network states were extracted that showed different expressions of eigenmodes. Furthermore, the eigenmode expression was related to overall cognitive performance and co-occurred with fluctuations in community structure of functional networks. These results implicate that ongoing time-resolved resting-state networks, even at short timescales, can to some extent be understood in terms of activation and deactivation of structural eigenmodes and that these eigenmodes play a role in the dynamic integration and segregation of information across the cortex, subserving cognitive functions.

Right fronto-parietal networks mediate the neurocognitive benefits of enriched environments.

Exposure to enriched environments throughout a lifetime, providing so-called reserve, protects against cognitive decline in later years. It has been hypothesized that high levels of alertness necessitated by enriched environments might strengthen the right fronto-parietal networks to facilitate this neurocognitive resilience. We have previously shown that enriched environments offset age-related deficits in selective attention by preserving grey matter within right fronto-parietal regions. Here, using neurite orientation dispersion and density imaging, we examined the relationship between enriched environments, microstructural properties of fronto-parietal white matter association pathways (three branches of the superior longitudinal fasciculus), structural brain health (atrophy), and attention (alertness, orienting and executive control) in a group of older adults. We show that exposure to enriched environments is associated with a lower orientation dispersion index within the right superior longitudinal fasciculus 1 which in turn mediates the relationship between enriched environments and alertness, as well as grey and white matter atrophy. This suggests that enriched environments may induce white matter plasticity (and prevent age-related dispersion of axons) within the right fronto-parietal networks to facilitate the preservation of neurocognitive health in later years.

The association between inadequate sleep and accelerated brain ageing.

Numerous studies indicate large heterogeneity in brain ageing, which can be attributed to modifiable lifestyle factors, including sleep. Inadequate sleep has been previously linked to gray (GM) and white (WM) matter changes. However, the reported findings are highly inconsistent. By contrast to previous research independently characterizing patterns of either GM or WM changes, we used here linked independent component analysis (FLICA) to examine covariation in GM, and WM in a group of older adults (n = 50). Next, we employed a novel technique to estimate the brain age delta (difference between chronological and brain age assessed using neuroimaging data) and study its associations with sleep quality and sleep fragmentation, hypothesizing that inadequate sleep accelerates brain ageing. FLICA revealed a number of multimodal components, associated with age, sleep quality, and sleep fragmentation. Subsequently, we show significant associations between brain age delta and inadequate sleep, suggesting 2 years deviation above the chronological age. Our findings indicate sensitivity of multimodal approaches and brain age delta in detecting link between inadequate sleep and accelerated brain ageing.

Anticholinergic drugs and forebrain magnetic resonance imaging changes in cognitively normal people and those with mild cognitive impairment.

BACKGROUND AND PURPOSE: Anticholinergic (AC) medication use is associated with cognitive decline and dementia, which may be related to an AC-induced central hypocholinergic state, but the exact mechanisms remain to be understood. We aimed to further elucidate the putative link between AC drug prescription, cognition, and structural and functional impairment of the forebrain cholinergic nucleus basalis of Meynert (NBM). METHODS: Cognitively normal (CN; n = 344) and mildly cognitively impaired (MCI; n = 224) Alzheimer's Disease Neuroimaging Initiative Phase 3 participants with good quality 3-T magnetic resonance imaging were included. Structural (regional gray matter [GM] density) and functional NBM integrity (functional connectivity [FC]) were compared between those on AC medication for > 1 year (AC+ ) and those without (AC- ) in each condition. AC burden was classed as mild, moderate, or severe. RESULTS: MCI AC+ participants (0.55 ± 0.03) showed lower NBM GM density compared to MCI AC- participants (0.56 ± 0.03, p = 0.002), but there was no structural AC effect in CN. NBM FC was lower in CN AC+ versus CN AC- (3.6 ± 0.5 vs. 3.9 ± 0.6, p = 0.001), and in MCI AC+ versus MCI AC- (3.3 ± 0.2 vs. 3.7 ± 0.5, p < 0.001), with larger effect size in MCI. NBM FC partially mediated the association between AC medication burden and cognition. CONCLUSIONS: Our findings provide novel support for a detrimental effect of mild AC medication on the forebrain cholinergic system characterized as functional central hypocholinergic that partially mediated AC-related cognitive impairment. Moreover, structural tissue damage suggests neurodegeneration, and larger effect sizes in MCI point to enhanced susceptibility for AC medication in those at risk of dementia.

Long-Term Connectome Analysis Reveals Reshaping of Visual, Spatial Networks in a Model With Vascular Dementia Features.

BACKGROUND: Connectome analysis of neuroimaging data is a rapidly expanding field that offers the potential to diagnose, characterize, and predict neurological disease. Animal models provide insight into biological mechanisms that underpin disease, but connectivity approaches are currently lagging in the rodent. METHODS: We present a pipeline adapted for structural and functional connectivity analysis of the mouse brain, and we tested it in a mouse model of vascular dementia. RESULTS: We observed lacunar infarctions, microbleeds, and progressive white matter change across 6 months. For the first time, we report that default mode network activity is disrupted in the mouse model. We also identified specific functional circuitry that was vulnerable to vascular stress, including perturbations in a sensorimotor, visual resting state network that were accompanied by deficits in visual and spatial memory tasks. CONCLUSIONS: These findings advance our understanding of the mouse connectome and provide insight into how it can be altered by vascular insufficiency.

The Human Connectome Project: A retrospective.

The Human Connectome Project (HCP) was launched in 2010 as an ambitious effort to accelerate advances in human neuroimaging, particularly for measures of brain connectivity; apply these advances to study a large number of healthy young adults; and freely share the data and tools with the scientific community. NIH awarded grants to two consortia; this retrospective focuses on the "WU-Minn-Ox" HCP consortium centered at Washington University, the University of Minnesota, and University of Oxford. In just over 6 years, the WU-Minn-Ox consortium succeeded in its core objectives by: 1) improving MR scanner hardware, pulse sequence design, and image reconstruction methods, 2) acquiring and analyzing multimodal MRI and MEG data of unprecedented quality together with behavioral measures from more than 1100 HCP participants, and 3) freely sharing the data (via the ConnectomeDB database) and associated analysis and visualization tools. To date, more than 27 Petabytes of data have been shared, and 1538 papers acknowledging HCP data use have been published. The "HCP-style" neuroimaging paradigm has emerged as a set of best-practice strategies for optimizing data acquisition and analysis. This article reviews the history of the HCP, including comments on key events and decisions associated with major project components. We discuss several scientific advances using HCP data, including improved cortical parcellations, analyses of connectivity based on functional and diffusion MRI, and analyses of brain-behavior relationships. We also touch upon our efforts to develop and share a variety of associated data processing and analysis tools along with detailed documentation, tutorials, and an educational course to train the next generation of neuroimagers. We conclude with a look forward at opportunities and challenges facing the human neuroimaging field from the perspective of the HCP consortium.

Modelling white matter in gyral blades as a continuous vector field.

Many brain imaging studies aim to measure structural connectivity with diffusion tractography. However, biases in tractography data, particularly near the boundary between white matter and cortical grey matter can limit the accuracy of such studies. When seeding from the white matter, streamlines tend to travel parallel to the convoluted cortical surface, largely avoiding sulcal fundi and terminating preferentially on gyral crowns. When seeding from the cortical grey matter, streamlines generally run near the cortical surface until reaching deep white matter. These so-called "gyral biases" limit the accuracy and effective resolution of cortical structural connectivity profiles estimated by tractography algorithms, and they do not reflect the expected distributions of axonal densities seen in invasive tracer studies or stains of myelinated fibres. We propose an algorithm that concurrently models fibre density and orientation using a divergence-free vector field within gyral blades to encourage an anatomically-justified streamline density distribution along the cortical white/grey-matter boundary while maintaining alignment with the diffusion MRI estimated fibre orientations. Using in vivo data from the Human Connectome Project, we show that this algorithm reduces tractography biases. We compare the structural connectomes to functional connectomes from resting-state fMRI, showing that our model improves cross-modal agreement. Finally, we find that after parcellation the changes in the structural connectome are very minor with slightly improved interhemispheric connections (i.e, more homotopic connectivity) and slightly worse intrahemispheric connections when compared to tracers.

Automated Detection of Candidate Subjects With Cerebral Microbleeds Using Machine Learning.

Cerebral microbleeds (CMBs) appear as small, circular, well defined hypointense lesions of a few mm in size on T2*-weighted gradient recalled echo (T2*-GRE) images and appear enhanced on susceptibility weighted images (SWI). Due to their small size, contrast variations and other mimics (e.g., blood vessels), CMBs are highly challenging to detect automatically. In large datasets (e.g., the UK Biobank dataset), exhaustively labelling CMBs manually is difficult and time consuming. Hence it would be useful to preselect candidate CMB subjects in order to focus on those for manual labelling, which is essential for training and testing automated CMB detection tools on these datasets. In this work, we aim to detect CMB candidate subjects from a larger dataset, UK Biobank, using a machine learning-based, computationally light pipeline. For our evaluation, we used 3 different datasets, with different intensity characteristics, acquired with different scanners. They include the UK Biobank dataset and two clinical datasets with different pathological conditions. We developed and evaluated our pipelines on different types of images, consisting of SWI or GRE images. We also used the UK Biobank dataset to compare our approach with alternative CMB preselection methods using non-imaging factors and/or imaging data. Finally, we evaluated the pipeline's generalisability across datasets. Our method provided subject-level detection accuracy > 80% on all the datasets (within-dataset results), and showed good generalisability across datasets, providing a consistent accuracy of over 80%, even when evaluated across different modalities.

Uncertainty modelling in deep learning for safer neuroimage enhancement: Demonstration in diffusion MRI.

Deep learning (DL) has shown great potential in medical image enhancement problems, such as super-resolution or image synthesis. However, to date, most existing approaches are based on deterministic models, neglecting the presence of different sources of uncertainty in such problems. Here we introduce methods to characterise different components of uncertainty, and demonstrate the ideas using diffusion MRI super-resolution. Specifically, we propose to account for intrinsic uncertainty through a heteroscedastic noise model and for parameter uncertainty through approximate Bayesian inference, and integrate the two to quantify predictive uncertainty over the output image. Moreover, we introduce a method to propagate the predictive uncertainty on a multi-channelled image to derived scalar parameters, and separately quantify the effects of intrinsic and parameter uncertainty therein. The methods are evaluated for super-resolution of two different signal representations of diffusion MR images-Diffusion Tensor images and Mean Apparent Propagator MRI-and their derived quantities such as mean diffusivity and fractional anisotropy, on multiple datasets of both healthy and pathological human brains. Results highlight three key potential benefits of modelling uncertainty for improving the safety of DL-based image enhancement systems. Firstly, modelling uncertainty improves the predictive performance even when test data departs from training data ("out-of-distribution" datasets). Secondly, the predictive uncertainty highly correlates with reconstruction errors, and is therefore capable of detecting predictive "failures". Results on both healthy subjects and patients with brain glioma or multiple sclerosis demonstrate that such an uncertainty measure enables subject-specific and voxel-wise risk assessment of the super-resolved images that can be accounted for in subsequent analysis. Thirdly, we show that the method for decomposing predictive uncertainty into its independent sources provides high-level "explanations" for the model performance by separately quantifying how much uncertainty arises from the inherent difficulty of the task or the limited training examples. The introduced concepts of uncertainty modelling extend naturally to many other imaging modalities and data enhancement applications.

A data-driven approach to optimising the encoding for multi-shell diffusion MRI with application to neonatal imaging.

Diffusion MRI has the potential to provide important information about the connectivity and microstructure of the human brain during normal and abnormal development, noninvasively and in vivo. Recent developments in MRI hardware and reconstruction methods now permit the acquisition of large amounts of data within relatively short scan times. This makes it possible to acquire more informative multi-shell data, with diffusion sensitisation applied along many directions over multiple b-value shells. Such schemes are characterised by the number of shells acquired, and the specific b-value and number of directions sampled for each shell. However, there is currently no clear consensus as to how to optimise these parameters. In this work, we propose a means of optimising multi-shell acquisition schemes by estimating the information content of the diffusion MRI signal, and optimising the acquisition parameters for sensitivity to the observed effects, in a manner agnostic to any particular diffusion analysis method that might subsequently be applied to the data. This method was used to design the acquisition scheme for the neonatal diffusion MRI sequence used in the developing Human Connectome Project (dHCP), which aims to acquire high quality data and make it freely available to the research community. The final protocol selected by the algorithm, and currently in use within the dHCP, consists of 20 b=0 images and diffusion-weighted images at b = 400, 1000 and 2600 s/mm2 with 64, 88 and 128 directions per shell, respectively.