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Arch Gen Psychiatry. 2010 August ; 67(8): 772–782. doi:10.1001/archgenpsychiatry.2010.85.
Impaired Visual Object Processing Across an Occipital- Frontal-

Hippocampal Brain Network in Schizophrenia: An integrated
neuroimaging study
Pejman Sehatpour1,2,*, Elisa C. Dias1, Pamela D. Butler1,2,3, Nadine Revheim1, David N.
Guilfoyle1, John J. Foxe1,2, and Daniel C. Javitt1,2,3,*
1Schizophrenia Research Center, Cognitive Neurophysiology Laboratory, Nathan S. Kline
Institute for Psychiatric Research, 140 Old Orangeburg Road, Orangeburg, New York 10962
2Program in Cognitive Neuroscience, Department of Psychology, The City College of the City
University of New York North Academic Complex, 138th St. & Convent Avenue, New York, NY
10031
3Departmentsof Psychiatry and Neuroscience, New York University School of Medicine, 550 First
Avenue, New York, NY 10016
Abstract
Background—Perceptual closure refers to the ability to identify objects with partial information.
Deficits in schizophrenia are indexed by impaired generation of the closure-related negativity
(NCL) from ventral stream visual cortex (lateral occipital complex, LOC), as part of a network of
brain regions that also includes dorsal stream visual regions, prefrontal cortex (PFC) and
hippocampus. This study evaluates network-level interactions during perceptual closure in
schizophrenia using parallel ERP, fMRI and neuropsychological assessment.
Methods—ERP were obtained from 24 patients and 20 healthy volunteers in response to

fragmented (closeable) and control scrambled (noncloseable) line drawings. fMRI were obtained
from 11 patients and 12 controls. Patterns of between group differences for predefined ERP
components and fMRI regions of interest were determined using both analysis of variance and
structural equation modeling. Global neuropsychological performance was assessed using

elements of the WAIS-III, WMS-III and MATRICS batteries.
Results—Patients showed impaired visual P1 generation, reflecting dorsal stream dysfunction,

along with impaired generation of NCL components over PFC and LOC. In fMRI, patients showed
impaired activation of dorsal and ventral visual regions, PFC and hippocampus. Impaired
activation of dorsal stream visual regions contributed significantly to impaired PFC activation.
Impaired PFC activation contributed significantly to impaired activation of hippocampus and
LOC. Impaired LOC and hippocampal activation contributed significantly to deficits on WAIS-III
Perceptual Organization Index (POI) and other tests of impaired perceptual processing in
schizophrenia.
*
Correspondence: Pejman Sehatpour or Daniel C. Javitt, Nathan S. Kline Institute for Psychiatric Research, Schizophrenia Research
Center, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA, Phone: (845) 398-6534, Fax: (845) 398-6545,
sehatpour@nki.rfmh.org, javitt@nki.rfmh.org.
Sehatpour et al. Page 2
Conclusion—Schizophrenia is associated with severe activation deficits across a distributed

network of sensory and higher order cognitive regions. Deficit in early visual processing within
the dorsal visual stream contributes significantly to impaired frontal activation which, in turn,
leads to dysregulation of hippocampus and ventral visual stream. Dysfunction within this network
underlies impairment in more traditional measures of neurocognitive dysfunction such as POI,
supporting distributed models of brain dysfunction in schizophrenia.
Keywords
Schizophrenia; fMRI; ERP; Perceptual Organization; NCL; Vision; Multimodal Imaging
INTRODUCTION
Cognitive dysfunction is a critical component of schizophrenia and a major predictor of
impaired long-term outcome 1. Although traditional models of schizophrenia focused on
dysfunction within a limited number of cognitive domains, more recent batteries incorporate
a wider range of domains, including perceptual-level testing 2.
Neurocognitive domains of interest 3, 4 have been expanded still further in cognitive

neuroscience-based initiatives, such as the ongoing CNTRICS (Cognitive Neuroscience

Treatment Research to Improve Cognition in Schizophrenia) initiative, which incorporates
processes such as sensory gain and integration alongside more neuropsychologically driven
domains 5. Nevertheless, the relationship between lower and higher levels of dysfunction, as
well as the neural substrates underlying these domains, remains an area of active research.
The present study investigates mechanisms underlying cognitive dysfunction in

schizophrenia using the perceptual closure task 6, which requires integration between lower
and higher level brain regions. Deficits in perceptual closure have previously been
demonstrated in schizophrenia 7-9, along with deficits in earlier stages of perceptual
processing 10-12. The present study utilizes event-related potentials (ERP) and functional
magnetic resonance imaging (fMRI), along with behavior13, to investigate mechanisms
underlying perceptual closure impairments in schizophrenia.
Perceptual closure refers to the ability of the brain to recognize an object even when
presented with only fragmentary information. Final common processes underlying closure
involve activation of neuronal structures located within ventral stream visual areas such as
lateral occipital complex (LOC) 14, 15. Nevertheless, closure processes depend upon both
bottom-up and top-down processes with convergence of these functions even at early
sensory and perceptual processing stages 16, 1718, 1920. The early visual system is divided
into separable magno- and parvocellular pathways, which project respectively to the dorsal
and ventral visual streams. One mode of visual form integration 16, 21 posits that the
magnocellular visual system is specialized for rapid conduction of low resolution “framing”
information via the dorsal stream to prefrontal regions, with feedback projection to ventral
regions, such as LOC. The parvocellular system, in contrast, provides slower, higher
resolution visual information directly to the LOC 22. Because of the more rapid transit of
information through the magnocellular/dorsal stream pathway than through the
parvocellular/ventral stream, information from the two pathways converges in LOC within
the temporal window of object identification. Most recently, we have demonstrated

significant synchrony between hippocampus and LOC underlying the closure process 23.
Given the widespread network involved in perceptual closure, this process thus provides an
ideal model system in which to investigate potential impairment of distributed large-scale

cortical networks24-28 in schizophrenia.
This study uses parallel ERP and fMRI to investigate stages of impaired perceptual
processing in schizophrenia. Prior ERP studies in schizophrenia have demonstrated impaired
magnocellular/dorsal stream activation, manifested as attenuation of the visual P1
component to magnocellularly biased stimuli 10, 2930, as well as impaired perceptual closure
as manifest by impaired generation of “closure negativity” (NCL) 8, 9. As opposed to P1,
which occurs with a latency of approximately 100 ms over dorsal visual regions and is
similar in amplitude to closeable and non-closeable stimuli, NCL occurs with a latency of
230-400 ms over LOC and is discontinuously large to closeable vs. non-closeable images,
suggesting that it represents the outcome of the perceptual closure process 14.
In normal volunteers, networks underlying perceptual closure have been further clarified
using fMRI and intracranial recording studies. fMRI studies, for example, have confirmed
the localization of NCL generators to LOC and have, in addition, demonstrated activation of
dorsal stream and prefrontal regions during the closure process 20, consistent with prior
fMRI literature 31, 32. Intracranial studies demonstrated additional involvement of
hippocampal formation 23. Because of generator geometry, activity in lateral inferior PFC
and hippocampus project poorly to the scalp and thus can only be assessed using fMRI or
intracranial recordings. This, is the first study to utilize combined ERP/fMRI to investigate
network function underlying impaired perceptual closure processing, in order to elucidate
the contribution of sensory as well as higher cognitive processes, in a convergent model of
object recognition in schizophrenia.
Perceptual closure is a cognitive neuroscience task developed to address particular activation

of neural substrates of object recognition. However concepts underlying closure overlap
with those incorporated into more traditional neuropsychological measures. In particular, the
Wechsler Adult Intelligence Scale (WAIS-III) includes the Picture Arrangement (PA) test,
as well as subtests comprising the Perceptual Organization Index (POI), which is included in
the calculation of performance IQ 33. In the present study, PA and POI were collected, along
with other subtests from WAIS-III, the Brief Visual Memory Task from the MATRICS2
(Measurement and Treatment Research to Improve Cognition in Schizophrenia) and the
Wechsler Memory Scale-III (WMS-III) 34, in order to characterize the dysregulation
observed in various nodes of the neural network engaged in closure processing within the
larger context of clinical neuropsychological dysfunctions in schizophrenia.
METHODS
Participants
Data were collected in two separate experiments. In experiment 1 (ERP), 24 male patients
meeting DSM-IV criteria for schizophrenia (n = 22) or schizoaffective (n = 2) disorder and
20 healthy volunteers (17 male) of similar age participated. In experiment 2 (fMRI), 11 (10
male) patients meeting criteria for schizophrenia (n = 9) or schizoaffective (n = 2) disorder

and 12 healthy volunteers (11 male) of similar age participated. Eight male patients and 9
controls (8 male) participated in both experiments, so that the total sample included 27
patients (26 male, 1 female) and 23 controls (20 male, 3 female). Experiment one consisted
of a single ERP session and experiment two was part of a larger fMRI study.
Patients were recruited from inpatient and outpatient facilities associated with the Nathan
Kline Institute for Psychiatric Research. Diagnoses were obtained using the Structured
Clinical Interview for DSM-IV (SCID) 35. Healthy volunteers with a history of SCID-
defined Axis I psychiatric disorder were excluded. Subjects were excluded if they had any
neurological or ophthalmologic disorders that might affect performance or met criteria for
alcohol or substance dependence within the last six months or abuse within the last month.
Informed consent was obtained after full explanation of procedures.
Patient and control groups did not differ significantly in age (patients, 38.9 ± 10.5 years;
controls, 33.3 ± 10.0 years). Brief Psychiatric Rating Scale (BPRS) 36 total score was 37.4 ±
9.4 (n=26) and Scale for the Assessment of Negative Symptoms (SANS) 37 total score
(including global scores) was 34.0 ± 16.0 (n=26). All patients were receiving antipsychotics
with 20 patients receiving atypical antipsychotics, 3 patients receiving typical

antipsychotics, and 4 patients receiving a combination of atypical and typical antipsychotics.
Chlorpromazine equivalents were 1225 ± 589.5 mg/day. Duration of illness was 18.1 ± 9.9
years.
Stimuli and task

Methods were as described previously for ERP and fMRI studies 20, 23. Briefly, fragmented
line drawings of natural and man-made objects were drawn from the normed Snodgrass and
Vanderwart picture set38, 39. From these images, segments containing black pixels were
randomly and cumulatively deleted to produce seven incrementally fragmented versions of
each picture40. From these images only pictures belonging to the third level of fragmentation
were utilized, hereafter simply referred to as “nonscrambled pictures.” Previous studies have
shown that at this level of fragmentation healthy participants correctly identify objects 73%
of the time 41. A set of “scrambled pictures”, serving as control stimuli, was generated by
dividing the images into 16 × 16 segments, which were then scrambled (Figure 1).
Stimulus presentation
For ERP, stimuli were presented on an Iiyama Vision Master Pro 502 monitor located 143
cm from the subject. Images subtended an average of 4.8° (±1.4°) of visual angle in the
vertical plane and 4.4° (±1.2°) in the horizontal plane. For fMRI, stimuli were delivered
through MR-compatible liquid crystal display goggles (Resonance Technology Inc.,
Northridge, CA).
Timing of stimulus presentation for the ERP study

For ERP each image appeared for 750 ms, followed by a blank screen for 800 ms. Then a
“Y|N” response prompt appeared for 200 ms, followed by a blank screen for 2200 ms.
Subjects were instructed to press one button when they recognized the image as an object
and another when they did not, following presentation of the “Y|N” prompt. Subjects’
response window extended for 2300 ms from the onset of the “Y|N” prompt. A total of 400
unique images, 200 nonscrambled and 200 scrambled, were presented in eight runs of 3.25
min each. No images were repeated.
Timing of stimulus presentation for the fMRI study

For fMRI, each image appeared for 500 ms, followed by a blank screen for 500 ms resulting
in a stimulus onset asynchrony of 1 sec. Nonscrambled, scrambled, and complete (not used
in the analyses of this study) stimulus conditions were presented in a block design. The
stimuli were presented in four 6.2-min runs of twelve blocks each. Each run consisted of
twelve blocks i.e. 4 scrambled, 4 nonscrambled and 4 complete stimulus blocks, pseudo
randomly distributed across the run such that a complete version of a stimulus was not
presented before the presentation of scrambled and incomplete versions. Each block
consisted of 24 unique images, and none was ever repeated. In order to insure central
fixation, subjects were asked to respond with their right index finger each time a target
image (a dog) was presented.,. Targets were presented with equal probability of 4.2%
occurrence across blocks. Only standard stimuli were included in the analysis.
EEG data acquisition and analysis

Continuous EEG was acquired using a BioSemi ActiveTwo electrode system with 168 scalp
electrodes, digitized at 512 Hz, re-referenced to the nose. Data were analyzed using BESA
version 5.1 (Brain Electric Source Analysis, MEGIS Software GmbH). Electrode channels
were subjected to an artifact criterion of ±120μV from −100 to 500 milliseconds. The
vertical and horizontal electro-oculograms (HEOG and VEOG) were, in addition, visually
inspected for blinks and large eye movements. For each subject, epochs were calculated for
a time window from −100 to 500 ms post-stimulus and baseline-corrected relative to the
prestimulus baseline. Accepted trials were then averaged separately for both nonscrambled
and scrambled stimulus conditions to compute the VEP. Only identified stimuli were
included in averages for nonscrambled stimuli.
A priori analysis 9, 20 tested between-group differences in amplitude of the ERP components

P1, N1, NCL, and frontal closure related activity (NfCL) within predetermined spatial and
temporal windows (see legends to Figures 2,3).
fMRI data acquisition and analysis

Images were acquired at the Center for Advanced Brain Imaging (CABI) at the Nathan
Kline Institute on a 3 Tesla MRRS (formerly SMIS, Guildford, U.K.) MRI system. This
system uses a 38 cm inner diameter (i.d.) gradient coil with gradient strength 40 mT/m, rise
time of 280 us, and a 30 cm i.d. transmission line radio frequency coil (Morris Instruments).
In each run, T2*-weighed echoplanar functional images (EPIs) (TR=2000, FA=90, matrix
size= 64×64, FOV=224 mm, voxel size = 3.5mm3) emphasizing the blood oxygenation level
dependent (BOLD) response were acquired while the participant attended to the visual
stimuli. High resolution (1mm3) T1-weighed anatomical images of the whole brain were
acquired from each subject using a standard three dimensional magnetization prepared rapid
gradient echo (MPRAGE) pulse sequence in order to allow volume statistical analyses of
signal changes. Head movement was minimized with the use of a custom-made head holder.
In all subjects, motion never exceeded 0.75 mm along any axis.
The BrainVoyager QX software package 42 was used to process the fMRI data. Each
subject’s data were analyzed separately. Preprocessing of functional scans included slice
scan time correction, head movement measurements, removal of linear trends and temporal
high pass filtering. Each subject’s functional data were co-registered with the anatomical
data. The functional data were then transformed into Talairach space 43 for the multisubject
analysis. Group statistical maps were obtained using a random-effect analysis of the BOLD
signal time series. To estimate the BOLD response associated with each condition,
regressors representing the timing of each of the stimulation epochs were convolved with a
canonical function adjusted with a double-gamma hemodynamic response delay 44 and used
in a multiple regression analysis. The resulting statistical maps were then grouped to obtain
activation maps (Figures 4, 5). The P values of the statistical maps were corrected for
multiple comparisons45, 46 and z-normalized. Different conditions were then contrasted
using a general linear model 47, 48.
Based on a priori hypothesis, four regions of interest (ROIs) were selected at dorsal visual
stream, LOC, PFC and hippocampal formation and the parameter estimates (beta values)
derived from the ROIs.
Clinical Variables
In addition to ERP and fMRI, several relevant neuropsychological measures were
administered. These included the WAIS-III Picture Arrangement (PA) test 33; the Perceptual
Organization Index (POI) battery, which consists of Picture completion (PC), Matrix
Reasoning (MR) and Block Design (BD) tests and the Processing Speed Index (PSI) from
the WAIS-III; the Working Memory Index (WMI) from the WMS-III 34; and the Brief
Visuospatial Memory Test (BVMT-R) 49 which assesses retention of visual memory over
time.
Statistical analyses
Between-group analyses for ERP and fMRI measures were performed using separate
repeated-measures multivariate analysis of variance (rmMANOVA) for each identified ERP
component (P1, N1, NCL, NfCL) and for each of the four ROIs in fMRI studies (dorsal
stream, LOC, PFC, hippocampus). Analyses were conducted using SPSS software (SPSS
Inc, Chicago, Il) with a between-subjects factor of group (patients and controls) and within-
subjects factors of condition (nonscrambled and scrambled) and hemisphere. All tests were
2-tailed with a preset α level of P<.05.
Interrelationship among measures was determined by linear regression, supplemented with

structural equation modeling (path analysis). Path analysis was implemented using AMOS
7.0 (SPSS Inc, Chicago, Il) 50. Selection among alternative models was determined by
minimizing χ2 variance, with paths entered according to the criterion χ2 to include =
(χ2without − χ2with), (dfwithout−dfwith). Residual error and goodness of fit measures including
Cmin/df, RMSEA and NFI were used to assess model integrity.
All significance levels are two-tailed with preset alpha level for significance of p<.05.
Values in text represent mean ± std. dev.
RESULTS
Behavioral Results
Patients recognized the nonscrambled objects 50.6 % of the time vs. 67.5% for controls (t =
−3.7, df = 42, p < .002). The groups did not differ in their reaction times (patients, 1600 ms
± 500 ms; controls, 1900 ms ± 400 ms; t = −1.6, df = 42, P = 0.1). Control values are similar
to those obtained previously 20.
Electrophysiological Results
ERP measures were assessed at predefined electrodes within predefined intervals based
upon prior studies with these stimuli in normal volunteers 20. Separate analyses were
conducted for the sensory components P1 and N1, and for closure-related components over
LOC (NCL) and PFC (NfCL).
Sensory potentials—P1 was maximal over dorsal stream electrodes (P05/P06) within the
90-110 ms interval (Figure 2). P1 amplitudes were significantly reduced in patients relative
to controls (F1,42 = 7.0, P < 0.01). The group × hemisphere (F1,42 = 4.3; P < 0.05)
interaction was also significant, reflecting differential asymmetry between groups. Group ×
condition (F1,42 = 1.3; P = 0.3) and group × condition × hemisphere (F1,42 = 0.02; P = 0.9)
interactions were not significant, reflecting similar P1 amplitude to nonscrambled and
scrambled stimuli.
N1 was maximal over ventral stream electrodes (P07/PO8) during the 160-180 ms latency
range. N1 amplitude (Figure 3) was not significantly different between groups (F1,42 = 1.8,
P = .19). Group × hemisphere (F1,42 = 0.96; P = 0.33), group × condition (F1,42 = 0.05; P =
0.82), and group × condition × hemisphere (F1,42 = 0.62; P = 0.44) interactions were also
non-significant.
Closure related potentials—Closure related activity was observed primarily over LOC,
with a smaller contribution over frontal regions (Figures 3). As in prior studies, the NCL was
defined as mean amplitude within a 300- to 330-millisecond-latency range over left and
right ventral stream electrodes (PO7/PO8). The expected significant main effect of condition
was observed (F1,42 = 22.4; P < 0.001), indicating differential activity across groups to
nonscrambled versus scrambled stimuli. A significant group × condition was also found
(F1,42 = 4.8; P < 0.04), indicating reduced differential activity to nonscrambled vs.
scrambled in patients (F1,23 = 3.9, P = 0.062) vs. controls (F1,19 = 20.0, P<.001). No
significant main or interaction effects involving hemisphere were observed. Group ×
hemisphere (F1,42 = 0.15; P = 0.7), condition × hemisphere (F1,42 = 0.94; P = 0.3), and
group × condition × hemisphere (F1,42 = 1.18; P = 0.3) interactions involving LOC were not
significant.
Bilateral differential activity was also observed over lateral-frontal scalp regions (FC5/FC6)
within the NCL time frame (F1,42 = 9.08; P < 0.004). The group × condition interaction was
not significant (F1,42 = 0.345; P < 0.56). Nevertheless, when analyses were conducted by
group a significant effect of condition was observed in the control group (F1,19 = 7.02, P =
0.016) but not in the patient group (F1,23 = 2.9, P = 0.1) (Figure 3).
fMRI Results
Both experimental conditions (nonscrambled and scrambled), activated widespread and
substantially overlapping cortical networks (Figure 4). BOLD activation patterns were
assessed within predefined ROIs based upon prior studies with these stimuli in normal
volunteers 20. Four brain regions - dorsal visual stream, ventral visual stream, lateral PFC,
and hippocampal formation - were interrogated by a MANOVA which revealed significant
main effects of region (F3,19 = 7.9; P = 0.001) and hemisphere (F1,21 = 11.8; P = 0.003). No
significant main effect of group was observed (F1,21 = 2.23; P = 0.15) indicating absence of
significant differences in the general activation of these brain regions across the two groups.
However, significant effects for group × condition (F1,21 = 37.4; P < 0.001), group ×
hemisphere (F1,21 = 5; P = 0.03) and region × hemisphere (F3,19 = 4.5; P = 0.016) were
observed. No other significant interactions were found. Following a main effect of region, a
set of preplanned ANOVAs were carried out to unpack the results observed at each region.
Significant group × condition interactions were observed at all four regions bilaterally,
indicating reduced closure-related activity in patients relative to controls (Table 1, Figure 5).
Correlation within ERP and fMRI measures

In order to determine contributions of early stage measures to subsequent closure-related
activity, separate sets of analyses were conducted for ERP and fMRI data. For ERP data,
correlational analyses using the differential activity to nonscrambled vs. scrambled stimuli
were employed. However, because the hippocampal node was not represented in scalp-
related activity, formal path analysis was not employed. For fMRI data, a path analysis
explored the interrelationship between ROIs, as well as the effect of cohort on pattern of
interrelationships. Because only 8 subjects participated in both ERP and fMRI studies,
correlation across modalities was not possible.
ERP—For both patients and controls, P1 amplitude correlated significantly with amplitude
of NfCL (patients: r=.64, p=.001; controls: r=.55, p=.012). Also, in both groups, strength of
NfCL correlated significantly with amplitude of NCL (patients: r=.75, p<.001; controls: r=.
76, p<.001). For patients (r=.64, p=.001), but not controls (r=.28, p=.24), deficits in P1
generation correlated significantly with deficits in NCL generation over LOC.
fMRI—Interrelationship among regions was was assessed using path analysis. An iterative
model was employed with paths added to the model only to the extent that they statistically
reduced free variance. Significant paths were observed from dorsal visual stream to PFC,
PFC to LOC, and PFC to hippocampal formation. In addition, a bidirectional interaction was
observed between hippocampal formation and ventral visual stream (Figure 6). When group
was entered into the model, significant independent effects of diagnosis were observed on
dorsal stream and frontal nodes, but not with hippocampal formation or ventral visual
stream, suggesting significant effects of pathological processing primarily on processing
within dorsal stream and frontal regions.
Correlation between ERP/fMRI and clinical measures

Mean Performance IQ in schizophrenia patients was 86.7 ± 17.3, which is significantly
lower than normative mean of 100 (t=3.68, df=22, p=.001). Patients showed significant
reductions in Picture Arrangement (PA) (t=2.25, p=.03), POI (t=2.62, p=.015) and PSI (PSI,
t=10.8, p<.001), and Working Memory Index (WMI) (t=3.46, p=.002) relative to published
norms, with greater deficit on PSI relative to POI (t=3.31, p=.003) (Table 2).
Deficits in fMRI activation of LOC correlated significantly with PA scores, as well as the
overall POI and MR subtest. In contrast, no significant correlation was observed between
LOC activity and the PSI, WMI or the BVMT-R (Table 2). Significant correlations were
also observed between hippocampal activation and several indices of visual processing, as
well as with the BVMT-R. No significant correlations were observed between frontal or
dorsal ROI activations and indices of perceptual closure (all p>.2). Similar correlations were
observed with differential N1 activation to nonscrambled vs. scrambled stimuli vs. both PA
(r=−.48, n=24, p=.017) and POI (r=−.41, p=.048), but not with PSI (r=−.11, p=.61), WMI
(r=−.24, p=.29) or BVMT-R (r=−.24, p=.29).
Reduced NCL generation correlated significantly with higher scores on PANSS total (r=.46,
n=24, p=.025), positive (r=.44, p=.03) and general (r=.45, p=.03) symptoms.
DISCUSSION
We have previously demonstrated reduced perceptual closure ability in schizophrenia using
both behavioral 9 and ERP 9 measures, along with impaired generation of the dorsal stream
P1 potential 11, suggesting significant contribution of early visual impairments51 to more
complex forms of visual processing. Since that time, additional evidence has accumulated
regarding the functional anatomy of the perceptual closure process using scalp ERP, fMRI
and direct intracranial recordings in humans, permitting more detailed hypothesis-driven
analysis of underlying physiological disturbances in schizophrenia.
This study confirms and extends previous findings in four ways. First, it replicates the prior
reports of impaired P1 and NCL generation using a more efficient paradigm recently
employed by us in healthy individuals 20, 23. Second, it combines ERP findings with results
of parallel fMRI investigation, permitting an improved characterization of the deficit in
schizophrenia, while third, providing a direct between-group comparison of fMRI activation

patterns in patients and controls. Finally, neuropsychological data were collected to enable
the characterization of the functional neuroanatomy of closure processes more fully within
the context of neuropsychological dysfunction in schizophrenia.
Here, as in previous studies, the earliest deficits were found in generation of the dorsal
stream P1 potential, suggesting failure of magnocellular and/or early stage cortical
processing, followed by impaired generation of NCL10, 29, 52. In addition here specific
measures were obtained for other brain regions that have been found to be involved in the
closure process, including PFC and hippocampus 23. Deficits in dorsal activation
significantly predicted deficits in frontal processing as assessed using both ERP and fMRI
measures. In both the ERP and fMRI experiments, the degree of correlation between dorsal
and prefrontal activation was similar in patients and in controls suggesting relatively normal
functional connectivity between these two regions in patients. However, the absolute level
of activation was dramatically reduced over both brain regions in patients, suggesting that
failure in processing at the level of dorsal stream visual cortex contributes directly to failures
in processing at subsequent nodes in the closure network.
The study also permits the first assessment of potential hippocampal involvement in
perceptual closure deficits in schizophrenia. Although hippocampus does not generate scalp-
recordable activity because of its location and orientation within brain, we have recently
demonstrated the involvement of hippocampal formation in the process of closure using
recordings from intracranial electrodes in epilepsy patients 23. In those recordings, a
significant, sustained β-synchrony interaction was observed between the hippocampal
formation and LOC during the NCL timeframe, suggesting that closure may depend upon a
matching process between sensory inputs and mnemonic representations activated within
hippocampus. In support, Bar and coworkers 32, 53 have postulated that the magnocellular
provides rapid low-resolution input to the frontal cortex, which then helps trigger top-down
object recognition. The failure of frontal and hippocampal activation observed here suggests
that this top-down mechanism is lost in schizophrenia, due primarily to loss of ascending
magnocellular/dorsal stream input. However, intrinsic abnormalities in hippocampal

function and structure have also been reported 54, leaving unresolved the degree to which
intrinsic hippocampal pathology may contribute to perceptual closure ability as well.
As in our earlier studies, prominent closure-related activity was observed to nonscrambled

vs. scrambled objects in LOC, consistent with the concept that LOC represents the locus of
conscious object identification 31, 32. However, several lines of evidence suggest that
activation deficits were not due to intrinsic structural dysfunction within LOC. First,
generation of the N1 potential, which reflects initial activation of LOC primarily via the
parvocellular stream, was unimpaired. Second, we have previously demonstrated intact N1
modulation in schizophrenia by illusory contour stimuli 19. As opposed to perceptual
closure, which depends upon recursive processing between brain regions and thus occurs
significantly after the visual N1, illusory contour-related activity overlaps the N1, suggesting
that it can be processed during the feedforward sweep 22. Behavioral modulations of
perceptual closure, such as repetition and word priming are also relatively intact 8,
suggesting intact intrinsic function of LOC and modulation by top-down influences. Third,
in our path analysis, illness-related effects were observed only at the level of dorsal stream
visual cortex, and, to a lesser extent, PFC, suggesting that impaired activation of LOC in this
task was driven primarily by impaired input from preceding stages of cortical analysis.
Other studies have also demonstrated intact ventral stream function to stimuli such as faces
using behavioral 55 and fMRI 56 measures.
Finally, this study assesses closure-related activity relative to traditional neuropsychological

measures. Performance IQ in the WAIS is made up of two indices: POI and PSI. Reduced
Performance IQ is a hallmark of schizophrenia. In the present sample, significant reductions
in both POI and PSI were observed relative to normative values, although reductions in PSI
were significantly more robust (p=.003) consistent with prior literature 57. Nevertheless,
here, impaired activation of LOC correlated specifically with overall POI impairment, as
well as reduced PA scores, but not with impairments in PSI, WMI or BVMT (Table 2). Thus
as expected, LOC impairment was most related to cognitive difficulties in perceptual
organization.
A significant correlation was also observed between hippocampal activation and PA scores,
and a nearly significant correlation with POI was also observed (Table 2), suggesting that
the interaction between hippocampus and LOC may also be critical for successful
completion of these tasks. In terms of subtests, a somewhat different pattern of correlations
was observed between regions, with LOC activation correlating only with MR, and
hippocampal activation correlating with both PC and MR. The differential pattern of
correlation may reflect the different mnemonic requirements of the PC vs. MR subtests, as
hippocampal activation correlated also with performance on the BVMT-R, whereas LOC
did not. As with LOC, hippocampal activity in this task did not correlate significantly with
performance on either the PSI or WMI, suggesting relative independence of perceptual
closure mechanisms from other aspects of cognitive dysfunction.
In summary, the present study represents the first multimodal imaging study of impaired
perceptual closure ability in schizophrenia, and highlights the importance of distributed
network dysfunction in the pathophysiology of cognitive dysfunction. In the case of

perceptual closure the critical network of regions begins in dorsal stream visual cortex, and
encompasses PFC, hippocampus and ventral stream visual regions as well. Deficits in early
stages of processing contribute significantly to impairments in subsequent frontal,
hippocampal and ventral stream processing. Dysfunction within this network contributes as
well to overall performance IQ impairments in schizophrenia, with particular relevance to
functions relating to processing of complex visual scenes. Overall, sensory input dysfunction
must be considered a strong contributor to neurocognitive dysfunction in schizophrenia.
ACKNOWLEDGEMENTS
We are ever grateful to all participants particularly the patients who donated their time and energy with grace and
dignity to this project. We would also like to acknowledge the assistance of Maria Jalbrzikowski in data collection
and analysis, Talia Kaplan and Heather Glubo in manuscript preparation.
Supported by NIMH grants MH49334 and MH84848 to DCJ
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Figure 1.
Examples of the stimuli: Closeable (nonscrambled) line-drawings are shown in the left panel
and noncloseable (scrambled) line-drawings are shown in the right panel. The figures from
top to bottom are: Anchor, Ball, and Banana.
Figure 2.
ERP responses to the nonscrambled and scrambled stimuli over posterior scalp, and scalp
voltage maps of the response to the nonscrambled stimuli. Voltage maps at 100ms show the
observed positivity (P1) in controls (top) and in patients (bottom). The graphs show scalp
recordings from two representative occipital electrodes (P05/P06) in controls (top) and in
patients (bottom) indicating no significant differences between the conditions in either
group. The bar-charts show significant differences between the groups in the amplitude of
responses to the nonscrambled stimuli.
Figure 3.
Voltage maps at 330ms (peak NCL activity) illustrate the relative negativity over lateral
occipital scalp for nonscrambled versus scrambled stimuli. The graphs show scalp recording
from two representative lateral occipital electrodes (PO7/PO8) and two representative lateral
frontal electrodes (FC5/FC6) in controls (left) and in patients (right). The blue ribbon in the
graphs show the tested window of time when the responses to the nonscrambled stimulus
condition (in red) produced significantly larger negativity when compared to the scrambled
pictures (in green). The bar-charts show significant differences between the groups in the
amplitude of responses to the nonscrambled versus scrambled stimuli at the lateral occipital
(NCL) but not at the frontal scalp (NfCL). The bar-charts also show no significant differences
between the groups in the amplitude of responses for N1.
Figure 4.
fMRI group activation maps for controls (left) and patients (right) in response to the
nonscrambled (top panel) and scrambled (bottom panel) conditions. The functional data are
presented on the Talairach normalized inflated brain of a single subject. All data are p ≤
0.05, corrected for multiple comparisons across the entire image volume. Areas of
significant BOLD signal in the visual stream and prefrontal cortical regions are observed.
Figure 5.
fMRI responses for the nonscrambled versus scrambled comparison in controls (left),
patients (middle) and the difference between the two groups (right). The fMRI activation
maps showing the difference between the two groups illustrate areas of significant BOLD
signal increase in the four regions of interest (ROI) namely, dorsal visual stream, ventral
visual stream, lateral frontal cortex, and hippocampal formation in controls compared to
patients. The bar-chart shows the magnitude of the BOLD signal increase in response to the
nonscrambled versus scrambled stimuli in controls and in patients at each ROI. Significant
differences between controls and patients are observed at the four ROIs bilaterally. Error
bars represent SEM.
Figure 6.
Differential activation indicated brain regions to closeable (nonscrambled) vs. noncloseable
(scrambled) images. Standard regression coefficients between regions are determined by
path analysis, based upon iterative path fitting. fMRI activations at dorsal stream and frontal
regions significantly predicted group affiliation. Goodness of fit measures vs. suggested rule
of thumb (Ro ) values 50 for the model are as follows: CMIN=1.036 (Ro <2.0), NFI .949
(Ro >.9); RMSEA .027 (Ro <.05); Hoelter .05=113
Table 1
Talairach coordinates for four predefined regions of interest (ROIs) and results of individual ANOVAs
showing main effect of group (control/patient) and group × condition (scrambled/nonscrambled) interaction.
ROI Talairach: X, Y, Z Group F(1, 21); p Group × Condition F(1, 21); p
Dorsal stream ±26, −79, 23 0.007; 0.93 27.04*; 0.0001
Ventral stream (LOC) ±27, −59, −8 1.782; 0.2 14.97*; 0.001
Frontal cortex ±33, 4, 40 5.5*; 0.03 14.26*; 0.001
Hippocampus ±24, −22, −23 0.442; 0.51 18.53*; 0.0001
*
p< 0.05
Table 2
Mean ±sd scores on indicated neuropsychological tests and their probability levels (p) relative to normative
means for schizophrenia patients (n=23), along with correlation coefficients (r) and probability levels (p) for
relationship with fMRI activation measures in indicated ROIs (n=11).
Measure Mean score Normative Ventral stream Hippocampus

(M ±sd; p) mean (LOC) (r; p) (r; p)
Picture arrangement (PA) 8.4* ±3.7; 0.03 10 0.73*; 0.01 0.65*; 0.03
Perceptual Organization Index (POI) 89.1* ±16.9; 0.003 100 0.67*; 0.02 0.6; 0.052
- Picture completion (PC) 7.1* ±3.1; 0.001 10 0.5; 0.12 0.75*; 0.008
-Matrix Reasoning (MR) 9.2 ±3.4; 0.22 10 0.74*; 0.009 0.62*; 0.04
-Block Design (BD) 8.3* ±3.2; 0.01 10 0.41; 0.21 0.39; 0.23
Processing Speed Index (PSI) 80.5* ±8.6; 0.001 100 0.3; 0.4 0.3; 0.4
Working Memory Index (WMI) 88.2* ±14.7; 0.001 100 −0.16; 0.65 0.25; 0.46
Brief Visual Memory Test (BVMT-R) 16.3* ±8.6; 0.001 25 0.35; 0.28 0.67*; 0.02
*
p< 0.05

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Arch Gen Psychiatry. 2010 August ; 67(8): 772–782. doi:10.1001/archgenpsychiatry.2010.85.

Impaired Visual Object Processing Across an Occipital- Frontal-

Methods—ERP were obtained from 24 patients and 20 healthy volunteers in response to

structural equation modeling. Global neuropsychological performance was assessed using

Results—Patients showed impaired visual P1 generation, reflecting dorsal stream dysfunction,

Conclusion—Schizophrenia is associated with severe activation deficits across a distributed

Neurocognitive domains of interest 3, 4 have been expanded still further in cognitive

neuroscience-based initiatives, such as the ongoing CNTRICS (Cognitive Neuroscience

The present study investigates mechanisms underlying cognitive dysfunction in

the temporal window of object identification. Most recently, we have demonstrated

ideal model system in which to investigate potential impairment of distributed large-scale

Perceptual closure is a cognitive neuroscience task developed to address particular activation

male) patients meeting criteria for schizophrenia (n = 9) or schizoaffective (n = 2) disorder

with 20 patients receiving atypical antipsychotics, 3 patients receiving typical

Stimuli and task

Timing of stimulus presentation for the ERP study

min each. No images were repeated.

Timing of stimulus presentation for the fMRI study

EEG data acquisition and analysis

A priori analysis 9, 20 tested between-group differences in amplitude of the ERP components

fMRI data acquisition and analysis

Interrelationship among measures was determined by linear regression, supplemented with

Correlation within ERP and fMRI measures

Correlation between ERP/fMRI and clinical measures

schizophrenia, while third, providing a direct between-group comparison of fMRI activation

magnocellular/dorsal stream input. However, intrinsic abnormalities in hippocampal

As in our earlier studies, prominent closure-related activity was observed to nonscrambled

Finally, this study assesses closure-related activity relative to traditional neuropsychological

network dysfunction in the pathophysiology of cognitive dysfunction. In the case of

Supported by NIMH grants MH49334 and MH84848 to DCJ

closure hypothesis. J Exp Psychol Gen. 1990; 119(3):276–296. [PubMed: 2145392]

1927. [PubMed: 15772373]

Cereb Cortex. 2002; 12(2):163–177. [PubMed: 11739264]

ROI Talairach: X, Y, Z Group F(1, 21); p Group × Condition F(1, 21); p

Dorsal stream ±26, −79, 23 0.007; 0.93 27.04*; 0.0001

Ventral stream (LOC) ±27, −59, −8 1.782; 0.2 14.97*; 0.001

Frontal cortex ±33, 4, 40 5.5*; 0.03 14.26*; 0.001

Hippocampus ±24, −22, −23 0.442; 0.51 18.53*; 0.0001

Measure Mean score Normative Ventral stream Hippocampus

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Frontal cortex ±33, 4, 40 5.5; 0.03 14.26; 0.001