Neuroinflammation in the normal-appearing white matter (NAWM) of the multiple sclerosis brain causes abnormalities at the nodes of Ranvier.

Changes to the structure of nodes of Ranvier in the normal-appearing white matter (NAWM) of multiple sclerosis (MS) brains are associated with chronic inflammation. We show that the paranodal domains in MS NAWM are longer on average than control, with Kv1.2 channels dislocated into the paranode. These pathological features are reproduced in a model of chronic meningeal inflammation generated by the injection of lentiviral vectors for the lymphotoxin-α (LTα) and interferon-γ (IFNγ) genes. We show that tumour necrosis factor (TNF), IFNγ, and glutamate can provoke paranodal elongation in cerebellar slice cultures, which could be reversed by an N-methyl-D-aspartate (NMDA) receptor blocker. When these changes were inserted into a computational model to simulate axonal conduction, a rapid decrease in velocity was observed, reaching conduction failure in small diameter axons. We suggest that glial cells activated by pro-inflammatory cytokines can produce high levels of glutamate, which triggers paranodal pathology, contributing to axonal damage and conduction deficits.

Accuracy and Acceptability of Wearable Motion Tracking for Inpatient Monitoring Using Smartwatches.

Inertial Measurement Units (IMUs) within an everyday consumer smartwatch offer a convenient and low-cost method to monitor the natural behaviour of hospital patients. However, their accuracy at quantifying limb motion, and clinical acceptability, have not yet been demonstrated. To this end we conducted a two-stage study: First, we compared the inertial accuracy of wrist-worn IMUs, both research-grade (Xsens MTw Awinda, and Axivity AX3) and consumer-grade (Apple Watch Series 3 and 5), and optical motion tracking (OptiTrack). Given the moderate to strong performance of the consumer-grade sensors, we then evaluated this sensor and surveyed the experiences and attitudes of hospital patients (N = 44) and staff (N = 15) following a clinical test in which patients wore smartwatches for 1.5-24 h in the second study. Results indicate that for acceleration, Xsens is more accurate than the Apple Series 5 and 3 smartwatches and Axivity AX3 (RMSE 1.66 ± 0.12 m·s-2; R2 0.78 ± 0.02; RMSE 2.29 ± 0.09 m·s-2; R2 0.56 ± 0.01; RMSE 2.14 ± 0.09 m·s-2; R2 0.49 ± 0.02; RMSE 4.12 ± 0.18 m·s-2; R2 0.34 ± 0.01 respectively). For angular velocity, Series 5 and 3 smartwatches achieved similar performances against Xsens with RMSE 0.22 ± 0.02 rad·s-1; R2 0.99 ± 0.00; and RMSE 0.18 ± 0.01 rad·s-1; R2 1.00± SE 0.00, respectively. Surveys indicated that in-patients and healthcare professionals strongly agreed that wearable motion sensors are easy to use, comfortable, unobtrusive, suitable for long-term use, and do not cause anxiety or limit daily activities. Our results suggest that consumer smartwatches achieved moderate to strong levels of accuracy compared to laboratory gold-standard and are acceptable for pervasive monitoring of motion/behaviour within hospital settings.

Axonal noise as a source of synaptic variability.

Post-synaptic potential (PSP) variability is typically attributed to mechanisms inside synapses, yet recent advances in experimental methods and biophysical understanding have led us to reconsider the role of axons as highly reliable transmission channels. We show that in many thin axons of our brain, the action potential (AP) waveform and thus the Ca++ signal controlling vesicle release at synapses will be significantly affected by the inherent variability of ion channel gating. We investigate how and to what extent fluctuations in the AP waveform explain observed PSP variability. Using both biophysical theory and stochastic simulations of central and peripheral nervous system axons from vertebrates and invertebrates, we show that channel noise in thin axons (<1 µm diameter) causes random fluctuations in AP waveforms. AP height and width, both experimentally characterised parameters of post-synaptic response amplitude, vary e.g. by up to 20 mV and 0.5 ms while a single AP propagates in C-fibre axons. We show how AP height and width variabilities increase with a ¾ power-law as diameter decreases and translate these fluctuations into post-synaptic response variability using biophysical data and models of synaptic transmission. We find for example that for mammalian unmyelinated axons with 0.2 µm diameter (matching cerebellar parallel fibres) axonal noise alone can explain half of the PSP variability in cerebellar synapses. We conclude that axonal variability may have considerable impact on synaptic response variability. Thus, in many experimental frameworks investigating synaptic transmission through paired-cell recordings or extracellular stimulation of presynaptic neurons, causes of variability may have been confounded. We thereby show how bottom-up aggregation of molecular noise sources contributes to our understanding of variability observed at higher levels of biological organisation.

Can Machine Learning Personalize Cardiovascular Therapy in Sepsis?

Large randomized trials in sepsis have generally failed to find effective novel treatments. This is increasingly attributed to patient heterogeneity, including heterogeneous cardiovascular changes in septic shock. We discuss the potential for machine learning systems to personalize cardiovascular resuscitation in sepsis. While the literature is replete with proofs of concept, the technological readiness of current systems is low, with a paucity of clinical trials and proven patient benefit. Systems may be vulnerable to confounding and poor generalization to new patient populations or contemporary patterns of care. Typical electronic health records do not capture rich enough data, at sufficient temporal resolution, to produce systems that make actionable treatment suggestions. To resolve these issues, we recommend a simultaneous focus on technical challenges and removing barriers to translation. This will involve improving data quality, adopting causally grounded models, prioritizing safety assessment and integration into healthcare workflows, conducting randomized clinical trials and aligning with regulatory requirements.

Noise in the nervous system.

Noise--random disturbances of signals--poses a fundamental problem for information processing and affects all aspects of nervous-system function. However, the nature, amount and impact of noise in the nervous system have only recently been addressed in a quantitative manner. Experimental and computational methods have shown that multiple noise sources contribute to cellular and behavioural trial-to-trial variability. We review the sources of noise in the nervous system, from the molecular to the behavioural level, and show how noise contributes to trial-to-trial variability. We highlight how noise affects neuronal networks and the principles the nervous system applies to counter detrimental effects of noise, and briefly discuss noise's potential benefits.

Towards AI-Controlled Movement Restoration: Learning FES-Cycling Stimulation with Reinforcement Learning.

Functional electrical stimulation (FES) has been increasingly integrated with other rehabilitation devices, including rehabilitation robots. FES cycling is one of the common FES applications in rehabilitation, which is performed by stimulating leg muscles in a certain pattern. The appropriate pattern varies across individuals and requires manual tuning which can be time-consuming and challenging for the individual user. Here, we present an AI-based method for finding the patterns, which requires no extra hardware or sensors. Our method starts with finding model-based patterns using reinforcement learning (RL) and customised cycling models. Next, our method fine-tunes the pattern using real cycling data and offline RL. We test our method both in simulation and experimentally on a stationary tricycle. Our method can robustly deliver model-based patterns for different cycling configurations. In the experimental evaluation, the model-based pattern can induce higher cycling speed than an EMG-based pattern. And by using just 100 seconds of cycling data, our method can deliver a fine-tuned pattern with better cycling performance. Beyond FES cycling, this work is a case study, displaying the feasibility and potential of human-in-the-loop AI in real-world rehabilitation.

Bill-EVR: An Embodied Virtual Reality Framework for Reward-and-Error-Based Motor Rehab-Learning.

VR rehabilitation is an established field by now, however, it often refers to computer screen-based interactive rehabilitation activities. In recent years, there was an increased use of VR-headsets, which can provide an immersive virtual environment for real-world tasks, but they are lacking any physical interaction with the task objects and any proprioceptive feedback. Here, we focus on Embodied Virtual Reality (EVR), an emerging field where not only the visual input via VR-headset but also the haptic feedback is physically correct. This happens because subjects interact with physical objects that are veridically aligned in Virtual Reality. This technology lets us manipulate motor performance and motor learning through visual feedback perturbations. Bill-EVR is a framework that allows interventions in the performance of real-world tasks, such as playing pool billiard, engaging end-users in motivating life-like situations to trigger motor (re)learning - subjects see in VR and handle the real-world cue stick, the pool table and shoot physical balls. Specifically, we developed our platform to isolate and evaluate different mechanisms of motor learning to investigate its two main components, error-based and reward-based motor adaptation. This understanding can provide insights for improvements in neurorehabilitation: indeed, reward-based mechanisms are putatively impaired by degradation of the dopaminergic system, such as in Parkinson's disease, while error-based mechanisms are essential for recovering from stroke-induced movement errors. Due to its fully customisable features, our EVR framework can be used to facilitate the improvement of several conditions, providing a valid extension of VR-based implementations and constituting a motor learning tool that can be completely tailored to the individual needs of patients.

EEG decoding for datasets with heterogenous electrode configurations using transfer learning graph neural networks.

Objective. Brain-machine interfacing (BMI) has greatly benefited from adopting machine learning methods for feature learning that require extensive data for training, which are often unavailable from a single dataset. Yet, it is difficult to combine data across labs or even data within the same lab collected over the years due to the variation in recording equipment and electrode layouts resulting in shifts in data distribution, changes in data dimensionality, and altered identity of data dimensions. Our objective is to overcome this limitation and learn from many different and diverse datasets across labs with different experimental protocols.Approach. To tackle the domain adaptation problem, we developed a novel machine learning framework combining graph neural networks (GNNs) and transfer learning methodologies for non-invasive motor imagery (MI) EEG decoding, as an example of BMI. Empirically, we focus on the challenges of learning from EEG data with different electrode layouts and varying numbers of electrodes. We utilize three MI EEG databases collected using very different numbers of EEG sensors (from 22 channels to 64) and layouts (from custom layouts to 10-20).Main results. Our model achieved the highest accuracy with lower standard deviations on the testing datasets. This indicates that the GNN-based transfer learning framework can effectively aggregate knowledge from multiple datasets with different electrode layouts, leading to improved generalization in subject-independent MI EEG classification.Significance. The findings of this study have important implications for brain-computer-interface research, as they highlight a promising method for overcoming the limitations posed by non-unified experimental setups. By enabling the integration of diverse datasets with varying electrode layouts, our proposed approach can help advance the development and application of BMI technologies.

Wearable full-body motion tracking of activities of daily living predicts disease trajectory in Duchenne muscular dystrophy.

Artificial intelligence has the potential to revolutionize healthcare, yet clinical trials in neurological diseases continue to rely on subjective, semiquantitative and motivation-dependent endpoints for drug development. To overcome this limitation, we collected a digital readout of whole-body movement behavior of patients with Duchenne muscular dystrophy (DMD) (n = 21) and age-matched controls (n = 17). Movement behavior was assessed while the participant engaged in everyday activities using a 17-sensor bodysuit during three clinical visits over the course of 12 months. We first defined new movement behavioral fingerprints capable of distinguishing DMD from controls. Then, we used machine learning algorithms that combined the behavioral fingerprints to make cross-sectional and longitudinal disease course predictions, which outperformed predictions derived from currently used clinical assessments. Finally, using Bayesian optimization, we constructed a behavioral biomarker, termed the KineDMD ethomic biomarker, which is derived from daily-life behavioral data and whose value progresses with age in an S-shaped sigmoid curve form. The biomarker developed in this study, derived from digital readouts of daily-life movement behavior, can predict disease progression in patients with muscular dystrophy and can potentially track the response to therapy.

A wearable motion capture suit and machine learning predict disease progression in Friedreich's ataxia.

Friedreich's ataxia (FA) is caused by a variant of the Frataxin (FXN) gene, leading to its downregulation and progressively impaired cardiac and neurological function. Current gold-standard clinical scales use simplistic behavioral assessments, which require 18- to 24-month-long trials to determine if therapies are beneficial. Here we captured full-body movement kinematics from patients with wearable sensors, enabling us to define digital behavioral features based on the data from nine FA patients (six females and three males) and nine age- and sex-matched controls, who performed the 8-m walk (8-MW) test and 9-hole peg test (9 HPT). We used machine learning to combine these features to longitudinally predict the clinical scores of the FA patients, and compared these with two standard clinical assessments, Spinocerebellar Ataxia Functional Index (SCAFI) and Scale for the Assessment and Rating of Ataxia (SARA). The digital behavioral features enabled longitudinal predictions of personal SARA and SCAFI scores 9 months into the future and were 1.7 and 4 times more precise than longitudinal predictions using only SARA and SCAFI scores, respectively. Unlike the two clinical scales, the digital behavioral features accurately predicted FXN gene expression levels for each FA patient in a cross-sectional manner. Our work demonstrates how data-derived wearable biomarkers can track personal disease trajectories and indicates the potential of such biomarkers for substantially reducing the duration or size of clinical trials testing disease-modifying therapies and for enabling behavioral transcriptomics.

Mindcraft, a Mobile Mental Health Monitoring Platform for Children and Young People: Development and Acceptability Pilot Study.

BACKGROUND: Children and young people's mental health is a growing public health concern, which is further exacerbated by the COVID-19 pandemic. Mobile health apps, particularly those using passive smartphone sensor data, present an opportunity to address this issue and support mental well-being. OBJECTIVE: This study aimed to develop and evaluate a mobile mental health platform for children and young people, Mindcraft, which integrates passive sensor data monitoring with active self-reported updates through an engaging user interface to monitor their well-being. METHODS: A user-centered design approach was used to develop Mindcraft, incorporating feedback from potential users. User acceptance testing was conducted with a group of 8 young people aged 15-17 years, followed by a pilot test with 39 secondary school students aged 14-18 years, which was conducted for a 2-week period. RESULTS: Mindcraft showed encouraging user engagement and retention. Users reported that they found the app to be a friendly tool helping them to increase their emotional awareness and gain a better understanding of themselves. Over 90% of users (36/39, 92.5%) answered all active data questions on the days they used the app. Passive data collection facilitated the gathering of a broader range of well-being metrics over time, with minimal user intervention. CONCLUSIONS: The Mindcraft app has shown promising results in monitoring mental health symptoms and promoting user engagement among children and young people during its development and initial testing. The app's user-centered design, the focus on privacy and transparency, and a combination of active and passive data collection strategies have all contributed to its efficacy and receptiveness among the target demographic. By continuing to refine and expand the app, the Mindcraft platform has the potential to contribute meaningfully to the field of mental health care for young people.

Assuring the safety of AI-based clinical decision support systems: a case study of the AI Clinician for sepsis treatment.

OBJECTIVES: Establishing confidence in the safety of Artificial Intelligence (AI)-based clinical decision support systems is important prior to clinical deployment and regulatory approval for systems with increasing autonomy. Here, we undertook safety assurance of the AI Clinician, a previously published reinforcement learning-based treatment recommendation system for sepsis. METHODS: As part of the safety assurance, we defined four clinical hazards in sepsis resuscitation based on clinical expert opinion and the existing literature. We then identified a set of unsafe scenarios, intended to limit the action space of the AI agent with the goal of reducing the likelihood of hazardous decisions. RESULTS: Using a subset of the Medical Information Mart for Intensive Care (MIMIC-III) database, we demonstrated that our previously published 'AI clinician' recommended fewer hazardous decisions than human clinicians in three out of our four predefined clinical scenarios, while the difference was not statistically significant in the fourth scenario. Then, we modified the reward function to satisfy our safety constraints and trained a new AI Clinician agent. The retrained model shows enhanced safety, without negatively impacting model performance. DISCUSSION: While some contextual patient information absent from the data may have pushed human clinicians to take hazardous actions, the data were curated to limit the impact of this confounder. CONCLUSION: These advances provide a use case for the systematic safety assurance of AI-based clinical systems towards the generation of explicit safety evidence, which could be replicated for other AI applications or other clinical contexts, and inform medical device regulatory bodies.

Variation in global COVID-19 symptoms by geography and by chronic disease: A global survey using the COVID-19 Symptom Mapper.

Background: COVID-19 is typically characterised by a triad of symptoms: cough, fever and loss of taste and smell, however, this varies globally. This study examines variations in COVID-19 symptom profiles based on underlying chronic disease and geographical location. Methods: Using a global online symptom survey of 78,299 responders in 190 countries between 09/04/2020 and 22/09/2020, we conducted an exploratory study to examine symptom profiles associated with a positive COVID-19 test result by country and underlying chronic disease (single, co- or multi-morbidities) using statistical and machine learning methods. Findings: From the results of 7980 COVID-19 tested positive responders, we find that symptom patterns differ by country. For example, India reported a lower proportion of headache (22.8% vs 47.8%, p<1e-13) and itchy eyes (7.3% vs. 16.5%, p=2e-8) than other countries. As with geographic location, we find people differed in their reported symptoms if they suffered from specific chronic diseases. For example, COVID-19 positive responders with asthma (25.3% vs. 13.7%, p=7e-6) were more likely to report shortness of breath compared to those with no underlying chronic disease. Interpretation: We have identified variation in COVID-19 symptom profiles depending on geographic location and underlying chronic disease. Failure to reflect this symptom variation in public health messaging may contribute to asymptomatic COVID-19 spread and put patients with chronic diseases at a greater risk of infection. Future work should focus on symptom profile variation in the emerging variants of the SARS-CoV-2 virus. This is crucial to speed up clinical diagnosis, predict prognostic outcomes and target treatment. Funding: We acknowledge funding to AAF by a UKRI Turing AI Fellowship and to CEC by a personal NIHR Career Development Fellowship (grant number NIHR-2016-090-015). JKQ has received grants from The Health Foundation, MRC, GSK, Bayer, BI, Asthma UK-British Lung Foundation, IQVIA, Chiesi AZ, and Insmed. This work is supported by BREATHE - The Health Data Research Hub for Respiratory Health [MC_PC_19004]. BREATHE is funded through the UK Research and Innovation Industrial Strategy Challenge Fund and delivered through Health Data Research UK. Imperial College London is grateful for the support from the Northwest London NIHR Applied Research Collaboration. The views expressed in this publication are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.

Movement-specific signaling is differentially distributed across motor cortex layer 5 projection neuron classes.

Motor cortex generates descending output necessary for executing a wide range of limb movements. Although movement-related activity has been described throughout motor cortex, the spatiotemporal organization of movement-specific signaling in deep layers remains largely unknown. Here we record layer 5B population dynamics in the caudal forelimb area of motor cortex while mice perform a forelimb push/pull task and find that most neurons show movement-invariant responses, with a minority displaying movement specificity. Using cell-type-specific imaging, we identify that invariant responses dominate pyramidal tract (PT) neuron activity, with a small subpopulation representing movement type, whereas a larger proportion of intratelencephalic (IT) neurons display movement-type-specific signaling. The proportion of IT neurons decoding movement-type peaks prior to movement initiation, whereas for PT neurons, this occurs during movement execution. Our data suggest that layer 5B population dynamics largely reflect movement-invariant signaling, with information related to movement-type being routed through relatively small, distributed subpopulations of projection neurons.

Deep learning multimodal fNIRS and EEG signals for bimanual grip force decoding.

Objective.Non-invasive brain-machine interfaces (BMIs) offer an alternative, safe and accessible way to interact with the environment. To enable meaningful and stable physical interactions, BMIs need to decode forces. Although previously addressed in the unimanual case, controlling forces from both hands would enable BMI-users to perform a greater range of interactions. We here investigate the decoding of hand-specific forces.Approach.We maximise cortical information by using electroencephalography (EEG) and functional near-infrared spectroscopy (fNIRS) and developing a deep-learning architecture with attention and residual layers (cnnatt) to improve their fusion. Our task required participants to generate hand-specific force profiles on which we trained and tested our deep-learning and linear decoders.Main results.The use of EEG and fNIRS improved the decoding of bimanual force and the deep-learning models outperformed the linear model. In both cases, the greatest gain in performance was due to the detection of force generation. In particular, the detection of forces was hand-specific and better for the right dominant hand andcnnattwas better at fusing EEG and fNIRS. Consequently, the study ofcnnattrevealed that forces from each hand were differently encoded at the cortical level.Cnnattalso revealed traces of the cortical activity being modulated by the level of force which was not previously found using linear models.Significance.Our results can be applied to avoid hand-cross talk during hand force decoding to improve the robustness of BMI robotic devices. In particular, we improve the fusion of EEG and fNIRS signals and offer hand-specific interpretability of the encoded forces which are valuable during motor rehabilitation assessment.

Embodied virtual reality for the study of real-world motor learning.

Motor-learning literature focuses on simple laboratory-tasks due to their controlled manner and the ease to apply manipulations to induce learning and adaptation. Recently, we introduced a billiards paradigm and demonstrated the feasibility of real-world-neuroscience using wearables for naturalistic full-body motion-tracking and mobile-brain-imaging. Here we developed an embodied virtual-reality (VR) environment to our real-world billiards paradigm, which allows to control the visual feedback for this complex real-world task, while maintaining sense of embodiment. The setup was validated by comparing real-world ball trajectories with the trajectories of the virtual balls, calculated by the physics engine. We then ran our short-term motor learning protocol in the embodied VR. Subjects played billiard shots when they held the physical cue and hit a physical ball on the table while seeing it all in VR. We found comparable short-term motor learning trends in the embodied VR to those we previously reported in the physical real-world task. Embodied VR can be used for learning real-world tasks in a highly controlled environment which enables applying visual manipulations, common in laboratory-tasks and rehabilitation, to a real-world full-body task. Embodied VR enables to manipulate feedback and apply perturbations to isolate and assess interactions between specific motor-learning components, thus enabling addressing the current questions of motor-learning in real-world tasks. Such a setup can potentially be used for rehabilitation, where VR is gaining popularity but the transfer to the real-world is currently limited, presumably, due to the lack of embodiment.

The measurement, evolution, and neural representation of action grammars of human behavior.

Human behaviors from toolmaking to language are thought to rely on a uniquely evolved capacity for hierarchical action sequencing. Testing this idea will require objective, generalizable methods for measuring the structural complexity of real-world behavior. Here we present a data-driven approach for extracting action grammars from basic ethograms, exemplified with respect to the evolutionarily relevant behavior of stone toolmaking. We analyzed sequences from the experimental replication of ~ 2.5 Mya Oldowan vs. ~ 0.5 Mya Acheulean tools, finding that, while using the same "alphabet" of elementary actions, Acheulean sequences are quantifiably more complex and Oldowan grammars are a subset of Acheulean grammars. We illustrate the utility of our complexity measures by re-analyzing data from an fMRI study of stone toolmaking to identify brain responses to structural complexity. Beyond specific implications regarding the co-evolution of language and technology, this exercise illustrates the general applicability of our method to investigate naturalistic human behavior and cognition.

Playing the piano with a robotic third thumb: assessing constraints of human augmentation.

Contemporary robotics gives us mechatronic capabilities for augmenting human bodies with extra limbs. However, how our motor control capabilities pose limits on such augmentation is an open question. We developed a Supernumerary Robotic 3rd Thumbs (SR3T) with two degrees-of-freedom controlled by the user's body to endow them with an extra contralateral thumb on the hand. We demonstrate that a pianist can learn to play the piano with 11 fingers within an hour. We then evaluate 6 naïve and 6 experienced piano players in their prior motor coordination and their capability in piano playing with the robotic augmentation. We show that individuals' augmented performance with the SR3T could be explained by our new custom motor coordination assessment, the Human Augmentation Motor Coordination Assessment (HAMCA) performed pre-augmentation. Our work demonstrates how supernumerary robotics can augment humans in skilled tasks and that individual differences in their augmentation capability are explainable by their individual motor coordination abilities.

Early life experience sets hard limits on motor learning as evidenced from artificial arm use.

The study of artificial arms provides a unique opportunity to address long-standing questions on sensorimotor plasticity and development. Learning to use an artificial arm arguably depends on fundamental building blocks of body representation and would therefore be impacted by early life experience. We tested artificial arm motor-control in two adult populations with upper-limb deficiencies: a congenital group-individuals who were born with a partial arm, and an acquired group-who lost their arm following amputation in adulthood. Brain plasticity research teaches us that the earlier we train to acquire new skills (or use a new technology) the better we benefit from this practice as adults. Instead, we found that although the congenital group started using an artificial arm as toddlers, they produced increased error noise and directional errors when reaching to visual targets, relative to the acquired group who performed similarly to controls. However, the earlier an individual with a congenital limb difference was fitted with an artificial arm, the better their motor control was. Since we found no group differences when reaching without visual feedback, we suggest that the ability to perform efficient visual-based corrective movements is highly dependent on either biological or artificial arm experience at a very young age. Subsequently, opportunities for sensorimotor plasticity become more limited.

Dissociable effects of age and Parkinson's disease on instruction-based learning.

The cognitive deficits associated with Parkinson's disease vary across individuals and change across time, with implications for prognosis and treatment. Key outstanding challenges are to define the distinct behavioural characteristics of this disorder and develop diagnostic paradigms that can assess these sensitively in individuals. In a previous study, we measured different aspects of attentional control in Parkinson's disease using an established fMRI switching paradigm. We observed no deficits for the aspects of attention the task was designed to examine; instead those with Parkinson's disease learnt the operational requirements of the task more slowly. We hypothesized that a subset of people with early-to-mid stage Parkinson's might be impaired when encoding rules for performing new tasks. Here, we directly test this hypothesis and investigate whether deficits in instruction-based learning represent a characteristic of Parkinson's Disease. Seventeen participants with Parkinson's disease (8 male; mean age: 61.2 years), 18 older adults (8 male; mean age: 61.3 years) and 20 younger adults (10 males; mean age: 26.7 years) undertook a simple instruction-based learning paradigm in the MRI scanner. They sorted sequences of coloured shapes according to binary discrimination rules that were updated at two-minute intervals. Unlike common reinforcement learning tasks, the rules were unambiguous, being explicitly presented; consequently, there was no requirement to monitor feedback or estimate contingencies. Despite its simplicity, a third of the Parkinson's group, but only one older adult, showed marked increases in errors, 4 SD greater than the worst performing young adult. The pattern of errors was consistent, reflecting a tendency to misbind discrimination rules. The misbinding behaviour was coupled with reduced frontal, parietal and anterior caudate activity when rules were being encoded, but not when attention was initially oriented to the instruction slides or when discrimination trials were performed. Concomitantly, Magnetic Resonance Spectroscopy showed reduced gamma-Aminobutyric acid levels within the mid-dorsolateral prefrontal cortices of individuals who made misbinding errors. These results demonstrate, for the first time, that a subset of early-to-mid stage people with Parkinson's show substantial deficits when binding new task rules in working memory. Given the ubiquity of instruction-based learning, these deficits are likely to impede daily living. They will also confound clinical assessment of other cognitive processes. Future work should determine the value of instruction-based learning as a sensitive early marker of cognitive decline and as a measure of responsiveness to therapy in Parkinson's disease.