The antisaccade task as a research tool in psychopathology: A critical review

The antisaccade task is a measure of volitional control of behavior sensitive to fronto-striatal dysfunction. Here we outline important issues concerning antisaccade methodology, consider recent evidence of the cognitive processes and neural mechanisms involved in task performance, and review how the task has been applied to study psychopathology. We conclude that the task yields reliable and sensitive measures of the processes involved in resolving the conflict between volitional and reflexive behavioral responses, a key cognitive deficit relevant to a number of neuropsychiatric conditions. Additionally, antisaccade deficits may reflect genetic liability for schizophrenia. Finally, the ease and accuracy with which the task can be administered, combined with its sensitivity to fronto-striatal dysfunction and the availability of suitable control conditions, may make it a useful benchmark tool for studies of potential cognitive enhancers

Neuropsychological and electrophysiological biomarkers of the schizophrenia spectrum

Schizophrenia is a neuropsychiatric disorder lying at the extreme of a spectrum of disorders that possibly share a common abnormality in neural connectivity. Efforts to reverse the core cognitive manifestations of schizophrenia using drug treatments have so far been unsuccessful. This thesis investigates the cognitive abnormalities and their electrophysiological correlates across the schizophrenia spectrum in order to identify and validate biomarkers for proof of concept studies of cognitive enhancers. Such studies in milder disorders of the schizophrenia spectrum such as schizotypal personality trait may be a crucial method in identifying new effective compounds, as reviewed in Chapter 3, and tested in Chapter 4. The latter features the results of a large three-centre study which probed the sensitivity of several neuropsychological measures to the schizotypy phenotype, as well as to the effects of amisulpride, risperidone and nicotine. Schizotypal volunteers showed impaired performance only on the more difficult tasks. The most consistent pharmacological finding was that amisulpride tended to improve performance in the high schizotypy group but to impair it in the average schizotypy controls. One interpretation is that the ability of low dose amisulpride to enhance dopamine function in frontal cortex reversed an impairment of dopamine function present in the high schizotypes which is thought to occur in schizophrenia. Chapter 5 explored the methodological question of whether low or average schizotypy individuals should be used as controls in cognitive comparisons versus high schizotypy. The results suggest that low schizotypes have the most intact cognitive performance and are therefore the control group of choice. Chapters 6, 7 and 8 tested the hypothesis that cognitive deficits are part of a larger information processing abnormality in the schizophrenia spectrum. In accordance, both high schizotypy and schizophrenia patients exhibited reduced amplitude of an early visual evoked potential P1 (Chapters 6 and 8, respectively) and disruptions of the underlying evoked neural oscillations (Chapters 7 and 8). The pattern of abnormalities suggested an inefficient top-down modulation of perception in the schizophrenia spectrum. These data argue that cognitive abnormalities and their electrophysiological correlate may be sensitive biomarkers of the core dysconnectivity deficit in schizophrenia. This thesis supports their use in proof of concept studies to foster the development of cognitive enhancers.EThOS - Electronic Theses Online ServiceThe University of ManchesterP1vitalGBUnited Kingdo

Neuropsychological and electrophysiological biomarkers of the schizophrenia spectrum

Schizophrenia is a neuropsychiatric disorder lying at the extreme of a spectrum of disorders that possibly share a common abnormality in neural connectivity. Efforts to reverse the core cognitive manifestations of schizophrenia using drug treatments have so far been unsuccessful. This thesis investigates the cognitive abnormalities and their electrophysiological correlates across the schizophrenia spectrum in order to identify and validate biomarkers for proof of concept studies of cognitive enhancers. Such studies in milder disorders of the schizophrenia spectrum such as schizotypal personality trait may be a crucial method in identifying new effective compounds, as reviewed in Chapter 3, and tested in Chapter 4. The latter features the results of a large three-centre study which probed the sensitivity of several neuropsychological measures to the schizotypy phenotype, as well as to the effects of amisulpride, risperidone and nicotine. Schizotypal volunteers showed impaired performance only on the more difficult tasks. The most consistent pharmacological finding was that amisulpride tended to improve performance in the high schizotypy group but to impair it in the average schizotypy controls. One interpretation is that the ability of low dose amisulpride to enhance dopamine function in frontal cortex reversed an impairment of dopamine function present in the high schizotypes which is thought to occur in schizophrenia. Chapter 5 explored the methodological question of whether low or average schizotypy individuals should be used as controls in cognitive comparisons versus high schizotypy. The results suggest that low schizotypes have the most intact cognitive performance and are therefore the control group of choice. Chapters 6, 7 and 8 tested the hypothesis that cognitive deficits are part of a larger information processing abnormality in the schizophrenia spectrum. In accordance, both high schizotypy and schizophrenia patients exhibited reduced amplitude of an early visual evoked potential P1 (Chapters 6 and 8, respectively) and disruptions of the underlying evoked neural oscillations (Chapters 7 and 8). The pattern of abnormalities suggested an inefficient top-down modulation of perception in the schizophrenia spectrum. These data argue that cognitive abnormalities and their electrophysiological correlate may be sensitive biomarkers of the core dysconnectivity deficit in schizophrenia. This thesis supports their use in proof of concept studies to foster the development of cognitive enhancers.EThOS - Electronic Theses Online ServiceThe University of ManchesterP1vitalGBUnited Kingdo

The off-prescription use of modafinil and methylphenidate: Perceived risks, benefits and impact on cognitive function

Many psychoactive pharmaceuticals, in addition to their intended clinical benefits, can also enhance cognitive functions in healthy populations. Popularity in cognitive enhancing drug (CED) use has raised concerns about its possible risks and harms. Modafinil and methylphenidate are, perhaps, the most consumed CEDs. This thesis sought to understand more about the modafinil and methylphenidate off-prescription user and whether they are self-medicating for poor cognitive performance or enhancing. Study 1, an online survey advertised on forum sites to reach the CED-using and student populations, revealed that CED users are mostly male, North American or British, educated, employed and in their mid-20s. Use of CEDs was associated with recreational drug use and psychiatric disorders. Daily use of modafinil was reported as providing the most benefits and that benefits increased with more frequent use. Modafinil was perceived as safe, whereas methylphenidate was perceived as more dangerous. Study 1 could not assess whether CED-using respondents were self-medicating or enhancing, therefore, Study 2, an online survey, addressed this via the Cognitive Failures Questionnaire (Broadbent, Cooper, Fitzgerald & Parks, 1982), the General Procrastination Questionnaire (Lay, 1986), and the Adult ADHD Self-Report Scale, in addition to questions on CED and recreational drug use. The results revealed that the CED-user groups reported having problems with inattention and procrastination compared with controls. Study 3, an experimental study, sought to verify this objectively. The cognitive performance of 43 reported off-prescription users of modafinil and methylphenidate and 47 controls was tested using the Arrow Flanker Task (Ridderinkhof, van der Molen, Band & Bashore, 1997) and the Antisaccade task (Hallett, 1978), together with the self-report Behaviour Rating Inventory of Executive Function - Adults questionnaire (Gioia, Isquith, Guy & Kenworthy, 2000). The results indicated that the CED-user group demonstrated good cognitive performance and therefore were likely to be enhancing rather than self-medicating. The implications of these findings are discussed in relation to future research, ethical debates, and government policy

Non-invasive monitoring of pharmacokinetics and pharmacodynamics for pharmacological drug profiling in children and adolescents

This thesis describes the potential role of non-invasive measurement of pharmacokinetics (pk) and pharmacodynamics (pd) in the research and development of central nervous system (cns) stimulants or depressants for children and adolescents. First, we evaluated the feasibility of using saliva as an alternative to plasma in two studies on psychostimulants (caffeine and methylphenidate). Second, neuropsychological and neurophysiological functions were measured longitudinally using the NeuroCart, a battery of tests developed at the Centre for Human Drug Research (chdr, Leiden, The Netherlands) that includes non-invasive tests for alertness, visuomotor coordination, motor control, memory, and subjective drug effects. Using a non-invasive approach, age-dependent differences in alcohol pk and pd were evaluated between healthy adolescents and adults. This thesis concludes with the report of two clinical trials that were designed to evaluate age-appropriate formulations of sedative drugs that have the potential for use in children.The publication of this thesis was financially supported by the foundation Centre for Human Drug Research (chdr), Leiden, the NetherlandsUBL - phd migration 201

The cerebellum in drug craving

Craving has been considered one of the core features of addiction. It can be defined as the urge or conscious desire to use a drug elicited by the drug itself, drug-associated cues or stressors. Craving plays a major role in relapse, even after prolonged periods of abstinence, as well as in the maintenance of drug seeking in non-abstinent addicts. The circuitry of craving includes medial parts of the prefrontal cortex, ventral striatal zones, ventral tegmental area, ventral pallidum, and limbic regions. Interestingly, the cerebellum shows reciprocal loops with many of these areas. The cerebellum has been linked traditionally to motor functions but increasing evidence indicates that this part of the brain is also involved in functions related to cognition, prediction, learning, and memory. Moreover, the functional neuroimaging studies that have addressed the study of craving in humans repeatedly demonstrate cerebellar activation when craving is elicited by the presentation of drug-related cues. However, the role of cerebellar activity in these craving episodes remains unknown. Therefore, the main goal of this review is to provide a brief update on craving studies and the traditional neural basis of this phenomenon, and then discuss and propose a hypothesis for the function of the cerebellum in craving episodes.This work was supported by grant UJI (14I307.01/1

Smooth Pursuit and Antisaccade Eye Movements as Endophenotypes in Schizophrenia Spectrum Research

Smooth pursuit eye movement (SPEM) and antisaccade deficits have been proposed as schizophrenia spectrum endophenotypes. An endophenotype is a behavioural or biological deficit thought to represent, more closely than the disease phenotype, the effects of an underlying disease gene. Oculomotor endophenotypes possess phenotypic homogeneity, well-understood neural correlates and objective assessment and may thus be used as phenotypes in linkage studies. This thesis investigated a number of issues concerning the reliability and validity of the SPEM and antisaccade tasks as schizophrenia spectrum endophenotypes (and two tasks thought to be unimpaired in the schizophrenia spectrum, visual fixation and prosaccades). The schizophrenia spectrum encompasses not only people with schizophrenia but any population with an increased frequency of schizophrenia-related phenotypes or genotypes, such as schizotypal individuals or first-degree relatives of schizophrenia patients. A valid endophenotype should thus be detected in these populations. Study I investigated reliability, namely internal consistency and temporal stability, of eye movements in healthy individuals. Study II utilised first-episode psychosis patients and healthy controls, aiming to detect behavioural oculomotor deficits in the absence of secondary confounds that may be encountered in chronic schizophrenia. Study III assessed performance in siblings discordant for schizophrenia. Study IV explored the relationship between psychometric schizotypy and oculomotor performance. Study V examined possible state effects of procyclidine, an anticholinergic compound often administered to schizophrenia patients, on performance in a patient group. The results generally confirmed the validity of the SPEM and antisaccade deficits as schizophrenia spectrum endophenotypes: Oculomotor performance was mostly stable both within and between assessments. SPEM and antisaccade impairments were observed in first­episode psychosis patients and schizophrenia patients and their healthy siblings. Antisaccade, but not SPEM, impairments were associated with high levels of schizotypy. State effects of procyclidine on SPEM and antisaccade performance were observed, suggesting the need to consider the influence of pharmacological treatment in future patient studies. These findings suggest that SPEM and antisaccade deficits may be studied profitably as endophenotypes in schizophrenia spectrum research