Neural Changes Associated With Relational ... - Semantic Scholar

Schizophrenia Bulletin vol. 36 no. 3 pp. 496–503, 2010 doi:10.1093/schbul/sbq037 Advance Access publication on April 23, 2010

Neural Changes Associated With Relational Learning in Schizophrenia

Laura M. Rowland*,1, Jacqueline A. Griego2, Elena A. Spieker1, Carlos R. Cortes1, and Henry H. Holcomb1,3 1

Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21228; Institute for Cognitive Science, University of Osnabru¨ck, 49076 Osnabruck, Germany; 3Department of Psychiatry, Johns Hopkins University, Baltimore, MD 21287 2

*To whom correspondence should be addressed; Maryland Psychiatric Research Center, PO Box 21247, Baltimore, MD 21228, USA; tel: 410-402-6803, fax: 410-402-6077, e-mail: [email protected].

provided with training, subjects with schizophrenia can successfully learn a relational learning paradigm called transverse patterning (TP).8 TP is equivalent to the childhood game ‘‘rock, paper, and scissors’’ that requires one to learn the relationship among 3 items.9 TP depends upon intact medial temporal lobe (MTL) function as illustrated by animal and human studies (ie, rodents,10 primates,11,12 and humans13,14). One functional magnetic resonance imaging (fMRI) study reported impaired performance and abnormal hippocampal and parietal activation during a relational learning task in schizophrenia.7 However, little is known about the neural changes that occur with successful relational learning in schizophrenia. This study investigated neural changes with fMRI before and following training on the relational learning paradigm TP in schizophrenia and healthy subjects. It is important to note that healthy subjects can achieve at least 80% accuracy on the TP task without training15 but subjects with schizophrenia cannot.8 Achieving this level of accuracy is necessary to ensure that subjects are learning the entire TP problem and not a subset. It was hypothesized that (1) subjects with schizophrenia would not show fMRI MTL and parietal activations during the TP condition pretraining but would following training and (2) control subjects would show fMRI MTL and parietal activations both pretraining and posttraining. This is the first study to report on neural changes associated with relational learning training in subjects with and without schizophrenia.

Relational learning, which is learning the relationship among items, is impaired in schizophrenia but can be improved with training. This study investigated neural changes with functional magnetic resonance imaging before and after training on a relational learning task in schizophrenia and healthy control subjects. Despite their acquiring similar relational learning performance, the groups exhibited different neural activation patterns before and following training. Controls engaged regions within the relational learning network that included frontal, parietal, and medial temporal lobe, before and following training. Controls also exhibited activation reductions in region and spatial extent with relational learning proficiency, a commonly observed phenomenon in successful learning. In contrast, subjects with schizophrenia displayed no positive activations compared with the control condition before training. After training, subjects with schizophrenia displayed bilateral inferior parietal region activation as predicted. Contrary to hypothesis, hippocampal activation was not observed following training in schizophrenia. These findings suggest that the parietal lobe may be receptive to cognitive training interventions and that successful relational learning may be achieved in schizophrenia through the use of alternative extrahippocampal brain regions. Key words: fMRI/hippocampus/training/transverse patterning/brain/relational memory

Introduction Learning and memory processes are particularly impaired in schizophrenia and are predictors of psychosocial function.1,2 Emerging evidence suggests that memory improvement in schizophrenia can be achieved with training or cognitive remediation strategies.3–5 Relational learning is described as learning the relationship among items and is impaired in schizophrenia.6,7 However, when

Method Subjects Seventeen outpatients with schizophrenia treated with antipsychotic medication and 17 healthy volunteers participated in this study. The inclusion/exclusion criteria for volunteers with schizophrenia were: (1) diagnosis of

Ó The Author 2010. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: [email protected].

496

Relational Learning in Schizophrenia

schizophrenia as determined with the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), Patient Version (SCID-P16), (2) no current or past neurological condition, (3) no DSM-IV substance abuse or dependence (other than nicotine) in the last 6 months, (4) clinically stable as determined by their treatment psychiatrist, (5) same type and dose antipsychotic for at least 3 months, and (6) right-handed. The inclusion/exclusion criteria for healthy volunteers were: (1) no past or present psychiatric disorder as determined with the Structured Clinical Interview for DSM-IV, Non-Patient Version (SCID-NP16), (2) no first-degree relatives with a diagnosis of a psychotic disorder, (3) no current or past neurological condition, (4) no DSM-IV substance abuse or dependence (other than nicotine) in the last 6 months, and (5) right-handed. Volunteers with schizophrenia were evaluated for their ability to provide informed consent before signing consent documents. All subjects gave written informed consent prior to participation in the study. This study was approved by the University of Maryland and Johns Hopkins University Internal Review Committees. Course of Events This study was conducted over 4 sessions. Psychiatric and neuropsychological assessments were conducted during session 1. Session 2 consisted of the first ‘‘pretraining’’ fMRI scan, session 3 consisted of behavioral TP training, and session 4 consisted of the second ‘‘posttraining’’ fMRI scan. Magnetic resonance (MR) scanning sessions took approximately 1 h and were approximately 1 week apart (mean = 7 days, standard deviation = 1) with the training session falling in between (mean = 3 days before second scan, standard deviation = 1). Patients were evaluated for psychopathology with the Brief Psychiatric Rating Scale (BPRS17) and the Scale for the Assessment of Negative Symptoms (SANS18). All subjects completed the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS19) as a measure of general cognitive function. Subjects were monetarily compensated for their time. Behavioral Task For the relational learning TP condition, subjects learned the relationship between 3 pairs of overlapping stimuli (eg, A > B, B > C, C > A); and for the nonrelational learning simple discrimination (SD) condition, subjects learned which item in the pair was correct for 3 pairs of nonoverlapping stimuli (eg, D > E, F > G, H > I). Training The training procedures are similar to previously described animal and human studies10,15,20 where the 2 conditions, TP and SD, were administered in a stepwise fashion. Subjects completed 6 phases. Phases 1–3 pertained to the SD condition and phases 4–6 pertained to the TP condition. Trials were presented in blocks

that contained 16 trials ‘‘per pair.’’ Advancement to the next phase required the subject to score 13 out of 16 correct responses per pair within a block. This criterion was important to ensure subjects were learning the entire problem and not a subset of it. A maximum of 10 blocks per phase was allowed. For phases 1 and 4 which included 1 pair, the maximum number of trials was 160; for phases 2 and 5 which included 2 pairs, the maximum number of trials was 320; and phases 3 and 6 which included 3 pairs, the maximum number of trials was 480. The last phase 6 of TP is considered hippocampal dependent. The computerized task was created with EPRIME software (Psychology Software Tools, Inc, Pittsburg, PA). See figure 1 for illustration. MR Scanning MR scanning was conducted on a 3-T Philips Intera with an 8-channel SENSE head coil at the FM Kirby Imaging Center, Kennedy Krieger Institutes, Johns Hopkins Medical Institutes (Philips Medical Systems, Best, The Netherlands). FMRI was acquired with single-shot gradient echo, echo-planar imaging. Volumes were obtained with ascending oblique slices parallel to the hippocampal axis (repetition time = 2.3 s, echo time = 30, flip angle = 70, slice thickness = 2.5, gap = 0.5, slices = 44, and field of view = 240 3 240). Slice thickness and orientation were chosen to optimize the signal obtained from the hippocampus. The imaging protocol consisted of fMRI scans during initial TP learning (ie, pretraining) and following training (posttraining). Due to the nature of the task, TP and SD events must be presented in groups to facilitate learning. Therefore, an event-related design consisting of alternating groups of 12 events of TP and SD was used. A trial started with a presentation of a stimulus pair for 2.5 s, followed by a response opportunity window that was pseudorandomly jittered at 1.5, 2, or 2.5 s where a fixation point was presented and ended with feedback of either a ‘‘O’’ for a correct response, an ‘‘X’’ for incorrect response, or a ‘‘?’’ for no response for 500 ms. Intertrial intervals were pseudorandomly jittered at 1.5, 2, or 2.5 s. Within each run, there were 36 TP tasks and 36 SD control trials, with occurrences of each type counterbalanced in a pseudorandom manner. The pretraining fMRI scan consisted of 4 runs totaling 144 trials per condition. The posttraining fMRI scan consisted of 3 runs totaling 108 trials per condition to allow for diffusion tensor imaging and proton magnetic resonance spectroscopy (1H-MRS) scanning not presented in this paper. Each fMRI time series was approximately 10 minutes long. Subjects were introduced to this task before the scan (during Visit 1) to ensure they understood the task procedures. Different stimuli were used for this introduction session. Analyses FMRI analyses were conducted with SPM2 (Wellcome Department of Cognitive Neurology, London, UK, 497

L. M. Rowland et al.

Fig. 1. Illustration of Task Conditions and Training. For a trial, one pair of stimuli is presented. The subject’s goal is to learn the correct item in each pair. A ‘‘þ’’ sign indicates the correct choice and a ‘‘’’ sign indicates an incorrect choice. The transverse patterning (TP) condition requires relational learning, whereby an item is correct or incorrect depending on the item it is paired with. The SD condition does not require relational learning. Training consisted of 6 phases, 1–3 for the SD condition and 4–6 for the TP condition. Trials were presented in blocks that contained 16 trials per pair. Advancement to the next phase required the subject to score 13 out of 16 correct responses per pair within a block. Phases 3 and 6 depict the full SD and TP task that were administered during the functional magnetic resonance imaging sessions.

http://www.fil.ion.ucl.ac.uk/spm/software/spm2). To allow for T1 equilibrium, the first 4 images (9.2 s) out of 306 were eliminated from analyses. Image preprocessing included correction for motion by coregistration to the first image in each series, correction for differences in slice acquisition times, normalization to a standard Montreal Neurological Institute template, and smoothed by convolution with a Gaussian kernel function (full width at half maximum = 10 mm). Data were analyzed with random effects using SPM2. The contrast [task – control, (TP-SD)] is presented. All within and between group comparisons were quantitatively assessed using dependent and independent t-tests, respectively. Statistical significance was set at P < .001, cluster extent size >10. Only correct trials were examined. Due to strong hypothesis regarding hippocampal involvement in relational learning, between group differences for blood oxygen level dependence (BOLD) activation within the whole hippocampus was examined with an region of interest (ROI) mask approach. The hippocampal mask was created with WFU_PickAtlas software toolbox21–23, and statistical significance was set at P < .005. In addition, the BOLD signal change was extracted from hippocampal ROIs (spherical, 5-mm radius) for each group using SPM2. Results Subject demographic and clinical characteristics are provided in table 1. As expected, volunteers with schizophre498

nia had fewer years of education (t(32) = 2.59, P < .05) and lower RBANS scores (t(32) = 2.33, P < .01) when compared with healthy controls. Covarying for these variables made no difference in the results presented in the following sections. There were no significant differences in age, gender, or ethnicity between groups (all P’s > .05). Behavior during fMRI Two 2 (group: schizophrenia, control) 3 2 (fMRI session: pretraining, posttraining) ANOVAs with repeated measures on fMRI session were conducted for TP and SD accuracies. There were no statistically significant interactions or group effects. There were significant main effects for fMRI session (TP: F(1,32) = 46.7, P < .05; SD: F(1,32) = 6.7, P < .05) indicating TP and SD performance improved from pretraining to posttraining averaged across groups. Simple effects analyses (Bonferronicorrected, alpha (significance) set to P < .0125) indicated that both groups significantly improved on the TP task with training (controls: t(16) = 3.5, P < .01, schizophrenia: t(16) = 7.1, P < .01), but only the schizophrenia group approached trend significance for improved performance on the SD task with training (schizophrenia: t(16) = 2.76, P = .014). Mean accuracy (standard deviation) during fMRI 1 for TP was schizophrenia: 63.2 (16.3), controls: 69.3 (18.4) and for SD was schizophrenia: 90.3 (14.7), controls: 95.4 (4.9). Means (standard deviations); during fMRI 2 for TP were schizophrenia: 82.0 (17.5), controls: 83.4 (18.3) and for SD were schizophrenia: 97.8 (4.8), controls: 96.5 (6.6).


Table 1. Subject Characteristics Schizophrenia (n = 17) Gender Male Female Age (years) Ethnicity Caucasian African American Asian

9 8 41.9 (11) 8 8 1

Control (n = 17)

9 8 40.8 (13.2) 10 6 1

Education (years)

13.2 (2.5)*

15.4 (2.7)

RBANS

89.8 (16.7)*

102.1 (13.8)

Psychiatric ratings SANS BPRS (total) BPRS (þ subscale) BPRS ( subscale) Level of function

28.7 (12.1) 31 (6.3) 8.4 (4.3) 8 (2.7) 24.2 (5.8)

Antipsychotic medications Olanzapine Risperidone Fluphenazine Clozapine Haloperidol Ziprasidone

2 6 3 4 1 1

Note: Mean (standard deviation). BPRS, Brief Psychiatric Rating Scale; RBANS, Repeatable Battery for the Assessment of Neuropsychological Status; SANS, Scale for the Assessment of Negative Symptoms. *P < .05 vs control.

FMRI Whole-brain fMRI results for pretraining and posttraining within and between groups are presented in table 2. Hippocampal ROI mask results for pretraining and posttraining within groups are presented in figure 2. Whole-Brain Analyses Within Groups. Results reveal different patterns of neural activation between groups in spite of similar performance. For controls, widespread activation in multiple regions within bilateral frontal, bilateral medial temporal, bilateral parietal, and right occipital lobes were present during the initial stages of TP learning. After training, only 4 regions in the right frontal, right temporal, and left parietal lobe were prominent. There were no significant negative activations in the control group. In contrast, subjects with schizophrenia had no significant positive activation during initial TP learning. However, there was a significant negative activation in the right inferior frontal gyrus, which may indicate that this region was more active during the control condition (SD) than the TP condition. Following training, bilateral parietal activation was prominent, and negative activations were observed in the left temporal and occipital lobes.

Whole-Brain Analyses between Groups. During initial TP learning, greater activation in right inferior frontal, right precentral gyrus, right inferior parietal, and left middle temporal regions was observed in the control compared with the schizophrenia group. Following training, greater activation in the right middle cingulate, right temporal, and left parietal regions was observed in the control compared with the schizophrenia group. Hippocampal Mask ROI Analyses. During initial TP learning, control compared with schizophrenia subjects revealed greater activation in the left posterior hippocampus. Control subjects exhibited a positive BOLD signal change, whereas schizophrenia subjects exhibited a negative BOLD signal change. Following training, control compared with schizophrenia subjects revealed greater activation in the right anterior hippocampus. Control subjects exhibited a positive BOLD signal change, whereas schizophrenia subjects exhibited a negative BOLD signal change. Discussion This study investigated the neural changes that occurred before and after training on the TP relational learning task in subjects with and without schizophrenia. Subjects with schizophrenia were not significantly different from control subjects with respect to relational learning performance before and following training. Despite similar relational learning performance, the groups exhibited different fMRI patterns before and after training. This study provides new evidence that successful relational learning in schizophrenia is accomplished through neural changes in brain regions different from that of healthy subjects. Importantly, subjects with schizophrenia accomplish relational learning through extrahippocampal brain regions. Different profiles of regional activation for subjects with and without schizophrenia in the pretraining and posttraining TP-SD contrast indicate different neural solutions to relational learning. The TP-SD contrast strongly reflects relational learning processes because those processes involved in perception, attention, discrimination, and motor response have been removed (ie, activations in SD). Healthy subjects engaged frontal, parietal, and medial temporal regions, which are part of a neural network commonly associated with relational learning.7,24–26 Activation in these regions was observed both pretraining and posttraining, but there were reductions in the spatial extent but enhanced regional specificity with learning. With respect to the frontal and parietal regions, multiple regions within these areas were engaged pretraining and these were reduced to one region in the right inferior frontal and one region in the left parietal (precuneus) posttraining. Such neural changes from a distributed to focal network are consistently reported across different types of learning.27–29 This likely reflects neural 499


Table 2. Whole-Brain Analysis Results Cluster Size (Voxel Number)

Brain Region

Z Score

Montreal Neurological Institute

4.56 3.26 4.1 3.41 3.45 4.02 3.55 3.33 3.98 3.3 3.87 3.43 3.86 3.92 3.51

50, 4, 40 20, 18, 52 50, 38, 6 40, 10, 26 6, 4, 28 32, 30, 4 12, 44, 2 12, 42, 2 8, 52, 12 8, 58, 38 8, 52, 12 38, 70, 34 10, 36, 28 14, 88, 2 34, 82, 2

Pretraining (Task - Control) Control group Positive activations

Right precentral gyrus Right precentral gyrus Right inferior frontal gyrus Right inferior frontal gyrus Left anterior cingulate gyrus Right insula Left posterior para/hippocampus Right posterior para/hippocampus Right precuneus Right precuneus Left precuneus Left inferior parietal Left posterior cingulate gyrus Right calcarine Right middle occipital gyrus

Negative activations Schizophrenia group Positive activations Negative activations Control vs schizophrenia

72 10 47 17 37 25 34 28 19 11 21 35 21 54 11 None

Right inferior frontal gyrus

None 114

4.14

48, 14, 16

Right inferior frontal gyrus Right inferior frontal gyrus Right inferior frontal gyrus Right precentral Right inferior parietal Left middle temporal gyrus

171 24 16 15 72 20 None

4.38 3.76 3.45 3.34 3.73 3.55

38, 10, 26 50, 30, 10 34, 30, 10 20, 18, 46 28, 62, 36 54, 32, 16

Right inferior frontal Right middle cingulate Left precuneus Right fusiform

16 10 33 32 None

3.72 3.38 3.77 4.12

26, 34, 6 10, 22, 44 8, 52, 58 32, 72, 16

Right inferior parietal Left inferior parietal Left superior temporal Left middle temporal Left superior occipital

44 10 85 29 14

3.83 3.39 4.08 3.56 4.08

38, 72, 50 24, 12, 18 44, 22, 2 52, 2, 20 8, 100, 12

Right middle cingulate Left precuneus Right fusiform Right inferior temporal gyrus

19 15 13 11

3.57 3.61 3.85 3.48

10, 6, 36 8, 54, 60 30, 70, 14 56, 56, 12

Schizophrenia vs control Posttraining (Task - Control) Control group Positive activations

Negative activations Schizophrenia group Positive activations Negative activations

Control vs schizophrenia

Schizophrenia vs control

changes associated with greater task precision and efficiency. With respect to the hippocampus, ROI analyses revealed that the left posterior hippocampus was engaged during early relational learning or pretraining, whereas the right anterior hippocampus was engaged during retrieval of relational information or posttraining. This is consistent with studies that report the posterior hippocampus involvement in encoding of relational informa500

None

tion30 and the anterior hippocampus involvement in the flexible retrieval of relational information.30–32 The distinction between posterior and anterior hippocampal activation could also be attributed to a different mnemonic process used pretraining vs posttraining. According to Giovanello et al,31 the posterior hippocampus is involved in ‘‘reinstatement of items’’ or ‘‘establishing a fixed perceptual representation,’’ processes that could


Fig. 2. Different Hippocampal Responses Before and After Relational Learning Training in Control and Schizophrenia Subjects. A. Before training: Left posterior hippocampal activation difference between control and schizophrenia groups (top) and percent signal change per group (bottom). Statistical threshold refers to voxel-based significance set at P < .005. B. After training: Right anterior hippocampal activation difference between control and schizophrenia groups (top) and percent signal change per group (bottom). Statistical threshold refers to voxel-based significance set at P < .005.

occur more often during pretraining, whereas the anterior hippocampus is involved in flexible retrieval of relational information which occurs more often posttraining after the relationship among the items has been successfully learned. The shift from the left to the right hemisphere may indicate that subjects used a linguistic strategy initially but then used a visualspatial strategy once relational learning became proficient. Unlike controls, subjects with schizophrenia did not follow the normal pattern of engaging a distributed network pretraining that narrowed to a smaller number of regions posttraining. This is consistent with previous studies showing increased activation following cognitive training in schizophrenia.5,33 Subjects with schizophrenia exhibited no positive activations pretraining but did exhibit a negative activation in the right inferior frontal region. This negative activation may reflect atypical frontal engagement during the SD condition. Inappropriate frontal activation is observed in persons with schizophrenia.34

By posttraining, subjects with schizophrenia exhibited positive activations in bilateral inferior parietal regions, a part of the relational learning network. Inferior parietal activation was also observed in healthy subjects but during pretraining. It is possible that TP training resulted in normalized inferior parietal activation in subjects with schizophrenia. Deficits in inferior parietal lobe function are reported in schizophrenia,35 but these results suggest that the inferior parietal lobe may be sensitive to cognitive training strategies in schizophrenia. Negative activations in lateral temporal and medial occipital regions were also observed posttraining, which may reflect greater engagement in the SD control condition. As expected there was no MTL activation pretraining. Contrary to hypothesis, hippocampal activation was not observed posttraining and did not ‘‘normalize’’ following training. This suggests that successful relational learning can be achieved through alternative brain networks that do not encompass the hippocampus. This is consistent with a case study reporting an amnesic with 501


extensive bilateral hippocampal damage who successfully learned TP problems that were based on semantic knowledge.36 He was successful at solving TP problems if he relied on known relations based on semantic knowledge and did not need to establish new relations among items. It is plausible that subjects with schizophrenia accomplished relational learning through the use of extrahippocampal brain regions. This seems likely because hippocampal abnormalities figure prominently in the pathophysiology of schizophrenia,37 and in a previous fMRI study, the hippocampus was not activated during a relational learning task and displayed a negative signal change similar to this study.7 The fMRI activation differences between controls and persons with schizophrenia may reflect different cognitive strategies. One strategy is based on learning the relationship among the items (ie, A beats B, B beats C, and C beats A), which is thought to be the predominant strategy for successful TP learning. A second strategy is learning the 6 possible configurations (ie, the winner positioned left or right in the pair) of the stimuli associated with winning. This reduces the TP relational task to a SD task. Following the completion of the study, subjects were asked how they solved the task. Both groups reported solving the TP problem through learning the relationship among the items and not by memorizing the ‘‘winner’’ in each of the 6 possible pairs. Based on this anecdotal evidence, it appears that subjects with schizophrenia did not rely on strategies different from controls for successful relational learning. There are some study limitations worth mentioning. First, the effect of antipsychotic medication on neural patterns in schizophrenia is not known. It is possible that altered brain activation observed in this study is due to a medication effect. Future studies investigating neural changes during relational learning in subjects with schizophrenia off antipsychotic medications are necessary. Second, it is possible that the neural patterns in schizophrenia would normalize with additional extensive training beyond what this study provided. Future studies incorporating multiple training sessions over several weeks are necessary to determine whether this is the case. It is very difficult to pinpoint the roots of altered neural patterns in schizophrenia. But the dynamic neural interactions between presynaptic and postsynaptic neurons that characterize learning may well be disrupted by GABA-glutamate dysfunctions. The extensive literature documenting a crucial role for glutamatergic neurotransmission in learning may provide clues regarding defective in schizophrenia. N-methyl-D-aspartate receptor hypofunction may critically diminish long-term potentiation and inhibitory–excitatory cooperation in the neocortex. Compromised structural connections between brain regions could also play a role in the altered neural patterns observed in this study. Future studies using multiple imaging methods may provide a clear picture of this fun502

damental component and help resolve neural alterations in schizophrenia. This is the first study to investigate brain changes with successful relational learning in schizophrenia using training. These findings provide important implications for schizophrenia: (1) the parietal lobe may be receptive to cognitive training and (2) successful relational learning of a translational ‘‘hippocampal-dependent’’ task may be achieved through the use of alternative extrahippocampal brain regions. In summary, this study reveals that subjects with schizophrenia have neural changes with learning but in different brain circuits than healthy controls. With training intervention, some brain regions may normalize (eg, parietal), whereas others (eg, hippocampus) do not.

Funding National Institute for Mental Health (grant K01MH077230 to L.M.R.); National Alliance for Research on Schizophrenia and Depression young investigator award to L.M.R. Acknowledgments We thank the volunteers, especially the patients, for participating in the study. We thank Terri Brawner, Kathleen Kahl, and Ivana Kusevic for conducting the MR scans. We thank Drs Robert Astur, Robert Schwarcz, and Carol Tamminga for their valuable help and guidance.

References 1. Evans JD, Bond GR, Meyer PS, et al. Cognitive and clinical predictors of success in vocational rehabilitation in schizophrenia. Schizophr Res. 2004;70:331–342. 2. Green MF. What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry. 1996;153:321–330. 3. Adcock RA, Dale C, Fisher M, et al. When top-down meets bottom-up: auditory training enhances verbal memory in schizophrenia. Schizophr Bull. 2009;35:1132–1141. 4. Fisher M, Holland C, Merzenich MM, Vinogradov S. Using neuro-based auditory training to improve verbal memory in schizophrenia. Am J Psychiatry. 2009;166:805–811. 5. Wexler BE, Anderson M, Fulbright RK, Gore JC. Preliminary evidence of improved verbal working memory performance and normalization of task-related frontal-lobe activation in schizophrenia following cognitive exercises. Am J Psychiatry. 2000;157:1694–1697. 6. Titone D, Ditman T, Holzman PS, Eichenbaum H, Levy DL. Transitive inference in schizophrenia: impairments in relational memory organization. Schizophr Res. 2004;68:235–247. 7. Ongur D, Cullen TJ, Wolf DH, et al. The neural basis of relational memory deficits in schizophrenia. Arch Gen Psychiatry. 2006;63:356–365.


8. Rowland LM, Astur RS, Spieker EA, Holcomb HH. The impact of training on relational learning in schizophrenia. Schizophr Bull. 2007;33:539. 9. Spence KW. The nature of response in discrimination learning. Psychol Rev. 1952;59:89–93. 10. Alvarado MC, Rudy JW. Rats with damage to the hippocampal-formation are impaired on transverse-patterning problem but not on elemental discriminations. Behav Neurosci. 1995;109:204–211. 11. Alvarado MC, Bachevalier J. Selective neurotoxic damage to the hippocampal formation impairs performance of the transverse patterning and location memory tasks in rhesus macaques. Hippocampus. 2005;15:118–131. 12. Alvarado MC, Bachevalier J. Comparison of the effects of damage to the perirhinal and parahippocampal cortex on transverse patterning and location memory in rhesus macaques. J Neurosci. 2005;25:1599–1609. 13. Rickard TC, Grafman J. Losing their configural mind. Amnesic patients fail on transverse patterning. J Cogn Neurosci. 1998;10:509–524. 14. Rickard TC, Verfaellie M, Grafman J. Transverse patterning and human amnesia. J Cogn Neurosci. 2006;18:1723–1733. 15. Astur RS, Ortiz ML, Sutherland RJ. Configural learning in humans: the transverse patterning problem. Psychobiol. 1998;26:176–182. 16. First MB, Spitzer RL, Gibbon M, Williams JBW. Structured Clinical Interview for DSM-IV Axis I Disorders, Non-Patient Edition (SCID-NP), Version 2. New York: Biometrics Research Department, New York State Psychiatric Institute; 1995. 17. Overall JF, Gorham DR. The brief psychiatric rating scale. Psychol Rep. 1962;10:799–812. 18. Andreasen NC. The Scale for the Assessment of Negative Symptoms. Iowa City: University of Iowa; 1984. 19. Gold JM, Queern C, Iannone VN, Buchanan RW. Repeatable battery for the assessment of neuropsychological status as a screening test in schizophrenia I: sensitivity, reliability, and validity. Am J Psychiatry. 1999;156:1944–1950. 20. Driscoll I, Hamilton DA, Petropoulos H, et al. The aging hippocampus: cognitive, biochemical and structural findings. Cereb Cortex. 2003;12:1344–1351. 21. Lancaster JL, Summerlin JL, Rainey L, Freitas CS, Fox PT. The Talairach Daemon, a database server for Talairach atlas labels. Neuroimage. 1997;5:S633. 22. Lancaster JL, Woldorff MG, Parsons LM, et al. Automated Talairach atlas labels for functional brain mapping. Hum Brain Mapp. 2000;10:120–131. 23. Maldjian JA, Laurienti PJ, Kraft RA, Burdette JH. An automated method for neuroanatomic and cytoarchitectonic

24. 25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35. 36.

37.

atlas-based interrogation of fMRI data sets. Neuroimage. 2003;19:1233–1239. Astur RS, Constable RT. Hippocampal dampening during a relational memory task. Behav Neurosci. 2004;118:667–675. Heckers S, Zalesak M, Weiss AP, Ditman T, Titone D. Hippocampal activation during transitive inference in humans. Hippocampus. 2004;14:153–162. Meltzer JA, Negishi M, Constable RT. Biphasic hemodynamic responses influence deactivation and may mask activation in block-design fMRI paradigms. Hum Brain Mapp. 2008;29:385–399. Gould RL, Brown RG, Owen AM, Bullmore ET, Williams SSR, Howard RJ. Functional neuroanatomy of successful paired associate learning in Alzheimer’s disease. Am J Psychiatry. 2005;162:2049–2060. Rowland LM, Shadmehr R, Kravitz D, Holcomb HH. Neural changes during with motor skill learning in schizophrenia. Psychiatry Res: Neuroimaging. 2008;163:1–12. Sakai K, Hikosaka O, Miyauchi S, Takino R, Sasaki Y, Pu¨tz B. Transition of brain activation from frontal to parietal areas in visuomotor sequence learning. J Neurosci. 1998;18:1827– 1840. Chua E, Schacter DL, Rand-Giovennetti E, Sperling RA. Evidence for a specific role of the anterior hippocampal region in successful associative encoding. Hippocampus. 2007;17:1071–1080. Giovannello KS, Schnyer D, Verfaellie M. Distinct hippocampal regions make unique contributions to relational memory. Hippocampus. 2009;9:111–117. Preston AR, Shrager Y, Dudukovic NM, Gabrieli JDE. Hippocampal contribution to novel use of relational information in declarative memory. Hippocampus. 2002;14:148–152. Wykes F, Brammer M, Mellers J, et al. Effects on the brain of a psychological treatment: cognitive remediation therapy. Br J Psychiatry. 2002;181:144–152. Manoach DS. Prefrontal cortex dysfunction during working memory performance in schizophrenia: reconciling discrepant findings. Schizophr Res. 2003;60:285–298. Torrey EF. Schizophrenia and the inferior parietal lobule. Schizophr Res. 2007;97:215–225. Moses SN, Ostreicher ML, Rosenbaum RS, Ryan JD. Successful transverse patterning in amnesia using semantic knowledge. Hippocampus. 2008;18(2):121–124. Harrison PJ. The hippocampus in schizophrenia: a review of the neuropathological evidence and its pathophysiological implications. Psychopharmacology. 2004;174(1): 151–162.

503