The main theme of this thesis is that there is a common structural basis for drugs acting on the central nervous system (CNS), and that this concept may be used to design new CNS-active drugs which have greater specificity and hence less side-effects. To develop these ideas, the biological basis of how drugs modify CMS neurotransmission is described, and illustrated using dopaminergic pathways. An account is then given of the use of physicochemical concepts in contemporary drug design. The complete conformational analysis of several antipsychotic drugs is used to illustrate some of these techniques in the development of a model for antipsychotic drug action. After reviewing current structure-activity studies in several classes of CNS drugs (antipsychotics, anti-depressants, stimulants, hal1ucinogens, anticonvulsants and analgesics), a hypothesis for a common structural basis of CNS drug action is proposed- This is based on a topographical comparison of the X-ray structures of eight representative CNS-active drugs, and consists of three parts: 1.there is a common structural basis for the activity of many different CNS-active drug classes; 2. an aromatic ring and a nitrogen atom are the primary binding groups whose topographical arrangement is fundamental to the activity of these drug classes; 3. the nature and placement of secondary binding determines different classes of CNS drug activity. A four-Point model for this common structural basis is then defined using 14- CNS-active drug structures that include the original eight used in proposing the hypothesis. The coordinates of this model are: R1 (0. 3.5, 0), R2 (0, -3.5, O), N (4.8. -0.3, 1.4), and R3 (6.3, 1.3, 0), where R1 and R2 represent the point locations of a hydrophobic interaction of the common aromatic ring with a receptor, and R3 locates the receptor point for a hydrogen bond involving the common nitrogen, N. Extended structures were used to define the receptor points R1, R2 and R3, and the complete conformational space of each of the 14 molecules was considered. It is then shoun that the model may be used to predict whether a given structure is likely to show CNS activity: a search over 1,000 entries in the current Merck Index shows a high probability (82%) of CNS activity in compounds fitting the structural model. Analysis of CNS neurotransmitters and neuropeptides shows that these fit the common model well. Based on the available evidence supporting chemical evolution, protein evolution, and the evolution of neurotransmitter functions, it is surmised that the aromatic ring/nitrogen atom pharmacophore proposed in the common model supports the idea of the evolution of CNS receptors and their neurotransmitters, possibly from an aromatic amine or acety1cho1ine acting as a primaeval communicating molecule. The third point in the hypothesis trilogy is then addressed. The extensive conformation-activity analyses that have resulted in well-defined models for five separate CNS drug classes are used to map out the locations of secondary binding groups relative to the common model for anti-psychotics, antidepressants, analgesics, anticholinergics, and anticonvulsants. With this information, and knowledge derived from receptor-binding data, it is postulated that drugs having specified activity could be designed. In order to generate novel structures having a high probability of CNS-activity, a process of drug design is described in which known CNS structures are superimposed topographically using the common model as a template. Atoms regarded as superfluous may be selectively deleted and the required secondary binding groups added in predicted locations to give novel structures. It is concluded that this process provides the basis for the rational design of new lead compounds which could further be optimized for potent and specific CNS activity.

Thesis (Ph. D.)--University of Missouri--Columbia, 2003. / Typescript. Vita. Includes bibliographical references (leaves 172-205). Also available on the Internet.

Thesis (Ph. D.)--University of Alabama at Birmingham, 2007. / Title from first page of PDF file (viewed Feb. 17, 2009). Includes bibliographical references.

Thesis (M.S.P.H.)--University of Michigan, 1938.

Thesis (M.S.P.H.)--University of Michigan, 1938.

A thesis submitted to the Faculty of Health Sciences of the University of the Witwatersrand, for the degree of Master of Science, Johannesburg, 2012 / HIV continues to affect thousands of children in South Africa. HIV not only has a negative impact on growth, morbidity and mortality but also adversely affects neurodevelopment. The virus is able to enter the central nervous system and cause damage which results in encephalopathy. A high percentage of infants infected with HIV are delayed. The roll out of HAART in South Africa was started in 2004 and in 2010 new guidelines to improve access were implemented. Although HAART is effective in improving growth, decreasing morbidity and mortality its effects on neurodevelopment are generally unknown. Very little high quality research has been done on the effects of HAART on neurodevelopment especially in developing countries and on infants.

Thesis (Ph.D.)--University of Alabama at Birmingham, 2009. / Title from PDF title page (viewed on Feb. 2, 2010). Includes bibliographical references.

The aim of the research described in this thesis is to improve our understanding of how the central nervous system (CNS) integrates feedback information from different sensory modalities to permit skill acquisition, and the subsequent consolidation of that skill, when exposed to a novel visuomotor environment. Indeed, such adaptation must be consolidated and recalled when appropriate such that we do not have to continually relearn skills we once possessed. By manipulating the sensory feedback available from the visual and proprioceptive systems during learning, it is possible to determine those facets of the sensory feedback that are essential for adaptation to occur. The thesis consists of seven chapters. The first and last provide a conceptual basis for, and an overall discussion of, the research. Chapter 2 reviews current visuomotor adaptation research, with particular focus on the manner in which information about novel tasks is stored within the CNS as we adapt, and the sensory information that is necessary to allow this adaptation to occur. Furthermore, this chapter serves to introduce many of the experimental techniques that are used to investigate motor learning in humans. Chapter 3 is a report of an investigation of the issues of interference and consolidation in an isometric target acquisition task. Exposure to a 30° counter-clockwise (CCW) rotation was followed by a period of rest, trials with no rotation, or trials with a 60° clockwise (CW) rotation. Retention of the initial adaptation was assessed 5 hours later. Full interference was manifested in circumstances in which either counter-rotated or non-rotated trials were encountered following the initial learning period. These results are consistent with the view that the observed interference is anterograde in nature, and highlight differences in the mechanisms employed by the CNS when compensating for novel kinematics (e.g. visuomotor rotations) compared with adapting to novel dynamics (e.g. external forces). Chapter 4 is a report of an investigation of the role of visual feedback in adapting to novel visuomotor environments in an isometric target acquisition task. Following trials with no rotation, participants adapted to a 60° CCW visuomotor rotation before returning to the non-rotated condition. Separate groups received either continuous visual feedback (CF) of cursor position during task execution or post-trial visual feedback (PF), both indicating task performance. One CF group were instructed to make any (feedback) modifications necessary during the task to reduce errors and acquire the target, while another CF group were instructed to make uncorrected, ballistic movements. Colour cues permitted the identification of the task environment (nonrotated/ rotated) on every trial. The results indicate that an automatic recalibration of the visuomotor mapping occurs when CF is provided, and suggest that performance improvements with PF may occur via the adoption of a cognitively mediated strategy. Furthermore, execution of feedback motor commands to correct errors did not enhance the adaptation that occurred when CF was provided, indicating that the perception of sensory errors (and not feedback commands that may be applied to reduce those errors) drives feedforward visuomotor adaptation. To investigate whether additional proprioceptive feedback associated with movement altered the adaptation patterns observed in chapter 4, a study similar to that reported in chapter 4 was undertaken, and is reported in chapter 5. In this instance a discrete, goaldirected, movement task replaced the isometric task. Subjects were deprived of vision of their arm, but were provided with PF or CF indicating task performance. The patterns of adaptation noted in the isometric task were also exhibited in this dynamic task, indicating that the timing of the visual feedback of task performance has a profound effect on how performance improvements in a novel visuomotor rotation occur. The experiment reported in Chapter 6 assessed the ability to adapt to two conflicting visuomotor rotations interleaved within the same training period, when each task variant (rotation) could be identified by contextual (colour) cues. While full dual adaptation was not observed, the results suggest that the colour cues may have been utilised to explicitly select distinct motor commands for each task rotation.

The aim of the research described in this thesis is to improve our understanding of how the central nervous system (CNS) integrates feedback information from different sensory modalities to permit skill acquisition, and the subsequent consolidation of that skill, when exposed to a novel visuomotor environment. Indeed, such adaptation must be consolidated and recalled when appropriate such that we do not have to continually relearn skills we once possessed. By manipulating the sensory feedback available from the visual and proprioceptive systems during learning, it is possible to determine those facets of the sensory feedback that are essential for adaptation to occur. The thesis consists of seven chapters. The first and last provide a conceptual basis for, and an overall discussion of, the research. Chapter 2 reviews current visuomotor adaptation research, with particular focus on the manner in which information about novel tasks is stored within the CNS as we adapt, and the sensory information that is necessary to allow this adaptation to occur. Furthermore, this chapter serves to introduce many of the experimental techniques that are used to investigate motor learning in humans. Chapter 3 is a report of an investigation of the issues of interference and consolidation in an isometric target acquisition task. Exposure to a 30° counter-clockwise (CCW) rotation was followed by a period of rest, trials with no rotation, or trials with a 60° clockwise (CW) rotation. Retention of the initial adaptation was assessed 5 hours later. Full interference was manifested in circumstances in which either counter-rotated or non-rotated trials were encountered following the initial learning period. These results are consistent with the view that the observed interference is anterograde in nature, and highlight differences in the mechanisms employed by the CNS when compensating for novel kinematics (e.g. visuomotor rotations) compared with adapting to novel dynamics (e.g. external forces). Chapter 4 is a report of an investigation of the role of visual feedback in adapting to novel visuomotor environments in an isometric target acquisition task. Following trials with no rotation, participants adapted to a 60° CCW visuomotor rotation before returning to the non-rotated condition. Separate groups received either continuous visual feedback (CF) of cursor position during task execution or post-trial visual feedback (PF), both indicating task performance. One CF group were instructed to make any (feedback) modifications necessary during the task to reduce errors and acquire the target, while another CF group were instructed to make uncorrected, ballistic movements. Colour cues permitted the identification of the task environment (nonrotated/ rotated) on every trial. The results indicate that an automatic recalibration of the visuomotor mapping occurs when CF is provided, and suggest that performance improvements with PF may occur via the adoption of a cognitively mediated strategy. Furthermore, execution of feedback motor commands to correct errors did not enhance the adaptation that occurred when CF was provided, indicating that the perception of sensory errors (and not feedback commands that may be applied to reduce those errors) drives feedforward visuomotor adaptation. To investigate whether additional proprioceptive feedback associated with movement altered the adaptation patterns observed in chapter 4, a study similar to that reported in chapter 4 was undertaken, and is reported in chapter 5. In this instance a discrete, goaldirected, movement task replaced the isometric task. Subjects were deprived of vision of their arm, but were provided with PF or CF indicating task performance. The patterns of adaptation noted in the isometric task were also exhibited in this dynamic task, indicating that the timing of the visual feedback of task performance has a profound effect on how performance improvements in a novel visuomotor rotation occur. The experiment reported in Chapter 6 assessed the ability to adapt to two conflicting visuomotor rotations interleaved within the same training period, when each task variant (rotation) could be identified by contextual (colour) cues. While full dual adaptation was not observed, the results suggest that the colour cues may have been utilised to explicitly select distinct motor commands for each task rotation.

Thesis (Ph. D.)--West Virginia University, 2010. / Title from document title page. Document formatted into pages; contains x, 102 p. : ill. (some col.). Includes abstract. Includes bibliographical references.