Functional Magnetic Resonance Imaging Activity During the Gradual Acquisition and Expression of Paired-Associate Memory

5720 • The Journal of Neuroscience, June 15, 2005 • 25(24):5720–5729 Behavioral/Systems/Cognitive Functional Magnetic Resonance Imaging Activity during the Gradual Acquisition and Expression of Paired-Associate Memory Jon R. Law,1 Marci A. Flanery,1 Sylvia Wirth,2 Marianna Yanike,2 Anne C. Smith,3 Loren M. Frank,4 Wendy A. Suzuki,2 Emery N. Brown,5,6 and Craig E. L. Stark1 1Department of Psychological and Brain Sciences, Johns Hopkins University, Baltimore, Maryland 21218, 2Center for Neural Science, New York University, New York, New York 10003, 3Department of Anesthesiology and Pain Medicine, University of California, Davis, California 95616, 4W. M. Keck Center for Integrative Neuroscience, University of California, San Francisco, San Francisco, California 94143, 5Neuroscience Statistics Research Laboratory, Department of Anesthesia and Critical Care, Massachusetts General Hospital, Boston, Massachusetts 02114, and 6Division of Health Sciences and Technology, Harvard Medical School/Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 Recent neurophysiological findings from the monkey hippocampus showed dramatic changes in the firing rate of individual hippocampal cells as a function of learning new associations. To extend these findings to humans, we used blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to examine the patterns of brain activity during learning of an analogous associative task. We observed bilateral, monotonic increases in activity during learning not only in the hippocampus but also in the parahip- pocampal and right perirhinal cortices. In addition, activity related to simple novelty signals was observed throughout the medial temporal lobe (MTL) memory system and in several frontal regions. A contrasting pattern was observed in a frontoparietal network in which a high level of activity was sustained until the association was well learned, at which point the activity decreased to baseline. Thus, we found that associative learning in humans is accompanied by striking increases in BOLD fMRI activity throughout the MTL as well as in the cingulate cortex and frontal lobe, consistent with neurophysiological findings in the monkey hippocampus. The finding that both the hippocampus and surrounding MTL cortex exhibited similar associative learning and novelty signals argues strongly against the view that there is a clear division of labor in the MTL in which the hippocampus is essential for forming associations and the cortex is involved in novelty detection. A second experiment addressed a striking aspect of the data from the first experiment by demonstrating a substan- tial effect of baseline task difficulty on MTL activity capable of rendering mnemonic activity as either “positive” or “negative.” Key words: medial temporal lobe; hippocampus; recollection; associative; explicit; declarative Introduction tive learning task. In this task, one of four saccades was randomly Memory researchers have long known that structures within the associated with each of several visual scenes on a trial-and-error medial temporal lobe (MTL), including the hippocampal region basis (location–scene association task). Twenty-eight percent of (CA fields, dentate gyrus, and subiculum) and the parahip- the scene-selective hippocampal neurons exhibited changes in pocampal, perirhinal, and entorhinal cortices, are necessary for firing rate correlated with the animal’s behavioral performance normal declarative memory (for review, see Squire et al., 2004). for a particular location–scene association (changing cells). One- Arbitrary association learning is one category of declarative half of the changing cells showed a selective increase in activity memory that is particularly sensitive to selective damage of the that was positively correlated with learning (sustained changing MTL (for review, see Eichenbaum, 2000; Brown and Aggleton, cells), whereas the remaining cells responded selectively to a par- 2001). To explore the patterns of neural activity during arbitrary ticular scene before learning and subsequently signaled learning association learning, Wirth et al. (2003) recorded single-unit ac- by returning to baseline levels of activity (baseline sustained tivity in the hippocampus while monkeys performed an associa- changing cells). A functional magnetic resonance imaging (fMRI) study by Toni et al. (2001) used a similar associative learning task in hu- Received Dec. 3, 2004; revised May 2, 2005; accepted May 4, 2005. ThisworkwassupportedbygrantsfromtheNationalScienceFoundation(BCS-0236431toC.E.L.S.),theNational mans to suggest that these changes in neural activity translate to Institute on Drug Abuse (DA015644 to E.N.B. and W.A.S.), and the National Institute of Mental Health (MH59733 to an overall increase in activity within the hippocampal/parahip- W.A.S., MH61637 to E.N.B.) and by a McKnight Award (W.A.S.). We thank Yuriko Sonada and the staff of the F. M. pocampal region. However, because of its blocked design, Toni et Kirby Center for Functional Brain Imaging for their assistance in data collection. al. (2001) could only use an averaged learning curve rather than Correspondence should be addressed to Dr. Craig E. L. Stark, Department of Psychological and Brain Sciences, Johns Hopkins University, Ames Hall 204, 3400 North Charles Street, Baltimore, MD 21218. E-mail: [email protected]. one based on individual trial-by-trial accuracy as used by Wirth et DOI:10.1523/JNEUROSCI.4935-04.2005 al. (2003). Moreover, the relative patterns of activation within the Copyright © 2005 Society for Neuroscience 0270-6474/05/255720-10$15.00/0 individual MTL structures during learning were not described. Law et al. • fMRI during Gradual Learning of Associative Memory J. Neurosci., June 15, 2005 • 25(24):5720–5729 • 5721 Figure 1. Sample stimulus and schematic diagram of trial structure. To examine the activation patterns in individual MTL struc- the four squares as the associate for the kaleidoscope stimulus by pushing tures during new associative learning, we conducted an fMRI the button that corresponded with one of the four squares. Immediately study in which subjects performed an associative learning task after the response, the endorsed square was illuminated with a translu- similar to the one described by Wirth et al. (2003). To compare cent white box indicating which response had been recorded. Finally, 800 activity to individual learning curves, we used the same state– ms of feedback were presented, indicating whether the endorsed response had been correct, incorrect, or not made within the response space smoothing algorithm for binary observations used by window. Because only correct/incorrect feedback was displayed, the par- Wirth et al. (2003) to compute a trial-by-trial probability correct ticipant was encouraged to remember correct responses and to try an curve for individual subjects (Smith and Brown, 2003; Smith et alternate response after making an incorrect response. The total duration al., 2004). This allowed us to group the fMRI activity by the for a single trial was 3000 ms. probability that the participant would be correct on each individ- To provide a reference for the fMRI signal and to be able to create ual trial. In experiment 1, we examined both the learning-related hemodynamic response profiles for all trial types of interest, baseline changes in activity as well as simple novelty signals throughout (also referred to as null) trials were interspersed randomly throughout the individual MTL structures as well as in areas beyond the MTL. the experiment (Dale, 1999). Baseline trials were identical to the memory Consistent with findings that discrete MTL structures often con- trials, except that a fixed, random visual static pattern was presented tribute to various declarative memory tasks in a coordinated way instead of a kaleidoscope image. In addition, one of the four squares was (Squire et al., 2004), we hypothesized that similar increases in assigned randomly as the target on each trial and was filled with white at 50% opacity, indicating the correct response that the participant should activity would be observed throughout the MTL. Experiment 2 make during the response window. The stimuli remained on the screen was performed to address an unexpected finding from experi- until the response was recorded or the trial came to an end. Thus, these ment 1. In experiment 1, we observed less blood oxygenation baseline trials were chosen to induce zero mnemonic demand as well as level-dependent (BOLD) activity in the mnemonic paired- to provide a stable level of activity from trial to trial, and not necessarily associate task compared with the easy baseline task. In experi- define an assessment of “zero activity” (Stark and Squire, 2001a). ment 2, we addressed this issue by examining the effect of a more Experiment 2 examined the below-baseline activations observed in difficult baseline task. experiment 1 and, more broadly, the effect of different baseline tasks on interpreting fMRI results. It was therefore identical to experiment 1, Materials and Methods except that the baseline trials were divided into two categories, easy trials Participants. Written, informed consent was obtained with local Institu- and difficult trials, to investigate the effect of non-mnemonic task diffi- tional Review Board approval from 21 healthy, right-handed participants culty on MTL activity. One-half of the baseline trials involved a task (12 females and 7 males; age range, 18–33 years; mean

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