Article Event-Related fMRI of Frontotemporal Activity During Word Encoding and Recognition in Schizophrenia J. Daniel Ragland, Ph.D. Objective: Neuropsychological studies were reproduced, but patients showed have demonstrated verbal episodic mem- greater parahippocampal activation rather Ruben C. Gur, Ph.D. ory deficits in schizophrenia during word than deficits in temporal lobe activation. encoding and retrieval. This study exam- During recognition, left dorsolateral pre- ined neural substrates of memory in an frontal cortex activation was lower in the Jeffrey Valdez, M.S. analysis that controlled for successful patients and right anterior prefrontal cor- retrieval. tex activation was preserved, as in the au- Bruce I. Turetsky, M.D. Method: Event-related blood-oxygen- thors’ previous study using positron emis- level-dependent (BOLD) functional mag- sion tomography. Successful retrieval was Mark Elliott, Ph.D. netic resonance imaging (fMRI) was used associated with greater right dorsolateral to measure brain activation during word prefrontal cortex activation in the compar- Christian Kohler, M.D. encoding and recognition in 14 patients ison subjects, whereas orbitofrontal, supe- with schizophrenia and 15 healthy com- rior frontal, mesial temporal, middle tem- Steve Siegel, M.D., Ph.D. parison subjects. An unbiased multiple poral, and inferior parietal regions were linear regression procedure was used to more active in the patients during success- Stephen Kanes, M.D. model the BOLD response, and task ef- ful retrieval. fects were detected by contrasting the sig- Conclusions: The pattern of prefrontal Raquel E. Gur, M.D., Ph.D. nal before and after stimulus onset. cortex underactivation and parahippo- Results: Patients attended during encod- campal overactivation in the patients sug- ing and had unimpaired reaction times gests that functional connectivity of dor- and normal response biases during recog- solateral prefrontal and temporal-limbic nition, but they had lower recognition dis- structures is disrupted by schizophrenia. criminability scores, compared with the This disruption may be reflected in the healthy subjects. Analysis of contrasts was memory strategies of patients with schizo- restricted to correct items. Previous find- phrenia, which include reliance on rote re- ings of a deficit in bilateral prefrontal cor- hearsal rather than associative semantic tex activation during encoding in patients processing. (Am J Psychiatry 2004; 161:1004–1015) Problems in verbal episodic memory in schizophrenia subregions show functional overlap across working, epi- have been well described, and evidence of prominent sodic, and semantic memory (10, 11). The importance of difficulties in encoding and free recall has been found (1, the hippocampus to memory was established in early 2). Long-term storage is relatively spared (3), and less se- studies of clinical pathology and was supported by func- vere impairments are noted on nonrelational recognition tional imaging that attributed hippocampal function to tasks (4). encoding and retrieval, novelty detection, and successful The neural underpinnings of memory can be studied retrieval (12, 13). with functional neuroimaging. A review concluded that Several investigators suggested that the reciprocal rela- the prefrontal cortex and hippocampus are most consis- tionships between the prefrontal cortex and the mesial tently implicated in schizophrenia (5). Hemispheric asym- temporal lobe in normal cognition (14) may be disrupted metry models have emphasized the importance of the left or reversed by schizophrenia (15, 16). For example, in a prefrontal cortex to episodic encoding and semantic re- verbal fluency study, investigators reported less prefrontal trieval and the right prefrontal cortex to episodic retrieval cortex activation and greater temporal lobe activation in (6). Subsequent studies supported a distinct role for the patients than in healthy comparison subjects (17). Other right anterior prefrontal cortex (Brodmann’s area 10) dur- studies reported hippocampal overactivation in patients ing episodic retrieval but found less evidence of hemi- during baseline assessment and prefrontal cortex overac- spheric and task specificity for the dorsolateral prefrontal tivation rather than hippocampal recruitment for recogni- cortex (Brodmann’s area 9, 46) (7, 8). The left dorsolateral tion of words that had undergone deep semantic process- prefrontal cortex appears to be involved in semantic orga- ing versus words that had undergone shallow perceptual nization during encoding (9), and several prefrontal cortex processing (18, 19). A subsequent study of the hippo- 1004 http://ajp.psychiatryonline.org Am J Psychiatry 161:6, June 2004 RAGLAND, GUR, VALDEZ, ET AL. campus involving word encoding and recognition also more severe symptoms did not change the overall pattern of fMRI found less activation in patients than in healthy compari- results (analysis available upon request). All patients were receiv- son subjects during both stages of processing (20). ing medication; two patients received only typical antipsychotics, nine received only atypical antipsychotics, and three received The purpose of the current study was to examine fron- both typical and atypical antipsychotics. The average dose of typ- totemporal function in schizophrenia by using a verbal ical antipsychotics was 68.7 mg/day in chlorpromazine equiva- episodic encoding and recognition paradigm that was pre- lents (SD=26.6, range=0–250), and the average dose of atypical viously established with positron emission tomography antipsychotics was 14.6 mg/day in olanzapine equivalents (SD= 2.6, range=0–35.8). No patient was receiving anticholinergic med- (PET) (8, 21). In previous studies, we found reduced left ication. The patients’ mean age at illness onset was 20.5 years prefrontal cortex activation during encoding and recogni- (SD=4.9), and the mean duration of illness was 12.2 years (SD= tion in patients with schizophrenia. Left superior temporal 7.6). After complete description of the study to the subjects, writ- activity was also reduced during encoding, while activation ten informed consent was obtained. in the left anterior cingulate, left mesial temporal, and right Tasks thalamic regions was reduced during recognition. How- Images were acquired during three conditions: word encoding, ever, right anterior prefrontal cortex activation during rec- letter n-back, and word recognition. Letter n-back (28) served as a ognition was preserved. Performance correlated with pre- distracter to prevent rehearsal, and the results for this condition frontal cortex activation in healthy participants and with will not be reported. Encoding and recognition utilized the Penn posterior activation in patients. One goal of the present Word Recognition Test (8, 21), adapted for event-related fMRI. study was to establish the reproducibility of the PET find- The task consists of 30 targets and 30 foils from a standard word list (29) balanced for frequency, concreteness, and imageability. ings with functional magnetic resonance imaging (fMRI). Words were visually presented for 3 seconds, with “jittered” inter- More important, event-related fMRI enables examination stimulus intervals ranging from 1 to 13 seconds (Figure 1). During of retrieval success. We hypothesized that the left prefron- interstimulus intervals, the subjects were instructed to fixate on a tal cortex regions are disrupted by schizophrenia during crosshair image and told to relax. During encoding, targets were both encoding and recognition but that schizophrenia pa- presented twice in pseudorandom order for a total of 60 trials. Participants were asked to try to remember the words (explicit en- tients would not differ from healthy comparison subjects coding) and make a left button press every time a word was pre- in activation in the right frontal pole during recognition. sented. The recognition task used the same timing parameters Retrieval success was hypothesized to be related to pre- and also consisted of 60 trials with pseudorandom presentation frontal cortex activity only in the comparison subjects. of the 30 targets and 30 foils. Participants were asked to make a left button press if they had seen the word during the encoding task and a right button press if the word had not been previously Method presented. The tasks were triggered by the scanner and coupled to image acquisition by using Power Laboratory (30) on a Macin- Participants tosh laptop computer. Stimuli were rear projected to the center of Participants were 14 patients with schizophrenia and 15 the visual field by using a PowerLite 7300 video projector (Epson healthy comparison subjects from the Schizophrenia Center at America, Inc., Long Beach, Calif.) and viewed through a mirror the University of Pennsylvania. Both groups included six female mounted on the head coil. Responses were recorded by means of subjects. The patient group excluded one subject with excessive a nonferromagnetic keypad (FORP, Current Design Inc., Philadel- movement artifact (i.e., >4 mm in any dimension) and two sub- phia). Practice sessions were provided, and all participants un- jects who could not comply with the research procedure. The derstood the instructions and use of the keypad. comparison subjects were matched with the patients in age Image Acquisition (comparison subjects: mean age=28.4 years, SD=7.0; patients: mean age=32.7 years , SD=8.3), parental education (comparison Data were acquired on a 4-T GE Signa Scanner (General Elec-