previous studies of traditional approaches to cognitive remediation in schizophrenia have been confounded by various methodological issues ( see refs 11,12 ) : small subject samples ,  open - label  conditions , treatment- as - usual control groups , unblinded assessments , and unspecified plans for statistical analysis . studies that avoided these issues have tended to find only small to moderate effect sizes . nonetheless , the following findings point to some interesting next steps for the field : with the exception of verbal learning and memory , the meta - analysis by mcgurk et al found no significant heterogeneity in effect sizes on various matricsdefined cognitive domains based on either the number of hours of training or the method employed . this indicates that for the majority of cognitive domains , neither the training method , nor the amount of training ( several hours to over 100 hours ) has been a key moderating variable . thus , although previous cognitive remediation approaches have provided modest nonspecific cognitive benefits , further refinement of the intervention and the use of rigorous study designs are critical next steps for the field . meta - analyses have also shown that in verbal memory , larger effect sizes are obtained when computerized training is given in a drill - and - practice approach for a large number of hours . significant synergy occurs when cognitive remediation is combined with a psychosocial intervention , such as vocational rehabilitation or social skills training . this indicates that appropriate cognitive training can prepare the individual with schizophrenia to benefit from ecologically meaningful learning events , and underscores the fact that optimal treatment in schizophrenia will necessitate multimodal approaches . over the past decade , clinical neuroscience research has unequivocally demonstrated that declarative memory ( those processes involved in recollection of facts and events ) is impaired in schizophrenia ; thus , in keeping with the meta - analysis findings discussed above , it seems clear that strategy coaching and other direct instruction methods are likely to be of only limited benefit for patients . further , the sensory processing deficits of schizophrenia , which demonstrate a strong association with higher - order cognitive dysfunction , may confer a bottleneck in the response to behavioral interventions . a neuroscience - guided approach to cognitive training in schizophrenia should therefore take into account the following factors : the use of both implicit learning , through which skills and abilities are acquired indirectly and without direct awareness , and repetitive practice , may be crucial for maximizing patients ' response to cognitive training . in addition , attention to sensory processing deficits may be necessary in order to drive an optimal response to cognitive treatments . basic experimental work with motor skill learning and motor cortex remapping indicates that significant cortical synaptogenesis and reorganization of task - specific representations occurs after an animal reaches the  flat congruent with the meta - analysis findings described earlier , this suggests that  dosing  and  intensity  of training is important : in order to drive maximally enduring and neurologically reliable cognitive gains , subjects must perform large numbers of learning trials and must train at threshold ( ie , training must be individually adapted to the capacities of each learner ) . during learning , the brain selectively promotes both  bottom - up  and  top - down  neural activity patterns that represent meaningful stimuli and behaviors ; successful learning is most efficiently driven by exercises which target all of the specific component  skills  of a given cognitive process . for example , intensive computerized frequency - sweep discrimination exercises markedly improve the ability of language - impaired children to recognize and respond to speech stimuli . for patients with schizophrenia , intensive training in a wide range of basic cognitive operations is likely to be necessary to improve higher - order functions ( eg , it may be necessary to train the representational fidelity of early sensory data ; vigilance ; working memory ; etc . before achieving significant gains in executive functions ) . learning - based plasticity is profoundly influenced by neuromodulatory neurotransmitters ; therefore , learning trials must be designed that are closely attended by the subject and that involve a heavy reward schedule . moreover , some of the medications currently used in schizophrenia may adversely affect the response to cognitive training strategies . we have been investigating the efficacy of a set of neuroscience - based cognitive training exercises designed with the considerations described above ( software developed by posit science , inc ) . subjects were randomly assigned to either 50 hours ( 1 hour per day , 5 days per week ) of a computer games control condition , or to 50 hours of computerized training that places implicit , increasing demands on auditory perception and accurate aural speech reception . frequency discrimination and phoneme recognition exercises targeted aspects of early auditory processing deficits of schizophrenia , which have been shown to affect higher - order cognitions such as verbal memory , reading ability , and social - emotional recognition . this psychophysical training was embedded within increasingly complex auditory and verbal working memory / verbal learning exercises that progress from simple frequency discrimination to phoneme identification and then recall of verbal instructions and narrative details . compared with age- and education - matched subjects in the computer games control condition , we found that subjects who underwent targeted cognitive training showed significant increases in working memory , verbal learning and memory , and global cognition ( figure 1 , table i ) . these data suggest that an intensive dose of computerized cognitive training focused on auditory and verbal processing results in improved verbal learning and memory in adults with schizophrenia . cognitive training subjects showed significantly greater improvement in verbal learning and memory measures from baseline to a 6-month follow - up assessment , indicating the durability of the cognitive training effects beyond the immediate post - training period . furthermore , improved cognition was significantly associated with improvements in quality of life at 6 months . serum anticholinergic activity ( saa ) , reflecting medication - induced anticholinergic burden , showed a significant negative correlation with cognitive improvement after training . consistent with basic science research , this suggests that the anticholinergic burden reduces the efficacy of cognitive training in driving cognitive improvement . subjects in the cognitive training condition showed a significant increase in serum brain - derived neurotrophic factor ( bdnf ) levels compared with the computer games control group . this suggests that bdnf may be a peripheral biomarker for the effects of intensive cognitive training , and provides an indication of neurobiological response induced by the training . normalization  of physiological response patterns in auditory cortex within the cognitive training group but not the computer games control group - indicating that adaptive plastic changes in auditory processing systems can be induced in schizophrenia patients in response to a behavioral training intervention . compared with age- and education - matched subjects in the computer games control condition , we found that subjects who underwent targeted cognitive training showed significant increases in working memory , verbal learning and memory , and global cognition ( figure 1 , table i ) . these data suggest that an intensive dose of computerized cognitive training focused on auditory and verbal processing results in improved verbal learning and memory in adults with schizophrenia . cognitive training subjects showed significantly greater improvement in verbal learning and memory measures from baseline to a 6-month follow - up assessment , indicating the durability of the cognitive training effects beyond the immediate post - training period . furthermore , improved cognition was significantly associated with improvements in quality of life at 6 months . serum anticholinergic activity ( saa ) , reflecting medication - induced anticholinergic burden , showed a significant negative correlation with cognitive improvement after training . consistent with basic science research , this suggests that the anticholinergic burden reduces the efficacy of cognitive training in driving cognitive improvement . subjects in the cognitive training condition showed a significant increase in serum brain - derived neurotrophic factor ( bdnf ) levels compared with the computer games control group . this suggests that bdnf may be a peripheral biomarker for the effects of intensive cognitive training , and provides an indication of neurobiological response induced by the training . normalization  of physiological response patterns in auditory cortex within the cognitive training group but not the computer games control group - indicating that adaptive plastic changes in auditory processing systems can be induced in schizophrenia patients in response to a behavioral training intervention . although these early data using a neuroscienceinformed approach to cognitive training in schizophrenia are promising , they require replication with larger , more representative samples across multiple treatment sites . in addition , they raise many crucial questions for future studies : what are the necessary and sufficient ingredients essential for successful cognitive training in schizophrenia ? what are the optimal methods , cognitive domains , and sequence of training ? what is the minimum amount of cognitive training that results in meaningful cognitive improvement in patients ? at what minimal frequency can training be delivered ? what is the relationship between individual patient profiles at baseline ( eg , genotype , biomarkers , neurocognitive profile ) and their ability to realize and retain benefits from cognitive training ( see , for example , refs 41 - 43 ) ? what is the influence of commonly prescribed anticholinergic and antidopaminergic medications on cognitive training outcomes ? how can we maximize the synergistic benefits of combining cognitive training with psychosocial rehabilitation treatments ? can targeted cognitive training be used to remit preexisting cognitive deficits and to promote recovery of function in young individuals who are in the very earliest phases of schizophrenia ? if the promising initial findings we describe here are replicated , we will enter an exciting time for the field of schiz - ophrenia treatment , one which will require active collaborations between basic and clinical neuroscientists with expertise in neuroplasticity ; researchers who perform clinical trials as well as experts in psychosocial remediation ; clinical and research psychopharmacologists , and designers of computer games . we will enter a time of paradigm shift , and we will have the privilege of developing novel beneficial treatments for our patients .
meta - analytic data from over a decade of research in cognitive remediation , when combined with recent findings from basic and clinical neuroscience , have resulted in a new understanding of the critical elements that can contribute to successful cognitive training approaches for schizophrenia . 
 some of these elements include : the use of computerized repetitive practice methods , high dosing schedules , a focus on sensory processing , and carefully constrained and individually adapted learning trials . in a preliminary randomized controlled trial of cognitive training exercises based on these principles , we demonstrated significant improvements in working memory , verbal learning and memory , and global cognition in patients with schizophrenia . 
 these cognitive improvements were accompanied by neurobiological findings suggestive of learning - induced cortical plasticity . 
 future directions for research and essential remaining questions are discussed .