A role for the cerebellum in the control of verbal interference: Comparison of bilingual and monolingual adults

We evaluate brain structure sensitivity to verbal interference in a sentence interpretation task, building on previously reported evidence that those with better control of verbal interference show higher grey matter density in the posterior paravermis of the right cerebellum. We compare brain structure sensitivity to verbal interference control across two groups, English monolingual (N = 41) and multilingual (N = 46) adults. Using voxel-based morphometry, our primary goal was to identify and explore differences in regional patterns of grey matter sensitivity to performance on the sentence interpretation task, controlling for group variability in age, nonverbal reasoning and vocabulary knowledge. There was no group difference in performance but there was a significant group effect in grey matter sensitivity to task performance in our region of interest: stronger sensitivity in the paravermis in bilinguals compared to monolinguals in accuracy performance in the high (relative to low) verbal interference condition. This effect was observed when the linguistic interference was presented in an unfamiliar language (Greek) but not when presented in the familiar language (English). Our findings suggest that multilanguage acquisition mediates regional involvement within the language network, conferring enhanced functional plasticity within structures (including the paravermis) in the service of control of linguistic interference

Development of a novel startle response task in Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD), an X-linked childhood-onset muscular dystrophy caused by loss of the protein dystrophin, can be associated with neurodevelopmental, emotional and behavioural problems. A DMD mouse model also displays a neuropsychiatric phenotype, including increased startle responses to threat which normalise when dystrophin is restored in the brain. We hypothesised that startle responses may also be increased in humans with DMD, which would have potential translational therapeutic implications. To investigate this, we first designed a novel discrimination fear-conditioning task and tested it in six healthy volunteers, followed by male DMD (n = 11) and Control (n = 9) participants aged 7–12 years. The aims of this methodological task development study were to: i) confirm the task efficacy; ii) optimise data processing procedures; iii) determine the most appropriate outcome measures. In the task, two neutral visual stimuli were presented: one ‘safe’ cue presented alone; one ‘threat’ cue paired with a threat stimulus (aversive noise) to enable conditioning of physiological startle responses (skin conductance response, SCR, and heart rate). Outcomes were the unconditioned physiological startle responses to the initial threat, and retention of conditioned responses in the absence of the threat stimulus. We present the protocol development and optimisation of data processing methods based on empirical data. We found that the task was effective in producing significantly higher physiological startle SCR in reinforced ‘threat’ trials compared to ‘safe’ trials (P < .001). Different data extraction methods were compared and optimised, and the optimal sampling window was derived empirically. SCR amplitude was the most effective physiological outcome measure when compared to SCR area and change in heart rate, with the best profile on data processing, the least variance, successful conditioned response retention (P = .01) and reliability assessment in test-retest analysis (rho = .86). The definition of this novel outcome will allow us to study this response in a DMD population

Evidence against a cognitive advantage in the older bilingual population

Recent evidence has challenged long-standing claims that multi-language acquisition confers long-term advantages in executive function and may protect against age-related cognitive deterioration. We assessed evidence for a bilingual advantage in older monolingual and bilingual residents matched on age, gender and socioeconomic status. A comprehensive battery of tests was administered to measure non-verbal reasoning, working memory capacity, visuo-spatial memory, response inhibition, problem-solving and language proficiency. Analyses revealed comparable performance in both groups, with no significant differences on any task (and the only trend, found for the Tower of London task performance, indicated a monolingual advantage). Overall, therefore, our findings run counter to the bilingual advantage hypothesis. We consider the implications of our study, and offer suggestions for future work in this area

The importance of socioeconomic status as a modulator of the bilingual advantage in cognitive ability

Between-group variability in socioeconomic status (SES) has been identified as a potentially important contributory factor in studies reporting cognitive advantages in bilinguals over monolinguals (the so called ‘bilingual advantage’). The present study addresses the potential importance of this alternative explanatory variable in a study of low and high SES bilingual and monolingual performance on the Simon task and the Tower of London task. Results indicated an overall bilingual response time advantage on the Simon task, despite equivalent error rates. Socioeconomic status was an important modulator in this effect, with evidence that bilingualism may be particularly important in promoting speed of processing advantages in low status individuals but have little impact in high status individuals. However, there was a monolingual advantage on the Tower of London test of executive planning ability. Together, our findings run counter to the central assertion of the bilingual advantage account, that the process of multi-language acquisition confers a broad cognitive advantage in executive function. We discuss these findings in the context of socioeconomic status as an important modulator in published studies advocating a bilingual cognitive advantage

Startle responses in Duchenne muscular dystrophy: a novel biomarker of brain dystrophin deficiency

Duchenne muscular dystrophy (DMD) is characterised by loss of dystrophin in muscle. Patients affected by DMD also have variable degree of intellectual disability and neurobehavioural co-morbidities. In contrast to muscle, in which a single full-length isoform (Dp427) is produced, multiple dystrophin isoforms are produced in the brain, and their deficiency accounts for the variability of CNS manifestations, with increased risk of comorbidities in patients carrying mutations affecting the 3’ end of gene, disrupting the shorter Dp140 and Dp71 isoforms. The mdx mouse model of DMD lacks Dp427 in muscle and CNS and exhibits exaggerated startle responses to threat, linked to the deficiency of dystrophin in limbic structures such as the amygdala, which normalise with postnatal brain dystrophin-restoration therapies. A pathological startle response is not a recognised feature of DMD, and its characterisation has implications for improved clinical management and translational research. To investigate startle responses in DMD, we used a novel fear-conditioning task in an observational study of 56 males aged 7-12 years (31 DMD, mean age 9.7±1.8 years; 25 Controls, mean age 9.6±1.4 years). Trials of two neutral visual stimuli were presented to participants: one ‘safe’ cue presented alone; one ‘threat’ cue paired with an aversive noise to enable conditioning of physiological startle responses (skin conductance response, SCR; heart rate, HR). Retention of conditioned physiological responses was subsequently tested with presentation of both cues without the aversive noise in an ‘extinction’ phase. Primary outcomes were the magnitude of the initial unconditioned SCR and HR change responses to the aversive ‘threat’ and acquisition and retention of conditioned responses after conditioning. Secondary outcomes were neuropsychological measures and genotype associations. The initial (unconditioned) mean SCR to threat was greater in DMD than Controls (Mean difference 3.0 µS (95% CI 1.0, 5.1), P=.004), associated with a significant threat-induced bradycardia only in the DMD group (mean difference -5.6 bpm (95% CI 0.51, 16.9); P=.04). DMD participants found the task more aversive than Controls, consequently early termination during the extinction phase occurred in 26% of the DMD group (vs. 0% Controls; P=.007). This study provides the first evidence that boys with DMD show increased unconditioned startle responses to threat, similar to the mdx mouse phenotype that also responds to brain dystrophin restoration. Our study provides new insights into the neurobiology underlying the complex neuropsychiatric co-morbidities in DMD and defines an objective measure of this CNS phenotype, which will be valuable for future CNS-targeted dystrophin-restoration studies

Development of a novel startle response task in Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD), an X-linked childhood-onset muscular dystrophy caused by loss of the protein dystrophin, can be associated with neurodevelopmental, emotional and behavioural problems. A DMD mouse model also displays a neuropsychiatric phenotype, including increased startle responses to threat which normalise when dystrophin is restored in the brain. We hypothesised that startle responses may also be increased in humans with DMD, which would have potential translational therapeutic implications. To investigate this, we first designed a novel discrimination fear-conditioning task and tested it in six healthy volunteers, followed by male DMD (n = 11) and Control (n = 9) participants aged 7-12 years. The aims of this methodological task development study were to: i) confirm the task efficacy; ii) optimise data processing procedures; iii) determine the most appropriate outcome measures. In the task, two neutral visual stimuli were presented: one 'safe' cue presented alone; one 'threat' cue paired with a threat stimulus (aversive noise) to enable conditioning of physiological startle responses (skin conductance response, SCR, and heart rate). Outcomes were the unconditioned physiological startle responses to the initial threat, and retention of conditioned responses in the absence of the threat stimulus. We present the protocol development and optimisation of data processing methods based on empirical data. We found that the task was effective in producing significantly higher physiological startle SCR in reinforced 'threat' trials compared to 'safe' trials (P < .001). Different data extraction methods were compared and optimised, and the optimal sampling window was derived empirically. SCR amplitude was the most effective physiological outcome measure when compared to SCR area and change in heart rate, with the best profile on data processing, the least variance, successful conditioned response retention (P = .01) and reliability assessment in test-retest analysis (rho = .86). The definition of this novel outcome will allow us to study this response in a DMD population

Out-patient triple chronotherapy for the rapid treatment and maintenance of response in depression : feasibility and pilot randomised controlled trial

Background Triple chronotherapy (sleep deprivation for 36 h, followed by 4 days of advancing the time of sleep and daily morning bright-light therapy for 6 months) has demonstrated benefits for the rapid treatment of depressive symptoms in four small controlled trials of in-patients. Aims To test the feasibility of recruitment and delivery of triple chronotherapy for out-patients with depression (ISRCTN17706836; NCT03405493). Method In a single-blind trial, 82 participants were randomised to triple chronotherapy or a control intervention. The primary outcome was the number of participants recruited per month and adherence to the protocol. Secondary outcomes included the 6-item Hamilton Rating Scale for Depression (HRSD-6) at 1 week. Timings of observer ratings were baseline and 1, 2, 4, 8 and 26 weeks after randomisation. Results The triple chronotherapy group stayed awake for the planned 36 h and 89.9% adhered to the plan of phase advance of their sleep over the following 4 days. We achieved our recruitment target (60 participants completed the trial within 13 months). There were no reported adverse side-effects. We found a significant difference between the groups by intention-to-treat analysis for the HRSD-6 at weeks 1, 8 and 26. There was a large effect size of Cohen's d = 0.8 on HRSD-6 score at week 1, increasing to d = 1.30 at week 26. A response (≥50% reduction in symptoms) was achieved by 33.3% in the triple chronotherapy group and 16.2% in the control group. This stayed relatively steady until week 26 (35.9 v. 13.9%). Conclusions Triple chronotherapy produced a significant and rapid benefit after 1 week in out-patients with depression that was sustained at 26 weeks. Cost-effectiveness trials with a larger clinical sample are required

Psychological test usage in duchenne muscular dystrophy: An EU multi-centre study

Aim: During the last two decades brain related comorbidities of Duchenne have received growing scientific and clinical interest and therefore systematic assessment of cognition, behaviour and learning is important. This study aims to describe the instruments currently being used in five neuromuscular clinics in Europe as well as the diagnoses being made in these clinics. Method: A Delphi based procedure was developed by which a questionnaire was sent to the psychologist in five of the seven participating clinics of the Brain Involvement In Dystrophinopathy (BIND) study. Instruments and diagnoses being used were inventoried for three domains of functioning (cognition, behaviour and academics) and three age groups (3–5 years, 6–18 years and adulthood 18+ years). Results: Data show wide diversity of tests being used in the five centres at different age groups and different domains. For the intelligence testing there is consensus in using the Wechsler scales, but all other domains such as memory, attention, behavioural problems and reading are tested in very different ways by different instruments in the participating centres. Conclusion: The heterogeneity of tests and diagnoses being used in current clinical practice underlines the importance for developing a Standard Operating Procedure (SOP) to improve both clinical practice and scientific research over different countries and improve comparative work

The Achilles Heel of Whistleblowing Protection

In 1777, before the passage of the Bill of Rights, 10 sailors and marines blew the whistle on fraud and misconduct harmful to the United States. The Founding Fathers unanimously supported the whistleblowers and provided them with monetary assistance for reasonable legal expenses necessary to prevent retaliation. In an effort to demonstrate their full support, the members of the Continental Congress unanimously enacted the first whistleblower legislation in the United States that read: ‘It is the duty of all persons in the service of the United States, as well as all other inhabitants thereof, to give the earliest information to Congress or any other proper authority of any misconduct, frauds or misdemeanors committed by any persons in the service of these states, which may come to their knowledge