Verbal learning and memory are among the most robustly abnormal cognitive functions in schizophrenia and are key targets for treatment (8). Impaired verbal memory is associated with poor community functioning and poor response to psychosocial rehabilitation programs (9–11); it may be the principal reason why the gains provided by such programs are lost once the intervention ends (12–14). We wondered whether it is possible to develop a novel approach to the remediation of verbal memory deficits in schizophrenia based on recent developments in clinical and basic neuroscience.

In schizophrenia, abnormalities are observed in fronto-temporal cortical networks during verbal working memory, word encoding, and word recognition (15, 16). However, disturbances are also present at the earliest stages of auditory processing—for example, in the abnormally low amplitudes of the mismatch negativity response obtained during the preattentive detection of auditory stimuli (17). In healthy individuals, a reduced mismatch negativity response is associated with lower verbal learning and memory performance and with poorer psychosocial functioning (18); in people with schizophrenia, reduced mismatch negativity responses are significantly associated with impaired verbal memory (19), with the inability to decode semantic and emotional aspects of speech (20), and with poor functional status (21, 22). These findings suggest that efficient auditory processing is crucial for the successful encoding and retrieval of verbal information and that disturbances in these elemental processes are related to higher-order cognitive dysfunction in schizophrenia (18–22).

This body of evidence, combined with the past decade of animal experiments in the basic neuroscience of learning-induced neuroplasticity (23), served as the rationale for the development of a cognitive training program that targets both early auditory processing and working memory operations, with the ultimate goal of improving verbal memory performance in schizophrenia. Specifically, we investigated the effects of an intensive 50-hour program of computerized training—delivered as a stand-alone treatment—that places implicit, increasing demands on auditory perception and accurate aural speech reception. The psychophysical training is embedded within a suite of increasingly complex auditory working memory and verbal learning exercises that are delivered with a frequent reward schedule and an individually adaptive, repetitive practice schedule. This approach capitalizes on the fact that the neural responses to repetitive practice appear to be normal in schizophrenia (24) and that implicit, or procedural, learning is engaged through the repetitive practice of continuously adjusting psychophysical exercises (25–28). The basic notion is that by improving the speed and accuracy of information processing in the auditory system, higher-order functions such as verbal encoding and verbal memory retrieval have more reliable signals on which to operate (29).

We predicted that this approach to cognitive training would produce enhanced verbal memory and global cognition performance in participants with schizophrenia. Our secondary objective was to examine whether subjects’ training-based psychophysical gains on a basic auditory discrimination task would be associated with improvement in their higher-order neuropsychological functions.

Several factors may have contributed to the enhanced response we obtained using this method. First, prior cognitive remediation approaches have not specifically targeted impaired perceptual processes, although a growing body of research has identified a number of early sensory deficits in schizophrenia and has related them to higher-order cognitive impairments (17, 19–22, 37). Second, as would be expected from a program that aims to improve psychophysical responses, the exercises harness the mechanisms of repetitive practice and procedural learning, which appear to be relatively intact in schizophrenia (24–28). Third, the exercises are delivered in an attentionally engaging and continuously adaptive manner. This preserves an 85% reward schedule while providing a sufficient number of error trials to ensure the neurological reliability of the desired response (23, 29). Finally, each exercise is practiced for many thousands of trials.

Indeed, consistent with our study, the meta-analysis by McGurk et al. demonstrated that a higher number of hours of training and drill-and-practice methods show a distinct positive relationship to the remediation of verbal learning and memory in schizophrenia (7). The large effect sizes obtained in the present study—not only in verbal learning and memory, but also in global cognition—may be due in part to the number of hours of the intervention. It is interesting that only two of the six exercises (or approximately 16 hours) were devoted to tasks that involved word stimuli or had an explicit learning/memory component; the majority (over 30 hours) focused on psychophysical processing of speech elements and on working memory load. At this point, we do not know whether the psychophysical components of the training program are critical or whether similar cognitive improvement could be obtained with sufficiently heavy dosing of simple computerized verbal working memory and verbal learning exercises.

Pursuant to this question, it is important to note that on the most basic exercise, requiring time and frequency resolution of rapidly presented FM sweeps, there was a wide range of progression at the individual level, from subjects who made essentially no performance gains on this exercise to those who became proficient with highly challenging stimuli. This finding indicates that although there was significant improvement on this exercise at a group level, individuals with schizophrenia vary widely in their ability to reliably increase their basic psychophysical auditory processing efficiency in response to training. Consistent with the “neuroplasticity-based” rationale of our approach, subjects who showed the largest training-induced gains in psychophysical performance showed the most improvement in verbal working memory and global cognition. We tentatively speculate that there was a significant relationship specifically between psychophysical gains and working memory because as the auditory cortex responds to the psychophysical training, a more salient verbal signal is “fed forward” into working memory operations; this then permits more efficient and accurate encoding of the verbal information, secondarily leading to improvement in long-term memory. Indeed, the basic neuroscience suggests that increased efficiency in lower-order auditory processes will generalize to higher-order cognitions owing to a more effective engagement of attentional and memory processes (29, 38). However, the hypothesized neural mechanisms underlying these behavioral observations require direct study, as is currently under way in our laboratory.

We observed no effect of the auditory training exercises on symptoms, but the subjects in this study were clinically stable with mild average PANSS symptom ratings. We also found no benefits for quality of life immediately after training, but patients who have been, on average, ill for 20 years may not show improvements in community functioning as a result of 10 weeks of computerized cognitive training. In a follow-up study of 22 subjects from this study, some of whom received an additional 50 hours of training, we found that many of the neurocognitive gains induced by the training endured 6 months after the intervention; we also found that neurocognitive gains showed a significant positive correlation with improved quality of life at the 6-month assessment point (39).

The limitations of this study include our modest number of subjects, their relatively high level of education, and their recruitment through self-referral or clinician referral, which limit the generalizability of our results and likely inflate our effect sizes. Further, we did not conduct an intent-to-treat analysis, although our attrition rate was low, probably because of our subject payment schedule (which may also have produced outcomes different from those in previous studies). Because of these factors, we do not know whether this intervention can be successfully adapted to real-world treatment settings and whether participants can adhere to the demanding training schedule required by this approach outside of a controlled laboratory environment.

Fig1