Our results demonstrate that schizophrenia patients are able to make significant, enduring cognitive gains as a result of the specific effects of stand-alone restorative neuroplasticity-based computerized cognitive training compared with schizophrenia patients in a control condition matched on hours of computer exposure, staff interaction, and other nonspecific effects. More importantly, these cognitive gains persist 6 months after the cessation of treatment. As predicted, subjects who completed 50 hours of exercises targeting early auditory perceptual processes showed enduring gains only on verbal learning/memory and cognitive control, while subjects who completed 100 hours of training showed the most benefit, with durable gains on measures of speed of processing, verbal learning/memory, cognitive control, and global cognition. Thus, a higher dose, and more “broad spectrum” training that targets auditory, visual, and cognitive control processes may confer the greatest benefit for patients. No effect on symptom ratings was evident either immediately after treatment or at the 6-month follow-up, but as subjects in this study were clinically stable with mild average PANSS symptom ratings at baseline, this may be due to a “ceiling” effect.
In this study, large effect sizes were shown immediately following treatment on measures of global cognition, speed of processing, verbal learning and memory, and cognitive control. At the 6-month follow-up, the effects showed durability and remained large on measures of verbal learning and memory and cognitive control and medium on measures of speed of processing and global cognition. As discussed in Fisher et al,27
we suspect that several factors may be contributing to the enhanced response we obtained using this approach as compared with conventional methods. First, prior cognitive remediation approaches have not specifically targeted the restoration of degraded perceptual processes, although a growing body of research has identified early sensory deficits in schizophrenia and has related them to higher order cognitive impairments.18–26
Second, the exercises are theoretically grounded in basic principles of learning-induced neuroplasticity, which were assiduously translated into core features of the program. Finally, the exercises aggressively harness the mechanisms of implicit learning and repetitive practice (which are relatively intact in schizophrenia38–42
). At this point, we do not know whether similar effect sizes could also be obtained from more “traditional” computer-assisted cognitive remediation programs, delivered as a stand-alone treatment, if they were administered for a sufficient number of hours.
We note that the current findings differ from our previous report27
in 2 respects. In our previous report, TCT and CG subject groups showed significant differences in verbal working memory after treatment. In the current report, these differences did not reach statistical significance that we suspect is due to the smaller sample size analyzed in the current study (a final cohort of subjects included in the previous report have not yet reached the 6-month posttraining assessment). We anticipate that in our final analyses on a larger sample, the effects on verbal working memory will reach statistical significance. Second, in our previous report, subject groups did not differ after treatment on the measure of speed of processing, while the current findings show significant group differences. We note that these differences are only evident among the subjects who completed the additional training modules (100 h of training). Schizophrenia subjects who have only completed 50 hours of training in our prior report, and in this report, do not show evidence of improved speed of processing. Thus, it appears that a longer training period, or additional training of visual and cognitive control processes, may be required to drive improvements in speed of processing.
The present findings also suggest that a longer training period results in more durable gains in functional outcome: Subjects who completed 100 hours of training showed larger gains on the QLS total mean item score at the 6-month follow-up compared with CG and TCT-50 subject groups, although this difference did not reach statistical significance. As displayed in , all 3 subject groups show gains on the QLS from baseline to after training, but only TCT subjects who completed 100 hours of training show continued gains at the 6-month follow-up, for a total change from baseline of 0.45. The clinical significance of gains on the QLS was tested by Cramer et al37
in a sample of 423 patients evaluated at 6 weeks, 3, 6, and 12 months. Patients judged as “improved” by clinicians showed an average QLS mean item score change of 0.23, while patients judged as “much better” showed an average change of 0.92. Our preliminary finding of a 0.45 gain suggests that clinically, the TCT-100 subjects would be judged as somewhere between “improved” and “much better.”
In the total sample of TCT subjects, significant positive associations were shown between change in cognition and change in functional outcome. While these results are consistent with prior research that suggests a relationship between cognitive improvement and improved functioning,4–7,11–13
as Fiszdon et al note, few studies have directly tested the temporal relationship between change in cognition and change in functioning.43
Most prior studies have relied on single time-point assessments of either variable (eg, baseline cognitive performance is used to predict change in functional outcome). Green and colleagues note that a critical question is the degree to which changes in cognition are linked to changes in functional outcome.44,45
This is especially germane to the study of cognitive remediation and other behavioral treatments because the cognitive functions that at baseline show associations to functioning may not be the same as those cognitive functions that, through their improvement, have the capacity to drive change in functional outcomes.
Interestingly, the small number of studies that has tested the relationship between change in cognition and change in functional outcome suggest that this may indeed be the case. For example, Reeder et al46
found that at baseline, social functioning was significantly associated with a number of cognitive measures; however, only change in schema generation predicted change in social functioning. Wykes et al5
also found that the variance in social functioning and symptoms at 6-month after treatment were partially accounted for by change on a measure of executive functioning (cognitive flexibility). In contrast, Fiszdon et al43
recently reported a negative association between change on the QLS interpersonal factor (social functioning) and change in executive functioning (Wisconsin Card Sorting Test), while positive associations were found between change in verbal memory and change in the QLS instrumental factor (occupational functioning).
Our results are consistent with Reeder et al46
and Wykes et al5
and indicate that change in cognitive control is significantly associated with change in functional outcome. Further, our results suggest that change in speed of processing may also be critically related to change in functional outcome. While replication of these results is required, our preliminary findings suggest that training of both “bottom-up” (speed of processing) and “top-down” (cognitive control) processes are important for driving changes in functional outcome and may provide a parsimonious explanation for the positive effects found for distinctly different cognitive treatment approaches (eg, drill-and-practice vs compensatory approaches). We note that our findings are preliminary and that research on the relationship between change in cognition and change in functional outcome is at a very early stage.
The main limitation of the present study is our small sample size due to the complexity of recruiting and retaining subjects through an intensive 8-month protocol that requires daily participation, followed by a 6-month follow-up. Such complexity also begs the question as to how transportable this intensive cognitive training approach will be to real-world treatment settings. Our data thus far suggest that the broadest enduring benefit for individuals with schizophrenia will accrue when 100 hours of training is delivered using modules that target auditory, visual, and cognitive control processes. However, our data also indicate that, if a primary goal of treatment is improved response to a psychosocial program, 50 hours (8–10 wks) of the auditory training module alone is sufficient to induce large beneficial effects, both immediately after training27
and at 6 months after treatment, on verbal declarative memory and cognitive control—domains especially relevant to successful vocational and social outcomes. This dosing schedule is well within the range employed by successful psychiatric rehabilitation programs that include computerized cognitive remediation.7–10
Optimal training appears to be achieved when a specific exercise (and each module consists of ~6 specific exercises) is practiced a total of 8–10 hours, for shorter periods of time (~15 min), on a more frequent basis. However, at this point, we do not know if similar cognitive gains could be achieved in schizophrenia patients with longer sessions delivered less frequently.
A second limitation is that subjects in the first cohort were randomly assigned on a 1:1 basis to either the auditory module or control condition; subjects in the following cohort were assigned on a 2:1 basis to all 3 training modules or control condition. Although this allows us to investigate the effects of “dosing” at the 6-month no-contact follow-up, it does attenuate our ability to draw firm conclusions about the overall 6-month follow-up results. Third, we cannot say whether the enhanced durability of cognitive gains across a wider range of measures in the subjects who received 100 hours of training is the result solely of the longer training period or whether it is due to the effects of a “broader” form of dosing, ie, to the use of an additional 2 modules that target different neural systems. Fourth, there were no statistically significant differences between groups on the change in functional outcome, and it is unknown whether this is the result of (1) an underpowered study, (2) insufficient sensitivity of the QLS as a measure of functioning, (3) true lack of direct effect of the training on functional status, and (4) the need to combine cognitive training with evidence-based psychosocial rehabilitation in order to maximally improve functioning in patients with schizophrenia. Such limitations must be addressed in future research.
The converging evidence over the last several years strongly indicates that the successful treatment of schizophrenia will require an empirically derived multimodal and sequential series of targeted therapies. Our data provide tantalizing early evidence that a highly specific form of computerized neuroplasticity-based cognitive training markedly improves key cognitive functions in a robust manner that endures 6 months beyond treatment. Further, our preliminary results show a strong and significant relationship between change in cognition and change in functional outcome 6 months after the cessation of treatment; we tentatively speculate that improvements in both “top-down” and “bottom-up” processes are necessary to drive enduring changes in functional outcome in schizophrenia. In total, these findings suggest that—as part of the treatment armamentarium—neuroplasticity-based cognitive training may prepare the patient to make optimal use of ecologically meaningful learning events and may create a critical window for successful psychosocial rehabilitation.