Project 2 - Translation
Disordered Learning and Memory
EEG Signatures
The electroencephalogram has been used to measure the activity of human neocortex for over a century. It is an affordable, non-invasive method that provides a high fidelity readout of the coordinated activity of large populations of synapses in the underlying neocortex and it has been used extensively in research and clinical settings around the world. It can be measured in babies and adults and it can be measured in wake and sleep. It can also measure resting state activity or the phasic response of the brain to events. Within the clinic, it has a major function in diagnosis in many neurological conditions, notably in epilepsy and sleep disorders, and can also be used for the stratification of patients and assessment of response to treatment. There are also a number of pronounced phenomena that can be measured with EEG in the frequency domain in resting state and in the event-related domain in response to temporally controlled sensory stimuli. One such phenomenon is mis-match negativity, in which adaptation is observed to a sequence of repeated sensory stimuli, pseudorandomly interleaved with unexpected 'oddball' stimuli, which produce a dramatically increased cortical response, reflective of the brain's detection of deviance from prediction (see figure below). The deviance detection assayed with the MMN assay with auditory or visual stimuli is very often observed to be diminished in schizophrenia, while adaptation effects measured to the same repeated frequent stimulus are often found to differ in autism spectrum disorder. However, there remains large gaps in our understanding about what underlying events occur in the brain to mediate this effect at either a systems, circuit or synaptic-level. Our work and that of others have shown that it relies upon the NMDA receptor, and it is suggested that there is a requirement for Hebbian plasticity in building an internal model that enables prediction, which is then violated by presentation of an oddball stimulus, though this theory remains speculative. Moreover, it has been speculated that inhibitory neuronal intermediaries are necessary for the MMN effect, and this idea has so far received some support in experimental findings. We and others continue to use interventional methods to investigate the underlying mechanisms at play in adaptation, deviance detection and other examples of useful EEG signatures
The electroencephalogram has been used to measure the activity of human neocortex for over a century. It is an affordable, non-invasive method that provides a high fidelity readout of the coordinated activity of large populations of synapses in the underlying neocortex and it has been used extensively in research and clinical settings around the world. It can be measured in babies and adults and it can be measured in wake and sleep. It can also measure resting state activity or the phasic response of the brain to events. Within the clinic, it has a major function in diagnosis in many neurological conditions, notably in epilepsy and sleep disorders, and can also be used for the stratification of patients and assessment of response to treatment. There are also a number of pronounced phenomena that can be measured with EEG in the frequency domain in resting state and in the event-related domain in response to temporally controlled sensory stimuli. One such phenomenon is mis-match negativity, in which adaptation is observed to a sequence of repeated sensory stimuli, pseudorandomly interleaved with unexpected 'oddball' stimuli, which produce a dramatically increased cortical response, reflective of the brain's detection of deviance from prediction (see figure below). The deviance detection assayed with the MMN assay with auditory or visual stimuli is very often observed to be diminished in schizophrenia, while adaptation effects measured to the same repeated frequent stimulus are often found to differ in autism spectrum disorder. However, there remains large gaps in our understanding about what underlying events occur in the brain to mediate this effect at either a systems, circuit or synaptic-level. Our work and that of others have shown that it relies upon the NMDA receptor, and it is suggested that there is a requirement for Hebbian plasticity in building an internal model that enables prediction, which is then violated by presentation of an oddball stimulus, though this theory remains speculative. Moreover, it has been speculated that inhibitory neuronal intermediaries are necessary for the MMN effect, and this idea has so far received some support in experimental findings. We and others continue to use interventional methods to investigate the underlying mechanisms at play in adaptation, deviance detection and other examples of useful EEG signatures
[Picture]
Mismatch negativity recorded in mouse primary visual cortex in response to repeated frequent oriented stimuli (orange) or an unexpected 'oddball' orientation (purple). Work conducted by Francesca Chaloner.
Neurodevelopmental Disorders
Neurodevelopmental disorders, including autism spectrum disorder, intellectual disability, attention deficit hyperactivity disorder, schizophrenia and epilepsy account for a major healthcare burden across the world. Many of these disorders feature aberrant sensory adaptation and habituation. It is unclear whether there is a common underlying cause across conditions. It is also unclear whether this cognitive symptom is a root cause of other non-cognitive symptoms found in those disorders. We have taken the approach of studying highly penetrant genetic causes of neurodevelopmental disorders in mice so that we can understand the role played by that genetic factor at a circuit level. We have initially focused on relatively common genetic forms of intellectual disability, including Fragile X syndrome, Tuberous Sclerosis Complex, Rett syndrome and Neurofibromatosis type 1, which are each caused by dysfunction in a single known gene. We are investigating how critical circuitry is modified in mouse models of these disorders to produce aberrant habituation and novelty detection. In the future, we aim to use this approach as a platform to test potential therapeutics to recover cognitive function in these models. The laboratory is currently part of the MRC Centre for Neurodevelopmental Disorders (CNDD) at KCL, which is a collection of laboratories across many schools and departments in the Institute of Psychiatry, Psychology and Neuroscience (IoPPN) that brings clinicians and non-clinician scientists together to supervise PhD projects that aim to translate scientific understanding into clinical progress.
Neurodevelopmental disorders, including autism spectrum disorder, intellectual disability, attention deficit hyperactivity disorder, schizophrenia and epilepsy account for a major healthcare burden across the world. Many of these disorders feature aberrant sensory adaptation and habituation. It is unclear whether there is a common underlying cause across conditions. It is also unclear whether this cognitive symptom is a root cause of other non-cognitive symptoms found in those disorders. We have taken the approach of studying highly penetrant genetic causes of neurodevelopmental disorders in mice so that we can understand the role played by that genetic factor at a circuit level. We have initially focused on relatively common genetic forms of intellectual disability, including Fragile X syndrome, Tuberous Sclerosis Complex, Rett syndrome and Neurofibromatosis type 1, which are each caused by dysfunction in a single known gene. We are investigating how critical circuitry is modified in mouse models of these disorders to produce aberrant habituation and novelty detection. In the future, we aim to use this approach as a platform to test potential therapeutics to recover cognitive function in these models. The laboratory is currently part of the MRC Centre for Neurodevelopmental Disorders (CNDD) at KCL, which is a collection of laboratories across many schools and departments in the Institute of Psychiatry, Psychology and Neuroscience (IoPPN) that brings clinicians and non-clinician scientists together to supervise PhD projects that aim to translate scientific understanding into clinical progress.
[Picture]
EEG recorded from freely moving mouse model of Fragile X Syndrome demonstrating elevated power in the gamma frequency range. Figure from Kornfeld-Sylla et al. 2026. Data collected and anaysed by Cigdem Gelegen.
Degenerative Neurological Disorders and Dementia
Our societies are becoming older on average as people live longer due to advances in healthcare. However, this progress has also meant that neurological disorders that predominate in the elderly are becoming more prevalent, including Alzheimer's Disease, Parkinson's disease, Vascular Dementia, Lewy Body Dementia, Fronto-Temporal Dementia and many other conditions. A primary symptom of many of these degenerative disorders is dementia, where failures of memory start to have a profound impact on individuals, eventually leading to a requirement for full-time care. Not only does dementia in its various forms cause great human distress, both for the individuals themselves and their families, but it creates an enormous economic burden for society. Thus, it is critical that we develop a deeper understanding of the causes and progression of these disorders, in the hope that more efficacious treatments can be developed. There is now some hope that there may be progress in treating several of these forms of dementia based on a growing understanding of the underlying pathology that leads to the irreversible death of different populations of neurons in the brain. However, it seems increasingly likely that treatment needs to be applied early in the progression of these disorders, long before neurons die, when there is a true opportunity to prevent damage and inexorable progress to dementia and there is now an appreciation that the actual origin of the disorder is likely to be in synaptic dysfunction. These critical early processes of synaptic dysfunction may not have a clear effect on cognition that can lead to diagnosis, given the cognitive reserve that many people have built up through their lifetime that masks progression to dementia, and it therefore seems that many diagnoses based on memory difficulties potentially occur decades after the critical early phase where treatment would be most efficacious. Thus, there is a deep need to understand the early synaptic pathophysiology that contributes to these conditions and, equally importantly, to develop ways of measuring this early synaptic dysregulation in humans using affordable and easy to implement methods that could be rolled out across the whole population so as to detect the very earliest stages of these various degenerative diseases. We are investigating how habituation and novelty detection is affected in mouse models of highly penetrant genetic causes of dementia. In addition, we are working to understand the basis of EEG phenomena that are known to be affected in dementia, as these hold promise as early and easily recorded markers of degenerative disorders.
Our societies are becoming older on average as people live longer due to advances in healthcare. However, this progress has also meant that neurological disorders that predominate in the elderly are becoming more prevalent, including Alzheimer's Disease, Parkinson's disease, Vascular Dementia, Lewy Body Dementia, Fronto-Temporal Dementia and many other conditions. A primary symptom of many of these degenerative disorders is dementia, where failures of memory start to have a profound impact on individuals, eventually leading to a requirement for full-time care. Not only does dementia in its various forms cause great human distress, both for the individuals themselves and their families, but it creates an enormous economic burden for society. Thus, it is critical that we develop a deeper understanding of the causes and progression of these disorders, in the hope that more efficacious treatments can be developed. There is now some hope that there may be progress in treating several of these forms of dementia based on a growing understanding of the underlying pathology that leads to the irreversible death of different populations of neurons in the brain. However, it seems increasingly likely that treatment needs to be applied early in the progression of these disorders, long before neurons die, when there is a true opportunity to prevent damage and inexorable progress to dementia and there is now an appreciation that the actual origin of the disorder is likely to be in synaptic dysfunction. These critical early processes of synaptic dysfunction may not have a clear effect on cognition that can lead to diagnosis, given the cognitive reserve that many people have built up through their lifetime that masks progression to dementia, and it therefore seems that many diagnoses based on memory difficulties potentially occur decades after the critical early phase where treatment would be most efficacious. Thus, there is a deep need to understand the early synaptic pathophysiology that contributes to these conditions and, equally importantly, to develop ways of measuring this early synaptic dysregulation in humans using affordable and easy to implement methods that could be rolled out across the whole population so as to detect the very earliest stages of these various degenerative diseases. We are investigating how habituation and novelty detection is affected in mouse models of highly penetrant genetic causes of dementia. In addition, we are working to understand the basis of EEG phenomena that are known to be affected in dementia, as these hold promise as early and easily recorded markers of degenerative disorders.