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Emotional deficits have long been observed in patients with schizophrenia (1,2), particularly in individuals with blunted affect (3). In 1950, Bleuler considered the deficit in affective function to be a core feature of schizophrenia (2). More recently, convergent evidence from neuro psychological, psychophysiological, and neuroimaging studies has found that temporolimbic-prefrontal circuits are central to the expression of emotion deficits in schizophrenia (4,5). Limbic-prefrontal systems show a reciprocal modulatory relation in emotion processing and representation (6). Specifically, various lines of evidence suggest involvement of the VLPFC in this metacognitive representation of one’s own emotional state (7). Most important, this area has been found to be activated during external and (or) internal induction of negative emotional states (for example, sadness, anxiety, and anger) (8–10). The VLPFC receives sensory inputs (olfactory, gustatory, visceral afferent, somatic sensory, and visual) as well as limbic inputs from the amygdala, entorhinal and perirhinal cortex, and subiculum (11). Therefore, the VLPFC plays an important role in integrating viscerosensory information with changes in subjects’ emotional states (6,11). Prefrontal cortex abnormalities have been observed in patients with schizophrenia. In 1974, Ingvar and Franzen coined the term “hypofrontality” to denote the relative decrease they found in their calculation of a ratio of frontal-to-postcentral blood flow in schizophrenia patients (12). Subsequent studies with PET, SPECT, and fMRI have confirmed this original finding. In 1992, using SPECT, Andreasen and colleagues investigated neuroleptic-naive schizophrenia patients, nonnaive schizophrenia patients who had been relatively chronically ill but were medication-free for at least 3 weeks, and healthy normal volunteers (13). Decreased prefrontal activation occurred only in the patients with high scores for negative symptoms. These results suggest that hypofrontality is related to negative symptoms and is not a long-term effect of neuroleptic treatment or of chronicity of illness. Notably, using rCBF during the resting state, Suzuki and colleagues demonstrated that hypofrontality correlates with blunted affect in schizophrenia (14). The lower the left frontal blood flow was in schizophrenia patients, the more pronounced were the negative symptoms, including blunted affect, avolition–apathy, and inattention. Hence, the authors argued that the negative symptoms in schizophrenia patients are related to left frontal lobe dysfunction. In a PET study, Liddle and associates showed that psychomotor poverty symptoms, which include blunted affect, poverty of speech, and decreased spontaneous movement, are associated with diminished bilateral frontal rCBF (15). More recently, numerous other authors have also advocated hypofrontality correlation with negative symptoms in schizophrenia. For example, while investigating rCBF in deficit and nondeficit types of schizophrenia, Vaiva and colleagues found that the patients with a deficit form of schizophrenia showed a significant bilateral reduction in SPECT perfusion in the right and left frontodorsolateral cortex, compared with the nondeficit schizophrenia patients (16). In another study, Wang and colleagues used rCBF SPECT imaging to assess 16 patients with chronic schizophrenia (negative symptoms) during the resting state (17). Results were assessed with Spearman’s correlation analysis. Total Scales of Assessment of Negative Symptoms scores were significantly negatively correlated with bilateral hypofrontality. Subscores for affect were negatively correlated with rCBF in the bilateral prefrontal and bilateral superior frontal areas. These results support the notion that frontal lobe dysfunction in schizophrenia is associated with negative symptoms. Further evidence comes from a recent metaanalysis indicating that diminished physiological activity in the prefrontal region, as measured with PET and SPECT (that is, hypofrontality), is the most prevalent of 25 brain-imaging findings associated with schizophrenia (18). In a similar vein, Roth and colleagues investigated neuropsychological performance and regional brain volumes in schizophrenia patients with high and low levels of apathy (19). They concluded that the high-apathy group had lower performance IQ scores than the low-apathy and comparison groups; only the high-apathy group showed significantly reduced bilateral frontal lobe volumes, relative to comparison subjects. To better understand the processes underlying hypofrontality and blunted affect dysfunction in schizophrenia, our study compared BA+ schizophrenia patients with BA– schizophrenia patients, using a passive viewing task involving a sad emotional situation. The concept of hypofrontality raises an important question about the phenotyping of schizophrenia: Is hypofrontality more pronounced in patients with blunted affect and social withdrawal, relative to other schizophrenia patients? To eliminate confounding factors that arise from symptom diversity, we focused on 2 samples of schizophrenia patients closely matched for sex, age, and parental education. To eliminate the confounding effect of poor task performance, we studied them during the passive viewing of sad film excerpts. To gauge the relation between symptoms and BOLD signal change, we remeasured symptoms just before the scan. MethodsSubjects Fourteen BA+ subjects and 11 BA– subjects participated in the study. The inclusion criteria were a diagnosis of schizophrenia according to DSM-IV criteria, no concomitant Axis I or Axis II disorder, and no medical or neurologic disease. We used the RSEB (3) to discriminate between the 2 groups of subjects: BA+ subjects scored higher than 17 on this scale, and BA– subjects scored lower than 10. In the BA+ group (11 men, 3 women), the mean age was 27.57 years, SD 8.90 (range 20 to 46 years), whereas in the BA– group (5 men, 6 women), it was 25.73 years, SD 4.43 (range 21 to 37 years). There was no difference in terms of education level—all subjects had finished high school. Subjects were stabilized with various types of antipsychotic medications; some subjects received 2 antipsychotic drugs. In the BA+ group, subjects received haloperidol (1 subject; 10 mg, SD 0.0), zuclopentixol (2 subjects; 150 mg, SD 0.0), risperidone (8 subjects; 3.3 mg, SD 1.4), or olanzapine (4 subjects; 21.2 mg, SD 6.2) and (or) quetiapine (10 subjects; 505 mg, SD 138). In the BA– group, subjects received haloperidol (3 subjects; 6.7 mg, SD 2.9), zuclopentixol (2 subjects; 125 mg, SD 35.0), risperidone (4 subjects; 5.5 mg, SD 3.5), or olanzapine (2 subjects; 17.5 mg, SD 3.5) and (or) quetiapine (2 subjects; 300 mg, SD 353). Using SPSS software (20), we conducted a 2-tailed independent sample t test and found no significant difference (t = 1.74, df 23, P = 0.17) between the 2 groups in dosage-equivalent estimation to 100 mg daily of chlorpromazine (21). However, it should be noted that a considerable number of subjects received typical antipsychotics, specifically in the BA– group (5/11 subjects, compared with 3/14 in the BA+ group). All subjects gave written informed consent after a detailed explanation. The local scientific and ethics committees approved the study. Psychiatric Assessment Psychiatric assessment measures included the DSM-IV, the PANSS (22,23), and the CDS (23). For more details about the results of the psychiatric assessment tests, please refer to Table 1.
fMRI Experimental Design We measured BOLD signal changes during 2 experimental conditions, a sad condition and a neutral condition, which were presented in counterbalanced order. Each block lasted 180 seconds (60 volumes x 3-second intervals) separated by resting periods of 18 seconds during which subjects viewed a blue cyan screen. Total scan time was 6.3 minutes. In addition, 6 volumes were collected during a rest period before the first block of film to allow T1 effects to stabilize; we excluded these from the analysis by eliminating the first 6 scans. Sad film excerpts depicted the death of a beloved person, either a father, a mother, or a friend. We matched the emotionally neutral film excerpts to the sad film excerpts with respect to the number and sex of the individuals involved. Emotionally neutral film excerpts depicted various human activities (for example, interviews, carpentry, or gardening). To assess subjective responses to the stimuli, immediately at the end of the run, we asked participants to rate the average intensity of sadness felt during the viewing of the sad film excerpts according to a visual analog rating scale ranging from 0 (absence of any emotional reaction) to 8 (strongest emotion ever felt in one’s lifetime). Image Acquisition and Analysis Echoplanar images were acquired on a 1.5 Tesla system (Magnetom Vision, Siemens Electric, Erlangen, Germany). Twenty-eight slices (5 mm thick) were acquired every 2.65 seconds in an inclined axial plane aligned with the ACPC axis. These T2*-weighted functional images were acquired with an echoplanar image pulse sequence (TE = 44 ms, Flip = 90°, FOV = 215 mm, Matrix = 64 x 64). Following functional scanning, high resolution data were acquired via a T1-weighted 3-dimensional volume acquisition obtained with a gradient echo pulse sequence (TE = 44 ms, Flip = 12°, FOV = 250 mm, Matrix = 256 ´ 256). We used SPM99 (24) implemented in MATLAB (25) to analyze the data. Automated algorithms were used to align each subject’s sequential MRI images, to spatially normalize them into the stereotactic space of Talairach and Tournoux (26) according to the Montreal Neurological Institute standard brain (based on 305 brains), and to smooth them (10 mm full width at half maximum). We determined the localization of the reported activation sites with the atlas of Talairach and Tournoux (26). For the statistical analysis, we convolved the time series of the images with the delayed boxcar function, which approximates the predicted activation patterns. Effects at each and every voxel were estimated using the general linear model. Voxel values for the contrasts of interest yielded a statistical parametric map of the t statistic, subsequently transformed to the unit normal distribution. We conducted our statistical analysis according to the random effects model so that inferences could be made at the population level (27). We modelled the signal time course for each subject with a boxcar function convolved with a hemodynamic response function and high-pass filtering (366 seconds), using the nonscaling function. This high-pass filter was applied to remove noise associated with low-frequency confounders (for example, a respiratory artifact). Each of the negative or neutral film excerpt conditions was contrasted with each of the others, thereby creating one contrast image per subject for each film condition. We entered these images into a 2-sample t test to investigate the significant activation differences between patient groups (BA+ minus BA– and vice versa for sad minus neutral). We used t statistics on a voxel-by-voxel basis to assess significant signal changes for each contrast (27). The resulting areas of activation were characterized in terms of their peak height and spatial extent. First, we investigated the main effect of the film excerpts by analyzing the 2 conditions together. We set the statistical threshold at P = 0.001 (uncorrected) for height and reported clusters larger than 5 contiguous voxels. Second, we subtracted the images of the sad film condition from the film excerpts of the neutral condition to determine the neural substrates of emotional sad film processing. For the 2-sample t test, we considered activation significant at P = 0.05 after correction for multiple comparisons. For all our analyses, we listed the region names (according to the human brain atlas of Talairach and Tournoux, 26), z values, and coordinates of activated foci in the tables. We performed a hypothesis-led analysis to test our prior hypothesis of reduced activation in VLPFC in BA+ schizophrenia patients compared with BA– schizophrenia patients during passive viewing of film excerpts. We applied the small volume correction function in SPM99 in a 12-mm radius spherical ROI in the VLPFC in each hemisphere, employing a criteria of P < 0.05 corrected for multiple comparisons. The centre of the spheres (Talairach coordinates 33, 34, –14; –33, 34, –14) were located at the centred coordinates of the VLPFC region where, using the same paradigm in healthy subjects, Levesque and others found increased activation during viewing of the sad film excerpt (10). In addition, using a whole-brain exploratory analysis, we examined the differences in neural correlates of sad feelings between the 2 groups. ResultsSelf-Report Data Interestingly, a t test revealed that viewing the sad film excerpts induced a mean level of sadness that was significantly higher in the BA– subjects (mean 5.9, SD 1.22; range 3 to 7) than in the BA+ subjects (mean 1.00, SD 1.52; range 0 to 5; t = –8.71, df 23; P < 0.0001). fMRI Results: Hypothesis-Led Analysis BA– Minus BA+. Using our ROI hypothesis-led analysis, a random-effects 2-sample t test during passive viewing of the sad film excerpts (relative to the emotionally neutral film excerpts) revealed significant activation in the right VLPFC (BA 47) (Table 2, Figure 1).
BA+ Minus BA–. Conversely, the random-effects model revealed that, during passive viewing of the sad film excerpts (relative to the emotionally neutral film excerpts), BA+ subjects showed no significant activation of the VLPFC, relative to BA– subjects (Table 2 and Figure 1). fMRI Results: Exploratory Analyses The differences in regional brain activity between BA+ and BA– patients with schizophrenia are presented in Table 3 and Figure 1.
The differential neural response to negative stimuli between BA+ and BA– patients could not be ascribed to poor attention (t = 1.38, df 23; P = 0.12) or lack of motivation (t = 0.61, df 23; P = 0.35) because the between-group differences on the PANSS were insignificant. DiscussionThese study results concur with previous functional (5, 13–15,28) and structural (19,29) investigations showing that schizophrenia patients have decreased prefrontal cortex activation and volume. However, few brain-imaging studies of schizophrenia have attempted to investigate the prefrontal cortex differentiated by patients’ clinical features or symptom severity. Using the RSEB, we divided schizophrenia patients into 2 groups, those with and without blunted affect, and found that BA+ patients reported experiencing less sadness according to their self-rating subjective scale. Similarly, they showed no activation in key prefrontal emotion-processing areas when compared with BA– patients. The main result from this study was that BA– patients, relative to BA+ patients, showed significant activity in the VLPFC, which is known to be involved in the metacognitive representation of one’s own emotional state (7), to be activated during external and (or) internal induction of negative emotional states (6–10), and to receive sensory inputs as well as limbic inputs (11). Hence, the VLPFC integrates viscerosensory information with information signalling changes in subjects’ emotional states (6,11). The neural correlates of sadness found in the exploratory analysis in BA– subjects are comparable to those reported in previous functional neuroimaging studies of sadness in normal subjects (7–10,30). The activation of the anterior temporal pole is particularly interesting. As well as limbic inputs, this paralimbic cortical region receives inputs from unimodal and heteromodal sensory regions. Mesulam suggested that the anterior temporopolar region is associated with imparting affective tone to the individual’s experience (31). In this context, it is possible that the activation of the anterior temporal pole seen in our study reflects the attribution of the emotional (sad) colour to the subjective experience externally induced by the sad film excerpts. In view of the reciprocal connections between various sites among brain regions engaged in emotion processing, abnormal function at any specific site might in principle lead to diminished activation at sites at an earlier stage and (or) at later stages in the pathway. A pattern of reciprocal activation at neocortex and limbic sites during emotion processing has been reported in various situations. Mayberg and associates reported that patients suffering from depression, and also healthy individuals experiencing induced sadness, exhibited relative overactivity of the anterior cingulate and underactivity of the frontal neocortex (32). Conversely, Kiehl and colleagues found that, during the processing of emotional words, inmate patients with antisocial personality disorder exhibited diminished activation in limbic areas, including the anterior cingulate and amygdala, and increased activation in the inferior frontal neocortex (33). Thus, in both healthy individuals and in patients with various pathological conditions in which emotional experience or expression is impaired (including depression and psychopathy), it appears that there is reciprocal activation of the limbic cortex and the lateral frontal neocortex. In situations where emotion is heightened (such as in depressive illness and induced sadness in healthy people), limbic overactivity is accompanied by neocortical underactivity, whereas in conditions (such as psychopathy) where emotional response appears to be diminished, limbic underactivity is associated with frontal neocortical overactivity. Our data suggest that this relation also appears in association with blunted affect in schizophrenia. Interestingly, BA+ patients with schizophrenia showed activity in the cerebellum and the midbrain. The brain stem is the source of several ascending neural pathways, each of which originates in distinct sets of nuclei. These pathways, which reach widespread regions of the cortex, affect the operations of the cerebral cortex both by modulating aspects of its overall activity and by conveying to specific regions the contents with which a subjective sense can be created (34). This may account, at least in part, for the differences in our BA– group results, compared with the BA+ results. Obviously, the emotional information was not transmitted to the prefrontal cortex (in the case of the BA+ group). Similarly, the midbrain has been found to evoke passive emotional coping strategies (that is, quiescence, immobility, and hyporeactivity) characterized by disengagement or withdrawal from the external environment and sympathoinhibition (for example, hypotension and bradycardia) (35,36). As a result of our findings, we propose that the term hypofrontality not be generalized to schizophrenia patients but to the subgroup with marked symptoms of blunted affect. Our results confirmed the findings of Liddle and others (15) and Tamminga and others (37), which included a brain region close to that which we observed in the BA+ patients of this study, whereas the findings of Andreasen’s study team were mainly medial (13) and those of Suzuki’s team were mainly dorsal (14). In fact, an analysis of correlation between rCBF and blunted affect based on Liddle’s data revealed that the strongest correlation was with underactivity in the right VLPFC (Peter Liddle, 2004, personal communication). Moreover, hypofrontality was not our sole observation: there was disturbed dysfunctional activation throughout the brain. The significant temporal and midbrain activity observed in the BA+ group may indicate a compensatory mechanism for inactivity in other regions. The BOLD signal variations were closely related and may reflect an overall imbalance in temporal and prefrontal excitatory (glutamatergic) and inhibitory (GABAergic) circuitry (13). The net result was disrupted processing of input and output. Similarly, Harrison and Eastwood showed that the synaptic pathology of schizophrenia, at least in the temporal lobe, primarily affects excitatory (glutamatergic) neurons (38). Other authors have argued that the inferred imbalance between excitatory and inhibitory circuitry may contribute to the involvement of this region in the pathophysiology of the disorder. For example, Friston and Frith (39) and Fletcher and colleagues (40) suggested that there is an abnormal pattern of frontotemporal interaction in schizophrenia, revealed as a failure of the commonly observed deactivations of the superior temporal cortex in the presence of prefrontal activation. Abnormal neural patterns have also been explored in terms of connectivity and encapsulated as a disintegration of frontotemporal connectivity (39). Sorting these principles out is important because of the potentially broad impact of using symptom-specific deficits to study schizophrenia. Some conceptual and methodological limitations could limit the generalizability of our results. One conceptual limitation is the definition of the term “emotional blunting” (or blunted affect). We use it to refer to both diminished outward expression of emotion and diminished range of subjective emotional experience. The RSEB, which provided the basis for classifying patients, includes items that assess both emotional expression and emotional experience (41). This is evident in the presentation of means for the 2 PANSS items: the PANSS “blunted affect” item refers to diminished outward expression and the PANSS “emotional withdrawal” item refers primarily to disturbances in emotional experience. Indeed, some authors have demonstrated diminished experience of negative emotions in response to evocative laboratory stimuli (42). Likewise, the task of separating primary blunted affect from secondary blunting is another methodological concern. Medication may have caused the differences in affect: the BA+ group included more patients taking 2 antipsychotics. Further, a significant number of subjects, specifically in the BA– group, received typical antipsychotics, which could have increased scores on the RSEB and PANSS “blunted affect” and “emotional withdrawal” items. Overall, our study suggests that schizophrenia patients with blunted affect are characterized by dysfunctional regions in the prefrontal cortex; however, their illness is clearly more complex than the term hypofrontality allows. Schizophrenia involves an imbalance in circuits distributed throughout the brain—including multiple cortical and subcortical regions—that leads to impaired ability to set priorities, to process and produce information, and to turn information into meaningful thoughts and behaviour. This imbalance in circuits is expressed as psychotic or negative symptoms (43). A characterization of brain function based on the segregationist approach is incomplete insofar as it neglects to describe the relations among different brain regions. Hence, further studies are needed to investigate the frontotemporal circuit in schizophrenia patients with blunted affect and social withdrawal. One of the clinical consequences of this study is the possibility of investigating cerebral changes in the BA+ patient group occurring after treatment with an antipsychotic (44). Funding and SupportThis study was supported by the Fonds de la Recherche en Santé du Québec and an Investigator-Initiated Trial Program of AstraZeneca. References1. Kraepelin E. Dementia praecox and paraphrenia. Barclay R, translator. Edinburgh (SCT): Livingstone; 1919. 2. Bleuler E. Dementia praecox or the group of schizophrenias. Zinkin J, translator. New York (NY): International Universities Press; 1950. 3. Abrams R, Taylor MA. A rating scale for emotional blunting. Am J Psychiatry 1978;135:226–9. 4. Sison CE, Alpert M, Fudge R, Stern RM. Constricted expressiveness and psychophysiological reactivity in schizophrenia. J Nerv Ment Dis 1996;184:589–97. 5. 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Restoration of frontal activation during a treatment with quetiapine: an fMRI study of blunted affect in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2005;29(1):21–6. Author(s)Manuscript received December 2004, revised, and accepted May 2005. 1. Psychiatrist, Department of Psychiatry, Centre de Recherche Fernand-Seguin, Hôpital Louis-Hippolyte Lafontaine, Université de Montréal; Professor of Psychiatry, Department of Psychiatry, Faculty of Medicine, Université de Montréal, Montreal, Quebec. 2. Doctoral Candidate, Department of Physiology, Centre de Recherche Fernand-Seguin, Hôpital Louis-Hippolyte Lafontaine, Université de Montréal; Doctoral Candidate, Department of Physiology, Program of Neurological Sciences, Faculty of Medicine, Université de Montréal, Montreal, Quebec. 3. Professor, Division of Psychiatry, School of Community Health Sciences, University of Nottingham, Nottingham, UK 4. Postdoctoral Fellow, Department of Psychiatry, Centre de Recherche Fernand-Seguin, Hôpital Louis-Hippolyte Lafontaine, Université de Montréal; MSc Candidate, Department of Psychiatry, Program of Biomedical Sciences, Faculty of Medicine, Université de Montréal, Montreal, Quebec. 5. Physicist and Researcher, Department of Radiology, Hôpital Notre-Dame, Centre Hospitalier de l’Université de Montréal (CHUM), Montreal, Quebec. 6. Psychiatrist, Department of Psychiatry, Centre de Recherche Fernand-Seguin, Hôpital Louis-Hippolyte Lafontaine, Université de Montréal, Montreal, Quebec. 7. Associate Professor, Departments of Neurological Sciences and of Radiology, and Centre de Recherche en Sciences Neurologiques, Université de Montréal, Montreal, Quebec. Address for correspondence: Dr E Stip, Centre de Recherche Fernand-Seguin, 7331 Rue Hochelaga, Montréal, QC H1N 3V2 e-mail: emmanuel.stip@umontreal.ca
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