Innovative methods for improving cognition, motivation and wellbeing in schizophrenia
Authors: Barbara J. Sahakian, George Savulich
Journal: World Psychiatry (2019)

Neuropsychiatric disorders involve impairment of cognition, motivation and their interaction1. Cognitive manifestations include attentional biases, aberrant learning, dysfunctional reward processing, and lack of top-down cognitive control by the prefrontal cortex. These cognitive manifestations are both "cold" or non-emotional and "hot" or social and emotional2. From a neurobiological perspective, these relate to two partially segregated loops: the "cold" loop including the dorsal lateral prefrontal cortex and the "hot" affective loop including the orbitofrontal cortex and the ventral striatum, with strong connections to the "emotional brain" including the amygdala2. There are three major problems in schizophrenia: positive symptoms, cognitive symptoms and motivational deficits, which include negative symptoms. Green et al3 make a compelling argument that cognitive impairments in both social and nonsocial domains are core features of the illness. Although antipsychotic medications treat hallucinations and delusions reasonably well, they have little impact on functional outcomes. One of the biggest challenges of this century is how to treat early and effectively the cognitive and motivational deficits in patients with schizophrenia in order to prevent their persistence and ensure the best possible outcome. Our group has focused on episodic memory impairments in neuropsychiatric disorders. Impaired episodic memory occurs early and strongly relates to functionality in patients with amnestic mild cognitive impairment, Alzheimer's disease and schizophrenia. Episodic memory is also a functional correlate that is impaired in patients with a first episode of psychosis and further declines as the illness becomes more chronic. This form of new learning and memory has been shown to utilize a neural circuitry including the hippocampus. Changes in hippocampal subfields, including volume loss in the hippocampal stratum layers and the dentate gyrus, have been implicated in memory dysfunction in first-episode and chronic schizophrenia4. Although cognitive dysfunction is acknowledged as a target for treatment by the US Food and Drug Administration (FDA), there are no licensed medications currently available. We thus propose that innovative pharmacological and non-pharmacological methods should be developed and implemented further to target both cognitive and motivational dysfunction in the symptomatic treatment of schizophrenia and other neuropsychiatric disorders, rather than focussing on diagnostic status. Interest in the cognitive-enhancing properties of modafinil has been the focus of considerable experimental medicine research over the last two decades. Modafinil is a wakefulness-promoting agent that has been shown to enhance cognitive performance and task-related motivation in healthy volunteers. Modafinil has also been found to have positive effects in clinical populations such as adults with attention-deficit/hyperactivity disorder (ADHD). The precise mechanism for the cognitive-enhancing effects is not clear, but this agent is thought to activate the dopaminergic, glutamatergic, noradrenergic and serotonergic systems in several brain regions, including the prefrontal cortex, hippocampus, hypothalamus and basal ganglia. It has been shown that modafinil improves episodic memory in patients with schizophrenia5. This agent has also been reported to selectively improve spatial working memory and emotional processing (e.g. affect recognition, which might help social and occupational functioning) in first-episode schizophrenia, as well as a range of cognitive domains – including attentional set shifting, visual memory and spatial planning – in chronic schizophrenia6. Importantly, there have been no safety concerns about exacerbating psychotic symptoms, and there is no evidence of abuse potential when administering modafinil at 200 mg/day. Simultaneously enhancing cognition and motivation may have broad down-stream effects on patients' functioning, quality of life and wellbeing6. It is also possible that improving memory or functioning more generally through cognitive enhancement could help protect against psychotic relapse. In addition to novel cognitive-enhancing drugs, non-pharmacological interventions also have the potential to target symptoms as low-risk non-invasive options for patients with schizophrenia. Cognitive remediation strategies generate moderate effect sizes on cognition and psychosocial functioning and a smaller effect size on psychiatric symptom severity in schizophrenia7. Cognitive training, in particular, has been shown to increase dopamine D1 receptor density in the brain and produce functional changes in the fronto-parietal network8. However, compliance with cognitive training may be problematic, leading to high drop out rates, thus requiring a more motivational approach. To overcome this challenge, a study from our laboratory recently combined cognitive training with gaming technology, showing that playing eight hours of the novel Wizard memory game (www.peak.net) on an iPad improved episodic memory and global functioning in patients with schizophrenia1. Importantly, high levels of enjoyment and task-related motivation were maintained throughout all hours of gameplay. Our game was also titrated in difficulty in real-time, akin to personalized medicine, to promote a sense of achievement whilst maintaining high levels of motivation and improving performance over time. We therefore maximized the effects of cognitive training by directly increasing active engagement with the intervention. Advantages of incorporating a cognitive training programme into a game are that it helps de-stigmatize treatment, since everyone plays games; it is convenient, as travel to a hospital or clinic is not necessary and specialist equipment is not required; it is not associated with side effects; and it is highly rewarding. Use of exciting new technology in mental health, in particular gaming platforms, could reach more patients inexpensively, including adolescents at ultra-high risk of schizophrenia. Gamified cognitive training could also yield benefits for mood and self-esteem, as improvements in memory function following gameplay could be attributed to the self rather than a drug. In order to identify changes in cognition, emotion and motivation, there is a need for objective and reliable measures for evaluating affective domains. EMOTICOM (www.cambridgecognition.com) is a novel neuropsychological test battery of emotion processing, motivation, impulsivity and social cognition. Recent evidence has shown that this battery is likely to be highly relevant to "hot" cognitive processes in paranoid schizophrenia, as one key aspect implicated in the formation and maintenance of a persecutory delusion is the hostile perception of others, including their beliefs and intentions9. EMOTICOM could also be used in treatment development and efficacy research, such as the evaluation of the neuropeptide oxytocin, which has shown some effects on social cognition in schizophrenia. Interventions such as oxytocin or modafinil, used in combination with gamified cognitive training, may synergize to increase plasticity and learning, promoting improvement in both "hot" and "cold" cognition as well as in social functioning. Augmentation therapies would be particularly useful for rehabilitating patients who have cognitive impairments that persist even after remission of the more acute symptoms. If young people with schizophrenia are to have the best chance of realizing their potential and of having good functionality and wellbeing, we will have to move to game-changing initiatives that prioritize early detection and early effective intervention. With a move to first-episode psychosis clinics and research studies focusing on children and adolescents with an ultra-high risk of schizophrenia, interventions that target cognition and motivation can be implemented much earlier in the course of the illness, before "rescuing" cognition is the only option. Good cognition and positive wellbeing are closely linked and both are required for a flourishing society.