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Stuttering: Our Current Knowledge, Research Opportunities, and Ways to Address Critical Gaps.
Our understanding of the neurobiological bases of stuttering remains limited, hampering development of effective treatments that are informed by basic science. Stuttering affects more than 5% of all preschool-age children and remains chronic in approximately 1% of adults worldwide. As a condition that affects a most fundamental human ability to engage in fluid and spontaneous verbal communication, stuttering can have substantial psychosocial, occupational, and educational impacts on those who are affected. This article summarizes invited talks and breakout sessions that were held in June 2023 as part of a 2-day workshop sponsored by the US National Institute on Deafness and Other Communication Disorders. The workshop encompassed topics including neurobiology, genetics, speech motor control, cognitive, social, and emotional impacts, and intervention. Updates on current research in these areas were summarized by each speaker, and critical gaps and priorities for future research were raised, and then discussed by participants. Research talks were followed by smaller, moderated breakout sessions intended to elicit diverse perspectives, including on the matter of defining therapeutic targets for stuttering. A major concern that emerged following participant discussion was whether priorities for treatment in older children and adults should focus on targeting core speech symptoms of stuttering, or on embracing effective communication regardless of whether the speaker exhibits overt stuttering. This article concludes with accumulated convergent points endorsed by most attendees on research and clinical priorities that may lead to breakthroughs with substantial potential to contribute to bettering the lives of those living with this complex speech disorder.
Reducing inequalities through greater diversity in clinical trials – As important for medical devices as for drugs and therapeutics
In medicine and public health, the randomised controlled trial (RCT) is generally considered the key generator of ‘gold standard’ evidence. However, basic and clinical research and trials are often unrepresentative of real-world populations. Recruiting insufficiently diverse cohorts of participants in trials (e.g. in terms of socioeconomic status, racial and ethnic background, or sex and gender) may not only overstate the general effectiveness of a technology; it may also actively increase health inequalities. We highlight some general issues in this domain, before discussing several specific illustrative examples in the context of medical devices. High quality evidence on factors that would improve trial recruitment is extremely limited. There is a clear need for research on candidate strategies for improving recruitment of under-represented groups in RCTs. These could include, for example, offering various forms of financial incentives; non-monetary incentives, such as preferential access to the technologies that are being tested if they are found to be effective; and various types of informational messages and nudges; as well as involvement of community partners and champions in the recruitment process. Ideally, recruitment practices should ultimately be based on evidence generated from RCTs. Studies Within a Trial (SWAT), where randomised experiments are built into the actual recruitment processes in RCTs, are an ideal way to gain this evidence. SWAT studies are seeing an increase in traction, as indicated by funding streams in bodies such as the UK-based NIHR. Making greater funding available for studies of this kind is needed to improve the evidence base on how best to improve diversity in trial recruitment.
"Invisible Dangers": Unconscious processing of angry vs fearful faces and its relationship to subjective anger.
Traditional paradigms for studying the unconscious processing of threatening facial expressions face methodological limitations and have predominantly focused on fear, leaving gaps in our understanding of anger. Additionally, it is unclear how the unconscious perception of anger influences subjective anger experiences. To address this, the current study employed Continuous Flash Suppression (CFS), a robust method for studying unconscious processing, to assess suppression times for angry, fearful and happy facial expressions. Following the administration of CFS, participants underwent an anger induction paradigm, and state anger symptoms were assessed at multiple timepoints. Suppression times for angry faces were compared to those for happy and fearful faces, and their relationship with state anger symptoms post-induction was examined. Results revealed that fearful faces broke suppression significantly faster than happy faces. Anger was slower to break suppression compared to fear, but no significant differences emerged between anger and happiness. In addition, the faster emergence into awareness of fear compared to anger was linked to an increased state anger after the induction, indicating that differences in the unconscious processing of these two emotions can potentially influence symptoms of subjective anger. These findings provide new insights into how angry and fearful faces are processed unconsciously, with implications for understanding the cognitive mechanisms underlying subjective anger.
Effect of lithium on circadian activity level and flexibility in patients with bipolar disorder: results from the Oxford Lithium Trial.
BACKGROUND: Disruption of circadian rest-activity is prevalent in patients with bipolar disorder (BD). Lithium's impact on circadian rhythms has been documented in cell lines, animal models, and pharmacogenomics studies in patients with BD. However, the causal relationship between such disruption and BD remains unclear. METHODS: We investigated the early effects of lithium on circadian rest-activity in an exploratory analysis of a randomised, placebo-controlled, double-blind six-week study on patients with BD. Participants were assigned to receive either lithium or a placebo in a 1:1 ratio. Circadian activity was monitored using actigraphy, and daily affect was assessed through ecological momentary assessment. A computational model was used to quantify different types of activity variability, and the impact of lithium on activity level, activity onset time and their variability were analysed using linear mixed models. FINDINGS: Of the thirty-five participants who began treatment, 19 received lithium and 16 received a placebo. Lithium significantly altered circadian rest-activity patterns, including reducing daytime activity levels (after 4 weeks, below as well: Cohen's d = -0.19, p = 0.002, linear mixed model, ibid.), advancing the onset of daytime activity (Cohen's d = -0.14, p = 0.018), and increasing the volatility of both daytime activity level (Cohen's d = 0.10, p = 0.002) and its onset time (Cohen's d = 0.13, p
FedDyS: Enhancing Federated Learning Efficiency with Dynamic Sample Selection
Federated learning (FL) trains models across multiple devices while keeping data localized, addressing privacy and efficiency issues. It faces challenges like data heterogeneity-where diverse local data might hinder the performance of a global model-and high computational costs on resource-limited devices like smartphones or IoT sensors. These constraints can prolong training times, increase energy use, and hasten device wear. To address these issues, this paper introduces FedDyS, a dynamic sample selection technique that reduces computational demands and mitigates data heterogeneity by eliminating non-essential training samples. This not only shrinks the training set size on local devices but also enhances data diversity, facilitating more efficient training and preserving data privacy. Additionally, FedDyS prevents the catastrophic forgetting effect, a common challenge in FL. Our experiments show that FedDyS surpasses traditional FL methods in accuracy and convergence speed, using less than 15% of the usual number of samples, making it ideal for low-resource settings. The code of FedDyS is publicly available: https://github.com/ensiyeKiya/FedDyS
Generating Phonetic Embeddings for Bulgarian Words with Neural Networks
Word embeddings can be considered the cornerstone of modern natural language processing. They are used in many NLP tasks and allow us to create models that can understand the meaning of words. Most word embeddings model the semantics of the words. In this paper, we create phoneme-based word embeddings, which model how a word sounds. This is accomplished by training a neural network that can automatically generate transcriptions of Bulgarian words. We used the Jaccard index and direct comparison metrics to measure the performance of neural networks. The models perform nearly perfectly with the task of generating transcriptions. The model’s word embeddings offer versatility across various applications, with its application in automatic paronym detection being particularly notable, as well as the task of detecting the language of origin of a Bulgarian word. The performance of this paronym detection is measured with the standard classifier metrics - accuracy, precision, recall, and F1.
Asymmetry in amyotrophic lateral sclerosis: clinical, neuroimaging and histological observations.
Amyotrophic lateral sclerosis is a progressive neurodegenerative disease of the motor system marked by significant phenotypic heterogeneity. Motor symptoms in the limbs consistently emerge focally and asymmetrically and, whilst variable, the pattern of regional progression related to the balance of clinical upper and lower motor neuron signs, upper versus lower limb onset and hand dominance to some extent. The neurobiological mechanisms and pathological correlates for this lateralised onset and non-random progression are uncertain. Cerebral neuroimaging studies have commonly reported structural and functional asymmetries in ALS, but the limited analysis of the pre-symptomatic phase has limited their implications. Post-mortem study of spinal cord provided strong evidence for focal pathology at symptom onset in ALS. Histopathological staging of molecular pathology in post mortem tissue lacks clinical correlation and an ordered, sequential temporal progression in life cannot be assumed. The development of integrated brain and cord MRI holds the hope of deepening understanding of the relationship between focal symptomatology and histopathological progression. This review considers the nature and implications of asymmetry in ALS across clinical, neuroimaging and post mortem histopathology, highlighting the current gaps in knowledge and the need for a broader investigative framework.
Comparison between EEG and MEG of static and dynamic resting-state networks.
The characterisation of resting-state networks (RSNs) using neuroimaging techniques has significantly contributed to our understanding of the organisation of brain activity. Prior work has demonstrated the electrophysiological basis of RSNs and their dynamic nature, revealing transient activations of brain networks with millisecond timescales. While previous research has confirmed the comparability of RSNs identified by electroencephalography (EEG) to those identified by magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI), most studies have utilised static analysis techniques, ignoring the dynamic nature of brain activity. Often, these studies use high-density EEG systems, which limit their applicability in clinical settings. Addressing these gaps, our research studies RSNs using medium-density EEG systems (61 sensors), comparing both static and dynamic brain network features to those obtained from a high-density MEG system (306 sensors). We assess the qualitative and quantitative comparability of EEG-derived RSNs to those from MEG, including their ability to capture age-related effects, and explore the reproducibility of dynamic RSNs within and across the modalities. Our findings suggest that both MEG and EEG offer comparable static and dynamic network descriptions, albeit with MEG offering some increased sensitivity and reproducibility. Such RSNs and their comparability across the two modalities remained consistent qualitatively but not quantitatively when the data were reconstructed without subject-specific structural MRI images.
Clinical and cost-effectiveness of lithium versus quetiapine augmentation for treatment-resistant depression: a pragmatic, open-label, parallel-group, randomised controlled superiority trial in the UK.
BACKGROUND: Lithium and quetiapine are first-line augmentation options for treatment-resistant depression; however, few studies have compared them directly, and none for longer than 8 weeks. We aimed to assess whether quetiapine augmentation therapy is more clinically effective and cost-effective than lithium for patients with treatment-resistant depression over 12 months. METHODS: We did this pragmatic, open-label, parallel-group, randomised controlled superiority trial at six National Health Service trusts in England. Eligible participants were adults (aged ≥18 years) with a current episode of major depressive disorder meeting DSM-5 criteria, with a score of 14 or higher on the 17-item Hamilton Depression Rating Scale at screening who had responded inadequately to two or more therapeutic antidepressant trials. Exclusion criteria included having a diagnosis of bipolar disorder or current psychosis. Participants were randomly assigned (1:1) to the decision to prescribe lithium or quetiapine, stratified by site, depression severity, and treatment resistance, using block randomisation with randomly varying block sizes. After randomisation, pre-prescribing safety checks were undertaken as per standard care before proceeding to trial medication initiation. The coprimary outcomes were depressive symptom severity over 12 months, measured weekly using the Quick Inventory of Depressive Symptomatology, and time to all-cause treatment discontinuation. Economic analyses compared the cost-effectiveness of the two treatments from both an NHS and personal social services perspective, and a societal perspective. Primary analyses were done in the intention-to-treat population, which included all randomly assigned participants. People with lived experience were involved in the trial. The trial is completed and registered with the International Standard Randomised Controlled Trial registry, ISRCTN16387615. FINDINGS: Between Dec 5, 2016, and July 26, 2021, 212 participants (97 [46%] male gender and 115 [54%] female gender) were randomly assigned to the decision to prescribe quetiapine (n=107) or lithium (n=105). The mean age of participants was 42·4 years (SD 14·0 years) and 188 (89%) of 212 participants were White, seven (3%) were of mixed ethnicity, nine (4%) participants were Asian, four (2%) were Black, three (1%) were of Other ethnicity, and ethnicity was not recorded for one (1%) participant. Participants in the quetiapine group had a significantly lower overall burden of depressive symptom severity than participants in the lithium group (area under the between-group differences curve -68·36 [95% CI -129·95 to -6·76; p=0·0296). Time to discontinuation did not significantly differ between the two groups. Quetiapine was more cost-effective than lithium. 32 serious adverse events were recorded in 18 participants, one of which was deemed possibly related to the trial medication in a female participant in the lithium group. The most common serious adverse event was overdose, occurring in three (3%) of 107 participants in the quetiapine group (seven events) and three (3%) of 105 participants in the lithium group (five events). INTERPRETATION: Results of the trial suggest that quetiapine is more clinically effective than lithium as a first-line augmentation option for reducing symptoms of depression in the long-term management of treatment-resistant depression, and is probably more cost-effective than lithium. FUNDING: National Institute for Health and Care Research Health Technology Assessment programme.
7 Tesla magnetic resonance spectroscopy estimates of GABA concentration relate to physiological measures of tonic inhibition in the human motor cortex.
GABAergic neurotransmission within the cortex plays a key role in learning and is altered in several brain diseases. Quantification of bulk GABA in the human brain is typically obtained by magnetic resonance spectroscopy (MRS). However, the interpretation of MRS-GABA is still debated. A recent mathematical simulation contends that MRS detects extrasynaptic GABA, mediating tonic inhibition. Nevertheless, no empirical data have yet confirmed this hypothesis. Here we collected ultra-high-field 7 Tesla MRS and transcranial magnetic stimulation coupled with high-density electroencephalography (TMS-hdEEG) from the motor cortex of 20 healthy participants (age 23.95 ± 6.4 years), while they were at rest. We first applied a neural mass model (NMM) to TMS-evoked potentials to disentangle the contribution of different GABAergic pools. We then assessed to which of these different pools MRS-GABA was related to by means of parametric empirical Bayesian (PEB) analysis. We found that MRS-GABA was mostly positively related to the NMM-derived measures of tonic inhibition and overall functionality of the GABAergic synapse. This relationship was reliable enough to predict MRS-GABA from NMM-GABA. These findings clarify the mesoscopic underpinnings of GABA levels measured by MRS. Our work will help fulfil the promises of MRS-GABA, enhancing our understanding of human behaviour, brain physiology and pathophysiology. KEY POINTS: GABA neurotransmission is essential for synaptic plasticity and learning (especially motor learning) and is altered in several brain disorders, such as epilepsy and stroke. Quantification of GABA in the human brain is typically obtained by magnetic resonance spectroscopy (MRS). However, the interpretation of MRS-GABA is still debated. By using a biophysical neural mass model, here we show that MRS-GABA relates to physiological measures of tonic inhibition in the human cortex.
Imaging the structural connectome with hybrid MRI-microscopy tractography.
Mapping how neurons are structurally wired into whole-brain networks can be challenging, particularly in larger brains where 3D microscopy is not available. Multi-modal datasets combining MRI and microscopy provide a solution, where high resolution but 2D microscopy can be complemented by whole-brain but lowresolution MRI. However, there lacks unified approaches to integrate and jointly analyse these multi-modal data in an insightful way. To address this gap, we introduce a data-fusion method for hybrid MRI-microscopy fibre orientation and connectome reconstruction. Specifically, we complement precise "in-plane" orientations from microscopy with "through-plane" information from MRI to construct 3D hybrid fibre orientations at resolutions far exceeding that of MRI whilst preserving microscopy's myelin specificity, resulting in superior fibre tracking. Our method is openly available, can be deployed on standard 2D microscopy, including different microscopy contrasts, and is species agnostic, facilitating neuroanatomical investigation in both animal models and human brains.
The behavioural effects of the serotonin 1A receptor agonist buspirone on cognition and emotional processing in healthy volunteers.
RATIONALE: The 5-HT1A receptor is expressed widely across the brain and is implicated in the mechanism of action of several therapeutics for mood disorders. However, there is limited and contradictory evidence about the role of this receptor in emotional processing and cognition. OBJECTIVES: The current study tested the acute effects of a single dose of the 5-HT1A agonist buspirone (20 mg), on a range of emotional processing (Emotional Test Battery) and cognitive (Auditory Verbal Learning Task (AVLT) and N-back) tasks in healthy, male and female volunteers (N = 62). The study was a randomised, double-blind, placebo controlled, parallel group design. RESULTS: Buspirone reduced accuracy for detection of facial expressions of disgust and increased misclassification of negative facial emotions. It had no significant effects on categorisation or recall of emotionally-valanced words. Buspirone also reduced recall accuracy in the AVLT but had no significant effect in the N-back task. Participants receiving buspirone were more likely to experience nausea, light-headedness and sleepiness. CONCLUSIONS: Acute buspirone administration produced a mild impairment in verbal memory and a subtle negative bias in emotional processing in healthy volunteers. These effects are consistent with the mixed effects of buspirone on pre- and post-synaptic 5-HT1A receptors.