Computerized Cognitive Training Targeting Brain Plasticity in Schizophrenia

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Computerized Cognitive Training Targeting Brain Plasticity in Schizophrenia

12

Bruno Biagianti*,{, Sophia Vinogradov*,{,1 *

San Francisco Department of Veterans Affairs Medical Center, San Francisco, CA, USA { Department of Psychiatry, University of California, San Francisco, CA, USA 1 Corresponding author: Tel.: (415) 750-2073; Fax: (415) 750-6996 e-mail address: [email protected]

Abstract Two important paradigm shifts have occurred recently in the field of schizophrenia research. First, we now understand schizophrenia to be a neurodevelopmental disorder, one that is characterized by aberrant patterns of activation and connectivity in cortical and subcortical neural networks that are present before illness onset and that worsen as an individual progresses into later stages of the disease. Second, we now understand that these abnormalities are not immutable and fixed, but instead can respond to interventions targeting brain plasticity, particularly when delivered in the prodromal and early phases of schizophrenia. In this chapter, we will first describe some of the neurocognitive impairments that characterize schizophrenia, highlighting the developmental course of the illness. We will then briefly review salient features of currently available computerized cognitive training programs that target these impairments. Next, we will present an overview of current research findings regarding neurobiological effects of computerized cognitive training in schizophrenia and how these results shed light on the critical neuroplasticity mechanisms that support successful training. Finally, we will present recommendations for future research to optimize computerized cognitive training programs, with an aim to promoting functional recovery.

Keywords schizophrenia, neurocognition, neurodevelopmental, cognitive training, neural system impairments

Schizophrenia is a serious psychiatric illness characterized by hallucinations, delusions, disorganized behavior, cognitive impairments, and poor psychosocial outcomes. Genetic liability factors interact with environmental insults, many of them occurring during the pre- and perinatal period, with the result that at-risk individuals are vulnerable to a range of environmental stressors (Fig. 1). This interaction of genes and environment leads to aberrations in brain development and neural network Progress in Brain Research, Volume 207, ISSN 0079-6123, http://dx.doi.org/10.1016/B978-0-444-63327-9.00011-4 © 2013 Elsevier B.V. All rights reserved.

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FIGURE 1 Neurodevelopmental model of schizophrenia, highlighting the pre-emptive period and intervention targets discussed in this review (adapted and modified by permission of Tyrone Cannon, PhD). DA, dopamine; HPA, hypothalamic-pituitary-adrenal.

functioning, which are not typically evident until adolescence or very early adulthood, when brain maturation is nearing completion (Andreasen, 2010; Hoffman and McGlashan, 1997). At that point, usually as a response to environmental stressors, the individual (who may until then have had no observable symptoms or only mild nonspecific symptoms), experiences “psychosis,” or a break with reality—often initially in mild or attenuated form, which if left untreated then progress into a full-blown psychotic episode. Schizophrenia must thus be understood as a neurodevelopmental neurocognitive disorder characterized by decreased efficiency and abnormal connectivity in cortical and subcortical neural networks—rendering young individuals particularly vulnerable to the deleterious effects of stress.

1 NEUROCOGNITIVE IMPAIRMENTS IN SCHIZOPHRENIA Abundant evidence indicates that, in addition to increased stress responsivity, individuals who are destined to develop schizophrenia show a range of neurocognitive impairments well before illness onset. Deficits in vigilance, speed of processing,

2 Shifting the View of Schizophrenia from Neurodegeneration

working memory, verbal learning and memory, executive functioning, global cognition, and IQ are observed prior to the first psychotic episode (Becker et al., 2010; Brewer et al., 2005; Eastvold et al., 2007; Jahshan et al., 2010; Keefe et al., 2006; Kim et al., 2011a,b; Lencz et al., 2006; Niendam et al., 2006; Seidman et al., 2006; Simon et al., 2007). From high risk status to first psychotic episode, individuals show continued cognitive impairment (Becker et al., 2010; Hawkins et al., 2008), or further cognitive decline (Jahshan et al., 2010; Keefe et al., 2006; Simon et al., 2007; Wood et al., 2007). A recent longitudinal study in a populationrepresentative sample indicated that a decline in processing speed was particularly characteristic, occurring gradually from childhood to beyond the early teen years (Meier et al., 2013). Cognitive deficits are not surprisingly associated with poorer functional outcome (Green, 1996; Green et al., 2000): in young individuals who have just experienced their first episode of psychosis, verbal memory, speed of processing, and attention have been shown to predict psychosocial and vocational functioning 7 years later (Milev et al., 2005). Interestingly, in both recent onset and chronic schizophrenia, cognitive functioning and symptom severity are for the most part independent of one another: cognitive deficits are present in the absence of florid symptoms, and while antipsychotic medications are effective in ameliorating some of the clinical symptoms, they have little effect on cognitive impairment or long-term outcome (Goldberg et al., 2007; Keefe et al., 2007). Given the relative independence of cognitive dysfunction and symptoms, as well as the deleterious effects of cognitive impairment on social and occupational outcomes and quality of life, it is clear that cognitive enhancement is a critical treatment goal in schizophrenia. Moreover, cognitive enhancement is likely to be a key means for intervening preemptively to ameliorate the course of illness, or perhaps even to inoculate the at-risk individual against the onset of a first psychotic episode.

2 SHIFTING THE VIEW OF SCHIZOPHRENIA FROM NEURODEGENERATION TO NEUROPLASTICITY AND RECOVERY The current picture in schizophrenia is one of a brain that has undergone aberrant patterns of neurodevelopment, with reduced functional (and possibly structural) connectivity among key higher-order neural systems and impaired cognitive and socioaffective operations. For most of the past century, the illness has been conceptualized as a neurodegenerative disease associated with progressive functional decline, a nihilistic perspective first embodied by Kraepelin’s original nomenclature of dementia praecox. In the past decade, however, it has become clear that with early detection and well-designed interventions, intact brain plasticity mechanisms can be harnessed to promote healthier neural system functioning, increased resiliency to stressors, symptom reduction, and functional recovery. Indeed, if applied early enough in the course of illness, it should be possible to harness these mechanisms to induce true pre-emption of the usual illness trajectory.

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Previously, there was a great deal of skepticism about the possibility of adaptive plasticity and neural system improvement in serious neuropsychiatric disorders such as schizophrenia. This was due in part to the fact that these illnesses are characterized by long-standing and fairly serious impairments in behavior and in multiple distributed limbic, prefrontal and frontostriatal neural circuits. Further, recent findings by Balu and Coyle (2011) indicate that many schizophrenia-risk genes are involved in regulating neuroplasticity, perhaps contributing to abnormal patterns of synapse formation and cortical connectivity. It is thus possible that there are some inherent limitations in the “brain plasticity” mechanisms of certain individuals with schizophrenia. Despite this skepticism, emerging data over the past 5 years suggest that it is possible to develop intensive computerized cognitive training methods that successfully harness the brain-learning machinery in schizophrenia to generate widespread adaptive behavioral and neural responses (Dale et al., 2010; Eack et al., 2009, 2010a; Fisher et al., 2009; Subramaniam et al., 2012). These adaptive improvements include better cognition and functioning as well as increases in gray matter volume and plastic changes in cortical activation patterns (e.g., Adcock et al., 2009; Eack et al., 2010b; Subramaniam et al., 2012). Positive results in younger individuals are particularly promising (Eack et al., 2010a; Fisher et al., 2013).

3 COMPUTERIZED COGNITIVE TRAINING IN SCHIZOPHRENIA: BEHAVIORAL RESULTS In this section, we briefly review the three most frequently studied computerized cognitive training programs in order to identify key components that appear to contribute to behavioral improvement in patients. Neuropsychological tests are categorized into the cognitive domains recommended by the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) committee (Nuechterlein and Dawson, 1984). Table 1 presents a summary of the rationale and key features for each of the programs.

3.1 CogPack (Marker Software) Designed in Germany, CogPack (Marker, 1987–2007) contains multiple exercises in: Visuomotor Skills, Vigilance/Comprehension/Reaction, Language Material, Memory, Numbers/Logic, Knowledge/Orientation/Everyday Skills, and Special Elements (e.g., executive functioning and tone and pitch discrimination). If a specific task is solved, the program goes on to another type of task, but if unsolved, a similar task is given. Training exercises cover a range of cognitive domains within the first six sessions, with subsequent sessions focusing on repeated practice of exercises across each domain (McGurk et al., 2005, 2007). Sartory et al. (2005) tested CogPack exercises which targeted attention, verbal ability, spatial ability, numerical ability, memory and processing speed. Inpatients with

Table 1 Scientific rationale and key features of commonly used computerized cognitive training programs in schizophrenia Program

Rationale

Key features

CogPack, Marker Software

Information on rationale and approach not available

• 64 programs for testing and training, each with several

CogRehab, Psychological Software Services

Brain Fitness Program Auditory Module, Posit Science Inc.

Originally developed for traumatic brain injury. Based on the rationale that diffuse traumatic lesions rarely have just one behavioral effect, and the degree to which a single behavior will be normal (or pathological) may depend on its interactions with other functional systems (Chen et al., 1997) Originally developed for children with learning disabilities but has been subsequently heavily modified and adapted for adults, with an emphasis on both individuals with schizophrenia and the cognitive decline associated with aging. Applied to patients with schizophrenia based on the known impairments in auditory processing and frontally mediated verbal memory operations

• • • • • • • • •

• •

variants for visuomotor, comprehension, reaction, vigilance, memory, language, intellectual, and professional skills Exercises can be edited and expanded Difficulty level and the sequence of exercises can be modified Hierarchical approach: training of fundamental cognitive functions followed by more complex functions 8 modules target 4 domains: simple attention and executive skills, visuospatial skills, memory, and problem solving 2 modules of increasing complexity within each domain Exercises follow a standard sequence and progression of difficulty. Subjects graduate to new tasks after reaching a prescribed performance level Exercises are grounded in basic principles of learninginduced neuroplasticity Intensive—many thousands of learning trials are performed for each specific exercise Neuroadaptive—the dimensions of each exercise (e.g., speed, working memory load) are parametrically and continuously modified on a trial-by-trial basis for each individual user during the course of each exercise in order to maintain performance at
80% accuracy Attentionally engaging—each trial is gated by a “ready” signal from the user to indicate and require directed attention Rewarding—correct responses are continuously rewarded by amusing auditory and visual stimuli in order to drive high levels of training compliance and to engage reward and novelty detection systems for successful learning

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schizophrenia (N ¼ 21) completed fifteen, 45 min daily sessions over 3 weeks and showed significant gains on immediate and delayed verbal memory as well as processing speed relative to 21 inpatients on a waitlist. Wo¨lwer et al. (2005) used CogPack tasks of attention, memory, and executive functioning, in combination with desk work and training of compensatory strategies (verbalization and self-instruction) among inpatients and outpatients (N ¼ 24) and also found gains on measures of verbal learning and memory compared to a “treatment as usual” group (N ¼ 25). McGurk et al. (2005, 2007b) tested the effects of 3 months of a combination of CogPack exercises (attention, psychomotor speed, learning and memory, and executive functions), therapist-guided compensatory strategies (“Thinking Skills for Work”), and supported employment among 23 schizophrenia outpatients versus participation in supported employment only (N ¼ 21). Similar to Sartory et al. (2005) and Wo¨lwer et al. (2005), subjects who completed the cognitive training showed gains on measures of verbal learning and processing speed. Importantly, over a 2–3-year period post-treatment, subjects who received cognitive training were more likely to work, held more jobs, worked more weeks and total hours, and earned more wages compared to subjects receiving supported employment alone. In a second study, the authors combined the training with vocational rehabilitation (N ¼ 18) and found similar cognitive effects and better work outcomes over a 2-year follow-up period relative to vocational rehabilitation alone (N ¼ 16) (McGurk et al., 2009). Lindenmayer et al. (2008) provided 45 inpatients with 24 h of CogPack exercises (attention and concentration, psychomotor speed, learning and memory, and executive functions) in conjunction with a work program in a psychiatric center. Relative to a computer games (CG) control group (N ¼ 40), subjects who completed the cognitive training showed gains on measures of verbal learning, processing speed, and global cognition. Further, over a 12-month follow-up, subjects who completed cognitive training worked more total weeks relative to subjects in the control group. CogPack showed positive effects on both cognition and quality of life in 50 outpatients in a rehabilitation program who completed 36 h of exercises in verbal memory, verbal fluency, psychomotor speed and coordination, executive functioning, working memory, attention, culture, language, and simple calculation skills (Cavallaro et al., 2009). Relative to subjects who completed computer-assisted non-domain-specific activities (N ¼ 36), subjects who completed CogPack showed gains on measures of attention, reasoning and problem solving, and the Quality of Life Scale, as well as durability of gains at 6- and 12-month follow-up (Poletti et al., 2010). CogPack appears to have consistent positive effects on verbal learning and memory and processing speed in schizophrenia (Table 2), and substantially improves vocational outcomes when combined with supported employment or vocational training programs (Table 3). Sample sizes studied have been relatively small, however, and control groups have varied widely. Additional research is required to determine the specificity of CogPack’s effects and to replicate the findings of improved quality of life.

3 Computerized Cognitive Training in Schizophrenia: Behavioral Results

Table 2 The effects of computerized cognitive training on cognition in schizophrenia Computerized Cognitive Training Program CogPack, Marker Software

Authors and sample size

Experimental and control conditions

Sartory et al., 2005 (N ¼ 42)

CogPack þ inpatient treatment versus occupational therapy þ inpatient treatment CogPack þ inpatient or outpatient treatment versus inpatient or outpatient treatment CogPack þ supported employment þ outpatient treatment versus supported employment þ outpatient treatment CogPak þ inpatient treatment versus computer games or typing skills þ inpatient treatment CogPack þ vocational rehab versus vocational rehab

Wo¨lwer et al., 2005 (N ¼ 77)

McGurk et al., 2005, 2007b (N ¼ 44)

Lindenmayer et al., 2008 (N ¼ 85) McGurk et al., 2009 (N ¼ 34)

CogRehab, Psychological Software Services

Cavallaro et al., 2009 (N ¼ 86); Poletti et al., 2010 (N ¼ 100) Hogarty et al., 2004 (N ¼ 121), 2006 (N ¼ 106)

Eack et al., 2009 (N ¼ 58), Eack et al., 2010a (N ¼ 58)

Bell et al., 2001 (N ¼ 65), 2003 (N ¼ 102), 2007 (N ¼ 116); Fiszdon et al., 2004 (N ¼ 94)

CogPack þ outpatient rehabilitation treatment versus outpatient rehabilitation treatment CET (CogRehab þ attention exercises þ social cognitive group exercises) versus Enriched Supportive Therapy CET (CogRehab þ attention exercises þ social cognitive group exercises) versus Enriched Supportive Therapy

CogRehab þ work therapy versus work therapy

Improvements in cognition (significant group  time interactions) Verbal learning, verbal memory, processing speed Verbal learning, verbal memory

Verbal learning, processing speed

Verbal learning, verbal memory, processing speed Verbal learning, verbal memory, processing speed Attention, executive functioning Global cognition, speed of processing at 12 and 24 months of treatment No cognitive gains at 12 months of treatment Global cognition at 24 months of treatment Working memory, executive functioning

Continued

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Table 2 The effects of computerized cognitive training on cognition in schizophrenia—cont’d Computerized Cognitive Training Program

Authors and sample size

Experimental and control conditions

Wexler and Bell 2005 (N ¼ 54); Greig et al., 2007 (N ¼ 62); Bell et al., 2008 (N ¼ 72) Kurtz et al., 2007 (N ¼ 42)

CogRehab þ vocational program versus vocational program

Working memory, executive functioning

CogRehab þ day treatment versus computer skills training þ day treatment CogRehab þ day treatment versus day treatment

Working memory

Benedict et al., 1994 (N ¼ 33) Brain Fitness Program Auditory Module, Posit Science Inc

Improvements in cognition (significant group  time interactions)

Fisher et al., 2009 (N ¼ 55); 2010 (N ¼ 32)

BFP auditory module þ outpatient status versus computer games þ outpatient status

Popov et al., 2011 (N ¼ 39)

BFP auditory module þ inpatient treatment versus CogPack þ inpatient treatment Brain Fitness Program Auditory Training þ weekly group adapted from NEAR þ outpatient status versus Computer games þ weekly healthy lifestyles groups þ outpatient status

Keefe et al., 2013 (N ¼ 53)

No significant group  time interactions Verbal working memory, verbal learning, verbal memory, global cognition Verbal working memory, verbal learning

Verbal learning, global cognition, auditory frequency discrimination

3.2 CogRehab (Psychological Software Services) The Psychological Software Services CogRehab software (Bracy, 1995), originally designed for patients with traumatic brain injury, has been used in a number of studies in schizophrenia. The exercises emphasize simple attention, executive skills, visuospatial skills, memory, and problem solving. Program parameters, such as difficulty level, are adjusted based on each individual’s progress through the program.

3 Computerized Cognitive Training in Schizophrenia: Behavioral Results

Table 3 The effects of computerized cognitive training on symptoms and functioning and durability of cognitive gains in schizophrenia Computerized Cognitive Training Program CogPack, Marker Software

Authors and sample size Sartory et al., 2005 (N ¼ 42) Wo¨lwer et al., 2005 (N ¼ 77) McGurk et al., 2005, 2007a (N ¼ 44)

The effect of training on symptoms and functioning and durability of cognitive gains

• None reported • None reported • Greater number of hours worked,

•

CogRehab, Psychological Software Services

Lindenmayer et al., 2008 (N ¼ 85) McGurk et al., 2009 (N ¼ 34)

•

Cavallaro et al., 2009 (N ¼ 86); Poletti et al., 2010 (N ¼ 100)

•

Hogarty et al., 2004 (N ¼ 121), 2006 (N ¼ 106)

•

•

•

•

Eack et al., 2009 (N ¼ 58), Eack et al., 2010a (N ¼ 58)

•

•

wages earned, and more jobs worked at 1-year and 2–3-year follow-ups Improvement in PANSS Depression and Autistic Preoccupation at post-training Greater number of weeks worked at 12-month follow-up Greater number of weeks worked at 12-month follow-up; greater number of internship hours and internship wages at 12-month follow-up Improved quality of life scores at post-training; durability of effects on cognition and quality of life at 6- and 12-month follow-up Improvement on clinician ratings of social adjustment at 12 months Improvement on clinician ratings of cognitive style, social cognition, and social adjustment at 24 months Durability of gains in speed of processing, cognitive style, social cognition, and social adjustment at 12-month follow-up Improvement on clinician ratings of cognitive style, social cognition, social adjustment, and symptoms at 12 and 24 months of treatment Greater proportion of CET subjects were employed at 24 months of treatment. Effect on employment was no longer significant at 12-month follow-up Continued

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Table 3 The effects of computerized cognitive training on symptoms and functioning and durability of cognitive gains in schizophrenia—cont’d Computerized Cognitive Training Program

Authors and sample size Bell et al., 2001 (N ¼ 65), 2003 (N ¼ 102), 2007 (N ¼ 116); Fiszdon et al., 2004 (N ¼ 94) Wexler and Bell 2005 (N ¼ 54); Greig et al., 2007 (N ¼ 62); Bell et al., 2008 (N ¼ 72)

The effect of training on symptoms and functioning and durability of cognitive gains

• Greater number of hours worked at 6-month follow-up

• Durability of cognitive gains at 6- and 12-month follow-up

• Greater number of hours worked

•

Brain Fitness Program Auditory Module, Posit Science Inc.

Kurtz et al., 2007 (N ¼ 42) Benedict et al., 1994 (N ¼ 33) Fisher et al., 2009 (N ¼ 55); 2010 (N ¼ 32)

• • • •

Popov et al., 2011 (N ¼ 39)

•

Keefe et al., 2013 (N ¼ 53)

•

at 12-month follow-up; higher quarterly employment rates and higher cumulative rates of competitive employment over 3 quarters Improvement on the PANSS Cognitive Component, Vocational Cognitive Rating Scale and Work Behavior Inventory at 12-month follow-up None reported None reported No significant group  time interactions at post-training or 6-month follow-up Improvements in cognition were significantly associated with improvements in functional outcome (QLS) at 6-month follow-up in cognitive training subjects No significant group  time interactions at post-training No significant group  time interactions at post-training

Cognitive enhancement therapy (CET) (Hogarty and Flesher, 1999, 2004, 2006) is a small-group approach for the treatment of social cognitive and neurocognitive deficits in schizophrenia. Subjects work in pairs and complete approximately 75 h of computerized cognitive training exercises, which also included attention exercises from the Orientation Remediation Module (Ben-Yishay et al., 1987), and CogRehab exercises of memory and problem solving. Four to six months cognitive training, subjects begin 1.5 h per week of social cognitive group therapy, with treatment delivered over a 2-year period. Hogarty et al. (2004) tested the effects of CET (N ¼ 67) relative to Enriched Supportive Therapy (EST, N ¼ 54) in outpatients with schizophrenia. At 12 months of treatment, the CET group showed significant gains in speed

3 Computerized Cognitive Training in Schizophrenia: Behavioral Results

of processing, global cognition, and social adjustment, while at 24 months of treatment, the CET group showed significant improvement across all measures relative to the EST group, with the exception of symptoms. EST participants also showed clinically meaningful change at 2 years of treatment on many of the outcome measures, including neurocognition. Although cognitive testing was performed by staff blind to group assignment, unblinded staff conducted clinical ratings, and the CET and EST conditions were not matched in terms of staff contact. Follow-up evaluation 1 year after the completion of treatment found durability of all effects with the exception of neurocognition, and a significant relationship between early improvements in speed of processing and the long-term effects of CET on social cognition and social adjustment. Eack et al. (2009) also examined the effects of CET (N ¼ 31) relative to EST (N ¼ 27) in individuals with recent-onset schizophrenia. After 1 year of CET treatment, improvements on the cognitive measures (speed of processing and global cognition) were not evident, but global cognition showed moderate improvement after 2 years of treatment. At both 1 and 2 years of treatment, CET subjects showed significant gains on measures of social cognition, and a significantly greater proportion of CET subjects were engaged in competitive employment at 2 years. A follow-up study 1 year later (Eack et al., 2010a) showed that the gains on social and symptom measures were broadly maintained, while the effect on employment was no longer significant. Cognitive assessments were not conducted at the follow-up. Neurocognitive Enhancement Therapy (NET) (Bell et al., 2001, 2003; Wexler and Bell, 2005) utilized CogRehab exercises of attention, memory, language, and executive functioning, some of which were modified for use with schizophrenia. Bell et al. (2001, 2003) compared the effects of NET þ work therapy (N ¼ 47) to the effects of work therapy alone (N ¼ 55). Subjects in the NET þ work therapy condition completed 26 weeks of 3–6 h of cognitive training, a feedback support group, and a weekly social information processing group and showed greater gains on measures of working memory and executive functioning compared to subjects receiving work therapy only. At 6-month follow-up, the gains in working memory were durable, with effect sizes ranging from 0.45 to 0.73 (Bell et al., 2003). At follow-up, the NET þ work therapy subjects worked significantly more hours compared to subjects who completed work therapy alone (Wexler and Bell, 2005). In a second study, the authors tested the effects of NET in combination with a vocational program (NET þ VOC ¼ 38) for 1 year relative to subjects receiving VOC only (N ¼ 34). NET þ VOC subjects showed greater gains on measures of working memory and executive functioning, markedly better vocational outcomes at 12-month follow-up (Wexler and Bell, 2005; Greig et al., 2007), and a significantly higher rate of employment at 24-month follow-up (Bell et al., 2008). Kurtz et al. (2007) used CogRehab tasks of attention and memory, two tasks of attention from Loong (1988), and a speed-reading task designed to increase language-processing speed. The cognitive training condition (N ¼ 23) was compared to a computer skills training condition (N ¼ 19), with 100 h of training over 1 year. Subjects in the cognitive training group showed greater gains in working memory

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compared to the computer skills training group. In this study, both groups received equivalent computer time and equivalent staff interaction. Interestingly, both groups showed improvements in processing speed, working memory, episodic memory (verbal and visual), and executive functioning, indicating that nonspecific engagement and stimulation has a salutary effect on neurocognition. In summary, in studies where CogRehab training exercises of attention and working memory have been used in sufficient doses, gains in working memory have been consistently reported (Table 2). Further, the addition of CogRehab has provided significant benefits on work outcomes in studies that added cognitive training to work therapy or vocational programs (Table 3). Again, sample sizes have been small, control groups have varied widely, and the specificity of the effects is not yet clear.

3.3 Brain Fitness Program—Auditory Training Module (BFP, PositScience, Inc.) Brain Fitness Program (BFP) is an auditory/verbal learning training program that is designed to restore and enhance auditory perceptual and working memory processes, with the goal of increasing the accuracy and temporal resolution of auditory inputs feeding working memory and long-term verbal memory processes. Unlike the CogPack and CogREhab, which have their origins in neuropsychological models of cognitive dysfunction, the design of BFP was explicitly rooted in experimental principles of maximizing neuroplastic changes in targeted distributed neural systems (in this case, the auditory/verbal learning system). BFP was originally designed to address the verbal memory impairments associated with aging, but has been applied to patients with schizophrenia based on the known impairments in auditory processing and frontally mediated verbal memory operations in the illness (Foucher et al., 2005; Friston and Frith, 1995; Javitt et al., 2000; Kasai, 2002; Kawakubo et al., 2006; Light and Braff, 2005; Ragland et al., 2004, 2007; Wible et al., 2001). Though many of the exercises have a heavy emphasis on perceptual processing, they also explicitly require sustained attention and working memory and repeatedly engage cognitive control and response-selection mechanisms. The exercises have the following features: (1) intensive—many thousands of learning trials are performed for each specific exercise; (2) neuroadaptive—the dimensions of each exercise (e.g., speed, working memory load) are parametrically and continuously modified on a trial-by-trial basis for each individual user during the course of each exercise in order to maintain performance at
80% accuracy; (3) attentionally engaging—each trial is gated by a “‘ready” signal from the user to indicate and require directed attention; (4) rewarding—correct responses are continuously rewarded by amusing auditory and visual stimuli in order to drive high levels of training compliance and to engage reward and novelty detection systems for successful learning. Our group has previously reported the effects of BFP delivered as a stand-alone treatment (Fisher et al., 2009). Twenty-nine schizophrenia outpatients completed

3 Computerized Cognitive Training in Schizophrenia: Behavioral Results

50 h of the training over a 10-week period and were compared to an active CG control condition (N ¼ 26) designed to control for the effects of computer exposure, contact with research personnel, and monetary payments. Relative to the control group, using a per protocol analysis, the auditory training showed positive effects on measures of verbal working memory, verbal learning and memory, and global cognition. Effect sizes in verbal learning and memory, and in global cognition, were large (Cohen’s d 0.86–0.89). At a 6-month no-contact follow-up, improved cognition was significantly associated with improved functional outcome. Popov et al. (2011) tested the effects of BFP compared to CogPack among inpatients in Germany. Patients in the BFP condition (N ¼ 20) completed 20 one-hour sessions over 4 weeks, while patients in the CogPack condition (N ¼ 19) followed the standard protocol recommended by the developers of 60–90 min sessions, three times per week, for 4 weeks. Both subject groups showed improvement in verbal learning and verbal memory; however, the BFP group showed significantly greater gains in verbal working memory and verbal learning. Patients who completed BFP also showed normalization of auditory sensory gating deficits not seen in the CogPack group (described in the next section). In a multisite feasibility study (Keefe et al., 2013), 25 outpatients were randomized to BFP plus weekly support groups, or to a CG control condition plus weekly healthy lifestyles groups (N ¼ 22). Subjects completed 3–5 one-hour sessions per week for 40 sessions or 12 weeks, whichever came first. After 20 sessions, in an intent-to-treat-analysis, the BFP group showed significant gains in verbal learning (d ¼ 0.69), auditory frequency discrimination (d ¼ 0.84), and global cognition (d ¼ 0.28) relative to the control group. However, at the endpoint of the study, the effects on verbal learning and global cognition did not reach significance. The authors suggest this is likely due to the study completion deadline—that 9 out of the 25 auditory training subjects did not complete the entire 40 sessions within the 12-week period, which may have reduced the efficacy of the training. A single-arm, open-label, multisite, trial of 40 training sessions, using a repeated baseline assessment design, found no overall gain in a cognition summary score in stable outpatients, but did find that participants with greater improvement in auditory processing speed (evidence of target engagement in auditory system) showed larger gains in cognition (Murthy et al., 2012). Finally, a pilot study of 10 weeks of an unspecified number of hours of auditory training combined with visual training exercises found no significant effects on cognitive or event-related potential measures compared to a TV watching control group or a treatment-as-usual group; however, methodological issues make interpretation/comparison difficult (e.g., interleaving training across visual and auditory domains, unequal baseline cognitive performance in subject groups, combining of raw scores across tests into a summary score; Rass et al., 2012). Once again, sample sizes have been small and study methods have varied, though three of the five studies have used an active control group that permitted maintenance of a double-blind. These early data suggest some specificity of BFP for verbal processes and global cognition.

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3.4 Comparative Effects of Computerized Cognitive Training in Schizophrenia The computerized programs reviewed above show some consistent patterns in terms of their benefits on specific cognitive domains. CogPack shows consistent patterns of improvement in measures of verbal learning, verbal memory, and processing speed, and also improves work outcomes when combined with vocational rehabilitation. CogRehab improved working memory in three out of six studies, executive functioning in two out of six studies (Table 2), and significantly improved work outcomes when combined with vocational rehabilitation (Table 3). These discrepancies are likely the result of differences in the exercises and assessment measures used, and in treatment intensity. For example, in studies where significant gains in working memory were found, subjects completed 3–6 h of cognitive training per week over a 5-month period (Bell et al., 2001, 2003) versus studies that used 1 h per week of training over a 1–2-year period (e.g. Hogarty et al., 2004; Eack et al., 2009). Finally, BFP shows consistent improvement on measures of verbal working memory, verbal learning, and global cognition in three double-blind studies with an active computer control condition, and greater improvement than CogPack in one study.

4 COMPUTERIZED COGNITIVE TRAINING IN SCHIZOPHRENIA: NEUROBIOLOGICAL RESULTS In this section, we examine what is currently known about the neurobiological effects of computerized cognitive training in schizophrenia. These findings point the way for research that will determine the critical physiological mechanisms that support successful neuroplastic changes in order to inform development of optimally efficient intervention strategies.

4.1 Serum Biomarker and Genetic Findings Serum compounds can serve as peripheral biomarkers of training-induced physiological changes and have the potential to increase our understanding of neurophysiological processes that are recruited by different types of training. In our clinical trial of BFP auditory training, we measured two compounds in the serum of participants before and after 50 h of training: brain-derived neurotrophic factor (BDNF) (Vinogradov et al., 2009a) and D-serine (Panizzutti et al., 2013). BDNF plays a key role to neuroplasticity, neurodevelopment and neuronal function, and decreases in normal BDNF levels are found in schizophrenia (Buckley et al., 2007). Consistent with these reports, we found significantly lower baseline serum BDNF levels in patients with schizophrenia relative to healthy control subjects; however, subjects who received BFP showed a significant increase in serum BDNF compared with subjects who were in the CG control group, and after training, achieved mean serum BDNF comparable to healthy subjects (Vinogradov et al., 2009a). While intriguing, the interpretation of

4 Computerized Cognitive Training in Schizophrenia

this finding is limited by the fact that the relationship between serum BDNF and brain processes is unknown. Dysfunction of glutamatergic neurotransmission mediated by the N-methyl-D-aspartate (NMDA) receptors and D-serine (an endogenous receptor agonist) may also be involved in the pathophysiology of schizophrenia (reviewed in Labrie et al., 2012). Since animal studies indicate that learning and memory can affect the levels of D-serine (Vargas-Lopes et al., 2011), we predicted that training-induced cognitive gains would be associated with changes in serum D-serine levels. At baseline, we found reduced serum D-serine in schizophrenia subjects compared to healthy control subjects, consistent with previous findings in both serum and cerebrospinal fluid (Bendikov et al., 2007; Hashimoto et al., 2003; Panizzutti et al., 2013). We also found a significant positive correlation between cognitive improvement, and increases in serum D-serine, in subjects who underwent 50 h of the BFP exercises, but not in subjects who were in the CG control condition. These results raise the possibility that D-serine and/or the NMDA receptor is involved in the neurophysiological changes induced by BFP cognitive training in schizophrenia. During this trial, we also determined the anticholinergic activity of medications taken by participants, as measured via serum radioimmunoassay. We found that improvements in global cognition after training were negatively correlated with serum anticholinergic burden; in fact, serum anticholinergic activity accounted for 20% of the variance in the change in global cognition independent of the effects of IQ, age, or symptom severity (Vinogradov et al., 2009b). These findings have implications for the design and evaluation of neuroplasticity-based cognitive treatments for schizophrenia in situations where participants are administered medications with anticholinergic burden. Finally, it is possible that common variants in genes known to influence cognition affect an individual’s response to cognitive training. One small study investigated the association between the COMT Val158Met polymorphism and neuropsychological improvement after 36 h of Cogpack exercises in 27 patients with schizophrenia (Bosia et al., 2007). Patients with the COMT Met allele made greater gains in cognitive flexibility than patients without the Met allele. In contrast, another study failed to observe a significant association between the COMT Val158Met polymorphism and cognitive improvement following therapist-led pencil-and-paper cognitive remediation therapy (Greenwood et al., 2011). In a recent small study, we genotyped 48 schizophrenia outpatients who had participated in our cognitive training studies using BFP. We analyzed the association between the training-induced improvement in global cognition, and DNA variants in three genes known to show a relationship with cognitive performance—DISC1, COMT, and BDNF. Changes in global cognition after training were nominally associated with single nucleotide polymorphisms in the COMT and DISC1 genes. The strongest association was with COMT rs165599, a SNP previously associated with neurocognition in healthy subjects (Panizzutti et al., 2013). It is probable that a wide number of gene variants that affect aspects of cognition or learning potential will play a significant role in determining the magnitude of patients’ response to cognitive training interventions.

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4.2 Psychophysical Findings What aspects of cognitive training are fundamental for optimal treatment response? Thus far, treatment duration, type of training, and participant characteristics do not show a significant moderating effect on outcomes (Grynszpan et al., 2011; McGurk et al., 2007; Wykes et al., 2011). However, we have found a significant association between gains on an auditory discrimination training exercise and gains in verbal working memory and global cognition, but not visual cognition (Fisher et al., 2009). We have replicated these data in a second subject sample, using a measure of auditory processing speed as an index of improvement in psychophysical processing (Fisher et al., 2010). These findings are consistent with data reported in Murthy et al. (2012) and suggest that generalized training to better global cognition only occurs when subjects can successfully engage basic perceptual learning processes. In a related study, 14 participants with schizophrenia were studied who completed a range of BFP computerized training modules in auditory, visual, and cognitive control processes. The gains in visual processing speed strongly predicted improvement in visual memory but not in auditory or verbal measures; however, the amount of time spent in visual training was not associated with these improvements (Surti et al., 2011). Taken together, these results indicate that the ability to show target engagement (learning) when exposed to targeted training is more robustly associated with cognitive improvement than is the amount of time spent doing exercises. The results also suggest that progress in this form of training is domainspecific. It is highly likely that there is individual variation in psychophysical components of learning potential and/or cortical plasticity responses and that this will be a fruitful avenue for further investigation.

4.3 Magnetoencephalography (MEG): Improvements in Neural Operations During Early Auditory Processes Using magnetoencephalography (MEG), we have shown that patients with schizophrenia demonstrate hemispheric asymmetry abnormalities in early neural response dynamics in auditory cortex during discrimination of syllable pairs. After 50 h (10 weeks) of BFP auditory training, schizophrenia subjects showed a trend toward normalization of the asymmetry, which was positively associated with gains in both task accuracy and verbal learning after training (Adcock et al., 2009). We have also shown that training enhances the M100 response in auditory cortex during syllable identification, as well as high gamma band activity in left dorsolateral prefrontal cortex (Dale et al., 2010). Training-related changes in neural activity in both auditory and prefrontal cortical regions correlated with training-related improvements in neuropsychological measures of executive function, primarily driven by enhancement of the M100. These results suggest that BFP training of auditory processing enhances both representational fidelity in auditory cortex and early engagement of prefrontal regions, and that this increased efficiency in the distributed neural system is associated with better executive function.

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In another MEG study, Miller and collaborators used measures of auditory sensory gating, a finding related to early auditory processing abnormalities in schizophrenia, to explore the effects of BFP auditory training and CogPack training (Popov et al., 2011). Four weeks (approximately 20 h) of BFP normalized sensory gating in patients with schizophrenia, while this effect was not evident in subjects who completed CogPack. These results indicate that exercises that specifically target perceptual discrimination ability in the auditory system—as opposed to providing more generalized cognitive training—may normalize early auditory gating impairments in schizophrenia. Weiss et al. (2011) also investigated the effects of this form of cognitive training on early perceptual operations. Two MEG recordings were acquired during performance of an FM sweep discrimination task used to improve the acuity of auditory processing, before and after 2.5 h of task practice. Practice increased power and mutual information, an index of communication between brain regions, in temporalparietal regions. Participants showed improved accuracy after practice, and these improvements correlated with the increase in power and mutual information. Overall, the emerging MEG data suggest that carefully designed computerized training of auditory processes can increase the fidelity, precision, and signal-to-noise ratio of early auditory representations in the brain, with important downstream behavioral effects.

4.4 Functional Magnetic Resonance Imaging (fMRI): Improvements in Neural Activation Patterns During Higher-Order Processes 4.4.1 Verbal Working Memory In 2000, Wexler, Anderson, Fulbright, and Gore showed that training-induced improvements in verbal working memory were associated with increased activation of the left inferior frontal cortex. Of the eight patients in this uncontrolled study, three made substantial gains in verbal working memory performance after 25 h of training on the task, and these subjects also showed increased task-related functional Magnetic Resonance Imaging (fMRI) activation in left inferior frontal cortex. A significant association between performance improvement and activation increase of the left inferior frontal cortex was observed across all eight patients (Wexler et al., 2000), indicating that task-related performance gains are related to increased recruitment of relevant cortical regions. More recently, nine patients who completed 25 h of CogPack exercises of attention and working memory plus training on a word N-back working memory task showed increased brain activation in several regions during both a word and a picture N-back task—including the dorsolateral prefrontal cortex, frontopolar cortex and anterior cingulate gyrus—as compared to nine patients who received social skills group therapy (Haut et al., 2010). There were significant activity-behavioral associations between improved working memory performance and increased activation within the regions of activity overlap for the word and picture N-back tasks (i.e., left frontopolar cortex and left dorsolateral prefrontal cortex). These findings suggest

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generalization of neurobehavioral improvements in verbal working memory to visual working memory. Bor et al. (2011) compared eight patients receiving 28 h of cognitive training, facilitated by a psychologist, of Rehacom software exercises in attention, working memory, logical thinking, and executive functions versus eight patients who did not receive training (single-blind randomized trial design). The between-group contrast of session 2 versus session 1 revealed increased activation in the training group in the left inferior/middle frontal gyrus, cingulate gyrus, and inferior parietal lobe during an untrained n-back working memory task. Increased activation in the left inferior/middle frontal gyrus was associated with improvements in attention and reasoning abilities, indicating some possible generalization of training effects.

4.4.2 Reality Monitoring In a double-blind randomized controlled trial, our group investigated the behavioral and neural effects of intensive computerized cognitive training in schizophrenia on an untrained meta-cognitive reality-monitoring task (Subramaniam et al., 2012). Reality monitoring—the ability to distinguish self-generated information from externally-presented information—is impaired in patients with schizophrenia; unlike healthy subjects, patients with schizophrenia do not show activation of the medial prefrontal cortex (mPFC) when performing reality-monitoring decisions (Subramaniam et al., 2012; Vinogradov et al., 2008). Thirty-one patients with schizophrenia were randomized to 80 h of either cognitive training (50 h of BFP auditory training plus 30 h of visual processing training combined with social cognition training (SCT)) or a CG control condition. At baseline, patients showed no significant recruitment of mPFC during the reality-monitoring task (Fig. 2B), in contrast to 15 healthy comparison subjects, in which activation of mPFC was significantly associated with accurate reality-monitoring performance (Fig. 2A). After cognitive training, patients showed improved reality monitoring, which was associated with increased task-related activation of the mPFC, similar to the brain-behavior associations observed at baseline in the healthy subjects (Fig. 2C). These behavioral and neural improvements were not observed in control patients who completed 80 h of CG. Remarkably, patients who showed larger traininginduced increases in mPFC activation during the reality-monitoring task also demonstrated better real-world social functioning 6 months later. Results of this study indicate that intensive cognitive training of basic cognitive processes can normalize brain-behavior associations during a non-trained higher-order reality-monitoring task, so that they more closely resemble what is observed in healthy subjects.

4.4.3 Social Cognition Habel et al. (2010) used fMRI to examine 10 patients who completed 9 h of computerized training of affect recognition (TAR); these patients showed increased activation in several regions—including the left middle and superior occipital lobe, the right inferior and superior parietal cortex, and bilateral inferior frontal cortices— as compared to 10 patients who did not receive TAR. Furthermore, activation

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FIGURE 2 Whole brain fMRI analysis during reality-monitoring task performance reveals signal increase within: (A) the medial prefrontal cortex (mPFC) in 15 Healthy Comparison Subjects (HC), (B) the posterior cingulate cortex, rather than the mPFC, in patients with schizophrenia (SZ) prior to computerized cognitive training, and (C) the mPFC in only the group of schizophrenia patients who completed 80 h of Active Training (SZ-AT) but not those who completed the Computer Games control condition (SZ-CG). From Subramaniam et al. (2012).

changes in patients after TAR exercises correlated with their behavioral improvement in emotion identification. More recently, in a double-blind randomized controlled trial, our group investigated the behavioral and neural effects of intensive computerized cognitive and social cognitive training in schizophrenia on a facial emotion recognition task (Hooker et al., 2013). Twenty-two schizophrenia participants were randomly assigned to either 50 h of auditory-based cognitive training plus SCT which consisted of exercises from the Microexpressions and Subtle Expressions Training Tool (METT/SETT, Eckman, 2003) and MindReading (Baron-Cohen et al., 2003) or to 50 h of a placebo CG condition. We found a group by session interaction which was driven by the SCT subjects who showed greater neural increases in two emotion-processing regions— including the superior temporal cortex and somatosensory-related cortex—as compared to the CG subjects. Furthermore, neural increases in these regions were correlated with behavioral improvement on an independent emotion perception measure (MSCEIT: Perceiving Emotions). Together, these findings suggest that combined cognitive and social cognitive training increased neural activation of the

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systems that supported better emotion recognition. Because facial emotion recognition has been shown to predict functional outcome even after accounting for the contribution of general cognition (Hooker and Park, 2002; Poole et al., 2000), these findings indicate that a combination of computerized basic cognitive and social cognitive training interventions has the highest likelihood of improving quality of life for people with schizophrenia. Overall, it appears unequivocally that the higher-order behavioral and neural impairments in schizophrenia are not fixed and that, even during complex operations such as verbal working memory, reality monitoring, and social cognition, they can demonstrate significant plasticity in response to well-designed cognitive training interventions.

4.5 Voxel-Based Morphometry: Sustaining Gray Matter Volume In a recent study, Eack et al. (2010a) showed that CET (60 h of CogRehab integrated with approximately 70 h of social cognitive group sessions and individual coaching over a 2-year period) was protective against gray matter loss in 30 outpatients with recent-onset schizophrenia. Patients who received CET showed preservation of gray matter volume over the 2 years of the study within the left hippocampus, parahippocampal gyrus, fusiform gyrus, and amygdala compared to the 23 outpatients who received enriched supportive individual therapy for the same period. Within the CET group, less gray matter decline in the left parahippocampal gyrus and fusiform gyrus and greater gray matter increases in left amygdala were all associated with greater 2-year improvement in social cognition/social behavior. Additionally, in the CET group, less loss of left parahippocampal gyrus and fusiform gyrus volumes were correlated with improvements in neurocognitive function. However, it is not clear whether these effects were mediated by the computerized cognitive training per se, or by the rich social skills group therapy and enhanced therapeutic contacts of the psychosocial components of CET, as might be suggested by the gray matter preservation in neural structures critically important for social-emotional functions. Nonetheless, these findings demonstrate that well-designed interventions can halt, or potentially reverse, the usual declines in gray matter volume that are observed in early phases of the illness.

5 FUTURE DIRECTIONS There is now a consensus in the field that cognitive training offers a number of significant advantages as we seek to develop meaningful approaches to not only treat, but to pre-empt schizophrenia. Over 10 years ago, Bentall and Morrison (2002) noted that, as compared to pharmacological treatments, behavioral interventions for schizophrenia have fewer deleterious side effects, are less stigmatizing, and target the presenting nonspecific symptoms through a normalizing approach. In addition, they are generally more tolerable and acceptable than medications

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(Morrison et al., 2004). We posit that, in at least some forms, they are also more scalable, and can be delivered via web-based technology to remote or underresourced clinical sites. More importantly, if we are able to achieve the goal of engendering adaptive plastic changes in impaired neural systems, then such methods can halt or reverse the pathological neural system changes that characterize schizophrenia. While the emerging data are promising, much important work remains to be done. A strong and rigorous approach to methodological issues such as sample size and sample characteristics, assessment criteria, clinical staging, and optimal trial design and data analytic approaches must be implemented in order to build a convincing evidence base. With the current rapid advances in the development of cognitive-enhancing medications, we must also be prepared to explore the most advantageous ways in which these agents can—and probably should—be combined with behavioral treatments in order to optimize patients’ outcomes (Keefe et al., 2011). Indeed, some agents may be of no value when given alone, but may substantially facilitate the effects of cognitive training in schizophrenia. Medications are not the only possible approaches to enhance the brain’s response to behavioral interventions. Exercise is a potent, safe, and highly valuable “neurotrophic agent” that should become a significant part of the treatment armamentarium for schizophrenia (see Pajonk et al., 2010). Neuromodulatory techniques such as direct current stimulation are known inducers of cortical plasticity (Celnik et al., 2009; Khedr et al., 2010). All of these areas are under active investigation at present in combination with cognitive training. Finally, advances in information technology and in interactive and entertainment software indicate that web-based treatment delivery methods can be developed that will generate the same interest, engagement, perceived value, and social acceptability as web-based games. Indeed, novel collaborative efforts are already underway to develop socially-networked browser-based cognitive therapy for schizophrenia as well as highly engaging game-like cognitive training tools for early psychosis patients. We are only a few steps away from the development of web-deliverable brain plasticity-based treatments for impaired neural systems that can be delivered on a scale never before imagined for any other behavioral intervention. We are at a conceptual threshold that could not have been imagined even a decade ago, facing the real possibility that we may be able to move beyond pre-emption in schizophrenia, to inoculation against its cognitive and psychosocial ravages.

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