Davinia Fernández-Espejo

Background: Children and young people (CYP) with moderate/severe acquired brain injury (ABI) often have problems with chronic cognitive fatigue. Methylphenidate, a controlled drug, and cognitive behavioural therapy have been used to manage fatigue, but their effects are not fully established, and they are not widely available. Transcranial direct current stimulation (tDCS) is a non‐invasive brain stimulation technique that has shown promise for managing fatigue in adults with neurological conditions. However, no studies have used tDCS to manage fatigue in CYP with ABI nor have involved patients to co‐create the intervention or research protocol. Objective: To co‐create a trial protocol for a study examining the feasibility of using tDCS as an intervention to manage fatigue in CYP with ABI and provide proof‐of‐concept for its efficacy through patient public involvement and engagement (PPIE). Design: Our co‐creation approach encompassed three key stages: co‐define, co‐design, and co‐refine to actively bring stakeholders together. The co‐define phase consisted of discussing end‐users' experiences and needs related to fatigue. We then co‐designed an intervention protocol to address fatigue using tDCS. The final phase invited stakeholder feedback to co‐refine the tDCS intervention, ensuring it was acceptable and sustainable. Setting and Participants: Stakeholders ( n = 42) included CYP with ABI and their parents as well as members of an established young persons' advisory group. Stakeholders participated in in‐person, online and hybrid focus groups, 1:1 meetings, and surveys, over five stages. Results: We followed the Medical Research Council guidelines for intervention development and used design thinking approaches to co‐create the tDCS intervention. This process led to the development of a study protocol where tDCS is delivered at home rather than in the hospital and to monitor sessions remotely via an online platform. The treatment duration was extended to 4 weeks to maximise the likelihood of detecting beneficial effects. Stakeholder contribution also led to the inclusion of children with neurodiversity and to making the research more accessible for everyone. Discussion and Conclusions: PPIE members were involved in co‐defining the problem, co‐designing the intervention, determining treatment parameters, selecting efficacy outcome measures, identifying barriers to adherence, developing mitigating strategies, and co‐producing and reviewing the research study protocol. This ongoing stakeholder involvement shaped the co‐creation process, balancing idealistic approaches with feasible steps. Our protocol considered implementation barriers from the start and balanced scientific needs with patient and family priorities. The PPIE members will continue to be involved in conducting the study and designing qualitative work, reinforcing their ongoing engagement. Patient or Public Contribution: To develop this study protocol, the PPIE members were actively involved in defining the problem, creating the intervention, determining treatment parameters, selecting the relevant outcome measures, identifying barriers to adherence, developing mitigating strategies, reviewing the research study protocol and writing the manuscript.

Large multi-site, multi-vendor MRI studies offer opportunities to advance clinical practice and neuroscience research by increasing sample sizes, especially in clinical populations. However, variability between scanners or sites can affect the reproducibility of quantitative MRI metrics, which is vital for using MRI beyond visual inspection of structural images. This study aimed to assess the reproducibility of MRI metrics for the mild traumatic brain injury-Predict (mTBI-Predict) consortium, spanning Philips and Siemens scanners across three sites. We conducted a travelling head study (n=1), acquiring repeated measurements from a healthy participant across three sites. Evaluated metrics included cortical thickness and subcortical volume from T1-weighted images, fractional anisotropy (FA) and mean diffusivity (MD) from diffusion-weighted imaging (DWI), temporal signal-to-noise ratio (tSNR) from echo planar imaging, and cerebral blood flow (CBF) from arterial spin labelling (ASL). Image quality metrics (point spread function and motion) were also assessed across all DWI, functional magnetic resonance imaging (fMRI), and pseudo-continuous arterial spin labelling (pCASL) data. Standardised pipelines were used for preprocessing and analysis. Within-subject coefficients of variation (wCV%) and linear regressions assessed repeatability and consistency. Structural measures, including cortical thickness, subcortical volume, FA, and MD, demonstrated excellent reproducibility (wCV ≤5%, R² ≥0.85) within and between-sites. Minimal differences in participant motion were observed across sessions. However, as expected, tSNR and CBF showed greater variability than structural measures, due to their functional nature. Despite this, wCV% remained below 10% for all metrics, a threshold indicating very good agreement for biological measures. These findings align with previous work, demonstrating the feasibility of obtaining comparable MRI measurements across sites for studying brain structure and function. This study lays the groundwork for further evaluation of clinically relevant MRI biomarkers for mTBI.

While it is well accepted that the human brain shifts between internal and external monitoring both during tasks and at rest, no task‐switching studies have focused on brain changes when switching from and to self‐referential processing. Using a cued task‐switching design, we explored the preparatory fMRI activation associated with switching not only within externally oriented tasks, but also within self‐referential tasks, as well as between these two domains. We found that preparing to perform internal tasks activated the default mode network, while preparing for external tasks activated regions of the dorsal attention network (DAN). Switch preparation activated left‐lateralised DAN regions with ventrolateral peaks as well as dorsal precuneus, posterior cingulate and supplementary motor area. These results show a dynamic pattern of communication across networks associated with external and internal domain processing and common preparatory activation in working memory and executive control regions. In particular, the dorsal precuneus was consistently engaged in task‐switch preparation, suggesting a key role of this region in cognitive control, in the context of switching across external and internal domains.

There is unmet clinical need for biomarkers to predict recovery or the development of long-term sequelae of mild traumatic brain injury, a highly prevalent condition causing a constellation of disabling symptoms. A substantial proportion of patients live with long-lasting sequelae affecting their quality of life and ability to work. At present, symptoms can be assessed through clinical tests; however, there are no imaging or laboratory tests fully reflective of pathophysiology routinely used by clinicians to characterize post-concussive symptoms. Magnetic resonance imaging has potential to link subtle pathophysiological alterations to clinical outcomes. Here, we review the state of the art of MRI research in adults with mild traumatic brain injury and provide recommendations to facilitate transition into clinical practice. Studies utilizing MRI can inform on pathophysiology of mild traumatic brain injury. They suggest presence of early cytotoxic and vasogenic oedema. They also show that mild traumatic brain injury results in cellular injury and microbleeds affecting the integrity of myelin and white matter tracts, all processes that appear to induce delayed vascular reactions and functional changes. Crucially, correlates between MRI parameters and post-concussive symptoms are emerging. Clinical sequences such as T1-weighted MRI, susceptibility-weighted MRI or fluid attenuation inversion recovery could be easily implementable in clinical practice, but are not sufficient, in isolation for prognostication. Diffusion sequences have shown promises and, although in need of analysis standardization, are a research priority. Lastly, arterial spin labelling is emerging as a high-utility research as it could become useful to assess delayed neurovascular response and possible long-term symptoms.

Background: Therapeutic options for patients with prolonged disorder of consciousness (PDOC) are limited. PDOC patients often exhibit a dissociation between their retained level of (covert) cognitive ability and their (overt) behavioural responses (cognitive-motor dissociation; CMD). This is linked to reduced coupling between thalamus and the primary motor cortex. Objective: To assess whether pairing tDCS with a concurrent passive mobilisation protocol (designed to be feasible in PDOC) can influence thalamo-M1 dynamics and whether these changes are enhanced after multiple stimulation sessions. Methods: We used Dynamic Causal Modelling (DCM) on functional magnetic resonance imaging (fMRI) data from 22 healthy participants to assess tDCS changes on effective connectivity within motor network areas during command-following. Results: We found that a single anodal tDCS session (paired with passive mobilisation of the thumb) decreased self-inhibition in the motor cortex, with five sessions further enhancing this effect. In addition, anodal tDCS increased thalamo-M1 excitation as compared to cathodal stimulation, with the effects maintained after 5 sessions. In turn, cathodal tDCS had opposing effects on these connections after one session but became more similar to anodal after 5. Conclusions: Together, our results suggest that pairing anodal tDCS with passive mobilisation across multiple sessions may facilitate behavioural command-following in PDOC patients with CMD. More broadly, they offer a mechanistic window into the neural underpinnings of the cumulative effects of multi-session tDCS.

Objective: Little is known about residual cognitive function in the earliest stages of serious brain injury. Functional neuroimaging has yielded valuable diagnostic and prognostic information in chronic disorders of consciousness, such as the vegetative state (also termed unresponsive wakefulness syndrome). The objective of the current study was to determine if functional neuroimaging could be efficacious in the assessment of cognitive function in acute disorders of consciousness, such as coma, where decisions about the withdrawal of life‐sustaining therapies are often made.Methods: A hierarchical functional magnetic resonance imaging (fMRI) approach assessed sound perception, speech perception, language comprehension, and covert command following in 17 critically ill patients admitted to the intensive care unit (ICU).Results: Preserved auditory function was observed in 15 patients (88%), whereas 5 (29%) also had preserved higher‐order language comprehension. Notably, one patient could willfully modulate his brain activity when instructed to do so, suggesting a level of covert conscious awareness that was entirely inconsistent with his clinical diagnosis at the time of the scan. Across patients, a positive relationship was also observed between fMRI responsivity and the level of functional recovery, such that patients with the greatest functional recovery had neural responses most similar to those observed in healthy control participants.Interpretation: These results suggest that fMRI may provide important diagnostic and prognostic information beyond standard clinical assessment in acutely unresponsive patients, which may aid discussions surrounding the continuation or removal of life‐sustaining therapies during the early post‐injury period. ANN NEUROL 2023;93:131–141

There is conflicting evidence over the ability to modulate mind-wandering propensity with anodal transcranial direct current stimulation (tDCS) over the left dorsolateral prefrontal cortex (prefrontal tDCS). Here, 20 participants received 20-min of active and sham prefrontal tDCS while in the MRI scanner, in two separate sessions (counterbalanced). In each session, they completed two runs of a sustained attention to response task (before and during tDCS), which included probes recording subjective responses of mind-wandering. We assessed the effects of tDCS on behavioural responses as well as functional and effective dynamics, via dynamic functional network connectivity (dFNC) and dynamic causal modelling analyses over regions of the default mode, salience and executive control networks. Behavioural results provided substantial evidence in support of no effect of tDCS on task performance nor mind-wandering propensity. Similarly, we found no effect of tDCS on frequency (how often) or dwell time (time spent) of underlying brain states nor effective connectivity. Overall, our results suggest that prefrontal tDCS is unable to modulate mind-wandering propensity or influence underlying brain function. This expands previous behavioural replication failures in suggesting that prefrontal tDCS may not lead to even subtle (i.e., under a behavioural threshold) changes in brain activity during self-generated cognition.

The exact mechanisms behind the effects of transcranial direct current stimulation (tDCS) at a network level are still poorly understood, with most studies to date focusing on local (cortical) effects and changes in motor-evoked potentials or BOLD signal. Here, we explored stationary and dynamic effective connectivity across the motor network at rest in two experiments where we applied tDCS over the primary motor cortex (M1-tDCS) or the cerebellum (cb-tDCS) respectively. Two cohorts of healthy volunteers (n = 21 and n = 22) received anodal, cathodal, and sham tDCS sessions (counterbalanced) during 20 minutes of resting-state functional magnetic resonance imaging (fMRI). We used spectral Dynamic Causal Modelling (DCM) and hierarchical Parametrical Empirical Bayes (PEB) to analyse data after (compared to a pre-tDCS baseline) and during stimulation. We also implemented a novel dynamic (sliding windows) DCM/PEB approach to model the nature of network reorganisation across time. In both experiments we found widespread effects of tDCS that extended beyond the targeted area and modulated effective connectivity between cortex, thalamus, and cerebellum. These changes were characterised by unique nonlinear temporal fingerprints across connections and polarities. Our results challenged the classic notion of anodal and cathodal tDCS as excitatory and inhibitory respectively, as well as the idea of a cumulative effect of tDCS over time. Instead, they described a rich set of changes with specific spatial and temporal patterns. Our work provides a starting point for advancing our understanding of network-level tDCS effects and optimise its cognitive and clinical applications.