SPECIAL SECTION ARTICLE
The puzzle of schizophrenia: Tracking the core role
of cognitive deficits
KEITH H. NUECHTERLEIN, KENNETH L. SUBOTNIK, JOSEPH VENTURA, MICHAEL F. GREEN,
DENISE GRETCHEN-DOORLY, AND ROBERT F. ASARNOW
University of California, Los Angeles
Cognitive deficits in schizophrenia are increasingly accepted as core features of this disorder that play a role as vulnerability indicators, as enduring
abnormalities during clinical remission, and as critical rate-limiting factors in functional recovery. This article demonstrates the lasting influence of Norman
Garmezy through his impact on one graduate student and then through his later collaborative research with colleagues. The promise of core cognitive deficits
as vulnerability indicators or endophenotypes was demonstrated in research with children born to a parent with schizophrenia as well as with biological
psychotic and clinically remitted periods and to have a strong predictive influence on likelihood of returning successfully to work or school. Converging
lines of evidence for the enduring core role of cognitive deficit in schizophrenia have led in recent years to a burgeoning interest in developing new
interventions that target cognition as a means of improving functional recovery in this disorder.
Schizophrenia is a severe and chronic mental illness that af-
fects 0.5% to 1.0% of theworld’s population, which amounts
to about two million people in the United States alone. Its
manifestations are varied from case to case, but usually in-
volve hallucinations, delusions, and cognitive disorganiza-
tion and often also affective flattening,avolition, and anhedo-
nia. Because of the disability and repeated hospital care that
often accompanies schizophrenia, the economic burden to
society is enormous, estimated at over $62 billion per year
in the United States alone (Wu et al., 2005).
The severity of this mental disorder and its impact on fam-
ilies and societyhave led ittobe the focusof averylarge body
of research since it was delineated from other mental disorders
about a century ago (Bleuler, 1950; Kraepelin, 1919), but its
specific etiology has remained a puzzle (Gottesman, 1991;
Gottesman & Shields, 1982; MacDonald & Schulz, 2009).
Norman Garmezy was drawn to the study of schizophrenia
by the severity of the disorder, the puzzle of its etiology, the
influence of David Shakow (Shakow, 1962), Eliot Rodnick
(Rodnick & Garmezy, 1957), and Leslie Phillips (Phillips,
1953). Through Norm’s superb mentoring, he inspired a series
of graduate students and later their students and colleagues to
pursue schizophrenia research (e.g., Sheldon Weintraub, Ray
Knight, Lee Marcus, Jon Rolf, Keith Nuechterlein). This arti-
on his University of California, Los Angeles (UCLA), col-
leagues. It is written from the point of view of that former stu-
dent, while including coauthorstoacknowledge their key roles
in later research at UCLA.
The presence of cognitive deficits in schizophrenia was
recognized early during the delineation of this disorder, but
appreciation for the centrality of cognitive deficits to vulner-
ability to the disorder and to functional outcome has in-
creased dramatically over time. Emil Kraepelin initially
viewed cognitive decline as sufficiently characteristic of the
disorder that he used the term dementia praecox to describe
it (Kraepelin, 1919). Kraepelin described a conspicuous at-
It is quite common for them to lose both inclination and ability on
their own initiative to keep their attention fixed for any length of
time. . . .In psychological experiments, the patients cannot stick to
the appointed exercise; they feel no need to collect their thoughts
in the appointed manner, or to reach a satisfactory solution. (p. 6)
EugenBleuler (Bleuler, 1950), inhis earlydescriptionsofthe
nature of schizophrenia, also noted several cognitive distur-
bances, including the selective and inhibitory aspects of at-
. . . it is evident that the uninterested or autistically encapsulated pa-
tients pay very little attention to the outer world. In contrast, how-
Address correspondence and reprint requests to: Keith H. Nuechterlein,
Semel Institute for Neuroscience and Human Behavior, University of Cali-
fornia, Los Angeles, 300 UCLA Medical Plaza, Room 2240, Los Angeles,
CA 90095-6968; E-mail: email@example.com.
Development and Psychopathology 24 (2012), 529–536
#Cambridge University Press 2012
ever, it is remarkable how many of the events which the patients
seem to ignore are registered nevertheless. The selectivity that nor-
mal attention ordinarily exercises among the sensory impressions
can be reduced to zero so that almost everything is recorded that
reaches the senses. Thus, the facilitating as well as the inhibiting
properties of attention are equally disturbed. (p. 68)
The Initial Focus on Attention
The prominence of the concept of attentional disturbance in
schizophrenia in experimental psychopathology during the
1970s (Garmezy, 1978) led several of Norm’s graduate stu-
dents to focus their research on various aspects of this cog-
nitive domain (Driscoll, 1984; Marcus, 1973; Nuechterlein,
1977, 1983; Phipps-Yonas, 1984). In an introduction to this
field as part of Norm’s Experimental Psychopathology semi-
nar, I reviewed and critiqued the large literature on reaction
time studies of schizophrenia, which focused primarily on at-
tentional disturbances (Nuechterlein, 1977).
For the present article, several aspects of that reaction time
literature are noteworthy as they bear on the core cognitive
tional disturbance in schizophrenia emphasized Shakow’s
for individuals with schizophrenia to lose the major goal or
rule that guided perception and readiness to respond over
time was evident in a marked inability to maintain response
aratory intervals varied from trial to trial (Rodnick & Sha-
kow, 1940; Zahn, Rosenthal, & Shakow, 1963). Schizophre-
nia patients are undulyaffected by the immediately preceding
preparatory interval in this situation, seemingly unable to
maintain optimal readiness to respond over the wider range
of time intervals that occur across a series of trials. Two
core deficits in schizophrenia emphasized in the current cog-
nitive neuroscience of schizophrenia, problems in goal main-
tenance, and control of attention (Carter et al., 2008), are re-
lated to this view that schizophrenia involves an inability to
maintain a task set over time.
Second, anotherconstruct that was prominent in the reac-
tion time literature of that period was a redundancy-associ-
ated deficit (Bellissimo & Steffy, 1972). Steffyand students
noted that simple reaction time in schizophrenia patients
slowed when several preparatory intervals of the same
length were presented in a row. Thus, temporal interval re-
dundancy was shown to impairoptimal readinessto respond
schizophrenia patients showan abnormally strong influence
of the immediately preceding preparatory interval, it is ap-
parent that optimal readiness to respond over time is easily
disrupted by immediate context in a series of reaction time
maintenance (Nuechterlein, 1977) was that similar deficits
were detectable in chronic schizophrenia (Rodnick & Sha-
kow, 1940; Zahn, Shakow, & Rosenthal, 1961) and acute
schizophrenia (Zahn & Rosenthal, 1965), suggesting that
this attentional disturbance was a pervasive feature of differ-
ent phases of the illness rather than a transient disturbance
limited to acute psychotic periods.
Children at Risk for Schizophrenia
The focus of experimental psychopathology in schizophrenia
was initially on studies of schizophrenia patients themselves
to characterize the cognitive deficits and the conditions that
contributed to them, and Norm Garmezy’s initial series of
studies reflected this orientation (Garmezy, 1952, 1966; Gar-
mezy & Rodnick, 1959). However, Norm and other leading
at risk fordeveloping schizophreniaoffered excitingopportu-
nities to examine features that precede the disorder and are
vulnerability or proneness factors rather than consequences
of the psychosis and its treatment (Erlenmeyer-Kimling &
Cornblatt, 1987; Garmezy, 1974; Garmezy & Streitman,
1974; Mednick & Schulsinger, 1968). This developmental
orientation to studying schizophrenia led Norm to establish
a project at the University of Minnesota that focused on chil-
dren born to mothers with schizophrenia to identify factors in
vulnerability to the illness as well as protective factors. Off-
spring of a parent with schizophrenia have a 5% to 15%
risk of developing schizophrenia, compared to a 0.5% to
1.0% risk in the general population (Gottesman & Shields,
1982), making them a “high-risk” group. The name of the
broader project that included the Minnesota high-risk studies,
Project Competence (Garmezy, 1974; Garmezy & Devine,
1984), reflected the inclusion of a search for determinants
of positive outcomes that Norm later pursued much more
broadly in his studies of resilience under stress (Garmezy,
Masten, & Tellegen, 1984).
One major theme in these studies of offspring of schizo-
phrenic mothers under Norm’s guidance was to determine
whether cognitive disturbances were detectable in late child-
hood and adolescence, years before the onset of schizophre-
nia and related disorders in a subset of these offspring. Fur-
thermore, these studies sought to determine the nature of
any cognitive disturbances and their specificity to vulnerabil-
sertations that pursued these themes. Lee Marcus (1973) fo-
cused on simple reaction time and preparatory interval
effects, SusanPhipps-Yonas(1984) onvisualversusauditory
reaction time and cross-modal interference effects (Phipps-
Yonas, 1984), and Regina Driscoll (1984) on incidental and
intentional learning, while I examined sustained, focused at-
tention with vigilance tasks (Nuechterlein, 1983).
A suggestion that children of a schizophrenic parent
may have a subtle attentional disturbance was evident in
the results of Marcus (1973), who found a significant over-
all reaction time slowing among such children relative to
their peers. This slowing was more pervasive across exper-
imental conditions than slowing found in other comparison
groups, particularly in that it cut across conditions providing
K. H. Nuechterlein et al.
information or incentives designed to improve performance.
In contrast, it was not clear whether this overall simple reac-
tiontime slowingwas duetoattentional deficit,asthe exces-
sive impact of previous preparatory intervals and other fea-
tures of major set disturbance were not present (Marcus,
To clarify whether a performance deficit was evident in
other tasks used to detect attentional deficit, particularly fail-
ures to maintain focused attention over time, I examined var-
iations of a vigilance task, the Continuous Performance Test
(CPT). CPTs are a class of vigilance tasks in which simple
stimuli, typically letters or numerals, are presented in a rapid
sequence (e.g., 1/s) over several minutes, and the subject is
asked to respond (e.g., with a button press) each time a spe-
cified target appears (Rosvold, Mirsky, Sarason, Bransome,
& Beck, 1956). A conventional CPT had shown sensitivity
to target detection deficits in chronic schizophrenia (Orzack
& Kornetsky, 1966) and remitted schizophrenia (Wohlberg
& Kornetsky, 1973), and a specialized CPT using playing
card stimuli had just been shown to detect a deficit among
children of a schizophrenic parent (Rutschmann, Cornblatt,
& Erlenmeyer-Kimling, 1977). Thus, Norm and I felt that
variations of this paradigm would be fruitful for detecting
and clarifying an attentional disturbance that might be an in-
dicator of vulnerability to schizophrenia.
for schizophrenia was likely a more subtle one than is found
in individuals with schizophrenia itself and wishing to isolate
sertation study CPT versions that involved cognitive burdens
that exceeded those of the conventional CPT (Nuechterlein,
1983). One new CPT version involved highly blurred visual
stimuli to burden early visual processing (the degraded stim-
ulus CPT), while another new CPT involved a strong re-
sponse inhibition demand (response reversal CPT). A con-
ventional CPT (Rosvold et al., 1956) and the playing
card CPT (Rutschmann et al., 1977) were included for
The children of schizophrenic mothers were found to
have a subtle deficit in ability to discriminate targets from
nontargets, an anomaly that was most clearly evident in a
factor score that cut across the CPT conditions (Nuechter-
lein, 1983). Children of mothers with other psychopathol-
Hyperactive children also did not show this particular form
of CPT disturbance, but instead had lowered response cau-
tion in signal detection theory analyses. The observation
that the subtle deficit in signal/noise discrimination (d0)
among children of schizophrenic mothers cut across incen-
tive feedback conditions in the degraded stimulus CPT sug-
gested that the vigilance disturbance was likely not a transi-
ent one that could be easily reversed by motivational
feedback (Nuechterlein, 1983; Nuechterlein, Phipps-Yonas,
Driscoll, & Garmezy, 1982). Thus, these findings supported
the hypothesisthat a subtle deficit in ability to maintain sus-
tained, focused attention in order to detect target stimuli is a
promising indicatorof avulnerabilityorproneness factor for
Stability of Attentional Deficit Across Clinical State
Encouraged by these dissertation findings and by Norm’s
supportive and enthusiastic mentorship, I followed up this re-
search direction in several ways with colleagues in my subse-
quent faculty position at UCLA. One key issue was whether
the deficit in sustained, focused attention was stable across
periods of psychosis and clinical remission in schizophrenia,
as several theorists argued was a key feature of avulnerability
marker (Zubin & Spring, 1977) or endophenotype (Gottes-
man & Gould, 2003) for schizophrenia.
To address this issue, we examined individuals who had
experienced a recent initial episode of schizophrenia and
who could be assessed during a period of full remission
from all psychiatric symptoms and again in a psychotic state
This longitudinal research design again showed the influence
of Norm, who emphasized the virtues of research strategies
that address the development of phenomena of interest over
time. As shown in Figure 1, we found that deficits in sig-
nal/noise discrimination on the degraded stimulus CPT
were large in both the clinically remitted and psychotic state
ical states. We found a similar pattern of stable deficit across
remitted and psychotic states on another measure that empha-
sized cognitive demands on early perceptual processes, target
detection in aforced-choice span of apprehension task (Asar-
involves working memory by requiring detection of a se-
quence of stimuli (3 followed by 7) revealed a somewhat dif-
ferent pattern. Although deficits in this working memory ver-
sion of the CPT were also significant in both remitted and
psychotic states, they increased substantially in magnitude
from remission to psychosis (Nuechterlein et al., 1992).
This overall pattern suggests that deficits in schizophrenia
involving early perceptual processes might be more stable
across clinical state, whereas those involving use of working
memory forcontextual cueing might worsen as psychosis ap-
proaches. Therefore, we suggested that the former were stable
vulnerability indicators for schizophrenia, whereas the latter
might serve as mediating vulnerability factors (Nuechterlein
et al., 1992). In this context, “mediating” is meant to suggest
viduals with schizophrenia (Nuechterlein & Dawson, 1984).
In acurrent series of studies in our Center for Neurocogni-
tion and Emotion in Schizophrenia at UCLA, we are seeking
to isolate the nature of attentional dysfunction in schizophre-
nia much more fully and to further clarify longitudinal stabil-
ity versuschangeintheinitial prodromal and first episode pe-
riods of this illness (Nuechterlein, Pashler, & Subotnik,
2006). Thesestudies employaseriesofdual-task interference
paradigms using choice reaction time tasks that are designed
The puzzle of schizophrenia
to isolate specific cognitive processes that cannot be com-
pleted in parallel in divided attention situations (Pashler,
1994). This translation of paradigms from basic cognitive
psychology to the experimental psychopathology of schizo-
phrenia should yield new insights into cognitive structure in
this disorder that gives rise to the core attentional deficits.
Cognitive Deficits in Parents and Siblings
of Schizophrenia Probands
Another key issuewas whether the cognitivedeficitsdetected
among offspring of a schizophrenic parent would also be
found among other first-degree relatives of schizophrenia
probands, as would be hypothesized if these deficits were a
reflection of increased genetic proneness to schizophrenia.
Furthermore, given that the immediate relatives of schizo-
phrenia probands showan increased frequencyof certain per-
sonality disorders that are part of a schizophrenia spectrum
(Kendler & Diehl, 1993; Kendler & Gruenberg, 1984), we
felt it was important to clarify whether the cognitive deficits
were closely tied to those personality disorder features or a
separable indicator of vulnerability to schizophrenia.
To pursue these issues, Robert Asarnowand I led a project
involving the biological parents and siblings of individuals
with either adult-onset schizophrenia or childhood-onset
schizophrenia, which we called the UCLA Family Study
(Asarnowet al., 2002; Nuechterlein et al.,2002). In the initial
phaseofthis project, weincluded thedegraded stimulus CPT,
the forced-choice span of apprehension task, and the Trail
cused attention, early perceptual processing, perceptual-mo-
tor speed, and working memory as potential cognitive fea-
tures of vulnerability to schizophrenia. In addition, we
conducted structured diagnostic interviews with each family
member to examine psychiatric symptoms that might be
part of a schizophrenia spectrum (Fogelson, Nuechterlein,
Asarnow, Subotnik, & Talovic, 1991).
We found that we could detect cognitive deficits among
these first-degree relatives of schizophrenia probands on the
degraded stimulus CPT, forced-choice span of apprehension,
and Trail Making Test—Part B that paralleled those found
among individuals with schizophrenia (Asarnow et al.,
2002; Nuechterlein et al., 1998). For the degraded stimulus
CPT and the Trail Making Test—Part B, performance of par-
ents of childhood-onset schizophrenia probands was signifi-
cantly worse than for the parents of community comparison
orattention-deficit/hyperactivity disorderchildren, indicating
some specificity for these cognitive deficits (Asarnow et al.,
2002). A combination of low cognitive scores was also found
to identify significantly more fathers and mothers of child-
hood-onset schizophrenia probands than parents of atten-
tion-deficit/hyperactivity disorder probands, as would be ex-
pected if some parents of schizophrenia probands carried a
high level of cognitive vulnerability to the disorder.
By combining the samples of relatives of childhood-onset
ine through factor analysis the interrelationships of these cog-
nitive scores with personality disorder symptom ratings for
more than 300 biological relatives of schizophrenia patients
(Nuechterlein et al., 2002). We found that cognitive perfor-
and degraded stimulus CPT loaded together on a factor with
only one schizotypal symptom, odd or eccentric behavior.
This cognitive disorganization factor was separable from fac-
Figure 1. Attention/vigilance deficits on the degraded stimulus Continuous Performance Test are stable across remitted and psychotic states in
recent-onset schizophrenia. Adapted from “Developmental Processes in Schizophrenic Disorders: Longitudinal Studies of Vulnerability and
Stress,” by K. H. Nuechterlein, M. E. Dawson, M. J. Gitlin, J. Ventura, M. J. Goldstein, K. S. Snyder, et al., 1992. Schizophrenia Bulletin,
18, 387–425. Copyright 1992 by Oxford University Press. Adapted with permission.
K. H. Nuechterlein et al.
tors representing positive schizotypy and negative schizotypy.
symptoms, the cognitive disorganization factor was also sepa-
rate from factors for paranoid symptoms, avoidant symptoms,
schizoid symptoms, and borderline symptoms (Nuechterlein
nerability factor for schizophrenia that is separable from any
proneness to schizophrenia manifested through schizophrenia
spectrum personality disorders.
Cognitive Factors as Key Contributors to Competence
The evidence that attentional disturbance and other cognitive
deficits serve as vulnerability factors for schizophrenia, present
in first-degree biological relativesof schizophrenia patients and
continuing to be present even during clinical remission in indi-
cognitive abnormalities play a role in everyday functioning in
schizophrenia. The link between cognitive functioning and
competence is one that was emphasized by Norm both in stud-
ies of stress resistance and resilience (Garmezyet al., 1984). At
UCLA the connection between cognitive deficitsand everyday
functioning in schizophrenia has been pursued extensively by
my former postdoctoral fellow and long-time colleague, Mi-
chael Green (1996; Green, Kern, Braff, & Mintz, 2000).
To examine the practical consequences of cognitive defi-
cits during the initial period of schizophrenia, we expanded
the battery of cognitive tasks to include more working mem-
attention and early perceptual processing that had been our
initial focus (Nuechterlein et al., 2011). We assessed these
cognitive abilities in patients with a recent first episode of
schizophrenia shortly after they joined our UCLA outpatient
research clinic and then followed them for a year while being
treated with a combination of antipsychotic medication, indi-
vidual case management, group skills training, and family
psychoeducation. We focused on predictors of return to
workor school, asthis functional outcome domain is particu-
phrenia (Ventura et al., 2011).
We derived three cognitive factorsthrough factoranalysis,
representing working memory, attention and early perceptual
processing, and verbal memory and processing speed. As
shown in Figure 2, we found that these three cognitive perfor-
mance dimensions were strong predictors of return toworkor
school by nine months after clinical stabilization, accounting
for 52% of the variance in this outcome (Nuechterlein et al.,
2011). Thus, as has been demonstrated inlaterchronic phases
of schizophrenia (Fett et al., 2011; Green, Kern, & Heaton,
2004), the level of cognitive impairment in schizophrenia is
a key rate-limiting factor in recovery of everyday functioning
in the period after initial onset of psychosis.
Improving Cognition in Schizophrenia
The mounting evidence that cognitive deficits in schizophre-
nia are enduring core features that are components of vulner-
ability to this illness, continue to be present in clinical remis-
Figure 2. A conceptual model showing possible factors influencing work functioning in recent-onset schizophrenic disorders. Adapted from
“Neurocognitive Predictors of Work Outcome in Recent-Onset Schizophrenia,” by K. H. Nuechterlein, K. L. Subotnik, M. F. Green,
J. Ventura, R. F. Asarnow, M. J. Gitlin, et al., 2011, Schizophrenia Bulletin, 37(Suppl. 2), S37. Copyright 2011 by Oxford University Press.
Adapted with permission.
The puzzle of schizophrenia
sions, and predict everyday functioning has made them acrit-
ical target for intervention development in recent years. The
National Institute of Mental Health (NIMH) in the United
States recognized the importance of developing new treat-
ments to improve cognition in schizophrenia and decided to
together leading investigators in multiple relevant fields to
develop pathways for evaluating promising new interven-
tions. UCLAwas fortunate to be awarded the NIMH contract
to lead this effort, titled Measurement and Treatment Re-
search to Improve Cognition in Schizophrenia (MATRICS),
with Stephen Marder as Principal Investigator, Michael
Green as Co-Principal Investigator, and Wayne Fenton as
the leader at NIMH (Marder & Fenton, 2004).
Consultation with the US Food and Drug Administration
initiative needed to be the development of a reliable and valid
batteryofcognitive measuresthat experts could agreewas ap-
in schizophrenia. The absence of such a consensus cognitive
battery was viewed by the FDA as a major roadblock to eval-
uating promising new pharmacological interventions that
were possible cognitive enhancers in schizophrenia, as each
clinical trial used a different set of cognitive measures, mak-
based on cognitive training have substantial promise (Wykes,
Huddy, Cellard, McGurk, & Czobor, 2011). However, al-
though not regulated by the FDA, these interventions might
studies used a standardized, well-accepted cognitive battery
that allowed direct comparison of different approaches.
Thus, a national committee of experts in cognition in schizo-
nitive domains and selecting the most reliable and valid brief
measures in each domain that would be appropriate for clini-
cal trials (Green et al., 2004; Nuechterlein et al., 2004).
ination of the scientific literature, we identified six cognitive
domains in which prominent deficits in schizophrenia had
been demonstrated, that were separable dimensions in factor
analytic studies, and that appeared potentially reversible
through interventions (Green, Nuechterlein, et al., 2004;
cent to include factor analytic studies, but which has promise
as an additional influence on functional outcome (Couture,
Penn, & Roberts, 2006) and serves as a mediator of relation-
ships between othercognitive deficits and everyday function-
ing (Sergi, Rassovsky, Nuechterlein, & Green, 2006).
Using input from over 125 experts in cognition in schizo-
phrenia, cognitive science, clinical trial methodology, psy-
chometrics, biostatistics, and neuropharmacology, the MA-
TRICS Neurocognition Committee evaluated over 90
possible cognitivetests (Nuechterlein et al.,2008).Thelitera-
ture on the most promising 36 teststo measure the seven cog-
nitive domains was carefully evaluated by a panel of experts,
rating each relevant criterion for inclusion in aconsensus bat-
tery. The 20 leading candidates from this step were directly
evaluated for reliability and validity in a five-site study of
schizophrenia patients. As a result, a final battery of 10 tests
was selected for the MATRICS Consensus Cognitive Battery
(Nuechterlein et al., 2008), summarized in Table 1. A five-
site study of a sample representative of the US census demo-
graphics for adults was completed to provide conorming for
these tests to allow cognitive profiles to be examined and to
enable the amount of change in each cognitive domain to
be compared in clinical trials (Kern et al., 2008).
Although this process was complex and time consuming,
the result is a consensus cognitive battery that is endorsed by
the NIMH and accepted by the FDA as the gold standard for
schizophrenia. The MATRICS Consensus Cognitive Battery
has been used in over 60 clinical trials evaluating potential
treatments for the cognitive deficits in schizophrenia and
other psychotic disorders (http://www.clinicaltrials.gov) and
is now available in 15 languages. We are very hopeful that
the availability of this battery will facilitate the successful re-
search evaluation and clinical use of cognitive training and
pharmacological approaches to improving the core cognitive
deficits that play a critical role in limiting functional recovery
of so many individuals suffering from schizophrenia.
The influence of Norman Garmezy on his students and
through them on their students and colleagues is readily ap-
parent in the research summarized in this article. The inspira-
tion, guidance, and support that Norm provided in the disser-
tations of many graduate students at the University of
Minnesota made him an amazing mentor. In this article we
describe the initial influences on one former graduate student
Table 1. Tests in the MATRICS Consensus Cognitive
Speed of processing
† Category fluency
† BACS symbol coding
† Trial Making A
† Continuous Performance Test
Identical pairs version
† Letter number span
† WMS-III spatial span
† Hopkins Verbal
† Brief Visuospatial
Reasoning and problem
† NAB mazes
† MSCEIT managing
Note: MATRICS, Measurement and Treatment Research to Improve Cogni-
tion in Schizophrenia; BACS, Brief Assessment of Cognition in Schizophre-
nia; NAB, Neuropsychological Assessment Battery; WMS-III, Wechsler
Memory Scale, Third Edition; MSCEIT, Mayer–Salovey–Caruso Emotional
K. H. Nuechterlein et al.
(K.H.N.), who was led by Norm to examine the literature on
attention in schizophrenia initially in his graduate seminar
and then through a dissertation study of attentional dysfunc-
tioninchildrenatrisk forlater development ofschizophrenia.
An initial review of the substantial literature on reaction
time abnormalities in schizophrenia helped to set the stage
for a career-long interest in the cognitive abnormalities that
characterize schizophrenia. A dissertation demonstration
deficit in target detection during sustained attention tasksthat
was not found in children of a parent with other forms of psy-
chopathology bolstered early support for the hypothesis that
attentional dysfunction was a potential vulnerability factor
and precursor of schizophrenia.
Later studies at UCLA have shown that the subtle deficits
in target detection during sustained attention tasks as well as
other deficits in early perceptual processing and working
memory also characterize parents and siblings of individuals
with schizophrenia, as hypothesized for a genetic vulnerabil-
ity indicatororendophenotype for this disorder. In patients in
the initial years of schizophrenia, these cognitive deficits are
present across psychotic and clinically remitted states, with
some measures showing unchanged levels of cognitive dys-
function during remission. Furthermore, the severity of cog-
nitive deficits plays a strong predictive role in whether an in-
dividual with schizophrenia successfully returns to work or
school after an initial psychotic episode, thereby highlighting
the key role of these cognitive deficits in functional recovery.
As a result of findings such asthese in the broader literature
on the core role of cognitive deficits in schizophrenia, cogni-
tion has become a prominent target for development of new
pharmacological and cognitive training interventions. The
NIMH-supported MATRICS initiative marked the beginning
of widespread recognition that pathways to facilitate develop-
ment of more effective interventions to reverse core cognitive
This effort continues at this time through research in many
countries, testing various approaches to cognitive training
and pharmacological intervention. We trust that Norman Gar-
of cognitive processes in schizophrenia and in competence
continues to play out in many ways as this field seeks ways
to reverse the core cognitive deficits that otherwise limit func-
tional recovery in this severe mental disorder.
Asarnow, R. F., Granholm, E. L., & Sherman, T. (1991). Span of apprehen-
sion in schizophrenia. In S. R. Steinhauer, J. H. Gruzelier, & J. Zubin
(Eds.), Neuropsychology, psychophysiology and information processing
(Vol. 5, pp. 335–370). Amsterdam: Elsevier Science.
Asarnow, R. F., Nuechterlein, K. H., Subotnik, K. L., Fogelson, D. L., Tor-
quato, R. D., Payne, D. L., et al. (2002). Neurocognitive impairments
in nonpsychotic parents of children with schizophrenia and attention-
deficit/hyperactivity disorder: The University of California, Los Angeles
Family Study. Archives of General Psychiatry, 59, 1053–1060.
Bellissimo, A., & Steffy, R. A. (1972). Redundancy-associated deficit in
schizophrenic reaction time performance. Journal of Abnormal Psychol-
ogy, 80, 299–307.
Bleuler, E. (1950). Dementia praecox or the group of schizophrenias (J. Zin-
kin, Trans.). New York: International Universities Press. (Original work
Carter, C. S., Barch, D. M., Buchanan, R. W., Bullmore, E., Krystal, J. H.,
Cohen, J., et al. (2008). Identifying cognitive mechanisms targeted for
of the Cognitive Neuroscience Treatment Research to Improve Cognition
in Schizophrenia Initiative. Biological Psychiatry, 64, 4–10.
Couture, S. M., Penn, D. L., & Roberts, D. L. (2006). The functional signif-
icance of social cognition in schizophrenia: A review. Schizophrenia
Bulletin, 32(Suppl. 1), S44–S63.
Driscoll, R.M. (1984).Incidentaland intentionallearningin childrenvulner-
able to psychopathology. In N. F. Watt, E. J. Anthony, L. C. Wynne, & J.
E. Rolf (Eds.), Children at risk for schizophrenia: A longitudinal per-
spective (pp. 320–326). New York: Cambridge University Press.
Erlenmeyer-Kimling, L., & Cornblatt, B. (1987). High-risk research in
schizophrenia: A summary of what has been learned. Journal of Psychi-
atric Research, 21, 401–411.
Fett, A. K., Viechtbauer, W., Dominguez, M. D., Penn, D. L., van Os, J., &
Krabbendam, L. (2011). The relationship between neurocognition and
ysis. Neuroscience and Biobehavioral Reviews, 35, 573–588.
Fogelson, D. L., Nuechterlein, K. H., Asarnow, R. F., Subotnik, K. L., & Ta-
lovic, S. A. (1991). Interrater reliability of the Structured Clinical Inter-
view for DSM-III-R, Axis II: schizophrenia spectrum and affective spec-
trum disorders. Psychiatry Research, 39, 55–63.
Garmezy, N. (1952). Stimulus differentiation by schizophrenic and normal
subjects under conditions of reward and punishment. Journal of Person-
ality, 20, 253–276.
Garmezy, N. (1966). The prediction of performance in schizophrenia. Pro-
ceedings of the Annual Meeting of the American Psychopathological
Association, 54, 129–181.
Garmezy, N. (1974). Children at risk: The search for the antecedents of
schizophrenia. Part II: Ongoing research programs, issues, and interven-
tion. Schizophrenia Bulletin, 1, 55–125.
Garmezy, N. (1978). Attentional processes in adult schizophrenia and chil-
dren at risk. Journal of Psychiatric Research, 14, 3–34.
Garmezy, N., & Devine, V. T. (1984). Project Competence: The Minnesota
studies of children vulnerable to psychopathology. In N. Watt, J. Rolf, &
E. J. Anthony (Eds.), Children at risk for schizophrenia (pp. 287–303).
Cambridge: Cambridge University Press.
Garmezy, N., Masten, A. S., & Tellegen, A. (1984). The study of stress and
competence in children: A building block for developmental psychopa-
thology. Child Development, 55, 97–111.
Garmezy, N., & Rodnick, E. H. (1959). Premorbid adjustment and perfor-
mance in schizophrenia: Implications for interpreting heterogeneity in
schizophrenia. Journal of Nervous and Mental Disease, 129, 450–466.
Garmezy, N., & Streitman, S. (1974). Children at risk: The search for the
antecedents of schizophrenia: Part I. Conceptual models and research
methods. Schizophrenia Bulletin, 1, 14–90.
Gottesman, I. I. (1991). Schizophrenia genesis: The origins of madness.
New York: W. H. Freeman.
Gottesman, I. I., & Gould, T. D. (2003). The endophenotype concept in psy-
chiatry: Etymology and strategic intentions. American Journal of Psy-
chiatry, 160, 636–645.
Gottesman, I. I., & Shields, J. A. (1982). Schizophrenia: The epigenetic puz-
zle. Cambridge: Cambridge University Press.
deficits in schizophrenia? American Journal of Psychiatry, 153, 321–
Green, M. F., Kern, R. S., Braff, D. L., & Mintz, J. (2000). Neurocognitive
deficits and functional outcome in schizophrenia: Are we measuring
the “right stuff”? Schizophrenia Bulletin, 26, 119–136.
Green, M. F., Kern, R. S., & Heaton, R. K. (2004). Longitudinal studies of
TRICS. Schizophrenia Research, 72, 41–51.
Green, M. F., Nuechterlein, K. H., Gold, J. M., Barch, D. M., Cohen, J., Es-
ical trials in schizophrenia: The NIMH-MATRICS conference to select
cognitive domains and test criteria. Biological Psychiatry, 56, 301–307.
The puzzle of schizophrenia
Kendler, K. S., & Diehl, S. R. (1993). The genetics of schizophrenia: A cur- Download full-text
Kendler, K. S., & Gruenberg, A. M. (1984). An independent analysis of the
Danish Adoption Study of Schizophrenia. VI. The relationship between
psychiatric disorders asdefined byDSM-IIIin the relativesand adoptees.
Archives of General Psychiatry, 41, 555–564.
Kern, R. S., Nuechterlein, K. H., Green, M. F., Baade, L. E., Fenton, W. S.,
Gold, J. M., et al. (2008). The MATRICS Consensus Cognitive Battery:
Part 2.Co-norming and standardization. American Journalof Psychiatry,
Kraepelin, E. (1919). Dementia praecox and paraphrenia. Edinburgh, Scot-
land: E. & S. Livingstone.
ery theory of schizophrenia should explain. Schizophrenia Research, 35,
Marcus, L. M. (1973). Studies of attention in children vulnerable to psycho-
pathology. Dissertation Abstracts International, 33, 5023B.
Marder, S. R., & Fenton, W. (2004). Measurement and treatment research to
improve cognition in schizophrenia: NIMH MATRICS initiative to sup-
portthe developmentofagentsfor improving cognitionin schizophrenia.
Schizophrenia Research, 72, 5–9.
lated to breakdown in children with schizophrenic mothers. In D. Rosen-
thal & S. S. Kety (Eds.), Transmission of schizophrenia (pp. 267–291).
New York: Pergamon Press.
Nuechterlein, K. H. (1977). Reaction time and attention in schizophrenia: A
critical evaluation of the data and theories. Schizophrenia Bulletin, 3,
Nuechterlein, K. H. (1983). Signal detection in vigilance tasks and behav-
ioral attributesamong offspringof schizophrenic mothersand amonghy-
peractive children. Journal of Abnormal Psychology, 92, 4–28.
D. L., Kendler, K. S., et al. (2002). The structure of schizotypy: Relation-
ships between neurocognitive and personality disorder features in rela-
Research, 54, 121–130.
Nuechterlein, K. H., Asarnow, R. F., Subotnik, K. L., Fogelson, D. L., Ven-
tura, J., Torquato, R., et al. (1998). Neurocognitive vulnerability factors
for schizophrenia: Convergence across genetic risk studies and longitu-
dinal trait/state studies. In M. F. Lenzenweger & R. H. Dworkin
(Eds.), Origins and development of schizophrenia: Advances in experi-
mental psychopathology (pp. 299–327). Washington, DC: American
& Heaton, R. K. (2004). Identification of separable cognitive factors in
schizophrenia. Schizophrenia Research, 72, 29–39.
model of schizophrenic episodes. Schizophrenia Bulletin, 10, 300–312.
Nuechterlein, K. H., Dawson, M. E., Gitlin, M. J., Ventura, J., Goldstein, M.
J.,Snyder,K. S.,et al.(1992).Developmentalprocessesinschizophrenic
disorders: Longitudinal studies of vulnerabilityand stress. Schizophrenia
Bulletin, 18, 387–425.
Nuechterlein, K. H., Green, M. F., Kern, R. S., Baade, L. E., Barch, D. M.,
Cohen, J. D., et al. (2008). The MATRICS Consensus Cognitive Battery:
Part 1. Test selection, reliability, and validity. American Journal of Psy-
chiatry, 165, 203–213.
sic attentional paradigms to schizophrenia research: Reconsidering the
nature of the deficits. Development and Psychopathology, 18, 831–851.
Nuechterlein, K. H., Phipps-Yonas, S., Driscoll, R. M., & Garmezy, N.
(1982). The role of different components of attention in children vulner-
able to schizophrenia. In M. J. Goldstein (Ed.), Preventive intervention in
schizophrenia: Are we ready? (pp. 54–77). Washington, DC: US Gov-
ernment Printing Office.
Nuechterlein, K. H., Subotnik, K. L., Green, M. F., Ventura, J., Asarnow, R. F.,
Gitlin, M. J., et al. (2011). Neurocognitive predictors of work outcome in
Orzack, M. H., & Kornetsky, C. (1966). Attention dysfunction in chronic
schizophrenia. Archives of General Psychiatry, 14, 323–326.
Pashler, H. (1994). Dual-task interference in simple tasks: Data and theory.
Psychological Bulletin, 116, 220–244.
of Nervous and Mental Disease, 117, 515–525.
Phipps-Yonas, S. (1984). Visual and auditory reaction time in children vul-
J. E. Rolf (Eds.), Children at risk for schizophrenia: A longitudinal per-
spective (pp. 312–319). New York: Cambridge University Press.
Reitan, R. M. (1958). Validity of the trail making test as an indicator of
organic brain damage. Perceptual and Motor Skills, 8, 271–276.
Rodnick, E. H., & Garmezy, N. (1957). An experimental approach to the
study of motivation in schizophrenia. Nebraska Symposium on Motiva-
tion (pp. 107–184). Lincoln, NE: University of Nebraska Press.
Rodnick, E. H., & Shakow, D. (1940). Set in the schizophrenic as measured
by a composite reaction time index. American Journal of Psychiatry, 97,
Rosvold, H. E., Mirsky, A. F., Sarason, I., Bransome, E. D., Jr., & Beck, L.
H. (1956). A continuous performance test of brain damage. Journal of
Consulting Psychology, 20, 343–350.
Rutschmann, J., Cornblatt, B., & Erlenmeyer-Kimling, L. (1977). Sustained
attention in children at risk for schizophrenia. Archives of General Psy-
chiatry, 34, 571–575.
Sergi, M. J., Rassovsky, Y., Nuechterlein, K. H., & Green, M. F. (2006). So-
functional status in schizophrenia. American Journal of Psychiatry, 163,
Shakow, D. (1962). Segmental set: A theoryof the formal psychological def-
icit in schizophrenia. Archives of General Psychiatry, 6, 1–17.
Ventura, J., Subotnik, K. L., Guzik, L. H., Hellemann, G. S., Gitlin, M. J.,
Wood, R. C., et al. (2011). Remission and recovery during the first out-
patient year of the early course of schizophrenia. Schizophrenia Re-
search, 132, 18–23.
Wohlberg, G. W., & Kornetsky, C. (1973). Sustained attention in remitted
schizophrenics. Archives of General Psychiatry, 28, 533–537.
Wu, E. Q., Birnbaum, H. G., Shi, L., Ball, D. E., Kessler, R. C., Moulis, M.,
et al. (2005). The economic burden of schizophrenia in the United States
in 2002. Journal of Clinical Psychiatry, 66, 1122–1129.
Wykes, T., Huddy, H., Cellard, C., McGurk, S. R., & Czobor, P. (2011). A
meta-analysis of cognitive remediation for schizophrenia: Methodology
and effect sizes. American Journal of Psychiatry, 168, 472–485.
Zahn, T. P., & Rosenthal, D. (1965). Preparatory set in acute schizophrenia.
Journal of Nervous and Mental Disease, 141, 352–358.
Social Psychology, 67, 44–52.
Zahn, T. P., Shakow, D., & Rosenthal, D. (1961). Reaction time in schizo-
phrenic and normal subjects as a function of preparatory and intertrial in-
tervals. Journal of Nervous and Mental Disease, 133, 283–287.
Zubin,J.,& Spring,B. (1977).Vulnerability—Anew view ofschizophrenia.
Journal of Abnormal Psychology, 86, 103–126.
K. H. Nuechterlein et al.