Cognitive Training for Neural System Dysfunction in Psychotic Disorders

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Key Take Home Points

TABLE. Proposed conceptualization of cognitive remediation vs targeted cognitive training

Over the last decade or so, our field has experienced a radical shift in our understanding of schizophrenia and other serious psychotic disorders, such as schizoaffective disorder and bipolar disorder with psychosis. We now understand that these are neurocognitive disorders (ie, how neural systems in the brain represent and process information). We also understand that they are neurodevelopmental disorders with genetic components and antecedents during gestation. The developmental course unfolds with increasing signs, symptoms, and cognitive dysfunction, until the onset of the first episode of psychosis during adolescence or early adulthood. Cognitive deficits are more significant determinants of functional outcome than are symptoms, although most current psychiatric treatments focus only (or mostly) on symptom management.

Accumulating evidence indicates that psychotic disorders constitute syndromes rather than diseases per se. Groups of patients can show a common clinical phenotype with multiple different etio-pathogenic factors that contribute to illness onset and expression. Patients with different clinical diagnostic phenotypes (such as schizophrenia rather than bipolar disorder with psychosis) can show similar underlying patterns of cognitive dysfunction and neurobiological abnormalities. New insights into the pathogenesis of psychotic disorders has spurred research focused on key domains of neural system dysfunction and on how brain plasticity mechanisms can be harnessed to drive healthier neural system functioning, improve cognition, and support functional recovery.

Cognitive and neural system dysfunction in psychotic disorders

Although the clinical symptoms of psychotic disorders are dramatic and are what most clinicians focus on as their treatment targets, impairments in a wide range of cognitive function are observed in these illnesses, ranging from the earliest stages of information processing in the brain, to higher-level abilities to abstract, to read social cues, to self-reflect, and to engage in meta-cognition. These various areas of cognitive dysfunction are accompanied by abnormalities in their neural system correlates. Moreover, patients exhibit a fair amount of cognitive and neural system heterogeneity, both within and across traditional diagnostic groupings-different patients will often have different patterns of impairment. Nonetheless, the following general categories of findings are commonly observed:

• Sensory and perceptual processing abnormalities: A range of subtle deficiencies in representing and processing auditory and visual information, including socially relevant information, that can show functional consequences.

• Learning and memory deficits: Impairments in how the brain encodes, learns, and makes decisions based on new information, including socially relevant information; responds to changes in rewarding or punishing contingencies in the environment; encodes and remembers autobiographical events (episodic memory); and learns associations and meanings (semantic memory).

• Executive dysfunction (ie, impaired cognitive control): Deficits in attention and working memory; problems with inhibitory control; impaired abstraction, reasoning, planning, sequencing.

In psychotic disorders, the emergent picture is one of a brain that has undergone aberrant patterns of neurodevelopment, with reduced functional connectivity among key neural systems and reduced efficiency in its cognitive and socio-affective operations.¹ This suggests that to improve cognition and functioning, it is essential to begin treatment as early as possible in the course of illness. Interventions designed to correct or compensate for abnormal neural system functioning must be started before irreversible maladaptive changes in the cortical and subcortical representational systems have taken root. Cognitive remediation and cognitive training approaches are used to improve cognition and are increasingly being studied in individuals who are in the early phases of illness.

Cognitive remediation vs cognitive training

Findings from meta-analyses indicate that a large variety of cognitive remediation protocols result in modest gains in overall cognitive functioning (effect sizes of about 0.4).^2-4 No specific cognitive remediation method has been proved to be most effective.

The term “cognitive remediation” is a good descriptor for an intervention that is often multi-modal, using several approaches simultaneously (Table). It can be conceptualized as a set of rehabilitative psychological treatments aimed at improving aspects of cognitive performance and behavior, which can of course also have effects on brain function and structure.

In contrast, the term “cognitive training” describes an explicitly neuroscience-informed approach to driving neural system plasticity in a well-defined neurocognitive operation or set of operations that may then generalize to other cognitive, behavioral, and functional domains. One of the best-studied examples of this kind of cognitive training utilizes approximately 10 hours of computerized visual speed-of-processing training in older adults. It has been associated with significantly improved cognition, lower rates of depression, and lower medical expenditures up to 10 years after the intervention.⁵

In our own research, we often go one step further and use the term “targeted cognitive training” when describing cognitive training exercises that are defined in terms of specific neurocognitive target(s). Examples of specific neurocognitive targets include auditory processing abnormalities or social cognitive impairments (eg, eye gaze detection, facial emotion recognition, vocal prosody recognition). This approach is best conceptualized as a neurological treatment aimed at driving brain changes in neural systems that will generalize to improvements in cognitive performance and behavior (Table). It can be delivered alone or as part of a larger treatment package.

A cognitive remediation approach

Eack and colleagues⁶ studied cognitive enhancement therapy (CET) vs enriched supportive therapy (EST) in 58 young individuals with prodromal schizophrenia; their average age was 26 years. CET combined 60 hours of computerized cognitive exercises using CogRehab software over 2 years in a specialized outpatient setting in conjunction with 45 sessions (90 minutes each) of social skills group exercises.

After 1 year of treatment, improvements on cognitive measures were not observed in CET participants compared with EST. After 2 years, moderate cognitive improvement was observable. Gains on measures of social cognition, cognitive style, social adjustment and symptoms were evident. At 1-year follow-up, gains on social and symptom measures were maintained and cognitive gains made during active training were significantly associated with improvement in functional outcome.⁷

It is interesting to note that cortical surface area and gray matter volume at baseline, especially in temporal cortex, moderated the effects of CET on social cognitive outcomes. Compared with the EST group, the CET group had greater gray matter preservation in the left hippocampus, the parahippocampal gyrus, and the fusiform gyrus as well as gray matter increases in the left amygdala. These findings were related to improved cognition.⁸ The EST group also had improved resting-state and task-related functional connectivity in the prefrontal cortical regions; these findings were also associated with improved cognition.^9,10

A targeted cognitive training approach

The effects of mobile targeted cognitive training of auditory processing (TCT) versus control condition computer games (CG) were studied in a double-blind randomized trial.¹¹ The study comprised  147 young adults with recent-onset schizophrenia (average age of 21 years) treated in two university-based first-episode clinics. Participants received laptop computers and instructions to complete 40 hours of training or the control condition games over approximately 8 weeks, performed on their own schedule at home. Check-ins and support were provided by the research team, but no other specific rehabilitation was provided beyond that which occurred as part of coordinated specialty care in the clinics.

Global cognition improvement was seen in the TCT group at immediate post-training assessments. Participants who completed at least 20 hours of TCT showed significant improvement in positive symptoms at 6-month follow-up compared with CG completers. Modeling of outcomes revealed that lower baseline global cognition and a higher level of education predicted greater improvement in global cognition after TCT.¹²

In a subgroup of participants who agreed to undergo serial imaging, Ramsay and colleagues¹³ saw a significant positive correlation between left thalamic volume and increased global cognition in the TCT group (n = 22) and a negative trend in the computer games CG group (n = 22). Lower baseline symptoms were related to both left thalamic volume preservation and improvements in global cognition following the training.

This intervention was also studied in adults with persistent illness (average age, 40 years) and demonstrated improved cognition in the TCT group and higher serum brain-derived neurotrophic factor (BDNF) levels. Moreover, magneto-encephalographic and fMRI findings were consistent with enhanced cortical activation patterns during early sensory processing and prefrontal executive functions. Patterns of association were seen between enhanced cognition and/or cortical functioning and longer-term functional gains.^14-18

Future directions

Are we ready to prescribe cognitive training to patients? It is one thing to have a highly promising evidence base emerging from clinical trials; it is another to know how to translate those findings into real-world treatment settings where models of implementation and reimbursement for cognitive remediation and/or cognitive training approaches are few and far between. Tools and education for clinicians that can allow them to assess and understand patterns of cognitive dysfunction in their patients are needed.

Cognitive training is a highly scalable and low-cost intervention, provided knowledgeable clinicians and staff can offer the necessary degree of support and guidance to patients. Ideally, cognitive training can be offered either as stand-alone cognitive treatment or as part of a broader enriched “remediation” program, depending on the needs of the individual; some individuals will be highly reliant on the structure and support of a formal multi-modal program and require group support, skills-building, etc, while others will be able to engage remotely, perhaps assisted only by an app that provides remote coaching (currently under study in our clinical trial NCT02782442).

Interested clinicians and consumers can consult PsyberGuide.org, a non-profit organization whose mission is to help consumers choose effective and accessible mobile health technologies, including cognitive training programs (PsyberGuide.org offers ratings on credibility, user experience, and the clarity of an app’s privacy policy). As we continue to refine our scientific understanding of cognitive training interventions for people with psychotic disorders, it may behoove us to begin to develop the programmatic infrastructure that allows us to assess cognition as a key treatment target for our patients.

Disclosures:

Dr Vinogradov is Professor and Department Head, Donald W. Hastings Endowed Chair, Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN. Dr Vinogradov reports that she is on the Speakers’ Bureau for Alkermes and Mindstrong.

References:

1. Sheffield JM, Kandala S, Tamminga CA, et al. Transdiagnostic associations between functional brain network integrity and cognition. JAMA Psychiatry. 2017;74:605-613.

2. McGurk SR, Twamley EW, Sitzer DI, et al. A meta-analysis of cognitive remediation in schizophrenia. Am J Psychiatry. 2007;164:1791-1802.

3. Wykes T, Huddy V, Cellard C, et al. A meta-analysis of cognitive remediation for schizophrenia: methodology and effect sizes. Am J Psychiatry. 2011;168:472-485.

4. Anaya C, Martinez Aran A, Ayuso-Mateos JL, et al. A systematic review of cognitive remediation for schizo-affective and affective disorders. J Affect Disord. 2012;142:13-21.

5. Edwards JD, Fausto BA, Tetlow AM, et al. Systematic review and meta-analyses of useful field of view cognitive training. Neurosci Biobehav Rev. 2018;84:72-91.

6. Eack SM, Greenwald DP, Hogarty SS, et al. Cognitive enhancement therapy for early-course schizophrenia: effects of a two-year randomized controlled trial. Psychiatr Serv. 2009;60:1468-1476.

7. Eack SM, Greenwald DP, Hogarty SS, Keshavan MS. One-year durability of the effects of cognitive enhancement therapy on functional outcome in early schizophrenia. Schizophr Res. 2010;120:210-216.

8. Eack SM, Hogarty GE, Cho RY, et al. Neuroprotective effects of cognitive enhancement therapy against gray matter loss in early schizophrenia: results from a 2-year randomized controlled trial. Arch Gen Psychiatry. 2010;67:674-682.

9. Keshavan MS, Eack SM, Prasad KM, et al. Longitudinal functional brain imaging study in early course schizophrenia before and after cognitive enhancement therapy. Neuroimage. 2017;151:55-64.

10. Eack SM, Newhill CE, Keshavan MS. Cognitive enhancement therapy improves resting-state functional connectivity in early course schizophrenia. J Soc Social Work Res. 2016;7:211-230.

11. Fisher M, Loewy R, Carter C, et al. Neuroplasticity-based auditory training via laptop computer improves cognition in young individuals with recent onset schizophrenia. Schizophr Bull. 2015;41:250-258.

12. Ramsay IS, Ma S, Fisher M, et al. Model selection and prediction of outcomes in recent onset schizophrenia patients who undergo cognitive training. Schizophr Res Cogn. 2018;11:1-5.

13. Ramsay IS, Fryer S, Boos A, et al. Response to targeted cognitive training correlates with change in thalamic volume in a randomized trial for early schizophrenia. Neuropsychopharmacol. 2018;43:590-597.

14. Fisher M, Holland C, Merzenich MM, Vinogradov S. Using neuroplasticity-based auditory training to improve verbal memory in schizophrenia. Am J Psychiatry. 2009;166:805-811.

15. Subramaniam K, Luks TL, Fisher M, et al. Computerized cognitive training restores neural activity within the reality monitoring network in schizophrenia. Neuron. 2012;73:842-853.

16. Subramaniam K, Luks TL, Garrett C, et al. Intensive cognitive training in schizophrenia enhances working memory and associated prefrontal cortical efficiency in a manner that drives long-term functional gains. Neuroimage. 2014;99:281-292.

17. Dale CL, Brown EG, Fisher M, et al. Auditory cortical plasticity drives training-induced cognitive changes in schizophrenia. Schizophr Bull. 2016;42:220-228.

18. Fisher M, Mellon SH, Wolkowitz O, Vinogradov S. Neuroscience-informed auditory training in schizophrenia: a final report of the effects on cognition and serum brain-derived neurotrophic factor. Schizophr Res Cogn. 2016;3:1-7. ❒