The evidence reviewed here suggests that a program of cognitive training that uses computer-based exercises to accomplish intensive remediation of auditory processing is associated with significant improvements in higher order cognitive performance, as well as detectable physiologic responses suggesting neurobiologic adaptation or restoration of neural system functioning.
Behaviorally, active cognitive training was associated with improvements not only in the trained functions of verbal working memory and immediate verbal learning but also improved verbal memory performance. Notably, improvements did not generalize to the visual modality, suggesting that the training method is anatomically and functionally specific, as expected. Improvements in neurocognitive status following training showed some evidence of durability after a 6-month no-contact follow-up and were significantly correlated with functional outcome as measured by increased quality-of-life ratings,50
suggesting that the program of training may be of functional benefit or, more likely, can open up a critical window for successful psychosocial rehabilitation.
Physiologically, active cognitive training exercises are associated with increases in peripheral biomarkers thought to be related to neuronal plasticity (BDNF) and to NMDA receptor activity (D
-serine/total serine ratio) and may possibly also result in restoration of neural response patterns typical of healthy subjects during early auditory processing of rapidly presented successive stimuli (ie, MEG M100 attenuation to the second syllable). Each of these physiological measures showed significant relationships to cognitive performance and/or function. For BDNF, active training was associated with an increase in serum BDNF levels, which before training were significantly lower in the schizophrenia participants and after training were equivalent to those of healthy subjects; this increase correlated with improved quality of life.51
-serine, the active training group showed correlations between individual in D
-serine/total serine and individual cognitive gains in global cognition, processing speed, and verbal learning and memory. Our very preliminary data on M100 measures of early auditory processing indicate that the level of second-syllable attenuation in the left hemisphere achieved after active training was related to better posttraining task accuracy, as well as better verbal learning scores. Overall, the changes observed in these 3 qualitatively different biomarkers suggest the extent of the neurobiological remodeling that must occur to support training effects and that may therefore be presumed to underlie restoration of function in impaired auditory/verbal processing systems.
The behavioral and physiological changes we observed beg questions about what specific components of training are critical to these observations. Because training of auditory representations always occurs alongside the training of attention, working memory, and executive function, it remains unclear what specific components of the exercises are the “active ingredients.” It is possible that the exercises work by training higher order cognitive processes per se rather than increasing the fidelity of sensory representations. Our preliminary findings of changes in early sensory processing evident in renormalization of hemispheric lateralization in M100 attenuation measures argue against this notion. Further, if training of some higher order cognitive process underlies the benefits observed, improvements in nonauditory functions like nonverbal working memory and visual learning and memory should also be evident, but they are not. The fact that improvement propagates to more complex functions within the trained modality but not to functions in the untrained modality, as well as our finding that training-induced psychophysical improvement is significantly correlated with improved cognition,49
supports the notion that the specific training of sensory representations is an important determinant of gains in these exercises.
Effect sizes of improvements on MATRICS-based cognitive outcome variables were quite robust compared with those reported across domains in recent meta-analysis of McGurk et al.68
Auditory training was associated with large effect sizes in the critical domains of verbal memory (0.89) and general cognition (0.87) compared with those calculated in a recent meta-analysis of RCTs using a range of conventional cognitive remediation methods in schizophrenia (eg, 0.39 and 0.41, respectively 68
). However, these differences cannot be attributed unequivocally and solely to the effects of training sensory representations. The exercises studied here differ from other training strategies in a number of ways: The schedule of training is delivered in a denser schedule than most other programs (5 h/wk); is more intensive, involving thousands of trials for each exercise; and is delivered in an individually adaptive manner so that the learner is always training at threshold with an 85% correct response rate. Thus, there are differences of degree as well as of kind that would be expected to increase the magnitude of gains in the current approach.
Early visual processing deficits are also evident in schizophrenia patients, as detailed elsewhere in this special issue. The training program described here targeted auditory processing rather than visual systems for a number of theoretical reasons related to the critical functional importance of verbal learning and memory deficits in schizophrenia.49
However, visual system impairments are also importantly related to function in schizophrenia, eg, in the domain of facial affect recognition.39
We are currently investigating additional cohorts of patients who complete training specifically developed to target visual processing, cognitive control, and social cognition, in addition to the auditory exercises employed here. The results of those training regimes are still accruing and should allow us to determine whether training multiple cognitive modalities provides synergistic or merely additive effects.
The intensive and demanding training schedule used here may call into question the general utility of this approach to cognitive enhancement in schizophrenia. Relative to other therapies, 50 hours of training delivered on a daily schedule of 1 h/d is highly challenging, and it may fairly be questioned whether patients (and clinicians) in real-world treatment settings can dedicate the time and effort necessary to engage in this form of treatment. However, the converse observation is also valid. The period of time required to successfully complete the auditory training program is equivalent to roughly 2 days out of a person's life—a small investment for a treatment that may have highly beneficial effects. Furthermore, it is not at all obvious that robust biological and generalizable neurocognitive gains would be evident after training programs that occupy such a small fraction of an individual's total experience. That such changes in physiology and function may also persist beyond the period of the intervention50
and are achieved without the risks associated with drug treatments makes this approach especially appropriate for use early in illness or in at-risk populations.
These convergent findings offer both behavioral and physiological evidence of adaptive neuroplasticity in the brains of individuals using cognitive exercises focused on early auditory processing. Clinical outcomes and neuropsychological improvements suggest robust treatment benefits for this method, which includes specific remediation of sensory representation. Further research is needed to determine whether benefits are specifically attributable to the exercises’ sensory component; however, early results show not only restoration of general biological markers associated with neuronal plasticity and learning but also imply specific renormalization of dysfunction of early sensory processing. Thus, our observations suggest that bottom-up sensory dysfunction is not only an important determinant of cognitive performance and function for schizophrenia patients but also an appropriate and effective treatment target.