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Objective Traumatic brain injury (TBI) is a common disabling condition with limited treatment options. Diffusion tensor imaging measures recovery of axonal injury in white matter (WM) tracts after TBI. Growth hormone deficiency (GHD) after TBI may impair axonal and neuropsychological recovery, and serum insulin‐like growth factor‐I (IGF‐I) may mediate this effect. We conducted a longitudinal study to determine the effects of baseline serum IGF‐I concentrations on WM tract and neuropsychological recovery after TBI. Methods Thirty‐nine adults after TBI (84.6% male, median age = 30.5 years, 87.2% moderate–severe, median time since TBI = 16.3 months, n = 4 with GHD) were scanned twice, 13.3 months (range = 12.1–14.9) apart, and 35 healthy controls were scanned once. Symptom and quality of life questionnaires and cognitive assessments were completed at both visits (n = 33). Our main outcome measure was fractional anisotropy (FA), a measure of WM tract integrity, in a priori regions of interest: splenium of corpus callosum (SPCC) and posterior limb of internal capsule (PLIC). Results At baseline, FA was reduced in many WM tracts including SPCC and PLIC following TBI compared to controls, indicating axonal injury, with longitudinal increases indicating axonal recovery. There was a significantly greater increase in SPCC FA over time in patients with serum IGF‐I above versus below the median for age. Only the higher IGF‐I group had significant improvements in immediate verbal memory recall over time. Interpretation WM recovery and memory improvements after TBI were greater in patients with higher serum IGF‐I at baseline. These findings suggest that the growth hormone/IGF‐I system may be a potential therapeutic target following TBI. Ann Neurol 2017;82:30–43

Background: Only one-third of patients with major depressive disorder achieve remission. One new and promising treatment, ketamine, may prove challenging to implement because of its abuse potential. Although clinicians’ views have been sought, we need patients’ views before large scale roll-out is considered.Aim: To explore patients and carers’ views to inform policy and practical decisions about the clinical use of ketamine.Method: We carried out a mixed-methods study using data from 44 participants in 21 focus groups in three sessions and an online survey with patients, carers and advocates during a consultation day. Focus groups explored participant’s views about ketamine as a form of treatment and the best way for ketamine to be prescribed and monitored. The qualitative data were analysed by two service user researchers using an exploratory framework analysis and was supplemented by a survey.Results: The ten themes generated were monitoring, information, effect on daily life, side effects, recreational use, effectiveness, appropriate support, cost, stigma and therapy. Discussion: Participants wanted better evidence on the safety of ketamine after long-term use and felt that monitoring was required. Collecting this information would provide evidence for Ketamine’s safe use and administration. There were, however, concerns about the misuse of this information. Practical issues of access were important: repeated travelling to clinics and a lack of sufficiently informed medical staff were key barriers. Conclusion: Clinicians have some similar and some different views to those of patients, carers and advocates, which need to be considered in any future roll-out of ketamine.

Summary Objectives Traumatic brain injury (TBI) is a major cause of long‐term disability with variable recovery. Preclinical studies suggest that vitamin D status influences the recovery after TBI. However, there is no published clinical data on links between vitamin D status and TBI outcomes. The aim was to determine the (i) prevalence of vitamin D deficiency/insufficiency, and associations of vitamin D status with (ii) demographic factors and TBI severity, and with (iii) cognitive function, symptoms and quality of life, in adults after TBI. Design Retrospective audit of patients seen between July 2009 and March 2015. Serum vitamin D (25‐hydroxy‐cholecalciferol) was categorized as deficient (70 nmol/l). Patients A total of 353 adults seen in tertiary hospital clinic (75·4% lighter skinned, 74·8% male, age median 35·1 year, range 26·6–48·3 year), 0·3–56·5 months after TBI (74·5% moderate–severe). Measurements Serum vitamin D concentrations; Addenbrooke's Cognitive Examination (ACE‐R), Beck Depression Inventory‐II (BDI‐II), SF‐36 Quality of Life, Pittsburgh Sleep Quality Index. Results In total, 46·5% of patients after TBI had vitamin D deficiency and 80·2% insufficiency/deficiency. Patients with vitamin D deficiency had lower ACE‐R scores than those of vitamin D replete (mean effect size ± SEM 4·5 ± 2·1, P = 0·034), and higher BDI‐II scores than those of vitamin D insufficient (4·5 ± 1·6, P = 0·003), correcting for age, gender, time since TBI and TBI severity. There was no association between vitamin D status and markers of TBI severity, sleep or quality of life. Conclusion Vitamin D deficiency is common in patients after TBI and associated with impaired cognitive function and more severe depressive symptoms.

Interactions between the Salience Network (SN) and the Default Mode Network (DMN) are thought to be important for cognitive control. However, evidence for a causal relationship between the networks is limited. Previously, we have reported that traumatic damage to white matter tracts within the SN predicts abnormal DMN function. Here we investigate the effect of this damage on network interactions that accompany changing motor control. We initially used fMRI of the Stop Signal Task to study response inhibition in humans. In healthy subjects, functional connectivity (FC) between the right anterior insula (rAI), a key node of the SN, and the DMN transiently increased during stopping. This change in FC was not seen in a group of traumatic brain injury (TBI) patients with impaired cognitive control. Furthermore, the amount of SN tract damage negatively correlated with FC between the networks. We confirmed these findings in a second group of TBI patients. Here, switching rather than inhibiting a motor response: (1) was accompanied by a similar increase in network FC in healthy controls; (2) was not seen in TBI patients; and (3) tract damage after TBI again correlated with FC breakdown. This shows that coupling between the rAI and DMN increases with cognitive control and that damage within the SN impairs this dynamic network interaction. This work provides compelling evidence for a model of cognitive control where the SN is involved in the attentional capture of salient external stimuli and signals the DMN to reduce its activity when attention is externally focused.

It is now widely accepted that cognitive control depends on the integrated operation of large-scale distributed brain networks. Recent methodological advances allow both structural and functional connectivity (FC) within these networks to be studied non- invasively in vivo. These approaches hold the promise of dramatically extending our understanding of the impact of traumatic brain injury (TBI) on cognitive control, which has the potential to help determine strategic targets for the rehabilitation of individuals with TBI.\ud \ud In the current thesis, structural and functional magnetic resonance imaging is combined to test the general hypothesis that cognitive deficits after TBI arise from functional disconnection within brain networks that mediate cognitive functions. Of particular interest are the interactions between two brain networks known as the Salience Network (SN) and the Default Mode Network (DMN). These networks are thought to be important for cognitive control however, how these networks interact during cognitive control is limited.\ud \ud This thesis largely investigates the effect of TBI on network interactions that accompany changing motor control. Functional MRI of the Stop Signal Task (SST) is initially used to study response inhibition. In healthy subjects, FC between the right anterior insula (rAI), a key node of the SN, and the DMN transiently increased during stopping. This change in FC was not seen in a group of TBI patients with impaired cognitive control. Furthermore, the amount of damage to the underlying white matter tract negatively correlated with the strength of FC between the networks.\ud \ud These findings are confirmed in a second group of TBI patients. In the second group, switching rather than inhibiting a motor response: (1) was accompanied by a similar increase in network FC in healthy controls; (2) was not seen in TBI patients; and (3) tract damage after TBI again correlated with FC breakdown. I also replicate this pattern of structure-function in a group of elderly participants who demonstrate similar cognitive control impairments as the TBI group.\ud \ud The findings show that FC between the rAI and DMN increases with cognitive control, and that the ability to efficiently regulate the FC between the rAI and DMN can be predicted by the structural integrity within a remote brain network previously proposed to be involved in switching between internally and externally directed attention. This work provides evidence for a model of cognitive control where the SN is involved in the attentional capture of salient external stimuli and signals the DMN to reduce its activity when attention is externally focused. It also identifies DMN dysfunction as underlying various cognitive deficits after TBI, and confirms the relevance of white matter damage in the development of brain dysfunctions after TBI.