An FMRI study of episodic encoding and recognition of words in patients with schizophrenia in remission

OBJECTIVE: Verbal memory deficits are among the most severe cognitive deficits observed in patients with schizophrenia. This study examined patterns of brain activity during episodic encoding and recognition of words in patients with schizophrenia. METHOD: Functional magnetic resonance imaging (fMRI) was used to study regional brain activation in 10 healthy male comparison subjects and 10 male outpatients with schizophrenia during performance of a modified version of the words subtest of Warrington's Recognition Memory Test. RESULTS: Despite having intact performance in word recognition, the patients with schizophrenia had less activation of the right dorsolateral and anterior prefrontal cortex, right anterior cingulate, and left lateral temporal cortex during word encoding, compared with the healthy comparison subjects. During word recognition, the patients had impairments in activation of the bilateral dorsolateral prefrontal and lateral temporal cortices. CONCLUSIONS: Schizophrenia was associated with attenuated frontotemporal activation during episodic encoding and recognition of words. These results from an fMRI study replicate earlier findings derived from a positron emission tomography study.     

Effect of schizophrenia on frontotemporal activity during word encoding and recognition: a PET cerebral blood flow study.

OBJECTIVE: Neuropsychological studies have shown that deficits in verbal episodic memory in schizophrenia occur primarily during encoding and retrieval stages of information processing. The current study used positron emission tomography to examine the effect of schizophrenia on change in cerebral blood flow (CBF) during these memory stages. METHOD: CBF was measured in 23 healthy comparison subjects and 23 patients with schizophrenia during four conditions: resting baseline, motor baseline, word encoding, and word recognition. The motor baseline was used as a reference that was subtracted from encoding and recognition conditions by using statistical parametric mapping. RESULTS: Patients' performance was similar to that of healthy comparison subjects. During word encoding, patients showed reduced activation of left prefrontal and superior temporal regions. Reduced left prefrontal activation in patients was also seen during word recognition, and additional differences were found in the left anterior cingulate, left mesial temporal lobe, and right thalamus. Although patients' performance was similar to that of healthy comparison subjects, left inferior prefrontal activation was associated with better performance only in the comparison subjects. CONCLUSIONS: Left frontotemporal activation during episodic encoding and retrieval, which is associated with better recognition in healthy people, is disrupted in schizophrenia despite relatively intact recognition performance and right prefrontal function. This may reflect impaired strategic use of semantic information to organize encoding and facilitate retrieval.     

Event-related fMRI of frontotemporal activity during word encoding and recognition in schizophrenia

OBJECTIVE: Neuropsychological studies have demonstrated verbal episodic memory deficits in schizophrenia during word encoding and retrieval. This study examined neural substrates of memory in an analysis that controlled for successful retrieval. METHOD: Event-related blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) was used to measure brain activation during word encoding and recognition in 14 patients with schizophrenia and 15 healthy comparison subjects. An unbiased multiple linear regression procedure was used to model the BOLD response, and task effects were detected by contrasting the signal before and after stimulus onset. RESULTS: Patients attended during encoding and had unimpaired reaction times and normal response biases during recognition, but they had lower recognition discriminability scores, compared with the healthy subjects. Analysis of contrasts was restricted to correct items. Previous findings of a deficit in bilateral prefrontal cortex activation during encoding in patients were reproduced, but patients showed greater parahippocampal activation rather than deficits in temporal lobe activation. During recognition, left dorsolateral prefrontal cortex activation was lower in the patients and right anterior prefrontal cortex activation was preserved, as in the authors' previous study using positron emission tomography. Successful retrieval was associated with greater right dorsolateral prefrontal cortex activation in the comparison subjects, whereas orbitofrontal, superior frontal, mesial temporal, middle temporal, and inferior parietal regions were more active in the patients during successful retrieval. CONCLUSIONS: The pattern of prefrontal cortex underactivation and parahippocampal overactivation in the patients suggests that functional connectivity of dorsolateral prefrontal and temporal-limbic structures is disrupted by schizophrenia. This disruption may be reflected in the memory strategies of patients with schizophrenia, which include reliance on rote rehearsal rather than associative semantic processing.     

Levels-of-processing effect on frontotemporal function in schizophrenia during word encoding and recognition

OBJECTIVE: Patients with schizophrenia improve episodic memory accuracy when given organizational strategies through levels-of-processing paradigms. This study tested if improvement is accompanied by normalized frontotemporal function. METHOD: Event-related blood-oxygen-level-dependent functional magnetic resonance imaging (fMRI) was used to measure activation during shallow (perceptual) and deep (semantic) word encoding and recognition in 14 patients with schizophrenia and 14 healthy comparison subjects. RESULTS: Despite slower and less accurate overall word classification, the patients showed normal levels-of-processing effects, with faster and more accurate recognition of deeply processed words. These effects were accompanied by left ventrolateral prefrontal activation during encoding in both groups, although the thalamus, hippocampus, and lingual gyrus were overactivated in the patients. During word recognition, the patients showed overactivation in the left frontal pole and had a less robust right prefrontal response. CONCLUSIONS: Evidence of normal levels-of-processing effects and left prefrontal activation suggests that patients with schizophrenia can form and maintain semantic representations when they are provided with organizational cues and can improve their word encoding and retrieval. Areas of overactivation suggest residual inefficiencies. Nevertheless, the effect of teaching organizational strategies on episodic memory and brain function is a worthwhile topic for future interventional studies.     

The influence of encoding strategy on episodic memory and cortical activity in schizophrenia.

BACKGROUND: Recent work suggests that episodic memory deficits in schizophrenia may be related to disturbances of encoding or retrieval. Schizophrenia patients appear to benefit from instruction in episodic memory strategies. We tested the hypothesis that providing effective encoding strategies to schizophrenia patients enhances encoding-related brain activity and recognition performance. METHODS: Seventeen schizophrenia patients and 26 healthy comparison subjects underwent functional magnetic resonance imaging scans while performing incidental encoding tasks of words and faces. Subjects were required to make either deep (abstract/concrete) or shallow (alphabetization) judgments for words and deep (gender) judgments for faces, followed by subsequent recognition tests. RESULTS: Schizophrenia and comparison subjects recognized significantly more words encoded deeply than shallowly, activated regions in inferior frontal cortex (Brodmann area 45/47) typically associated with deep and successful encoding of words, and showed greater left frontal activation for the processing of words compared with faces. However, during deep encoding and material-specific processing (words vs. faces), participants with schizophrenia activated regions not activated by control subjects, including several in prefrontal cortex. CONCLUSIONS: Our findings suggest that a deficit in use of effective strategies influences episodic memory performance in schizophrenia and that abnormalities in functional brain activation persist even when such strategies are applied.     

Reduced hippocampal activation during encoding and recognition of words in schizophrenia patients

OBJECTIVE: In patients with schizophrenia, impaired hippocampal activation either during encoding or recognition tasks has been observed in a few functional imaging experiments. In this fMRI study, the authors report results of word encoding and recognition in schizophrenia patients and healthy comparison subjects, with a special focus on correcting for behavioral recognition success in order to prevent a bias related to lower task performance in the schizophrenia patients. METHOD: The verbal encoding and recognition tasks were both first analyzed irrespective of recognition success. In a second analysis, recognition success was included in the block-designed encoding task as a covariate of no interest, and incorrectly classified items were rejected from the analysis of the event-related recognition task. RESULTS: Patients performed poorer on the recognition task than the comparison subjects. Bilateral hippocampal activation during encoding and recognition was observed in both groups. Right hippocampal activation in patients during recognition became significant only after exclusion of wrongly classified items. Group comparison revealed greater activation in the healthy comparison subjects in the left anterior hippocampus during encoding and bilaterally during recognition. Greater bilateral hippocampal activation in the healthy subjects and greater activation in the right anterior hippocampus in the schizophrenic patients were revealed after presentation of novel words, which were intermixed with previously encoded words in the recognition task. After exclusion of incorrectly classified items, the differences in the right hippocampus remained significant. CONCLUSIONS: This study provides evidence for disturbed hippocampal function during verbal encoding and recognition in patients with schizophrenia. It extends previous studies by correcting for the possible confound of differences in behavioral task performance. This approach further supports the concept of hippocampal dysfunction in schizophrenia.     

Brain activation patterns during a selective attention test--a functional MRI study in healthy volunteers and unmedicated patients during an acute episode of schizophrenia

In a previous functional magnetic resonance imaging (fMRI) study of high functioning outpatients with remitted schizophrenia, we found increased activity compared with healthy subjects across multiple areas of the brain, including the dorsolateral frontal cortex and the anterior cingulate, during a modified Stroop task. The same fMRI procedure was used in this subsequent study to investigate eight unmedicated patients during an acute episode of schizophrenia and eight healthy control subjects. Patients showed a reduced activation in dorsolateral prefrontal, anterior cingulate and parietal regions and a higher activation in temporal regions and posterior cingulate compared to healthy controls. Healthy controls showed a trend towards higher accuracy in the modified Stroop task compared to schizophrenia patients. Treatment with second generation antipsychotics may improve executive performance in patients with schizophrenia and facilitate a normalization of functional hypofrontality after symptomatic improvement.     

Brain activation patterns during a selective attention test — a functional MRI study in healthy volunteers and unmedicated patients during an acute episode of schizophrenia

In a previous functional magnetic resonance imaging (fMRI) study of high functioning outpatients with remitted schizophrenia, we found increased activity compared with healthy subjects across multiple areas of the brain, including the dorsolateral frontal cortex and the anterior cingulate, during a modified Stroop task. The same fMRI procedure was used in this subsequent study to investigate eight unmedicated patients during an acute episode of schizophrenia and eight healthy control subjects. Patients showed a reduced activation in dorsolateral prefrontal, anterior cingulate and parietal regions and a higher activation in temporal regions and posterior cingulate compared to healthy controls. Healthy controls showed a trend towards higher accuracy in the modified Stroop task compared to schizophrenia patients. Treatment with second generation antipsychotics may improve executive performance in patients with schizophrenia and facilitate a normalization of functional hypofrontality after symptomatic improvement.     

A functional magnetic resonance imaging study of social cognition in schizophrenia during an acute episode and after recovery

OBJECTIVE: Difficulty with social interactions is a characteristic of schizophrenia. The authors used functional magnetic resonance imaging (fMRI) to investigate brain activation changes during a social cognition paradigm in patients with schizophrenia during and after an acute episode and their association with social and executive function. METHOD: In a longitudinal study design, 14 patients with schizophrenia experiencing an acute episode had an fMRI scan. They returned for a follow-up scan after clinical improvement. Fourteen healthy comparison subjects were also scanned twice with approximately the same time interval between scans as in the patient group. The authors employed a social cognition fMRI paradigm involving empathic and forgivability judgments. Schizophrenia symptoms, social functioning and illness insight scales, and the Wisconsin Card Sorting Test were used to examine whether improvement on these measures was associated with recovery of brain activation in response to the social cognition paradigm. RESULTS: After recovery from the acute episode, patients exhibited increased activation in the left medial prefrontal cortex, which was, in turn, significantly correlated with improved insight and social functioning. Decreased symptom severity and improved performance on the Wisconsin Card Sorting Test were not significantly associated with increased left medial prefrontal cortex activation. CONCLUSIONS: This is the first study to the authors' knowledge to use a social cognition paradigm to reveal improved left medial prefrontal cortex activation in schizophrenia after recovery from an acute episode. These results suggest that restored left medial prefrontal cortex activation may mediate improvement of insight and social functioning in patients with schizophrenia.     

Language lateralization in unmedicated patients during an acute episode of schizophrenia: a functional MRI study

In a previous fMRI study of high-functioning outpatients with remitted schizophrenia, we found that healthy subjects and schizophrenia patients showed similar patterns of activation during a verbal fluency task. However, the activation in controls was primarily in Broca's area on the left, while it was more bilateral for schizophrenia patients, implicating a reduced language lateralization in schizophrenia patients. The same fMRI procedure was used in this subsequent study to investigate unmedicated patients during an acute episode of schizophrenia. Schizophrenia patients showed reduced language lateralization in the frontal cortex, because of a more bilateral activation of Broca's area compared with a primarily left hemisphere activation in healthy controls. Furthermore decreased lateralization was correlated to the severity of hallucinations. Although patients with schizophrenia showed a significantly reduced performance on the verbal fluency task when compared with healthy subjects, we were not able to find evidence of decreased language-related activity in the left hemisphere. These results suggest that decreased language lateralization is also evident in unmedicated patients experiencing an acute episode of schizophrenia.     

Abnormalities in the thalamus and prefrontal cortex during episodic object recognition in schizophrenia.

BACKGROUND: Many patients with schizophrenia demonstrate memory deficits. We studied patterns of brain activity during episodic recognition of new and previously seen three-dimensional objects. METHODS: We used (15)O positron emission tomography to study regional cerebral blood flow in eight normal subjects and nine patients with schizophrenia during a visual object recognition task. RESULTS: In comparison with control subjects, patients with schizophrenia showed less regional cerebral blood flow increases in the pulvinar region of the right thalamus and the right prefrontal cortex during the recognition of new objects and significantly greater left prefrontal cortex regional cerebral blood flow increases during the recognition of previously seen objects. Patients with schizophrenia exhibited alarm rates to new objects similar to those of control subjects, but significantly lower recognition rates for previously seen objects. CONCLUSIONS: Schizophrenia is associated with attenuated right thalamic and right prefrontal activation during the recognition of novel visual stimuli and with increased left prefrontal cortical activation during impaired episodic recognition of previously seen visual stimuli. This study provides further evidence for abnormal thalamic and prefrontal cortex function in schizophrenia.     

Intact suppression of increased false recognition in schizophrenia

OBJECTIVE: Recognition memory is impaired in patients with schizophrenia, as they rely largely on item familiarity, rather than conscious recollection, to make mnemonic decisions. False recognition of novel items (foils) is increased in schizophrenia and may relate to this deficit in conscious recollection. By studying pictures of the target word during encoding, healthy adults can suppress false recognition. This study examined the effect of pictorial encoding on subsequent recognition of repeated foils in patients with schizophrenia. METHOD: The study included 40 patients with schizophrenia and 32 healthy comparison subjects. After incidental encoding of 60 words or pictures, subjects were tested for recognition of target items intermixed with 60 new foils. These new foils were subsequently repeated following either a two- or 24-word delay. Subjects were instructed to label these repeated foils as new and not to mistake them for old target words. RESULTS: Schizophrenic patients showed greater overall false recognition of repeated foils. The rate of false recognition of repeated foils was lower after picture encoding than after word encoding. Despite higher levels of false recognition of repeated new items, patients and comparison subjects demonstrated a similar degree of false recognition suppression after picture, as compared to word, encoding. CONCLUSIONS: Patients with schizophrenia displayed greater false recognition of repeated foils than comparison subjects, suggesting both a decrement of item- (or source-) specific recollection and a consequent reliance on familiarity in schizophrenia. Despite these deficits, presenting pictorial information at encoding allowed schizophrenic subjects to suppress false recognition to a similar degree as the comparison group, implying the intact use of a high-level cognitive strategy in this population.     

Impaired hippocampal recruitment during normal modulation of memory performance in schizophrenia.

BACKGROUND: Patients with schizophrenia demonstrate poor verbal memory, ascribed to impaired prefrontal and hippocampal function. Healthy adults can increase recall accuracy following encoding interventions, such as item repetition and the formation of semantic associations. We examined the effects of these interventions on both memory performance and retrieval-related hippocampal activity in healthy adults and patients with schizophrenia. METHODS: Twelve patients with schizophrenia and twelve healthy control subjects participated. During study, subjects counted either the number of meanings or T-junctions in words seen only once or repeated four times. At test, O15-positron emission tomography scans were acquired while subjects completed word-stems with previously studied items. RESULTS: Control subjects recalled more words overall, but both groups demonstrated similar performance benefits following deeper encoding. Both item repetition and the use of a semantic encoding task were associated with memory retrieval-related hippocampal recruitment in control but not schizophrenic participants. Patients with schizophrenia demonstrated greater activation of prefrontal cortical areas during word retrieval. CONCLUSIONS: Despite a lack of hippocampal recruitment, patients with schizophrenia showed intact modulation of memory performance following both encoding interventions. Impaired hippocampal recruitment, in concert with greater prefrontal activation, may reflect a specific deficit in conscious recollection in schizophrenia.     

Episodic memory in schizophrenia: the influence of strategy use on behavior and brain activation

Individuals with schizophrenia demonstrate behavioral and neurobiological deficits in episodic memory. However, recent work suggests that episodic memory deficits in schizophrenia may be mitigated through specific encoding strategies. The current study directly compared brain activity and memory performance associated with two different verbal encoding orientations in the same group of schizophrenia participants, in order to more fully characterize the role of strategy in memory processing in this population. Participants included 18 individuals with schizophrenia and 15 healthy comparison participants. Participants encoded words under two conditions during separate fMRI scanning runs. During Incidental encoding, participants were required to make abstract/concrete judgments for each word. During Intentional encoding, participants were instructed to memorize each word for a later memory test. Free recall and a recognition task (utilizing the Remember/Know paradigm) were performed outside of the scanner. Consistent with prior work, schizophrenia participants recognized more words encoded Incidentally than Intentionally, although free recall remained substantially impaired. Schizophrenia participants were also less likely to give Remember judgments for old words and more likely to give Guess judgments for both old and new words. When functional magnetic resonance imaging data were examined, we found that Incidental encoding was associated with substantially fewer between-group differences (Control>Schizophrenia) than Intentional encoding. Furthermore, schizophrenia participants exhibited intact activity during encoding of items that were subsequently retrieved. Our results suggest that use of an Incidental encoding strategy improved recognition memory among individuals with schizophrenia and resulted in a pattern of encoding-related brain activity that was more similar to that seen in control participants. However, we found that Incidental encoding did not improve free recall in schizophrenia participants and abnormal brain activity in some regions was observed, despite improvements in recognition memory.     

Abnormalities of thalamic activation and cognition in schizophrenia

OBJECTIVE: Functional and structural magnetic resonance imaging (MRI) was used to investigate relationships among structure, functional activation, and cognitive deficits related to the thalamus in individuals with schizophrenia and healthy comparison subjects. METHOD: Thirty-six schizophrenia subjects and 28 healthy comparison subjects matched by age, gender, race, and parental socioeconomic status underwent structural and functional MRI while performing a series of memory tasks, including an N-back task (working memory), intentional memorization of a series of pictures or words (episodic encoding), and a yes/no recognition task. Functional activation magnitudes in seven regions of interest within the thalamic complex, as defined by anatomical and functional criteria, were computed for each group. RESULTS: Participants with schizophrenia exhibited decreased activation within the whole thalamus, the anterior nuclei, and the medial dorsal nucleus. These nuclei overlap with subregions of the thalamic surface that the authors previously reported to exhibit morphological abnormalities in schizophrenia. However, there were no significant correlations between specific dimensions of thalamic shape variation (i.e., eigenvectors) and the activation patterns within thalamic regions of interest. Better performance on the working memory task among individuals with schizophrenia was significantly associated with increased activation in the anterior nuclei, the centromedian nucleus, the pulvinar, and the ventrolateral nuclei. CONCLUSIONS: These results suggest that there are limited relationships between morphological and functional abnormalities of the thalamus in schizophrenia subjects and highlight the importance of investigating relationships between brain structure and function.     

Anterior cingulate cortex activation during cognitive interference in schizophrenia

BACKGROUND: Previous studies have reported evidence of structural and functional abnormalities in the anterior cingulate cortex of patients with schizophrenia. METHOD: The authors studied 19 male patients with chronic schizophrenia and 15 healthy male comparison subjects with functional magnetic resonance imaging and the novel Multi-Source Interference Task, a task designed to elicit robust dorsal anterior cingulate cortex activation in individual subjects. Group averaged and individual (region-of-interest-based) brain activation patterns were compared during the performance of control and interference trials. RESULTS: Performance (reaction times and accuracy) did not differ between healthy subjects and patients with schizophrenia. Comparison of interference and neutral blocks revealed activation in the medial wall of the prefrontal cortex in 93% (N=14) of the healthy subjects and 84% (N=16) of the subjects with schizophrenia. Sixty-seven percent (N=10) of the healthy subjects but only 16% (N=3) of the subjects with schizophrenia displayed maximum medial wall activation within the dorsal anterior cingulate cortex. CONCLUSIONS: The Multi-Source Interference Task produced robust activation in the medial wall of the prefrontal cortex during cognitive interference. Analysis of individual activation patterns revealed medial wall abnormalities in schizophrenia patients.     

Parietal dysfunction is associated with increased outcome-related decision-making in schizophrenia patients.

BACKGROUND: Decision-making is a complex process and depends on a network of fronto-parietal and cingulate areas. Decision-making dysfunctions in schizophrenia patients are characterized by an alternation between stereotypic and unpredictable responses. This study tested the hypothesis that schizophrenia patients show less decision-making-related activation in the prefrontal and parietal cortex.METHODS: Fifteen schizophrenia patients were matched with fifteen normal comparison subjects. During functional magnetic resonance imaging (fMRI) scanning, subjects were tested on the two-choice prediction task (predicting the location of a randomly presented stimulus) and the two-choice response task (responding according to the location of the stimulus).RESULTS: Schizophrenia patients relative to comparison subjects generated more outcome-dependent responses. Schizophrenia patients and normal comparison subjects showed decision-making-related activation in right prefrontal cortex, insula, anterior cingulate, and bilateral precuneus. Schizophrenia patients showed less activation in inferior, medial prefrontal, and right superior temporal cortex and more activation in the postcentral and inferior parietal cortex. Decision-making-related activation in both right prefrontal and bilateral parietal cortex was higher in medicated compared to unmedicated schizophrenia patients.CONCLUSIONS: These results support the hypothesis that the interaction between prefrontal and parietal cortex during decision-making by schizophrenia patients is dysregulated, which results in an increased outcome-dependent response selection.     

A 4.0-T fMRI study of brain connectivity during word fluency in first-episode schizophrenia

OBJECTIVE: To use functional magnetic resonance imaging (fMRI) to investigate functional connectivity, and hence, underlying neural networks, in never-treated, first-episode patients with schizophrenia using a word fluency paradigm known to activate prefrontal, anterior cingulate, and thalamic regions. Abnormal connectivity between the prefrontal cortex (PFC) and other brain regions has been demonstrated in chronic, medicated patients in previous positron emission tomography (PET) studies, but has not to our knowledge, previously been demonstrated using both first-episode, drug-na?ve patients and fMRI technology. METHODS: A 4.0-Tesla (T) fMRI was used to examine activation and functional connectivity [psychophysiological interactions (PPIs)] during a word fluency task compared to silent reading in 10 never-treated, first-episode patients with schizophrenia and 10 healthy volunteers of comparable age, sex, handedness, and parental education. RESULTS: Compared to healthy volunteers, the schizophrenia patient group exhibited less activation during the word fluency task, mostly in the right anterior cingulate and prefrontal regions. Psychophysiological interactions between right anterior cingulate and other parts of the brain revealed a localized interaction with the left temporal lobe in healthy volunteers during the task and a widespread unfocussed interaction in patients. CONCLUSION: These findings suggest anterior cingulate involvement in the neuronal circuitry underlying schizophrenia.     

Altered neural function during episodic memory encoding and retrieval in major depression

Memory impairments are common in major depression. Neural processing during non‐emotional episodic memory in depressed patients has only sparsely been investigated, since the majority of studies have focused on emotional stimuli. The aim of this study was to explore neural correlates of episodic memory in depressive patients and to assess brain regions related to subsequent memory performance. Forty‐six participants (23 depressed patients) performed a non‐emotional episodic memory encoding and retrieval task while brain activation was measured with functional magnetic resonance imaging. Patients with depression showed decreased activation in the right prefrontal cortex and right cingulate cortex during memory encoding, but increased activation in the right inferior frontal gyrus (IFG) during recognition memory. While a strong association between hippocampal and parahippocampal activation during memory encoding with subsequent memory performance became evident in healthy controls, this relationship was absent in patients with depression. Taken together, these findings demonstrate that memory related brain regions are affected in their appropriate functioning during memory encoding in depressed patients. Therefore, patients with depression may rely to a greater degree on other brain regions such as the IFG during episodic memory retrieval. Hum Brain Mapp 35:4293–4302, 2014. © 2014 Wiley Periodicals, Inc .     

Smaller anterior hippocampal formation volume in antipsychotic-naive patients with first-episode schizophrenia

OBJECTIVE: The authors investigated volumetric alterations of the anterior hippocampal formation in patients experiencing a first episode of schizophrenia relative to healthy comparison subjects. METHOD: From contiguous 1.5-mm coronal magnetic resonance images, the hippocampal formation was divided into posterior and anterior segments, and the anterior hippocampal formation was separated from the amygdala. Volumes of the posterior and anterior hippocampal formation and amygdala were computed in 46 (31 male and 15 female) patients experiencing a first episode of schizophrenia and in 34 (21 male and 13 female) healthy comparison subjects. Twenty-four patients were antipsychotic naive at the time of the scan. RESULTS: Patients had significantly reduced total (right plus left) anterior hippocampal formation volume relative to healthy comparison subjects but did not differ in volumes of either the posterior hippocampal formation or amygdala. Similar findings were obtained when analyses were restricted to the antipsychotic-naive subgroup of patients. CONCLUSIONS: These findings suggest that volumetric abnormalities of the hippocampus-amygdala complex may be specific to the anterior hippocampal formation in patients experiencing a first episode of schizophrenia and are consistent with hypotheses regarding abnormal frontolimbic connectivity playing a role in the pathophysiology of the disorder.