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Original Article |

The Neural Basis of Relational Memory Deficits in Schizophrenia FREE

Dost Öngür, MD, PhD; Thomas J. Cullen, MD, PhD; Daniel H. Wolf, MD, PhD; Michael Rohan, SM; Paul Barreira, MD; Martin Zalesak, MSc; Stephan Heckers, MD
[+] Author Affiliations

Author Affiliations: Schizophrenia and Bipolar Disorder Program, McLean Hospital and Harvard Medical School (Drs Öngür, Cullen, Wolf, Barreira, and Heckers), Brain Imaging Center, McLean Hospital (Mr Rohan), and Division of Health Sciences and Technology, Harvard–Massachusetts Institute of Technology (Mr Zalesak), Boston, Mass.


Arch Gen Psychiatry. 2006;63(4):356-365. doi:10.1001/archpsyc.63.4.356.
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Published online

Context  Memory deficits are common in schizophrenia. Recent studies have demonstrated that relational memory is particularly impaired.

Objective  To study the neural correlates of relational memory in schizophrenia using functional magnetic resonance imaging.

Design  Cross-sectional case-control study.

Setting  Academic medical center.

Subjects  Twenty patients with schizophrenia and 17 control subjects.

Main Outcome Measures  Behavioral performance and brain activity were assessed during the discrimination of previously seen and novel pairs of visual stimuli, which varied in the degree of relational memory load. We performed whole-brain and region-of-interest (hippocampus) analyses.

Results  Schizophrenic subjects displayed normal activation of the presupplementary motor area and ventral prefrontal cortex, but significantly decreased recruitment of the right parietal cortex and anterior cingulate cortex when discriminating novel pairs derived from a sequence of stimuli. Discrimination accuracy was decreased in schizophrenia only when the flexible representation of a sequence was required. This selective deficit was associated with decreased activation of the right parietal cortex and left hippocampus.

Conclusions  Schizophrenia is characterized by a specific deficit of relational memory, which is associated with impaired function of the parietal cortex and hippocampus. Abnormal relational memory may be at the core of 2 prominent features of schizophrenia, ie, cognitive deficits and psychosis.

Figures in this Article

Schizophrenia is associated with deficits in several domains of cognition.1 Memory is particularly impaired26 and results in a significant decline of social functioning.7 However, most patients with schizophrenia (hereafter referred to as schizophrenic patients or subjects) present with only subtle memory deficits on clinical examination, unlike patients with amnesia and dementia.8 This pattern is compatible with the hypothesis that memory deficits in schizophrenia are not widespread but limited to specific domains.6,9

Selective deficits, associated with dysfunction in specific brain regions, would be ideal candidates to better understand the neural basis of cognition in schizophrenia. Recent behavioral studies of schizophrenic subjects have demonstrated such selective deficits for the episodic and relational forms of memory.1015

Episodic memory refers to the ability to recollect events.16 Several studies have demonstrated a selective impairment of episodic memory in schizophrenia, leaving intact the ability to remember facts.1013 Relational memory refers to the ability to learn associations between individual items.1719 One form of relational memory is transitive inference, ie, the ability to infer that A>C, knowing that A>B and B>C. In contrast to episodic memory, transitive inference can be studied in animals as well as humans, which facilitates the search for the neural basis of relational memory function.2022

Titone et al14 recently demonstrated that schizophrenic patients show a relational memory deficit during transitive inference. They trained subjects to discriminate a sequence of visual stimulus pairs (A>B, B>C, C>D, and D>E). The schizophrenic subjects were able to correctly identify the novel pairing of the 2 end items (AE), but they were significantly impaired when discriminating the novel pairing of 2 stimuli embedded within the sequence (BD). Thus, the study provided evidence that schizophrenic subjects are impaired when they have to rely on the flexible representation of a sequence. Deficits of relational memory impair the ability to draw correct inferences based on prior learning, which may contribute to formal thought disorder and delusional thinking in schizophrenia.23,24

We used a recently developed functional neuroimaging paradigm22 to study the neural basis of transitive inference in schizophrenia. We hypothesized that schizophrenic subjects would be impaired selectively during transitive inference judgments and that this deficit would be associated with a decreased activation of brain regions previously found to support transitive inference in humans.2022 Specifically, we hypothesized that the hippocampus, known to be crucial for transitive inference22,25 and relational memory,18,26 would be dysfunctional in schizophrenia.

SUBJECTS

After approval of the study protocol by the McLean Hospital Institutional Review Board, Belmont, Mass, we obtained written consent from 17 healthy control subjects and 20 patients with schizophrenia and schizoaffective disorder recruited from an academic psychiatric hospital community. All subjects underwent a Structured Clinical Interview for DSM-IV, supplemented by information from treating physicians when available. Controls with significant medical, neurological, or psychiatric illness and schizophrenic patients with significant medical or neurological illness or a history of substance dependence were excluded. Two controls and 4 schizophrenic subjects were excluded from analysis because their performance accuracy in the overlapping pairs during off-line training (<66%) and during functional magnetic resonance imaging (fMRI) (<80%) did not meet our a priori criteria. One schizophrenic subject was excluded because of incomplete imaging data.

Our study group included 10 male and 5 female controls, as well as 11 male and 4 female patients with schizophrenia and schizoaffective disorder. The subject groups were matched for mean ± SD age (control group, 38.1 ± 10.3 years; schizophrenia group, 39.7 ± 11.1 years), parental education (control group, 14.6 ± 2.5 years; schizophrenia group, 14.4 ± 3.0 years), and premorbid verbal IQ as estimated by the North American Adult Reading Test (NAART) score (control group, 118.3 ± 5.2; schizophrenia group, 113.3 ± 9.5). Thirteen patients received a diagnosis of schizophrenia and 2 patients received a diagnosis of schizoaffective disorder according to the DSM-IV.27 The following mean ± SD scores on clinical scales were obtained in the patient group: Positive and Negative Syndrome Scale, 57.2 ± 9.6 (positive subscale, 13.8 ± 3.8; negative subscale, 18.1 ± 5.0; general subscale, 25.3 ± 5.0)28; Abnormal Involuntary Movements Scale, 0.5 ± 1.129; and Beck Depression Inventory, 15.0 ± 9.6.30 All subjects were right-handed except for 1 left-handed male schizophrenic patient according to the Edinburgh Handedness Inventory.31

EXPERIMENTAL PARADIGM

We used a paradigm recently described in detail.22 Before fMRI, subjects were trained to identify the winner in 4 nonoverlapping pairs of visual stimuli (condition P) and in 4 pairs forming a sequence of 5 stimuli (condition S) (Figure 1 and Table 1). During scanning they were asked to remember the previously seen pairs or to make inferences on novel pairings, drawn from nonoverlapping pairs (condition IP) or from the sequence of overlapping items (condition IS). The experiment was designed primarily to study which brain regions were more active during transitive inferences (condition IS) compared with nontransitive inferences (condition IP). In addition, the design allowed us to contrast novel pairs that differed in the number of items with an ambiguous reinforcement history as follows: (1) no ambiguous item (ie, a previous winner plus a previous loser; all pairs in condition IP); (2) 1 item with ambiguous (50% winner) reinforcement history (all pairs in condition IS except for BD); and (3) 2 items with ambiguous reinforcement history (the BD pair) (Figure 1 and Table 1).

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Figure 1.

Stimulus set and task conditions. Before functional magnetic resonance imaging (fMRI), subjects were trained to discriminate nonoverlapping pairs (condition P) and an overlapping sequence of pairs (condition S). The reinforced item within each pair is shown on the left. Items highlighted with red were reinforced in one pairing and not reinforced in the other. During fMRI, subjects were asked to recollect the correct response for previously seen pairs and to infer the correct response for novel pairings of items. For novel pairs drawn from the nonoverlapping stimulus set (condition IP), each item was previously reinforced or nonreinforced but not both (ambiguity score, 0). Novel pairings drawn from the overlapping sequence of pairs (condition IS) contained 1 or 2 items with ambiguous reinforcement history (ambiguity score 1 and 2, respectively). No letters were shown in the experiment, and the presentation of the pairs and the position of the 2 stimuli within each pair were randomized.

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STIMULI

Two sets of pattern fills (8 for the nonoverlapping pairs and 5 for the overlapping pairs) were randomly assigned to pairs of pentagonal and ellipsoid shapes for each participant, and the positions of the pattern fills were rotated across subjects.

TRAINING BEFORE SCANNING

Identical to a previously published procedure from our group,22 participants were shown pairs of visual items on a computer screen and asked to indicate by button push which “hid” a smiling face. The left/right position of individual patterns for each pair was counterbalanced. A correct guess during training revealed the smiling face under the visual pattern, and an incorrect guess moved the selected visual pattern but the smiling face did not appear. Participants were trained first on nonoverlapping pairs (a-h; Table 1), then on the sequence of overlapping pairs (A-E; Table 1). For each condition, there were 3 training blocks, consisting of 60, 60, and 24 trials. Participants saw an equal number of each of the pairs in the overlapping and nonoverlapping stimulus sets during training. After completion of the training blocks, participants were tested on a mixture of overlapping and nonoverlapping pairs in a single block of 48 trials containing 6 instances of each of the 8 stimulus pairs. Subjects who did not perform to our criterion of 66% correct for each stimulus pair (7 controls and 9 schizophrenic subjects) received an additional training block of 24 trials of the kind they failed (overlapping pairs in all cases). These subjects were then retested with the same 48-trial mixed block before proceeding to fMRI.

TASK DURING fMRI

All subjects participated in two 5-minute fMRI scans. Each fMRI started and ended with 30-second fixation trials. In between, 8 blocks of trials were presented in the order of P, IP, S, IS, P, IP, S, and IS or S, IS, P, IP, S, IS, P, and IP. In each block, 10 trials were presented for 3 seconds each, resulting in a total of 8 presentations for each of the 5 novel pairs of the IP and IS conditions. For each trial, subjects were instructed to indicate by button press which item they thought would be associated with a smiling face on the basis of previous experience; the smiling face was not presented.

FUNCTIONAL MRI

Subjects lay on the padded bed of a 3-T scanner (Siemens AG, Munich, Germany) in a dimly illuminated room. Foam padding was used to stabilize the head. Stimuli were generated using Presentation software (Neurobehavioral Systems Inc, Albany, Calif) on a personal computer. Images were projected onto a screen and viewed by the subjects via a tilted mirror placed in front of their eyes. After acquisition of high-resolution anatomical images for each subject, fMRI began with an initial sagittal localizer scan. The 2 fMRI scans lasted 5 minutes 5 seconds each. The first 5 seconds of each series was discarded to allow T1 signal equilibration. This was followed by collection of 120 blood oxygenation level–dependent (BOLD) functional brain images (echo time, 30 milliseconds; repetition time, 2500 milliseconds; 35 coronal sections [5 mm thick] perpendicular to the anterior commissure–posterior commissure line, starting anteriorly at the frontal pole, no skip; voxel size, 3.1 × 3.1 × 5 mm; field of view, 200 mm; flip angle, 90°).

We acquired 2 types of images to assess signal distortion due to susceptibility artifacts in the BOLD images. First, an anatomical image matched to the functional BOLD images was acquired.32 These anatomical images were acquired using the standard head coil in the coronal plane with multishot spin-echo echoplanar imaging (echo time, 80 milliseconds; repetition time, 3000 milliseconds; 1 image per section; matrix, 256 × 256 with 4 averages; field of view, 200 mm; 3-mm section thickness with no skip). These are susceptible to the same distortions as BOLD images are and were used to outline hippocampal regions of interest (ROIs) that could be overlaid on functional images. The second set of special-purpose images were field maps, which characterize field inhomogeneities that cause distortions of functional images.33

DATA ANALYSIS
Behavioral Data

Accuracy and response latency were analyzed using a repeated-measures 2 (sequence) × 2 (inference) analysis of variance (ANOVA) with diagnosis as the between-subjects factor. The IS condition was further analyzed as BD and non-BD pairs, using a 2 (diagnosis) × 2 (stimulus pair) ANOVA.

Structural Neuroimaging Data

We used a previously described morphometric protocol34 to calculate hippocampal volume in high-resolution anatomical images with the 3-dimensional Slicer program (http://www.slicer.org). Volumes were analyzed using repeated-measures 2 (hemisphere) × 2 (region) ANOVA with diagnosis as the between-subjects factor.

Functional Neuroimaging Data

Analysis was performed using FEAT (fMRI Expert Analysis Tool), version 5.1, part of the Oxford Centre for Functional Magnetic Resonance Imaging of the Brain (FMRIB) software library (www.fmrib.ox.ac.uk/fsl). Higher-level analysis was performed using FLAME (FMRIB Local Analysis of Mixed Effects).35 Functional data were corrected for head motion, transformed to MNI (Montreal Neurological Institute) template space, and smoothed using a 3-dimensional 8-mm full-width/half-maximum gaussian kernel to allow application of the gaussian random field theory for statistical analysis. Functional images were analyzed in 3 stages in a mixed-effects model. During the first stage, fixed-effects analysis was used. A design matrix was created for each subject that included the effects of the 5 conditions (P, IP, S, IS, and fixation baseline) and the first 2 principal components of motion parameters to explain the time course of BOLD signal change at each voxel. Motion parameters were included to account for BOLD signal changes related to head motion. The 5 effects of interest were modeled as blocks with a boxcar function convolved with 2 gamma functions. The general linear model was used to obtain parameter estimates corresponding to the magnitude of the BOLD signal response for each block type. The contrast used to study brain activation specifically related to transitive inference was (IS − S) − (IP − P).22

In addition to this block design approach, we also performed an event-related analysis focusing on BOLD signal changes related to the BD pairs (Table 1). In this analysis, the design matrix included the effects of 6 trial types (P, IP, S, IS [BD], IS [non-BD], and fixation baseline) with a trial duration of 3 seconds (the duration of stimulus presentation). For each subject, 8 BD presentations (ie, 4 per run) interspersed throughout the IS condition, as well as 32 other IS (non-BD) pairs and 40 each of the P, IP, and S pairs (in blocks of 10 trials), were modeled. The 8 BD trials were in positions 3 + 10, 3 + 5, 4 + 9, and 4 + 9 of the 4 IS blocks. Trial-related BOLD signal change was assessed by convolving a vector of the onset times of the stimuli with a double gamma hemodynamic response function. The general linear model was used to obtain parameter estimates corresponding to the magnitude of the BOLD signal response to each trial type. In both cases, statistical parametric maps were constructed using linear contrasts of parameter estimates for the effects of interest. The contrast used to study brain activation during BD trials was (IS[BD] − IS[non-BD]).

At a second-level analysis, the effects of runs 1 and 2 were modeled for controls and schizophrenic subjects. At a third-level analysis, individual contrast images were entered into a random-effects analysis. One- and 2-sample unpaired t tests were used to test for the main effects and interactions of within- and between-group effects.36 For the whole-brain analysis, we masked the group-wise contrast images with the activation image from the first group to ensure that the findings represented true activations in that group (eg, control>schizophrenia group contrast was masked with activations in the control group). Activations within the previously defined network of brain regions supporting transitive inference judgments22 were considered significant at a voxel extent threshold of 5 or more voxels, with P≤.001, uncorrected for multiple comparisons.

Given our strong a priori hypothesis of hippocampal abnormalities during transitive inference in schizophrenia, we used 2 ROI approaches to study hippocampal activation. First, we delineated left and right anterior and posterior hippocampal volumes on the mean structural image of all study subjects and limited the whole-brain contrast image analysis to the hippocampus using these 4 masks. Activations were considered significant at P≤.05, corrected for multiple comparisons within the hippocampal ROIs. Second, to confirm any significant activation within the 4 hippocampal ROIs, we outlined hippocampal regions on echoplanar-matched anatomical images. These images, representing the same degree of distortion,37 provided high-fidelity registration with the BOLD images and allowed us to define the hippocampus along anatomical landmarks. After delineation, we coregistered the ROIs and the EP-matched anatomical images and calculated mean time courses across the ROI for individual subjects. We then extracted epochs of activity in response to a presentation of BD pairs scaled as percentage of signal change from the onset of the BD trials, and compared patterns of change across the 2 groups.

BEHAVIORAL DATA
Accuracy

Both groups were less accurate when recognizing novel pairs (main effect of inference, F1,28 = 16.33 [P<.001]; nonsignificant inference × diagnosis interaction, F1,28 = 1.20 [P = .28]) or pairs taken from the sequence (main effect of sequence, F1,28 = 20.90 [P<.001]; nonsignificant interaction of sequence × diagnosis, F1,28 = 0.18 [P = .67]) (Table 2). This indicates normal transitive inference performance in schizophrenia when all trials are analyzed together.

However, the 2 groups differed in their ability to correctly evaluate the novel-pair BD, which combines 2 stimuli rewarded equally often (50%) during training (Table 1 and Figure 1). Control subjects achieved similar accuracy for the BD pair and the remaining IS pairs (F1,14 = 1.21 [P = .29]), whereas schizophrenic subjects were selectively impaired on the BD pairs but not the remaining IS pairs (F1,14 = 7.93 [P = .01]) (Table 2 and Figure 2). A repeated-measures ANOVA revealed that this diagnosis × stimulus pair interaction approached significance (F1,28 = 3.63 [P = .07]), consistent with a specific deficit of schizophrenic subjects on the BD pairs.

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Figure 2.

Accuracy for 3 different inference tasks. Accuracy was highest when both stimuli in novel pairings had an unambiguous reinforcement history (condition IP; ambiguity score, 0) and lowest when both stimuli could only be inferred from their position within the sequence (BD; ambiguity score, 2). The schizophrenia group showed a selective deficit in the BD transitive inference pairs. Error bars represent SEM.

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Response Latency

Subjects needed more time to identify the pairs taken from the sequence (main effect of sequence, F1,28 = 73.12 [P<.001]; nonsignificant diagnosis × sequence interaction, F1,28 = 0.44 [P = .51) (Table 2). Control but not schizophrenic subjects needed more time to identify the previously rewarded stimulus in novel pairs (nonsignificant main effect of inference, F1,28 = 0.48 [P = .49]; diagnosis × inference interaction, F1,28 = 8.98 [P = .006]) (Table 2). This interaction was weaker if only the response latencies for correct responses were considered (F1,28 = 4.35 [P = .046]), because schizophrenic subjects tended to respond faster when the IS trials were identified incorrectly (mean ± SD, 1547.4 ± 258.9 milliseconds for correct and 1219.8 ± 245.9 milliseconds for incorrect trials) (t = 2.19; [2-tailed P = .04]).

Neither group showed a significant relationship between NAART scores and accuracy or reaction times during the P, IP, S, or IS blocks (not shown) or during BD trials specifically (r = 0.22 [P = .46] and r = 0.44 [P = .12], respectively).

MRI DATA
Volumetric Data

Mean ± SD hippocampal volume for left anterior, left posterior, right anterior, and right posterior regions did not differ between the control (1407 ± 269, 1307 ± 231, 1514 ± 193, and 1355 ± 250 mm3, respectively) and the schizophrenia (1352 ± 327, 1364 ± 134, 1497 ± 213, 1396 ± 222 mm3, respectively) groups (main effect of diagnosis, F1,28 = 0.01 [P = .91]; diagnosis × hemisphere interaction, F1,28 = 0.06 [P = .81]; diagnosis × anterior/posterior region interaction, F1,28 = 0.54 [P = .47]; diagnosis × hemisphere × region interaction, F1,28 = 0.31 [P = .58]).

fMRI Data

We explored the neural basis of transitive inference in control and schizophrenic subjects with the following 2 types of analyses: (1) all transitive inference trials compared with all nontransitive inference trials, and (2) the 8 BD transitive inference trials compared with the 32 non-BD transitive inference trials.

Transitive Inference

Consistent with our previously identified transitive inference network, control subjects showed significantly greater activation in the bilateral parietal cortex, premotor cortex, presupplementary motor area (pre-SMA), bilateral ventral prefrontal cortex, bilateral posterior temporal cortex, pulvinar, and right hippocampus and entorhinal cortex (Table 3). In contrast, schizophrenic patients showed significantly greater activation in only 3 brain regions: the pre-SMA, ventral prefrontal, and posterior temporal cortex (Table 3). A direct comparison of the 2 groups revealed significantly decreased activation during transitive inference judgments in schizophrenia in the right parietal cortex and anterior cingulate cortex (Table 3 and Figure 3). Parameter estimates extracted from these 2 regions were not correlated with delusional thinking, conceptual disorganization, or total Positive and Negative Syndrome Scale scores. The hippocampal ROI analysis did not reveal any significant differences between the 2 groups. All of these analyses were confirmed when using BOLD images that were corrected for field inhomogeneity–induced distortions.

Table Graphic Jump LocationTable 3. Brain Activations During Transitive Inference Condition*
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Figure 3.

Magnetic resonance imaging shows abnormal brain activity in schizophrenia during transitive inference. Brain areas show significantly greater activity in healthy control subjects than in schizophrenic patients during the transitive inference condition. Both loci were mapped onto axial, parasagittal, and coronal slices from the mean structural image of the 30 study subjects (P<.001, uncorrected). Color bar indicates z scores.

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BD Trials

To explore the neural basis of the selective deficit for BD pairs in schizophrenia, we studied whether brain activation differed between the BD trials and the remaining non-BD transitive inference trials. In the whole-brain analysis, we found that only the bilateral parietal cortex was more significantly activated during BD trials in controls (Table 4). In schizophrenic subjects, we found activation in several frontal cortical areas (Table 4). A direct comparison of the 2 groups revealed greater right parietal cortex activation in healthy controls (Table 4 and Figure 4A).

Table Graphic Jump LocationTable 4. Brain Activations During Hard Transitive Inference Condition*
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Figure 4.

Abnormal brain activity in schizophrenia during trials when both stimuli could only be inferred from their position within the sequence (BD trials). A, The right parietal cortex showed significantly greater activity in healthy control subjects than in schizophrenic patients during BD trials, mapped onto a coronal slice from the mean structural image of the 30 study subjects (P<.001, uncorrected). B, Significantly greater activation in healthy controls than in schizophrenic patients in the left anterior hippocampus during BD trials, mapped onto a coronal slice from the mean structural image of the 30 study subjects (P<.05, corrected). C, Parameter estimates extracted from the differentially activated left anterior hippocampal cluster (in part B). Signal increase in controls and signal decrease in schizophrenic patients were seen during BD trials. D, Group-averaged time series of blood oxygenation–level dependent signal for the anatomically defined left anterior hippocampal region of interest during BD trials. Signal change is plotted relative to the presentation of the BD pair (time point, 0). Color bars in A and B indicate z scores.

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The ROI analysis of the 4 hippocampal regions revealed significantly stronger activation of the left anterior hippocampus in the control group (33 voxels; coordinates of peak activation at −14, −10, and −24; z = 2.59 [P<.05, corrected for multiple comparisons]) (Figure 4B). Parameter estimates for this differentially activated region showed increased activation in the control group and decreased activation in the schizophrenia group during BD trials (Figure 4C); these estimates were not correlated with delusional thinking, conceptual disorganization, or total Positive and Negative Syndrome Scale scores. This difference in left anterior hippocampal activation was confirmed in a second analysis, which revealed that the control group showed a blood flow increase in response to BD trials, whereas the schizophrenia group did not (Figure 4D).

We have identified the neural correlates of a selective relational memory deficit in schizophrenia. Subjects with schizophrenia were able to draw correct transitive inferences about novel stimulus pairs if at least 1 stimulus had an unambiguous reinforcement history. However, they were impaired if reward contingencies were ambiguous and the flexible representation of a sequence was required for discrimination. This confirms and extends a previous study of relational memory in schizophrenia.14 In addition, our data provide novel evidence that this relational memory deficit in schizophrenia is associated with impaired function of the right parietal cortex and medial temporal lobe (MTL).

TRANSITIVE INFERENCE NETWORK IN CONTROL AND SCHIZOPHRENIA GROUPS

In this study, we replicate a previous finding22 that a network of brain areas (including the pre-SMA, bilateral parietal cortex, prefrontal cortex, and hippocampus) is associated with transitive inference in healthy controls. We now show normal activation of 2 nodes (ie, pre-SMA and ventral prefrontal cortex) and decreased activation of 2 other nodes (ie, right parietal and anterior cingulate cortices) within this network during transitive inference in schizophrenia.

Activation of the pre-SMA is an integral feature of transitive inference tasks.21,22 This is in line with previous studies suggesting that the pre-SMA is involved in the control of motor sequences39 and that this region is activated during sequence learning.40,41 Previous studies in schizophrenia showed robust pre-SMA activation during cognitive task performance in schizophrenia.42,43 Our results indicate that the function of the pre-SMA is also not impaired in schizophrenia during relational memory tasks that require the storage and retrieval of a sequence.

The parietal cortex (Brodmann areas 40 and 7) also appears to be a crucial node within the transitive inference network. Activation of this area during transitive inference in humans was reported by 2 previous neuroimaging studies of healthy volunteers.21,22 It is likely that the storage of a flexible representation of visual stimuli, necessary to correctly discriminate transitive inference trials, requires access to the parietal cortex. This is supported by the demonstration of strong reciprocal connections between the parietal and prefrontal cortices and the MTL, including the entorhinal cortex and presubiculum.44,45 A proposed role of the parietal cortex for the storage of flexible representations of stimuli is in line with recent neuroimaging studies that have demonstrated parietal cortex activation during judgments of semantic distance while comparing numbers46 and during judgments of analogy.47 In addition, 2 aspects of transitive inference, ie, attention and decision making, have been linked closely to the parietal cortex.48,49

Herein we report reduced recruitment of parietal cortex in schizophrenia during transitive inference judgments in general and during BD trials in particular. This pattern indicates abnormal parietal cortex function in schizophrenia not only during trials in which performance is significantly impaired (ie, BD), but also when performance is not significantly different. This is consistent with a fundamental parietal cortex deficit in schizophrenia.50 Previous studies have demonstrated that abnormalities of attention, working memory, decision making, and motor control in schizophrenia are related to dysfunction of a parietal-prefrontal network.5155 Furthermore, the first-rank symptom of passivity or “made” experiences and the core features of catatonia (stupor and mutism) have been associated with abnormal activity of the parietal cortex.5658 These results have led some to suggest an important role of the parietal cortex for the cognitive deficits and psychotic features of schizophrenia, especially in “representationally guided behaviors.”50 Our data support such notions and link the abnormal pattern of parietal cortex activation to impaired relational memory in schizophrenia.

ABNORMALITIES IN THE MTL

Two lines of evidence compelled us to examine MTL function during transitive inference. First, transitive inference requires an intact hippocampal formation in animals18,25 and is associated with hippocampal activation in humans.18,20,22 Second, a large body of literature indicates that significant structural and functional abnormalities exist in the MTL in schizophrenia59 and that memory deficits have been associated with abnormal recruitment of the hippocampus in neuroimaging studies.6065

We found that subjects with schizophrenia were impaired in recruiting the left hippocampus during BD trials, linking deficits in relational memory to abnormal hippocampal function. This provides compelling evidence that impaired hippocampal function contributes to memory deficits in schizophrenia. It remains to be seen how region-specific abnormalities of interneurons66 and excitatory synaptic neurotransmission67 in the hippocampus of schizophrenia subjects are related to the deficits of relational memory reported herein. Animal models of relational memory are ideally situated to test the hypothesis of impaired hippocampal inhibition in schizophrenia.68 Aberrant afferent signals from the association cortex, including the parietal cortex,44 may contribute to the abnormal hippocampal signaling in schizophrenia.

LIMITATIONS

As in all neuroimaging studies of schizophrenia, our patient group was self-selected. They were stable, treated outpatients, able and willing to tolerate a training session in a challenging paradigm, followed by fMRI. Although this limits the generalizability of our findings, the study of medicated, stable outpatients has been proposed as ideal for the exploration of cognitive deficits and their treatment in schizophrenic patients.69 The relatively high premorbid IQ of our subjects, as estimated by the NAART, is not typical for the population of schizophrenic patients at large,70 but the lack of a relationship between NAART scores and performance indicates that this did not bias our results. Finally, although the finding of normal hippocampal volume in our patient group is in contrast to the findings of many other studies,71 it avoids the confound of volume differences in the analysis of hippocampal activation patterns.

The experiment included a total of 8 BD and 32 non-BD IS trials per subject. Furthermore, stimulus onset asynchrony was fixed at 3 seconds and not jittered. Both of these factors likely limited our power to detect differences in the event-related analysis of BD trials. The fact that we still found significant group differences highlights their robust nature. It would be desirable to test the neural basis of transitive inference with a design that includes 6 stimuli (A-F), allowing for 3 BD-like pairs of stimuli (B>D, B>E, and C>E). However, preliminary data from this experimental paradigm in young healthy controls indicate that schizophrenic subjects would unlikely be able to achieve accuracy sufficient for a valid neuroimaging experiment.

Our study was performed using a 3-T MRI scanner, where distortions and loss of the BOLD signal in the temporal and frontal lobes are significant. We confirmed our findings in the medial temporal lobe with unwarped functional images and with an ROI analysis that used anatomical images matched for the degree of distortion. However, it is possible that the power to detect group differences in brain activation varies between regions and that the parietal cortex yielded an underlying pathology more readily than did the hippocampus.

IMPLICATIONS

In this study, subjects needed to access the mental representation of a sequence to infer relationships between items in novel configurations. Recent accounts of transitive inference link the cerebral cortex to the storage of stimulus representations and the hippocampus to the access of these representations to make inferences about the relationships between items.18 We have found reduced activity in the anterior cingulate cortex, right parietal cortex, and hippocampus in schizophrenia during transitive inference judgments. Thus, we conclude that patients with schizophrenia are impaired at multiple levels, including storage of stimulus representations (in the parietal cortex), flexible retrieval and comparison of stimuli (in the hippocampus), and error monitoring and attention (in the anterior cingulate cortex72). However, hippocampal abnormalities made a unique impact on performance because schizophrenic patients were behaviorally impaired only when flexible access to sequentially arranged stimuli was needed (the BD condition).

Because relational memory deficits can lead to inferential thinking abnormalities, including a “jump-to-conclusions” cognitive style, they may be related to the delusions and thought disorder of schizophrenia.23,24,73 Thus, an impaired ability to retrieve a flexible representation of prior experience might be at the core of 2 prominent features of schizophrenia, ie, memory deficits and psychosis. This is not a simple relationship, however, as there was no correlation between brain activation and the degree of psychosis in our patient group. Relational memory deficits may contribute to the formation of delusions but might not be linked to the degree of delusions at the time of study. In the future, it would be helpful to compare schizophrenic patients with and without delusions with the transitive inference task.

Studying the neural basis of cognitive deficits in schizophrenia promises to uncover new treatment targets.74 The selective relational memory deficit described herein is attractive because animal models of transitive inference are well established25,75 and recent studies have demonstrated a transitive inference network in humans,2022 providing the opportunity to study treatment effects in several species. Given the abnormalities in multiple brain areas during transitive inference in schizophrenia, we speculate that investigation of this neuroimaging phenotype and genes implicated in neural development and neurotransmission, such as neuregulin 1, may prove fruitful.

Correspondence: Dost Öngür, MD, PhD, Schizophrenia and Bipolar Disorder Program, Room AB320, McLean Hospital, 115 Mill St, Belmont, MA 02478 (dongur@partners.org).

Submitted for Publication: May 9, 2005; final revision received September 15, 2005; accepted October 4, 2005.

Funding/Support: This study was supported by grant R01 MH070560 from the National Institute of Mental Health, Rockville, Md (Dr Heckers); and by the National Alliance for Research on Schizophrenia and Depression Research Partners Program, Great Neck, NY, funded by Donald and Jean Stone (Dr Öngür).

Acknowledgment: We thank Alex Scerbo, Ian Greenhouse, and Tali Ditman for their help in conducting the experiment.

Goldberg  TEDavid  AGold  JM Neurocognitive deficits in schizophrenia. In:Hirsch  SRWeinberger  DReds.Schizophrenia. Oxford, England Blackwell Publishing2004;168- 184
Saykin  AJGur  RCGur  REMozley  PDMozley  LHResnick  SMKester  DBStafiniak  P Neuropsychological function in schizophrenia: selective impairment in memory and learning. Arch Gen Psychiatry 1991;48618- 624
PubMed
Heinrichs  RWZakzanis  KK Neurocognitive deficit in schizophrenia: a quantitative review of the evidence. Neuropsychology 1998;12426- 445
PubMed
Aleman  AHijman  Rde Haan  EHFKahn  RS Memory impairment in schizophrenia: a meta-analysis. Am J Psychiatry 1999;1561358- 1366
PubMed
Pelletier  MAchim  AMMontoya  ALal  SLepage  M Cognitive and clinical moderators of recognition memory in schizophrenia: a meta-analysis. Schizophr Res 2005;74233- 252
PubMed
Cirillo  MASeidman  LJ Verbal declarative memory dysfunction in schizophrenia: from clinical assessment to genetics and brain mechanisms. Neuropsychol Rev 2003;1343- 77
PubMed
Green  MF What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry 1996;153321- 330
PubMed
Budson  AEPrice  BH Memory dysfunction. N Engl J Med 2005;352692- 699
PubMed
Weiss  APHeckers  S Neuroimaging of declarative memory in schizophrenia. Scand J Psychol 2001;42239- 250
PubMed
Huron  CDanion  JMGiacomoni  FGrange  DRobert  PRizzo  L Impairment of recognition memory with, but not without, conscious recollection in schizophrenia. Am J Psychiatry 1995;1521737- 1742
PubMed
Danion  JMRizzo  LBruant  A Functional mechanisms underlying impaired recognition memory and conscious awareness in patients with schizophrenia. Arch Gen Psychiatry 1999;56639- 644
PubMed
Tendolkar  IRuhrmann  SBrockhaus  APukrop  RKlosterkötter  J Remembering or knowing: electrophysiological evidence for an episodic memory deficit in schizophrenia. Psychol Med 2002;321261- 1271
PubMed
Huron  CDanion  J-M Impairment of constructive memory in schizophrenia. Int Clin Psychopharmacol 2002;17127- 133
PubMed
Titone  DDitman  THolzman  PSEichenbaum  HLevy  DL Transitive inference in schizophrenia: impairments in relational memory organization. Schizophr Res 2004;68235- 247
PubMed
Chin  RBYouens  KETamminga  CA Differences in cognitive performance between medicated and non-medicated schizophrenics and normals on the transitive inference task [abstract]. Schizophr Bull 2005;31352- 353
Tulving  E Episodic memory: from mind to brain. Annu Rev Psychol 2002;531- 25
PubMed
Eichenbaum  HOtto  TCohen  NJ Two functional components of the hippocampal memory system. Behav Brain Sci 1994;17449- 517
Eichenbaum  H Hippocampus: cognitive processes and neural representations that underlie declarative memory. Neuron 2004;44109- 120
PubMed
Howard  MWFotedar  MSDatey  AVHasselmo  ME The temporal context model in spatial navigation and relational learning: toward a common explanation of medial temporal lobe function across domains. Psychol Rev 2005;11275- 116
PubMed
Nagode  JCPardo  JV Human hippocampal activation during transitive inference. Neuroreport 2002;13939- 944
PubMed
Acuna  BDEliassen  JCDonoghue  JPSanes  JN Frontal and parietal lobe activation during transitive inference in humans. Cereb Cortex 2002;121312- 1321
PubMed
Heckers  SZalesak  MWeiss  APDitman  TTitone  D Hippocampal activation during transitive inference in humans. Hippocampus 2004;14153- 162
PubMed
Linney  YMPeters  ERAyton  P Reasoning biases in delusion-prone individuals. Br J Clin Psychol 1998;37285- 302
PubMed
Mujica-Parodi  LRMalaspina  DSackeim  HA Logical processing, affect, and delusional thought in schizophrenia. Harv Rev Psychiatry 2000;873- 83
PubMed
Dusek  JAEichenbaum  H The hippocampus and memory for orderly stimulus relations. Proc Natl Acad Sci U S A 1997;947109- 7114
PubMed
Prince  SEDaselaar  SMCabeza  R Neural correlates of relational memory: successful encoding and retrieval of semantic and perceptual associations. J Neurosci 2005;251203- 1210
PubMed
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.  Washington, DC American Psychiatric Association1994;
Kay  SRFiszbein  AOpler  LA The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr Bull 1987;13261- 276
PubMed
Guy  W ECDEU Assessment Manual for Psychopharmacology.  Washington, DC US Dept of Health, Education, and Welfare1976;
Beck  ATWard  CHMendelson  MMock  JErbaugh  J An inventory for measuring depression. Arch Gen Psychiatry 1961;4561- 571
PubMed
Oldfield  RC The assessment and analysis of handedness: the Edinburgh Inventory. Neuropsychologia 1971;997- 113
PubMed
Rohan  MLKillgore  WDSEskesen  JGRenshaw  PFYurgelun-Todd  DA Match-Warped EPI Anatomic Images and the Amygdala: Locating Activation in Hard Places.  Glasgow, Scotland International Society for Magnetic Resonance in Medicine2001;1237
Jezzard  PBalaban  RS Correction for geometric distortion in echo planar images from B0 field variations. Magn Reson Med 1995;3465- 73
PubMed
Weiss  APDewitt  IGoff  DDitman  THeckers  S Anterior and posterior hippocampal volumes in schizophrenia. Schizophr Res 2005;73103- 112
PubMed
Smith  SMJenkinson  MWoolrich  MWBeckmann  CFBehrens  TEJohansen-Berg  HBannister  PRDe Luca  MDrobnjak  IFlitney  DENiazy  RKSaunders  JVickers  JZhang  YDe Stefano  NBrady  JMMatthews  PM Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage 2004;23 ((suppl 1)) S208- S219
PubMed
Woolrich  MWBehrens  TEBeckmann  CFJenkinson  MSmith  SM Multilevel linear modelling for fMRI group analysis using bayesian inference. Neuroimage 2004;211732- 1747
PubMed
Cusack  RBrett  MOsswald  K An evaluation of the use of magnetic field maps to undistort echo-planar images. Neuroimage 2003;18127- 142
PubMed
Talairach  JTournoux  P Co-planar Sterotactic Atlas of the Human Brain.  New York, NY Thieme Medical Publishers Inc1988;
Boecker  HDagher  ACeballos-Baumann  AOPassingham  RESamuel  MFriston  KJPoline  JDettmers  CConrad  BBrooks  DJ Role of the human rostral supplementary motor area and the basal ganglia in motor sequence control: investigations with H215O PET. J Neurophysiol 1998;791070- 1080
PubMed
Hikosaka  OSakai  KMiyauchi  STakino  RSasaki  YPutz  B Activation of human presupplementary motor area in learning of sequential procedures: a functional MRI study. J Neurophysiol 1996;76617- 621
PubMed
Sakai  KHikosaka  OMiyauchi  SSasaki  YFujimaki  NPutz  B Presupplementary motor area activation during sequence learning reflects visuo-motor association. J Neurosci 1999;19RC1
PubMed
Yücel  MPantelis  CStuart  GWWood  SJMaruff  PVelakoulis  DPipingas  ACrowe  SFTochon-Danguy  HJEgan  GF Anterior cingulate activation during Stroop task performance: a PET to MRI coregistration study of individual patients with schizophrenia. Am J Psychiatry 2002;159251- 254
PubMed
Heckers  SWeiss  APDeckersbach  TGoff  DCMorecraft  RJBush  G Anterior cingulate cortex activation during cognitive interference in schizophrenia. Am J Psychiatry 2004;161707- 715
PubMed
Seltzer  BPandya  DN Further observations on parieto-temporal connections in the rhesus monkey. Exp Brain Res 1984;55301- 312
PubMed
Mesulam  M-Med Principles of Behavioral Neurology. 2nd New York, NY Oxford University Press Inc2000;
Pinel  PDehaene  SRiviere  DLeBihan  D Modulation of parietal activation by semantic distance in a number comparison task. Neuroimage 2001;141013- 1026
PubMed
Wharton  CMGrafman  JFlitman  SSHansen  EKBrauner  JMarks  AHonda  M Toward neuroanatomical models of analogy: a positron emission tomography study of analogical mapping. Cognit Psychol 2000;40173- 197
PubMed
Platt  MLGlimcher  PW Neural correlates of decision variables in parietal cortex. Nature 1999;400233- 238
PubMed
Behrmann  MGeng  JJShomstein  S Parietal cortex and attention. Curr Opin Neurobiol 2004;14212- 217
PubMed
Pearlson  GDPetty  RGRoss  CATien  AY Schizophrenia: a disease of heteromodal association cortex? Neuropsychopharmacology 1996;141- 17
PubMed
Manoach  DSHalpern  EFKramer  TSChang  YGoff  DCRauch  SLKennedy  DNGollub  RL Test-retest reliability of a functional MRI working memory paradigm in normal and schizophrenic subjects. Am J Psychiatry 2001;158955- 958
PubMed
Ojeda  NOrtuno  FArbizu  JLopez  PMarti-Climent  JMPenuelas  ICervera-Enguix  S Functional neuroanatomy of sustained attention in schizophrenia: contribution of parietal cortices. Hum Brain Mapp 2002;17116- 130
PubMed
Paulus  MPHozack  NEZauscher  BEFrank  LGrown  GGMcDowell  JBraff  DL Parietal dysfunction is associated with increased outcome-related decision-making in schizophrenia patients. Biol Psychiatry 2002;51995- 1004
PubMed
Quintana  JWong  TOrtiz-Portillo  EKovalik  EDavidson  TMarder  SRMazziotta  JC Prefrontal-posterior parietal networks in schizophrenia: primary dysfunctions and secondary compensations. Biol Psychiatry 2003;5312- 24
PubMed
Danckert  JSaoud  MMaruff  P Attention, motor control and motor imagery in schizophrenia: implications for the role of the parietal cortex. Schizophr Res 2004;70241- 261
PubMed
Spence  SABrooks  DJHirsch  SRLiddle  PFMeehan  JGrasby  PMA PET study of voluntary movement in schizophrenic patients experiencing passivity phenomena (delusions of alien control). Brain 1997;1201997- 2011
PubMed
Blakemore  SJOakley  DAFrith  CD Delusions of alien control in the normal brain. Neuropsychologia 2003;411058- 1067
PubMed
Northoff  G Neuroimaging and neurophysiology. In:Caroff  SNMann  SCFrancis  AFricchione  GLeds.Catatonia: From Psychopathology to Neurobiology. Washington, DC American Psychiatric Publishing Inc2004;77- 91
Heckers  S Neuroimaging studies of the hippocampus in schizophrenia. Hippocampus 2001;11520- 528
PubMed
Heckers  SRauch  SLGoff  DSavage  CRSchacter  DLFischman  AJAlpert  NM Impaired recruitment of the hippocampus during conscious recollection in schizophrenia. Nat Neurosci 1998;1318- 323
PubMed
Ragland  JDGur  RCRaz  JSchroeder  LKohler  CGSmith  RJAlavi  AGur  RE Effect of schizophrenia on frontotemporal activity during word encoding and recognition: a PET cerebral blood flow study. Am J Psychiatry 2001;1581114- 1125
PubMed
Eyler Zorrilla  LTJeste  DVPaulus  MBrown  GG Functional abnormalities of medial temporal cortex during novel picture learning among patients with chronic schizophrenia. Schizophr Res 2003;59187- 198
PubMed
Weiss  APSchacter  DLGoff  DCRauch  SLAlpert  NMFischman  AJHeckers  S Impaired hippocampal recruitment during normal modulation of memory performance in schizophrenia. Biol Psychiatry 2003;5348- 55
PubMed
Hofer  AWeiss  EMGolaszewski  SMSiedentopf  CMBrinkhoff  CKremser  CFelber  SFleischhacker  WW An fMRI study of episodic encoding and recognition of words in patients with schizophrenia in remission. Am J Psychiatry 2003;160911- 918
PubMed
Weiss  APZalesak  MDeWitt  IGoff  DKunkel  LHeckers  S Impaired hippocampal function during the detection of novel words in schizophrenia. Biol Psychiatry 2004;55668- 675
PubMed
Benes  FMBerretta  S Gabaergic interneurons: implications for understanding schizophrenia and bipolar disorder. Neuropsychopharmacology 2001;251- 27
PubMed
Harrison  PJ The hippocampus in schizophrenia: a review of the neuropathological evidence and its pathophysiological implications. Psychopharmacology (Berl) 2004;174151- 162
Greene  R Circuit analysis of NMDAR hypofunction in the hippocampus, in vitro, and psychosis of schizophrenia. Hippocampus 2001;11569- 577
PubMed
Buchanan  RWDavis  MGoff  DGreen  MFKeefe  RSLeon  ACNuechterlein  KHLaughren  TLevin  RStover  EFenton  WMarder  SR A summary of the FDA-NIMH-MATRICS workshop on clinical trial design for neurocognitive drugs for schizophrenia. Schizophr Bull 2005;315- 19
PubMed
Aylward  EWalker  EBettes  B Intelligence in schizophrenia: meta-analysis of the research. Schizophr Bull 1984;10430- 459
PubMed
Wright  ICRabe-Hesketh  SWoodruff  PWDavid  ASMurray  RMBullmore  ET Meta-analysis of regional brain volumes in schizophrenia. Am J Psychiatry 2000;15716- 25
PubMed
Carter  CSBraver  TSBarch  DMBotvinick  MMNoll  DCohen  JD Anterior cingulate cortex, error detection, and the online monitoring of performance. Science 1998;280747- 749
PubMed
Freeman  DGarety  PAKuipers  EFowler  DBebbington  PE A cognitive model of persecutory delusions. Br J Clin Psychol 2002;41331- 347
PubMed
Hyman  SEFenton  WS Medicine: what are the right targets for psychopharmacology? Science 2003;299350- 351
PubMed
Van Elzakker  MO’Reilly  RCRudy  JW Transitivity, flexibility, conjunctive representations, and the hippocampus, I: an empirical analysis. Hippocampus 2003;13334- 340
PubMed

Figures

Place holder to copy figure label and caption
Figure 1.

Stimulus set and task conditions. Before functional magnetic resonance imaging (fMRI), subjects were trained to discriminate nonoverlapping pairs (condition P) and an overlapping sequence of pairs (condition S). The reinforced item within each pair is shown on the left. Items highlighted with red were reinforced in one pairing and not reinforced in the other. During fMRI, subjects were asked to recollect the correct response for previously seen pairs and to infer the correct response for novel pairings of items. For novel pairs drawn from the nonoverlapping stimulus set (condition IP), each item was previously reinforced or nonreinforced but not both (ambiguity score, 0). Novel pairings drawn from the overlapping sequence of pairs (condition IS) contained 1 or 2 items with ambiguous reinforcement history (ambiguity score 1 and 2, respectively). No letters were shown in the experiment, and the presentation of the pairs and the position of the 2 stimuli within each pair were randomized.

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

Accuracy for 3 different inference tasks. Accuracy was highest when both stimuli in novel pairings had an unambiguous reinforcement history (condition IP; ambiguity score, 0) and lowest when both stimuli could only be inferred from their position within the sequence (BD; ambiguity score, 2). The schizophrenia group showed a selective deficit in the BD transitive inference pairs. Error bars represent SEM.

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

Magnetic resonance imaging shows abnormal brain activity in schizophrenia during transitive inference. Brain areas show significantly greater activity in healthy control subjects than in schizophrenic patients during the transitive inference condition. Both loci were mapped onto axial, parasagittal, and coronal slices from the mean structural image of the 30 study subjects (P<.001, uncorrected). Color bar indicates z scores.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Abnormal brain activity in schizophrenia during trials when both stimuli could only be inferred from their position within the sequence (BD trials). A, The right parietal cortex showed significantly greater activity in healthy control subjects than in schizophrenic patients during BD trials, mapped onto a coronal slice from the mean structural image of the 30 study subjects (P<.001, uncorrected). B, Significantly greater activation in healthy controls than in schizophrenic patients in the left anterior hippocampus during BD trials, mapped onto a coronal slice from the mean structural image of the 30 study subjects (P<.05, corrected). C, Parameter estimates extracted from the differentially activated left anterior hippocampal cluster (in part B). Signal increase in controls and signal decrease in schizophrenic patients were seen during BD trials. D, Group-averaged time series of blood oxygenation–level dependent signal for the anatomically defined left anterior hippocampal region of interest during BD trials. Signal change is plotted relative to the presentation of the BD pair (time point, 0). Color bars in A and B indicate z scores.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 3. Brain Activations During Transitive Inference Condition*
Table Graphic Jump LocationTable 4. Brain Activations During Hard Transitive Inference Condition*

References

Goldberg  TEDavid  AGold  JM Neurocognitive deficits in schizophrenia. In:Hirsch  SRWeinberger  DReds.Schizophrenia. Oxford, England Blackwell Publishing2004;168- 184
Saykin  AJGur  RCGur  REMozley  PDMozley  LHResnick  SMKester  DBStafiniak  P Neuropsychological function in schizophrenia: selective impairment in memory and learning. Arch Gen Psychiatry 1991;48618- 624
PubMed
Heinrichs  RWZakzanis  KK Neurocognitive deficit in schizophrenia: a quantitative review of the evidence. Neuropsychology 1998;12426- 445
PubMed
Aleman  AHijman  Rde Haan  EHFKahn  RS Memory impairment in schizophrenia: a meta-analysis. Am J Psychiatry 1999;1561358- 1366
PubMed
Pelletier  MAchim  AMMontoya  ALal  SLepage  M Cognitive and clinical moderators of recognition memory in schizophrenia: a meta-analysis. Schizophr Res 2005;74233- 252
PubMed
Cirillo  MASeidman  LJ Verbal declarative memory dysfunction in schizophrenia: from clinical assessment to genetics and brain mechanisms. Neuropsychol Rev 2003;1343- 77
PubMed
Green  MF What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry 1996;153321- 330
PubMed
Budson  AEPrice  BH Memory dysfunction. N Engl J Med 2005;352692- 699
PubMed
Weiss  APHeckers  S Neuroimaging of declarative memory in schizophrenia. Scand J Psychol 2001;42239- 250
PubMed
Huron  CDanion  JMGiacomoni  FGrange  DRobert  PRizzo  L Impairment of recognition memory with, but not without, conscious recollection in schizophrenia. Am J Psychiatry 1995;1521737- 1742
PubMed
Danion  JMRizzo  LBruant  A Functional mechanisms underlying impaired recognition memory and conscious awareness in patients with schizophrenia. Arch Gen Psychiatry 1999;56639- 644
PubMed
Tendolkar  IRuhrmann  SBrockhaus  APukrop  RKlosterkötter  J Remembering or knowing: electrophysiological evidence for an episodic memory deficit in schizophrenia. Psychol Med 2002;321261- 1271
PubMed
Huron  CDanion  J-M Impairment of constructive memory in schizophrenia. Int Clin Psychopharmacol 2002;17127- 133
PubMed
Titone  DDitman  THolzman  PSEichenbaum  HLevy  DL Transitive inference in schizophrenia: impairments in relational memory organization. Schizophr Res 2004;68235- 247
PubMed
Chin  RBYouens  KETamminga  CA Differences in cognitive performance between medicated and non-medicated schizophrenics and normals on the transitive inference task [abstract]. Schizophr Bull 2005;31352- 353
Tulving  E Episodic memory: from mind to brain. Annu Rev Psychol 2002;531- 25
PubMed
Eichenbaum  HOtto  TCohen  NJ Two functional components of the hippocampal memory system. Behav Brain Sci 1994;17449- 517
Eichenbaum  H Hippocampus: cognitive processes and neural representations that underlie declarative memory. Neuron 2004;44109- 120
PubMed
Howard  MWFotedar  MSDatey  AVHasselmo  ME The temporal context model in spatial navigation and relational learning: toward a common explanation of medial temporal lobe function across domains. Psychol Rev 2005;11275- 116
PubMed
Nagode  JCPardo  JV Human hippocampal activation during transitive inference. Neuroreport 2002;13939- 944
PubMed
Acuna  BDEliassen  JCDonoghue  JPSanes  JN Frontal and parietal lobe activation during transitive inference in humans. Cereb Cortex 2002;121312- 1321
PubMed
Heckers  SZalesak  MWeiss  APDitman  TTitone  D Hippocampal activation during transitive inference in humans. Hippocampus 2004;14153- 162
PubMed
Linney  YMPeters  ERAyton  P Reasoning biases in delusion-prone individuals. Br J Clin Psychol 1998;37285- 302
PubMed
Mujica-Parodi  LRMalaspina  DSackeim  HA Logical processing, affect, and delusional thought in schizophrenia. Harv Rev Psychiatry 2000;873- 83
PubMed
Dusek  JAEichenbaum  H The hippocampus and memory for orderly stimulus relations. Proc Natl Acad Sci U S A 1997;947109- 7114
PubMed
Prince  SEDaselaar  SMCabeza  R Neural correlates of relational memory: successful encoding and retrieval of semantic and perceptual associations. J Neurosci 2005;251203- 1210
PubMed
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.  Washington, DC American Psychiatric Association1994;
Kay  SRFiszbein  AOpler  LA The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr Bull 1987;13261- 276
PubMed
Guy  W ECDEU Assessment Manual for Psychopharmacology.  Washington, DC US Dept of Health, Education, and Welfare1976;
Beck  ATWard  CHMendelson  MMock  JErbaugh  J An inventory for measuring depression. Arch Gen Psychiatry 1961;4561- 571
PubMed
Oldfield  RC The assessment and analysis of handedness: the Edinburgh Inventory. Neuropsychologia 1971;997- 113
PubMed
Rohan  MLKillgore  WDSEskesen  JGRenshaw  PFYurgelun-Todd  DA Match-Warped EPI Anatomic Images and the Amygdala: Locating Activation in Hard Places.  Glasgow, Scotland International Society for Magnetic Resonance in Medicine2001;1237
Jezzard  PBalaban  RS Correction for geometric distortion in echo planar images from B0 field variations. Magn Reson Med 1995;3465- 73
PubMed
Weiss  APDewitt  IGoff  DDitman  THeckers  S Anterior and posterior hippocampal volumes in schizophrenia. Schizophr Res 2005;73103- 112
PubMed
Smith  SMJenkinson  MWoolrich  MWBeckmann  CFBehrens  TEJohansen-Berg  HBannister  PRDe Luca  MDrobnjak  IFlitney  DENiazy  RKSaunders  JVickers  JZhang  YDe Stefano  NBrady  JMMatthews  PM Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage 2004;23 ((suppl 1)) S208- S219
PubMed
Woolrich  MWBehrens  TEBeckmann  CFJenkinson  MSmith  SM Multilevel linear modelling for fMRI group analysis using bayesian inference. Neuroimage 2004;211732- 1747
PubMed
Cusack  RBrett  MOsswald  K An evaluation of the use of magnetic field maps to undistort echo-planar images. Neuroimage 2003;18127- 142
PubMed
Talairach  JTournoux  P Co-planar Sterotactic Atlas of the Human Brain.  New York, NY Thieme Medical Publishers Inc1988;
Boecker  HDagher  ACeballos-Baumann  AOPassingham  RESamuel  MFriston  KJPoline  JDettmers  CConrad  BBrooks  DJ Role of the human rostral supplementary motor area and the basal ganglia in motor sequence control: investigations with H215O PET. J Neurophysiol 1998;791070- 1080
PubMed
Hikosaka  OSakai  KMiyauchi  STakino  RSasaki  YPutz  B Activation of human presupplementary motor area in learning of sequential procedures: a functional MRI study. J Neurophysiol 1996;76617- 621
PubMed
Sakai  KHikosaka  OMiyauchi  SSasaki  YFujimaki  NPutz  B Presupplementary motor area activation during sequence learning reflects visuo-motor association. J Neurosci 1999;19RC1
PubMed
Yücel  MPantelis  CStuart  GWWood  SJMaruff  PVelakoulis  DPipingas  ACrowe  SFTochon-Danguy  HJEgan  GF Anterior cingulate activation during Stroop task performance: a PET to MRI coregistration study of individual patients with schizophrenia. Am J Psychiatry 2002;159251- 254
PubMed
Heckers  SWeiss  APDeckersbach  TGoff  DCMorecraft  RJBush  G Anterior cingulate cortex activation during cognitive interference in schizophrenia. Am J Psychiatry 2004;161707- 715
PubMed
Seltzer  BPandya  DN Further observations on parieto-temporal connections in the rhesus monkey. Exp Brain Res 1984;55301- 312
PubMed
Mesulam  M-Med Principles of Behavioral Neurology. 2nd New York, NY Oxford University Press Inc2000;
Pinel  PDehaene  SRiviere  DLeBihan  D Modulation of parietal activation by semantic distance in a number comparison task. Neuroimage 2001;141013- 1026
PubMed
Wharton  CMGrafman  JFlitman  SSHansen  EKBrauner  JMarks  AHonda  M Toward neuroanatomical models of analogy: a positron emission tomography study of analogical mapping. Cognit Psychol 2000;40173- 197
PubMed
Platt  MLGlimcher  PW Neural correlates of decision variables in parietal cortex. Nature 1999;400233- 238
PubMed
Behrmann  MGeng  JJShomstein  S Parietal cortex and attention. Curr Opin Neurobiol 2004;14212- 217
PubMed
Pearlson  GDPetty  RGRoss  CATien  AY Schizophrenia: a disease of heteromodal association cortex? Neuropsychopharmacology 1996;141- 17
PubMed
Manoach  DSHalpern  EFKramer  TSChang  YGoff  DCRauch  SLKennedy  DNGollub  RL Test-retest reliability of a functional MRI working memory paradigm in normal and schizophrenic subjects. Am J Psychiatry 2001;158955- 958
PubMed
Ojeda  NOrtuno  FArbizu  JLopez  PMarti-Climent  JMPenuelas  ICervera-Enguix  S Functional neuroanatomy of sustained attention in schizophrenia: contribution of parietal cortices. Hum Brain Mapp 2002;17116- 130
PubMed
Paulus  MPHozack  NEZauscher  BEFrank  LGrown  GGMcDowell  JBraff  DL Parietal dysfunction is associated with increased outcome-related decision-making in schizophrenia patients. Biol Psychiatry 2002;51995- 1004
PubMed
Quintana  JWong  TOrtiz-Portillo  EKovalik  EDavidson  TMarder  SRMazziotta  JC Prefrontal-posterior parietal networks in schizophrenia: primary dysfunctions and secondary compensations. Biol Psychiatry 2003;5312- 24
PubMed
Danckert  JSaoud  MMaruff  P Attention, motor control and motor imagery in schizophrenia: implications for the role of the parietal cortex. Schizophr Res 2004;70241- 261
PubMed
Spence  SABrooks  DJHirsch  SRLiddle  PFMeehan  JGrasby  PMA PET study of voluntary movement in schizophrenic patients experiencing passivity phenomena (delusions of alien control). Brain 1997;1201997- 2011
PubMed
Blakemore  SJOakley  DAFrith  CD Delusions of alien control in the normal brain. Neuropsychologia 2003;411058- 1067
PubMed
Northoff  G Neuroimaging and neurophysiology. In:Caroff  SNMann  SCFrancis  AFricchione  GLeds.Catatonia: From Psychopathology to Neurobiology. Washington, DC American Psychiatric Publishing Inc2004;77- 91
Heckers  S Neuroimaging studies of the hippocampus in schizophrenia. Hippocampus 2001;11520- 528
PubMed
Heckers  SRauch  SLGoff  DSavage  CRSchacter  DLFischman  AJAlpert  NM Impaired recruitment of the hippocampus during conscious recollection in schizophrenia. Nat Neurosci 1998;1318- 323
PubMed
Ragland  JDGur  RCRaz  JSchroeder  LKohler  CGSmith  RJAlavi  AGur  RE Effect of schizophrenia on frontotemporal activity during word encoding and recognition: a PET cerebral blood flow study. Am J Psychiatry 2001;1581114- 1125
PubMed
Eyler Zorrilla  LTJeste  DVPaulus  MBrown  GG Functional abnormalities of medial temporal cortex during novel picture learning among patients with chronic schizophrenia. Schizophr Res 2003;59187- 198
PubMed
Weiss  APSchacter  DLGoff  DCRauch  SLAlpert  NMFischman  AJHeckers  S Impaired hippocampal recruitment during normal modulation of memory performance in schizophrenia. Biol Psychiatry 2003;5348- 55
PubMed
Hofer  AWeiss  EMGolaszewski  SMSiedentopf  CMBrinkhoff  CKremser  CFelber  SFleischhacker  WW An fMRI study of episodic encoding and recognition of words in patients with schizophrenia in remission. Am J Psychiatry 2003;160911- 918
PubMed
Weiss  APZalesak  MDeWitt  IGoff  DKunkel  LHeckers  S Impaired hippocampal function during the detection of novel words in schizophrenia. Biol Psychiatry 2004;55668- 675
PubMed
Benes  FMBerretta  S Gabaergic interneurons: implications for understanding schizophrenia and bipolar disorder. Neuropsychopharmacology 2001;251- 27
PubMed
Harrison  PJ The hippocampus in schizophrenia: a review of the neuropathological evidence and its pathophysiological implications. Psychopharmacology (Berl) 2004;174151- 162
Greene  R Circuit analysis of NMDAR hypofunction in the hippocampus, in vitro, and psychosis of schizophrenia. Hippocampus 2001;11569- 577
PubMed
Buchanan  RWDavis  MGoff  DGreen  MFKeefe  RSLeon  ACNuechterlein  KHLaughren  TLevin  RStover  EFenton  WMarder  SR A summary of the FDA-NIMH-MATRICS workshop on clinical trial design for neurocognitive drugs for schizophrenia. Schizophr Bull 2005;315- 19
PubMed
Aylward  EWalker  EBettes  B Intelligence in schizophrenia: meta-analysis of the research. Schizophr Bull 1984;10430- 459
PubMed
Wright  ICRabe-Hesketh  SWoodruff  PWDavid  ASMurray  RMBullmore  ET Meta-analysis of regional brain volumes in schizophrenia. Am J Psychiatry 2000;15716- 25
PubMed
Carter  CSBraver  TSBarch  DMBotvinick  MMNoll  DCohen  JD Anterior cingulate cortex, error detection, and the online monitoring of performance. Science 1998;280747- 749
PubMed
Freeman  DGarety  PAKuipers  EFowler  DBebbington  PE A cognitive model of persecutory delusions. Br J Clin Psychol 2002;41331- 347
PubMed
Hyman  SEFenton  WS Medicine: what are the right targets for psychopharmacology? Science 2003;299350- 351
PubMed
Van Elzakker  MO’Reilly  RCRudy  JW Transitivity, flexibility, conjunctive representations, and the hippocampus, I: an empirical analysis. Hippocampus 2003;13334- 340
PubMed

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