Willed action and its impairment in schizophrenia

Schizophrenia is a disabling psychiatric disorder characterised by positive symptoms (those which the patients experience and are abnormal by their presence such as hallucinations) and negative signs (when the patients lack some element of normal behaviour such as poverty of speech). Frith (1992) suggested that some of the signs and symptoms of schizophrenia reflect a dysfunction of "willed" actions while the processes involved in "stimulus driven" actions remain largely intact. The patients can perform routine acts elicited by environmental stimuli, but have difficulty in producing spontaneous behaviour in the absence of external cues. The aim of this thesis is to examine this hypothesis using a variety of experimental paradigms and procedures to asses willed initiation and preparation as well as willed suppression of action in schizophrenia. The aim of Study 1 was to assess the initiation and preparation of willed actions in 10 patients with schizophrenia and 13 controls using reaction time (RT) tasks that differ in the degree to which they involve volitionally controlled versus stimulus-driven responses. Study 2 examined performance of 11 patients with schizophrenia and 13 normal controls on two motor tasks (placing pegs in a pegboard and repetitive index finger tapping) under unimanual, bimanual and dual task conditions. The aim of Study 3 was to examine the above hypothesis by measuring movement related potentials (MRPs) prior to self-initiated and externally-triggered movements in three groups: 6 patients with schizophrenia with high ratings of negative signs, 5 patients with of schizophrenia with high ratings of positive symptoms and 6 normal controls. Studies 4, 5 and 6 examined willed suppression. Go no-go RT tests have both a relevant stimulus requiring a response and to-be-ignored stimuli requiring the response to be withheld, i.e. response inhibition. The aim of Study 4 was to examine the ability to withhold a response in conditions with increased complexity of decision-making for identifying 'go' stimuli in 14 patients with schizophrenia and 12 normal controls. The aim of Study 5 was to examine the ability to withhold a response in conditions with greater dimensional overlap between the non-target no-go and the target go stimuli in 14 patients with schizophrenia and 12 normal controls. The patients were divided into two groups, the 'high symptom' group consisted of the 7 patients with ratings of positive symptoms higher than the group median of 9, and the 'low symptom' group consisted of the 7 patients with positive symptom ratings below 9. The patients with 'high symptom' ratings had slower RTs than the controls which were significant for the SRT conditions of both tasks, and approached significance for the CRT conditions of both tasks. The differences in SRT or CRT between the 'low symptom' group and the controls were not statistically significant for either task. In Study 5 the controls showed greater slowing between CRT1 and CRT2 than between CRT2 and CRT3, whereas the RTs of 'low symptom' patients did not differ at all between CRT1 and CRT2 and slowed greatly for CRT3. Both patient groups had slower response times than controls in the Hayling test, and produced significantly fewer words in the alternating word fluency task compared to the controls. Performance on the cognitive tasks correlated with performance on the no-go tasks. Negative priming refers to the slowing of reaction times that occurs when an ignored distractor stimulus in a first trial (prime) becomes the target stimulus in the subsequent trial (probe) (Tipper, 1985). Unlike normal controls, patients with schizophrenia fail to show significant negative priming, that is, the significant delay of reaction times on probe trials are not present (Beech et al., 1989; David, 1995). The aim of study 6 was to examine the spatial negative priming effect in schizophrenia using a new paradigm that allows the effects of perceptual mismatch on RT to be considered independently of any spatial negative priming effects. The patients with schizophrenia did not show any spatial negative priming in conditions with or without perceptual mismatch. These results constitute the first unequivocal demonstration of impaired inhibitory processes in schizophrenia based on reduced negative priming effects. These results provide some overall but not uniformly consistent support for the hypothesis that patients with schizophrenia have an impairment in willed action while stimulus driven action remains intact. (Abstract shortened by UMI.

Discovery of candidate genes and pathways in the endometrium regulating ovine blastocyst growth and conceptus elongation

Copyright © 2009 the American Physiological SocietyEstablishment of pregnancy in ruminants requires blastocyst growth to form an elongated conceptus that produces interferon tau, the pregnancy recognition signal, and initiates implantation. Blastocyst growth and development requires secretions from the uterine endometrium. An early increase in circulating concentrations of progesterone (P4) stimulates blastocyst growth and elongation in ruminants. This study utilized sheep as a model to identify candidate genes and regulatory networks in the endometrium that govern preimplantation blastocyst growth and development. Ewes were treated daily with either P4 or corn oil vehicle from day 1.5 after mating to either day 9 or day 12 of pregnancy when endometrium was obtained by hysterectomy. Microarray analyses revealed many differentially expressed genes in the endometria affected by day of pregnancy and early P4 treatment. In situ hybridization analyses revealed that many differentially expressed genes were expressed in a cell-specific manner within the endometrium. The Database for Annotation, Visualization, and Integrated Discovery (DAVID) was used to identify functional groups of genes and biological processes in the endometrium that are associated with growth and development of preimplantation blastocysts. Notably, biological processes affected by day of pregnancy and/or early P4 treatment included lipid biosynthesis and metabolism, angiogenesis, transport, extracellular space, defense and inflammatory response, proteolysis, amino acid transport and metabolism, and hormone metabolism. This transcriptomic data provides novel insights into the biology of endometrial function and preimplantation blastocyst growth and development in sheep.M. Carey Satterfield, Gwonhwa Song, Kelli J. Kochan, Penny K. Riggs, Rebecca M. Simmons, Christine G. Elsik, David L. Adelson, Fuller W. Bazer, Huaijun Zhou and Thomas E. Spence