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Original Article |

Reduced Dorsal and Orbital Prefrontal Gray Matter Volumes in Schizophrenia FREE

Raquel E. Gur, MD, PhD; Patricia E. Cowell, PhD; Amanda Latshaw, BS; Bruce I. Turetsky, MD; Robert I. Grossman, MD; Steven E. Arnold, MD; Warren B. Bilker, PhD; Ruben C. Gur, PhD
[+] Author Affiliations

From the Schizophrenia Research Center, Neuropsychiatry Section, Department of Psychiatry (Drs R. E. Gur, Cowell, Turetsky, Grossman, Arnold, Bilker, and R. C. Gur and Ms Latshaw) and the Departments of Radiology (Dr Grossman) and Biostatistics and Epidemiology (Dr Bilker), University of Pennsylvania School of Medicine, Philadelphia.


Arch Gen Psychiatry. 2000;57(8):761-768. doi:10.1001/archpsyc.57.8.761.
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Published online

Background  Converging neuroanatomic, neurophysiological, and neurobehavioral evidence implicate prefrontal subregions in schizophrenia. Neuroanatomic studies with magnetic resonance (MR) imaging enable regional volume parcellation. Inconsistent reports may relate to variable methods and small samples. We attempted to resolve volume differences within sectors of the prefrontal lobe in a large sample, relating volumes to clinical and neurocognitive features.

Methods  Magnetic resonance imaging was performed in 70 patients with schizophrenia (40 men and 30 women; 29 neuroleptic naive and 41 previously treated) and 81 healthy controls (34 men and 47 women). Gray and white matter volumes of the dorsolateral, dorsomedial, orbitolateral, and orbitomedial prefrontal cortex were quantified. Symptoms, functioning, and neurocognition were assessed concurrently.

Results  Reduced prefrontal gray matter volume was observed in patients. The reduction was evident for the dorsolateral area in men (9%) and women (11%), for the dorsomedial area only in men (9%), and for orbital regions only in women (23% and 10% for lateral and medial, respectively). The reduction of orbital volume in women was associated with poorer premorbid functioning, more severe negative symptoms, and depression. Volume of dorsal cortex was positively associated with better performance on abstraction and attention tasks across all groups.

Conclusions  Schizophrenia is associated with reduced gray matter volume in prefrontal cortex, which affects men and women in the dorsolateral sector. The effects are moderated by sex for dorsomedial and orbital regions and are related to symptom severity and cognitive function. This is not a by-product of treatment, since the differences are evident in neuroleptic-naive patients.

Figures in this Article

THE PREFRONTAL cortex is complex and heterogenous, with subregions varying in cytoarchitecture and connectivity to primary, multimodal association areas and subcortical nuclei.14 It modulates cognition, executive functions—abstraction, attention, inhibition, planning, and working memory—motivation, and emotion.13 These neurobehavioral domains are aberrant in schizophrenia, leading to examination with structural59 and functional neuroimaging.912 Human in vivo and postmortem research has converged with primate findings to elucidate intercellular processes modulating cortical circuitry.1,1317 Magnetic resonance imaging can parcellate gray matter (GM) and white matter (WM) volumes, addressing feature variability of gyri and sulci.

Morphometric prefrontal studies in schizophrenia differed in magnetic field, scanning parameters, slice thickness and contiguity, image processing, and regions examined. Consequently, findings seem inconsistent, with some researchers noting no differences between patients and control subjects5,18,19 and others observing volume reduction in GM,6,20 WM,7 or both.21,22 Few investigations related subregional volumes to clinical or neurocognitive parameters. Higher right orbitofrontal volume was associated with positive symptom severity in 10 men23; dorsolateral volume, with performance on abstraction, attention, and memory in 17 patients.24 Sample sizes and partial inclusion of subfrontal regions notwithstanding, these studies support the hypothesis that increased volume is associated with better performance. Sex differences were not examined, but these merit investigation, considering evidence of a more benign presentation and course and greater preponderance of affective symptoms in women.25,26

A previous report from our laboratory found no reduction in frontal lobe volume, unsegmented for GM and WM (5-mm slice thickness), in 71 patients compared with 77 healthy controls.27 Our present study examines the volume of medial and lateral aspects of the dorsal and orbital prefrontal subregions using thin (1-mm) slices and an imaging sequence optimal for GM/WM segmentation. We hypothesized the following: (1) reduced dorsolateral volume in men and women with schizophrenia1,912; (2) milder reduction in women across regions; (3) volume reduction for GM, present in first-episode patients28; and (4) positive association of prefrontal volumes with neurocognitive performance in patients and controls, specifically for executive functions (abstraction and attention).28 We offered no directional hypothesis relating volume to symptom severity, but we expected higher volumes to be associated with better functioning.

SUBJECTS

The sample included 70 patients with schizophrenia (40 men and 30 women) and 81 healthy controls (34 men and 47 women) from the Schizophrenia Research Center at the University of Pennsylvania School of Medicine, Philadelphia. Participants were right-handed and aged 18 through 45 years. They are a subsample, similar demographically and clinically, for whom we previously reported whole-brain data.28 The DSM-IV29 diagnosis was established using medical, neurologic, and psychiatric (Structured Clinical Interview for DSM-IV–Patient Version [SCID-P]30) evaluations performed by trained research psychiatrists.31 Patients with schizophreniform disorder at entry met criteria for schizophrenia at follow-up. The healthy controls, recruited using advertisements, underwent medical, neurologic, and psychiatric (SCID–Non-Patient Edition [SCID-NP]32) evaluations using established procedures.33 Subjects had no history of a disorder or event that might affect brain function (substance use or dependence, hypertension, cerebrovascular disease, seizure disorder, head trauma with loss of consciousness, or endocrine disorder) (Table 1). There were 29 neuroleptic-naive (16 men and 13 women) and 41 previously treated patients (24 men and 17 women). Clinical assessments, neurocognitive testing, and MR imaging were conducted within a week. After complete description of the study, written informed consent was obtained before participation.

ASSESSMENT
Clinical

Symptoms and functioning were assessed by reliable (intraclass correlation coefficient >0.85) investigators.31 Ratings included the Scale for the Assessment of Negative Symptoms (SANS34), Scale for the Assessment of Positive Symptoms (SAPS35), and the Hamilton Depression Scale (HAM),36 obtained for correlations between mood and orbital prefrontal volume. Functional assessment included the Premorbid Adjustment scale (PAS)37 and Quality of Life Scale (QLS).38 The sample was mildly to moderately impaired (Table 2).

Table Graphic Jump LocationTable 2. Symptoms and Function in Men and Women With Schizophrenia*
Neurocognitive

We used a standardized battery39,40 to measure the following 6 neurocognitive domains in z scores: Abstraction-Flexibility, Attention, Verbal memory, Spatial memory, Verbal abilities, and Spatial abilities. The battery was administered by trained fellows supervised by investigators. Specific tests and procedures were published.39,40

MR IMAGING MEASUREMENTS
Image Acquisition

Magnetic resonance imaging scans were acquired on a 1.5-T scanner (Signa; General Electric Co, Milwaukee, Wis) with a spoiled gradient-recalled pulse sequence using the following parameters: flip angle of 35°, repetition time of 35 milliseconds, echo time of 6 milliseconds, field of view of 24 cm, 1 repetition, 1-mm slice thickness, and no interslice gaps. Transaxial images were in planes parallel to the orbitomeatal line, with resolution of 0.9375 × 0.9375 mm. Images were resliced along the anterior-to-posterior commissural (AC-PC) axis to standardize for head tilt. The axial MR image is rotated according to the AC-PC axis in the transaxial plane, the eyeballs in the coronal plane, and midline in the sagittal plane. Sagittal images are rotated so that the AC-PC axes are oriented to straight horizontal positions. No parenchymal lesions or skull abnormalities were evident neuroradiologically.

Prefrontal Subregions

Subdivisions were derived with neuroradiological and neuroanatomic input, using topographical triangulation and tissue segmentation techniques to maximize the precision and reliability of region delineation. Prefrontal cortex was divided into dorsolateral, dorsomedial, and lateral and medial orbital sectors. Regions were drawn on the sagittal series with 3-dimensional visualization tools (Figure 1).

Place holder to copy figure label and caption
Figure 1.

Illustration of region placement for the prefrontal cortex. Magnetic resonance imaging segmentation is illustrated on the upper right corner, where gray matter is depicted in white, white matter in light gray, and cerebrospinal fluid in black. AC-PC indicates anterior commissure–posterior commissure; CC, corpus callosum; DMP, dorsomedial prefrontal; OMP, orbitomedial prefrontal; DLP, dorsolateral prefrontal; and OLP, orbitolateral prefrontal.

Graphic Jump Location

The prefrontal region for each hemisphere extends from midline to the lateral cortical perimeters. The dorsal and orbital regions are separated by a line drawn at the level of the AC. This dividing landmark is used throughout the mediolateral extent of the frontal lobe. The inferior genu of the corpus callosum at midline marks the posterior border of the dorsal prefrontal region. The posterior border of the orbitomedial region is a line drawn from coordinates determined by the anterior tip of the corpus callosum and the inferior cortical border at the first appearance of caudate. Laterally, the posterior border of this region is a line drawn from the head of the caudate. The posterior border of the orbitolateral region is marked by the caudate and the insula. For dorsal and orbital regions, an axial view of the gray-white segmented image is used to determine the border between the medial and lateral regions; they are divided by the medial-most aspect of cortical GM, which runs along the transverse orbital sulcus at the slice superior to the last view of the medial orbital sulcus.

The dorsal prefrontal region includes the frontal pole and frontomarginal, superior frontal, and anterior sections of the middle and inferior gyri; portions of the anterior cingulate may also be included at midline. The lateral portion of the dorsal region includes the lateral aspects of the Brodmann areas 8, 9, 45, 46, and dorsolateral aspects of area 10. The medial portion of this region corresponds to the medial aspects of areas 8 and 9, dorsal portions of areas 32 and 24, and dorsomedial aspects of area 10. The orbital prefrontal region includes the rectal, medial orbital, and suborbital gyri; the ventral portion of the mesial superior gyrus; and the anterior, posterior, and lateral orbital gyri. The lateral portion of the orbital region includes area 47, lateral portions of area 11, and inferolateral portions of area 10. The medial portion of the orbital region corresponds to areas 12, 25, medial 11, inferomedial 10, and ventral 32 and 24.

Reliability

Two raters (P.E.C. and A.L.) independently parcellated 10 randomly selected cases (5 controls and 5 patients). The unbiased intraclass correlations for the 4 sectors in each hemisphere for GM and WM ranged from 0.88 to 0.98.

Image Processing

Brain volume was extracted by semiautomatically stripping scalp, skull, and meninges using optimal thresholding and morphologic operations previously detailed.41,42 The stripped parenchyma was segmented into GM and WM using adaptive Bayesian algorithms.28,43,44

DATA ANALYSIS

Brain volumes in milliliters were dependent measures in multivariate analyses of covariance (MANCOVA), with diagnosis and sex as grouping factors and region (dorsal vs orbital × lateral vs medial) by hemisphere by compartment (GM and WM) as repeated-measures (within-group) factors. Because patients were about 2 years older, and because age affects brain volume, age was a covariate. Analysis was also performed comparing patients experiencing a first episode with patients treated previously and comparing deficit with nondeficit subtypes.45 Cranial volume calculated from T2-weighted images and total brain GM volume were also covaried in separate analyses because of sex and diagnosis effects,27,28,42,46 without altering the findings.

To associate volumes with neurocognition, we correlated GM in subregions with performance on the 6 domains. Two domains, Abstraction-Flexibility and Attention, are hypothesized to relate to prefrontal functioning. This was tested with a Pearson correlation coefficient with α level set at .05. Correlations with the other 4 domains were exploratory, and the P value was Bonferroni-corrected, so that a P value of .01 (.05/4) was considered significant at P = .05. The link between volumes and clinical variables was examined by correlating GM with symptom severity (SANS, SAPS, and HAM) where we had no directional expectations, premorbid function (PAS average) and quality of life (QLS) where higher volumes are expected to correlate with more favorable ratings. Here P values were Bonferroni-corrected using the 5 measures in the denominator so that a P value of .01 was considered significant at P = .05. All P values were 2-tailed.

MR IMAGING

The MANCOVA showed an effect of diagnosis (F16,130 = 2.09 [P = .005]), indicating that patients had overall smaller prefrontal volumes (Table 3). The main effect for sex was not significant, indicating that after correction for cranial volume, men and women do not differ in prefrontal cortex volume. A within-group main effect was obtained for compartment (F1,145 = 33.55 [P<.001]), GM having higher volume than WM in these regions. A dorsal vs orbital by compartment interaction (F1,145 = 29.74 [P<.001]) indicated that this difference was more pronounced for orbital than for dorsal regions. A compartment by diagnosis interaction (F1,145 = 18.36 [P<.001]) reflected that the reduced prefrontal parenchymal volume in patients was specific to GM. A dorsal vs orbital by compartment by diagnosis interaction (F1,145 = 7.66 [P = .007]) indicated a disproportionate reduction in patients for the dorsal GM compartment. There were several significant interactions involving diagnosis and sex (Figure 2): for diagnosis by sex (F16,130 = 2.68 [P<.001]), women with schizophrenia showed greater overall reduction than men relative to their healthy counterparts; lateral vs medial by diagnosis by sex (F1,145 = 7.22 [P = .006]), indicated that this sex difference was more pronounced in lateral than in medial prefrontal regions; and dorsal vs orbital by compartment by diagnosis by sex (F1,145 = 4.60 [P = .03]) indicated that for GM, women with schizophrenia showed reduction in dorsal and orbital cortex, whereas men showed reduced volume only in dorsal prefrontal cortex.

Table Graphic Jump LocationTable 3. Prefrontal Volumes for Patients With Schizophrenia and Healthy Controls*
Place holder to copy figure label and caption
Figure 2.

Mean (± SEM) for gray matter volume of healthy men and women and patients with schizophrenia for lateral and medial aspects of dorsal and orbital prefrontal cortex. HC indicates healthy controls (37 men and 44 women); SCH, patients with schizophrenia (40 men and 30 women).

Graphic Jump Location

Several significant interactions involved hemisphere, indicating the following lateralized effects: hemisphere by diagnosis (F1,145 = 4.40 [P = .04]), hemisphere by diagnosis by sex (F1,145 = 6.59 [P = .01]), dorsal vs orbital by hemisphere by diagnosis by sex (F1,145 = 6.11 [P = .02]), and lateral vs medial by compartment by hemisphere by sex (F1,145 = 5.39 [P = .02]). Follow-up univariate contrasts traced the source of these interactions to the dorsolateral GM, where for women with schizophrenia the reduction was lateralized to the right. Although for healthy people and men with schizophrenia the dorsolateral region is relatively larger on the right, in women with schizophrenia it is symmetrical. No other effects were significant. Analyses within patient groups by neuroleptic status (naive vs previously treated) and by the deficit-nondeficit classification showed no significant effects or interactions.

Within the limited age range, several regions correlated with age. For healthy men, age was associated with decreased volume in dorsolateral (r = −0.49; P = .003) and in dorsomedial (r = −0.46 [P = .006]) cortex. In healthy women, the dorsomedial and orbitolateral volumes correlated with age (r = −0.29 [P = .046] and r = −0.30 [P = .04], respectively). For patients, dorsomedial volume correlated with age for men (r = −0.38 [P = .02]) and for women (r = −0.36 [P = .047]). This supported covarying age in the correlational analyses, which did not affect significance of reported correlations.

CORRELATION OF MR IMAGING WITH ASSESSMENT MEASURES
Clinical

Since the differences between patients and controls were in GM, only GM volumes were correlated with clinical measures, reducing the number of statistical tests. Correlations were computed separately for men and women with schizophrenia because of the interactions of neuroanatomic measures with sex. In men, volume did not correlate with any clinical measure. In women, lower volume in the lateral and medial orbital cortex was associated with more severe negative symptoms (SANS) (r = −0.44 [P = .03] and r = −0.37 [P = .05], respectively) and with poorer premorbid adjustment (r = −0.50 [P = .02] and r = −0.58 [P = .006], respectively). Lower orbitomedial volume was associated with more depressed mood (HAM) (r = −0.40 [P = .045]). There were no correlations for men or women between volumes and duration of illness.

Neurocognitive

The correlations for healthy men were significant between dorsolateral volume and Abstraction (r32 = 0.51 [P = .01]) and between dorsolateral and dorsomedial volumes and Attention (r = 0.34 [P = .05] and r = 0.39 [P = .03], respectively). For healthy women, larger volumes of dorsolateral and dorsomedial regions were associated with better Abstraction (r45 = 0.44 [P = .002] and r = 0.40 [P = .02], respectively). Exploratory analysis of other neurocognitive domains showed that larger volumes of lateral and medial orbital cortex was associated with better Spatial memory (r = 0.46 [P = .004] and r = 0.40 [P = .02], respectively), and lateral orbital volume with better Spatial ability (r = 0.38 [P = .04]). The correlations between volume and performance were attenuated in men with schizophrenia, and only that between dorsomedial volume and Attention reached significance (r = 0.33 [P = .05]). In women with schizophrenia, higher dorsolateral volume was associated with better Attention (r28 = 0.40 [P = .04]). Higher volume of orbitomedial region was associated with better Verbal memory (r = 0.49 [P = .04]).

High-resolution MR imaging with reliable procedures for examination of prefrontal sectors found that patients with schizophrenia have volume reduction specific to GM, which is more marked in dorsal than in orbital cortex. Reduced prefrontal GM is evident in first-episode neuroleptic-naive patients, confirming observations that neuroanatomic abnormalities manifest at clinical presentation.28,4749 Our results differ from studies reporting no prefrontal reduction,19 reduced WM overall and GM in the inferior region,22 and increased right, relative to left, orbital volume in men.23 It is difficult to interpret these discrepancies, since the studies vary in the number and demarcation of subregions, imaging parameters, and sample sizes. Differences could be missed in smaller samples using thicker slices. Our volume estimates are comparable with studies for regions that overlap.

The prefrontal cortex contains sectors with distinct anatomic and functional connections.14 Postmortem studies report cellular differences between patients with schizophrenia and comparison subjects, including increased neuronal density and decreased cortical thickness, suggesting reduced intraneuronal neuropil.1 This is consistent with MR spectroscopy documenting dorsolateral aberrations of neuronal integrity measures.5052 Our results further demonstrate that prefrontal volume reduction is limited to GM and exceeds the global reduction, as indicated by the covariance analyses that partial out cranial and global GM volumes.

We documented sex differences in the effects of schizophrenia on regional anatomy of prefrontal cortex, which were not hitherto examined with sufficient power. Women with schizophrenia had similar reduction (11%) to men (9%) for dorsolateral prefrontal cortex, supporting the hypothesis that this region is dysfunctional in schizophrenia.1,1012 However, in women this reduction was lateralized to the right hemisphere. Women also showed smaller reduction (5%) than men (9.0%) for dorsomedial cortex.

In contrast to equal or lesser aberrations in women compared with men with schizophrenia for dorsal cortex, only women showed lower volume in orbitofrontal cortex exceeding the 6% whole-brain reduction (23% and 10% for orbitolateral and orbitomedial, respectively, compared with 0% and 5%, respectively, in men). The impact of lesions in orbital regions on emotional and social behavior has been noted in neurodegenerative disorders and more focal insults.3,4 Thus, reduced orbital cortex may relate to the greater preponderance of affective symptoms in women with schizophrenia.26 This link is supported by the association between lower orbitofrontal volumes and higher depression ratings. Caudal and rostral regions of the orbitofrontal cortex have extensive connections to limbic cortices and the amygdala.3,4 Orbitofrontal cortex plays a role in emotion and olfactory processes, both showing normal sex differences and impairment in schizophrenia.5356

Exploratory analyses of correlations between volumes and clinical measures showed associations only in women and only for the orbital regions. This suggests that although dorsal prefrontal reduction occurs in both sexes with schizophrenia, its magnitude is unrelated to clinical severity within the present range of mild to moderate symptoms. However, in women with lateral and medial orbital volume reduction, depressive as well as negative symptoms are relatively more prominent although, as a group, they tend to have less severe negative symptoms.25,57 Although these results are tentative and should be interpreted with caution, our study provides a step toward elucidating neural underpinnings of sex differences and encourages further investigation.

Consistent with reports on whole brain measures,42,5860 higher volume of dorsal and orbital cortex were associated with better neurocognitive performance in healthy people and in patients. Similar to the clinical measures, the correlations were stronger for women than for men with schizophrenia. These correlations sustained correction for age and cranial and whole brain volumes. The general similarity of volume and performance correlations for patients and controls indicates that although schizophrenia is associated with reduced volume and performance, it does not alter the fundamental coupling between anatomy and behavior. The results underscore the need to examine the extent to which tissue integrity is necessary for adequate performance. Measures obtained with functional imaging could be limited in accounting for the cognitive deficits unless anatomy is also considered. Nonetheless, our results support neuroimaging, postmortem, and nonhuman primate studies that implicate prefrontal regions in schizophrenia.

We limited the parcellation to major sectors of prefrontal cortex where high reliability can be achieved. The results encourage further evaluation of smaller components. Such studies in large samples will be feasible with more automated procedures using warping algorithms to accommodate variability in the complex sulcal and gyral patterns of cortical regions. Another shortcoming of our study is the limited age range of participants, which does not provide a life-span perspective necessary for accurate evaluation of age effects as they interact with sex. Finally, the cross-sectional design precludes evaluation of change.

Accepted for publication March 24, 2000.

This research was supported by grants MH-42191, MH-43880, MH-01336, and MO1RR0040 from the National Institutes of Health, Rockville, Md.

We thank Richard A. Adler for assistance in image analysis and Tamara Kostick for assistance in manuscript preparation.

Reprints: Raquel E. Gur, MD, PhD, Neuropsychiatry, University of Pennsylvania, 10th Floor, Gates Bldg, Philadelphia, PA 19104 (e-mail: raquel@bbl.psycha.upenn.edu).

Goldman-Rakic  PSSelemon  LD Functional and anatomical aspects of prefrontal pathology in schizophrenia. Schizophr Bull. 1997;23437- 458
Link to Article
Fuster  JM The Prefrontal Cortex: Anatomy, Physiology and Neuropsychology of the Frontal Lobe.  New York, NY Raven Press1989;
Van Hoesen  GWMorecraft  RJSemendeferi  K Functional neuroanatomy of the limbic system and prefrontal cortex. Fogel  BSSchiffer  RSRao  SMedsNeuropsychiatry. Baltimore, Md Williams & Wilkins1996;113- 143
Hof  PRMufson  EJMorrison  JH Human orbitofrontal cortex: cytoarchitecture and quantitative immunohistochemical parcellation. J Comp Neurol. 1995;35948- 68
Link to Article
Andreasen  NCEhrhardt  JCSwayze  V  IIAlliger  RJYuh  WTCCohen  GZiebell  S Magnetic resonance imaging of the brain in schizophrenia: the pathophysiologic significance of structural abnormalities. Arch Gen Psychiatry. 1990;4735- 44
Link to Article
Zipursky  RBLim  KOSullivan  EVBrown  BWPfefferbaum  A Widespread cerebral gray matter volume deficits in schizophrenia. Arch Gen Psychiatry. 1992;49195- 205
Link to Article
Breier  ABuchanan  RWElkashef  AMunson  RCKirkpatrick  BGellad  F Brain morphology and schizophrenia: a magnetic resonance imaging study of limbic, prefrontal cortex, and caudate structures. Arch Gen Psychiatry. 1992;49921- 926
Link to Article
Sullivan  EVLim  KOMathalon  DHMarsh  LBeal  DMHarris  DHoff  ALFaustman  WOPfefferbaum  A A profile of cortical gray matter volume deficits characteristic of schizophrenia. Cereb Cortex. 1998;8117- 124
Link to Article
Gur  REPearlson  GD Neuroimaging in schizophrenia research. Schizophr Bull. 1993;19337- 353
Link to Article
Weinberger  DRBerman  KFZec  RF Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia, I: regional cerebral blood flow evidence. Arch Gen Psychiatry. 1986;43114- 126
Link to Article
Andreasen  NCO'Leary  DSFlaum  MNopoulos  PWatkins  GLBoles Ponto  LLHichwa  RD Hypofrontality in schizophrenia: distributed dysfunctional circuits in neuroleptic-naive patients. Lancet. 1997;3491730- 1734
Link to Article
Buchsbaum  MSHaier  RJPotkin  SGNeuchterlein  KBracha  HSKatz  MLohr  JWu  JLottenberg  SJerabek  PATrenary  MTafalla  RReynolds  CBunney  WE Frontostriatal disorder of cerebral metabolism in never-medicated schizophrenics. Arch Gen Psychiatry. 1992;49935- 942
Link to Article
Akbarian  SBunney  WEPotkin  SGWigal  SBHagman  JOSandman  CAJones  EG Altered distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase cells in frontal lobe of schizophrenics implies disturbances of cortical development. Arch Gen Psychiatry. 1993;50169- 177
Link to Article
Benes  FMMcSparren  JBird  EDSanGiovanni  JPVincent  SL Deficits in small interneurons in prefrontal and cingulate cortex of schizophrenic and schizoaffective patients. Arch Gen Psychiatry. 1991;48996- 1001
Link to Article
Selemon  LDRajkowska  GGoldman-Rakic  PS Abnormally high neuronal density in two widespread areas of the schizophrenic cortex: a morphometric analysis of prefrontal area 9 and occipital area 17. Arch Gen Psychiatry. 1995;52805- 818
Link to Article
Daviss  SRLewis  DA Local circuit neurons of the prefrontal cortex in schizophrenia: selective increase in the density of calbindin-immunoreactive neurons. Psychiatry Res. 1995;5981- 96
Link to Article
Arnold  SETrojanowski  JQ Recent advances in the neuropathology of schizophrenia. Acta Neuropathol (Berl). 1996;92217- 231
Link to Article
Wible  CGShenton  MEHokama  HKikinis  RJolesz  FAMetcalf  DMcCarley  RW Prefrontal cortex and schizophrenia: a quantitative magnetic resonance imaging study. Arch Gen Psychiatry. 1995;52279- 288
Link to Article
Wible  CGShenton  MEFischer  IAAllard  JEKikinis  RJolesz  FAIosifescu  DVMcCarley  RW Parcellation of the human prefrontal cortex using MRI. Psychiatry Res. 1997;7629- 40
Link to Article
Schlaepfer  TEHarris  GJTien  AYPeng  LWLee  SFederman  EBChase  GABarta  PEPearlson  GD Decreased regional cortical gray matter volume in schizophrenia. Am J Psychiatry. 1994;151842- 848
Andreasen  NCFlashman  LFlaum  MArndt  SSwayze  V  IIO'Leary  DSEhrhardt  JCYuh  WTC Regional brain abnormalities in schizophrenia measured with magnetic resonance imaging. JAMA. 1994;2721763- 1769
Link to Article
Buchanan  RWVladar  KBarta  PEPearlson  GD Structural evaluation of the prefrontal cortex in schizophrenia. Am J Psychiatry. 1998;1551049- 1055
Szeszko  PRBilder  RMLencz  TPollack  SAlvir  JMJAshtari  MWu  HLieberman  JA Investigation of frontal lobe subregions in first-episode schizophrenia. Psychiatry Res. 1999;901- 15
Link to Article
Seidman  LJYurgelun-Todd  DKremen  WSWoods  BTGoldstein  JMFaraone  SVTsuang  MT Relationship of prefrontal and temporal lobe MRI measures to neuropsychological performance in chronic schizophrenia. Biol Psychiatry. 1994;35235- 246
Link to Article
Gur  REPetty  RGTuretsky  BIGur  RC Schizophrenia throughout life: sex differences in severity and profile of symptoms. Schizophr Res. 1996;211- 12
Link to Article
Kohler  CGGur  RCSwanson  CSPetty  RGur  RE Depression in schizophrenia, I: association with neuropsychological deficits. Biol Psychiatry. 1998;43165- 172
Link to Article
Turetsky  BTCowell  PEGur  RCGrossman  RIShtasel  DLGur  RE Frontal and temporal lobe brain volumes in schizophrenia: relationship to symptomatology and clinical subtype. Arch Gen Psychiatry. 1995;521061- 1070
Link to Article
Gur  RETuretsky  BIBilker  WBGur  RC Reduced gray matter volume in schizophrenia. Arch Gen Psychiatry. 1999;56905- 911
Link to Article
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.  Washington, DC American Psychiatric Association1994;
Spitzer  RLWilliams  JBWGibbon  M Structured Clinical Interview for DSM-IV: Patient Version (SCID-P).  New York New York State Psychiatric Institute1994;
Gur  REMozley  DResnick  SMLevick  SErwin  RSaykin  AJGur  RC Relations among clinical scales in schizophrenia: overlap and subtypes. Am J Psychiatry. 1991;148472- 478
First  MBSpitzer  RLGibbon  MWilliams  JBW Structured Clinical Interview for DSM-IV Axis I Disorders, Non-Patient Edition (SCID-NP).  New York New York State Psychiatric Institute/Biometrics Research Department1995;
Shtasel  DLGur  REMozley  PDRichards  JTaleff  MMHeimberg  CGallacher  FGur  RC Volunteers for biomedical research: recruitment and screening of normal controls. Arch Gen Psychiatry. 1991;481022- 1025
Link to Article
Andreasen  NC The Scale for the Assessment of Negative Symptoms (SANS).  Iowa City The University of Iowa1984;
Andreasen  NC The Scale for the Assessment of Positive Symptoms (SAPS).  Iowa City The University of Iowa1984;
Hamilton  M A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;2356- 62
Link to Article
Harris  JG An abbreviated form of the Phillips Rating Scale of Premorbid Adjustment in schizophrenia. J Abnorm Psychol. 1975;84129- 137
Link to Article
Heinrichs  DWHanlon  TECarpenter  WT  Jr The Quality of Life Scale: an instrument for rating the schizophrenic deficit syndrome. Schizophr Bull. 1984;10388- 398
Link to Article
Saykin  AJShtasel  DLGur  REKester  DBMozley  LHStafiniak  PGur  RC Neuropsychological deficits in neuroleptic naive, first-episode schizophrenic patients. Arch Gen Psychiatry. 1994;51124- 131
Link to Article
Censits  DMRagland  JDGur  RCGur  RE Neuropsychological evidence supporting a neurodevelopmental model of schizophrenia: a longitudinal study. Schizophr Res. 1997;24289- 298
Link to Article
Yan  MXHKarp  JS Segmentation of 3D MR using an adaptive K-means clustering algorithm. Proc IEEE Med Imaging Conf. 1994;41529- 1533
Gur  RCTuretsky  BIMatsui  MYan  MXHBilker  WHughett  PGur  RE Sex differences in brain gray and white matter in healthy young adults: correlations with cognitive performance. J Neurosci. 1999;194065- 4072
Yan  MXHKarp  JS Image registration of MR and PET based on surface matching and principal axes fitting. Proc IEEE Med Imaging Conf. 1994;41677- 1681
Yan  MXHKarp  JS Information processing in medical imaging. Bizais  YBarillot  CDiPaol  RedsInformation Processing in Medical Imaging. Norwell, Mass Kluwer Academic Publishers1995;201- 213
Carpenter  WTHeinrichs  DWWagman  AMI Deficit and nondeficit forms of schizophrenia: the concept. Am J Psychiatry. 1988;145578- 583
Cowell  PEKostianovsky  DJGur  RCTuretsky  BIGur  RE Sex differences in neuroanatomical and clinical correlations in schizophrenia. Am J Psychiatry. 1996;153799- 805
Lim  KOTew  WKushner  MChow  KMatsumoto  BDeLisi  LE Cortical gray matter volume deficit in patients with first-episode schizophrenia. Am J Psychiatry. 1996;1531548- 1553
Zipursky  RBLambe  EKKapur  SMikulis  DJ Cerebral gray matter deficits in first episode psychosis. Arch Gen Psychiatry. 1998;55540- 546
Link to Article
Nopoulos  PTorres  IFlaum  MAndreasen  NCEhrhardt  JCYuh  WTC Brain morphology in first-episode schizophrenia. Am J Psychiatry. 1995;1521721- 1723
Pettegrew  JWKeshavan  MSPanchalingam  KStrychor  SKaplan  DBTretta  MGAllen  M Alterations in brain high-energy phosphate and membrane phospholipid metabolism in first-episode, drug-naive schizophrenics: a pilot study of the dorsal prefrontal cortex by in vivo phosphorus 31 nuclear magnetic resonance spectroscopy. Arch Gen Psychiatry. 1991;48563- 568
Link to Article
Bertolino  ANawroz  SMattay  VSBarnett  ASDuyn  JHMoonen  CTWFrank  JATedeschi  GWeinberger  DR Regionally specific pattern of neurochemical pathology in schizophrenia as assessed by multislice proton magnetic resonance spectroscopic imaging. Am J Psychiatry. 1996;1531554- 1563
Cecil  KMLenkinski  REGur  REGur  RC Proton magnetic resonance spectroscopy in the frontal and temporal lobes of neuroleptic naive patients with schizophrenia. Neuropsychopharmacology. 1999;20131- 140
Link to Article
Kring  AMGordon  AH Sex differences in emotion: expression, experience, and physiology. J Pers Soc Psychol. 1998;74686- 703
Link to Article
Doty  RLApplebaum  SZusho  HSettle  RG Sex differences in odor identification ability: a cross-cultural analysis. Neuropsychologia. 1985;23667- 672
Link to Article
Moberg  PJDoty  RLTuretsky  BIArnold  SEMahr  RNGur  RCBilker  WGur  RE Deterioration of olfactory identification abilities in patients with schizophrenia. Am J Psychiatry. 1998;1551463- 1464
Heimberg  CGur  REErwin  RJShtasel  DLGur  RC Facial emotion discrimination, III: behavioral findings in schizophrenia. Psychiatry Res. 1992;42253- 265
Link to Article
Goldstein  JMSeidman  LJGoodman  JMKoren  DLee  HWeintraub  STsuang  MT Are there sex differences in neuropsychological functions among patients with schizophrenia? Am J Psychiatry. 1998;1551358- 1364
Andreasen  NCFlaum  MSwayze  V  IIO'Leary  DSAlliger  RCohen  GEhrhardt  JYuh  WT Intelligence and brain structure in normal individuals. Am J Psychiatry. 1993;150130- 134
Kareken  DAGur  RCMozley  PDMozley  LHSaykin  AJShtasel  DLGur  RE Cognitive functioning and neuroanatomic volume measures in schizophrenia. Neuropsychology. 1995;9211- 219
Link to Article
Reiss  ALAbrams  MTSinger  HSRoss  JLDenckla  MB Brain development, gender and IQ in children: a volumetric imaging study. Brain. 1996;1191763- 1774
Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Illustration of region placement for the prefrontal cortex. Magnetic resonance imaging segmentation is illustrated on the upper right corner, where gray matter is depicted in white, white matter in light gray, and cerebrospinal fluid in black. AC-PC indicates anterior commissure–posterior commissure; CC, corpus callosum; DMP, dorsomedial prefrontal; OMP, orbitomedial prefrontal; DLP, dorsolateral prefrontal; and OLP, orbitolateral prefrontal.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Mean (± SEM) for gray matter volume of healthy men and women and patients with schizophrenia for lateral and medial aspects of dorsal and orbital prefrontal cortex. HC indicates healthy controls (37 men and 44 women); SCH, patients with schizophrenia (40 men and 30 women).

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 2. Symptoms and Function in Men and Women With Schizophrenia*
Table Graphic Jump LocationTable 3. Prefrontal Volumes for Patients With Schizophrenia and Healthy Controls*

References

Goldman-Rakic  PSSelemon  LD Functional and anatomical aspects of prefrontal pathology in schizophrenia. Schizophr Bull. 1997;23437- 458
Link to Article
Fuster  JM The Prefrontal Cortex: Anatomy, Physiology and Neuropsychology of the Frontal Lobe.  New York, NY Raven Press1989;
Van Hoesen  GWMorecraft  RJSemendeferi  K Functional neuroanatomy of the limbic system and prefrontal cortex. Fogel  BSSchiffer  RSRao  SMedsNeuropsychiatry. Baltimore, Md Williams & Wilkins1996;113- 143
Hof  PRMufson  EJMorrison  JH Human orbitofrontal cortex: cytoarchitecture and quantitative immunohistochemical parcellation. J Comp Neurol. 1995;35948- 68
Link to Article
Andreasen  NCEhrhardt  JCSwayze  V  IIAlliger  RJYuh  WTCCohen  GZiebell  S Magnetic resonance imaging of the brain in schizophrenia: the pathophysiologic significance of structural abnormalities. Arch Gen Psychiatry. 1990;4735- 44
Link to Article
Zipursky  RBLim  KOSullivan  EVBrown  BWPfefferbaum  A Widespread cerebral gray matter volume deficits in schizophrenia. Arch Gen Psychiatry. 1992;49195- 205
Link to Article
Breier  ABuchanan  RWElkashef  AMunson  RCKirkpatrick  BGellad  F Brain morphology and schizophrenia: a magnetic resonance imaging study of limbic, prefrontal cortex, and caudate structures. Arch Gen Psychiatry. 1992;49921- 926
Link to Article
Sullivan  EVLim  KOMathalon  DHMarsh  LBeal  DMHarris  DHoff  ALFaustman  WOPfefferbaum  A A profile of cortical gray matter volume deficits characteristic of schizophrenia. Cereb Cortex. 1998;8117- 124
Link to Article
Gur  REPearlson  GD Neuroimaging in schizophrenia research. Schizophr Bull. 1993;19337- 353
Link to Article
Weinberger  DRBerman  KFZec  RF Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia, I: regional cerebral blood flow evidence. Arch Gen Psychiatry. 1986;43114- 126
Link to Article
Andreasen  NCO'Leary  DSFlaum  MNopoulos  PWatkins  GLBoles Ponto  LLHichwa  RD Hypofrontality in schizophrenia: distributed dysfunctional circuits in neuroleptic-naive patients. Lancet. 1997;3491730- 1734
Link to Article
Buchsbaum  MSHaier  RJPotkin  SGNeuchterlein  KBracha  HSKatz  MLohr  JWu  JLottenberg  SJerabek  PATrenary  MTafalla  RReynolds  CBunney  WE Frontostriatal disorder of cerebral metabolism in never-medicated schizophrenics. Arch Gen Psychiatry. 1992;49935- 942
Link to Article
Akbarian  SBunney  WEPotkin  SGWigal  SBHagman  JOSandman  CAJones  EG Altered distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase cells in frontal lobe of schizophrenics implies disturbances of cortical development. Arch Gen Psychiatry. 1993;50169- 177
Link to Article
Benes  FMMcSparren  JBird  EDSanGiovanni  JPVincent  SL Deficits in small interneurons in prefrontal and cingulate cortex of schizophrenic and schizoaffective patients. Arch Gen Psychiatry. 1991;48996- 1001
Link to Article
Selemon  LDRajkowska  GGoldman-Rakic  PS Abnormally high neuronal density in two widespread areas of the schizophrenic cortex: a morphometric analysis of prefrontal area 9 and occipital area 17. Arch Gen Psychiatry. 1995;52805- 818
Link to Article
Daviss  SRLewis  DA Local circuit neurons of the prefrontal cortex in schizophrenia: selective increase in the density of calbindin-immunoreactive neurons. Psychiatry Res. 1995;5981- 96
Link to Article
Arnold  SETrojanowski  JQ Recent advances in the neuropathology of schizophrenia. Acta Neuropathol (Berl). 1996;92217- 231
Link to Article
Wible  CGShenton  MEHokama  HKikinis  RJolesz  FAMetcalf  DMcCarley  RW Prefrontal cortex and schizophrenia: a quantitative magnetic resonance imaging study. Arch Gen Psychiatry. 1995;52279- 288
Link to Article
Wible  CGShenton  MEFischer  IAAllard  JEKikinis  RJolesz  FAIosifescu  DVMcCarley  RW Parcellation of the human prefrontal cortex using MRI. Psychiatry Res. 1997;7629- 40
Link to Article
Schlaepfer  TEHarris  GJTien  AYPeng  LWLee  SFederman  EBChase  GABarta  PEPearlson  GD Decreased regional cortical gray matter volume in schizophrenia. Am J Psychiatry. 1994;151842- 848
Andreasen  NCFlashman  LFlaum  MArndt  SSwayze  V  IIO'Leary  DSEhrhardt  JCYuh  WTC Regional brain abnormalities in schizophrenia measured with magnetic resonance imaging. JAMA. 1994;2721763- 1769
Link to Article
Buchanan  RWVladar  KBarta  PEPearlson  GD Structural evaluation of the prefrontal cortex in schizophrenia. Am J Psychiatry. 1998;1551049- 1055
Szeszko  PRBilder  RMLencz  TPollack  SAlvir  JMJAshtari  MWu  HLieberman  JA Investigation of frontal lobe subregions in first-episode schizophrenia. Psychiatry Res. 1999;901- 15
Link to Article
Seidman  LJYurgelun-Todd  DKremen  WSWoods  BTGoldstein  JMFaraone  SVTsuang  MT Relationship of prefrontal and temporal lobe MRI measures to neuropsychological performance in chronic schizophrenia. Biol Psychiatry. 1994;35235- 246
Link to Article
Gur  REPetty  RGTuretsky  BIGur  RC Schizophrenia throughout life: sex differences in severity and profile of symptoms. Schizophr Res. 1996;211- 12
Link to Article
Kohler  CGGur  RCSwanson  CSPetty  RGur  RE Depression in schizophrenia, I: association with neuropsychological deficits. Biol Psychiatry. 1998;43165- 172
Link to Article
Turetsky  BTCowell  PEGur  RCGrossman  RIShtasel  DLGur  RE Frontal and temporal lobe brain volumes in schizophrenia: relationship to symptomatology and clinical subtype. Arch Gen Psychiatry. 1995;521061- 1070
Link to Article
Gur  RETuretsky  BIBilker  WBGur  RC Reduced gray matter volume in schizophrenia. Arch Gen Psychiatry. 1999;56905- 911
Link to Article
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.  Washington, DC American Psychiatric Association1994;
Spitzer  RLWilliams  JBWGibbon  M Structured Clinical Interview for DSM-IV: Patient Version (SCID-P).  New York New York State Psychiatric Institute1994;
Gur  REMozley  DResnick  SMLevick  SErwin  RSaykin  AJGur  RC Relations among clinical scales in schizophrenia: overlap and subtypes. Am J Psychiatry. 1991;148472- 478
First  MBSpitzer  RLGibbon  MWilliams  JBW Structured Clinical Interview for DSM-IV Axis I Disorders, Non-Patient Edition (SCID-NP).  New York New York State Psychiatric Institute/Biometrics Research Department1995;
Shtasel  DLGur  REMozley  PDRichards  JTaleff  MMHeimberg  CGallacher  FGur  RC Volunteers for biomedical research: recruitment and screening of normal controls. Arch Gen Psychiatry. 1991;481022- 1025
Link to Article
Andreasen  NC The Scale for the Assessment of Negative Symptoms (SANS).  Iowa City The University of Iowa1984;
Andreasen  NC The Scale for the Assessment of Positive Symptoms (SAPS).  Iowa City The University of Iowa1984;
Hamilton  M A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;2356- 62
Link to Article
Harris  JG An abbreviated form of the Phillips Rating Scale of Premorbid Adjustment in schizophrenia. J Abnorm Psychol. 1975;84129- 137
Link to Article
Heinrichs  DWHanlon  TECarpenter  WT  Jr The Quality of Life Scale: an instrument for rating the schizophrenic deficit syndrome. Schizophr Bull. 1984;10388- 398
Link to Article
Saykin  AJShtasel  DLGur  REKester  DBMozley  LHStafiniak  PGur  RC Neuropsychological deficits in neuroleptic naive, first-episode schizophrenic patients. Arch Gen Psychiatry. 1994;51124- 131
Link to Article
Censits  DMRagland  JDGur  RCGur  RE Neuropsychological evidence supporting a neurodevelopmental model of schizophrenia: a longitudinal study. Schizophr Res. 1997;24289- 298
Link to Article
Yan  MXHKarp  JS Segmentation of 3D MR using an adaptive K-means clustering algorithm. Proc IEEE Med Imaging Conf. 1994;41529- 1533
Gur  RCTuretsky  BIMatsui  MYan  MXHBilker  WHughett  PGur  RE Sex differences in brain gray and white matter in healthy young adults: correlations with cognitive performance. J Neurosci. 1999;194065- 4072
Yan  MXHKarp  JS Image registration of MR and PET based on surface matching and principal axes fitting. Proc IEEE Med Imaging Conf. 1994;41677- 1681
Yan  MXHKarp  JS Information processing in medical imaging. Bizais  YBarillot  CDiPaol  RedsInformation Processing in Medical Imaging. Norwell, Mass Kluwer Academic Publishers1995;201- 213
Carpenter  WTHeinrichs  DWWagman  AMI Deficit and nondeficit forms of schizophrenia: the concept. Am J Psychiatry. 1988;145578- 583
Cowell  PEKostianovsky  DJGur  RCTuretsky  BIGur  RE Sex differences in neuroanatomical and clinical correlations in schizophrenia. Am J Psychiatry. 1996;153799- 805
Lim  KOTew  WKushner  MChow  KMatsumoto  BDeLisi  LE Cortical gray matter volume deficit in patients with first-episode schizophrenia. Am J Psychiatry. 1996;1531548- 1553
Zipursky  RBLambe  EKKapur  SMikulis  DJ Cerebral gray matter deficits in first episode psychosis. Arch Gen Psychiatry. 1998;55540- 546
Link to Article
Nopoulos  PTorres  IFlaum  MAndreasen  NCEhrhardt  JCYuh  WTC Brain morphology in first-episode schizophrenia. Am J Psychiatry. 1995;1521721- 1723
Pettegrew  JWKeshavan  MSPanchalingam  KStrychor  SKaplan  DBTretta  MGAllen  M Alterations in brain high-energy phosphate and membrane phospholipid metabolism in first-episode, drug-naive schizophrenics: a pilot study of the dorsal prefrontal cortex by in vivo phosphorus 31 nuclear magnetic resonance spectroscopy. Arch Gen Psychiatry. 1991;48563- 568
Link to Article
Bertolino  ANawroz  SMattay  VSBarnett  ASDuyn  JHMoonen  CTWFrank  JATedeschi  GWeinberger  DR Regionally specific pattern of neurochemical pathology in schizophrenia as assessed by multislice proton magnetic resonance spectroscopic imaging. Am J Psychiatry. 1996;1531554- 1563
Cecil  KMLenkinski  REGur  REGur  RC Proton magnetic resonance spectroscopy in the frontal and temporal lobes of neuroleptic naive patients with schizophrenia. Neuropsychopharmacology. 1999;20131- 140
Link to Article
Kring  AMGordon  AH Sex differences in emotion: expression, experience, and physiology. J Pers Soc Psychol. 1998;74686- 703
Link to Article
Doty  RLApplebaum  SZusho  HSettle  RG Sex differences in odor identification ability: a cross-cultural analysis. Neuropsychologia. 1985;23667- 672
Link to Article
Moberg  PJDoty  RLTuretsky  BIArnold  SEMahr  RNGur  RCBilker  WGur  RE Deterioration of olfactory identification abilities in patients with schizophrenia. Am J Psychiatry. 1998;1551463- 1464
Heimberg  CGur  REErwin  RJShtasel  DLGur  RC Facial emotion discrimination, III: behavioral findings in schizophrenia. Psychiatry Res. 1992;42253- 265
Link to Article
Goldstein  JMSeidman  LJGoodman  JMKoren  DLee  HWeintraub  STsuang  MT Are there sex differences in neuropsychological functions among patients with schizophrenia? Am J Psychiatry. 1998;1551358- 1364
Andreasen  NCFlaum  MSwayze  V  IIO'Leary  DSAlliger  RCohen  GEhrhardt  JYuh  WT Intelligence and brain structure in normal individuals. Am J Psychiatry. 1993;150130- 134
Kareken  DAGur  RCMozley  PDMozley  LHSaykin  AJShtasel  DLGur  RE Cognitive functioning and neuroanatomic volume measures in schizophrenia. Neuropsychology. 1995;9211- 219
Link to Article
Reiss  ALAbrams  MTSinger  HSRoss  JLDenckla  MB Brain development, gender and IQ in children: a volumetric imaging study. Brain. 1996;1191763- 1774
Link to Article

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