Functional network correlates of language and semiology in epilepsy

Epilepsy surgery is appropriate for 2-3% of all epilepsy diagnoses. The goal of the presurgical workup is to delineate the seizure network and to identify the risks associated with surgery. While interpretation of functional MRI and results in EEG-fMRI studies have largely focused on anatomical parameters, the focus of this thesis was to investigate canonical intrinsic connectivity networks in language function and seizure semiology. Epilepsy surgery aims to remove brain areas that generate seizures. Language dysfunction is frequently observed after anterior temporal lobe resection (ATLR), and the presurgical workup seeks to identify the risks associated with surgical outcome. The principal aim of experimental studies was to elaborate understanding of language function as expressed in the recruitment of relevant connectivity networks and to evaluate whether it has value in the prediction of language decline after anterior temporal lobe resection. Using cognitive fMRI, we assessed brain areas defined by parameters of anatomy and canonical intrinsic connectivity networks (ICN) that are involved in language function, specifically word retrieval as expressed in naming and fluency. fMRI data was quantified by lateralisation indices and by ICN_atlas metrics in a priori defined ICN and anatomical regions of interest. Reliability of language ICN recruitment was studied in 59 patients and 30 healthy controls who were included in our language experiments. New and established language fMRI paradigms were employed on a three Tesla scanner, while intellectual ability, language performance and emotional status were established for all subjects with standard psychometric assessment. Patients who had surgery were reinvestigated at an early postoperative stage of four months after anterior temporal lobe resection. A major part of the work sought to elucidate the association between fMRI patterns and disease characteristics including features of anxiety and depression, and prediction of postoperative language outcome. We studied the efficiency of reorganisation of language function associated with disease features prior to and following surgery. A further aim of experimental work was to use EEG-fMRI data to investigate the relationship between canonical intrinsic connectivity networks and seizure semiology, potentially providing an avenue for characterising the seizure network in the presurgical workup. The association of clinical signs with the EEG-fMRI informed activation patterns were studied using the data from eighteen patients’ whose seizures and simultaneous EEG-fMRI activations were reported in a previous study. The accuracy of ICN_atlas was validated and the ICN construct upheld in the language maps of TLE patients. The ICN construct was not evident in ictal fMRI maps and simulated ICN_atlas data. Intrinsic connectivity network recruitment was stable between sessions in controls. Amodal linguistic processing and the relevance of temporal intrinsic connectivity networks for naming and that of frontal intrinsic connectivity networks for word retrieval in the context of fluency was evident in intrinsic connectivity networks regions. The relevance of intrinsic connectivity networks in the study of language was further reiterated by significant association between some disease features and language performance, and disease features and activation in intrinsic connectivity networks. However, the anterior temporal lobe (ATL) showed significantly greater activation compared to intrinsic connectivity networks – a result which indicated that ATL functional language networks are better studied in the context of the anatomically demarked ATL, rather than its functionally connected intrinsic connectivity networks. Activation in temporal lobe networks served as a predictor for naming and fluency impairment after ATLR and an increasing likelihood of significant decline with greater magnitude of left lateralisation. Impairment of awareness served as a significant classifying feature of clinical expression and was significantly associated with the inhibition of normal brain functions. Canonical intrinsic connectivity networks including the default mode network were recruited along an anterior-posterior anatomical axis and were not significantly associated with clinical signs

Modern Developments in Transcranial Magnetic Stimulation (TMS) – Applications and Perspectives in Clinical Neuroscience

Transcranial magnetic stimulation (TMS) is being increasingly used in neuroscience and clinics. Modern advances include but are not limited to the combination of TMS with precise neuronavigation as well as the integration of TMS into a multimodal environment, e.g., by guiding the TMS application using complementary techniques such as functional magnetic resonance imaging (fMRI), electroencephalography (EEG), diffusion tensor imaging (DTI), or magnetoencephalography (MEG). Furthermore, the impact of stimulation can be identified and characterized by such multimodal approaches, helping to shed light on the basic neurophysiology and TMS effects in the human brain. Against this background, the aim of this Special Issue was to explore advancements in the field of TMS considering both investigations in healthy subjects as well as patients

Laryngeal reinnervation: feasibility studies and development of trial outcome measures

The unifying theme of this thesis is a series of research studies that collectively amount to a feasibility study for clinical trials of laryngeal reinnervation for the treatment of vocal fold paralysis. The question ‘Does laryngeal reinnervation or thyroplasty give better voice results for patients with unilateral vocal fold paralysis (UVFP)?’ remains outstanding; a question that ideally requires a randomised control trial. However, randomised control trials in surgery face inherent surgeons’ equipoise and recruitment issues that may lead to its failure. I performed a national survey of UK ENT consultants exploring their perception and obtaining crude numbers of eligible UVFP patients under their care for such trial, which revealed that the majority of ENT surgeons are receptive to the trial and the size of the potential patient pool is promising. I interviewed eligible UVFP patients to explore issues around the recruitment process, and this suggested that the proposed trial is feasible. Some phraseology used during recruitment that needed changing was identified, which may optimise the recruitment process for a trial. In voice surgery trials, outcome measures should be multidimensional and standardised. Acoustic analysis has been proposed but has limitations. OperaVOX is a potential new acoustic analysis software developed to resolve some of these factors. I demonstrated that OperaVOX is statistically comparable to the ‘gold standard’, Multidimensional Voice Programme, for most principal phonatory outcome measures. Another outcome measure- video-laryngostroboscopy, allows visual evaluation of characteristics and vibratory pattern of vocal folds. It is typically subjective that requires inter- and intra-rater reliability study. Here, I demonstrated that certain parameters depicted substantial inter- and intra-rater reliability. However, I showed that rater training is required to improve the reliability of other parameters. I investigated MRI as a potential non-invasive method to evaluate vocal muscles’ denervation and reinnervation. I found that signal changes on the T2-weighted MRI larynx images correlated with electrophysiological results with good repeatability. Another MRI sequence, dynamic contrast enhanced- and diffusion weighted MRI, suggested reduced perfusion in paralysed muscles, whilst cine-MRI for vocal fold mobility assessment demonstrated considerable potential as a method to grade vocal fold mobility. Finally, I present a small prospective case series of non-selective and selective laryngeal reinnervation in UVFP and unilateral vagal paralysis following vagal tumour excision respectively concomitant with injection laryngoplasty. Voice improvement was demonstrated by voice handicap index-10 and other multidimensional outcome measures, and these were supported by laryngeal electromyography and T2-weighted MRI outcomes. To my knowledge, this is the first multidimensional prospective study of laryngeal reinnervation and also the first to suggest that 3T MRI may be a promising outcome measure for future reinnervation trials. In summary, I have shown that a randomised trial of laryngeal reinnervation versus thyroplasty is feasible in the UK, and have validated patient- and observer-rated outcome measures. I have also shown that MRI may offer an alternative to electromyography in the assessment of laryngeal neuromuscular function in future trials and the clinic

The effects of strength training on intermuscular coordination during maximal cycling

In natural movement tasks individual muscles are seldom required to generate force in isolation and instead most functional movements arise from the cooperation of several muscles acting together – intermuscular coordination. Contemporary studies of movement coordination are often undertaken using the ecological dynamics theoretical framework and Newell’s model of constraints. Ecological dynamics examines human performance from a person-environment scale of analysis considering how people interact with a specific task and the performance environment, and the role these constraints play in the emergent coordination patterns. Pedalling is an ideal task to study intermuscular coordination since it is a natural movement task that can be accurately manipulated. Sprint cyclists often undertake gym-based strength training to increase muscle strength and size. Therefore, the aim of this programme of research was to understand how cyclists adapt their intermuscular coordination patterns during maximal cycling owing to changing organismic constraints (muscle size, strength and fatigue) caused by the gym-based strength training using the theoretical framework of ecological dynamics. In accordance with the theoretical framework of ecological dynamics and Newell’s model of constraints this programme of research highlighted the influence of the constraints acting on the cyclists’ coordination patterns that emerge. Different movement and coordination patterns were observed for maximal cycling when the task constraints were changed from sprinting on a fixed ergometer in the laboratory to a track bicycle in the velodrome. This finding implies it is important to undertake biomechanical analyses of movement organisation in elite sports practice in a representative environment. Also, following a gym-based strength training intervention the cyclists’ crank power increased, but there were no changes in joint moments, power or muscle activation which suggested that the cyclists might adopt individual coordination strategies following the change in their organismic constraints after the strength training intervention

Examining behavioural and electrophysiological markers of mental workload in individuals with and without a history of concussion

Objectives: The goal of this thesis was to examine the neurocognitive mechanisms of mental workload for the purpose of improving our knowledge of the long-term effects of concussion. Four experiments were performed manipulating mental workload in individuals with and without a history of concussion. Studies one and two increased mental workload by manipulating set size (i.e., number of items to be remembered) and task condition (single-task, dual-task) in individuals with and without a history of concussion, respectively. In addition, event-related potentials (ERPs) were recorded to examine the neural correlates of information processing that are affected by mental workload. Study three examined mental workload by changing the requirements of the task through the manipulation of pattern configuration characteristics. The fourth study examined mental workload in individuals with and without a history of concussion using three types of workload manipulation: set size, task condition, and pattern configuration complexity. Methods: Thirty-six participants (20 no-concussion, 16 asymptomatic) were recruited for studies one and two, and assessed using a dual-task paradigm involving a computerised eCorsi block task and auditory oddball task that progressively increased in workload (i.e., set size, task condition). ERPs were used to study the sensory and cognitive stages of information processing as a function of mental workload. Seventeen participants (14 no-concussion, 3 asymptomatic) were tested in study three using a computer and phone version of the eCorsi task, which manipulated workload by changing the average angle of a patterns at set sizes of five to eight blocks. Study four examined secondary auditory oddball performance as a function of eCorsi pattern complexity in nineteen participants (9 no-concussion, 10 asymptomatic). Results: The no concussion group showed reduced eCorsi recall accuracy as set size increased, which was maintained between task conditions (single, dual). In contrast, auditory oddball performance decreased (i.e., poorer accuracy, longer response times [RTs]) as mental workload increased (task, set size). ERP’s showed amplitude reductions in early sensory (P50) and later cognitive (P300) potentials when both tasks were performed simultaneously compared to alone. In contrast, later sensory (N100) ERP increased in amplitude. Sensory gating was consistent at both P50 and N100 potentials as a function of mental workload. The concussion history group showed poorer auditory (lower accuracy, more errors of commission, and longer RTs) when both tasks were performed simultaneously whereas no between-group differences were found on the eCorsi task. ERPs indicated poorer sensory gating (P50, N100) and cognitive processing (i.e., reduced P300 amplitude) in the asymptomatic group, which changed as a function of workload. Investigating the properties of the dual-task showed reduced eCorsi recall accuracy in hard patterns (smaller angles, more crosses, and longer distances) compared to easy patterns; however, this did not affect auditory oddball measures. Conclusions: Sensory and cognitive processes change as a function of mental workload (task, set size) and in those with a history of concussion suggesting these individuals have problems gating in important information, which may affect the efficiency of later cognitive processes and subsequent behavioural performance. Importantly, mental workload can be increased by task condition (single, dual), set size (# of items to remember), and path configuration difficulty (easy, hard), which reflect different types of load. These findings are particularly useful in the development of sensitive neurocognitive tests for identifying persisting deficits in individuals with a history of concussion

Respiratory Muscle Strength Training to Improve Vocal Function of Patients with Presbyphonia

Background: Presbyphonia is an age-related voice disorder characterized by vocal fold atrophy, and its effects on voice are potentially compounded by declines in respiratory function. We assessed: 1) the relationships between respiratory and voice function; 2) the effect of adding respiratory exercises to voice therapy; and 3) the impact of baseline respiratory function on the response to therapy in patients with presbyphonia. Methods: Twenty-one participants underwent respiratory and voice assessments, from which relationships were drawn. Ten of these participants were blocked-randomized to receive either voice exercises only, or voice exercises combined with inspiratory muscle strength training or expiratory muscle strength training, for a duration of four weeks. Results: FVC, FEV1, and MEP had an impact on phonation physiology through their effect on aerodynamic resistance and vocal fold pliability. Percent predicted values of FVC and FEV1 were strong predictors of perceived voice handicap. IMST induced the largest improvements in perceived handicap, and a lower baseline respiratory function was associated with a greater improvement, regardless of the intervention received. Conclusion: Respiratory function impacts voice and the response to behavioral voice therapy. Adding IMST to voice exercises improves self-reported outcomes even in patients with a normal respiratory function

Reorganisation of sensorimotor function in children with brain disease

Introduction: In this study, paradigms were developed for the investigation of sensorimotor function in children using functional MRI (fMRI), somatosensory evoked potential (SEP) recordings and behavioural measures. These techniques were applied both to normal controls subjects and to children with brain disease. A major aim was to investigate the remarkable recovery of function that can take place following brain injury sustained early in life. Methods: Three fMRI paradigms were developed, namely active movement of the hand, passive flexion/extension movement of the fingers and median nerve stimulation. In addition, SEPs of functional cortical responses to stimulation of the median nerve were recorded at high temporal resolution. Finally, the extent of residual or recovered sensory and motor hand function was assessed using behavioural tests, including grip strength and double simultaneous stimulation. In one set of investigations, all three techniques were applied to children following hemispherectomy or children following vascular damage to the middle cerebral artery territory, to examine the pattern of residual sensorimotor function following brain injury. In a second study, fMRI was carried out in pre-surgical paediatric patients for mapping of the sensorimotor cortex in preparation for surgical resection of lesions in the vicinity of this cortical region. Results and Discussion: fMRI was successful in locating the hand cortical sensorimotor area in 11 out of 12 paediatric patients pre-operatively, and was of value to the neurosurgeon in helping to delineate the boundaries of subsequent cortical resection. In patients following stroke and hemispherectomy, a combination of fMRI, SEP and behavioural techniques provided evidence for inter-hemispheric reorganisation of sensorimotor function through ipsilateral sensorimotor pathways, and also suggested an increase in the involvement of ipsilateral secondary sensorimotor areas. The data also indicate that cortical sensorimotor reorganisation and functional recovery can be seen in patient both with congenital disease and with late-onset acquired disease, suggesting that factors additional to age at injury may influence the degree of residual function resulting from cerebral reorganisation. Informed consent was obtained for all patients and controls, and the study was approved by the Great Ormond Street Hospital for Children/Institute of Child Health Research Ethics Committee

THE AUDITORY BRAINSTEM RESPONSE IN HEALTHY ADULTS AND ADULTS WITH ALCOHOL DEPENDENCE SYNDROME

The Auditory Brainstem Response (ABR) assesses brainstem function. This thesis explores the click and speech ABR in both healthy adults and adults with alcohol dependence syndrome (ADS). Experiment One undertook auditory-cognitive assessment including ABRs, of 60 healthy adults (30 women), aged 18-30 years. For waves III and V of the click ABR, women’s responses were earlier than men’s by 0.14ms and 0.19ms. For the speech ABR, onset and offset measures were earlier in women by at least 0.43ms. No effect for left vs. right ear was found in either case. Inter-rater reliability was found to be high (ICC2,1 ≥0.89) for the click ABR and good (ICC2,1 ≥0.75) for six of the seven peaks of the speech ABR. A comparison of ABRs to those from an older group of 12 adults aged 31-49 years (six women, matched control group for Experiment Two) found the stimulus to response lag for the speech ABR, was earlier (0.78ms) in the older women but within the expected range. Click and speech ABRs were repeated after 12 weeks and the representation of F0 for women was greater by 4.8 μV at the second recording. Experiment Two assessed the auditory-cognitive profile and ABRs of 16 adults (six women) aged 29-49 years, undergoing a treatment and rehabilitation programme for people with ADS. All participants had hearing thresholds within normal limits, but exhibited deficits in auditory-cognitive profiles compared to matched, healthy adults, including their click and speech ABRs. For the click ABR, men had significant delays in wave III (0.18ms) and wave V (0.22ms). For women there were significant delays for wave I (0.11ms) and wave V (0.22ms). For the speech ABR, men had significant delays in the onset measures of waves V (0.40ms) and A (0.36ms). Women had significant delays in waves V (0.45ms), A (0.48ms) E (0.66ms) and O (0.42ms). Testing was repeated after 12 weeks of abstinence and significant improvements in the click and speech ABR were observed. For men, average click ABR latencies improved for wave III (0.12ms) and wave V (0.22ms) and for women, wave V (0.08ms) improved. Significant improvements were also found for discrete peak and onset measures of the speech ABRs for both men and women. For men, average speech ABR latencies improved for wave A (0.23ms) and the duration of the VA complex (0.15ms). For women there were improvements in wave V (0.10ms), A (0.12ms) and E (0.33ms). These results add to the body of knowledge about the ABR and support its value as a clinical tool. They also provide new information about auditory-cognitive function in adults with ADS, for whom beneficial effects of abstinence are demonstrated. The ABR has a potential role in identifying people most at risk of alcohol related brain damage and in monitoring recovery with abstinence. Keywords Auditory Brainstem Response, Frequency Following Response, Speech ABR, Reliability, Alcohol Dependence Syndrome, Abstinence