Lateral and Medial Hypofrontality in First-Episode Schizophrenia: Functional Activity in a Medication-Naive State and Effects of Short-Term Atypical Antipsychotic Treatment

Participants at baseline were 23 medication-naive patients with first-episode schizophrenia and 24 healthy comparison subjects. Of these participants, a subset of 11 patients and 16 comparison subjects were scanned again after 4 weeks. All patients were part of a larger study of first-episode psychosis and were recruited if they were experiencing any type of psychotic symptom and it was their first psychiatric hospitalization or contact with outpatient psychiatric services. After baseline assessments, patients were treated naturalistically by their treating psychiatrists and followed longitudinally. Diagnostic confirmation occurred 6 months after index hospitalization through case conferences based on chart review and assessment with the Structured Clinical Interview for DSM-IV (SCID). Two of the patients had limited previous exposure to neuroleptics before baseline, but exclusion criteria were enforced by limiting total lifetime continuous treatment to 2 weeks or less with no more than three doses of oral neuroleptics during the month preceding study entry. Four patients had previous exposure to antidepressants, and two had been exposed to anxiolytics. All psychotropic medications were washed out at least 72 hours before the baseline scan. After baseline, five patients dropped out of the study, two were excluded from follow-up analysis because of poor medication compliance, and one was excluded because of poor comprehension of the task during the second scan.

Healthy comparison participants, recruited through community advertisements, were evaluated with the nonpatient version of the SCID and were excluded for any lifetime history of an axis I disorder or family history of psychotic disorders. Exclusion criteria for both patients and comparison subjects were the following: 1) age older than 50 or younger than 12, 2) DSM-IV mental retardation, 3) substance dependence within the past 6 months or substance abuse within the past month, or 4) lifetime history of significant neurologic disorder or head trauma or current medical condition that could influence CNS function or structure. See Table 1 for summary of demographic and clinical variables.

All participants provided written informed consent after the procedures had been fully explained. Additional safeguards to ensure that informed consent for patients was properly obtained included having them repeat back information about research participation to check comprehension and screening out patients who were floridly psychotic or exhibited obvious cognitive impairment.

Participants viewed a centrally presented red or green square at the beginning of each trial. An arrow probe appeared 7 seconds later in the same location pointing either to the left or to the right. The green square cue required subjects to respond to the probe with a button press using the ipsilateral hand (i.e., the hand on the same side toward which the arrow was pointing), whereas the red square cue required a response with the contralateral hand, a reversal of the usual stimulus-response mapping. This task, Preparing to Overcome Prepotency, exploits the Simon spatial incompatibility effect (25) in which an imperative stimulus appearing opposite to the response side results in slower response times than when stimulus and response appear on the same side. The Simon effect was augmented by an expectancy manipulation, such that same-sided responding was more frequent (green square cues were presented in 70% of the trials). During the period after a red square cue and before the arrow probe, subjects had to recall and maintain the instructions associated with the cue in order to successfully overcome the prepotent response tendency and respond with the contralateral hand. In this period we predicted a greater activation of the dorsolateral prefrontal cortex with red square cues relative to green square cues. At the time of response to the arrow probe, it was predicted that the conflict inherent in overriding the more automatic response would engage the anterior cingulate cortex.

The Preparing to Overcome Prepotency task was presented in five blocks of 24 trials. Stimulus durations were 500 msec, with a 7-second interval between cue and probe and an 11.5-second interval following the probe to allow for resolution of the hemodynamic response. Subjects practiced the task before being scanned and were instructed to respond as quickly and accurately as possible.

Given the a priori hypotheses involving the dorsolateral prefrontal cortex and anterior cingulate cortex, we first conducted confirmatory analyses using previously identified functional regions of interest that showed control-related activation within the dorsolateral prefrontal cortex (Brodmann’s area 9, Talairach coordinates: x=–41, y=18, z=28; 37 voxels [15]) and conflict-related activation within the anterior cingulate cortex (Brodmann’s area 32, Talairach coordinates: x=0, y=15, z=41; 23 voxels [29]). These regions were brought into the common MNI reference space by using the same aforementioned transformation algorithms. Time series for each region of interest were then generated for each subject, and average change in activation from baseline for the cue period (scans 1–5) and the probe period (scans 6–13) were examined separately. Following the confirmatory analyses, exploratory analyses of the entire image were performed by using voxel-wise analyses of variance (ANOVAs) with subject as a random factor, group as a between-subject factor (comparison subjects versus schizophrenia patients), and cue (green versus red) and scan (1–5 [cue period] versus 6–13 [probe period]) as within-subject factors. fMRI data were analyzed for correct trials only, ensuring analysis of on-task performance. Voxel-wise statistical maps were thresholded for significance at p<0.005 (uncorrected) using an 8-voxel contiguity criterion (30). Correlations between individual differences in brain activity, symptoms, and task performance were also examined.

Table 2 shows basic performance data on the Preparing to Overcome Prepotency task. In a series of repeated-measures ANOVAs (two performance measures and two time points), main effects of condition were observed (all F>5.25, all p<0.03), indicating slower response times and higher error rates across groups on red cue (contralateral) trials compared with green cue (ipsilateral) trials. For response times at both time points, main effects of group were also observed (F>4.70, p<0.04), reflecting slower overall response times in patients. None of the ANOVAs revealed significant group-by-condition interactions (F<2.0, p>0.18).

In order to more directly examine the effect of medication on dorsolateral prefrontal cortex and anterior cingulate cortex functioning, time-series data were analyzed only for the subset of patients who returned for follow-up testing (N=11). Baseline dorsolateral prefrontal cortex and anterior cingulate cortex activity for these patients is shown in the first panel in Figure 2. For dorsolateral prefrontal cortex activity, a two-by-two-by-five within-group ANOVA, with run (baseline versus 4-week), condition (red versus green square cue) and scan number (1 through 5) as within-subject factors resulted in no significant main effects or interactions (all p>0.25).

For anterior cingulate cortex activity, within-group ANOVAs revealed main effects of run (F=5.36, df=1, 10, p<0.05) and scan (F=13.26, df=7, 70, p<0.001), with a significant run-by-condition interaction (F=5.29, df=1, 10, p<0.05) and a significant run-by-condition-by-scan interaction (F=2.53, df=7, 70, p<0.05). The latter result reflects a greater anterior cingulate cortex response to trials with red square cues than green square cues at 4 weeks compared with baseline.

A within-group exploratory analysis across the entire image of the baseline data showed a network of control-related activation (red square cue > green square cue) in both groups during the cue period in lateral frontal regions (left Brodmann’s area 10), medial frontal regions (Brodmann’s area 8, rostral Brodmann’s area 32, and Brodmann’s area 24/23), and parietal regions (Brodmann’s area 40; right in healthy subjects, left in patients). During the arrow probe period, both groups activated medial frontal regions (right Brodmann’s area 9/10) and right primary motor and superior parietal regions (left Brodmann’s area 7/40). Healthy comparison subjects activated the caudal anterior cingulate cortex (Brodmann’s area 32). A between-group analysis was consistent with the confirmatory analysis for cue activity, with comparison subjects showing significantly greater left dorsolateral prefrontal cortex activity regions (Brodmann’s area 8 and Brodmann’s area 9) than patients. Bilateral superior parietal regions (Brodmann’s area 7 and Brodmann’s area 40/7) and right inferior parietal regions (Brodmann’s area 7) showed a similar pattern. Although patients failed to show significant anterior cingulate cortex activity during the probe, no significant between-group differences were observed in this region. Patients did show reduced activation in the left inferior frontal gyrus (Brodmann’s area 44), supplementary motor area (Brodmann’s area 6), right postcentral gyrus (Brodmann’s area 3), and left superior parietal cortex (Brodmann’s area 7).

Correlations between maximum dorsolateral prefrontal cortex and anterior cingulate cortex activation during red square trials and symptoms were examined in patients. At baseline, patients with greater disorganization symptoms had lower dorsolateral prefrontal cortex activation (r=–0.58, p<0.01), whereas the correlations with the other two symptom dimensions were not significant (reality distortion: r=0.16; poverty symptoms: r=–0.27). Conflict-related activation in the anterior cingulate cortex during the probe period was associated with both disorganization symptoms (r=–0.54, p<0.05) and poverty symptoms (r=–0.50, p<0.05) but not with reality distortion (r=0.20). At 4 weeks, no significant correlations were found between activation and symptoms. Furthermore, there were no significant correlations between change in symptom ratings and change in maximum dorsolateral prefrontal cortex or anterior cingulate cortex activation from baseline to 4 weeks.

Correlations in comparison subjects at baseline between response time interference and maximum fMRI signal for red square trials were consistent with those reported in MacDonald et al. (15), who used a similar task design (cue-period dorsolateral prefrontal cortex activity: r=–0.35, p<0.05, one-tailed; probe-period anterior cingulate cortex activity: r=0.33, p=0.06, one-tailed). In patients at baseline, neither of these correlations was significant nor were they significant at 4 weeks in either subject group.

A subset of patients and healthy participants underwent repeat fMRI after the patients had received 4 weeks of atypical antipsychotic treatment. There was no significant improvement in dorsolateral prefrontal cortex function over this interval. In comparison, Honey et al. (22) indicated increased right prefrontal activation during a working memory task with substitution of risperidone for typical antipsychotic medications. However, the average time that patients were treated before the repeat scan (6 weeks) was longer than in the present study (31 days). We are currently conducting a further study with an 8-week stabilization period to ensure that medication effects on cognition and brain functioning, if present, have sufficient time to emerge.

We did observe a significant medication effect on anterior cingulate cortex functioning during the response period of the task. These results are consistent with those of Honey et al. (22) and Lahti et al. (21), who both reported greater supplementary motor area/cingulate (Brodmann’s area 6/32) activity with atypical relative to typical antipsychotics. Thus, the present findings contribute to an emerging literature whereby anterior cingulate cortex functioning appears to be among the most consistently sensitive to treatment effects. The mechanism by which short-term atypical antipsychotic regimens enhance task-related anterior cingulate cortex functioning is unknown, but a likely candidate is increased cortical dopamine availability (33), since there is evidence for modulation of impaired anterior cingulate cortex activation by experimental dopaminergic manipulation in schizophrenia (34).

Limitations of the present study include a small number of first-episode patients for the analysis of treatment effects, a relatively brief duration of treatment, and treatment with different atypical antipsychotics with different receptor binding profiles. Since the first two factors would result in lower power to detect treatment effects and the latter in increased variability, our reported negative finding with regard to a treatment effect on dorsolateral prefrontal cortex functioning should be interpreted with some reservation, whereas the treatment effect observed for anterior cingulate cortex functioning can be interpreted with more confidence. Another general limitation was the lack of clear behavioral effect in the scanner that would reflect a context-processing deficit (although some would consider this an advantage, since performance was not different across groups). In contrast, we found that data from the AX version of the Continuous Performance Test in these same participants at baseline indicated a specific context-processing deficit: patients had greater BX errors than healthy subjects (a high context-processing demand condition) but a similar number of AY errors (a task-difficulty control condition; see Barch et al. [17] for task details). We infer from these divergent behavioral results that the Preparing to Overcome Prepotency task is less sensitive to group differences in context processing than the AX version of the Continuous Performance Test possibly because of the long interval between cue and probe used in the scanner. This long delay might have enabled subjects to use a different strategy to maintain a level of performance comparable to that of healthy subjects, such as encoding and rehearsing the cue as an item independent of context, and then retrieving the appropriate stimulus-response mapping at the onset of the probe.

In conclusion, the current study found evidence for hypoactivation of both the dorsolateral prefrontal cortex and anterior cingulate cortex at illness onset. Impairments in frontal lobe functions were associated with core clinical features of schizophrenia before the initiation of antipsychotic medication. Short-term medication effects on conflict-related anterior cingulate cortex activation were observed, whereas medication effects on control-related dorsolateral prefrontal cortex activation were not significant. These findings contribute to an emerging picture in the literature of the demonstrated short-term benefit of atypical antipsychotics to the brain circuitry that underlies impaired cognition in schizophrenia.