0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Article |

Regionally Specific Disturbance of Dorsolateral Prefrontal–Hippocampal Functional Connectivity in Schizophrenia FREE

Andreas S. Meyer-Lindenberg, MD, PhD; Rosanna K. Olsen; Philip D. Kohn; Timothy Brown; Michael F. Egan, MD; Daniel R. Weinberger, MD; Karen Faith Berman, MD
[+] Author Affiliations

Author Affiliations: Unit on Integrative Neuroimaging #1Drs Meyer-Lindenberg and Berman, Ms Olsen, and Messrs Kohn and Brown) and Genes, Cognition, and Psychosis Program (Drs Meyer-Lindenberg, Egan, Weinberger, and Berman; Ms Olsen; and Messrs Kohn and Brown), National Institute of Mental Health, Bethesda, Md.


Arch Gen Psychiatry. 2005;62(4):379-386. doi:10.1001/archpsyc.62.4.379.
Text Size: A A A
Published online

Background  Two brain regions often implicated in schizophrenia are the dorsolateral prefrontal cortex (DLPFC) and the hippocampal formation (HF). It has been hypothesized that the pathophysiology of the disorder might involve an alteration of functional interactions between medial temporal and prefrontal areas.

Methods  We used neuroimaging data acquired during a working memory challenge and a sensorimotor control task in 22 medication-free schizophrenic patients and 22 performance-, age-, and sex-matched healthy subjects to investigate “functional connectivity” between HF and DLPFC in schizophrenia. The HF blood flow, measured with positron emission tomography, was assessed within a probabilistic template. Brain areas whose activity was positively or negatively coupled to HF were identified using voxelwise analysis of covariance throughout the entire brain and analyzed using a random effects model.

Results  During working memory, patients showed reduced activation of the right DLPFC and left cerebellum. In both groups, inverse correlations were observed between the HF and the contralateral DLPFC and inferior parietal lobule. While these did not differ between diagnostic groups during the control task, the working memory challenge revealed a specific abnormality in DLPFC-HF functional connectivity—while the right DLPFC was significantly coupled to the left HF in both groups during the control task, this correlation was not seen in healthy subjects during working memory but persisted undiminished in patients, resulting in a significant task-by-group interaction.

Conclusions  Our results suggest a regionally specific alteration of HF-DLPFC functional connectivity in schizophrenia that manifests as an unmodulated persistence of an HF-DLPFC linkage during working memory activation. Thus, a mechanism by which HF dysfunction may manifest in schizophrenia is by inappropriate reciprocal modulatory interaction with the DLPFC.

Figures in this Article

Much interest in schizophrenia research has centered on the dorsolateral prefrontal cortex (DLPFC)1 and the hippocampal formation (HF),2 brain regions where multiple abnormalities are demonstrated by converging evidence from neuropathologic findings3,4 and structural5 and functional6,7 neuroimaging. Since the HF provides important input to the DLPFC8 and because neonatal HF lesions in animals induce postpubertally manifested changes in prefrontal cortex9 mimicking aspects of schizophrenic pathophysiology, it has been hypothesized that the interaction between these two regions might be particularly disturbed in the disorder.10,11 This so-called “disconnection” hypothesis12 is also attractive since the HF is selectively vulnerable to some obstetrical insults,13 and a disturbed interaction with the DLPFC would thus offer an explanation of epidemiological data linking schizophrenia to early neurodevelopmental disturbances.14 Previous neuroimaging studies of schizophrenia have observed patterns of abnormal activity prominently involving temporal lobe areas and the DLPFC.15,16 However, no neuroimaging data exist that specifically target the HF to examine its functional connections in schizophrenia.

To identify interactions of the HF with other brain areas, we used the “functional connectivity” approach popular in neuroimaging. It is based on linear covariation; as an operational definition, two brain regions are said to be functionally connected if their activities covary from scan to scan,17 the temporal resolution depending on the imaging modality used.18 This measure therefore describes a functional linkage and should not be assumed to imply anatomical or causal connections. We measured cerebral blood flow using positron emission tomography (PET) in 22 patients with schizophrenia and 22 matched healthy subjects and canvassed the entire brain voxel by voxel using analysis of covariance to identify areas whose blood flow was significantly (positively or negatively) linked to that of the HF. Our a priori hypothesis, based on the data cited, was that the most prominent disturbance of HF connectivity in schizophrenia would involve the link to the DLPFC. Since prefrontal cortex dysfunction is a well-replicated feature of the disorder, we employed a working memory paradigm to investigate whether DLPFC-related cognitive dysfunction could be linked to abnormalities of HF-DLPFC interaction.

SUBJECTS

Twenty-two patients with DSM-IV–diagnosed schizophrenia participated in this study. All had been previously treated with neuroleptics. Two weeks prior to the experiment, all medication was withdrawn. Twenty-two subjects matched for performance on the task, age, sex, and handedness without any history or signs of neuropsychiatric or other illness and not taking medication were studied as a control group. Matching was achieved from a larger group of controls scanned as part of an ongoing protocol. Demographic data are summarized in Table 1. All subjects participated after giving informed consent as approved by the National Institute of Mental Health Institutional Review Board and the National Institutes of Health Radiation Safety Committee. Subjects abstained from caffeine and nicotine for 4 hours prior to the scanning session.

Table Graphic Jump LocationTable 1. Demographics, Performance, and Symptoms*
NEUROIMAGING EXPERIMENT

The behavioral paradigm and imaging procedures have been detailed elsewhere.15 Subjects performed a version of the n-back working memory task. During the 0-back sensorimotor control condition, subjects were instructed to press one of 4 buttons corresponding to a single digit (1, 2, 3, or 4 presented randomly). During the working memory 2-back condition, subjects were to press the button corresponding to the numeral that had been displayed two screens previously. Performance was assessed by the percentage of correct responses. Multiple PET regional cerebral blood flow (rCBF) measurements were made for each subject (7 each of the 0-back and 2-back tasks in alternation, with injection of 10 mCi of radioactive water [H215O] per scan) on an Advance 3-dimensional scanner #1General Electric, Milwaukee, Wis). Images were attenuation-corrected and reconstructed (32 planes, 6.5 mm full width half maximum). After subtraction of background activity and registration,19 images were normalized to an average template, scaled proportionally to remove global flow variations, and smoothed (10 mm3 full width half maximum Gaussian kernel) using Statistical Parametric Mapping version 99 software (Wellcome Department of Cognitive Neurology, London, England).

ANALYSIS OF IMAGING DATA

The HF was defined in normalized space using a publicly available probabilistic brain atlas (International Consortium for Brain Mapping20). Probability volumes for the HF were thresholded at 50% a priori, resulting in a volume-of-interest that included the hippocampus proper and the entorhinal cortex (Figure 1). Average activity within these templates was extracted for each scan. For each subject, mean-centered within-condition average hippocampal activity was used as a covariate of interest in analysis of covariance to identify voxels whose activity showed significant covariation, positive or negative, with HF rCBF. This procedure ensured that this comparison was independent of the task (activation) effect. Using this analysis, 2 brain areas are called functionally connected if their rCBF covaries over time (in this case, from scan to scan, acquired 6 minutes apart).17

Place holder to copy figure label and caption
Figure 1.

The left and right hippocampal volumes of interest, as derived from the International Consortium for Brain Mapping probabilistic brain atlas, rendered on 3-dimensional reconstructions of a representative brain.

Graphic Jump Location

Using Statistical Parametric Mapping version 99 software, effects at each voxel were estimated according to the general linear model, and regionally specific effects were computed by analysis of covariance using linear contrasts identifying brain regions activated or deactivated by the working memory task, differences in the activation-deactivation patterns between the diagnostic groups, and HF functional connectivity. In this context, activation refers to greater activity during the 2-back task than during the 0-back task, while deactivation denotes greater activity during the 0-back task than during the 2-back task.

Finally, comparison between groups to identify regions showing a significant across-task change in functional connectivity or a change in activation was performed using a random effects approach. For this we estimated the appropriate statistic image for each subject separately (first level) and entered the subject-specific maps into a second-level analysis.21 Maps were thresholded at P < .01 (z = 3.09), and correction for multiple comparisons was effected by controlling for cluster size (resulting in a cluster-level correction threshold of P < .05, corrected).

Localization of maxima is reported in the coordinate space of Talairach and Tournoux22 as millimeters relative to the anterior commissure. Brodmann areas, if given, are approximate and were identified by adjusting for differences between the Brain Mapping Consortium template and the Talairach and Tournoux atlas by affine transformation.

BEHAVIOR

The performance of patients and controls was matched for both the 0-back and 2-back tasks (Table 1). Subjects performed significantly above the 25% chance level (P < .001 by t test, both groups).

ACTIVATIONS

Statistical maps of the main effect of task condition as well as the group × task interaction are shown in Figure 2. Detailed coordinates and z scores of these contrasts are available on request from the authors. They were similar to results previously reported for 13 of these patients and controls.15 The working memory (2-back) condition led to significant activations of the DLPFC and inferior parietal lobule (iPL) bilaterally, left anterior cingulate, right thalamus, and cerebellar hemispheres. Deactivations were seen in the left parahippocampal gyrus and bilaterally in inferotemporal areas, medial frontal cortex, medial parietal lobule, lateral temporal cortex, and angular gyri. Analysis of the group × task interaction (Figure 2, right) in this performance-matched sample showed significant differences in 2 regions: right DLPFC (x, y, z = 44, 14, 36; z = 4.26; P < .001) and left cerebellar hemisphere (x, y, z = −34, −76, −40; z = 4.22; P < .001).

Place holder to copy figure label and caption
Figure 2.

Left, Main effect of task-significant activations (red) and deactivations (blue), comparing the working memory condition (2-back) with its sensorimotor control (0-back). Right, Task × group interaction analysis of regional cerebral blood flow data, showing regions where healthy subjects activate significantly more (red) or less (blue) than patients. Highlighted voxels are significant at P ≤ .01 (P ≤ .05 corrected for multiple comparisons).

Graphic Jump Location
FUNCTIONAL CONNECTIVITY ANALYSIS

Results of the connectivity analyses are summarized in Figure 3 and Table 2. For both groups, regions showing positive covariation with the hippocampal formation included the ipsilateral temporal lobe, anterior cingulate, and medial frontal cortex, but these findings were not significant after within-group correction using the random effects model. Patterns were similar for the 0-back and 2-back tasks, and no within-group differences emerged on testing. Statistics showing positive functional connectivity using a fixed effects model are available from the authors as supplementary material (http://cbdb.nimh.nih.gov/arch05), while we focus here on results for negative covariation.

Place holder to copy figure label and caption
Figure 3.

Top left, Cutout showing area of significant group × task interaction of left hippocampal formation connectivity in the right dorsolateral prefrontal cortex. Bottom left, Mean values for covariation with left hippocampal formation in the region of interaction, showing significant coupling during both the 2-back and 0-back tasks in patients but only during the 0-back task in controls. Error bars indicate standard errors. Center and right, Analysis of covariance maps showing areas that were significantly negatively correlated with left hippocampal formation regional cerebral blood flow. Highlighted voxels are significant at P ≤ .01 (P ≤ .05 corrected for multiple comparisons).

Graphic Jump Location
Table Graphic Jump LocationTable 2. Maxima of Areas Negatively Correlated With Left Hippocampal Regional Cerebral Blood Flow
LEFT HF
Controls

In controls, the statistical map for negative correlations with left HF activity (Figure 3, blue voxels) showed the strongest inverse link with the contralateral DLPFC, followed by the iPL. Connectivity was significantly different between task conditions: the coupling of the HF to the DLPFC (and to a lesser degree the iPL) was significantly diminished during the 2-back task (x, y, z = 34, 24, 36; z = 3.52; P < .01).

Patients

In patients, the pattern of negative correlations with left HF activity (Figure 3, blue voxels) was similar to that of controls during the 0-back task. However, during the working memory condition, the left HF–right DLPFC connectivity persisted undiminished in the patients, in marked contrast to control subjects (Figure 3). Reflecting this persistent linkage during the 2-back task, patients, unlike controls, did not show a significant difference between task conditions.

GROUP DIFFERENCES IN LEFT HF FUNCTIONAL CONNECTIVITY

Formal testing for group × task interaction for HF functional connectivity identified a selective change of left HF connectivity to the middle frontal gyrus in the right DLPFC (x, y, z = 36, 44, 4; z = 4.73; P < .001), reflecting the fact that this area became relatively uncoupled during the 2-back task in control subjects but not in patients (Figure 3, right). There were no other significant group differences in the connectivity-by-task interaction.

To ascertain whether the observed Brodmann area 46−HF connectivity change occurred selectively in this circuit or was also present in other areas with which the DLPFC but not the HF was significantly linked, we extracted the average rCBF in the right DLPFC area that showed significant coupling with the left HF and investigated its positive and negative connectivity. Positive functional connectivity was seen with the surrounding DLPFC, iPL, and cingulate (especially retrosplenial) areas. Examination of negative DLPFC covariation confirmed the HF connectivity findings (significant at the chosen threshold [P < .05, corrected, cluster level] during the 0- and 2-back tasks in patients but only during the 0-back task in healthy subjects), and testing of the group × task interaction for functional connectivity did not reveal significant between-group differences in any additional regions.

Finally, to check whether differences in variance might have increased the power to detect correlations in the schizophrenia groups, the variance of the hippocampal region of interest used for the covariate analysis was compared between groups using the Levene test. No significant difference in variance was found (F1,610 = 2.28, P = .14).

RIGHT HF

Connectivity of the right hippocampus was qualitatively similar to that of the left side but did not survive correction for multiple comparisons. Detailed coordinates from a fixed effects analysis are available from the authors as supplementary material (http://cbdb.nimh.nih.gov/arch05). Again, patterns of positive right HF connectivity were similar between tasks and did not differ between patients and controls. In patients, the pattern of areas covarying negatively with the right HF was similar to the left side and again did not change appreciably with task conditions. In controls, the right HF showed no negative connectivity during the 0-back or 2-back task.

FUNCTIONAL SUBSYSTEMS

In this study we used functional connectivity to delineate brain regions whose activity covaried with that of the HF. We identified a group of brain regions that were negatively functionally coupled to the HF during performance of a cognitive test paradigm, most prominently the iPL and DLPFC. This could reflect inverse functional connectivity of the HF with each of these structures. Alternatively, the HF may show strong negative covariation with only some of them if the remaining subregions are strongly (positively) interconnected among themselves. Neuroanatomical evidence exists for both of these explanations. Direct connections of the iPL to the HF have been described,23,24 as have pathways connecting the DLPFC and HF.8,25 In favor of the second explanation, the DLPFC and iPL are known to have strong reciprocal connections.2628 The fact that the correlation between these structures carries a negative sign does not imply that our observations indicate inhibitory interactions in the neurophysiological sense, since inhibition and excitation can result in similar effects on blood flow and correlations.29

The regions showing negative functional connectivity with the HF within condition are also important for working memory function.30,31 Indeed, they were found to be activated during working memory by contrasting 2-back and 0-back rCBF. In contrast, the role of the HF itself in working memory is less clear. Hippocampectomized patients are able to perform working memory tasks of the kind presented here without impairments.32 While the HF may be involved in binding of features33 or recall of highly familiar items,34 most neuropsychological and imaging data35 suggest that white matter performance is dominated by DLPFC-iPL functionality. It may even be advantageous during the n-back task not to encode the presented items in long-term memory to avoid potential interference effects. In accordance with this, our data showed a relative deactivation of the HF and the regions to which it was positively correlated during the 2-back task. Moreover, healthy subjects also showed diminished functional coupling between the HF and DLPFC (Brodmann area 46) under working memory load. This suggests that, under normal circumstances, the HF is not only relatively deactivated but also less functionally coupled to this portion of the brain regions underlying executive function during working memory.

DIFFERENCES BETWEEN PATIENTS AND HEALTHY SUBJECTS
Activations

Patients showed significantly decreased activation in the DLPFC and cerebellum relative to controls. The finding of hypofrontality is similar to our own previous results with this paradigm15 and many others.36 The fact that it was present even in this performance-matched sample demonstrates that hypofrontality is a signature of disease-related working memory–related prefrontal dysfunction in PET, while functional magnetic resonance imaging studies with the same paradigm show a similar localization of abnormalities but more complex directionality effects.37 A trend for relatively higher rCBF during working memory in patients than in controls was found in the entorhinal cortex but did not survive correction for multiple comparisons (x, y, z = −24, −12, −28; z = 3.89; P < .001, uncorrected). Since this region is deactivated during working memory in controls, this represents attenuated deactivation in patients.

Functional Connectivity

The main goal of this study was to investigate differences in HF functional connectivity between patients and healthy subjects. The negative connectivity of the left HF showed a significant difference (Figure 3). Patients and controls exhibited the same pattern of connectivity to the iPL and contralateral DLPFC during the sensorimotor control task, but the imposition of a working memory load led to a group difference—while HF-DLPFC connectivity was attenuated in healthy subjects, the functional linkage between these regions persisted undiminished in patients (Figure 3), as reflected in a significant group-by-task interaction of HF connectivity. The middle frontal gyrus in the right DLPFC was the only brain region showing this effect.

Our analysis thus uncovered a disturbance of left HF–right DLPFC functional connectivity in patients that only became apparent during working memory load. Since an alteration was found only in the covariation with DLPFC and the entire brain was canvassed, this suggests regional specificity of the observed interaction effect. Indeed, the analysis of connectivity of the right DLPFC showed no additional loci of functional connectivity with a group-by-task interaction, making the observed effect attributable to the relationship between the DLPFC and HF alone. Since these analyses were conducted within task, it is unlikely that they were influenced by the activation differences between groups discussed above.

Since the left HF–right DLPFC linkage was diminished during working memory in healthy subjects, we interpret its persistence in patients as dysfunctional. This is supported by the data summarized above showing that HF functionality is not necessary for working memory performance. Our analyses suggest a twofold mechanism by which, in the normal case, DLPFC and HF function is compartmentalized during a working memory load: First, during working memory the DLPFC was activated while the HF was deactivated. Second, the analysis of within-condition connectivity showed that the two structures became relatively uncoupled under working memory load in healthy controls only. In patients, this was abnormal on both accounts: DLPFC activation and HF deactivation were significantly diminished, and the coupling of these structures persisted during working memory. It is important to note that our data do not imply that the observed persistent within-condition negative interaction between the HF and DLPFC is responsible for the deactivation deficit of the HF in patients during working memory compared with the control task—it is not the negative sign of the interaction but the fact that it persists during working memory that suggests that the task-related uncoupling of these structures in patients is deficient.

Together with the well-replicated finding of DLPFC activation deficits in schizophrenia, the importance of the DLPFC for working memory, and the status of working memory dysfunction as a core deficit in the neuropsychology of schizophrenia, our results are consistent with the possibility that the observed failure to modulate HF-DLPFC linkage and the lack of HF-DLPFC compartmentalization might to some degree contribute to the DLPFC dysfunction that is a signature of that disorder. This theory is supported by a previous finding that HF volume predicted DLPFC activation, but, importantly, only in patients, not in healthy subjects, underscoring the pathological nature of this correlation,10 and the theory is consistent with animal data showing that early lesions in the HF lead to DLPFC dysfunction with a maturational delay.38 Specifically, emergence of behavioral abnormalities akin to schizophrenia39 and working memory dysfunction in animals has been documented.

Since the observed effect involves a covariation, no inferences about causality can be made. It is conceivable that impaired DLPFC function could be the cause of the observed pathological functional linkage during working memory. The findings of a neuroimaging study of working memory activation in monozygotic twins, one of whom sustained a traumatic frontal lobe injury, are consistent with this interpretation since the injured twin had increased HF activation and decreased DLPFC activity.40 Seen from this angle, our findings could be a consequence of DLPFC inadequacy during working memory. The observed persistent linkage of the right DLPFC with the left HF could correspond to an alternative strategy involving declarative memory. In this context we note that abnormalities were only found for right DLPFC–left HF covariation. While we have not seen consistent laterality effects for prefrontal effects in normal controls41 and schizophrenic patients,15 the recent literature shows differential effects for left and right DLPFC in the generation vs execution of a cognitive plan42 and in inductive vs deductive reasoning,43 meriting further inquiries into the contribution of functional connectivity to laterality effects in DLPFC functional specialization.

Previous analyses of functional connectivity of the DLPFC using a seed voxel outside the area identified here as the locus of abnormal HF-DLPFC interaction during verbal fluency did not identify the HF as being differentially linked to this structure but rather the superior temporal gyrus.44,45 This finding and other reports of dysconnectivity during verbal fluency46 suggest that functional abnormalities in connectivity may be task dependent and that further insight into disturbed connectivity might be gathered by querying other regions of the DLPFC, in accordance with the animal-model observation that early HF lesions may lead to reorganization of intraprefrontal circuitry.1 We also note that regions such as the cerebellum and superior temporal gyrus were functionally connected to the HF in schizophrenic patients but not in controls during the 0-back task. While there was no significant between-group difference in these areas, further research might demonstrate that they are part of a more distributed dysfunctional network associated with working memory impairment in schizophrenia.

LIMITATIONS OF THIS APPROACH

To operationalize the degree of linkage between brain regions, our study employed functional connectivity, which is based on covariance. The advantages and disadvantages of this approach have been discussed in detail elsewhere.15,17 Limitations arise because observed functional connectivity does not imply anatomical connectivity (although, as seen here, neuroanatomical data were consistent with the results obtained by this method), neuronal interactions need not be linear, and linear correlation does not imply causality. However, much neuroimaging evidence suggests that linear correlations do capture an important aspect of neuronal interactions across different scales. It would be of interest to extend the present data using analysis methods that allow the investigation of directional interactions and models of causal relationships, such as effective connectivity.47

In using an anatomically defined region to quantify HF activity, the present analysis represents a potential advance over the use of seed voxels or spherical volumes of interest to query connectivity. Future work could extend this approach by regional parcellation of the HF into subregions to assess their individual connectivity profiles. The observation that the entorhinal portion of the parahippocampal gyrus was the part of the HF region of interest where a deactivation deficit in patients was identified suggests that this might be the subregion associated with the observed connectivity changes, since the entorhinal cortex forms the main port of entry and exit for interactions of the HF with the neocortex.48,49

Since we studied patients with chronic illness, it would be of interest to extend the findings to the early stages of the disease. This would also remove the confounding effect of previous neuroleptic treatment, which might have had an effect on the observed interactions even though treatment was withdrawn before the study. Finally, we required temporary abstinence from nicotine and caffeine because of the effects of these substances on rCBF.50,51 Since more patients than controls consumed cigarettes and coffee, this might have contributed to group differences during abstinence as well; however, no data on such effects are available, and there is no suggestion that such effects, if present, would be regionally selective.

In summary, our analysis of connectivity in schizophrenia indicates a regionally specific alteration of HF-DLPFC functional linkage by demonstrating unmodulated persistence of coupling of these structures during a working memory load condition in patients but not in controls. Since animals with hippocampal lesions also show a dysregulation of striatal dopamine metabolism and because a tight correspondence between this dysregulation and prefrontal cortex dysfunction in schizophrenic patients has been demonstrated,52 the present finding suggests a possible causal account of the emergence of these aspects of schizophrenic pathophysiology from HF dysfunction. Such a sequence of events would lead from a primary, early developmental insult to the HF via deficits in HF-DLPFC connectivity and induced maturational deficits in DLPFC circuitry to DLPFC dysfunction, which accounts for the core neuropsychology of the disorder and is linked to dopaminergic disinhibition. This theory is in agreement with a neurodevelopmental hypothesis of schizophrenia.14 While it is highly implausible that this complex, frequent, and heterogeneous disorder can be reduced to a single causal chain, this formulation may help to guide further research in suggesting a study of persistent inhibitory HF-DLPFC interactions in humans with schizophrenia and animal models of the disorder.

Correspondence: Andreas S. Meyer-Lindenberg, MD, PhD, 10-4C101, 9000 Rockville Pike, Bethesda, MD 20892-1365 (andreasml@nih.gov).

Submitted for Publication: June 30, 2004; final revision received September 21, 2004; accepted September 29, 2004.

Weinberger  DREgan  MFBertolino  ACallicott  JHMattay  VSLipska  BKBerman  KFGoldberg  TE Prefrontal neurons and the genetics of schizophrenia. Biol Psychiatry 2001;50825- 844
PubMed Link to Article
Weinberger  DR Cell biology of the hippocampal formation in schizophrenia. Biol Psychiatry 1999;45395- 402
PubMed Link to Article
Arnold  SETrojanowski  JQ Recent advances in defining the neuropathology of schizophrenia. Acta Neuropathol (Berl) 1996;92217- 231
PubMed Link to Article
Harrison  PJEastwood  SL Neuropathological studies of synaptic connectivity in the hippocampal formation in schizophrenia. Hippocampus 2001;11508- 519
PubMed Link to Article
Heckers  S Neuroimaging studies of the hippocampus in schizophrenia. Hippocampus 2001;11520- 528
PubMed Link to Article
Heckers  SRauch  SLGoff  DSavage  CRSchacter  DLFischman  AJAlpert  NM Impaired recruitment of the hippocampus during conscious recollection in schizophrenia. Nat Neurosci 1998;1318- 323
PubMed Link to Article
Carter  CSPerlstein  WGanguli  RBrar  JMintun  MCohen  JD Functional hypofrontality and working memory dysfunction in schizophrenia. Am J Psychiatry 1998;1551285- 1287
PubMed
Goldman-Rakic  PSSelemon  LDSchwartz  ML Dual pathways connecting the dorsolateral prefrontal cortex with the hippocampal formation and parahippocampal cortex in the rhesus monkey. Neuroscience 1984;12719- 743
PubMed Link to Article
Bertolino  ASaunders  RCMattay  VSBachevalier  JFrank  JAWeinberger  DR Altered development of prefrontal neurons in rhesus monkeys with neonatal mesial temporo-limbic lesions: a proton magnetic resonance spectroscopic imaging study. Cereb Cortex 1997;7740- 748
PubMed Link to Article
Weinberger  DRBerman  KFSuddath  RTorrey  EF Evidence of dysfunction of a prefrontal-limbic network in schizophrenia: a magnetic resonance imaging and regional cerebral blood flow study of discordant monozygotic twins. Am J Psychiatry 1992;149890- 897
PubMed
Fletcher  P The missing link: a failure of fronto-hippocampal integration in schizophrenia. Nat Neurosci 1998;1266- 267
PubMed Link to Article
Friston  KJ The disconnection hypothesis. Schizophr Res 1998;30115- 125
PubMed Link to Article
Schmidt-Kastner  RFreund  TF Selective vulnerability of the hippocampus in brain ischemia. Neuroscience 1991;40599- 636
PubMed Link to Article
Weinberger  DR Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 1987;44660- 669
PubMed Link to Article
Meyer-Lindenberg  APoline  JBKohn  PDKohn  PDHolt  JLEgan  MFWeinberger  DRBerman  KF Evidence for abnormal cortical functional connectivity during working memory in schizophrenia. Am J Psychiatry 2001;1581809- 1817
PubMed Link to Article
Friston  KJFrith  CD Schizophrenia: a disconnection syndrome? Clin Neurosci 1995;389- 97
PubMed
Friston  KJFrith  CDLiddle  PFFrackowiak  RS Functional connectivity: the principal-component analysis of large (PET) data sets. J Cereb Blood Flow Metab 1993;135- 14
PubMed Link to Article
Horwitz  B The elusive concept of brain connectivity. Neuroimage 2003;19466- 470
PubMed Link to Article
Woods  RPGrafton  STHolmes  CJCherry  SRMazziotta  JC Automated image registration, I: general methods and intrasubject, intramodality validation. J Comput Assist Tomogr 1998;22139- 152
PubMed Link to Article
Mazziotta  JToga  AEvans  AFox  PLancaster  JZilles  KWoods  RPaus  TSimpson  GPike  BHolmes  CCollins  LThompson  PMacDonald  DIacoboni  MSchormann  TAmunts  KPalomero-Gallagher  NGeyer  SParsons  LNarr  KKabani  NLe Goualher  GBoomsma  DCannon  TKawashima  RMazoyer  B A probabilistic atlas and reference system for the human brain: International Consortium for Brain Mapping (ICBM). Philos Trans R Soc Lond B Biol Sci 2001;3561293- 1322
PubMed Link to Article
Friston  KJHolmes  APWorsley  KJ How many subjects constitute a study? Neuroimage 1999;101- 5
PubMed Link to Article
Talairach  JTournoux  P Co-planar Stereotaxic Atlas of the Human Brain.  New York, NY Thieme1988;
Clower  DMWest  RALynch  JCStrick  PL The inferior parietal lobule is the target of output from the superior colliculus, hippocampus, and cerebellum. J Neurosci 2001;216283- 6291
PubMed
Ding  SLVan Hoesen  GRockland  KS Inferior parietal lobule projections to the presubiculum and neighboring ventromedial temporal cortical areas. J Comp Neurol 2000;425510- 530
PubMed Link to Article
Carr  DBSesack  SR Hippocampal afferents to the rat prefrontal cortex: synaptic targets and relation to dopamine terminals. J Comp Neurol 1996;3691- 15
PubMed Link to Article
Cavada  CGoldman-Rakic  PS Posterior parietal cortex in rhesus monkey, I: parcellation of areas based on distinctive limbic and sensory corticocortical connections. J Comp Neurol 1989;287393- 421
PubMed Link to Article
Cavada  CGoldman-Rakic  PS Posterior parietal cortex in rhesus monkey, II: evidence for segregated corticocortical networks linking sensory and limbic areas with the frontal lobe. J Comp Neurol 1989;287422- 445
PubMed Link to Article
Chafee  MVGoldman-Rakic  PS Matching patterns of activity in primate prefrontal area 8a and parietal area 7ip neurons during a spatial working memory task. J Neurophysiol 1998;792919- 2940
PubMed
Tagamets  MAHorwitz  B Interpreting PET and fMRI measures of functional neural activity: the effects of synaptic inhibition on cortical activation in human imaging studies. Brain Res Bull 2001;54267- 273
PubMed Link to Article
Smith  EEJonides  J Neuroimaging analyses of human working memory. Proc Natl Acad Sci U S A 1998;9512061- 12068
PubMed Link to Article
Carpenter  PAJust  MAReichle  ED Working memory and executive function: evidence from neuroimaging. Curr Opin Neurobiol 2000;10195- 199
PubMed Link to Article
Milner  B Disorders of learning and memory after temporal lobe lesions in man. Clin Neurosurg 1972;19421- 446
PubMed
Mitchell  KJJohnson  MKRaye  CLD'Esposito  M fMRI evidence of age-related hippocampal dysfunction in feature binding in working memory. Brain Res Cogn Brain Res 2000;10197- 206
PubMed Link to Article
Stern  CESherman  SJKirchhoff  BAHasselmo  ME Medial temporal and prefrontal contributions to working memory tasks with novel and familiar stimuli. Hippocampus 2001;11337- 346
PubMed Link to Article
Abrahams  SMorris  RGPolkey  CEJarosz  JMCox  TCGraves  MPickering  A Hippocampal involvement in spatial and working memory: a structural MRI analysis of patients with unilateral mesial temporal lobe sclerosis. Brain Cogn 1999;4139- 65
PubMed Link to Article
Berman  KF Functional neuroimaging in schizophrenia. Davis  KLCharney  DCCoyle  JTNemeroff  Ceds.Neuropsychopharmacology: The Fifth Generation of Progress. Philadelphia, Pa Lippincott Williams & Wilkins2001;745- 756
Callicott  JHMattay  VSVerchinski  BAMarenco  SEgan  MFWeinberger  DR Complexity of prefrontal cortical dysfunction in schizophrenia: more than up or down. Am J Psychiatry 2003;1602209- 2215
PubMed Link to Article
Lipska  BKWeinberger  DR To model a psychiatric disorder in animals: schizophrenia as a reality test. Neuropsychopharmacology 2000;23223- 239
PubMed Link to Article
Lipska  BKWeinberger  DR Delayed effects of neonatal hippocampal damage on haloperidol-induced catalepsy and apomorphine-induced stereotypic behaviors in the rat. Brain Res Dev Brain Res 1993;75213- 222
PubMed Link to Article
Kirkby  BSVan Horn  JDOstrem  JLWeinberger  DRBerman  KF Cognitive activation during PET: a case study of monozygotic twins discordant for closed head injury. Neuropsychologia 1996;34689- 697
PubMed Link to Article
Van Horn  JDBerman  KFWeinberger  DR Functional lateralization of the prefrontal cortex during traditional frontal lobe tasks. Biol Psychiatry 1996;39389- 399
PubMed Link to Article
Newman  SDCarpenter  PAVarma  SJust  MA Frontal and parietal participation in problem solving in the Tower of London: fMRI and computational modeling of planning and high-level perception. Neuropsychologia 2003;411668- 1682
PubMed Link to Article
Goel  VDolan  RJ Differential involvement of left prefrontal cortexin inductive and deductive reasoning. Cognition 2004;93B109- B121
PubMed Link to Article
Fletcher  PCFrith  CDGrasby  PMFriston  KJDolan  RJ Local and distributed effects of apomorphine on fronto-temporal function in acute unmedicated schizophrenia. J Neurosci 1996;167055- 7062
PubMed
Fletcher  PMcKenna  PJFriston  KJFrith  CDDolan  RJ Abnormal cingulate modulation of fronto-temporal connectivity in schizophrenia. Neuroimage 1999;9337- 342
PubMed Link to Article
Lawrie  SMBuechel  CWhalley  HCFrith  CDFriston  KJJohnstone  EC Reduced frontotemporal functional connectivity in schizophrenia associated with auditory hallucinations. Biol Psychiatry 2002;511008- 1011
PubMed Link to Article
Buchel  CCoull  JTFriston  KJ The predictive value of changes in effective connectivity for human learning. Science 1999;2831538- 1541
PubMed Link to Article
Insausti  RHerrero  MTWitter  MP Entorhinal cortex of the rat: cytoarchitectonic subdivisions and the origin and distribution of cortical efferents. Hippocampus 1997;7146- 183
PubMed Link to Article
Burwell  RDAmaral  DG Cortical afferents of the perirhinal, postrhinal, and entorhinal cortices of the rat. J Comp Neurol 1998;398179- 205
PubMed Link to Article
Cameron  OGModell  JGHariharan  M Caffeine and human cerebral blood flow: a positron emission tomography study. Life Sci 1990;471141- 1146
PubMed Link to Article
Rose  JEBehm  FMWestman  ECMathew  RJLondon  EDHawk  TCTurkington  TGColeman  RE PET studies of the influences of nicotine on neural systems in cigarette smokers. Am J Psychiatry 2003;160323- 333
PubMed Link to Article
Meyer-Lindenberg  AMiletich  RSKohn  PDKohn  PDEsposito  GCarson  REQuarantelli  MWeinberger  DRBerman  KF Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia. Nat Neurosci 2002;5267- 271
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

The left and right hippocampal volumes of interest, as derived from the International Consortium for Brain Mapping probabilistic brain atlas, rendered on 3-dimensional reconstructions of a representative brain.

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

Left, Main effect of task-significant activations (red) and deactivations (blue), comparing the working memory condition (2-back) with its sensorimotor control (0-back). Right, Task × group interaction analysis of regional cerebral blood flow data, showing regions where healthy subjects activate significantly more (red) or less (blue) than patients. Highlighted voxels are significant at P ≤ .01 (P ≤ .05 corrected for multiple comparisons).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Top left, Cutout showing area of significant group × task interaction of left hippocampal formation connectivity in the right dorsolateral prefrontal cortex. Bottom left, Mean values for covariation with left hippocampal formation in the region of interaction, showing significant coupling during both the 2-back and 0-back tasks in patients but only during the 0-back task in controls. Error bars indicate standard errors. Center and right, Analysis of covariance maps showing areas that were significantly negatively correlated with left hippocampal formation regional cerebral blood flow. Highlighted voxels are significant at P ≤ .01 (P ≤ .05 corrected for multiple comparisons).

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Demographics, Performance, and Symptoms*
Table Graphic Jump LocationTable 2. Maxima of Areas Negatively Correlated With Left Hippocampal Regional Cerebral Blood Flow

References

Weinberger  DREgan  MFBertolino  ACallicott  JHMattay  VSLipska  BKBerman  KFGoldberg  TE Prefrontal neurons and the genetics of schizophrenia. Biol Psychiatry 2001;50825- 844
PubMed Link to Article
Weinberger  DR Cell biology of the hippocampal formation in schizophrenia. Biol Psychiatry 1999;45395- 402
PubMed Link to Article
Arnold  SETrojanowski  JQ Recent advances in defining the neuropathology of schizophrenia. Acta Neuropathol (Berl) 1996;92217- 231
PubMed Link to Article
Harrison  PJEastwood  SL Neuropathological studies of synaptic connectivity in the hippocampal formation in schizophrenia. Hippocampus 2001;11508- 519
PubMed Link to Article
Heckers  S Neuroimaging studies of the hippocampus in schizophrenia. Hippocampus 2001;11520- 528
PubMed Link to Article
Heckers  SRauch  SLGoff  DSavage  CRSchacter  DLFischman  AJAlpert  NM Impaired recruitment of the hippocampus during conscious recollection in schizophrenia. Nat Neurosci 1998;1318- 323
PubMed Link to Article
Carter  CSPerlstein  WGanguli  RBrar  JMintun  MCohen  JD Functional hypofrontality and working memory dysfunction in schizophrenia. Am J Psychiatry 1998;1551285- 1287
PubMed
Goldman-Rakic  PSSelemon  LDSchwartz  ML Dual pathways connecting the dorsolateral prefrontal cortex with the hippocampal formation and parahippocampal cortex in the rhesus monkey. Neuroscience 1984;12719- 743
PubMed Link to Article
Bertolino  ASaunders  RCMattay  VSBachevalier  JFrank  JAWeinberger  DR Altered development of prefrontal neurons in rhesus monkeys with neonatal mesial temporo-limbic lesions: a proton magnetic resonance spectroscopic imaging study. Cereb Cortex 1997;7740- 748
PubMed Link to Article
Weinberger  DRBerman  KFSuddath  RTorrey  EF Evidence of dysfunction of a prefrontal-limbic network in schizophrenia: a magnetic resonance imaging and regional cerebral blood flow study of discordant monozygotic twins. Am J Psychiatry 1992;149890- 897
PubMed
Fletcher  P The missing link: a failure of fronto-hippocampal integration in schizophrenia. Nat Neurosci 1998;1266- 267
PubMed Link to Article
Friston  KJ The disconnection hypothesis. Schizophr Res 1998;30115- 125
PubMed Link to Article
Schmidt-Kastner  RFreund  TF Selective vulnerability of the hippocampus in brain ischemia. Neuroscience 1991;40599- 636
PubMed Link to Article
Weinberger  DR Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 1987;44660- 669
PubMed Link to Article
Meyer-Lindenberg  APoline  JBKohn  PDKohn  PDHolt  JLEgan  MFWeinberger  DRBerman  KF Evidence for abnormal cortical functional connectivity during working memory in schizophrenia. Am J Psychiatry 2001;1581809- 1817
PubMed Link to Article
Friston  KJFrith  CD Schizophrenia: a disconnection syndrome? Clin Neurosci 1995;389- 97
PubMed
Friston  KJFrith  CDLiddle  PFFrackowiak  RS Functional connectivity: the principal-component analysis of large (PET) data sets. J Cereb Blood Flow Metab 1993;135- 14
PubMed Link to Article
Horwitz  B The elusive concept of brain connectivity. Neuroimage 2003;19466- 470
PubMed Link to Article
Woods  RPGrafton  STHolmes  CJCherry  SRMazziotta  JC Automated image registration, I: general methods and intrasubject, intramodality validation. J Comput Assist Tomogr 1998;22139- 152
PubMed Link to Article
Mazziotta  JToga  AEvans  AFox  PLancaster  JZilles  KWoods  RPaus  TSimpson  GPike  BHolmes  CCollins  LThompson  PMacDonald  DIacoboni  MSchormann  TAmunts  KPalomero-Gallagher  NGeyer  SParsons  LNarr  KKabani  NLe Goualher  GBoomsma  DCannon  TKawashima  RMazoyer  B A probabilistic atlas and reference system for the human brain: International Consortium for Brain Mapping (ICBM). Philos Trans R Soc Lond B Biol Sci 2001;3561293- 1322
PubMed Link to Article
Friston  KJHolmes  APWorsley  KJ How many subjects constitute a study? Neuroimage 1999;101- 5
PubMed Link to Article
Talairach  JTournoux  P Co-planar Stereotaxic Atlas of the Human Brain.  New York, NY Thieme1988;
Clower  DMWest  RALynch  JCStrick  PL The inferior parietal lobule is the target of output from the superior colliculus, hippocampus, and cerebellum. J Neurosci 2001;216283- 6291
PubMed
Ding  SLVan Hoesen  GRockland  KS Inferior parietal lobule projections to the presubiculum and neighboring ventromedial temporal cortical areas. J Comp Neurol 2000;425510- 530
PubMed Link to Article
Carr  DBSesack  SR Hippocampal afferents to the rat prefrontal cortex: synaptic targets and relation to dopamine terminals. J Comp Neurol 1996;3691- 15
PubMed Link to Article
Cavada  CGoldman-Rakic  PS Posterior parietal cortex in rhesus monkey, I: parcellation of areas based on distinctive limbic and sensory corticocortical connections. J Comp Neurol 1989;287393- 421
PubMed Link to Article
Cavada  CGoldman-Rakic  PS Posterior parietal cortex in rhesus monkey, II: evidence for segregated corticocortical networks linking sensory and limbic areas with the frontal lobe. J Comp Neurol 1989;287422- 445
PubMed Link to Article
Chafee  MVGoldman-Rakic  PS Matching patterns of activity in primate prefrontal area 8a and parietal area 7ip neurons during a spatial working memory task. J Neurophysiol 1998;792919- 2940
PubMed
Tagamets  MAHorwitz  B Interpreting PET and fMRI measures of functional neural activity: the effects of synaptic inhibition on cortical activation in human imaging studies. Brain Res Bull 2001;54267- 273
PubMed Link to Article
Smith  EEJonides  J Neuroimaging analyses of human working memory. Proc Natl Acad Sci U S A 1998;9512061- 12068
PubMed Link to Article
Carpenter  PAJust  MAReichle  ED Working memory and executive function: evidence from neuroimaging. Curr Opin Neurobiol 2000;10195- 199
PubMed Link to Article
Milner  B Disorders of learning and memory after temporal lobe lesions in man. Clin Neurosurg 1972;19421- 446
PubMed
Mitchell  KJJohnson  MKRaye  CLD'Esposito  M fMRI evidence of age-related hippocampal dysfunction in feature binding in working memory. Brain Res Cogn Brain Res 2000;10197- 206
PubMed Link to Article
Stern  CESherman  SJKirchhoff  BAHasselmo  ME Medial temporal and prefrontal contributions to working memory tasks with novel and familiar stimuli. Hippocampus 2001;11337- 346
PubMed Link to Article
Abrahams  SMorris  RGPolkey  CEJarosz  JMCox  TCGraves  MPickering  A Hippocampal involvement in spatial and working memory: a structural MRI analysis of patients with unilateral mesial temporal lobe sclerosis. Brain Cogn 1999;4139- 65
PubMed Link to Article
Berman  KF Functional neuroimaging in schizophrenia. Davis  KLCharney  DCCoyle  JTNemeroff  Ceds.Neuropsychopharmacology: The Fifth Generation of Progress. Philadelphia, Pa Lippincott Williams & Wilkins2001;745- 756
Callicott  JHMattay  VSVerchinski  BAMarenco  SEgan  MFWeinberger  DR Complexity of prefrontal cortical dysfunction in schizophrenia: more than up or down. Am J Psychiatry 2003;1602209- 2215
PubMed Link to Article
Lipska  BKWeinberger  DR To model a psychiatric disorder in animals: schizophrenia as a reality test. Neuropsychopharmacology 2000;23223- 239
PubMed Link to Article
Lipska  BKWeinberger  DR Delayed effects of neonatal hippocampal damage on haloperidol-induced catalepsy and apomorphine-induced stereotypic behaviors in the rat. Brain Res Dev Brain Res 1993;75213- 222
PubMed Link to Article
Kirkby  BSVan Horn  JDOstrem  JLWeinberger  DRBerman  KF Cognitive activation during PET: a case study of monozygotic twins discordant for closed head injury. Neuropsychologia 1996;34689- 697
PubMed Link to Article
Van Horn  JDBerman  KFWeinberger  DR Functional lateralization of the prefrontal cortex during traditional frontal lobe tasks. Biol Psychiatry 1996;39389- 399
PubMed Link to Article
Newman  SDCarpenter  PAVarma  SJust  MA Frontal and parietal participation in problem solving in the Tower of London: fMRI and computational modeling of planning and high-level perception. Neuropsychologia 2003;411668- 1682
PubMed Link to Article
Goel  VDolan  RJ Differential involvement of left prefrontal cortexin inductive and deductive reasoning. Cognition 2004;93B109- B121
PubMed Link to Article
Fletcher  PCFrith  CDGrasby  PMFriston  KJDolan  RJ Local and distributed effects of apomorphine on fronto-temporal function in acute unmedicated schizophrenia. J Neurosci 1996;167055- 7062
PubMed
Fletcher  PMcKenna  PJFriston  KJFrith  CDDolan  RJ Abnormal cingulate modulation of fronto-temporal connectivity in schizophrenia. Neuroimage 1999;9337- 342
PubMed Link to Article
Lawrie  SMBuechel  CWhalley  HCFrith  CDFriston  KJJohnstone  EC Reduced frontotemporal functional connectivity in schizophrenia associated with auditory hallucinations. Biol Psychiatry 2002;511008- 1011
PubMed Link to Article
Buchel  CCoull  JTFriston  KJ The predictive value of changes in effective connectivity for human learning. Science 1999;2831538- 1541
PubMed Link to Article
Insausti  RHerrero  MTWitter  MP Entorhinal cortex of the rat: cytoarchitectonic subdivisions and the origin and distribution of cortical efferents. Hippocampus 1997;7146- 183
PubMed Link to Article
Burwell  RDAmaral  DG Cortical afferents of the perirhinal, postrhinal, and entorhinal cortices of the rat. J Comp Neurol 1998;398179- 205
PubMed Link to Article
Cameron  OGModell  JGHariharan  M Caffeine and human cerebral blood flow: a positron emission tomography study. Life Sci 1990;471141- 1146
PubMed Link to Article
Rose  JEBehm  FMWestman  ECMathew  RJLondon  EDHawk  TCTurkington  TGColeman  RE PET studies of the influences of nicotine on neural systems in cigarette smokers. Am J Psychiatry 2003;160323- 333
PubMed Link to Article
Meyer-Lindenberg  AMiletich  RSKohn  PDKohn  PDEsposito  GCarson  REQuarantelli  MWeinberger  DRBerman  KF Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia. Nat Neurosci 2002;5267- 271
PubMed Link to Article

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 232

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections