OBJECTIVE:This study investigated neurophysiological and behavioural adaptations in reward learning and decision making which may contribute to the development and persistence of alcohol use disorder. METHODS:20 abstinent alcohol dependent participants (mean abstinence: 20 months, range 1-76) and 26 healthy controls completed an electroencephalography (EEG) probabilistic reversal learning paradigm. Reinforcement learning modelling, event-related potentials (ERPs), and unsupervised machine learning (tensor decomposition) were used to characterise spatiotemporal patterns of reward valuation. RESULTS:Behavioural performance and learning were comparable between groups. In alcohol dependent compared to healthy control participants, feedback related negativity was reduced for positive and negative outcomes. No group differences were observed in the feedback P3; however, substantial variability was present within the alcohol dependent group, with longer abstinence associated with decreased P3. Tensor decomposition revealed early centro-frontal hyperactivity linked to alcohol dependence and associated with early abstinence. CONCLUSIONS:Findings suggest altered neural processing of reward learning in alcohol dependence, with indications of neurophysiological adaptation over prolonged abstinence. Data-driven tensor decomposition identified clinically meaningful EEG markers of reward valuation. SIGNIFICANCE:We provide mechanistic insights into neural adaptations associated with abstinence and present proof-of-concept EEG-based markers of alcohol dependence that merit further longitudinal evaluation.

Maladaptive reward learning and decision-making circuity are key factors in the onset and progression of alcohol use disorder and have therefore emerged as key targets for neuropsychological and pharmacological interventions. Probabilistic reversal learning studies have consistently reported impaired learning in recently detoxified alcohol dependent (AD) participants. However, the neural and behavioural changes associated with reward learning which occur throughout abstinence remain unexplored. Here, we show that AD participants, with mean abstinence of 20 months, exhibit intact behavioural performance within an electroencephalography (EEG) probabilistic reversal learning task. Reinforcement learning modelling reveals reward and punishment related learning rates and exploration rates are comparable between AD and healthy control (HC) participants, suggesting recovery of even the nuanced aspects of learning in longer term abstinence. However, EEG analysis indicates that AD, compared to HC participants, show globally elevated event-related potential (ERP) feedback related negativity (FRN) following reward valuation. Furthermore, Feedback-P3 valence prediction error signal is negatively associated with abstinence duration indicating a potential state marker of AD recovery. We then employ unsupervised machine learning (canonical polyadic tensor decomposition) to identify spatiotemporal EEG patterns of reward valuation in a purely data-driven manner. Classification analysis shows these tensor components can predict group membership with 80.4% accuracy. By probing group differences in tensor components, we discover early hyperfunctioning in centro-frontal regions linked to alcohol dependence and associated with early abstinence. The clinically meaningful EEG biomarkers presented here could guide the development of more targeted treatments and support big data approaches to objective patient monitoring. ### Competing Interest Statement The authors have declared no competing interest.

Gait rehabilitation using auditory cues can help older adults and people with Parkinson’s improve walking performance. While auditory cues are convenient and can reliably modify gait cadence, it is not clear if auditory cues can reliably modify stride length (SL), another key gait performance metric. Existing algorithms also do not address habituation or fluctuation in motor capability, and have not been evaluated with target populations or under dual-task conditions. In this study, we develop an adaptive auditory cueing framework that aims to modulate SL and cadence. The framework monitors the gait parameters and learns a personalized cue-response model to relate the gait parameters to the input cues. The cue-response model is represented using a multi-output Gaussian Process (MOGP) and is used during optimization to select the cue to provide. The adaptive cueing approach is benchmarked against the fixed approach, where cues are provided at a fixed cadence. The two approaches are tested under single and dual-task conditions with 13 older adults (OA) and 8 people with Parkinson’s (PwP). The results show that more than half of the OA and PwP in the study can change both SL and cadence using auditory cues. The fixed approach is best at changing people’s gait without secondary task, however, the addition of the secondary task significantly degrades effectiveness at changing SL. The adaptive approach can maintain the same level of SL change regardless of the presence of the secondary task. A separate analysis is conducted to identify factors that influence the performance of the adaptive framework. Gait information from the previous time step, along with the previous input cue, can improve its prediction accuracy. More diversity in the initialization data can also improve the GP model. Finally, we did not find a strong correlation between stride length and cadence when the parameters are contingent upon input cues.

Blue carbon habitats, including salt marshes, can sequester carbon at rates that are an order of magnitude greater than terrestrial forests. This ecosystem service may be under threat from nitrate (NO3-) enrichment, which can shift the microbial community and stimulate decomposition of organic matter. Despite efforts to mitigate nitrogen loading, salt marshes continue to experience chronic NO3- enrichment, however, the long-term consequence of this enrichment on carbon storage remains unclear. To investigate the effect of chronic NO3- exposure on salt marsh organic matter decomposition, we collected sediments from three sites across a range of prior NO3- exposure: a relatively pristine marsh, a marsh enriched to ~70 μmol L-1 NO3- in the flooding seawater for 13 years, and a marsh enriched between 100 and 1000 μmol L-1 for 40 years from wastewater treatment effluent. We collected sediments from 20 to 25 cm depth and determined that sediments from the most chronically enriched site had less bioavailable organic matter and a distinct assemblage of active microbial taxa compared to the other two sites. We also performed a controlled anaerobic decomposition experiment to test whether the legacy of NO3- exposure influenced the functional response to additional NO3-. We found significant changes to microbial community composition resulting from experimental NO3- addition. Experimental NO3- addition also increased microbial respiration in sediments collected from all sites. However, sediments from the most chronically enriched site exhibited the smallest increase, the lowest rates of total NO3- reduction by dissimilatory nitrate reduction to ammonium (DNRA), and the highest DNF:DNRA ratios. Our results suggest that chronic exposure to elevated NO3- may lead to residual pools of organic matter that are less biologically available for decomposition. Thus, it is important to consider the legacy of nutrient exposure when examining the carbon cycle of salt marsh sediments.

People with Parkinson’s Disease experience gait impairments that significantly impact their quality of life. Visual, auditory, and tactile cues can alleviate gait impairments, but they can become less effective due to the progressive nature of the disease and changes in people’s motor capability. In this study, we develop a human-in-the-loop (HIL) framework that monitors two key gait parameters, stride length and cadence, and continuously learns a person-specific model of how the parameters change in response to the feedback. The model is then used in an optimization algorithm to improve the gait parameters. This feasibility study examines whether auditory cues can be used to influence stride length in people without gait impairments. The results demonstrate the benefits of the HIL framework in maintaining people’s stride length in the presence of a secondary task.Clinical relevance— This paper proposes a gait rehabilitation framework that provides a personalized cueing strategy based on the person’s real-time response to cues. The proposed approach has potential application to people with Parkinson’s Disease.

Clinical motion analysis involves quantitative measurement of gait patterns to identify gait anomalies that currently or have the potential to impact function, activities of daily living and participation. Clinical motion analysis services are equipped with motion capture technology and comprise specialised staff who deliver 3 -dimensional motion analysis services to children and adults who present with varying levels of gait impairment. Data is then used to inform intervention recommendations to clinicians with a view to maintaining independent, functional and pain free walking (or appropriate mobility).The ANZ-CMAG (established in 2013) identified a need to establish recommendations to assist in standardising practice guidelines for both current and new clinical motion analysis services within the region. The group serves to promote collaboration between services in quality assurance processes, clinical practices, data sets and research activities. The clinical practice recommendations described in this paper cover: i) requirements for a motion analysis service (including staffing, facilities and equipment), ii) patient assessments (requirements, clinical information and data gathered, reporting and interpretation of patient data), iii) quality assurance processes (including motion capture system / biomechanical models & limitations, marker placement, data storage / record keeping, creation of normative dataset); iv) helpful resources.Better outcomes for children and adults with gait deviations is dependent upon accurate measurement and evaluation of walking and requires input from multidisciplinary clinical teams with specialist knowledge and skills. The ANZ-CMAG hopes these clinical practice recommendations are beneficial to motion analysis services with an aim to improve clinical practices, patient outcomes, and support research collaboration.

A wealth of functional magnetic resonance imaging monetary incentive delay task (MIDT) research has shown alcohol dependency is associated with a hypoactive striatal response during gain anticipation (gain > neutral) and loss anticipation (loss > neutral). Electroencephalography (EEG) holds clinical advantages over fMRI (high temporal resolution, low cost, portable) however its use to study reward processing in alcohol dependence is limited. We aimed to carry out the first EEG MIDT (eMIDT) study in alcohol dependence. 21 abstinent alcohol dependent individuals and 26 controls performed an MIDT while neural activity was recorded using 64-channel EEG. Trial averaged event-related potentials (ERPs) and single-trial machine learning discriminant analyses were applied to EEG data. Clinical variables related to severity of dependence were collected and relationships with ERP data explored. Alcohol dependent individuals, compared with healthy controls, had blunted cue-P3 amplitudes for gain and loss anticipation (interaction: p = 0.019); and elevated contingent negative variation amplitudes for all conditions (gain, loss, neutral)(main effect: p < 0.001) which was associated with increased alcohol consumption (p = 0.002). The machine learning analyses demonstrated alcohol dependent individuals had reduced ability to discriminate between loss and neutral cues between 328 - 350 ms (p = 0.040), 354 - 367 ms (p = 0.047) and 525 - 572 ms (p = 0.022). The eMIDT approach is demonstrated to be a low-cost, sensitive measure of dysfunctional anticipatory reward processing in alcohol dependence, which we propose is ideal for big data approaches to prognostic psychiatry and translation into clinical practice.

People with Parkinson's (PwP) experience gait impairments that can be improved through cue training, where visual, auditory, or haptic cues are provided to guide the walker's cadence or step length. There are two types of cueing strategies: open and closed-loop. Closed-loop cueing may be more effective in addressing habituation and cue dependency, but has to date been rarely validated with PwP. In this study, we adapt a human-in-the-loop framework to conduct preliminary analysis with four PwP. The closed-loop framework learns an individualized model of the walker's responsiveness to cues and generates an optimized cue based on the model. In this feasibility study, we determine whether participants in early stages of Parkinson's can respond to the novel cueing framework, and compare the performance of the framework to two alternative cueing strategies (fixed/proportional approaches) in changing the participant's cadence to two target cadences (speed up/slow down). The preliminary results show that the selection of the target cadence has an impact on the participant's gait performance. With the appropriate target, the framework and the fixed approaches perform similarly in slowing the participants' cadence. However, the proposed framework demonstrates better efficiency, explainability, and robustness across participants. Participants also have the highest retention rate in the absence of cues with the proposed framework. Finally, there is no clear benefit of using the proportional approach.

Impaired cognition is associated with lower quality of life and poor outcomes in schizophrenia. Brain glutamate may contribute to both clinical outcomes and cognition, but these relationships are not well-understood. We studied a multicentre cohort of 85 participants with non-affective psychosis using proton magnetic resonance spectroscopy. Glutamate neurometabolites were measured in the anterior cingulate cortex (ACC). Cognition was assessed using the Brief Assessment for Cognition in Schizophrenia (BACS). Patients were categorised as antipsychotic responders or non-responders based on treatment history and current symptom severity. Inverted U-shaped associations between glutamate or Glx (glutamate + glutamine) with BACS subscale and total scores were examined with regression analyses. We then tested for an interaction effect of the antipsychotic response group on the relationship between glutamate and cognition. ACC glutamate and Glx had a positive linear association with verbal memory after adjusting for age, sex and chlorpromazine equivalent dose (glutamate, β = 3.73, 95% CI = 1.26–6.20, P = 0.004; Glx, β = 3.38, 95% CI = 0.84–5.91, P = 0.01). This association did not differ between good and poor antipsychotic response groups. ACC glutamate was also positively associated with total BACS score (β = 3.12, 95% CI = 0.01–6.23, P = 0.046), but this was not significant after controlling for antipsychotic dose. Lower glutamatergic metabolites in the ACC were associated with worse verbal memory, and this relationship was independent of antipsychotic response. Further research on relationships between glutamate and cognition in antipsychotic responsive and non-responsive illness could aid the stratification of patient groups for targeted treatment interventions.

Evidence suggests that alcohol dependence (AD) is associated with microstructural deficits in white matter, but the relationship with lifetime alcohol exposure and the impact of polydrug dependence is not well understood. Using diffusion tensor magnetic resonance (MR) imaging, we examined white matter microstructure in relation to alcohol and polydrug dependence using data from the Imperial College Cambridge Manchester (ICCAM) platform study. Tract-based spatial statistics were used to examine fractional anisotropy (FA) in a cohort of abstinent AD participants, most of whom had a lifetime history of dependence to nicotine. A further subgroup also had a lifetime history of dependence to cocaine and/or opiates. Individuals with AD had lower FA throughout the corpus callosum, and negative associations with alcohol and nicotine exposure were found. A group-by-age interaction effect was found showing greater reductions with age in the alcohol-dependent group within corpus callosum, overlapping with the group difference. We found no evidence of recovery with abstinence. A comparison of alcohol-only- and alcohol-polydrug-dependent groups found no differences in FA. Overall, our findings show that AD is associated with lower FA and suggest that these alterations are primarily driven by lifetime alcohol consumption and cigarette smoking, showing no relationship with exposure to other substances such as cocaine, opiates or cannabis. Reductions in FA across the adult lifespan are more pronounced in AD and offer further support for the notion of accelerated ageing in relation to alcohol dependence. These findings highlight there may be lasting structural differences in white matter in alcohol dependence, despite continued abstinence.

Evidence suggests that reward processing and impulsivity contribute to the pathophysiology of addiction. However, the relationship between the two is currently not well characterised.

Background: Classification of gait in adults with hereditary spastic paresis is limited. Our aim was to use a previously established system to classify gait. Methods: Forty-nine participants were retrospectively recruited and grouped into existing classifications based on sagittal plane knee joint kinematic data extracted from a 3D analysis. Waveform analysis was used to compare the grouped data to determine if and where differences in the subjective classifications appeared. Findings: Classification of gait patterns in adults with hereditary spastic paresis is successful. Differences between groups in line with the classification system were confirmed by statistical analysis. Crouch gait is illustrated by a flexed knee throughout stance phase. Recurvatum gait is dominated by knee hyperextension in mid-late stance. Stiff-knee gait demonstrates limited knee range of motion in stance and jump-knee gait is characterised by less knee flexion in early and mid-stance phase than all groups. Sagittal plane hip and ankle kinematics compliment group differences at the knee joint. The jump-knee group is more flexed at the hip than all groups during loading response phase and mid-stance; and the recurvatum group is more extended at the hip than the crouch, jump -knee, and stiff-knee groups during mid and late-stance phase. There is less ankle dorsiflexion throughout stance phase in the recurvatum group than in all other groups. Interpretation: Sagittal plane knee joint kinematic data can be subjectively used to classify gait features in adults with hereditary spastic paresis. Novel analysis show hip and ankle sagittal plane kinematics can be used to further assist classification.

Alcohol use disorder is characterised by disrupted reward learning, underpinned by dysfunctional cortico-striatal reward pathways, although relatively little is known about the biology of reward processing in populations who engage in risky alcohol use. Cues that trigger reward anticipation can be categorized according to their learnt valence (i.e., positive vs. negative outcomes) and motivational salience (i.e., incentive vs. neutral cues). Separating EEG signals associated with these dimensions is challenging because of their inherent collinearity, but the recent application of machine learning methods to single EEG trials affords a solution. Here, the Alcohol Use Disorders Identification Test (AUDIT) was used to quantify risky alcohol use, with participants split into high alcohol (HA) (n = 22, mean AUDIT score: 13.82) and low alcohol (LA) (n = 22, mean AUDIT score: 5.77) groups. We applied machine learning multivariate single-trial classification to the electroencephalography (EEG) data collected during reward anticipation. The LA group demonstrated significant valence discrimination in the early stages of reward anticipation within the cue-P3 time window (400-550 ms), whereas the HA group was insensitive to valence within this time window. Notably, the LA, but not the HA group demonstrated a relationship between single-trial variability in the early valence component and reaction times for gain and loss trials. This study evidences disrupted hypoactive valence sensitivity in the HA group, revealing potential neurophysiological markers for risky drinking behaviours which place individuals at-risk of adverse health events.

IntroductionNegative affective states contribute to the chronic-relapsing nature of addiction. Mesolimbic dopamine D3 receptors are well placed to modulate emotion and are dysregulated in substance dependence. Selective antagonists might restore dopaminergic hypofunction, thus representing a potential treatment target. We investigated the effects of selective D3 antagonist, GSK598809, on the neural response to negative emotional processing in substance dependent individuals and healthy controls.MethodologyFunctional MRI BOLD response was assessed during an evocative image task, 2 h following acute administration of GSK598809 (60 mg) or placebo in a multi-site, double-blind, pseudo-randomised, cross-over design. Abstinent drug dependent individuals (DD, n = 36) comprising alcohol-only (AO, n = 19) and cocaine-alcohol polydrug (PD, n = 17) groups, and matched controls (n = 32) were presented with aversive and neutral images in a block design (contrast of interest: aversive > neutral). Whole-brain mixed-effects and a priori ROI analyses tested for group and drug effects, with identical models exploring subgroup effects.ResultsNo group differences in task-related BOLD signal were identified between DD and controls. However, subgroup analysis revealed greater amygdala/insular BOLD signal in PD compared with AO groups. Following drug administration, GSK598809 increased BOLD response across HC and DD groups in thalamus, caudate, putamen, and pallidum, and reduced BOLD response in insular and opercular cortices relative to placebo. Multivariate analyses in a priori ROIs revealed differential effects of D3 antagonism according to subgroup in substantia nigra; GSK598809 increased BOLD response in AO and decreased response in PD groups.ConclusionAcute GSK598809 modulates the BOLD response to aversive image processing, providing evidence that D3 antagonism may impact emotional regulation. Enhanced BOLD response within D3-rich mesolimbic regions is consistent with its pharmacology and with attenuation of substance-related hypodopaminergic function. However, the lack of group differences in task-related BOLD response and the non-specific effect of GSK598809 between groups makes it difficult to ascertain whether D3 antagonism is likely to be normalising or restorative in our abstinent populations. The suggestion of differential D3 modulation between AO and PD subgroups is intriguing, raising the possibility of divergent treatment responses. Further study is needed to determine whether D3 antagonism should be recommended as a treatment target in substance dependence.

External feedback in the form of visual, auditory and tactile cues has been used to assist patients to overcome mobility challenges. However, these cues can become less effective over time. There is limited research on adapting cues to account for inter and intra-personal variations in cue responsiveness. We propose a cue-provision framework that consists of a gait performance monitoring algorithm and an adaptive cueing strategy to improve gait performance. The proposed approach learns a model of the person's response to cues using Gaussian Process regression. The model is then used within an on-line optimization algorithm to generate cues to improve gait performance. We conduct a study with healthy participants to evaluate the ability of the adaptive cueing strategy to influence human gait, and compare its effectiveness to two other cueing approaches: the standard fixed cue approach and a proportional cue approach. The results show that adaptive cueing is more effective in changing the person's gait state once the response model is learned compared to the other methods.

To identify gait and balance measures that are responsive to change during the timeline of a clinical trial in Friedreich ataxia (FRDA), we administered a battery of potential measures three times over a 12-month period. Sixty-one ambulant individuals with FRDA underwent assessment of gait and balance at baseline, 6 months and 12 months. Outcomes included GAITRite® spatiotemporal gait parameters; Biodex Balance System Postural Stability Test (PST) and Limits of Stability; Berg Balance Scale (BBS); Timed 25-Foot Walk Test; Dynamic Gait Index (DGI); SenseWear MF Armband step and energy activity; and the Friedreich Ataxia Rating Scale Upright Stability Subscale (FARS USS). The standardised response mean (SRM) or correlation coefficients were reported as effect size indices for comparison of internal responsiveness. Internal responsiveness was also analysed in subgroups. SenseWear Armband daily step count had the largest effect size of all the variables over 6 months (SRM = −0.615), while the PST medial–lateral index had the largest effect size (SRM = 0.829) over 12 months. The FARS USS (SRM = 0.824) and BBS (SRM = −0.720) were the only outcomes able to detect change over 12 months in all subgroups. The DGI was the most responsive outcome in children, detecting a mean change of −2.59 (95% CI −3.52 to −1.66, p < 0.001, SRM = −1.429). In conclusion, the FARS USS and BBS are highly responsive and can detect change in a wide range of ambulant individuals with FRDA. However, therapeutic effects in children may be best measured by the DGI.

Animal models have shown that chronic alcohol exposure is associated with persistent neuroadaptations in amygdala synaptic function, whereas human studies have consistently reported amygdala grey‐matter volume (GMV) reductions in alcohol dependent patients (ADP). We hypothesised that chronic alcohol use associated with neuroadaptations may entail a reconfiguration of the amygdala's functional interactions and that these mechanisms may be affected by structural atrophy. We compared amygdala resting state functional connectivity (RSFC) using a whole brain seed‐based approach and amygdala GMV in abstinent ADP ( n = 20) and healthy controls (HC; n = 39), balanced for age, gender and levels of head motion. The potential moderating influence of age, cumulative alcohol exposure, abstinence length and head motion was further examined in the two groups separately using correlational analyses. We found increased amygdala RSFC with substantia nigra/ventral tegmental area (SN/VTA) in ADP compared with HC. As expected, amygdala GMV was lower in ADP. Multiple regression analyses of the ADP group showed that amygdala‐SN/VTA RSFC increases were primarily associated with cumulative alcohol exposure rather than age, whereas amygdala GMV reductions were primarily associated with age rather than cumulative alcohol exposure. The same association between age and amygdala GMV was not observed amongst HC. Importantly, amygdala GMV and amygdala‐SN/VTA RSFC were uncorrelated in ADP, and neither measure was correlated with abstinence length. These results suggest that chronic alcohol exposure is associated with persistent elevations in amygdala‐SN/VTA RSFC and accelerated age‐related grey‐matter atrophy through potentially distinct mechanisms.

The variability in the response to antipsychotic medication in schizophrenia may reflect between-patient differences in neurobiology. Recent cross-sectional neuroimaging studies suggest that a poorer therapeutic response is associated with relatively normal striatal dopamine synthesis capacity but elevated anterior cingulate cortex (ACC) glutamate levels. We sought to test whether these measures can differentiate patients with psychosis who are antipsychotic responsive from those who are antipsychotic nonresponsive in a multicenter cross-sectional study. 1H-magnetic resonance spectroscopy (1H-MRS) was used to measure glutamate levels (Glucorr) in the ACC and in the right striatum in 92 patients across 4 sites (48 responders [R] and 44 nonresponders [NR]). In 54 patients at 2 sites (25 R and 29 NR), we additionally acquired 3,4-dihydroxy-6-[18F]fluoro-l-phenylalanine (18F-DOPA) positron emission tomography (PET) to index striatal dopamine function (Kicer, min-1). The mean ACC Glucorr was higher in the NR than the R group after adjustment for age and sex (F1,80 = 4.27; P = .04). This was associated with an area under the curve for the group discrimination of 0.59. There were no group differences in striatal dopamine function or striatal Glucorr. The results provide partial further support for a role of ACC glutamate, but not striatal dopamine synthesis, in determining the nature of the response to antipsychotic medication. The low discriminative accuracy might be improved in groups with greater clinical separation or increased in future studies that focus on the antipsychotic response at an earlier stage of the disorder and integrate other candidate predictive biomarkers. Greater harmonization of multicenter PET and 1H-MRS may also improve sensitivity.