Title: Developing electroencephalography as a tool to predict delirium and long-term cognitive outcome after traumatic brain injury.
Funder: Department of Health and Social Care

Abstract: Approximately 1 million patients are hospitalised every year in Europe after Traumatic Brain Injury (TBI). The most severe TBI patients are admitted to Intensive Care Units (ICU) and receive high-dose sedation to prevent and reduce brain oedema. Clinicians stop sedation when an assessment of neurological recovery is required. While a few patients remain comatose or only partially regain awareness, the majority of patients recover but many experience delirium on recovery. Delirium can present as an altered mental state with confusion, disorientation, poor attention, amnesia and motor agitation (hyperactive subtype), drowsiness (hypoactive subtype), or both (mixed subtype).Delirium is frequent in the general ICU population (up to 87%) and is associated with longer ICU stay and increased adverse outcomes. Due to the heterogeneity of symptoms, the poor reproducibility of screening tools and lack of reliable prediction models, delirium is often under-recognised and difficult to predict.The role of malfunctioning brain networks in the pathophysiology of delirium development is being progressively supported by electroencephalography (EEG) and brain imaging findings. TBI patients are at the highest risk of brain network dysfunction; the injury itself leads to structural damage of brain connections and neurotransmitter imbalance triggered by high-dose sedative drugs disrupts the brain's functional connectivity.Delirium in ICU isone of the top three priorities for intensive care research and its management represents a significant unmet need for patients who survive TBI. During this fellowship, my ultimate aim is to develop a bedside tool based on EEG functional connectivity to identify patients at high risk of developing delirium following TBI. I will achieve this goal by performing: 1) an international audit of >2000 ICU patients, 2) an observational EEG study in 150 ICU patients following TBI and 3) an anaesthesia EEG study in healthy volunteers.This will allow me to a) describe the prevalence and clinical features of delirium;b) allow early prediction of delirium by separating the EEG signatures of prolonged sedation from those of persistent neurological impairment andc) understand brain mechanisms underlying each delirium subtype and their impact on long-term outcome.The international audit on the practices of sedation, analgesia and delirium management in ICU (SAnDMAN study) is funded and underway. It will identify the prevalence of delirium and its subtypes and provide an international collaborative framework for future validation of the developed EEG metrics in a larger sample of ICU patients. In the observational patient and healthy volunteer studies, I will test my hypotheses that: 1) the degree of impaired information processing (measured as EEG functional connectivity) correlates with delirium severity in TBI patients in ICU; 2) persistent impaired connectivity at two weeks is associated with long-term cognitive impairment; 3) evoked-responses to tactile and auditory stimuli of patients with hyperactive and hypoactive delirium resemble the responses elicited in healthy volunteers receiving excitatory (ketamine) and depressant (dexmedetomidine) drugs, respectively. The proposed research project will be carried out in the Anaesthesia Neuroimaging Group, based in the University of Oxford and the John Radcliffe Hospital.

Lay abstract: Head injury is one of the leading causes of disability in young people aged 16-40 years and affects many older people after slips or falls. Most severe head injuries require urgent admission to intensive care units (ICU), where patients are often kept asleep with anaesthetic drugs to help them recover. Both the head injury and the anaesthetic drugs cause a phase of unconsciousness during the recovery period. Most patients recover well but many (30 to 90%) develop delirium when they recover consciousness.Delirium is a state of mental confusion during which the affected person may become agitated or restless, see things that are not there, suffer memory loss, have trouble focusing on conversations or tasks, or become very drowsy. Delirium can last for over a month and delay recovery and rehabilitation after head injury. It can be very difficult to diagnose as patients cannot always communicate or understand what is going on. It is therefore highly distressing for both the head injured individuals and their families. In some cases, this may cause severe long-term mental health problems. For these reasons, both patients and ICU professionals from the UK Intensive Care Society believe it is very important to conduct more research into delirium after head injury.It is still unclear how delirium develops, especially after head injury. It is thought that delirium stops the brain from working normally, causing 'malfunctions' in the connections between brain regions. International research has confirmed this occurs in ICU patients admitted after heart surgery. They measured the brain's electrical activity using electroencephalography (EEG) by attaching small sensors to the scalp. In my research, I will use EEG to predict whether head injured patients develop delirium during their ICU stay. I want to find out what symptoms of delirium correspond with particular abnormal brain functions to help doctors select the most appropriate treatment for each head injured patient.Over a period of 4 years, I will recruit 150 adults after head injury from the Neuro ICU at the John Radcliffe Hospital in Oxford. In each patient, I will record an EEG when 1) doctors stop the anaesthesia, 2) when the patients wake up, and 3) again after two weeks. Each time, I will study the brain's activity at rest and in response to sounds and touch. I will compare these responses in three groups of head injured patients - those with delirium with agitation, those with delirium with sleepiness and those with mixed symptoms. With the help of two Research Nurses and the Head Injury Neuropsychology team, I will invite all patients for a follow-up outpatient appointment six months after the head injury and perform an interview and another EEG.My research will firstly identify the incidence of delirium during ICU stay after head injury. I will perform statistical analyses to identify how well the brain is connected and how this changes with delirium. I will test whether there is a relationship between the amount (or type of) malfunctioning brain connections and the sort of delirium experienced. To understand how these malfunctions occur, I will compare the EEG responses to sound and touch in agitated and sleepy delirium patients with those of healthy individuals who receive stimulant or depressant anaesthetic drugs, respectively. Overall, I hope to develop an EEG tool to predict whether delirium will occur and help doctors choose the most appropriate treatment for each individual patient. This research has the potential to reduce the long-term emotional and physical burden on patients and their families. It will help doctors understand why some patients make a poor recovery and guide further research to help these patients.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL