work showing that various CDR measures relate closely to activities of daily living. The sensitiv... more work showing that various CDR measures relate closely to activities of daily living. The sensitivity of the CDR system to anticholinesterases will be described in Alzheimer's disease, dementia with Lewy bodies and Parkinson's dementia. Finally, the CDR system has a large normative database which allows treatment effects in dementia to be put into an unambiguous clinical perspective.
Attention-deficit hyperactivity disorder (ADHD) is the most prevalent behavioral diagnosis in chi... more Attention-deficit hyperactivity disorder (ADHD) is the most prevalent behavioral diagnosis in children, with an estimated 500 000 children affected in the United Kingdom alone. The need for an appropriate and effective intervention for children with ADHD is a growing concern for educators and childcare agencies. This randomized controlled clinical trial evaluated the impact of the HeartMath self-regulation skills and coherence training program (Institute of HeartMath, Boulder Creek, California) on a population of 38 children with ADHD in academic year groups 6, 7, and 8. Learning of the skills was supported with heart rhythm coherence monitoring and feedback technology designed to facilitate self-induced shifts in cardiac coherence. The cognitive drug research system was used to assess cognitive functioning as the primary outcome measure. Secondary outcome measures assessed teacher and student reposted changes in behavior. Participants demonstrated significant improvements in variou...
A double-blind, randomized, placebo-controlled study assessed the effects of sertraline on the ph... more A double-blind, randomized, placebo-controlled study assessed the effects of sertraline on the pharmacokinetics and pharmacodynamics of phenytoin in 30 healthy male volunteers. All subjects received phenytoin throughout the study. The dose of phenytoin was 100 mg three times daily; steady-state trough plasma phenytoin concentrations were determined on Day 6. Concurrent treatment with sertraline (16 subjects) or placebo (13 subjects) was initiated on Day 8 and continued throughout the study in those subjects whose trough plasma phenytoin concentrations were between 5 and 20 micrograms/mL. The dose of sertraline was increased from 50 to 200 mg/day over 7 days; the 200-mg dose was then administered for 10 days. The plasma phenytoin concentration-time profile was determined on Day 7 before the start of sertraline or placebo dosing and at the end of dosing on Day 24. Psychometric testing was done before and after dosing on Days 0, 7, and 24. There were no significant differences between ...
Biomonitoring for Physiological and Cognitive Performance during Military Operations, 2005
ABSTRACT The Cognitive Drug Research (CDR) computerized assessment system has been in use in worl... more ABSTRACT The Cognitive Drug Research (CDR) computerized assessment system has been in use in worldwide clinical trials for over 20 years. It is a computer based system which assesses core aspects of human cognitive function including attention, information, working memory and long-term memory. It has been extensively validated and can be performed by a wide range of clinical populations including patients with various types of dementia. It is currently in worldwide use in clinical trials to evaluate new medicines, as well as a variety of programs involving the effects of age, stressors illnesses and trauma upon human cognitive function. Besides being highly sensitive to drugs which will impair or improve function, its utility has been maintained over the last two decades by constantly increasing the number of platforms upon which it can operate. Besides notebook versions, the system can be used on a wrist worn device, PDA, via tht telephone and over the internet. It is the most widely used automated cognitive function assessment system in worldwide clinical research. It has dozens of parallel forms and requires little training to use or administer. The basic development of the system wil be identified, and the huge databases (normative, patient population, drug effects) which have been built up from hundreds of clinical trials will be described. The system is available for use in virtually any environment or type of trial.
Practice effects are characteristic of nearly all standard cognitive tasks when repeated during s... more Practice effects are characteristic of nearly all standard cognitive tasks when repeated during serial assessments and are frequently important confounders in clinical trials.
Drug Discovery and Evaluation: Methods in Clinical Pharmacology, 2011
ABSTRACT In early phase clinical trials of new medicines, two of the major CNS pharmacodynamic qu... more ABSTRACT In early phase clinical trials of new medicines, two of the major CNS pharmacodynamic questions that can be directly and widely addressed are first, whether the compounds have positive or negative effects on aspects of cognitive function and second, whether they will alter various mood states. The use both of tests of cognitive function and of self-rating scales of mood, alertness, sleepiness, etc., has a long history in clinical pharmacology, and the methods which have become established in this field will be reviewed. Many if not all CNS disorders have various profiles of alterations to cognitive function and mood, some being characterized by the cognitive deficits, for example, ADHD and dementia, and others the mood changes, for example, depression. Traditionally, cognitive function tests were used in clinical pharmacology to determine if the compound was likely to pose safety risks, by disrupting various aspects of cognitive function which are crucial for everyday activities, such as car driving. However, in the last 20 years or so, this application has broadened to seek potential benefits to cognitive function, because the opportunity to correct cognitive dysfunction has become the target of many medicines. Obvious limitations to what can be addressed in early clinical pharmacology studies are, for example, the complex behavioral problems exhibited in schizophrenia, or whether the mechanism of correcting cognitive dysfunction can be evaluated in healthy volunteers. This review will initially focus on the established techniques that are currently employed in clinical pharmacology for the assessment of human performance and various mood states. The review will then consider various measures of brain activity, starting with electroencephalography (EEG) that has a long history in clinical pharmacology; but also imaging and nuclear medicine techniques as they have started to make valuable contributions to this field and hold great future potential. The review will close by considering models that have been widely used in clinical pharmacology to help assess the therapeutic potential of new medicines.
In persons with multiple sclerosis (MS) a lowered self-efficacy negatively affects physical activ... more In persons with multiple sclerosis (MS) a lowered self-efficacy negatively affects physical activities. Against this background we studied the relationship between self-efficacy and cognitive performance in the early stages of MS. Thirty-three patients with Clinically Isolated Syndrome (CIS) and early Relapsing Remitting MS (eRRMS) were assessed for self-efficacy (MSSES-18), cognition (CDR System), fatigue (MFIS-5), depressive symptoms (BDI), disease impact (MSIS-29), and disability (EDSS). Correlative analyses were performed between self-efficacy and cognitive scores, and stepwise regression analyses identified predictors of cognition and self-efficacy. Good correlations existed between total self-efficacy and Power of Attention (r= 0.65;P< 0.001), Reaction Time Variability (r= 0.57;P< 0.001), and Speed of Memory (r= 0.53;P< 0.01), and between control self-efficacy and Reaction Time Variability (r= 0.55;P< 0.01). Total self-efficacy predicted 40% of Power of Attention, ...
The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), 2002
Elevated cortisol and cognitive impairments have been described in anorexia nervosa, but the rela... more Elevated cortisol and cognitive impairments have been described in anorexia nervosa, but the relationship between these two variables has not been adequately explored. We profiled the pattern and extent of the cognitive impairment in anorexia nervosa and determined how this related to cortisol secretion. Twenty patients with anorexia nervosa and a matched control group completed a computerized cognitive assessment battery. Diurnal cortisol secretion was measured by serial saliva sampling. Patients were significantly impaired on tasks of attention, long-term memory and working memory. Both groups showed the expected diurnal variation in cortisol production, but no evidence was found for patient cortisol hypersecretion. No correlation was found between cortisol secretion and any of the cognitive task measures. These data suggest that at least some of the cognitive impairments seen in anorexia nervosa are attributable to something other than a basal increase in cortisol secretion. The ...
It has previously been demonstrated in separate studies that single doses of Ginkgo biloba, Panax... more It has previously been demonstrated in separate studies that single doses of Ginkgo biloba, Panax ginseng, and a combination of the two extracts can improve different aspects of cognitive performance in healthy young volunteers. The present study directly compared the effects of single doses of G. biloba, ginseng, and a product combining the two on aspects of mood and cognitive performance in the same cohort of healthy, young adult volunteers. The study followed a randomised placebo-controlled, double-blind, balanced, cross-over design. Twenty participants received 360 mg of ginkgo, 400 mg of ginseng, 960 mg of a product combining the two extracts, and a matching placebo. Treatment order was dictated by random allocation to a Latin square, with a 7-day wash-out period between treatments. Cognitive testing comprised completion of the Cognitive Drug Research (CDR) computerised assessment battery and two serial subtraction mental arithmetic tasks. Mood was assessed with Bond-Lader visu...
A double-blind, randomized, placebo-controlled study was conducted in 14 healthy male volunteers ... more A double-blind, randomized, placebo-controlled study was conducted in 14 healthy male volunteers to assess the effects of sertraline on the pharmacokinetics and pharmacodynamics of carbamazepine. Subjects received carbamazepine 200 mg once daily for 2 days and every 12 hours thereafter. On Days 16 to 32, subjects also received either sertraline or placebo daily. The dose of sertraline was increased from 50 to 200 mg daily over 7 days; the 200-mg dose was given for 10 days. Samples for pharmacokinetic analyses were obtained on Days 15 and 32; trough plasma concentrations of carbamazepine and its principal metabolite, carbamazepine-10, 11-epoxide (CBZ-E), were determined daily beginning on Day 13. Cognitive function testing was performed on Day 1 before carbamazepine dosing (baseline), Day 15 (carbamazepine alone), and Day 32 (carbamazepine plus sertraline or placebo). There were no significant differences between the sertraline and placebo groups in any of the pharmacokinetic paramet...
work showing that various CDR measures relate closely to activities of daily living. The sensitiv... more work showing that various CDR measures relate closely to activities of daily living. The sensitivity of the CDR system to anticholinesterases will be described in Alzheimer's disease, dementia with Lewy bodies and Parkinson's dementia. Finally, the CDR system has a large normative database which allows treatment effects in dementia to be put into an unambiguous clinical perspective.
Attention-deficit hyperactivity disorder (ADHD) is the most prevalent behavioral diagnosis in chi... more Attention-deficit hyperactivity disorder (ADHD) is the most prevalent behavioral diagnosis in children, with an estimated 500 000 children affected in the United Kingdom alone. The need for an appropriate and effective intervention for children with ADHD is a growing concern for educators and childcare agencies. This randomized controlled clinical trial evaluated the impact of the HeartMath self-regulation skills and coherence training program (Institute of HeartMath, Boulder Creek, California) on a population of 38 children with ADHD in academic year groups 6, 7, and 8. Learning of the skills was supported with heart rhythm coherence monitoring and feedback technology designed to facilitate self-induced shifts in cardiac coherence. The cognitive drug research system was used to assess cognitive functioning as the primary outcome measure. Secondary outcome measures assessed teacher and student reposted changes in behavior. Participants demonstrated significant improvements in variou...
A double-blind, randomized, placebo-controlled study assessed the effects of sertraline on the ph... more A double-blind, randomized, placebo-controlled study assessed the effects of sertraline on the pharmacokinetics and pharmacodynamics of phenytoin in 30 healthy male volunteers. All subjects received phenytoin throughout the study. The dose of phenytoin was 100 mg three times daily; steady-state trough plasma phenytoin concentrations were determined on Day 6. Concurrent treatment with sertraline (16 subjects) or placebo (13 subjects) was initiated on Day 8 and continued throughout the study in those subjects whose trough plasma phenytoin concentrations were between 5 and 20 micrograms/mL. The dose of sertraline was increased from 50 to 200 mg/day over 7 days; the 200-mg dose was then administered for 10 days. The plasma phenytoin concentration-time profile was determined on Day 7 before the start of sertraline or placebo dosing and at the end of dosing on Day 24. Psychometric testing was done before and after dosing on Days 0, 7, and 24. There were no significant differences between ...
Biomonitoring for Physiological and Cognitive Performance during Military Operations, 2005
ABSTRACT The Cognitive Drug Research (CDR) computerized assessment system has been in use in worl... more ABSTRACT The Cognitive Drug Research (CDR) computerized assessment system has been in use in worldwide clinical trials for over 20 years. It is a computer based system which assesses core aspects of human cognitive function including attention, information, working memory and long-term memory. It has been extensively validated and can be performed by a wide range of clinical populations including patients with various types of dementia. It is currently in worldwide use in clinical trials to evaluate new medicines, as well as a variety of programs involving the effects of age, stressors illnesses and trauma upon human cognitive function. Besides being highly sensitive to drugs which will impair or improve function, its utility has been maintained over the last two decades by constantly increasing the number of platforms upon which it can operate. Besides notebook versions, the system can be used on a wrist worn device, PDA, via tht telephone and over the internet. It is the most widely used automated cognitive function assessment system in worldwide clinical research. It has dozens of parallel forms and requires little training to use or administer. The basic development of the system wil be identified, and the huge databases (normative, patient population, drug effects) which have been built up from hundreds of clinical trials will be described. The system is available for use in virtually any environment or type of trial.
Practice effects are characteristic of nearly all standard cognitive tasks when repeated during s... more Practice effects are characteristic of nearly all standard cognitive tasks when repeated during serial assessments and are frequently important confounders in clinical trials.
Drug Discovery and Evaluation: Methods in Clinical Pharmacology, 2011
ABSTRACT In early phase clinical trials of new medicines, two of the major CNS pharmacodynamic qu... more ABSTRACT In early phase clinical trials of new medicines, two of the major CNS pharmacodynamic questions that can be directly and widely addressed are first, whether the compounds have positive or negative effects on aspects of cognitive function and second, whether they will alter various mood states. The use both of tests of cognitive function and of self-rating scales of mood, alertness, sleepiness, etc., has a long history in clinical pharmacology, and the methods which have become established in this field will be reviewed. Many if not all CNS disorders have various profiles of alterations to cognitive function and mood, some being characterized by the cognitive deficits, for example, ADHD and dementia, and others the mood changes, for example, depression. Traditionally, cognitive function tests were used in clinical pharmacology to determine if the compound was likely to pose safety risks, by disrupting various aspects of cognitive function which are crucial for everyday activities, such as car driving. However, in the last 20 years or so, this application has broadened to seek potential benefits to cognitive function, because the opportunity to correct cognitive dysfunction has become the target of many medicines. Obvious limitations to what can be addressed in early clinical pharmacology studies are, for example, the complex behavioral problems exhibited in schizophrenia, or whether the mechanism of correcting cognitive dysfunction can be evaluated in healthy volunteers. This review will initially focus on the established techniques that are currently employed in clinical pharmacology for the assessment of human performance and various mood states. The review will then consider various measures of brain activity, starting with electroencephalography (EEG) that has a long history in clinical pharmacology; but also imaging and nuclear medicine techniques as they have started to make valuable contributions to this field and hold great future potential. The review will close by considering models that have been widely used in clinical pharmacology to help assess the therapeutic potential of new medicines.
In persons with multiple sclerosis (MS) a lowered self-efficacy negatively affects physical activ... more In persons with multiple sclerosis (MS) a lowered self-efficacy negatively affects physical activities. Against this background we studied the relationship between self-efficacy and cognitive performance in the early stages of MS. Thirty-three patients with Clinically Isolated Syndrome (CIS) and early Relapsing Remitting MS (eRRMS) were assessed for self-efficacy (MSSES-18), cognition (CDR System), fatigue (MFIS-5), depressive symptoms (BDI), disease impact (MSIS-29), and disability (EDSS). Correlative analyses were performed between self-efficacy and cognitive scores, and stepwise regression analyses identified predictors of cognition and self-efficacy. Good correlations existed between total self-efficacy and Power of Attention (r= 0.65;P< 0.001), Reaction Time Variability (r= 0.57;P< 0.001), and Speed of Memory (r= 0.53;P< 0.01), and between control self-efficacy and Reaction Time Variability (r= 0.55;P< 0.01). Total self-efficacy predicted 40% of Power of Attention, ...
The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), 2002
Elevated cortisol and cognitive impairments have been described in anorexia nervosa, but the rela... more Elevated cortisol and cognitive impairments have been described in anorexia nervosa, but the relationship between these two variables has not been adequately explored. We profiled the pattern and extent of the cognitive impairment in anorexia nervosa and determined how this related to cortisol secretion. Twenty patients with anorexia nervosa and a matched control group completed a computerized cognitive assessment battery. Diurnal cortisol secretion was measured by serial saliva sampling. Patients were significantly impaired on tasks of attention, long-term memory and working memory. Both groups showed the expected diurnal variation in cortisol production, but no evidence was found for patient cortisol hypersecretion. No correlation was found between cortisol secretion and any of the cognitive task measures. These data suggest that at least some of the cognitive impairments seen in anorexia nervosa are attributable to something other than a basal increase in cortisol secretion. The ...
It has previously been demonstrated in separate studies that single doses of Ginkgo biloba, Panax... more It has previously been demonstrated in separate studies that single doses of Ginkgo biloba, Panax ginseng, and a combination of the two extracts can improve different aspects of cognitive performance in healthy young volunteers. The present study directly compared the effects of single doses of G. biloba, ginseng, and a product combining the two on aspects of mood and cognitive performance in the same cohort of healthy, young adult volunteers. The study followed a randomised placebo-controlled, double-blind, balanced, cross-over design. Twenty participants received 360 mg of ginkgo, 400 mg of ginseng, 960 mg of a product combining the two extracts, and a matching placebo. Treatment order was dictated by random allocation to a Latin square, with a 7-day wash-out period between treatments. Cognitive testing comprised completion of the Cognitive Drug Research (CDR) computerised assessment battery and two serial subtraction mental arithmetic tasks. Mood was assessed with Bond-Lader visu...
A double-blind, randomized, placebo-controlled study was conducted in 14 healthy male volunteers ... more A double-blind, randomized, placebo-controlled study was conducted in 14 healthy male volunteers to assess the effects of sertraline on the pharmacokinetics and pharmacodynamics of carbamazepine. Subjects received carbamazepine 200 mg once daily for 2 days and every 12 hours thereafter. On Days 16 to 32, subjects also received either sertraline or placebo daily. The dose of sertraline was increased from 50 to 200 mg daily over 7 days; the 200-mg dose was given for 10 days. Samples for pharmacokinetic analyses were obtained on Days 15 and 32; trough plasma concentrations of carbamazepine and its principal metabolite, carbamazepine-10, 11-epoxide (CBZ-E), were determined daily beginning on Day 13. Cognitive function testing was performed on Day 1 before carbamazepine dosing (baseline), Day 15 (carbamazepine alone), and Day 32 (carbamazepine plus sertraline or placebo). There were no significant differences between the sertraline and placebo groups in any of the pharmacokinetic paramet...
The ability to form memories is based on synaptic plasticity. Synaptic plasticity is a cellular p... more The ability to form memories is based on synaptic plasticity. Synaptic plasticity is a cellular process which results in lasting changes in neurotransmission. Research with non-human species has shown that long term potentiation (LTP), an example of synaptic plasticity, facilitates the acquisition of new learning (Figure 1). Various experimental manipulations have shown that over expression of cAMP response element binding (CREB) protein will facilitate LTP and thus new learning. CREB is one of the proteins involved in modulating the biochemical pathways which lead to synaptic changes seen in LTP (Figure 1). Levels of CREB can be indirectly increased by the presence of phosphodiesterase 4 (PDE4) inhibitors1. Drugs that act as PDE4 inhibitors therefore have an important role to play in the development of new pharmaceutical drugs that target learning/memory disorders. Behavioural manipulations have shown that the imposition of a 15-minute delay between learning trials (‘spaced’ learning) can facilitate the acquisition of new learning after significant test delays as compared with ‘massed’ trials in which there is no delay between learning trials. This project aimed to design a model for the assessment of PDE4 drug effects. CDR has validated the use of this paradigm in a 3-way crossover trial of human study participants. This study tested the impact of a single trial, ‘spaced’ trials (x5) and ‘massed’ trials (x5) on CDR Word Recall 24 hours after learning.
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Papers by Keith Wesnes