Danielle C. Turner

Modafinil improves cognition and attentional set shifting in patients with chronic schizophrenia

Modafinil, a novel cognitive enhancer, selectively improves neuropsychological task performance in healthy volunteers and adult patients with attention deficit hyperactivity disorder (ADHD). It has been argued that persistent cognitive deficits in patients with schizophrenia are responsible for the failure of many patients to rehabilitate socially even when psychotic symptoms are in remission. The present study examined the potential of modafinil as a cognitive enhancer in schizophrenia. Twenty chronic patients with a diagnosis of schizophrenia were entered into a double-blind, randomized, placebo-controlled crossover study using a 200 mg dose of modafinil. Modafinil had some cognitive enhancing properties in schizophrenia similar to those observed in healthy adults and adult patients with ADHD. Improvement was seen on short-term verbal memory span, with trends towards improved visual memory and spatial planning. This was accompanied by slowed response latency on the spatial planning task. No effect on stop-signal performance was seen. Importantly, significant improvement in attentional set shifting was seen, despite no effect of modafinil on this task being seen in healthy volunteers or ADHD patients. Modafinil may have potential as an important therapy for cognitive impairment in patients with schizophrenia, particularly because of its beneficial effects on attentional set shifting.

Association Between Response Inhibition and Working Memory in Adult ADHD: A Link to Right Frontal Cortex Pathology?

BACKGROUND We sought to assess the relationship between response inhibition and working memory in adult patients with attention-deficit/hyperactivity disorder (ADHD) and neurosurgical patients with frontal lobe damage. METHODS The stop-signal reaction time (SSRT) test and a spatial working memory (SWM) task were administered to 20 adult patients with ADHD and a group of matched controls. The same tasks were administered to 21 patients with lesions to right frontal cortex and 19 patients with left frontal lesions. RESULTS The SSRT test, but not choice reaction time, was significantly associated with search errors on the SWM task in both the adult ADHD and right frontal patients. In the right frontal patients, impaired performance on both variables was correlated with the volume of damage to the inferior frontal gyrus. CONCLUSIONS Response inhibition and working memory impairments in ADHD may stem from a common pathologic process rather than being distinct deficits. Such pathology could relate to right frontal-cortex abnormalities in ADHD, consistent with prior reports, as well as with the demonstration here of a significant association between SSRT and SWM in right frontal patients.

Subdissociative dose ketamine produces a deficit in manipulation but not maintenance of the contents of working memory.

We investigated the effects of subdissociative dose ketamine on executive processes during a working memory task. A total of 11 healthy volunteers participated in a double-blind, placebo-controlled, randomized, within-subjects study. They attended on three occasions, receiving intravenous infusions of placebo, a lower ketamine dose, and a higher ketamine dose. On each occasion, they underwent a series of tasks engaging working memory function in verbal and visuo-spatial domains. Further tasks explored aspects of long-term memory, planning, attention, and perceptual processing. With respect to working memory/executive function, a highly specific pattern of impairment was observed. Impairments were seen only at the higher dose of ketamine and restricted to a subgroup of the verbal working memory tasks: While visuo-spatial working memory showed no evidence of impairment, and while simple maintenance processes during verbal working memory were also unimpaired, higher dose ketamine produced a significant impairment in the manipulation of information within working memory. This process-specific effect of ketamine was reflected in a drug-by-task interaction. The specificity of this ketamine effect suggests that the earliest effect of NMDA receptor blockade is in higher order control of executive function rather than in more basic maintenance processes.

Ketamine Effects on Memory Reconsolidation Favor a Learning Model of Delusions

Delusions are the persistent and often bizarre beliefs that characterise psychosis. Previous studies have suggested that their emergence may be explained by disturbances in prediction error-dependent learning. Here we set up complementary studies in order to examine whether such a disturbance also modulates memory reconsolidation and hence explains their remarkable persistence. First, we quantified individual brain responses to prediction error in a causal learning task in 18 human subjects (8 female). Next, a placebo-controlled within-subjects study of the impact of ketamine was set up on the same individuals. We determined the influence of this NMDA receptor antagonist (previously shown to induce aberrant prediction error signal and lead to transient alterations in perception and belief) on the evolution of a fear memory over a 72 hour period: they initially underwent Pavlovian fear conditioning; 24 hours later, during ketamine or placebo administration, the conditioned stimulus (CS) was presented once, without reinforcement; memory strength was then tested again 24 hours later. Re-presentation of the CS under ketamine led to a stronger subsequent memory than under placebo. Moreover, the degree of strengthening correlated with individual vulnerability to ketamines psychotogenic effects and with prediction error brain signal. This finding was partially replicated in an independent sample with an appetitive learning procedure (in 8 human subjects, 4 female). These results suggest a link between altered prediction error, memory strength and psychosis. They point to a core disruption that may explain not only the emergence of delusional beliefs but also their persistence.

The Effects of a Subpsychotic Dose of Ketamine on Recognition and Source Memory for Agency: Implications for Pharmacological Modelling of Core Symptoms of Schizophrenia

Ketamine is increasingly used to model the cognitive deficits and symptoms of schizophrenia. We investigated the extent to which ketamine administration in healthy volunteers reproduces the deficits in episodic recognition memory and agency source monitoring reported in schizophrenia. Intravenous infusions of placebo or 100 ng/ml ketamine were administered to 12 healthy volunteers in a double-blind, placebo-controlled, randomized, within-subjects study. In response to presented words, the subject or experimenter performed a deep or shallow encoding task, providing a 2(drug) × 2(depth of processing) × 2(agency) factorial design. At test, subjects discriminated old/new words, and recalled the sources (task and agent). Data were analyzed using multinomial modelling to identify item recognition, source memory for agency and task, and guessing biases. Under ketamine, item recognition and cued recall of deeply encoded items were impaired, replicating previous findings. In contrast to schizophrenia, there was a reduced tendency to externalize agency source guessing biases under ketamine. While the recognition memory deficit observed with ketamine is consistent with previous work and with schizophrenia, the changes in source memory differ from those reported in schizophrenic patients. This difference may account for the pattern of psychopathology induced by ketamine.

Neuroethics of Cognitive Enhancement

The prospect of being able to take safe and effective drugs to improve mental functioning is becoming a reality. With the potential for widespread use of cognitive enhancers by large sectors of the population, this article discusses the rationale behind the development of these drugs and how society might benefit from them. Important ethical questions and scenarios are also raised. Scientists are urged to explore the implications of their work and engage in active debate with a wide range of interested stakeholders about the ethical and moral consequences of these new technologies to ensure maximal benefit with minimal harm.

Methamphetamine-Induced Disruption of Frontostriatal Reward Learning Signals: Relation to Psychotic Symptoms

OBJECTIVE Frontostriatal circuitry is critical to learning processes, and its disruption may underlie maladaptive decision making and the generation of psychotic symptoms in schizophrenia. However, there is a paucity of evidence directly examining the role of modulatory neurotransmitters on frontostriatal function in humans. In order to probe the effects of modulation on frontostriatal circuitry during learning and to test whether disruptions in learning processes may be related to the pathogenesis of psychosis, the authors explored the brain representations of reward prediction error and incentive value, two key reinforcement learning parameters, before and after methamphetamine challenge. METHOD Healthy volunteers (N=18) underwent functional MRI (fMRI) scanning while performing a reward learning task on three occasions: after placebo, after methamphetamine infusion (0.3 mg/kg body weight), and after pretreatment with 400 mg of amisulpride and then methamphetamine infusion. Brain fMRI representations of learning signals, calculated using a reinforcement Q-learning algorithm, were compared across drug conditions. RESULTS In the placebo condition, reward prediction error was coded in the ventral striatum bilaterally and incentive value in the ventromedial prefrontal cortex bilaterally. Reward prediction error and incentive value signals were disrupted by methamphetamine in the left nucleus accumbens and left ventromedial prefrontal cortex, respectively. Psychotic symptoms were significantly correlated with incentive value disruption in the ventromedial prefrontal and posterior cingulate cortex. Amisulpride pretreatment did not significantly alter methamphetamine-induced effects. CONCLUSIONS The results demonstrate that methamphetamine impairs brain representations of computational parameters that underpin learning. They also demonstrate a significant link between psychosis and abnormal monoamine-regulated learning signals in the prefrontal and cingulate cortices.

A review of the use of modafinil for attention-deficit hyperactivity disorder.

Modafinil (Provigil™) is a novel wakefulness-promoting agent that has been shown to have greater efficacy than placebo in the treatment of attention-deficit hyperactivity disorder (ADHD) in children and adults. In particular, three large, drug-company sponsored trials of a film-coated formulation of modafinil (modafinil-ADHD; Sparlon™) in children and adolescents with ADHD demonstrated consistent improvements in ADHD symptoms compared with placebo. Mean reductions in symptom ratings (measured using the ADHD-Rating Scale-IV school version questionnaire) ranged from 15.0 to 19.7 (7.3 to 10.1 for placebo). The most common adverse events were insomnia, headache and decreased appetite. Modafinil was generally well tolerated with most side effects considered mild to moderate in severity. Modafinil may have advantages over current therapies for ADHD in that it can be administered once daily and has fewer reinforcing properties than traditional stimulants. Modafinil could potentially be a valuable new treatment option for patients with ADHD. However, rigorous comparative studies with current first-line treatments for ADHD and longer-term independent studies are necessary before modafinil’s role in the treatment of ADHD can be fully established.

Experimental Psychology and Research into Brain Science, Addiction and Drugs

Publisher Summary Experimental psychology is ideally placed to determine the cognitive and emotional effects of psychoactive substances, and the contribution of cognition and emotion to addiction. This chapter illustrates the advances that are made in exploring the effects of psychoactive substance use using tools and techniques that focus on the understanding of learning, reward, motivation, and cognition. This understanding is central for preventing and treating the devastating effects of psychoactive drug addiction and improving the quality of life for patients suffering from cognitive impairment. The understanding helps to develop robust theories of human behavior in the context of psychoactive substance use. The chapter focuses mainly on drugs, but it is possible that in the future many of the same considerations apply to nonchemical approaches such as transcranial magnetic stimulation or neural prosthetics. The chapter describes how one uses experimental psychology to embrace the new opportunities presenting themselves as our insight into psychotropic drugs, addiction, and cognitive enhancement deepens. It is thus imperative to use experimental psychology paradigms to screen drugs to ensure the safest possible use of current and future psychotropic effects.

Association between serotonin transporter binding, physiological and environmental factors in healthy male subjects

GlaxoSmithKline Clinical Imaging Centre, UK GlaxoSmithKline Discovery Statistics, UK GlaxoSmithKline Discovery Medicine, UK Bristol-Myers Squib, USA Dept. of Psychiatry, Yale University, USA Dept. of Psychiatry, Cambridge University, UK MRC Cognition and Brain Sciences Unit, Cambridge, UK Dept. of Neuropsychology and Psychopharmacology, Universiteit Maastricht, The Netherlands Division of Neurosciences and Mental Health, Imperial College London, UK