Clinical Trial
clinical trial
Applied cognitive neuroscience to improve learning and therapeutics
Advancements in cognitive neuroscience have provided profound insights into the workings of the human brain and the methods used offer opportunities to enhance performance, cognition, and mental health. Drawing upon interdisciplinary collaborations in the University of California San Diego, Human Performance Optimization Lab, this talk explores the application of cognitive neuroscience principles in three domains to improve human performance and alleviate mental health challenges. The first section will discuss studies addressing the role of vision and oculomotor function in athletic performance and the potential to train these foundational abilities to improve performance and sports outcomes. The second domain considers the use of electrophysiological measurements of the brain and heart to detect, and possibly predict, errors in manual performance, as shown in a series of studies with surgeons as they perform robot-assisted surgery. Lastly, findings from clinical trials testing personalized interventional treatments for mood disorders will be discussed in which the temporal and spatial parameters of transcranial magnetic stimulation (TMS) are individualized to test if personalization improves treatment response and can be used as predictive biomarkers to guide treatment selection. Together, these translational studies use the measurement tools and constructs of cognitive neuroscience to improve human performance and well-being.
Attending to the ups and downs of Lewy body dementia: An exploration of cognitive fluctuations
Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) share similarities in pathology and clinical presentation and come under the umbrella term of Lewy body dementias (LBD). Fluctuating cognition is a key symptom in LBD and manifests as altered levels of alertness and attention, with a marked difference between best and worst performance. Cognition and alertness can change over seconds or minutes to hours and days of obtundation. Cognitive fluctuations can have significant impacts on the quality of life of people with LBD as well as potentially contribute to the exacerbation of other transient symptoms including, for example, hallucinations and psychosis as well as making it difficult to measure cognitive effect size benefits in clinical trials of LBD. However, this significant symptom in LBD is poorly understood. In my presentation I will discuss the phenomenology of cognitive fluctuations, how we can measure it clinically and limitations of these approaches. I will then outline the work of our group and others which has been focussed on unpicking the aetiological basis of cognitive fluctuations in LBD using a variety of imaging approaches (e.g. SPECT, sMRI, fMRI and EEG). I will then briefly explore future research directions.
Fragile minds in a scary world: trauma and post traumatic stress in very young children
Post traumatic stress disorder (PTSD) is a prevalent and disabling condition that affects larger numbers of children and adolescents worldwide. Until recently, we have understood little about the nature of PTSD reactions in our youngest children (aged under 8 years old). This talk describes our work over the last 15 years working with this very young age group. It overviews how we need a markedly different PTSD diagnosis for very young children, data on the prevalence of this new diagnostic algorithm, and the development of a psychological intervention and its evaluation in a clinical trial.
Fidelity and Replication: Modelling the Impact of Protocol Deviations on Effect Size
Cognitive science and cognitive neuroscience researchers have agreed that the replication of findings is important for establishing which ideas (or theories) are integral to the study of cognition across the lifespan. Recently, high-profile papers have called into question findings that were once thought to be unassailable. Much attention has been paid to how p-hacking, publication bias, and sample size are responsible for failed replications. However, much less attention has been paid to the fidelity by which researchers enact study protocols. Researchers conducting education or clinical trials are aware of the importance in fidelity – or the extent to which the protocols are delivered in the same way across participants. Nevertheless, this idea has not been applied to cognitive contexts. This seminar discusses factors that impact the replicability of findings alongside recent models suggesting that even small fidelity deviations have real impacts on the data collected.
Can we have jam today and jam tomorrow ?Improving outcomes for older people living with mental illness using applied and translational research
This talk will examine how approaches such as ‘big data’ and new ways of delivering clinical trials can improve current services for older people with mental illness (jam today) and identify and deliver new treatments in the future (jam tomorrow).
Designing the BEARS (Both Ears) Virtual Reality Training Package to Improve Spatial Hearing in Young People with Bilateral Cochlear Implant
Results: the main areas which were modified based on participatory feedback were the variety of immersive scenarios to cover a range of ages and interests, the number of levels of complexity to ensure small improvements were measured, the feedback and reward schemes to ensure positive reinforcement, and specific provision for participants with balance issues, who had difficulties when using head-mounted displays. The effectiveness of the finalised BEARS suite will be evaluated in a large-scale clinical trial. We have added in additional login options for other members of the family and based on patient feedback we have improved the accompanying reward schemes. Conclusions: Through participatory design we have developed a training package (BEARS) for young people with bilateral cochlear implants. The training games are appropriate for use by the study population and ultimately should lead to patients taking control of their own management and reducing the reliance upon outpatient-based rehabilitation programmes. Virtual reality training provides a more relevant and engaging approach to rehabilitation for young people.
Ebselen: a lithium-mimetic without lithium side-effects?
Development of new medications for mental health conditions is a pressing need given the high proportion of people not responding to available treatments. We hope that presenting ebselen to a wider audience will inspire further studies on this promising agent with a benign side-effects profile. Laboratory research, animal research and human studies suggest that ebselen shares many features with the mood stabilising drug lithium, creating a promise of a drug that would have a similar clinical effect but without lithium’s troublesome side-effect profile and toxicity. Both drugs have a common biological target, inositol monophosphatase, whose inhibition is thought key to lithium’s therapeutic effect. Both drugs have neuroprotective action and reduce oxidative stress. In animal studies, ebselen affected neurotransmitters involved in the development of mental health symptoms, and in particular, produced effects of serotonin function very similar to lithium. Both ebselen and lithium share behavioural effects: antidepressant-like effects in rodent models of depression and decrease in behavioural impulsivity, a property associated with lithium's anti-suicidal action. Human neuropsychological studies support an antidepressant profile for ebselen based on its positive impact on emotional processing and reward seeking. Our group currently is exploring ebselen’s effects in patients with mood disorders. A completed ‘add-on’ clinical trial in mania showed ebselen’s superiority over placebo after three weeks of treatment. Our ongoing experimental research explores ebselen’s antidepressant profile in patients with treatment resistant depression. If successful, this will lead to a clinical trial of ebselen as an antidepressant augmentation agent, similar to lithium.
PET imaging in brain diseases
Talk 1. PET based biomarkers of treatment efficacy in temporal lobe epilepsy A critical aspect of drug development involves identifying robust biomarkers of treatment response for use as surrogate endpoints in clinical trials. However, these biomarkers also have the capacity to inform mechanisms of disease pathogenesis and therapeutic efficacy. In this webinar, Dr Bianca Jupp will report on a series of studies using the GABAA PET ligand, [18F]-Flumazenil, to establish biomarkers of treatment response to a novel therapeutic for temporal lobe epilepsy, identifying affinity at this receptor as a key predictor of treatment outcome. Dr Bianca Jupp is a Research Fellow in the Department of Neuroscience, Monash University and Lead PET/CT Scientist at the Alfred Research Alliance–Monash Biomedical Imaging facility. Her research focuses on neuroimaging and its capacity to inform the neurobiology underlying neurological and neuropsychiatric disorders. Talk 2. The development of a PET radiotracer for reparative microglia Imaging of neuroinflammation is currently hindered by the technical limitations associated with TSPO imaging. In this webinar, Dr Lucy Vivash will discuss the development of PET radiotracers that specifically image reparative microglia through targeting the receptor kinase MerTK. This includes medicinal chemistry design and testing, radiochemistry, and in vitro and in vivo testing of lead tracers. Dr Lucy Vivash is a Research Fellow in the Department of Neuroscience, Monash University. Her research focuses on the preclinical development and clinical translation of novel PET radiotracers for the imaging of neurodegenerative diseases.
Genetic-based brain machine interfaces for visual restoration
Visual restoration is certainly the greatest challenge for brain-machine interfaces with the high pixel number and high refreshing rate. In the recent year, we brought retinal prostheses and optogenetic therapy up to successful clinical trials. Concerning visual restoration at the cortical level, prostheses have shown efficacy for limited periods of time and limited pixel numbers. We are investigating the potential of sonogenetics to develop a non-contact brain machine interface allowing long-lasting activation of the visual cortex. The presentation will introduce our genetic-based brain machine interfaces for visual restoration at the retinal and cortical levels.
Multimodal imaging in Dementia with Lewy bodies
Dementia with Lewy bodies (DLB) is a synucleinopathy but more than half of patients with DLB also have varying degrees of tau and amyloid-β co-pathology. Identifying and tracking the pathologic heterogeneity of DLB with multi-modal biomarkers is critical for the design of clinical trials that target each pathology early in the disease at a time when prevention or delaying the transition to dementia is possible. Furthermore, longitudinal evaluation of multi-modal biomarkers contributes to our understanding of the type and extent of the pathologic progression and serves to characterize the temporal emergence of the associated phenotypic expression. This talk will focus on the utility of multi-modal imaging in DLB.
NMC4 Short Talk: Decoding finger movements from human posterior parietal cortex
Restoring hand function is a top priority for individuals with tetraplegia. This challenge motivates considerable research on brain-computer interfaces (BCIs), which bypass damaged neural pathways to control paralyzed or prosthetic limbs. Here, we demonstrate the BCI control of a prosthetic hand using intracortical recordings from the posterior parietal cortex (PPC). As part of an ongoing clinical trial, two participants with cervical spinal cord injury were each implanted with a 96-channel array in the left PPC. Across four sessions each, we recorded neural activity while they attempted to press individual fingers of the contralateral (right) hand. Single neurons modulated selectively for different finger movements. Offline, we accurately classified finger movements from neural firing rates using linear discriminant analysis (LDA) with cross-validation (accuracy = 90%; chance = 17%). Finally, the participants used the neural classifier online to control all five fingers of a BCI hand. Online control accuracy (86%; chance = 17%) exceeded previous state-of-the-art finger BCIs. Furthermore, offline, we could classify both flexion and extension of the right fingers, as well as flexion of all ten fingers. Our results indicate that neural recordings from PPC can be used to control prosthetic fingers, which may help contribute to a hand restoration strategy for people with tetraplegia.
Neural mechanisms of altered states of consciousness under psychedelics
Interest in psychedelic compounds is growing due to their remarkable potential for understanding altered neural states and their breakthrough status to treat various psychiatric disorders. However, there are major knowledge gaps regarding how psychedelics affect the brain. The Computational Neuroscience Laboratory at the Turner Institute for Brain and Mental Health, Monash University, uses multimodal neuroimaging to test hypotheses of the brain’s functional reorganisation under psychedelics, informed by the accounts of hierarchical predictive processing, using dynamic causal modelling (DCM). DCM is a generative modelling technique which allows to infer the directed connectivity among brain regions using functional brain imaging measurements. In this webinar, Associate Professor Adeel Razi and PhD candidate Devon Stoliker will showcase a series of previous and new findings of how changes to synaptic mechanisms, under the control of serotonin receptors, across the brain hierarchy influence sensory and associative brain connectivity. Understanding these neural mechanisms of subjective and therapeutic effects of psychedelics is critical for rational development of novel treatments and for the design and success of future clinical trials. Associate Professor Adeel Razi is a NHMRC Investigator Fellow and CIFAR Azrieli Global Scholar at the Turner Institute of Brain and Mental Health, Monash University. He performs cross-disciplinary research combining engineering, physics, and machine-learning. Devon Stoliker is a PhD candidate at the Turner Institute for Brain and Mental Health, Monash University. His interest in consciousness and psychiatry has led him to investigate the neural mechanisms of classic psychedelic effects in the brain.
Psychological mechanisms and functions of 5-HT and SSRIs in potential therapeutic change: Lessons from the serotonergic modulation of action selection, learning, affect, and social cognition
Uncertainty regarding which psychological mechanisms are fundamental in mediating SSRI treatment outcomes and wide-ranging variability in their efficacy has raised more questions than it has solved. Since subjective mood states are an abstract scientific construct, only available through self-report in humans, and likely involving input from multiple top-down and bottom-up signals, it has been difficult to model at what level SSRIs interact with this process. Converging translational evidence indicates a role for serotonin in modulating context-dependent parameters of action selection, affect, and social cognition; and concurrently supporting learning mechanisms, which promote adaptability and behavioural flexibility. We examine the theoretical basis, ecological validity, and interaction of these constructs and how they may or may not exert a clinical benefit. Specifically, we bridge crucial gaps between disparate lines of research, particularly findings from animal models and human clinical trials, which often seem to present irreconcilable differences. In determining how SSRIs exert their effects, our approach examines the endogenous functions of 5-HT neurons, how 5-HT manipulations affect behaviour in different contexts, and how their therapeutic effects may be exerted in humans – which may illuminate issues of translational models, hierarchical mechanisms, idiographic variables, and social cognition.
Hughlings Jackson Lecture: Making Progress in Progressive MS – the Ultimate Challenge!
On April 22, 2021, Dr. Alan J Thompson of the University College London and the UCL Institute of Neurology, London, UK will deliver the Hughlings Jackson Lecture entitled, “Making Progress in Progressive MS – the Ultimate Challenge!” Established in 1935, the Hughlings Jackson Lecture is The Neuro’s premier scientific lecture. It honors the legacy of British neurologist John Hughlings Jackson (1835-1911) who pioneered the development of neurology as a medical specialty. Talk Abstract : The international focus on progressive MS, driven by the Progressive MS Alliance amongst others, together with recent encouraging results from clinical trials have raised the profile and emphasised the importance of understanding, treating and ultimately preventing progression in MS. Effective treatment for Progressive MS is now regarded as the single most important issue facing the MS community. There are several important challenges to developing new treatments for progressive MS. Fundamental to any development in treatment is a better understanding of the mechanisms of tissue injury underpinning progression which will in turn allow the identification of new targets against which treatments can be directed. There are additional complications in determining when progression actually starts, determining the impact of aging and defining the progressive clinical phenotypes – an area which has become increasingly complex in recent months. Evaluating potential new treatments in progressive MS also poses particular challenges including trial design and the selection of appropriate clinical and imaging outcomes - in particular, identifying an imaging biomarker for phase II trials of progressive MS. Despite these challenges, considerable progress is being made in developing new treatments targeting the innate immune system and exploring neuroprotective strategies. Further advances are being driven by a number of international networks, funded by the Progressive MS Alliance. Overall we are seeing encouraging progress as a result of co-ordinated global collaboration which offers real possibilities for truly effective treatment of progression.
Towards a Translational Neuroscience of Consciousness
The cognitive neuroscience of conscious perception has seen considerable growth over the past few decades. Confirming an influential hypothesis driven by earlier studies of neuropsychological patients, we have found that the lateral and polar prefrontal cortices play important causal roles in the generation of subjective experiences. However, this basic empirical finding has been hotly contested by researchers with different theoretical commitments, and the differences are at times difficult to resolve. To address the controversies, I suggest one alternative venue may be to look for clinical applications derived from current theories. I outline an example in which we used closed-loop fMRI combined with machine learning to nonconsciously manipulate the physiological responses to threatening stimuli, such as spiders or snakes. A clinical trial involving patients with phobia is currently taking place. I also outline how this theoretical framework may be extended to other diseases. Ultimately, a truly meaningful understanding of the fundamental nature of our mental existence should lead to useful insights for our colleagues on the clinical frontlines. If we use this as a yardstick, whoever loses the esoteric theoretical debates, both science and the patients will always win.
Gene Therapy for Neurodegeneration
One of the major challenges in developing therapeutics for the neurodegenerative disorders is the blood-brain barrier, limiting the availability of systemically administered therapies such as recombinant proteins or monoclonal antibodies from reaching the brain. Direct central nervous system (CNS) gene therapy using adeno-associated virus vectors expressing a therapeutic protein, monoclonal antibody or inhibiting RNA-coding sequences has two characteristics ideal for therapy of neurodegenerative disorders: circumventing the blood-brain barrier by directly expressing the therapy in the brain and the ability to provide persistent therapy with only a single administration. There are several critical parameters relevant to successful CNS gene therapy, including choice of vector, design of the gene to be expressed, delivery/route of administration, dose and anti-vector immune responses. The presentation will focus on these issues, the current status of clinical trials of gene therapy for neurodegeneration and specific challenges that will need to be overcome to ensure the success of these therapies.
Cognition, behaviour and clinical trials in SYNGAP1
Multimodal brain imaging to predict progression of Alzheimer’s disease
Cross-sectional and longitudinal multimodal brain imaging studies using positron emission tomography (PET) and magnetic resonance imaging (MRI) have provided detailed insight into the pathophysiological progression of Alzheimer’s disease. It starts at an asymptomatic stage with widespread gradual accumulation of beta-amyloid and spread of pathological tau deposits. Subsequently changes of functional connectivity and glucose metabolism associated with mild cognitive impairment and brain atrophy may develop. However, the rate of progression to a symptomatic stage and ultimately dementia varies considerably between individuals. Mathematical models have been developed to describe disease progression, which may be used to identify markers that determine the current stage and likely rate of progression. Both are very important to improve the efficacy of clinical trials. In this lecture, I will provide an overview on current research and future perspectives in this area.
Biomarkers for Addiction Treatment Development: fMRI Drug Cue Reactivity as an Example
This webinar is mainly focused on “Biomarkers for Addiction Treatment Development: fMRI Drug Cue Reactivity as an Example”. Biomarkers and Biotypes of Drug Addiction: funding opportunities at NIDA, Tanya Ramey (NIDA, US) Neuroimaging-based Biomarker Development for Clinical Trials, Owen Carmicheal (Pennington Biomedical Research Center, USA) ENIGMA-Addiction Cue Reactivity Initiative (ACRI) and Checklist, Hamed Ekhtiari (Laureate Institute for Brain Research, USA) ENIGMA-ACRI Checklist: Participant Characteristics, General fMRI Information, General Task Information, Cue Information, Task-related Assessments, Pre-Post Scanning Consideration (James Prisciandaro, Medical University of South Carolina, USA; Marc Kaufman, McLean Hospital/Harvard Medical School, USA; Anna Zilverstand, University of Minnesota; Torsten Wüstenberg, Charité Medical University Berlin, Germany; Falk Kiefer, University of Heidelberg, Germany; Amy Janes, Harvard Medical School, USA) How to Add fMRI Drug Cue Reactivity to the ENIGMA Consortium: Road Ahead, Hugh Garavan, University of Vermont)
Effectiveness of action observation treatment integrated with virtual reality in the motor rehabilitation of stroke patients: A randomized controlled clinical trial
FENS Forum 2024