精神病抑郁症的异常脑活动

Article Am J Psychiatry 168:2, February 2011 ajp.psychiatryonline.org 173 of these cognitive impairments to neural function is not clear. For example, impairments in the function of tem- poral lobe memory systems, prefrontal lobe executive regions, or visual and attention networks could underlie working memory defi cits in psychotic major depression. Working memory tasks require the temporary mainte- nance and manipulation of information as well as sustained attention. The neurofunctional system subserving verbal working memory has been studied extensively in healthy comparison subjects using functional MRI (fMRI). Studies consistently show that the dorsolateral prefrontal cortex, typically in Brodmann’s area 46, sustains activation during the delay periods in which individuals hold information in working memory (11) and suppresses activation to nonrel- evant stimuli (12). The sustained attention and target detec- tion component of a working memory task often activates a right hemisphere attention system, including regions of the temporoparietal cortex and inferior and middle frontal gyri. This network is consistently activated during detection of task-relevant stimuli, especially when they are infrequent (13). In the left hemisphere, the inferior parietal region is believed to be part of a storage buffer for verbal information An estimated 5%–20% of patients with major depres- sion experience psychotic symptoms, including halluci- nations and delusions (1, 2). Psychotic major depression is associated with more severe psychomotor symptoms and guilt (3, 4), signifi cantly greater impairment, longer illness duration, and greater likelihood of recurrence compared with nonpsychotic major depression (1, 5, 6). However, the severity of a depressive episode does not necessarily determine whether psychotic features will be present (7). Unfortunately, psychotic major depression is frequently misdiagnosed (8), which can deter effective treatment. A better understanding of the brain pathophysiology underlying psychotic major depression can lead to earlier detection and more effective treatments. Neuropsycho- logical data from our lab have shown that patients with psychotic major depression have greater cognitive impair- ment than do patients with nonpsychotic major depres- sion or healthy comparison subjects on tests of working memory, verbal memory, and psychomotor speed but not on tests of simple verbal attention (9), which implies abnormal brain circuits associated with memory encod- ing and executive function (10). However, the relationship (Am J Psychiatry 2011; 168:173–182) Amy Garrett, Ph.D. Ryan Kelly, B.S. Rowena Gomez, Ph.D. Jennifer Keller, Ph.D. Alan F. Schatzberg, M.D. Allan L. Reiss, M.D. Objective: The authors sought to bet- ter understand the neural circuitry asso- ciated with working memory defi cits in psychotic major depression by examining brain function during an N-back task. Method: Study subjects were 16 patients with psychotic major depression, 15 pa- tients with nonpsychotic major depres- sion, and 19 healthy comparison subjects. Functional MRI data were collected while participants responded to letter stimuli that were repeated from the previous trial (1-back) or the one before that (2-back). Results: Relative to the healthy compari- son group, both the psychotic and non- psychotic major depression groups had signifi cantly greater activation in the right parahippocampal gyrus during the 2-back task, and the psychotic major depression group showed this overactivation during the 1-back task as well. The nonpsychotic major depression group showed signifi - cantly lower activation than other groups in the right dorsolateral prefrontal cortex and greater activation than the healthy comparison group in the superior occipi- tal cortex. The psychotic major depres- sion group was unique in showing greater activation than both other groups in the right temporoparietal junction, a cluster that also demonstrated connectivity with activation in the left prefrontal cortex. Conclusions: The psychotic major de- pression group showed aberrant parahip- pocampal activation at a lower demand level than observed in nonpsychotic ma- jor depression. While the nonpsychotic major depression group showed abnor- malities in frontal executive regions, the psychotic major depression group showed abnormalities in temporoparietal regions associated with orienting to unex- pected stimuli. Considering the functional connectivity of this cluster with left dor- solateral prefrontal cortex regions, these fi ndings may refl ect neural compensation for sensory gating defi cits in psychotic major depression. Aberrant Brain Activation During a Working Memory Task in Psychotic Major Depression This article is the subject of a CME course (p. 227) BRAIN ACTIVATION DURING WORKING MEMORY IN PSYCHOTIC MAJOR DEPRESSION 174 ajp.psychiatryonline.org Am J Psychiatry 168:2, February 2011 symptoms. Patients were excluded if they had active suicidality, obsessive-compulsive disorder, or bipolar disorder or had abused substances or received ECT within the past 6 months. All par- ticipants were allowed to continue their psychiatric medications but were required to maintain a stable medication regimen for at least 1 week before the study. Healthy comparison subjects, recruited through advertise- ments, had to score less than 6 on the HAM-D, have no psychotic symptoms, and have no current or past axis I diagnoses according to SCID criteria. Exclusion criteria for all participants included major medical illness, history of seizures or head injury, pregnancy or lactation, age <18 years, or use of estrogen supplements or birth control pills. The study included 22 patients with psychotic major depression, 21 patients with nonpsychotic major depression, and 24 healthy comparison subjects. All participants gave written informed consent and received $250 for their participation. The study was approved by the Institutional Review Board of Stanford University. The N-Back Task Participants performed an N-back task during image acquisi- tion. The task had three types of alternating blocks: four 1-back, four 2-back, and six control (“press for Z”) blocks. For all blocks, a succession of uniform-size single letters was presented, in both upper- and lowercase. Each letter was presented for 500 msec, with a 1,500 msec intertrial interval showing a fi xation cross. Each block contained 12 letters and lasted for 24 seconds. Brief instruc- tions were shown for 4 seconds at the beginning of the block (e.g., “Press for 1-back”). During the 1-back blocks, participants pressed the button when the current letter matched the one pre- sented one trial back, e.g., a repeated letter such as A—A. During 2-back blocks, participants pressed the button when the current letter matched the one presented two trials back, e.g., in a “sand- wich” pattern such as A—B—A. During the “press for Z” blocks, participants pressed the button whenever the current letter was a Z. Participants pressed with the right index fi nger on a hand- held button box. Stimuli were projected onto a screen and viewed through a mirror attached to the head coil. All participants prac- ticed the task before the scan. The scan lasted 7 minutes and 48 seconds, during which 232 frames were acquired. The E-Prime software program (www.pstnet.com) was used to present the task and collect responses. fMRI Data Acquisition and Processing Images were acquired on a 3-T General Electric (GE) Signa scanner using a standard GE whole-head coil (Lx platform, gradi- ents 40 mT/m, 150 T/m/sec; GE Medical Systems, Milwaukee). A custom-built head restraint system and foam padding prevented head movement. A high-order shim (31) reduced blurring and sig- nal loss from fi eld inhomogeneities. Twenty-eight axial slices (4 mm thick, 0.5 mm skip) parallel to the anterior and posterior com- missures and covering the whole brain were imaged using a T 2 *- weighted spiral pulse sequence (32) (repetition time=2,000 msec, echo time=30 msec, fl ip angle=80°, interleave=1, fi eld of view=200 mm2, matrix=64×64, inplane spatial resolution=3.125 mm2). fMRI data were processed using SPM5 (www.fi l.ion.ucl.ac.uk/ spm). Images were realigned to the third volume. Image distortion and spin history errors caused by abrupt motions were repaired by interpolation from the nearest unaffected volumes. These methods were implemented in the ArtRepair toolbox for SPM (http://cibsr. stanford.edu/tools/ArtRepair/ArtRepair.htm). Data were normal- ized to the Montreal Neurological Institute (MNI) echo-planar image template and resampled to a 2-mm3 matrix using sinc inter- polation. Data were smoothed with a 4-mm full width at half maxi- mum Gaussian fi lter and high-pass fi ltered at 120 seconds. Individual statistics were computed using a fi xed-effects model and a block design comparing 1-back with press for Z, and 2-back (14). The hippocampus is also active during the delay period of a working memory task, but the parahippocampal gyrus, in contrast, is activated during the encoding and recogni- tion parts of the working memory task and predicts success- ful long-term memory encoding (15). Because of the widespread brain circuitry involved, patients with various psychiatric disorders have been found to show abnormal brain activation during working memory tasks. Patients with nonpsychotic major depression show abnormal prefrontal function during a verbal working mem- ory task, which emphasizes the importance of comparing patients with psychotic and nonpsychotic major depres- sion (16–22). Because patients with schizophrenia also display defi cits in working memory, several neuroimaging studies have found dorsolateral prefrontal cortex defi cits in schizophrenia relative to comparison subjects (23–25) and to patients with nonpsychotic major depression (24, 26), which suggests a common substrate for working memory defi cits across diagnoses but with greater severity in schizo- phrenia. Given that psychotic major depression involves symptoms of both nonpsychotic major depression and schizophrenia, these patients may share common defi cits in executive function. However, because high cortisol levels in psychotic major depression (9) are likely to affect hippo- campal and parahippocampal systems as well, defi cits in medial temporal lobe regions may differentiate psychotic major depression from nonpsychotic major depression. In this study, we investigated the neural correlates of a verbal working memory task in patients with psychotic major depression in order to better understand the brain circuitry underlying working memory defi cits in psy- chotic major depression. Patients with nonpsychotic major depression and healthy comparison subjects were included to differentiate between depressive subtypes as well as between these subtypes and unaffected indi- viduals. We predicted that the psychotic major depres- sion group would show a unique pattern of activation that refl ects abnormalities in medial temporal lobe and pari- etal regions and similarities to the nonpsychotic major depression group in prefrontal regions. Method Participants Participants were recruited from outpatient psychiatric clinics at Stanford University and through advertisements in the sur- rounding communities. Patients with psychotic and nonpsychotic major depression were diagnosed with the Structured Clinical Interview for DSM-IV (SCID) (27), and diagnoses were confi rmed by the treating psychiatrist when available. Patients had to score at least 18 on the 21-item Hamilton Depression Rating Scale (HAM-D) (28) and at least 7 on the Thase Core Endogenomorphic Scale (29) to verify signifi cant depressive and endogenous symp- toms, respectively. Patients with psychotic major depression had to score at least 5 on the positive symptom subscale of the Brief Psychiatric Rating Scale (BPRS; 30). All patients met DSM-IV criteria for current unipolar major depressive episode. Patients with nonpsychotic major depression had no history of psychotic GARRETT, KELLY, GOMEZ, ET AL. Am J Psychiatry 168:2, February 2011 ajp.psychiatryonline.org 175 with press for Z. Group t tests used a random-effects model to examine activation within and between each group. A dual-signif- icance corrected threshold of height at p=0.01 and cluster extent at p=0.01 was used within groups. To determine the location of signifi cant clusters, coordinates were fi rst converted to the Talai- rach template using the mni2tal function (http://imaging.mrc- cbu.cam.ac.uk/imaging/MniTalairach), and then brain regions were localized using the Talairach Daemon software (http://www. talairach.org/client.html) and also visually inspected by an expe- rienced neuroimager (A.G.). A multivariate analysis of variance was conducted in SPM5 using the independent factor group and the repeated factor task (1-back minus press for Z, and 2-back minus press for Z). Gender and response time were used as covariates (see below). A thresh- old of p=0.001, extent=10 defi ned signifi cant activation that dif- fered among the three groups across task conditions (main effect of group). Mean activation levels (t-scores) were extracted from signifi cant clusters using MarsBar (http://marsbar.sourceforge. net/). Between-group t tests were then performed using SPSS (http://www.spss.com/) with a corrected signifi cance threshold of p=0.0125 (or p=0.05/4 regions tested). A connectivity analysis was conducted using the Psychophysi- ological Interaction module of SPM5. This post hoc analysis located brain regions functionally associated with the temporo- parietal junction region in the psychotic major depression group. The temporoparietal junction cluster that was signifi cantly increased in the psychotic major depression group was used as the seed region. For each participant, a 6-mm3 box was placed on the maximum voxel in the cluster. The average time course of the voxels that surpassed threshold (p=0.01) was extracted. A multi- ple regression identifi ed voxels showing a signifi cant interaction between that time course and the 2-back-press-for-Z contrast for each participant. A random-effects analysis combined individual results into a group result using a cluster-corrected threshold of dual height and extent at p=0.01. Results Data for fi ve participants with psychotic major depres- sion, two with nonpsychotic major depression, and three healthy comparison subjects were excluded because of response box failure resulting in N-back task accuracy below 50%. Scan data from one patient with psychotic major depression, four patients with nonpsychotic major depression, and two healthy comparison subjects were excluded because of movement artifacts during more than 20% of the scan. This left 16 participants in the psychotic major depression group, 15 in the nonpsychotic major depression group, and 19 in the healthy comparison group. Table 1 summarizes participants’ clinical and demo- graphic characteristics. There were no group differences in age, handedness, or years of education, but the groups differed in gender distribution. The groups had similar IQ, as measured by full-scale estimates of premorbid intellec- tual functioning. The patients for whom medication data were available had established antidepressant medication regimens with no changes; the psychotic major depression group (N=6) had an average of 20.3 weeks of antidepressant use (range=3–56, SD=19.9) and 9.8 weeks of antipsychotic use (range=5–26, SD=9.2). The nonpsychotic major depres- sion group (N=9) had an average of 42.6 weeks of antide- pressant use (range=4–156, SD=56.4). N-Back Task Performance Results All participants performed the task with a high degree of accuracy (Table 1). Response time for the 2-back task was different between groups, and further comparisons showed that this was due to signifi cantly slower response time in the nonpsychotic major depression group com- pared to the healthy comparison group (p=0.002), even when controlling for group differences in gender (p=0.007). Therefore, all comparisons with the nonpsy- chotic major depression group during the 2-back task included response time as a covariate. fMRI Results Tables 2 and 3 list regions that were signifi cantly acti- vated during the 1-back and 2-back tasks within each group. All three groups activated regions typically associ- ated with verbal working memory tasks, such as the left supramarginal gyrus, left inferior frontal gyrus, and left and right inferior parietal lobe. Between-Group Analysis of Variance Four clusters of activation were signifi cant (Figure 1). Activation in the right parahippocampal gyrus was sig- nifi cantly greater during both the 1-back and 2-back tasks in the psychotic major depression group relative to the healthy comparison group. The nonpsychotic major depression group showed greater parahippocampal acti- vation during the 2-back task relative to the comparison group. The nonpsychotic major depression group showed signifi cantly less activation in the right dorsolateral pre- frontal cortex during the 2-back task relative to both groups and greater occipital cortex activation relative to the healthy comparison group during both tasks. The psy- chotic major depression group had signifi cantly greater activation in the right temporoparietal junction during the 2-back task relative to both the nonpsychotic major depression and healthy comparison groups and nonsig- nifi cantly greater activation during the 1-back task. An important question is whether differences between the psychotic and nonpsychotic major depression groups can be attributed solely to differences in severity of depres- sive symptoms. However, group differences in brain acti- vation did not change when covaried for HAM-D score. Also, we attempted to better understand the infl uence of medication on our results by examining brain activation in medicated compared with unmedicated participants. Only the nonpsychotic major depression group contained a suffi cient number of unmedicated participants to per- form this analysis. With the group divided into unmedi- cated (N=6) and medicated (N=9) subgroups, none of the regions were signifi cantly different between subgroups. Connectivity Results The psychophysiological interaction analysis was con- ducted to better understand functional circuits involv- ing the temporoparietal junction during the 2-back task. Results showed that activation in a single large cluster in BRAIN ACTIVATION DURING WORKING MEMORY IN PSYCHOTIC MAJOR DEPRESSION 176 ajp.psychiatryonline.org Am J Psychiatry 168:2, February 2011 TABLE 1. Clinical, Demographic, and Task Performance Measures, by Group, in a Study of the Neural Circuitry Associated With Working Memory Defi cits in Psychotic Major Depression Measure Psychotic Major Depression Group (N=16) Nonpsychotic Major Depression Group (N=15) Healthy Comparison Group (N=19) Mean SD Mean SD Mean SD Age (years) 34.13 10.68 39.81 12.74 34.85 12.54 Education (years) 16.25a 3.72 14.40 1.40 15.95 2.15 IQb 111.56 9.40 104.00 10.63 111.28 9.35 Hamilton Depression Rating Scale (21-item) scorec 27.88 3.52 24.20 3.30 0.58 0.84 Brief Psychiatric Rating Scale scored 28.75 5.36 15.73 2.71 0.42 0.69 Brief Psychiatric Rating Scale positive symptom subscoree 8.38 3.70 0.13 0.35 0.00 0.00 Length of current depressive episode (weeks) 165.8f 198.4 155.5g 217.1 Task performance 1-Back % Correct 97.25 1.13 96.41 1.20 97.26 1.05 Response time 581.7 28.24 650.0 29.96 556.7 26.35 2-Back % Correct 98.47 2.84 99.03 0.38 99.77 0.33 Response timeh 629.6 30.28 683.9 32.13 559.7 28.26 N % N % N % Femalei 7 43.8