Cognitive training in schizophrenia: golden age or wild west?

C OMMENTARY Cognitive Training in Schizophrenia: Golden Age or Wild West? Sophia Vinogradov, Melissa Fisher, and Srikantan Nagarajan ix years ago, at the first Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) meeting, a neuroscientist questioned whether attention dysfunction was malleable in schizophrenia, despite a recent report that patients were 5 times more likely to work when cognitive remediation was combined with supported employ- ment (1). The idea that impaired neural systems could demon- strate learning-induced plasticity was not part of the biological research lexicon at that point in time. Experimental neuroscien- tists were rightfully skeptical of a broad array of cognitive remediation interventions that were often studied under non- blinded and variously controlled conditions. Perplexing, also, was the homogeneity of effect sizes, despite widely varying treatment approaches, outcome measures, and length of intervention. S trained coach for 40 sessions of pencil-and-paper exercises in cognitive flexibility, working memory, and planning. After CRT, they demonstrated a reduction in overactivation of the central executive neural network independent component (CEN) as well as increased white matter integrity in the genu of the corpus callosum, compared with patients who met with a therapist for 40 sessions to discuss how to cope with symptoms and identify warning signs of relapse. Penade´s et al. (3) have driven the final nail into the coffin on the idea that the brain in schizophrenia is not malleable! The question is malleable in response to what? Which neurobehavioral mechanisms are driving that malleability? And what exactly does it represent in terms of both short-term and long-term significance? Golden Age or Wild West? Malleable in Response to What? Six years later, the field is at a tipping point. The systems neuroscience of learning-induced plasticity is a mature and sophisticated area of inquiry. Concomitantly, trials of cognitive enhancing medications in schizophrenia have been disappoint- ing, and investigators increasingly recognize that medications will need to be combined with cognitive enrichment strategies to drive meaningful clinical improvement. Studies of computerized cognitive training in schizophrenia show consistent patterns of increased prefrontal cortical activation as compared with various control conditions; the increased activation correlates with improvements in the trained cognitive domain, and in one instance, with transfer to an untrained meta-cognitive task and with better functioning at 6-month follow-up (2). Why, then, is the story not over? Why, when it comes to understanding how to optimize functionally meaningful and enduring cognitive improvement in schizophrenia, does it seem as if we have entered the Wild West rather than the Golden Age? How does one make sense of the plethora of computerized and noncomputerized behavioral training approaches described in the literature? Do we have any evidence whatsoever on the critical neural mechanisms that drive functionally meaningful change? Not surprisingly, the answers to these questions are complex, as highlighted by the report of Penade´s et al. (3) in this issue. Put simply, the field is poised between two opposing perspectives: one that more broadly focuses on treatment development versus a targeted focus on plasticity in defined neural systems (Table). In the study by Penade´s et al. (3), which belongs to the broad cognitive remediation legacy, 15 individuals with schizophrenia engaged in cognitive remediation therapy (CRT), meeting with a We do not know from the report by Penade´s et al. (3) whether the participants were blind to group allocation. We do not know whether the therapists in the control condition had the same training/enthusiasm/expectations for a positive outcome as did the CRT coaches, and we do not know whether the assessment personnel were blind to group assignment. Not only are all three factors a potential source of bias in the outcome data, they may actually represent critical mechanisms of neurobehavioral change. Almost half a century ago, Wagner (4) investigated brief attention and abstraction training in schizophrenia and found that the experimenter was a positive social reinforcer who clearly “enhanced the motivational condition of the subjects” and contributed to their improved cognitive performance. More recent research has established unequivocally that motivational factors and beliefs substantially affect people’s ability to recruit cognitive and neural resources to sustain learning over time (5). Thus, in the study by Penade´s et al. (3), as in many previous published reports, we cannot separate out the effects of nonspecific cognitive enhancing factors, such as therapist enthu- siasm, participant motivation and expectations, and general cognitive and socioaffective stimulation, from the effects of a specific neurobehavioral training strategy in a defined neural system (in this case, strategy coaching for executive functions and working memory). Such nonspecific cognitive enhancement is by no means a bad thing, and in clinical settings one would want to harness it as intentionally as possible, but in an experimental design, it confounds our ability to isolate and identify the precise mechanisms that drive critical responses in neural systems of interest. In this light, it is sobering to consider the highly rigorous double-blind study by Dickinson et al. (6) comparing a cognitive remediation program for schizophrenia based on problem-solving educational software plus therapist coaching versus game-based software plus coaching. This study tightly controlled for the effects of nonspecific cognitive enhan- cing factors such as participant expectation and therapist motivation and contact and found no significant group differences on neurocognitive or functional outcome measures, From the Departments of Psychiatry, (SV, MF) and Radiology and Biomedical Imaging (SN), University of California, San Francisco, San Francisco, California, and San Francisco Department of Veterans Affairs Medical Center (SV, MF), San Francisco, California. Address correspondence to Sophia Vinogradov, M.D., 116A–SFDVAMC, 4150 Clement Street, San Francisco, CA 94121; E-mail: sophia. vinogradov@ucsf.edu. Received Mar 20, 2013; accepted Mar 21, 2013. http://dx.doi.org/10.1016/j.biopsych.2013.03.015 BIOL PSYCHIATRY 2013;73:935–937 Published by Elsevier Inc on behalf of Society of Biological Psychiatry