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Neural correlates of derived relational responding on tests of stimulus equivalence

Neural correlates of derived relational responding on tests of stimulus equivalence Background: An essential component of cognition and language involves the formation of new conditional relations between stimuli based upon prior experiences. Results of investigations on transitive inference (TI) highlight a prominent role for the medial temporal lobe in maintaining associative relations among sequentially arranged stimuli (A > B > C > D > E). In this investigation, medial temporal lobe activity was assessed while subjects completed "Stimulus Equivalence" (SE) tests that required deriving conditional relations among stimuli within a class (A ≡ B ≡ C). Methods: Stimuli consisted of six consonant-vowel-consonant triads divided into two classes (A1, B1, C1; A2, B2, C2). A simultaneous matching-to-sample task and differential reinforcement were employed during pretraining to establish the conditional relations A1:B1 and B1:C1 in class 1 and A2:B2 and B2:C2 in class 2. During functional neuroimaging, recombined stimulus pairs were presented and subjects judged (yes/no) whether stimuli were related. SE tests involved presenting three different types of within-class pairs: Symmetrical (B1 A1; C1 B1; B2 A2; C2 B2), and Transitive (A1 C1; A2 C2) and Equivalence (C1 A1; C2 A2) relations separated by a nodal stimulus. Cross- class 'Foils' consisting of unrelated stimuli (e.g., A1 C2) were also presented. Results: Relative to cross-class Foils, Transitive and Equivalence relations requiring inferential judgments elicited bilateral activation in the anterior hippocampus while Symmetrical relations elicited activation in the parahippocampus. Relative to each derived relation, Foils generally elicited bilateral activation in the parahippocampus, as well as in frontal and parietal lobe regions. Conclusion: Activation observed in the hippocampus to nodal-dependent derived conditional relations (Transitive and Equivalence relations) highlights its involvement in maintaining relational structure and flexible memory expression among stimuli within a class (A ≡ B ≡ C). formances and successful functioning of humans, and Background Considerable evidence highlights a role for the hippocam- have previously been studied with serial transitive infer- pus in mediating our ability to derive relations among ence (TI) paradigms. While this type of derived relational stimuli [1-6] and maintaining representational flexibility responding [8] is ubiquitous in everyday life, it is also the [7]. These two skills underlie many types of complex per- focal point of many Stimulus Equivalence (SE) based clin- Page 1 of 8 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:6 http://www.behavioralandbrainfunctions.com/content/4/1/6 ical-educational interventions, which are designed to system or the autonomic system for at least 2 weeks, and teach children and individuals with cognitive dysfunction without a personal history of psychiatric disorder or a psy- conditional relations among dissimilar stimuli, such as chiatric history in first-degree relatives. Informed, written words, pictures and objects. For example, during SE train- consent was obtained from all subjects according to the ing an individual may learn that when presented the spo- institutional guidelines established by the Johns Hopkins ken word 'cat' (sample stimulus A1), selection of the Human Subjects Protection Committee. printed word "CAT" (comparison B1), but not the printed word "DOG" (comparison B2) produces reward. This dif- Experimental conditions ferential reinforcement procedure establishes the audi- Training tory-visual conditional relation A1:B1. With additional Behavioral training occurred approximately three hours training, a second visual-tactile conditional relation may before neuroimaging and lasted one hour. Figure 1 shows be established between the word "CAT" (sample B1) and the linear training structure (A-B-C) and the simultaneous the tactile properties of a real feline (comparison C1), rel- matching to sample (MTS) procedure used to establish a ative to a canine (comparison C2), resulting in the condi- set of class-specific 'premises'. On each trial, a sample tional relation B1:C1. Decades of basic and clinical stimulus was presented on the left side of a computer research has shown these trained 'premises' lay the foun- screen and two comparison stimuli presented on the right. dation for the emergence of several new conditional rela- Subjects were instructed that the sample stimulus was tions that include Symmetry (B1:A1 and C1:B1), 'related' to one of the two comparisons and the task was Transitivity (A1:C1), and Equivalence (C1:A1) ([9], but to discover the relation by choosing one comparison (see also see 8 for a different perspective). Thus, the resulting [13,14] for additional discussion of MTS procedures). stimulus class (A1 ≡ B1 ≡ C1) contains elements that are After comparison selection, feedback ('correct' or 'wrong') conditionally related, but not hierarchically or sequen- was provided. Two classes of stimuli were employed (des- tially related, which markedly differs from serially ordered ignated 1 and 2), with each class containing three conso- stimuli employed in TI paradigms (e.g., A > B > C > D > E) nant-vowel-consonant triads, such as XUR. For simplicity, stimuli within each class will be referenced with a letter- The present investigation coupled BOLD fMRI and a SE number combination (Class 1 = A1, B1, C1; Class 2 = A2, methodology to examine medial temporal lobe involve- B2, C2). Within each class, training established the condi- ment in derived relational responding. Findings relating tional relations as follows: A1:B1, A2:B2, B1:C1 and the involvement of SE in frontal-parietal and frontal-sub- B2:C2. Each conditional relation was trained individually cortical networks [10-12] would show consistency with in blocks of 20 trials until correct responding exceeded other investigations using TI tests [2,6] and offer an addi- 90% accuracy, typically within 2–3 blocks. Finally, sub- tional investigative tool for understanding complex learn- ing as well as the role of the hippocampus. However, medial temporal lobe involvement in SE has been elusive, but may be anticipated based on findings obtained using serial TI paradigms [3,6]. One potential reason prior investigations have not observed medial temporal lobe involvement particularly in the hippocampus, is that the baseline comparator conditions used also contained a for- mal relation, such as matching two identical circles [10] or an explicit rule [2]. Consequently, both experimental and baseline conditions may have elicited similar levels of hippocampal activation. In the present investigation, a Behavior neuroima Figure 1al trainin ging g of premise pairs and SE testing during comparator condition was designed that consisted of Behavioral training of premise pairs and SE testing during unrelated or unpaired stimuli [3]. These 'Foils' were con- neuroimaging. The matching-to-sample pre-imaging proce- structed by recombining stimuli from different classes, dure used to establish four premise pairs in two distinct such as A1:C2. The hypothesis that derived relational classes (Class 1: A1:B1, B1:C1 and Class 2: A2:B2, B2:C2). responding would be mediated by the hippocampus was During functional neuroimaging, two stimuli were presented assessed by contrasting activation elicited by each derived (e.g., A2 C2) and subjects made yes/no judgments indicating relation to activation elicited by Foils. whether the stimuli were conditionally related. Within-class derived relations consisted of Symmetry (B A; C B), Transi- Methods tivity (A C) and Equivalence (C A) relations. Foils consisted Twenty healthy, right-handed adults participated. Sub- of unrelated cross-class stimulus pairs that were not condi- tionally related (e.g., A1 B2). jects reported being between 18 and 50 years of age, right handed, free of medications affecting the central nervous Page 2 of 8 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:6 http://www.behavioralandbrainfunctions.com/content/4/1/6 jects completed SE tests in which a block of 20 trials con- contiguous slices were obtained angled parallel to the tained the AB and BC premise pairs for each class intercommissural line. intermixed with the following derived relations: Symme- try (B1 A1; C1 B1; B2 A2; C2 B2), Transitivity (A1 C1; A2 Functional neuroimaging analyses C2) and Equivalence (C 1 A1; C 2 A2). No corrective feed- For a subject's imaging data to be included in the analysis, back was provided. For all subjects, response accuracy for head movement during the two functional runs was each AB and BC premise and each derived relation required to be limited to less than 2 mm. All preprocess- exceeded 90% correct. ing and data analyses were performed using statistical par- ametric mapping software, version 2 [15-18]. EPI images Neuroimaging were slice-timing corrected to adjust for the lag between SE tests were completed during two BOLD functional neu- slices during each TR, corrected for head motion during roimaging runs. On each trial, a stimulus pair was pre- scanning, and normalized to a standard template brain sented (e.g., A2 C2). Instructions described the stimulus from the Montreal Neurological Institute (MNI) to get all presentation, duration of trials, session length, and participants into the same space. After normalization, mm. EPI images were then explained that the goal of the task was to press the 'yes' voxels were resampled to 2 button if the stimulus pair were related and the 'no' but- spatially smoothed using a 6 mm full-width-half-maxi- ton if they were not. As shown in Figure 1, SE tests to mum (FWHM) Gaussian kernel. High pass filtering was assess derived relational responding involved presenting applied to the time series of EPI images to remove the low Symmetry, Transitivity and Equivalence relations. Because frequency drift in EPI signal and then subjected to a con- subjects received exposure to each derived relation prior ventional two-level analysis. At the first level, individual- to imaging, subsequent activation patterns were not asso- subject models were constructed in which a linear regres- ciated with acquisition, but rather with maintenance. sion analysis was performed between the observed event Medial temporal lobe involvement in such derived rela- related EPI signals and onset times of each derived rela- tional responding was assessed by contrasting activation tion (Symmetry, Transitivity, Equivalence) and the base- to derived relations relative to cross-class "Foils" con- line condition (Foils) associated with correct responding. structed using stimuli from Class 1 and Class 2, such as A1 Subsequent contrast images were produced by performing B2. Thus, the fundamental difference between derived voxel-wise comparisons between each derived relation relations and foils was the presence of an untrained con- and Foils. Contrast images were carried to a second 'ran- ditional relation. A total of 36 Symmetry, 36 Transitivity, dom effects' level and subjected to ANOVA. The thresh- 36 Equivalence and 30 Foil trials were presented. olds P < .005, uncorrected for multiple comparisons, and 20 contiguous voxels were employed. The location of vox- Functional neuroimaging task and acquisition parameters els with significant activation was summarized by their Subjects were placed in the scanner and handed a local maxima separated by at least 8 mm, and by convert- response box containing 'yes' and 'no' response buttons. Using an event related design, stimulus pairs were ran- domly presented for 2000 ms, followed by a blank screen averaging 3000 ms, which effectively 'jittered' stimulus presentations across time such that stimulus onsets were separated by an average of 5 s. Functional MRI images were obtained on a 3 T Philips MRI scanner while Eprime software controlled stimulus presentation rate and recorded timing and response data. Stimuli were pre- sented on a rear screen monitor viewed through a mirror anchored to a standard head coil. After an initial series of sagittal T1-weighted localizers, a set of oblique T1- weighted images, angled parallel to the intercommissural line, were gathered. The fMRI data were acquired at the Mean reaction t re Figure 2 lations and foil imes associated s with recognition of derived same slice locations. The T1 parameters were a repetition Mean reaction times associated with recognition of derived time (TR) of 500 ms and an estimation time (TE) of 11 relations and foils. Response accuracy for each subject to ms. Functional MRI data were gathered using a single-shot each derived relation and Foils exceeded 90%. Reaction echo planar imaging (EPI) sequence with a TR of 3000 ms, times were significantly faster to Transitive, Equivalence and a TE of 50 ms, and a 90-degree flip angle. The matrix size Symmetrical relations relative to Foils (P < .001) and signifi- was 64 × 64 and the field of view 24 cm, yielding voxels cantly faster to Transitive and Equivalence relations relative to Symmetrical relations (P < .05). measuring 3 × 3 mm in plane. Using these parameters, 43 Page 3 of 8 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:6 http://www.behavioralandbrainfunctions.com/content/4/1/6 Table 1: Regions differentially activated to derived relations relative to cross-class foils Talairach Contrast Region X Y Z Volume (mm3) Transitivity > Foils Left Posterior Cingulate -4 -47 23 22 Medial Frontal Gyrus -12 61 12 469 Medial Frontal Gyrus -2 60 -6 (469) Hippocampus -22 -14 -13 55 Superior Temporal Gyrus -53 -6 0 20 Middle Frontal Gyrus -32 41 -5 39 Superior Temporal Gyrus -40 17 -19 20 Right Anterior Cingulate 4 54 -1 (469) Superior Temporal Gyrus 48 -6 -6 69 Inferior Frontal Gyrus 51 42 -11 30 Medial Frontal Gyrus 14 51 7 22 Hippocampus 34 -12 -13 69 Equivalence > Foils Left Hippocampus -30 -16 -14 63 Middle Frontal Gyrus -30 42 -7 26 Middle Temporal Gyrus -38 -35 -3 29 Caudate Tail -32 -33 0 (29) Medial Frontal Gyrus -8 59 14 47 Medial Frontal Gyrus -10 58 -6 54 Right Anterior Cingulate 2 27 -8 45 Anterior Cingulate 4 5 -10 40 Medial Frontal Gyrus 6 60 -5 (54) Hippocampus 30 -18 -11 20 Symmetry > Foils Left Paracentral Lobule -6 -27 44 27 Medial Frontal Gyrus -16 43 14 29 Right Medial Frontal Gyrus 14 54 -6 64 Anterior Cingulate 4 41 0 27 Medial Frontal Gyrus 6 48 -6 (27) Parahippocampus 26 -35 -7 32 Medial Frontal Gyrus 18 51 5 27 Superior Frontal Gyrus 16 55 14 (27) () Denotes secondary local maxima within cluster ing the maxima coordinates from MNI to Talairach coor- sitive and Equivalence relations elicited bilateral activa- dinate space using linear transformations [19]. tion in the anterior hippocampus, which overlapped Coordinates were finally assigned neuroanatomic labels considerably (see insert), while Symmetrical relations using the Talairach Daemon [20] and Talairach atlas [21]. elicited activation in the nearby parahippocampus. These results suggest hippocampal involvement was limited to Results derived relations maintained by an intervening or nodal Behavioral stimulus (i.e., B1 and B2). For each subject, response accuracy exceeded 90% correct for each derived relation and Foils during neuroimaging. Foils > Derived contrasts Reaction times presented in Figure 2 reveal significantly Relative to derived relations, Foils did not elicit activation faster responding to Transitive, Equivalence and Symmet- in the hippocampus. Figure 3 shows Foils contrasted with rical relations relative to Foils (P < .001) and significantly Transitive and Equivalence relations elicited bilateral acti- faster responding to Transitive and Equivalence relations vation in the parahippocampus — no differences were relative to Symmetrical relations (P < .05). observed when contrasted with Symmetrical relations. Table 2 and Figure 4 also highlights considerable activa- Derived > Foils contrasts tion to Foils in dorsal, inferior, and medial frontal Table 1 highlights regions showing activation for each regions, inferior and superior parietal regions, and middle derived relation relative to Foils. Figure 3 shows that Tran- and superior temporal regions, as well as in the thalamus, Page 4 of 8 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:6 http://www.behavioralandbrainfunctions.com/content/4/1/6 Discussion The present findings highlighting activation in the hip- pocampus to nodal-dependent derived conditional rela- tions (Transitive and Equivalence relations) and activation in the parahippocampus to cross-class Foils is generally consistent with results obtained using serial TI paradigms [3,6]. Accordingly, the present findings offer additional support for human hippocampal involvement in maintaining relational structure and flexible memory expression [7]. In the serial TI paradigm subjects learn a sequence of over- lapping premise pairs (i.e., A > B > C > D > E) and infer- ence (B > D) rests on knowledge of stimulus order. Commonly there is one, sometimes two, tests of infer- ence. While prior investigations have shown hippocampal activation during inference, it remains unclear whether such findings are restricted to conditions involving serial learning. One argument offered against the serial TI para- digm as a test of inference is based on the grounds that it is an associative task with stimuli not falling along a linear dimension and inferences may be a function of a value transfer between and among the S+ and S- stimuli [23]. The results obtained in the present investigation using the SE paradigm appear to make some headway in clarifying Derived < > Foils contrasts with Figure 3 in the medial temporal lobe hippocampal involvement in maintaining relational Derived < > Foils contrasts within the medial temporal lobe. structure and inference. First, it was reassuring to observe The first row of statistical parametric maps highlights that hippocampal activation during Transitive relations (A:C) Symmetry relations (B:A; C:B) contrasted with Foils (i.e, which parallels results reported during TI tests (B > D). unrelated stimulus pairs, e.g. A1 C2) elicited activation within But in addition, we also observed hippocampal activation the right anterior parahippocampus, bordering the hippoc- during Equivalence relations (C:A). This finding demon- ampus, whereas Transitive (A:C) and Equivalence (C:A) rela- strates that hippocampal involvement is not dependent tions contrasted with Foils elicited bilateral activation within upon serial order within TI tasks and also that involve- a similar region of the anterior hippocampus. The second ment is independent of the linear A, B, C training we row of statistical parametric maps shows Foils contrasted employed. It is informative that Symmetry relations (B:A, Transitive (A:C) and Equivalence (C:A) relations elicited acti- vation in the parahippocampus. Corresponding plots for each C:B) did not elicit hippocampal activation. This finding contrast highlight parameter estimate differences. may clarify that hippocampal activation reported during TI tests does not occur more generally to presentations of novel relations, but rather, activation is restricted to rela- tions with intervening nodal stimuli. Lastly, prior investi- gations employing the serial TI paradigm have shown hippocampal activation during acquisition [6,12], with cerebellum, posterior cingulate and striatum. The differ- one study highlighting deactivation after learning was ences in the extent of activation presented in Figure 4 completed [4]. In contrast, we ensured there was accurate appears to correlate with the reaction times differences relational responding after training and prior to imaging. presented in Figure 2. The considerable amount of activa- Therefore, our findings highlighting hippocampal activa- tion observed to Foils relative to the derived relations, tion during neuroimaging suggests the region may play a especially for 'nodal' relations, suggests discriminating the role in maintenance. Whether this is restricted to our use absence of a conditional relation may recruit a similar set of stimulus classes remains unclear. Nevertheless, given of regions as discriminating the presence of a conditional the hypothesis that the hippocampus maintains relational relation, but to a significantly greater degree. This finding structure, it seems expected that the hippocampus would is not inconsistent with the idea that increased activation, show involvement after initial acquisition. particularly in frontal regions, reflects a conflict between an incorrect set of stimulus relations and a learned set of The application of SE paradigms holds the promise of stimulus relations [22]. opening up many new avenues of research on the role of Page 5 of 8 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:6 http://www.behavioralandbrainfunctions.com/content/4/1/6 Table 2: Regions differentially activated to cross-class foils relative to derived relations Talairach Contrast Region X Y Z Volume (mm 3) Foils > Symmetry Left Anterior lobe -12 -57 -22 122 Inferior Frontal Gyrus -46 24 15 140 Middle Frontal Gyrus -34 59 6 53 Inferior Parietal Lobule -48 -64 40 40 Postcentral Gyrus -59 -14 30 64 Posterior Lobe 0 -71 -25 243 Precuneus -16 -60 42 30 Middle Temporal Gyrus -51 -61 25 (91) Superior Temporal Gyrus -51 -54 14 91 Right Anterior lobe 2 -53 -9 97 Inferior Frontal Gyrus 55 19 23 (155) Medial Frontal Gyrus 8 12 47 393 Middle Frontal Gyrus 44 19 32 155 Insula 38 24 10 42 Middle Occipital Gyrus 42 -68 7 48 Lingual Gyrus 16 -76 -3 113 Inferior Parietal Lobule 51 -58 40 130 Postcentral Gyrus 38 -27 46 440 Posterior Lobe 4 -79 -20 (243) Precentral gyrus 44 -12 41 (440) Middle Temporal Gyrus 55 2 -29 32 Superior Temporal Gyrus 48 -37 6 27 Foils > Transitivity Left Cingulate -6 -10 39 52 Inferior Frontal Gyrus -30 22 6 (13448) Middle Frontal Gyrus -38 54 1 222 Lateral Globus Pallidus -14 6 2 29 Substania Nigra -10 -16 -9 288 Posterior Lobe 0 -69 -27 (10168) Lateral Posterior Nuc. -16 -21 14 22 Right Cingulate 8 -7 45 55 Medial Frontal Gyrus 14 -9 50 (55) Middle Frontal Gyrus 44 43 13 34 Midbrain 4 -20 -14 (288) Middle Occipital Gyrus 30 -71 15 28 Lingual Gyrus 16 -64 -5 10168 Pons 10 -42 -33 34 Posterior Lobe 38 -59 -19 (10168) Precentral Gyrus 38 -13 43 13448 Putamen 24 2 9 20 Middle Temporal Gyrus 48 -39 0 52 Superior Temporal Gyrus 63 -42 9 30 Ventral Lateral Nuc. 14 -13 10 (45) Pulvinar 16 -23 16 (45) Foils > Equivalence Left Anterior lobe -34 -51 -16 (42397) Caudate Body -12 8 7 (460) Caudate Head -12 15 -2 (460) Cingulate -2 -33 33 178 Middle Frontal Gyrus -40 53 5 423 Superior Frontal Gyrus -30 55 17 (423) Lateral Globus Pallidus -14 6 0 460 Midbrain -6 -24 -11 (1554) Paracentral Lobule -16 -31 48 65 Putamen -30 -17 0 26 Superior Temporal Gyrus -61 -44 17 123 Page 6 of 8 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:6 http://www.behavioralandbrainfunctions.com/content/4/1/6 Table 2: Regions differentially activated to cross-class foils relative to derived relations (Continued) Right Claustrum 30 -3 17 72 Inferior Frontal Gyrus 53 15 -6 48 Insula 34 -23 16 (66) Midbrain 6 -24 -6 1554 Inferior Occipital Gyrus 42 -76 -1 42397 Inferior Parietal Lobule 57 -40 22 (129) Posterior Cingulate 6 -40 24 (178) Putamen 18 10 0 288 Middle Temporal Gyrus 57 -62 12 23 Superior Temporal Gyrus 44 -25 5 268 Transverse Temporal Gyrus 53 -15 10 (268) () Denotes secondary local maxima within cluster the hippocampal complex in maintaining relational struc- maintaining relational structure the hippocampal com- ture, especially across different sensory modalities. In the plex may play a central role in assigning functional prop- Introduction, we provided an example of a clinically erties to stimuli that are conditionally related. If the based SE intervention used to establish derived relations hippocampal complex mediates relations among stimuli, among visual, auditory and tactile stimuli. There are no then changes in the functional properties of one stimulus barriers we see that would limit the inclusion of taste, tex- would be expected to propagate to other related stimuli ture or odor into a class. This cross-modal feature of the SE via the relational network. Numerous behavioral studies paradigm stands in marked contrast with contemporary employing extensions of the basic SE paradigm have suc- applications of serial TI paradigms where either necessity cessfully shown how the function of one stimulus in a or convention dictates the use of stimuli from the same class, e.g. A1, may be transferred to other stimuli in the sensory modality. It is also plausible to suggest that while class, such as B1 and C1 [24]. This process is known as "transfer of function" and illustrates how stimuli may acquire functional properties through the relational net- work without direct experience. Here is seems important to note that transfer of function occurs to stimuli that are physically dissimilar, consequently, transfer is not simply a matter of stimulus generalization, which depends upon stimuli sharing physical properties. Relatedly, numerous behavioral studies have also successfully shown how changing the function of one stimulus in a class can change the functional properties of other stimuli in the class [25]. This process is referred to as "transformation of function" (for a review on transfer and transformation see [26]). In sum, the results of the present investigation, and probable role of the hippocampal complex in transfer/ transformation of stimulus function, underscore the broad functionality of SE based preparations. New appli- cations of the SE methodology promises to extend neuro- science research on medial temporal lobe functioning and higher cognitive functioning, as well as provide new insights into the effectiveness of SE based clinical treat- ments. Differen Figure 4 tial activation to Foils relative to derived relations Differential activation to Foils relative to derived relations. Conclusion Three-dimensional renderings of activation to Foils con- Activation observed in the hippocampus to nodal- trasted with Symmetrical, Transitive and Equivalence rela- dependent derived conditional relations (Transitive and tions. Results highlight pronounced frontal and parietal Equivalence relations) highlights its involvement in activation to Foils relative to Transitive and Equivalence rela- maintaining relational structure and flexible memory tions. These considerable magnitude differences appear to expression among stimuli within a class (A ≡ B ≡ C). index conflict between recognition of incorrect stimulus rela- tions relative to recognition of correct derived stimulus rela- tions. Page 7 of 8 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:6 http://www.behavioralandbrainfunctions.com/content/4/1/6 22. Menon V, Mackenzie K, Rivera SM, Reiss AL: Prefrontal cortex Competing interests involvement in processing incorrect arithmetic equations: The author(s) declare that they have no competing inter- evidence from event-related fMRI. Hum Brain Mapp 2002, ests. 16:119-130. 23. Zentall TR, Clement TS: Simultaneous discrimination learning: Stimulus interactions. Anim Learn Behav 2001, 29:311-325. Authors' contributions 24. Perkins DR, Dougher MJ, Greenway DE: Contextual control by function and form of transfer of functions. J Exp Anal Behav MS, RH and MC were responsible for the fMRI design. 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Friston KJ, Ashburner J, Frith CD, Poline JB, Heather JD, Frackowiak "BioMed Central will be the most significant development for RSJ: Spatial registration and normalization of images. Human Brain Mapp 1995, 3:165-189. disseminating the results of biomedical researc h in our lifetime." 17. Friston KJ, Worsley KJ, Frackowiak RSJ: Statistical parametric Sir Paul Nurse, Cancer Research UK maps in functional imaging: A general linear approach [Abstract]. Human Brain Mapp 1995, 2:189-210. Your research papers will be: 18. Holmes AP, Friston KJ: Generalisability, random effects and available free of charge to the entire biomedical community population inference. NeuroImage: Abstracts of the 4th International peer reviewed and published immediately upon acceptance Conference on Functional Mapping of the Human Brain 1998, 7:S754. 19. The MNI brain and the talairach atlas [http://imaging.mrc- cited in PubMed and archived on PubMed Central cbu.cam.ac.uk/imaging/MniTalairach] yours — you keep the copyright 20. Talairch daemon client [http://www.talairach.org/daemon.html] 21. Talairach J, Tournoux P: Co-planar stereotaxic atlas of the BioMedcentral Submit your manuscript here: human brain. New York: Thieme; 1988. http://www.biomedcentral.com/info/publishing_adv.asp Page 8 of 8 (page number not for citation purposes) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Behavioral and Brain Functions Springer Journals

Neural correlates of derived relational responding on tests of stimulus equivalence

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Springer Journals
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Copyright © 2008 by Schlund et al; licensee BioMed Central Ltd.
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Biomedicine; Neurosciences; Neurology; Behavioral Therapy; Psychiatry
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Abstract

Background: An essential component of cognition and language involves the formation of new conditional relations between stimuli based upon prior experiences. Results of investigations on transitive inference (TI) highlight a prominent role for the medial temporal lobe in maintaining associative relations among sequentially arranged stimuli (A > B > C > D > E). In this investigation, medial temporal lobe activity was assessed while subjects completed "Stimulus Equivalence" (SE) tests that required deriving conditional relations among stimuli within a class (A ≡ B ≡ C). Methods: Stimuli consisted of six consonant-vowel-consonant triads divided into two classes (A1, B1, C1; A2, B2, C2). A simultaneous matching-to-sample task and differential reinforcement were employed during pretraining to establish the conditional relations A1:B1 and B1:C1 in class 1 and A2:B2 and B2:C2 in class 2. During functional neuroimaging, recombined stimulus pairs were presented and subjects judged (yes/no) whether stimuli were related. SE tests involved presenting three different types of within-class pairs: Symmetrical (B1 A1; C1 B1; B2 A2; C2 B2), and Transitive (A1 C1; A2 C2) and Equivalence (C1 A1; C2 A2) relations separated by a nodal stimulus. Cross- class 'Foils' consisting of unrelated stimuli (e.g., A1 C2) were also presented. Results: Relative to cross-class Foils, Transitive and Equivalence relations requiring inferential judgments elicited bilateral activation in the anterior hippocampus while Symmetrical relations elicited activation in the parahippocampus. Relative to each derived relation, Foils generally elicited bilateral activation in the parahippocampus, as well as in frontal and parietal lobe regions. Conclusion: Activation observed in the hippocampus to nodal-dependent derived conditional relations (Transitive and Equivalence relations) highlights its involvement in maintaining relational structure and flexible memory expression among stimuli within a class (A ≡ B ≡ C). formances and successful functioning of humans, and Background Considerable evidence highlights a role for the hippocam- have previously been studied with serial transitive infer- pus in mediating our ability to derive relations among ence (TI) paradigms. While this type of derived relational stimuli [1-6] and maintaining representational flexibility responding [8] is ubiquitous in everyday life, it is also the [7]. These two skills underlie many types of complex per- focal point of many Stimulus Equivalence (SE) based clin- Page 1 of 8 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:6 http://www.behavioralandbrainfunctions.com/content/4/1/6 ical-educational interventions, which are designed to system or the autonomic system for at least 2 weeks, and teach children and individuals with cognitive dysfunction without a personal history of psychiatric disorder or a psy- conditional relations among dissimilar stimuli, such as chiatric history in first-degree relatives. Informed, written words, pictures and objects. For example, during SE train- consent was obtained from all subjects according to the ing an individual may learn that when presented the spo- institutional guidelines established by the Johns Hopkins ken word 'cat' (sample stimulus A1), selection of the Human Subjects Protection Committee. printed word "CAT" (comparison B1), but not the printed word "DOG" (comparison B2) produces reward. This dif- Experimental conditions ferential reinforcement procedure establishes the audi- Training tory-visual conditional relation A1:B1. With additional Behavioral training occurred approximately three hours training, a second visual-tactile conditional relation may before neuroimaging and lasted one hour. Figure 1 shows be established between the word "CAT" (sample B1) and the linear training structure (A-B-C) and the simultaneous the tactile properties of a real feline (comparison C1), rel- matching to sample (MTS) procedure used to establish a ative to a canine (comparison C2), resulting in the condi- set of class-specific 'premises'. On each trial, a sample tional relation B1:C1. Decades of basic and clinical stimulus was presented on the left side of a computer research has shown these trained 'premises' lay the foun- screen and two comparison stimuli presented on the right. dation for the emergence of several new conditional rela- Subjects were instructed that the sample stimulus was tions that include Symmetry (B1:A1 and C1:B1), 'related' to one of the two comparisons and the task was Transitivity (A1:C1), and Equivalence (C1:A1) ([9], but to discover the relation by choosing one comparison (see also see 8 for a different perspective). Thus, the resulting [13,14] for additional discussion of MTS procedures). stimulus class (A1 ≡ B1 ≡ C1) contains elements that are After comparison selection, feedback ('correct' or 'wrong') conditionally related, but not hierarchically or sequen- was provided. Two classes of stimuli were employed (des- tially related, which markedly differs from serially ordered ignated 1 and 2), with each class containing three conso- stimuli employed in TI paradigms (e.g., A > B > C > D > E) nant-vowel-consonant triads, such as XUR. For simplicity, stimuli within each class will be referenced with a letter- The present investigation coupled BOLD fMRI and a SE number combination (Class 1 = A1, B1, C1; Class 2 = A2, methodology to examine medial temporal lobe involve- B2, C2). Within each class, training established the condi- ment in derived relational responding. Findings relating tional relations as follows: A1:B1, A2:B2, B1:C1 and the involvement of SE in frontal-parietal and frontal-sub- B2:C2. Each conditional relation was trained individually cortical networks [10-12] would show consistency with in blocks of 20 trials until correct responding exceeded other investigations using TI tests [2,6] and offer an addi- 90% accuracy, typically within 2–3 blocks. Finally, sub- tional investigative tool for understanding complex learn- ing as well as the role of the hippocampus. However, medial temporal lobe involvement in SE has been elusive, but may be anticipated based on findings obtained using serial TI paradigms [3,6]. One potential reason prior investigations have not observed medial temporal lobe involvement particularly in the hippocampus, is that the baseline comparator conditions used also contained a for- mal relation, such as matching two identical circles [10] or an explicit rule [2]. Consequently, both experimental and baseline conditions may have elicited similar levels of hippocampal activation. In the present investigation, a Behavior neuroima Figure 1al trainin ging g of premise pairs and SE testing during comparator condition was designed that consisted of Behavioral training of premise pairs and SE testing during unrelated or unpaired stimuli [3]. These 'Foils' were con- neuroimaging. The matching-to-sample pre-imaging proce- structed by recombining stimuli from different classes, dure used to establish four premise pairs in two distinct such as A1:C2. The hypothesis that derived relational classes (Class 1: A1:B1, B1:C1 and Class 2: A2:B2, B2:C2). responding would be mediated by the hippocampus was During functional neuroimaging, two stimuli were presented assessed by contrasting activation elicited by each derived (e.g., A2 C2) and subjects made yes/no judgments indicating relation to activation elicited by Foils. whether the stimuli were conditionally related. Within-class derived relations consisted of Symmetry (B A; C B), Transi- Methods tivity (A C) and Equivalence (C A) relations. Foils consisted Twenty healthy, right-handed adults participated. Sub- of unrelated cross-class stimulus pairs that were not condi- tionally related (e.g., A1 B2). jects reported being between 18 and 50 years of age, right handed, free of medications affecting the central nervous Page 2 of 8 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:6 http://www.behavioralandbrainfunctions.com/content/4/1/6 jects completed SE tests in which a block of 20 trials con- contiguous slices were obtained angled parallel to the tained the AB and BC premise pairs for each class intercommissural line. intermixed with the following derived relations: Symme- try (B1 A1; C1 B1; B2 A2; C2 B2), Transitivity (A1 C1; A2 Functional neuroimaging analyses C2) and Equivalence (C 1 A1; C 2 A2). No corrective feed- For a subject's imaging data to be included in the analysis, back was provided. For all subjects, response accuracy for head movement during the two functional runs was each AB and BC premise and each derived relation required to be limited to less than 2 mm. All preprocess- exceeded 90% correct. ing and data analyses were performed using statistical par- ametric mapping software, version 2 [15-18]. EPI images Neuroimaging were slice-timing corrected to adjust for the lag between SE tests were completed during two BOLD functional neu- slices during each TR, corrected for head motion during roimaging runs. On each trial, a stimulus pair was pre- scanning, and normalized to a standard template brain sented (e.g., A2 C2). Instructions described the stimulus from the Montreal Neurological Institute (MNI) to get all presentation, duration of trials, session length, and participants into the same space. After normalization, mm. EPI images were then explained that the goal of the task was to press the 'yes' voxels were resampled to 2 button if the stimulus pair were related and the 'no' but- spatially smoothed using a 6 mm full-width-half-maxi- ton if they were not. As shown in Figure 1, SE tests to mum (FWHM) Gaussian kernel. High pass filtering was assess derived relational responding involved presenting applied to the time series of EPI images to remove the low Symmetry, Transitivity and Equivalence relations. Because frequency drift in EPI signal and then subjected to a con- subjects received exposure to each derived relation prior ventional two-level analysis. At the first level, individual- to imaging, subsequent activation patterns were not asso- subject models were constructed in which a linear regres- ciated with acquisition, but rather with maintenance. sion analysis was performed between the observed event Medial temporal lobe involvement in such derived rela- related EPI signals and onset times of each derived rela- tional responding was assessed by contrasting activation tion (Symmetry, Transitivity, Equivalence) and the base- to derived relations relative to cross-class "Foils" con- line condition (Foils) associated with correct responding. structed using stimuli from Class 1 and Class 2, such as A1 Subsequent contrast images were produced by performing B2. Thus, the fundamental difference between derived voxel-wise comparisons between each derived relation relations and foils was the presence of an untrained con- and Foils. Contrast images were carried to a second 'ran- ditional relation. A total of 36 Symmetry, 36 Transitivity, dom effects' level and subjected to ANOVA. The thresh- 36 Equivalence and 30 Foil trials were presented. olds P < .005, uncorrected for multiple comparisons, and 20 contiguous voxels were employed. The location of vox- Functional neuroimaging task and acquisition parameters els with significant activation was summarized by their Subjects were placed in the scanner and handed a local maxima separated by at least 8 mm, and by convert- response box containing 'yes' and 'no' response buttons. Using an event related design, stimulus pairs were ran- domly presented for 2000 ms, followed by a blank screen averaging 3000 ms, which effectively 'jittered' stimulus presentations across time such that stimulus onsets were separated by an average of 5 s. Functional MRI images were obtained on a 3 T Philips MRI scanner while Eprime software controlled stimulus presentation rate and recorded timing and response data. Stimuli were pre- sented on a rear screen monitor viewed through a mirror anchored to a standard head coil. After an initial series of sagittal T1-weighted localizers, a set of oblique T1- weighted images, angled parallel to the intercommissural line, were gathered. The fMRI data were acquired at the Mean reaction t re Figure 2 lations and foil imes associated s with recognition of derived same slice locations. The T1 parameters were a repetition Mean reaction times associated with recognition of derived time (TR) of 500 ms and an estimation time (TE) of 11 relations and foils. Response accuracy for each subject to ms. Functional MRI data were gathered using a single-shot each derived relation and Foils exceeded 90%. Reaction echo planar imaging (EPI) sequence with a TR of 3000 ms, times were significantly faster to Transitive, Equivalence and a TE of 50 ms, and a 90-degree flip angle. The matrix size Symmetrical relations relative to Foils (P < .001) and signifi- was 64 × 64 and the field of view 24 cm, yielding voxels cantly faster to Transitive and Equivalence relations relative to Symmetrical relations (P < .05). measuring 3 × 3 mm in plane. Using these parameters, 43 Page 3 of 8 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:6 http://www.behavioralandbrainfunctions.com/content/4/1/6 Table 1: Regions differentially activated to derived relations relative to cross-class foils Talairach Contrast Region X Y Z Volume (mm3) Transitivity > Foils Left Posterior Cingulate -4 -47 23 22 Medial Frontal Gyrus -12 61 12 469 Medial Frontal Gyrus -2 60 -6 (469) Hippocampus -22 -14 -13 55 Superior Temporal Gyrus -53 -6 0 20 Middle Frontal Gyrus -32 41 -5 39 Superior Temporal Gyrus -40 17 -19 20 Right Anterior Cingulate 4 54 -1 (469) Superior Temporal Gyrus 48 -6 -6 69 Inferior Frontal Gyrus 51 42 -11 30 Medial Frontal Gyrus 14 51 7 22 Hippocampus 34 -12 -13 69 Equivalence > Foils Left Hippocampus -30 -16 -14 63 Middle Frontal Gyrus -30 42 -7 26 Middle Temporal Gyrus -38 -35 -3 29 Caudate Tail -32 -33 0 (29) Medial Frontal Gyrus -8 59 14 47 Medial Frontal Gyrus -10 58 -6 54 Right Anterior Cingulate 2 27 -8 45 Anterior Cingulate 4 5 -10 40 Medial Frontal Gyrus 6 60 -5 (54) Hippocampus 30 -18 -11 20 Symmetry > Foils Left Paracentral Lobule -6 -27 44 27 Medial Frontal Gyrus -16 43 14 29 Right Medial Frontal Gyrus 14 54 -6 64 Anterior Cingulate 4 41 0 27 Medial Frontal Gyrus 6 48 -6 (27) Parahippocampus 26 -35 -7 32 Medial Frontal Gyrus 18 51 5 27 Superior Frontal Gyrus 16 55 14 (27) () Denotes secondary local maxima within cluster ing the maxima coordinates from MNI to Talairach coor- sitive and Equivalence relations elicited bilateral activa- dinate space using linear transformations [19]. tion in the anterior hippocampus, which overlapped Coordinates were finally assigned neuroanatomic labels considerably (see insert), while Symmetrical relations using the Talairach Daemon [20] and Talairach atlas [21]. elicited activation in the nearby parahippocampus. These results suggest hippocampal involvement was limited to Results derived relations maintained by an intervening or nodal Behavioral stimulus (i.e., B1 and B2). For each subject, response accuracy exceeded 90% correct for each derived relation and Foils during neuroimaging. Foils > Derived contrasts Reaction times presented in Figure 2 reveal significantly Relative to derived relations, Foils did not elicit activation faster responding to Transitive, Equivalence and Symmet- in the hippocampus. Figure 3 shows Foils contrasted with rical relations relative to Foils (P < .001) and significantly Transitive and Equivalence relations elicited bilateral acti- faster responding to Transitive and Equivalence relations vation in the parahippocampus — no differences were relative to Symmetrical relations (P < .05). observed when contrasted with Symmetrical relations. Table 2 and Figure 4 also highlights considerable activa- Derived > Foils contrasts tion to Foils in dorsal, inferior, and medial frontal Table 1 highlights regions showing activation for each regions, inferior and superior parietal regions, and middle derived relation relative to Foils. Figure 3 shows that Tran- and superior temporal regions, as well as in the thalamus, Page 4 of 8 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:6 http://www.behavioralandbrainfunctions.com/content/4/1/6 Discussion The present findings highlighting activation in the hip- pocampus to nodal-dependent derived conditional rela- tions (Transitive and Equivalence relations) and activation in the parahippocampus to cross-class Foils is generally consistent with results obtained using serial TI paradigms [3,6]. Accordingly, the present findings offer additional support for human hippocampal involvement in maintaining relational structure and flexible memory expression [7]. In the serial TI paradigm subjects learn a sequence of over- lapping premise pairs (i.e., A > B > C > D > E) and infer- ence (B > D) rests on knowledge of stimulus order. Commonly there is one, sometimes two, tests of infer- ence. While prior investigations have shown hippocampal activation during inference, it remains unclear whether such findings are restricted to conditions involving serial learning. One argument offered against the serial TI para- digm as a test of inference is based on the grounds that it is an associative task with stimuli not falling along a linear dimension and inferences may be a function of a value transfer between and among the S+ and S- stimuli [23]. The results obtained in the present investigation using the SE paradigm appear to make some headway in clarifying Derived < > Foils contrasts with Figure 3 in the medial temporal lobe hippocampal involvement in maintaining relational Derived < > Foils contrasts within the medial temporal lobe. structure and inference. First, it was reassuring to observe The first row of statistical parametric maps highlights that hippocampal activation during Transitive relations (A:C) Symmetry relations (B:A; C:B) contrasted with Foils (i.e, which parallels results reported during TI tests (B > D). unrelated stimulus pairs, e.g. A1 C2) elicited activation within But in addition, we also observed hippocampal activation the right anterior parahippocampus, bordering the hippoc- during Equivalence relations (C:A). This finding demon- ampus, whereas Transitive (A:C) and Equivalence (C:A) rela- strates that hippocampal involvement is not dependent tions contrasted with Foils elicited bilateral activation within upon serial order within TI tasks and also that involve- a similar region of the anterior hippocampus. The second ment is independent of the linear A, B, C training we row of statistical parametric maps shows Foils contrasted employed. It is informative that Symmetry relations (B:A, Transitive (A:C) and Equivalence (C:A) relations elicited acti- vation in the parahippocampus. Corresponding plots for each C:B) did not elicit hippocampal activation. This finding contrast highlight parameter estimate differences. may clarify that hippocampal activation reported during TI tests does not occur more generally to presentations of novel relations, but rather, activation is restricted to rela- tions with intervening nodal stimuli. Lastly, prior investi- gations employing the serial TI paradigm have shown hippocampal activation during acquisition [6,12], with cerebellum, posterior cingulate and striatum. The differ- one study highlighting deactivation after learning was ences in the extent of activation presented in Figure 4 completed [4]. In contrast, we ensured there was accurate appears to correlate with the reaction times differences relational responding after training and prior to imaging. presented in Figure 2. The considerable amount of activa- Therefore, our findings highlighting hippocampal activa- tion observed to Foils relative to the derived relations, tion during neuroimaging suggests the region may play a especially for 'nodal' relations, suggests discriminating the role in maintenance. Whether this is restricted to our use absence of a conditional relation may recruit a similar set of stimulus classes remains unclear. Nevertheless, given of regions as discriminating the presence of a conditional the hypothesis that the hippocampus maintains relational relation, but to a significantly greater degree. This finding structure, it seems expected that the hippocampus would is not inconsistent with the idea that increased activation, show involvement after initial acquisition. particularly in frontal regions, reflects a conflict between an incorrect set of stimulus relations and a learned set of The application of SE paradigms holds the promise of stimulus relations [22]. opening up many new avenues of research on the role of Page 5 of 8 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:6 http://www.behavioralandbrainfunctions.com/content/4/1/6 Table 2: Regions differentially activated to cross-class foils relative to derived relations Talairach Contrast Region X Y Z Volume (mm 3) Foils > Symmetry Left Anterior lobe -12 -57 -22 122 Inferior Frontal Gyrus -46 24 15 140 Middle Frontal Gyrus -34 59 6 53 Inferior Parietal Lobule -48 -64 40 40 Postcentral Gyrus -59 -14 30 64 Posterior Lobe 0 -71 -25 243 Precuneus -16 -60 42 30 Middle Temporal Gyrus -51 -61 25 (91) Superior Temporal Gyrus -51 -54 14 91 Right Anterior lobe 2 -53 -9 97 Inferior Frontal Gyrus 55 19 23 (155) Medial Frontal Gyrus 8 12 47 393 Middle Frontal Gyrus 44 19 32 155 Insula 38 24 10 42 Middle Occipital Gyrus 42 -68 7 48 Lingual Gyrus 16 -76 -3 113 Inferior Parietal Lobule 51 -58 40 130 Postcentral Gyrus 38 -27 46 440 Posterior Lobe 4 -79 -20 (243) Precentral gyrus 44 -12 41 (440) Middle Temporal Gyrus 55 2 -29 32 Superior Temporal Gyrus 48 -37 6 27 Foils > Transitivity Left Cingulate -6 -10 39 52 Inferior Frontal Gyrus -30 22 6 (13448) Middle Frontal Gyrus -38 54 1 222 Lateral Globus Pallidus -14 6 2 29 Substania Nigra -10 -16 -9 288 Posterior Lobe 0 -69 -27 (10168) Lateral Posterior Nuc. -16 -21 14 22 Right Cingulate 8 -7 45 55 Medial Frontal Gyrus 14 -9 50 (55) Middle Frontal Gyrus 44 43 13 34 Midbrain 4 -20 -14 (288) Middle Occipital Gyrus 30 -71 15 28 Lingual Gyrus 16 -64 -5 10168 Pons 10 -42 -33 34 Posterior Lobe 38 -59 -19 (10168) Precentral Gyrus 38 -13 43 13448 Putamen 24 2 9 20 Middle Temporal Gyrus 48 -39 0 52 Superior Temporal Gyrus 63 -42 9 30 Ventral Lateral Nuc. 14 -13 10 (45) Pulvinar 16 -23 16 (45) Foils > Equivalence Left Anterior lobe -34 -51 -16 (42397) Caudate Body -12 8 7 (460) Caudate Head -12 15 -2 (460) Cingulate -2 -33 33 178 Middle Frontal Gyrus -40 53 5 423 Superior Frontal Gyrus -30 55 17 (423) Lateral Globus Pallidus -14 6 0 460 Midbrain -6 -24 -11 (1554) Paracentral Lobule -16 -31 48 65 Putamen -30 -17 0 26 Superior Temporal Gyrus -61 -44 17 123 Page 6 of 8 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:6 http://www.behavioralandbrainfunctions.com/content/4/1/6 Table 2: Regions differentially activated to cross-class foils relative to derived relations (Continued) Right Claustrum 30 -3 17 72 Inferior Frontal Gyrus 53 15 -6 48 Insula 34 -23 16 (66) Midbrain 6 -24 -6 1554 Inferior Occipital Gyrus 42 -76 -1 42397 Inferior Parietal Lobule 57 -40 22 (129) Posterior Cingulate 6 -40 24 (178) Putamen 18 10 0 288 Middle Temporal Gyrus 57 -62 12 23 Superior Temporal Gyrus 44 -25 5 268 Transverse Temporal Gyrus 53 -15 10 (268) () Denotes secondary local maxima within cluster the hippocampal complex in maintaining relational struc- maintaining relational structure the hippocampal com- ture, especially across different sensory modalities. In the plex may play a central role in assigning functional prop- Introduction, we provided an example of a clinically erties to stimuli that are conditionally related. If the based SE intervention used to establish derived relations hippocampal complex mediates relations among stimuli, among visual, auditory and tactile stimuli. There are no then changes in the functional properties of one stimulus barriers we see that would limit the inclusion of taste, tex- would be expected to propagate to other related stimuli ture or odor into a class. This cross-modal feature of the SE via the relational network. Numerous behavioral studies paradigm stands in marked contrast with contemporary employing extensions of the basic SE paradigm have suc- applications of serial TI paradigms where either necessity cessfully shown how the function of one stimulus in a or convention dictates the use of stimuli from the same class, e.g. A1, may be transferred to other stimuli in the sensory modality. It is also plausible to suggest that while class, such as B1 and C1 [24]. This process is known as "transfer of function" and illustrates how stimuli may acquire functional properties through the relational net- work without direct experience. Here is seems important to note that transfer of function occurs to stimuli that are physically dissimilar, consequently, transfer is not simply a matter of stimulus generalization, which depends upon stimuli sharing physical properties. Relatedly, numerous behavioral studies have also successfully shown how changing the function of one stimulus in a class can change the functional properties of other stimuli in the class [25]. This process is referred to as "transformation of function" (for a review on transfer and transformation see [26]). In sum, the results of the present investigation, and probable role of the hippocampal complex in transfer/ transformation of stimulus function, underscore the broad functionality of SE based preparations. New appli- cations of the SE methodology promises to extend neuro- science research on medial temporal lobe functioning and higher cognitive functioning, as well as provide new insights into the effectiveness of SE based clinical treat- ments. Differen Figure 4 tial activation to Foils relative to derived relations Differential activation to Foils relative to derived relations. Conclusion Three-dimensional renderings of activation to Foils con- Activation observed in the hippocampus to nodal- trasted with Symmetrical, Transitive and Equivalence rela- dependent derived conditional relations (Transitive and tions. Results highlight pronounced frontal and parietal Equivalence relations) highlights its involvement in activation to Foils relative to Transitive and Equivalence rela- maintaining relational structure and flexible memory tions. These considerable magnitude differences appear to expression among stimuli within a class (A ≡ B ≡ C). index conflict between recognition of incorrect stimulus rela- tions relative to recognition of correct derived stimulus rela- tions. Page 7 of 8 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:6 http://www.behavioralandbrainfunctions.com/content/4/1/6 22. Menon V, Mackenzie K, Rivera SM, Reiss AL: Prefrontal cortex Competing interests involvement in processing incorrect arithmetic equations: The author(s) declare that they have no competing inter- evidence from event-related fMRI. Hum Brain Mapp 2002, ests. 16:119-130. 23. Zentall TR, Clement TS: Simultaneous discrimination learning: Stimulus interactions. Anim Learn Behav 2001, 29:311-325. Authors' contributions 24. Perkins DR, Dougher MJ, Greenway DE: Contextual control by function and form of transfer of functions. J Exp Anal Behav MS, RH and MC were responsible for the fMRI design. 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The MNI brain and the talairach atlas [http://imaging.mrc- cited in PubMed and archived on PubMed Central cbu.cam.ac.uk/imaging/MniTalairach] yours — you keep the copyright 20. Talairch daemon client [http://www.talairach.org/daemon.html] 21. Talairach J, Tournoux P: Co-planar stereotaxic atlas of the BioMedcentral Submit your manuscript here: human brain. New York: Thieme; 1988. http://www.biomedcentral.com/info/publishing_adv.asp Page 8 of 8 (page number not for citation purposes)

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