When Top-Down Meets Bottom-Up: Auditory Training Enhances Verbal
Memory in Schizophrenia
R. Alison Adcock2, Corby Dale3, Melissa Fisher4,5,
Stephanie Aldebot4,5, Alexander Genevsky4,5,
Gregory V. Simpson3, Srikantan Nagarajan3, and
2Duke University Department of Psychiatry and Center for
Cognitive Neuroscience;3Department of Radiology;4Department
of Psychiatry, University of California, San Francisco, CA;
5San Francisco Department of Veterans Affairs Medical Center,
San Francisco, CA
A critical research priority for our field is to develop treat-
ments that enhance cognitive functioning in schizophrenia
and thereby attenuate the functional losses associated
with the illness. In this article, we describe such a treatment
method that is grounded in emerging research on the wide-
spread sensory processing impairments of schizophrenia, as
nitive training exercises that make use of principles derived
from the past 2 decades of basic science research in learn-
not only the higher order or ‘‘top-down’’ processes of cog-
nition but also the content building blocks of accurate and
efficient sensory representations to simultaneously achieve
‘‘bottom-up’’ remediation. We then summarize our experi-
ence to date and briefly review our behavioral and serum
biomarker findings from a randomized controlled trial of
this method in outpatients with long-term symptoms of
schizophrenia. Finally, we present promising early psycho-
physiologicalevidencethat supports thehypothesis that this
cognitive training method induces changes in aspects of im-
paired bottom-up sensory processing in schizophrenia. We
conclude with the observation that neuroplasticity-based
cognitive training brings patients closer to physiological
patterns seen in healthy participants, suggesting that it
changes the brain in an adaptive manner in schizophrenia.
Key words: schizophrenia/cognition/cognitive training/
Schizophrenia is profoundly disabling; the symptoms and
yearsago translateto functionallossesthatare costlyboth
for many decades positive symptoms were the key targets
from cognitive impairment, the use of antipsychotic med-
ications has revealed that stable deficits in both cognition
and function persist across fluctuations in positive symp-
tom burden1and that cognition and function are strongly
ods that specifically enhance cognition and thereby atten-
uate the functional losses associated with schizophrenia.
In this article, we will describe such a treatment method
that is grounded in emerging research on the widespread
sensory processing impairments of schizophrenia, as
described elsewhere in this special issue. We will first
describe the rationale for this treatment approach, which
ciples derived from the past 2 decades of basic science
research in learning-induced neuroplasticity and that
tions. We will then summarize our experience to date and
outpatients with long-term symptoms of schizophrenia.
Finally, we will present promising early psychophysiologi-
training method normalizes aspects of impaired sensory
processing in the illness.
What Is the Rationale for Targeting Sensory Processing in
the Treatment of Schizophrenia?
Schizophrenia Is Characterized by Impaired Sensory
As early as Bleuler, authors have argued that the sensory
disturbances common among schizophrenia patients
1To whom correspondence should be addressed; 116C—4150
Clement Street, San Francisco, CA 94121; tel: 415-221-4810 x 3106,
fax: 415-379-5574, e-mail: email@example.com.
Schizophrenia Bulletin vol. 35 no. 6 pp. 1132–1141, 2009
Advance Access publication on September 10, 2009
? The Author 2009. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved.
For permissions, please email: firstname.lastname@example.org.
arise from demonstrable dysfunction in ‘‘higher order’’
cognitive processes,6–8but Bleuler’s famous assertion
that ‘‘sensory response to external stimulus is quite
strated,eg, bythe researchpresentedin thisspecial issue).
In the context of designing cognitive interventions, as in
basic cognitive neuroscience, it may be counterproduc-
tive to attempt to localize a primary deficit in schizophre-
nia either to faculties like attention, working memory,
and executive function, which have historically often
been described as top-down processes associated with
higher order (frontal or parietal) association cortex, or
to bottom-up sensory processing historically associated
with posterior cortical regions. There is now abundant
experimental evidence that the top-down behavioral phe-
the integration of multiple brain systems that manifest as
early in processing as primary sensory cortex9–13and that
have on impact perception via enhanced cortical repre-
sentations of the external world (and of memory). Con-
versely, degradedor ambiguousneural representationsof
sensory information—eg, representations of objectively
noisy or ambiguous information—take a toll on perfor-
mance not only by transmitting unreliable information
but also by taxing working memory and attentional
systems. Importantly, any putative primary pathophysi-
ological insult in schizophrenia that impairs the ability to
actively maintain an accurate representation in working
memory or attentional focus of an action-outcome goal
or of a behavioral context (as has been proposed by mul-
tiple authors14–17) would be expected to have an impact
on the fidelity and efficiency of cortical representations
that are fundamentally sensory.
Indeed, an accumulation of convergent behavioral and
physiological data has explicated and specified the his-
torical observations of sensory disturbances in patients.
For instance, behavioral demonstrations of early audi-
tory processing impairments in schizophrenia subjects
include deficits in tone matching18–20
perception, particularly in noise.21–23Evidence from
event-related potentials in electroencephalography and
magnetoencephalography (MEG), which allow the fine-
grained decomposition of neurophysiological correlates
of auditory processing, further suggests impairments in
initial sensory registration,24–26prediction and temporal
integration in paired speech stimulus in noise paradigms
data, 2009), expectancy violation in mismatch negativity
and early obligatory responses to
auditory stimuli in N1/P1 paradigms.30,32–34Such early
status and outcome35but also with the likelihood to de-
velop schizophrenia among at-risk youth.36
The etiology and pathophysiology of sensory deficits
have important implications for our understanding of
schizophrenia, as is described elsewhere in this special
issue. The critical points for the current discussion are
that sensory processing deficits in schizophrenia patients:
(a) unequivocally exist, (b) impair higher order cognition,
as outlined below, and thus (c) may limit a patient’s
ability to make cognitive improvements unless specifi-
Sensory Representation Impacts Higher Order Cognition
The proposition that the quality of elemental sensory
representations is important to processes that operate
on those representations is hardly surprising. Although
cognitive operations are not strictly serial in nature but
rather integrative and parallel, deficiencies in cortical
representations of sensory information—eg, of pitch or
the resolution of temporal information—would be
expected not only to impair speech comprehension32
and verbal memory37but also prosody38and emotion
detection, cognitive functions correlated with effective
social interactions and functional outcome.39
However, the requirement to disambiguate degraded
bottom-up sensory representations, as occurs in low
signal-to-noise sensory inputs,40also appears to increase
attentional load,41,42thus decreasing performance indi-
rectly via competition for top-down resources. Such real-
location of attentional resources to shore up perceptions
at the cost of ‘‘higher order’’ functions like processing
speed and working memory encoding has been demon-
strated in multiple populations from healthy controls
under noisy conditions,41,43to schizophrenia patients,44
to healthy older adults.45
Improvements in Sensory Representations Should Thus
Benefit Higher Order Cognitive Processing
If the fidelity, precision, and signal-to-noise ratio of sen-
sory representations are important determinants of over-
all cognitive performance, as argued above, poor quality
sensory representations could prove to be rate-limiting
factors in any cognitive remediation paradigm regardless
of the explicit content of the training exercises. From this
impairments in schizophrenia, it follows that optimum
cognitive training programs for remediation of cognitive
deficits in schizophrenia should include training exercises
that target not only top-down functions like attention,
working memory, and executive function but also specif-
ically remedy the precision of sensory representations
that facilitate cognitive function from the bottom-up.
ItIs Possible to DevelopCognitive Training Exercises for
Schizophrenia That Simultaneously Target Bottom-Up
and Top-Down Processing
The cognitive training exercises we have been investigat-
ing are explicitly designed to improve early perceptual
processing along with working memory capacity. Psy-
chophysical training that places implicit, increasing
Auditory Training Enhances Verbal Memory
demands on auditoryperception and accurate aural speech
reception is embedded within increasingly complex audi-
tory working memory and verbal learning exercises. The
exercises implement the findings from basic neuroscience
research delineating the behavioral and biological determi-
nants of significant neurophysiological change mediated
via alterations in synaptic connection and neuronal net-
work functioning (hereafter termed ‘‘neural plasticity’’)
in adult brains. Such plastic changes are epitomized by
the refinement or remapping of cortical receptive fields
but span a wide range of physiologically demonstrable
alterations in function. A rich literature (eg, Mercado
et al46and Bao et al47) has shown that neural plasticity
of heightened neuromodulatory neurotransmission (ie, re-
lease of neurotransmitters like dopamine, acetylcholine,
and norepinephrine that are implicated in top-down func-
tions like attention, executive function, and working mem-
ory, in response to behaviorally relevant stimuli). The
exercises we have investigated are thus (1) intensive, with
thousands of trials per exercise, 2) attentionally engaging,
with self-paced initiation of each learning trial and closely
regulated task difficulty, (3) adaptive, with the critical
appear to be intact in schizophrenia.48
What Results Have Been Obtained to Date Using an
Auditory Training Approach?
Description of the Auditory Training Intervention
We briefly review here the results we have obtained in our
ongoing RCT of computerized ‘‘neuroplasticity based’’
auditory training vs a commercial computer games (CGs)
long-term schizophrenia, registered at ClinicalTrials.gov
NCT00312962 (as reported previously49–52). Volunteer
participants are stratified by age, gender, education, and
symptom severity and randomly assigned to either 50
hours of auditory training (AT) or 50 hours of a CGs con-
trol condition (1 h/d, 5 d/wk). Before and after the inter-
vention, they receive symptom, quality-of-life, and
cognitive assessments (based on Measurement and Treat-
ment Research to Improve Cognition in Schizophrenia
[MATRICS]53recommendations) by personnel blind to
group assignment. Healthy controls are assessed at re-
peated time points but do not undergo cognitive training.
The goal of this study is to test the hypothesis that by im-
the auditory system—while simultaneously training work-
ing memory functions—participants will improve their
‘‘downstream’’ verbal memory performance.
Auditory training exercises, developed by PositScience
Corporation, are presented in a continuously adaptive
manner in that they first establish the precise parameters
to maintain approximately 85% correct performance;
once that threshold is determined, task difficulty
increases systematically and parametrically as perfor-
mance improves. In all exercises, correct performance
is heavily rewarded in a game-like fashion through novel
and amusing visual and auditory embellishments as well
asthe accumulation ofpoints. (See Fisheret al49formore
of computer exposure, contact with research personnel,
and monetary payments for participation. CG subjects
rotate through 16 different enjoyable commercially avail-
able games (eg, visuospatial puzzle games, clue-gathering
mystery games, pinball-style games), playing 4–5 games
on any given day, and are monitored by staff in the same
manner as the AT subjects.
Cognitive Improvement After auditory Training
At baseline, there were no significant differences between
the AT group (N = 29) and CG control group (N = 26)
on measures of symptom ratings or on cognitive perfor-
mance measures.49,50After training, repeated-measures
analysis of variance (ANOVA) revealed a significant
group-by-time interaction (table 1) with the AT group
showing improvement in the cognitive outcome variables
of verbal working memory (letter-number span), verbal
learning (Hopkins Verbal Learning Test, immediate
recall), verbal memory (Hopkins Verbal Learning Test,
delayed recall), and global cognition (composite score
of all MATRICS53-recommended measures). There
were no group-by-time interactions on change scores
in speed of processing (symbol coding, category
fluency-animals, Trail Making Test Part A), nonverbal
working memory (Wechsler Memory Scale-III, spatial
span), visual learning (Brief Visuospatial Memory
Test-Revised, immediate recall), visual memory (Brief
Visuospatial Memory Test-Revised, delayed recall), or
Intelligence Test) or on symptom change or quality-
An examination of the effect sizes computed for each
outcome measure revealed very strong positive effects on
verbal cognition measures for the AT condition but with
no differential effect between conditions on visual cogni-
tion measures (figure 1). We also examined the relation-
ship between training-induced psychophysical gains in
the most basic auditory exercise (time-order discrimina-
tion of frequency modulation sweeps) and cognitive
improvement. We found that auditory psychophysical
gains, as assessed by the amount of the exercise content
completed by each participant, showed a significant
R. A. Adcock et al.
positive correlation with the z-score change in verbal
working memory and in global cognition (Pearson
r = .46, 2-tailed P < .03, and r = 0.39, P < .04, respec-
tively; see figure 2 for relationship with global cognition).
This finding indicates that those subjects who were able
to make the most progress through basic psychophysical
auditory training also showed the most improvement in
higher order cognitive outcome measures.
based auditory training
psychophysical efficiency and auditory/verbal working
memory induces robust improvements in verbal and
validity for the specificity of the effects, suggesting that
this training is, as predicted by the underlying neurosci-
ence rationale, specifically enhancing functioning in the
neural systems that subserve verbal cognition.
We have also examined the durability of the cognitive
improvements after a 6-month no-contact follow-up
jects, some of whom received additional training in visual
cises. We found significant group-by-time interactions,
from baseline to posttraining to the 6-month follow-up;
the cognitive training subjects showed significantly
greater improvement in verbal learning and memory
measures(F = 4.49,P = .03)frombaselinetothe6-month
follow-up,indicating the durability of the cognitive train-
ing effects beyond the immediate posttraining period. Al-
early data, we note that all subjects were randomly
assigned to the different treatment groups. More impor-
tantly, significant correlations were observed between
change in cognition and improvement in quality-of-life
measures 6 months after the intervention in the 22 cogni-
tive training subjects. The association between improve-
ments in functional status at 6 months and cognitive
gains are important to note in light of the specificity of
training effects to the auditory/verbal modality.
Serum Biomarker Findings After Auditory Training
We examined serum brain-derived neurotrophic factor
(BDNF) and serum D-serine in a subgroup of our study
subjects, hypothesizing that these compounds may
potentially serve as peripheral biomarkers for training-
Table 1. Between-Group Comparison of Change in Cognition in 29 Schizophrenia Subjects Undergoing 50 h Neuroplasticity-Based
computerized AT Vs 26 Matched Schizophrenia Subjects Undergoing 50 h of a CGs Control Condition
AT (N = 29) CG (N = 26)
Verbal working memory4.46 (.04)0.58
Verbal learning9.97 (<.01) 0.86
Verbal memory8.60 (<.01)0.89
Nonverbal working memory 0.04 (.85)0.05
Visual learning1.64 (.21) 0.35
Visual memory0.28 (.60)0.15
Note: Baseline and posttraining age-adjusted z scores are presented, with results of repeated-measures analysis of variance and effect
sizes. AT, auditory training; CG, computer game.
Fig. 1. Effect Sizes (With SE) of Computerized Neuroplasticity-Based Auditory Training on Measures of Verbal Vs Visual Cognition in
Patients With Schizophrenia, as Compared With Schizophrenia Patients Undergoing a Computer Games Control Condition. The figure
effects of targeted auditory training on verbal/auditory-based domains of cognitive function as compared with visual domains.
Auditory Training Enhances Verbal Memory
induced physiological changes (R. Panizzutti, M. Fisher,
C. Holland, and S. Vinogradov, unpublished data,
2009).51This prediction was based on 2 notions: (1)
decreases in apoptosis and increases in BDNF signaling
are observed in response to cognitive stimulation54,55and
(2) the cognitive pathophysiology of schizophrenia may
be associated with impairments in N-methyl-D-aspartic
acid (NMDA) receptor activity—a critical component
of learning and memory processes56; if these processes
are partially restored, this may in turn increase levels
of D-serine, a key NMDA receptor coagonist.
At baseline, schizophrenia subjects (N = 56) had a sig-
nificantly lower mean BDNF level of 25.27 ng/ml
(SD = 10.34), compared with a mean of 31.30 (SD = 8.95)
inhealthycomparisonsubjects(N = 16)(t = 2.11,P< .04),
et al58). There were no differences between patients
assigned to AT (mean = 25.03 ng/ml, SD = 11.21) vs
CG(mean=25.54ng/ml,SD = 9.44).Repeated-measures
and CG schizophrenia subgroups in BDNF change from
baseline, to week 2, to posttraining (wk 10), F2,53= 3.47,
P = .04. Post hoc contrasts revealed that the AT and CG
subgroups differed significantly in BDNF serum level
from baseline to week 2, F1,54= 4.97, P = .03, and from
baseline to week 10, F1,54= 6.10, P = .02. After training,
ofthehealthysubjects(mean = 32.23ng/ml,SD = 15.10),
while the CG group’s BDNF levels did not change signif-
icantly (mean = 23.97 ng/ml, SD = 11.21). The increase in
withanincreaseinquality-of-lifescores(Pearsonr = 0.44,
2-tailed P = .01). These data indicate that the neuroplas-
ticity-based cognitive exercises, but not the CGs, induce
a biological response involving neurotrophins over the
with aspects of improved quality of life in schizophrenia
patients. Several lines of evidence suggest that there is
and neurotrophic responses in the brain, but at present
our understanding of these processes is speculative.59–62
Atbaseline, theratioof D-serine/totalserine,covarying
for age, was significantly lower in the schizophrenia sub-
jects (0.80 6 0.11%, N = 42) as compared with healthy
subjects (1.31 6 0.20%, N = 15) (F1,54= 5.12, P < .03).
Although there are open questions about how closely se-
rum and cerebrospinal fluid (CSF) D-serine reflect the
levels in neural tissue, there is strong evidence for de-
creased D-serine levels or decreased D/L serine ratio in
CSF63,64in schizophrenia patients, and similar findings
have been reported for serum levels.63–66Our baseline
findings are consistent with these prior reports. While
there was no significant group-by-time interaction in
mean D-serine/total serine baseline to posttraining ratio,
cognitive gains in the AT group were significantly corre-
lated with increases in D-serine/total serine ratio. In the
AT group, D-serine/total serine increases were correlated
with improvements in speed of processing (Pearson
r = 0.73, 2-tailed P < .001), verbal learning and mem-
ory (r = 0.53, P < .01), and global cognition (r = 0.49,
P < .02). Although the relationship between serum
D-serine and neural plasticity is incompletely understood,
these results parallel relationships between D-serine and
symptom burden67and raise the possibility that changes
in serum D-serine reflect the brain’s ability to generate
training-induced cognitive improvements.
Further support for the notion that this form of
cognitive training relies on the engagement of key neuro-
modulatory systems in the brain comes indirectly from
the observation that medication-related serum anticho-
linergic activity, as measured via radioimmunoassay, was
negatively correlated with improvement in global cogni-
tion (Pearson r = ?0.46, 2-tailed P < .02, N = 25);
squared semipartial correlations indicated that serum
Fig. 2.Association Between Psychophysical Improvementonthe Auditory TrainingExercise forTime-Order Discrimination ofFrequency
Modulation Sweeps (Percent of Exercise content Completed) and Improvement in Global Cognition Composite Score (Pearson r 5 0.39,
2-tailed P 5 .04, N 5 25).
R. A. Adcock et al.
anticholinergic activity uniquely accounted for 20% of
the variance in global cognition change in the AT sub-
jects. Consistent with demonstrations in animal models
of the critical role of cholinergic projections in learn-
ing-inducedplasticity,46theseresults indicatethat cholin-
ergic blockade from psychotropic medications reduces
the brain’s ability to adapt in response to the cognitive
What Are the Preliminary Data on Psychophysiological
Effects of Auditory Training?
We report here highly preliminary data from an ongoing
study of measures of early neural response dynamics to
rapidly presented auditory stimuli obtained before and
after auditory training in our RCT participants. We
are using MEG to reveal the time course of stimulus-
locked activity over bilateral auditory cortices during
discrimination of syllable pairs that differ either in
voice-onset time (VOT, ie, requiring integration of
rapidly changing temporal features of stimuli) or place
of articulation (ie, requiring discrimination of spectral
features of stimuli) (C.L. Dale, A.M. Findlay, and
scription of rationale, experimental tasks, and data ac-
In the MEG analysis reported here, we focus on the
M100 response arising from auditory cortex during the
discrimination of 2 syllables differing in VOT (eg, ‘‘Ba-
Pa’’), presented in quiet, the first syllable occurring at
trial start (0–400 ms) and the second syllable 500 millisec-
onds later (500–900 ms). Schizophrenia subjects under-
went this MEG task at baseline and again in a second
session after 50 hours (approximately 10 wk) of auditory
training exercises; healthy comparison subjects under-
went MEG at baseline and in a second session after 10
weeks but did not engage in cognitive training. (Data
from computer games control subjects are in final stages
of acquisition and processing and are not reported here).
To assess the efficiency with which subjects process the
successive VOT stimuli, the amplitude of the M100
response to the first syllable was subtracted from the
M100 response to the second syllable, resulting in an
overall measure of ‘‘attenuation’’ that represents the nor-
mal suppression of neural activity associated with second
syllable presentation due to ongoing first syllable pro-
cessing. At baseline, schizophrenia subjects (N = 18)
showed a hemispheric asymmetry in their attenuation
of the M100 response to the second syllable (hemisphere:
F1,17= 9.139, P = .008), while healthy comparison sub-
jects(N = 14)did not(hemisphere:
P = .52), an effect that produced a significant baseline
group difference, as seen in figure 3 (group 3 hemisphere:
F1,30= 4.379, P = .045). This finding indicates that indi-
viduals with schizophrenia show hemispheric asymmetry
abnormalities in early neural response dynamics during
the rapid temporal integration of auditory stimuli.
After auditory training, the attenuation of the M100
response to second syllable presentation showed a trend
toward normalization in schizophrenia subjects, reflected
in a reduction of hemispheric asymmetry relative to the
pretraining attenuation response (session 3 hemi 3
group: F1,30= 3.853, P = .059). After training, attenua-
tion increased in the schizophrenia subjects in the left
to baseline levels, roughly converging to the mean atten-
uation levels observed in healthy comparison subjects
across hemispheres (figure 3). Post hoc analyses confirm
that the between-session difference in asymmetrical
response was occurring primarily in the schizophrenia
group (session 3 hemisphere: F1,17= 9.094, P = .008)
but not in the healthy comparison subjects (session 3
hemisphere: F1,13= 0.540, P = .475). These findings
suggest that the auditory training exercises have had
a ‘‘normalizing’’ effect on the temporal integration of
rapidly presented successive auditory stimuli as it occurs
Correlation analyses revealed that the posttraining
changes in M100 attenuation during this task seen in
the schizophrenia participants were correlated with
both task performance and training-related changes in
after training correlated with task accuracy such that
baseline,schizophreniapatients(n 5 18)showedsignificanthemisphericasymmetryofattenuation,relativetohealthycomparisonsubjects
(n 5 14). After auditory training exercises, this asymmetry was reduced and resembled normal patterns.
Auditory Training Enhances Verbal Memory
better performance in the second session was associated
session, irrespective of baseline attenuation levels (r =
?0.643, P = .004, n = 18). Furthermore, changes in left
hemisphere attenuation correlated significantly with
improved performance after cognitive training on verbal
learning (r = ?0.470, 2-tailed P = .049, n = 18).
suggest that the cognitive training exercises, which aim to
increase the efficiency with which incoming auditory
information is processed, promote physiological changes
processing across left and right hemispheres in patients
with schizophrenia. The changes in physiological activity
that we observed in the left hemisphere were associated
with both task accuracy and verbal learning gains.
Thus, it appears that training-induced normalization of
the hemispheric asymmetries in early auditory processing
seen at baseline in schizophrenia may induce improve-
be predicted by the basic science rationale of this ap-
sample size and the highly preliminary nature of these
data. Replication of these early neural responses to train-
ing and further research with larger subject samples is
clearly required before firm conclusions can be drawn.
The evidence reviewed here suggests that a program of
cognitive training that uses computer-based exercises
to accomplish intensive remediation of auditory process-
ing is associated with significant improvements in higher
order cognitive performance, as well as detectable phys-
iologic 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
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 func-
tional outcome as measured by increased quality-of-life
ratings,50suggesting that the program of training may
ical 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 ra-
tio) and may possibly also result in restoration of neural
response patterns typical of healthy subjects during early
auditory processing of rapidly presented successive stim-
uli (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
jects; this increase correlated with improved quality of
life.51For D-serine, the active training group showed
correlations between individual in D-serine/total serine
ing speed, and verbal learning and memory. Our very pre-
liminary data on M100 measures of early auditory
processing indicate that the level of second-syllable atten-
uation 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 ob-
servedinthese 3 qualitatively differentbiomarkers suggest
the extent of the neurobiological remodeling that must oc-
cur 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
are critical to these observations. Because training of au-
ditory representations always occurs alongside the train-
ing 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 renormal-
ization of hemispheric lateralization in M100 attenuation
measures argue against this notion. Further, if training of
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 func-
tions within the trained modality but not to functions in
the untrained modality, as well as our finding that train-
ing-induced psychophysical improvement is significantly
correlated with improved cognition,49supports the no-
tion 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.68Auditory training was asso-
ciated 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
R. A. Adcock et al.
0.41, respectively68). 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 in-
tensive, 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 in-
crease the magnitude of gains in the current approach.
Early visual processing deficits are also evident in
schizophrenia patients, as detailedelsewhere inthis special
issue. The training program described here targeted audi-
tory processing rather than visual systems for a number of
theoretical reasons related tothe critical functional impor-
tance of verbal learning and memory deficits in schizo-
phrenia.49However, visual system impairments are also
importantly related to function in schizophrenia, eg, in
the domain of facial affect recognition.39We 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 modali-
ties provides synergistic or merely additive effects.
The intensive and demanding training schedule used
here may call into question the general utility of this ap-
proach to cognitive enhancement in schizophrenia. Rel-
ative 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 au-
ditory 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
neurocognitive gains would be evident after training pro-
total experience. That such changes in physiology and
function may also persist beyond the period of the inter-
vention50and are achieved without the risks associated
with drug treatments makes this approach especially ap-
propriate 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 neu-
ropsychological improvements suggest robust treatment
benefits for this method, which includes specific remedi-
ation of sensory representation. Further research is
needed to determine whether benefits are specifically
attributable to the exercises’ sensory component; how-
ever, 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 obser-
vations suggest that bottom-up sensory dysfunction is
not only an important determinant of cognitive perfor-
mance and function for schizophrenia patients but also
an appropriate and effective treatment target.
National Alliance for Research on Schizophrenia and De-
pression (Young Investigator Award to R.A.A.); National
to S.V.); San Francisco Department of Veterans Affairs
Medical Center, San Francisco, CA; National Institutes
of Health/National Center for Research Resources Uni-
versity of California San Francisco Center for Clinical
and Translational Science (Grant UL1 RR024131).
Drs Adcock, Dale, Fisher, Simpson, Nagarajan, and
Vinogradov report no competing interests. The contents
of the article are solely the responsibility of the authors
and do not necessarily represent the official views of the
National Institutes of Health.
1. Keefe RS, Bilder RM, Harvey PD, et al. Baseline neurocog-
nitive deficits in the CATIE schizophrenia trial. Neuropsycho-
2. Velligan DI, Mahurin RK, Diamond PL, Hazleton BC,
Eckert SL, Miller AL. The functional significance of symp-
tomatology and cognitive function in schizophrenia. Schiz-
ophr Res. 1997;25:21–31.
3. Green MF, Kern RS, Braff DL, Mintz J. Neurocognitive
deficits and functional outcome in schizophrenia: are we mea-
suring the ‘‘right stuff’’? Schizophr Bull. 2000;26:119–136.
4. Ritsner MS. Predicting quality of life impairment in chronic
schizophrenia from cognitive variables. Qual Life Res.
5. Kurtz MM, Wexler BE, Fujimoto M, Shagan DS, Seltzer JC.
Symptoms versus neurocognition as predictors of change in
life skills in schizophrenia after outpatient rehabilitation.
Schizophr Res. 2008;102:303–311.
6. Frith CD. Consciousness, information processing and schizo-
phrenia. Br J Psychiatry. 1979;134:225–235.
ception of self-produced sensory stimuli inpatients with auditory
hallucinations and passivity experiences: evidence for a break-
down in self-monitoring. Psychol Med. 2000;30:1131–1139.
Auditory Training Enhances Verbal Memory
8. Ford JM, Mathalon DH. Corollary discharge dysfunction in
schizophrenia: can it explain auditory hallucinations? Int
J Psychophysiol. 2005;58:179–189.
9. Kastner S, De Weerd P, Desimone R, Ungerleider LG. Mech-
anisms of directed attention in the human extrastriate cortex
as revealed by functional MRI. Science. 1998;282:108–111.
10. Adcock RA, Constable RT, Gore JC, Goldman-Rakic PS. Func-
tional neuroanatomy of executive processes involved in dual-task
performance. Proc Natl Acad Sci U S A. 2000;97:3567–3572.
11. Kastner S, Ungerleider LG. Mechanisms of visual attention
in the human cortex. Annu Rev Neurosci. 2000;23:315–341.
12. Worden MS, Foxe JJ, Wang N, Simpson GV. Anticipatory
biasing of visuospatial attention indexed by retinotopically
specific alpha-band electroencephalography increases over
occipital cortex. J Neurosci. 2000;20:RC63.
13. Woldorff MG, Liotti M, Seabolt M, Busse L, Lancaster JL,
Fox PT. The temporal dynamics of the effects in occipital cor-
tex of visual-spatial selective attention. Brain Res Cogn Brain
14. Goldman-Rakic PS. Working memory dysfunction in schizo-
phrenia. J Neuropsychiatry Clin Neurosci. 1994;6:348–357.
15. Barch DM, Carter CS. Selective attention in schizophrenia:
relationship to verbal working memory. Schizophr Res.
16. Carter CS, Perlstein W, Ganguli R, Brar J, Mintun M,
Cohen JD. Functional hypofrontality and working memory
dysfunction in schizophrenia. Am J Psychiatry. 1998;155:
17. MacDonald AW, Goghari VM, Hicks BM, Flory JD,
Carter CS, Manuck SB. A convergent-divergent approach
to context processing, general intellectual functioning, and
the genetic liability to schizophrenia. Neuropsychology.
18. Jonsson CO, Sjo ¨stedt A. Auditory perception in schizophre-
nia: a second study of the Intonation test. Acta Psychiatr
19. Javitt DC, Shelley A, Ritter W. Associated deficits in mis-
match negativity generation and tone matching in schizophre-
nia. Clin Neurophysiol. 2000;111:1733–1737.
20. Rabinowicz EF, Silipo G, Goldman R, Javitt DC. Auditory
sensory dysfunction in schizophrenia: imprecision or distract-
ibility? Arch Gen Psychiatry. 2000;57:1149–1155.
21. HoffmanRE, RapaportJ, Mazure CM, Quinlan DM. Selective
speech perception alterations in schizophrenic patients report-
ing hallucinated ‘‘voices’’. Am J Psychiatry. 1999;156:393–399.
22. McKay CM, Headlam DM, Copolov DL. Central auditory
processing in patients with auditory hallucinations. Am J Psy-
23. Vercammen A, de Haan EH, Aleman A. Hearing a voice in
the noise: auditory hallucinations and speech perception. Psy-
chol Med. 2008;38:1177–1184.
24. Force RB, Venables NC, Sponheim SR. An auditory process-
ing abnormality specific to liability for schizophrenia. Schiz-
ophr Res. 2008;103:298–310.
25. Blumenfeld LD, Clementz BA. Response to the first stimulus
determines reduced auditory evoked response suppression in
schizophrenia: single trials analysis using MEG. Clin Neuro-
26. Todd J, Michie PT, Budd TW, Rock D, Jablensky AV. Audi-
tory sensory memory in schizophrenia: inadequate trace for-
mation? Psychiatry Res. 2000;96:99–115.
27. Tho ¨nnessen H, Zvyagintsev M, Harke KC, et al. Optimized
mismatch negativity paradigm reflects deficits in schizophre-
nia patients. A combined EEG and MEG study. Biol Psychol.
28. Umbricht D, Krljes S. Mismatch negativity in schizophrenia:
a meta-analysis. Schizophr Res. 2005;76:1–23.
29. Michie PT, Budd TW, Todd J, et al. Duration and frequency
mismatch negativity in schizophrenia. Clin Neurophysiol.
30. Javitt DC. Intracortical mechanisms of mismatch negativity
dysfunction in schizophrenia. Audiol Neurootol. 2000;5:
31. Na ¨a ¨ta ¨nen R, Ka ¨hko ¨nen S. Central auditory dysfunction in
schizophrenia as revealed by the mismatch negativity
(MMN) and its magnetic equivalent MMNm: a review. Int
J Neuropsychopharmacol. 2009;12:125–135.
32. Kugler BT, Caudrey DJ. Phoneme discrimination in schizo-
phrenia. Br J Psychiatry. 1983;142:53–59.
33. Budd TW, Barry RJ, Gordon E, Rennie C, Michie PT. Dec-
rement of the N1 auditory event-related potential with stimu-
J Psychophysiol. 1998;31:51–68.
34. Ford JM, Mathalon DH, Kalba S, Marsh L, Pfefferbaum A.
N1 and P300 abnormalities in patients with schizophrenia,
epilepsy, and epilepsy with schizophrenia-like features. Biol
35. Light GA, Braff DL. Mismatch negativity deficits are associ-
ated with poor functioning in schizophrenia patients. Arch
Gen Psychiatry. 2005;62:127–136.
36. Klosterko ¨tter J, Hellmich M, Steinmeyer EM, Schultze-
Lutter F. Diagnosing schizophrenia in the initial prodromal
phase. Arch Gen Psychiatry. 2001;58:158–164.
37. Kawakubo Y, Kasai K, Kudo N, et al. Phonetic mismatch
negativity predicts verbal memory deficits in schizophrenia.
38. Leitman DI, Foxe JJ, Butler PD, Saperstein A, Revheim N,
Javitt DC. Sensory contributions to impaired prosodic pro-
cessing in schizophrenia. Biol Psychiatry. 2005;58:56–61.
39. Leitman DI, Laukka P, Juslin PN, Saccente E, Butler P, Jav-
itt DC. Getting the cue: sensory contributions to auditory
emotion recognition impairments in schizophrenia. Schizophr
Bull. September 23, 2008; doi:10.1093/schbul/sbn115.
40. Heinrich A, Schneider BA, Craik FI. Investigating the influ-
ence of continuous babble on auditory short-term memory
performance. Q J Exp Psychol. 2006;61:735–751.
41. Pichora-Fuller MK, Schneider BA, Daneman M. How young
and old adults listen to and remember speech in noise. J
Acoust Soc Am. 1995;97:593–608.
42. Murphy DR, Craik FI, Li KZ, Schneider BA. Comparing the
effects of aging and background noise on short-term memory
performance. Psychol Aging. 2000;15:323–334.
43. Pichora-Fuller MK, Schneider BA, Macdonald E, Pass HE,
Brown S. Temporal jitter disrupts speech intelligibility: a sim-
ulation of auditory aging. Hear Res. 2007;223:114–121.
44. Javitt DC, Liederman E, Cienfuegos A, Shelley AM. Panmo-
dal processing imprecision as a basis for dysfunction of tran-
sient memory storage systems in schizophrenia. Schizophr
45. Schneider BA, Daneman M, Pichora-Fuller MK. Listening in
aging adults: from discourse comprehension to psychoacous-
tics. Can J Exp Psychol. 2002;56:139–152.
46. Mercado E, Bao S, Ordun ˜a I, Gluck MA, Merzenich MM.
Basal forebrain stimulation changes cortical sensitivities to
complex sound. Neuroreport. 2001;12:2283–2287.
R. A. Adcock et al.
47. Bao S, Chan VT, Merzenich MM. Cortical remodelling in- Download full-text
duced by activity of ventral tegmental dopamine neurons.
48. Koch K, Wagner G, Nenadic I, et al. Temporal modeling
demonstrates preserved overlearning processes in schizophre-
nia: an fMRI study. Neuroscience. 2007;146:1474–1483.
49. Fisher M, Holland C, Merzenich MM, Vinogradov S. Using
neuroplasticity-based auditory training to improve verbal
memory in schizophrenia. Am J Psychiatry. 2009;166:805–811.
50. Fisher M, Holland C, Subramaniam K, Vinogradov S.
5, 2009; doi:10.1093/schbul/sbn170.
51. Vinogradov S, Fisher M, Holland C, Shelly W, Wolkowitz O,
Mellon SH. Is serum brain-derived neurotrophic factor a bio-
marker for cognitive enhancement in schizophrenia? [pub-
lished online ahead of print April 14, 2009]. Biol Psychiatry.
52. Vinogradov S, Fisher M, Warm H, Holland C, Kirshner M,
Pollock B. The cognitive cost of anticholinergic burden:
decreased response to cognitive training in schizophrenia.
[published online ahead of print July 1, 2009]. Am J Psychia-
53. Nuechterlein KH, Green MF. MATRICS Consensus Cogni-
tive Battery Manual. Los Angeles, CA: MATRICS Assess-
ment, Inc; 2006.
54. Russo-Neustadt A, Beard RC, Cotman CW. Exercise, antide-
pressant medications, and enhanced brain derived neurotrophic
factor expression. Neuropsychopharmacology. 1999;21:679–682.
55. Young D, Lawlor PA, Leone P, Dragunow M, DuringMJ. En-
vironmental enrichment inhibits spontaneous apoptosis, pre-
56. Javitt DC, Zukin SR. Recent advances in the phencyclidine
model of schizophrenia. Am J Psychiatry. 1991;148:1301–1308.
57. Buckley PF, Mahadik S, Pillai A, Terry A, Jr. Neurotrophins
and schizophrenia. Schizophr Res. 2007;94:1–11.
58. Rizos EN, Rontos I, Laskos E, et al. Investigation of serum
BDNF levels in drug-naive patients with schizophrenia. Prog
Neuropsychopharmacol Biol Psychiatry. 2008;32:1308–1311.
59. Lang UE, Hellweg R, Seifert F, Schubert F, Gallinat J. Cor-
relation between serum brain-derived neurotrophic factor
level and an in vivo marker of cortical integrity. Biol Psychi-
60. Karege F, Perret G, Bondolfi G, Schwald M, Bertschy G,
Aubry JM. Decreased serum brain-derived neurotrophic fac-
tor levels in major depressed patients. Psychiatry Res.
61. Pan W, Banks WA, Fasold MB, Bluth J, Kastin AJ. Transport
of brain-derived neurotrophic factor across the blood-brain
barrier. Neuropharmacology. 1998;37:1553–1561.
62. Lee HY, Kim YK. Plasma brain-derived neurotrophic factor
as a peripheral marker for the action mechanism of antide-
pressants. Neuropsychobiology. 2008;57:194–199.
63. Bendikov I, Nadri C, Amar S, et al. A CSF and postmortem
brain study of D-serine metabolic parameters in schizophre-
nia. Schizophr Res. 2007;90:41–51.
fluid of drug naive schizophrenic patients. Prog Neuropsycho-
pharmacol Biol Psychiatry. 2005;29:767–769.
65. Yamada K, Ohnishi T, Hashimoto K, et al. Identification of
multiple serine racemase (SRR) mRNA isoforms and genetic
analyses of SRR and DAO in schizophrenia and D-serine
levels. Biol Psychiatry. 2005;57:1493–1503.
66. Hashimoto K, Fukushima T, Shimizu E, et al. Decreased se-
rum levels of D-serine in patients with schizophrenia: evi-
dence in support of the N-methyl-D-aspartate receptor
hypofunction hypothesis of schizophrenia. Arch Gen Psychia-
67. Ohnuma T, Sakai Y, Maeshima H, et al. Changes in plasma
glycine, L-serine, and D-serine levels in patients with
schizophrenia as their clinical symptoms improve: results
from the Juntendo University Schizophrenia Projects
(JUSP). Prog Neuropsychopharmacol Biol Psychiatry. 2008;
Auditory Training Enhances Verbal Memory