Music therapy, neural processing, and craving reduction: an RCT protocol for a mixed methods feasibility study in a Community Substance Misuse Treatment Service.

BACKGROUND: Music therapy has been shown to be effective for multiple clinical endpoints associated with substance use disorder such as craving reduction, emotion regulation, depression, and anxiety, but there are a lack of studies investigating those effects in UK Community Substance Misuse Treatment Services (CSMTSs). Furthermore, there is a demand for identifying music therapy mechanisms of change and related brain processes for substance use disorder treatment. The present study aims to evaluate the feasibility and acceptability of music therapy and a pre-test, post-test, and in-session measurement battery in a CSMTS. METHODS: Fifteen participants, from a community service based in London, will take part in a mixed-methods non-blind randomized-controlled trial. Ten participants will receive six-weekly sessions of music therapy in addition to the standard treatment offered by the CSMTS-five of them will receive individual music therapy and five of them will receive group music therapy-while a further five participants will act as a control group receiving standard treatment only. Satisfaction and acceptability will be evaluated in focus groups with service users and staff members following the final treatment session. Moreover, attendance and completion rates will be monitored throughout the intervention. Subjective and behavioral indexes will be assessed before and after the interventions to explore the effects of music therapy on craving, substance use, symptoms of depression and anxiety, inhibitory control, and will be correlated with associated neurophysiological signatures. In-session analysis of two individual music therapy sessions will serve to explore how music and emotion are processed in the brain within the therapy. The data collected at each step will be included in an intention-to-treat analysis basis. DISCUSSION: This study will provide a first report on the feasibility of music therapy as an intervention for participants with substance use disorder engaged within a community service. It will also provide valuable information regarding the implementation of a multifaceted methodology that includes neurophysiological, questionnaire-based, and behavioral assessments in this cohort. Notwithstanding the limitation of a small sample size, the present study will provide novel preliminary data regarding neurophysiological outcomes in participants with substance use disorder that received music therapy. TRIAL REGISTRATION: ClinicalTrails.gov, NCT0518061, Registered 6 January 2022, https://clinicaltrials.gov/ct2/show/NCT05180617.

Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis.

OBJECTIVE: To describe a distinctive seizure semiology that closely associates with voltage-gated potassium channel (VGKC)-complex/Lgi1 antibodies and commonly precedes the onset of limbic encephalitis (LE). METHODS: Twenty-nine patients were identified by the authors (n = 15) or referring clinicians (n = 14). The temporal progression of clinical features and serum sodium, brain magnetic resonance imaging (MRI), positron emission tomography/single photon emission computed tomography, and VGKC-complex antibodies was studied. RESULTS: Videos and still images showed a distinctive adult-onset, frequent, brief dystonic seizure semiology that predominantly affected the arm and ipsilateral face. We have termed these faciobrachial dystonic seizures (FBDS). All patients tested during their illness had antibodies to VGKC complexes; the specific antigenic target was Lgi1 in 89%. Whereas 3 patients never developed LE, 20 of the remaining 26 (77%) experienced FBDS prior to the development of the amnesia and confusion that characterize LE. During the prodrome of FBDS alone, patients had normal sodium and brain MRIs, but electroencephalography demonstrated ictal epileptiform activity in 7 patients (24%). Following development of LE, the patients often developed other seizure semiologies, including typical mesial temporal lobe seizures. At this stage, investigations commonly showed hyponatremia and MRI hippocampal high T2 signal; functional brain imaging showed evidence of basal ganglia involvement in 5/8. Antiepileptic drugs (AEDs) were generally ineffective and in 41% were associated with cutaneous reactions that were often severe. By contrast, immunotherapies produced a clear, and often dramatic, reduction in FBDS frequency. INTERPRETATION: Recognition of FBDS should prompt testing for VGKC-complex/Lgi1 antibodies. AEDs often produce adverse effects; treatment with immunotherapies may prevent the development of LE with its potential for cerebral atrophy and cognitive impairment.

Bilateral Carpal Tunnel Syndrome Following COVID-19 Vaccination: A Case Report.

Coronavirus disease 2019 (COVID-19) continues to pose significant health challenges, with insights into long-term disease sequelae emerging. The post-viral effects resulting from COVID-19 are being investigated and 'long COVID-19' is now a recognised phenomenon. As part of the spectrum of comorbidities, acute-onset neuropathy is associated with infection. The public health response aimed at limiting morbidity and mortality is rooted in vaccination programmes. With the extensive roll-out of novel vaccinations, there has been careful monitoring of temporally associated health problems. Some of the documented associations include neuropathy and entrapment neuropathies. This case report details a patient presenting with bilateral carpal tunnel syndrome (CTS) post their second dose of AZD1222 (ChAdOx1 nCoV-19) vaccination. Though we do not claim causality, the emerging post-vaccination immune-mediated effects may ultimately be proven to include neuropathy exacerbation. Meticulous recording of such associations is required as it is of great relevance to the hand surgeon managing CTS. Level of Evidence: Level V (Therapeutic).

Remyelination in humans due to a retinoid-X receptor agonist is age-dependent.

Remyelination efficiency declines with advancing age in animal models, but this has been harder to demonstrate in people with multiple sclerosis. We show that bexarotene, a putatively remyelinating retinoid-X receptor agonist, shortened the visual evoked potential latency in patients with chronic optic neuropathy aged under 42 years only (with the effect diminishing by 0.45 ms per year of age); and increased the magnetization transfer ratio of deep gray matter lesions in those under 43 years only. Addressing this age-related decline in human remyelination capacity will be an important step in the development of remyelinating therapies that work across the lifespan.

Parkinson's disease--the continuing search for biomarkers.

There is currently no well-established biomarker for Parkinson's disease. The need to better diagnose the condition, define the subtypes of disease, and follow its course independent of any symptomatic drug effects is well-established. In this review, we will begin by reviewing the evidence for biological fluid biomarkers in Parkinson's disease. We will then touch upon the role of brain imaging in diagnosis and defining prognosis, as well as the value of studying motor phenotype and its potential applications for characterising Parkinson's disease subtypes with differing natural histories.

Mononeuritis multiplex: an unexpectedly frequent feature of severe COVID-19.

The prolonged mechanical ventilation that is often required by patients with severe COVID-19 is expected to result in significant intensive care unit-acquired weakness (ICUAW) in many of the survivors. However, in our post-COVID-19 follow-up clinic we have found that, as well as the anticipated global weakness related to loss of muscle mass, a significant proportion of these patients also have disabling focal neurological deficits relating to multiple axonal mononeuropathies. Amongst the 69 patients with severe COVID-19 that have been discharged from the intensive care units in our hospital, we have seen 11 individuals (16%) with such a mononeuritis multiplex. In many instances, the multi-focal nature of the weakness in these patients was initially unrecognised as symptoms were wrongly assumed to relate simply to "critical illness neuromyopathy". While mononeuropathy is well recognised as an occasional complication of intensive care, our experience suggests that such deficits are surprisingly frequent and often disabling in patients recovering from severe COVID-19.

Safety and efficacy of bexarotene in patients with relapsing-remitting multiple sclerosis (CCMR One): a randomised, double-blind, placebo-controlled, parallel-group, phase 2a study.

BACKGROUND: Progressive disability in multiple sclerosis occurs because CNS axons degenerate as a late consequence of demyelination. In animals, retinoic acid receptor RXR-gamma agonists promote remyelination. We aimed to assess the safety and efficacy of a non-selective retinoid X receptor agonist in promoting remyelination in people with multiple sclerosis. METHODS: This randomised, double-blind, placebo-controlled, parallel-group, phase 2a trial (CCMR One) recruited patients with relapsing-remitting multiple sclerosis from two centres in the UK. Eligible participants were aged 18-50 years and had been receiving dimethyl fumarate for at least 6 months. Via a web-based system run by an independent statistician, participants were randomly assigned (1:1), by probability-weighted minimisation using four binary factors, to receive 300 mg/m2 of body surface area per day of oral bexarotene or oral placebo for 6 months. Participants, investigators, and outcome assessors were masked to treatment allocation. MRI scans were done at baseline and at 6 months. The primary safety outcome was the number of adverse events and withdrawals attributable to bexarotene. The primary efficacy outcome was the patient-level change in mean lesional magnetisation transfer ratio between baseline and month 6 for lesions that had a baseline magnetisation transfer ratio less than the within-patient median. We analysed the primary safety outcome in the safety population, which comprised participants who received at least one dose of their allocated treatment. We analysed the primary efficacy outcome in the intention-to-treat population, which comprised all patients who completed the study. This study is registered in the ISRCTN Registry, 14265371, and has been completed. FINDINGS: Between Jan 17, 2017, and May 17, 2019, 52 participants were randomly assigned to receive either bexarotene (n=26) or placebo (n=26). Participants who received bexarotene had a higher mean number of adverse events (6·12 [SD 3·09]; 159 events in total) than did participants who received placebo (1·63 [SD 1·50]; 39 events in total). All bexarotene-treated participants had at least one adverse event, which included central hypothyroidism (n=26 vs none on placebo), hypertriglyceridaemia (n=24 vs none on placebo), rash (n=13 vs one on placebo), and neutropenia (n=10 vs none on placebo). Five (19%) participants on bexarotene and two (8%) on placebo discontinued the study drug due to adverse events. One episode of cholecystitis in a placebo-treated participant was the only serious adverse event. The change in mean lesional magnetisation transfer ratio was not different between the bexarotene group (0·25 percentage units [pu; SD 0·98]) and the placebo group (0·09 pu [0·84]; adjusted bexarotene-placebo difference 0·16 pu, 95% CI -0·39 to 0·71; p=0·55). INTERPRETATION: We do not recommend the use of bexarotene to treat patients with multiple sclerosis because of its poor tolerability and negative primary efficacy outcome. However, statistically significant effects were seen in some exploratory MRI and electrophysiological analyses, suggesting that other retinoid X receptor agonists might have small biological effects that could be investigated in further studies. FUNDING: Multiple Sclerosis Society of the United Kingdom.

Visualising disease progression on multiple variables with vector plots and path plots.

BACKGROUND: It is often desirable to observe how a disease progresses over time in individual patients, rather than graphing group averages; and since multiple outcomes are typically recorded on each patient, it would be advantageous to visualise disease progression on multiple variables simultaneously. METHODS: A variety of vector plots and a path plot have been developed for this purpose, and data from a longitudinal Huntington's disease study are used to illustrate the utility of these graphical methods for exploratory data analysis. RESULTS: Initial and final values for three outcome variables can be easily visualised per patient, along with the change in these variables over time. In addition to the disease trajectory, the path individual patients take from initial to final observation can be traced. Categorical variables can be coded with different types of vectors or paths (e.g. different colours, line types, line thickness) and separate panels can be used to include further categorical or continuous variables, allowing clear visualisation of further information for each individual. In addition, summary statistics such as mean vectors, bivariate interquartile ranges and convex polygons can be included to assist in interpreting trajectories, comparing groups, and detecting multivariate outliers. CONCLUSION: Vector and path plots are useful graphical methods for exploratory data analysis when individual-level information on multiple variables over time is desired, and they have several advantages over plotting each variable separately.

Animal models of neurodegenerative diseases.

Animal models of neurodegenerative disease are excellent tools for studying pathogenesis and therapies including cellular transplantation. In this chapter, we describe different models of Huntington's disease and Parkinson's disease, stereotactic surgery (used in creation of lesion models and transplantation) and finally transplantation studies in these models.

Huntington disease patients and transgenic mice have similar pro-catabolic serum metabolite profiles.

There has been considerable progress recently towards developing therapeutic strategies for Huntington's disease (HD), with several compounds showing beneficial effects in transgenic mouse models. However, human trials in HD are difficult, costly and time-consuming due to the slow disease course, insidious onset and patient-to-patient variability. Identification of molecular biomarkers associated with disease progression will aid the development of effective therapies by allowing further validation of animal models and by providing hopefully more sensitive measures of disease progression. Here, we apply metabolic profiling by gas chromatography-time-of-flight-mass spectrometry to serum samples from human HD patients and a transgenic mouse model in a hypothesis-generating search for disease biomarkers. We observed clear differences in metabolic profiles between transgenic mice and wild-type littermates, with a trend for similar differences in human patients and control subjects. Thus, the metabolites responsible for distinguishing transgenic mice also comprised a metabolic signature tentatively associated with the human disease. The candidate biomarkers composing this HD-associated metabolic signature in mouse and humans are indicative of a change to a pro-catabolic phenotype in early HD preceding symptom onset, with changes in various markers of fatty acid breakdown (including glycerol and malonate) and also in certain aliphatic amino acids. Our data raise the prospect of a robust molecular definition of progression of HD prior to symptom onset, and if validated in a genuinely prospective fashion these biomarker trajectories could facilitate the development of useful therapies for this disease.

Neurogenesis in diseases of the central nervous system.

Neurogenesis is altered in ageing, and diseases of the central nervous system (CNS) such as neurodegenerative disorders. We discuss the process of neurogenesis, its relevance for disorders of the CNS, the dynamic nature of neurogenesis, how and why it may be abnormal in ageing, and disease, and possibilities to ameliorate abnormal neurogenesis in disease.

Advances in EEG: home video telemetry, high frequency oscillations and electrical source imaging.

Over the last two decades, technological advances in electroencephalography (EEG) have allowed us to extend its clinical utility for the evaluation of patients with epilepsy. This article reviews three main areas in which substantial advances have been made in the diagnosis and pre-surgical planning of patients with epilepsy. Firstly, the development of small portable video-EEG systems have allowed some patients to record their attacks at home, thereby improving diagnosis, with consequent substantial healthcare and economic implications. Secondly, in specialist centres carrying out epilepsy surgery, there has been considerable interest in whether bursts of very high frequency EEG activity can help to determine the regions of the brain likely to be generating the seizures. Identification of these discharges, initially only recorded from intracranial electrodes, may thus allow better surgical planning and improve surgical outcomes. Finally we discuss the contribution of electrical source imaging in the pre-surgical evaluation of patients with focal epilepsy, and its prospects for the future.

Hemodynamic response to burst-suppressed and discontinuous electroencephalography activity in infants with hypoxic ischemic encephalopathy.

Burst suppression (BS) is an electroencephalographic state associated with a profound inactivation of the brain. BS and pathological discontinuous electroencephalography (EEG) are often observed in term-age infants with neurological injury and can be indicative of a poor outcome and lifelong disability. Little is known about the neurophysiological mechanisms of BS or how the condition relates to the functional state of the neonatal brain. We used simultaneous EEG and diffuse optical tomography (DOT) to investigate whether bursts of EEG activity in infants with hypoxic ischemic encephalopathy are associated with an observable cerebral hemodynamic response. We were able to identify significant changes in concentration of both oxy and deoxyhemoglobin that are temporally correlated with EEG bursts and present a relatively consistent morphology across six infants. Furthermore, DOT reveals patient-specific spatial distributions of this hemodynamic response that may be indicative of a complex pattern of cortical activation underlying discontinuous EEG activity that is not readily apparent in scalp EEG.

Errata: Hemodynamic response to burst-suppressed and discontinuous electroencephalography activity in infants with hypoxic ischemic encephalopathy.

[This corrects the article DOI: 10.1117/1.NPh.3.3.031408.].

Skin and platelet alpha-synuclein as peripheral biomarkers of Parkinson's disease.

Parkinson's disease (PD) is a heterogeneous disease that can be difficult to diagnose, and for which we have no simple effective biomarker. In this study we have investigated whether peripheral alpha-synuclein might represent a useful biomarker given that it has a central role in the pathogenesis of PD. We found that full length and truncated alpha-synuclein is present in platelets, but the amount is very variable and does not correlate with disease presence or severity. Furthermore, we show that alpha-synuclein can be detected by immunoblotting in some, but not all, human skin biopsies, but again its level does not correlate with disease presence or severity. We conclude that skin or platelet alpha-synuclein would not be an appropriate diagnostic biomarker for PD.

Long-term remission with rituximab in refractory leucine-rich glioma inactivated 1 antibody encephalitis.

Autoimmune encephalitis associated with antibodies to leucine-rich glioma inactivated 1 (LGI1) is recently described and there is a lack of detailed reports on the treatment of relapsing or refractory cases and long-term outcomes. Two case reports are presented. Both cases had faciobrachial dystonic seizures (FBDS) and received rituximab after relapsing or refractory disease. Both cases achieved sustained clinical remission of up to 15 and 56 months respectively. Rituximab use allowed withdrawal of corticosteroids and was well tolerated. Randomized clinical trials are needed in LGI1 encephalitis and other autoimmune encephalitides.

Mapping cortical haemodynamics during neonatal seizures using diffuse optical tomography: a case study.

Seizures in the newborn brain represent a major challenge to neonatal medicine. Neonatal seizures are poorly classified, under-diagnosed, difficult to treat and are associated with poor neurodevelopmental outcome. Video-EEG is the current gold-standard approach for seizure detection and monitoring. Interpreting neonatal EEG requires expertise and the impact of seizures on the developing brain remains poorly understood. In this case study we present the first ever images of the haemodynamic impact of seizures on the human infant brain, obtained using simultaneous diffuse optical tomography (DOT) and video-EEG with whole-scalp coverage. Seven discrete periods of ictal electrographic activity were observed during a 60 minute recording of an infant with hypoxic-ischaemic encephalopathy. The resulting DOT images show a remarkably consistent, high-amplitude, biphasic pattern of changes in cortical blood volume and oxygenation in response to each electrographic event. While there is spatial variation across the cortex, the dominant haemodynamic response to seizure activity consists of an initial increase in cortical blood volume prior to a large and extended decrease typically lasting several minutes. This case study demonstrates the wealth of physiologically and clinically relevant information that DOT-EEG techniques can yield. The consistency and scale of the haemodynamic responses observed here also suggest that DOT-EEG has the potential to provide improved detection of neonatal seizures.

Techniques and applications of EMG: measuring motor units from structure to function.

Needle electromyography (EMG) is an established method of evaluating motor unit and muscle fibre function and pathology in clinical practice, while the development of advanced techniques including single-fibre EMG and combined recordings with other modalities have become increasingly useful in research. The development of quantitative EMG in particular had led to greater reproducibility and inter-rater reliability. This review provides an overview of standard needle EMG as well as discussing advanced recording and analysis techniques and their increasing role in clinical research.