Clinical evaluation of thalamic deep brain stimulation for movement disorders in multiple sclerosis

Disorders of movement are recognized features of multiple sclerosis (MS). They often involve the upper limbs, headland trunk and can prevent a person from carrying out the simplest of daily activities such as holding a drink and feeding themselves. This may have enormous psychological consequences, often leading to frustration, embarrassment (particularly in social situations), withdrawal and increased dependence on others.Treatment of these disorders of movement, which are usually refractory to medical therapy, has been by thalamotomy, a neuroablative technique. Results have been variable and often unsatisfactory in the long term. Recently thalamic deep brain stimulation (DBS) has been proposed after its successful use in the treatment of Parkinsonian tremor. Relatively little information exists on the use of this treatment in patients with MS. Studies carried out so far have been on very small cohorts and have used non-validated outcome scales and short follow-up. There is little data on the effect of the movement disorder on a person's disability, handicap and quality of life (QOL); the perception of ability after surgery; and on the costs involved in thalamic DBSThe work presented here had 3 principal objectives: first to develop and validate a scale for measuring movement disorders in MS (MDMS); secondly to evaluate the effect of thalamic DBS on impairment, disability, handicap and aspects of quality of life (QOL) relevant to these patients; and thirdly to estimate the costs associated with thalamic DBS.The Modified Fahn's Tremor Rating Scale (MFTRS) was developed and validated for the purposes of this study. Results of the validity, reliability and responsiveness of the MFTRS, as given in the published paper, showed that it can be used with confidence in the clinical setting.Thirty seven patients with MDMS were assessed before operation. Fifteen patients underwent thalamic surgery. The target arm was assessed 1, 3, 6 and 12 months after operation using the MFTRS, which measured severity of tremor, and the Jebsen Test of Hand Function (JTHF) which measured performance of 7 subtests of upper limb function. Information concerning the influence of the movement disorder on overall disability, handicap and QOL was collected at or over 12 months and was compared with that of the pre-operative assessment using various subjective rating scales and questionnaires.Results showed that thalamic DBS significantly reduced the severity of tremor amplitude and significantly improved performance of the Jebsen subtests when the DBS was on at each post-operative assessments (1, 3, 6, and 12 months) compared with pre-operatively (all p values < 0.02). However, these symptomatic and changes in function did not translate into significant improvements in patients' performance in activities of daily living and thus there were no apparent economic benefits (ie. savings in future care-costs). Also there was no change in patients' perceptions of their handicap or in most aspects of QOL: the only significant change was that patients perceived themselves to be less anxious 12 months after the operation (p-0.03). The overall impact was therefore clinically limited.This prospective study has illustrated the benefits and limitations of thalamic DBS in patients with MDMS, and has highlighted the post-operative rehabilitation and follow-up requirements and the resulting health economic implications associated with its use. The validation of the MFTRS not only enabled the effect of thalamic DBS to be evaluated but also provided a major contribution to the assessment of MDMS

Designing a comprehensive system for analysis of handwriting biomechanics in relation to neuromotor control of handwriting

A comprehensive system for investigation of biomechanical and neuromuscular processes involved with producing handwriting and drawing was developed. The system included a pen-like grip measuring device that enabled the variations of finger grip force associated with writing and drawing to be measured while holding the pen in tripod grip. The pen was integrated with a digitiser tablet for recording x,ycoordinates and pressure of the nib and a motion analysis system for recording the limb and hand kinematics. It was observed that for line drawing in the y-direction of the tablet, finger forces were directly related to pen tip movement and finger forces were modulated in a repeatable and predictable fashion, while this was not the case for line drawing in the x-direction. This was evidence for longstanding assumptions. Wrist rotation was required for production of lines in the x-direction without excessive deviation. For writing tasks, it was observed that no two tasks performed by one subject share an identical writing process, not even when the writing results are (nearly) identical. The neuromuscular control apparatus is highly flexible and works in a coordinated fashion that allows production of nearly equal end-results by means of different mechanical and therefore neuromuscular processes. For spiral drawing, tremor that originates from the fingers, hand and arm was quantified with the transducer pen. Limb joint kinematics were displayed in three dimensions with colour coding of coordinate sample numbers. This method can reveal the origin of some forms of limb tremor. Pen grip force patterns during signature writing were found to be characteristic for subjects, which relate to their individual pen-hand interaction, resulting from fine control of distal joints. Variation between trials of the same subject was observed, revealing adaptations of the computational processes during writing. The potential for signature verification by means of finger force recording was explored.A comprehensive system for investigation of biomechanical and neuromuscular processes involved with producing handwriting and drawing was developed. The system included a pen-like grip measuring device that enabled the variations of finger grip force associated with writing and drawing to be measured while holding the pen in tripod grip. The pen was integrated with a digitiser tablet for recording x,ycoordinates and pressure of the nib and a motion analysis system for recording the limb and hand kinematics. It was observed that for line drawing in the y-direction of the tablet, finger forces were directly related to pen tip movement and finger forces were modulated in a repeatable and predictable fashion, while this was not the case for line drawing in the x-direction. This was evidence for longstanding assumptions. Wrist rotation was required for production of lines in the x-direction without excessive deviation. For writing tasks, it was observed that no two tasks performed by one subject share an identical writing process, not even when the writing results are (nearly) identical. The neuromuscular control apparatus is highly flexible and works in a coordinated fashion that allows production of nearly equal end-results by means of different mechanical and therefore neuromuscular processes. For spiral drawing, tremor that originates from the fingers, hand and arm was quantified with the transducer pen. Limb joint kinematics were displayed in three dimensions with colour coding of coordinate sample numbers. This method can reveal the origin of some forms of limb tremor. Pen grip force patterns during signature writing were found to be characteristic for subjects, which relate to their individual pen-hand interaction, resulting from fine control of distal joints. Variation between trials of the same subject was observed, revealing adaptations of the computational processes during writing. The potential for signature verification by means of finger force recording was explored

The clinical spectrum and pathophysiology of neuropathic tremor

This thesis describes a series of studies involving patients with neuropathies and healthy controls. In the studies of disease, two groups were recruited: patients with inflammatory neuropathies and those with hereditary neuropathies. Each group was separated into those with and those without tremor and compared with healthy controls. Clinical assessments and neurophysiological tests were employed to correlate cerebellar function with tremor. The final study of healthy participants investigated the effect of transcranial direct current stimulation (TDCS) on the cerebellum during finger tapping. 1) Tremor was most common in IgM paraproteinaemic neuropathies, also occurring in 58% of those with chronic inflammatory demyelinating polyradiculoneuropathy and 56% of those with multifocal motor neuropathy with conduction block (MMNCB). Tremor was generally refractory to treatment and contributed to disability in some patients. Although tremor severity correlated with F wave latency, it was insufficient to distinguish those with, from those without tremor. 2) Impaired eyeblink classical conditioning and paired associative stimulation in patients with inflammatory neuropathy and tremor differentiated them from neuropathy patients without tremor and healthy controls, strongly suggesting impairment of cerebellar function is linked to the production of tremor in these patients. 3) The prevalence study in CMT1A patients revealed tremor in 21% and in 42% of those it caused impairment. Eyeblink conditioning, visuomotor adaptation and electro-oculography were no different between tremulous and non-tremulous patients and healthy controls. This argues against a prominent role for an abnormal cerebellum in tremor generation in the patients studied. Rather, they suggest an enhancement of the central neurogenic component of physiological tremor as a possible mechanism. 4) TDCS of the lateral cerebellum and its effect on paced finger tapping was examined. There was no effect on accuracy or variability of the intertap interval, providing no support for a direct role of the cerebellum in event based timing

A Longtitudinal Analysis of Cognitive and Eye Movement Deficits in Alzheimer's Disease.

The main purpose of this thesis was to investigate longitudinally, cognitive and eye movement deficits in Alzheimer's disease. A key aspect of the work was to examine the potential utility of saccadic eye movements in the diagnosis of Alzheimer's disease. Study I investigated saccadic error rates and error correction in Alzheimer's disease, other dementias and healthy elderly control participants using reflexive and voluntary saccade paradigms, to identify salient findings for further analysis. Study II explored the fixation offset effect in Alzheimer's disease, other dementias and healthy elderly control participants, to study the attention (fixation) disengagement deficit previously reported in Alzheimer's disease. Study III examined the effects of normal aging and disease, comparing Alzheimer's disease patients and other dementia types with healthy young adult control participants, healthy elderly control participants and Parkinson's disease patients. Study IV assessed the potential effects of acetylcholinesterase inhibitors on baseline data to eliminate medication effects. Study V investigated repeated measures data for salient observations from Studies I and II in Alzheimer's disease patients and healthy elderly control participants over an 18 month period. Study VI evaluated salient saccadic eye movement and neuropsychological assessment variables, with a view to generating regression models that could predict dementia. Alzheimer's disease patients were found to commit inhibition errors that increased in proportion according to the demands of the voluntary saccade task. Error-correction analysis, revealed that a high proportion of errors remain uncorrected in the antisaccade task, a finding apparently specific to dementia. The results were found to be consistent with the notion that the voluntary saccade tasks require selective attention, the facilitation of which is dependent on task goals being sufficiently activated in working memory. The magnitude of fixation offset effect was greater for Alzheimer's disease patients than controls and Parkinson's disease patients at baseline, but the longitudinal analysis showed that this magnitude decreased over subsequent test sessions. The large initial magnitude of fixation offset effect is believed to have been caused by over compensation of volitional compensation strategies at baseline, when the Alzheimer's disease patients had mild dementia. Regression models using antisaccade variables and neuropsychological assessment scores as predictors both performed well. It is feasible that models could be developed that would enable a reduced set of neuropsychological assessments to be used and three predictors from one antisaccade task. The results confirm that the antisaccade task is a useful model paradigm for the study of oculomotor dysfunction in dementia

Locomotor patterns and persistent activity in self-organizing neural models

The thesis investigates principles of self-organization that may account for the observed structure and behaviour of neural networks that generate locomotor behaviour and complex spatiotemporal patterns such as spiral waves, metastable states and persistent activity. This relates to the general neuroscience problem of finding the correspondence between the structure of neural networks and their function. This question is both extremely important and difficult to answer because the structure of a neural network defines a specific type of neural dynamics which underpins some function of the neural system and also influences the structure and parameters of the network including connection strengths. This loop of influences results in a stable and reliable neural dynamics that realises a neural function. In order to study the relationship between neural network structure and spatiotemporal dynamics, several computational models of plastic neural networks with different architectures are developed. Plasticity includes both modification of synaptic connection strengths and adaptation of neuronal thresholds. This approach is based on a consideration of general modelling concepts and focuses on a relatively simple neural network which is still complex enough to generate a broad spectrum of spatio-temporal patterns of neural activity such as spiral waves, persistent activity, metastability and phase transitions. Having considered the dynamics of networks with fixed architectures, we go on to consider the question of how a neural circuit which realizes some particular function establishes its architecture of connections. The approach adopted here is to model the developmental process which results in a particular neural network structure which is relevant to some particular functionality; specifically we develop a biologically realistic model of the tadpole spinal cord. This model describes the self-organized process through which the anatomical structure of the full spinal cord of the tadpole develops. Electrophysiological modelling shows that this architecture can generate electrical activity corresponding to the experimentally observed swimming behaviour

Complexity, Emergent Systems and Complex Biological Systems:\ud Complex Systems Theory and Biodynamics. [Edited book by I.C. Baianu, with listed contributors (2011)]

An overview is presented of System dynamics, the study of the behaviour of complex systems, Dynamical system in mathematics Dynamic programming in computer science and control theory, Complex systems biology, Neurodynamics and Psychodynamics.\u

Handbook on clinical neurology and neurosurgery

HANDBOOKNEUROLOGYNEUROSURGERYКЛИНИЧЕСКАЯ НЕВРОЛОГИЯНЕВРОЛОГИЯНЕЙРОХИРУРГИЯThis handbook includes main parts of clinical neurology and neurosurgery

Balance : Art and Nature

Directly relating aesthetic depravation to its environmental counterpart, Grande describes society as only capable of consuming, rather the appreciating, both art and nature. The author argues for the need for artists, using nature as a model, to create socially progressive and responsible work and extrapolates on the problems of postmodern art and the increasing pervasiveness of technology. Contemporary art (predominantely Canadian) reinforcing the "status quo" is critically examined along with the work of such artists as Goldsworthy, Kapoor, and Gormley. 205 bibl. ref