Task-induced deactivation of midline cortical regions in schizophrenia assessed with fMRI

Task-induced deactivations (TIDs) of midline cortical regions are readily observed in fMRI studies and may reflect elements of a 'default-mode' of brain function associated with self-directed mental processes at rest. In this study, we examined this TID phenomenon in schizophrenia and its relevance to patients' symptoms, task performance and level of emotional awareness. Relative to control subjects, patients showed significantly greater TID of the rostral anterior cingulate (rAC)/medial prefrontal cortex (mPFC) and precuneus (PrC)/posterior cingulate cortex (PC). The magnitude of prefrontal TIDs was associated with patients' task performance and emotional awareness for others. The nature of these associations suggests a complex interchange between cognitive and emotional influences on the resting-state activity of these prefrontal 'default mode' regions in schizophrenia.     

Ketamine alters neural processing of facial emotion recognition in healthy men: an fMRI study

Disruption of facial emotion perception occurs in neuropsychiatric disorders where the expression of emotion is dulled or blunted, for example depersonalization disorder and schizophrenia. It has been suggested that, in the clinical context of emotional blunting, there is a shift in the relative contribution of brain regions subserving cognitive and emotional processing. The non-competitive glutamate receptor antagonist ketamine produces such emotional blunting in healthy subjects. Therefore, we hypothesised that in healthy subjects ketamine would elicit neural responses to emotional stimuli which mimicked those reported in depersonalization disorder and schizophrenia. Thus, we predicted that ketamine would produce reduced activity in limbic and visual brain regions involved in emotion processing, and increased activity in dorsal regions of the prefrontal cortex and cingulate gyrus, both associated with cognitive processing and, putatively, with emotion regulation. Measuring BOLD signal change in fMRI, we examined the neural correlates of ketamine-induced emotional blunting in eight young right-handed healthy men receiving an infusion of ketamine or saline placebo while viewing alternating 30 s blocks of faces displaying fear versus neutral expressions. The normal pattern of neural response occurred in limbic and visual cortex to fearful faces during the placebo infusion. Ketamine abolished this: significant BOLD signal change was demonstrated only in left visual cortex. However, with ketamine, neural responses were demonstrated to neutral expressions in visual cortex, cerebellum and left posterior cingulate gyrus. Emotional blunting may be associated with reduced limbic responses to emotional stimuli and a relative increase in the visual cortical response to neutral stimuli.     

Reduced neural activity of the prefrontal cognitive control circuitry during response inhibition to negative words in people with schizophrenia

Background: Schizophrenia is characterized by deficits in executive control and impairments in emotion processing. This study assessed the nature and extent of potential alterations in the neural substrates supporting the interaction between cognitive control mechanisms and emotion attribution processes in people with schizophrenia. Methods: Functional magnetic resonance imaging was performed during a verbal emotional go/no-go task. People with schizophrenia and healthy controls responded to word stimuli of a prespecified emotional valence (positive, negative or neutral) while inhibiting responses to stimuli of a different valence. Results: We enrolled 20 people with schizophrenia and 23 controls in the study. Healthy controls activated an extensive dorsal prefrontal-parietal network while inhibiting responses to negative words compared to neutral words, but showed deactivation of the midcingulate cortex while inhibiting responses to positive words compared to neutral words. People with schizophrenia failed to activate this network during response inhibition to negative words, whereas during response inhibition to positive words they did not deactivate the cingulate, but showed increased responsivity in the frontal cortex. Limitations: Sample heterogeneity is characteristic of studies of schizophrenia and may have contributed to more variable neural responses in the patient sample despite the care taken to control for potentially confounding variables. Conclusion: Our results showed that schizophrenia is associated with aberrant modulation of neural responses during the interaction between cognitive control and emotion processing. Failure of the frontal circuitry to regulate goal-directed behaviour based on emotion attributions may contribute to deficits in psychosocial functioning in daily life.     

The influence of emotional distraction on verbal working memory: an fMRI investigation comparing individuals with schizophrenia and healthy adults

The ability to maintain information over short periods of time (i.e., working memory) is critically important in a variety of cognitive functions including language, planning, and decision-making. Recent functional Magnetic Resonance Imaging (fMRI) research with healthy adults has shown that brain activations evoked during the delay interval of working memory tasks can be reduced by the presentation of distracting emotional events, suggesting that emotional events may take working-memory processes momentarily offline. Both executive function and emotional processing are disrupted in schizophrenia, and here we sought to elucidate the effect of emotional distraction upon brain activity in schizophrenic and healthy adults performing a verbal working memory task. During the delay period between the memoranda and memory probe items, emotional and neutral distractors differentially influenced brain activity in these groups. In healthy adults, the hemodynamic response from posterior cingulate, orbital frontal cortex, and the parietal lobe strongly differentiated emotional from neutral distractors. In striking contrast, schizophrenic adults showed no significant differences in brain activation when processing emotional and neutral distractors. Moreover, the influence of emotional distractors extended into the memory probe period in healthy, but not schizophrenic, adults. The results suggest that although emotional items are highly salient for healthy adults, emotional items are no more distracting than neutral ones to individuals with schizophrenia.     

The neuroanatomical basis of affective mentalizing in schizophrenia: comparison of patients with schizophrenia and patients with localized prefrontal lesions

Patients with schizophrenia show impaired emotional and social behavior, such as misinterpretation of social situations and lack of Theory of Mind (ToM). However, the neuroanatomical basis of impaired ToM and its nature in schizophrenia is still largely unknown. Based on previous findings, the present study suggests that impaired social cognition observed in schizophrenic patients may be similar to that observed in patients with prefrontal (PFC) damage due to impaired ‘affective ToM’ abilities, rather than to a general impairment in ToM. We examined the behavioral and neural mechanisms that underlie the social and communicative impairments observed in patients with schizophrenia and with PFC damage, by looking at differential patterns of ToM impairment in these individuals. The performance of 24 patients with schizophrenia was compared to the responses of patients with localized lesions in the ventromedial (VM) or dorsolateral PFC, patients with non-frontal lesions, and healthy control subjects. Patients with schizophrenia and those with VM lesions were impaired on ‘affective ToM’ tasks but not in cognitive ToM conditions. It was concluded that the pattern of mentalizing impairments in schizophrenia resembled those seen in patients with lesions of the frontal lobe, particularly with VM damage, providing support for the notion of a disturbance of the fronto-limbic circuits in schizophrenia.     

Impairment of autonoetic awareness for emotional events in schizophrenia.

OBJECTIVE: To investigate the subjective states of awareness accompanying recognition of emotional events in patients with schizophrenia. METHOD: During the learning phase, a set of neutral pictures associated with emotional sentences was presented to 24 patients with schizophrenia and 24 healthy control subjects. During the test phase, participants had to recognize target pictures and valence and to report their subjective state of awareness (Remember, Know, or Guess) associated with recognition of pictures and valence. RESULTS: Patients with schizophrenia exhibited poor recognition of pictures and emotional valence. The frequency of Remember responses associated with recognition of pictures and of valence was lower in patients than in control subjects. CONCLUSIONS: Autonoetic awareness for emotional events is reduced in schizophrenia, with patients presenting difficulties in consciously recollecting the specific details that make events emotional.     

Associational projections of the anterior midline cortex in the rat: intracingulate and retrosplenial connections

Past studies indicate that distinct areas of anterior midline cortex in the rat contribute to diverse functions, such as autonomic nervous system regulation and learning, but the anatomical substrate for these functions has not been fully elucidated. The present study characterizes the associational connections within the midline cortex of the rat by using the anterograde transport of Phaseolus vulgaris leucoagglutinin and Fluororuby. The prelimbic area and the rostral part of the anterior cingulate area (both dorsal and ventral subdivisions) are extensively interconnected with each other. In addition, the caudal half of anterior cingulate cortex has extensive projections to precentral medial cortex and caudally directed projections to retrosplenial cortex. Other cortical areas within anterior midline cortex have relatively limited cortical–cortical projections. The infralimbic, dorsal peduncular, and medial precentral cortices have dense intrinsic projections, but have either very limited or no projections to other areas in the anterior midline cortex. Although it has been suggested that cortical–cortical projections from anterior cingulate cortex and prelimbic cortex to infralimbic cortex may be important for linking learning processes with an autonomic nervous system response, the paucity of direct projections between these areas calls this hypothesis into question. Conversely, the results suggest that the anterior midline cortex contains two regions that are functionally and connectionally distinct.     

Neural correlates of using distancing to regulate emotional responses to social situations

Cognitive reappraisal is a commonly used and highly adaptive strategy for emotion regulation that has been studied in healthy volunteers. Most studies to date have focused on forms of reappraisal that involve reinterpreting the meaning of stimuli and have intermixed social and non-social emotional stimuli. Here we examined the neural correlates of the regulation of negative emotion elicited by social situations using a less studied form of reappraisal known as distancing. Whole brain fMRI data were obtained as participants viewed aversive and neutral social scenes with instructions to either simply look at and respond naturally to the images or to downregulate their emotional responses by distancing. Three key findings were obtained accompanied with the reduced aversive response behaviorally. First, across both instruction types, aversive social images activated the amygdala. Second, across both image types, distancing activated the precuneus and posterior cingulate cortex (PCC), intraparietal sulci (IPS), and middle/superior temporal gyrus (M/STG). Third, when distancing one's self from aversive images, activity increased in dorsal anterior cingulate (dACC), medial prefrontal cortex (mPFC), lateral prefrontal cortex, precuneus and PCC, IPS, and M/STG, meanwhile, and decreased in the amygdala. These findings demonstrate that distancing from aversive social cues modulates amygdala activity via engagement of networks implicated in social perception, perspective-taking, and attentional allocation.     

Social appraisal in chronic psychosis: Role of medial frontal and occipital networks

Persons with schizophrenia often appraise other individuals as threatening or persecutory. To evaluate social appraisal in schizophrenia, we probed brain networks with a task in which subjects judged whether or not they liked face stimuli with emotional expressions. We predicted that appraising negative expressions would engage patients, more than controls, and negative faces would be related to higher levels of negative affect and produce increased activity in the medial frontal cortex, an area involved in social appraisal. Twenty-one stable outpatients with chronic non-affective psychosis (16 schizophrenic, 5 schizoaffective) and 21 healthy subjects underwent functional magnetic resonance imaging. Compared with the control subjects, patients were slower to respond, but particularly slow when they judged negatively-valenced faces, a slowness correlated with negative affect in the psychosis patients. Appraisal activated the medial prefrontal cortex (mPFC) across all face valences. For negative expressions, patients exhibited greater activation of the dorsal anterior cingulate cortex (dACC). A psychophysiological interaction analysis of the dACC revealed co-modulation of the mPFC in controls, significantly less in patients, and a trend for co-modulation of occipital cortex in the patients. Activity in occipital cortex correlated with poor social adjustment and impaired social cognition, and co-modulation of the occipital gyrus by the dACC was correlated with poorer social cognition. The findings link appraisal of negative affect with aberrant activation of the medial frontal cortex, while early sensory processing of this social cognitive task was linked with poor social function, reflecting either top-down or bottom-up influences.     

Functional imaging of emotional memory in bipolar disorder and schizophrenia

Objectives: Although in current diagnostic criteria there exists a distinction between bipolar disorder and schizophrenia, many patients manifest features of both disorders, and it is unclear which aspects, if any, confer diagnostic specificity. In the present study, we investigate whether there are differences in medial temporal lobe (MTL) activation in bipolar disorder and schizophrenia. We also investigate associations between activation levels and symptom severity across the disorders. Methods: Functional magnetic resonance imaging scans were conducted on 14 healthy controls, 14 patients with bipolar disorder, and 15 patients with schizophrenia undergoing an emotional memory paradigm. Results: All groups demonstrated the expected pattern of behavioural responses during encoding and retrieval, and there were no significant group differences in performance. Robust MTL activation was seen in all three groups during viewing of emotional scenes, which correlated significantly with recognition memory for emotional stimuli. The bipolar group demonstrated relatively greater increases in activation for emotional versus neutral scenes in the left hippocampus than both controls and patients with schizophrenia. There was a significant positive correlation between mania scores and activation in the anterior cingulate, and a significant negative correlation between depression scores and activation in the dorsolateral prefrontal cortex. Conclusion: These results provide evidence that there are distinct patterns of activation in the MTL during an emotional memory task in bipolar disorder and schizophrenia. They also demonstrate that different mood states are associated with different neurobiological responses to emotion across the patient groups.     

Key functional circuitry altered in schizophrenia involves parietal regions associated with sense of self

There is still no clear consensus as to which of the many functional and structural changes in the brain in schizophrenia are of most importance, although the main focus to date has been on those in the frontal and cingulate cortices. In the present study, we have used a novel holistic approach to identify brain‐wide functional connectivity changes in medicated schizophrenia patients, and functional connectivity changes were analyzed using resting‐state fMRI data from 69 medicated schizophrenia patients and 62 healthy controls. As far as we are aware, this is the largest population reported in the literature for a resting‐state study. Voxel‐based morphometry was also used to investigate gray and white matter volume changes. Changes were correlated with illness duration/symptom severity and a support vector machine analysis assessed predictive validity. A network involving the inferior parietal lobule, superior parietal gyrus, precuneus, superior marginal, and angular gyri was by far the most affected (68% predictive validity compared with 82% using all connections) and different components correlated with illness duration and positive and negative symptom severity. Smaller changes occurred in emotional memory and sensory and motor processing networks along with weakened interhemispheric connections. Our findings identify the key functional circuitry altered in schizophrenia involving the default network midline cortical system and the cortical mirror neuron system, both playing important roles in sensory and cognitive processing and particularly self‐processing, all of which are affected in this disorder. Interestingly, the functional connectivity changes with the strongest links to schizophrenia involved parietal rather than frontal regions. Hum Brain Mapp 35:123–139, 2014. © 2012 Wiley Periodicals, Inc.     

Multi-level comparison of empathy in schizophrenia: An fMRI study of a cartoon task

Empathy deficits might play a role in social dysfunction in schizophrenia. However, few studies have investigated the neuroanatomical underpinnings of the subcomponents of empathy in schizophrenia. This study investigated the hemodynamic responses to three subcomponents of empathy in patients with schizophrenia (N = 15) and healthy volunteers (N = 18), performing an empathy cartoon task during functional magnetic resonance imaging. The experiment used a block design with four conditions: cognitive, emotional, and inhibitory empathy, and physical causality control. Data were analyzed by comparing the blood-oxygen-level-dependent (BOLD) signal activation between the two groups. The cognitive empathy condition activated the right temporal pole to a lesser extent in the patient group than in comparison subjects. In the emotional and inhibitory conditions, the patients showed greater activation in the left insula and in the right middle/inferior frontal cortex, respectively. These findings add to our understanding of the impaired empathy in patients with schizophrenia by identifying a multi-level cortical dysfunction that underlies a deficit in each subcomponent of empathy and highlighting the importance of the fronto-temporal cortical network in ability to empathize.     

Subjective emotional over-arousal to neutral social scenes in paranoid schizophrenia

From the clinical practice and some experimental studies, it is apparent that paranoid schizophrenia patients tend to assign emotional salience to neutral social stimuli. This aberrant cognitive bias has been conceptualized to result from increased emotional arousal, but direct empirical data are scarce. The aim of the present study was to quantify the subjective emotional arousal (SEA) evoked by emotionally non-salient (neutral) compared to emotionally salient (negative) social stimuli in schizophrenia patients and healthy controls. Thirty male inpatients with paranoid schizophrenia psychosis and 30 demographically matched healthy controls rated their level of SEA in response to neutral and negative social scenes from the International Affective Picture System and the Munich Affective Picture System. Schizophrenia patients compared to healthy controls had an increased overall SEA level. This relatively higher SEA was evoked only by the neutral but not by the negative social scenes. To our knowledge, the present study is the first designed to directly demonstrate subjective emotional over-arousal to neutral social scenes in paranoid schizophrenia. This finding might explain previous clinical and experimental data and could be viewed as the missing link between the primary neurobiological and secondary psychological mechanisms of paranoid psychotic-symptom formation. Furthermore, despite being very short and easy to perform, the task we used appeared to be sensitive enough to reveal emotional dysregulation, in terms of emotional disinhibition/hyperactivation in paranoid schizophrenia patients. Thus, it could have further research and clinical applications, including as a neurobehavioral probe for imaging studies.     

An fMRI study of theory of mind in schizophrenic patients with "passivity" symptoms

Several studies have shown that patients with schizophrenia underactivate brain regions involved in theory of mind relative to controls during functional brain imaging. However, in most studies the samples were fairly heterogeneous in terms of clinical symptomatology. We examined a group of nine patients with first episode or recurrent episodes, who clinically presented with predominant "passivity" symptoms such as third-person auditory hallucinations or delusion of control, using a cartoon-based theory of mind task and compared activation patterns with a group of 13 healthy controls. All patients responded well to antipsychotic treatment and were only mildly symptomatic at the time of testing. The patient group showed significantly less activation of the right anterior cingulate cortex (ACC) and right insula compared with controls, but greater activation in dorsal areas of the medial prefrontal cortex, right temporal areas and left temporo-parietal junction. Patients with schizophrenia with predominant "passivity" symptoms and good response to antipsychotic treatment show a markedly diverging pattern of brain activation during theory of mind task performance compared with healthy controls. These findings suggest abnormal activation of those brain areas involved in the evaluation of self-reference during mental state attribution.     

Paracingulate morphologic differences in males with established schizophrenia: a magnetic resonance imaging morphometric study.

BACKGROUND: Our previous work on sulcal-gyral brain morphology in healthy volunteers revealed that males were characterized by greater cortical folding in the left versus right anterior cingulate cortex. Given the evidence showing an absence or reversal of normal anatomical asymmetries in patients with schizophrenia, the current study examined the anterior cingulate cortex sulcal-gyral patterns in patients with schizophrenia. METHODS: Using high-resolution magnetic resonance imaging, we examined anterior cingulate cortex surface morphology in a group of 55 patients with established schizophrenia and 75 healthy controls. All subjects were male and right-handed. Depending on the presence of a paracingulate sulcus and its antero-posterior extent, three types of anterior cingulate cortex sulcal patterns were identified: "prominent," "present," and "absent." Measures of overall cerebral hemispheric folding were used as independent variables and as covariates to ascertain the specificity of the findings to the anterior cingulate cortex. RESULTS: Examination of anterior cingulate cortex morphology showed that, compared with controls, patients with schizophrenia lacked the leftward anterior cingulate cortex sulcal asymmetry, which was explained by reduced folding in the left anterior cingulate cortex. These differences were over and above differences in cortical folding across the entire left hemisphere. CONCLUSIONS: These findings suggest that, in male patients with schizophrenia, there is a disturbance in the neurodevelopment of the left anterior cingulate cortex, as well as a more general aberration of left hemisphere development.     

Expecting unpleasant stimuli – An fMRI study

Expecting forthcoming events and preparing adequate responses are important cognitive functions that help the individual to deal with the environment. The emotional valence of an event is decisive for the resulting action. Revealing the underlying mechanisms may help to understand the dysfunctional information processing in depression and anxiety that are associated with negative expectation of the future. We were interested in selective brain activity during the expectation of unpleasant visual stimuli. Twelve healthy female subjects were biased to expect and then perceive emotionally unpleasant, pleasant or neutral stimuli during functional magnetic resonance imaging. Expecting unpleasant stimuli relative to expecting pleasant and neutral stimuli resulted in activation of mainly cingulate cortex, insula, prefrontal areas, thalamus, hypothalamus and striatum. While certain areas were also active during subsequent presentation of the emotional stimuli, distinct regions of the anterior cingulate gyrus and the thalamus were solely active during expectation of the unpleasant stimuli. The identified areas may reflect a network for internal adaptation and preparation processes in order to react adequately to expected unpleasant events. They are known as well to be altered in depression. Disorders of this network may be relevant for psychiatric disorders such as depression.     

Effects of psychotic state and task demand on prefrontal function in schizophrenia: an fMRI study of overt verbal fluency

OBJECTIVE: Impaired prefrontal cortical function is regarded as a central feature of schizophrenia. Although many neuroimaging studies have found evidence of abnormal prefrontal activation when patients with schizophrenia perform cognitive tasks, the extent to which this abnormality depends on the presence of active psychotic symptoms and on the demands of the task is unclear. The authors tested the hypothesis that prefrontal functional abnormalities in schizophrenia would be more evident in patients with active psychosis than in patients who were in remission and would become more apparent in the face of increasing task demands. METHOD: The authors used functional magnetic resonance imaging (fMRI) to examine prefrontal cortical activity during a paced letter verbal fluency task in three groups of subjects: acutely psychotic patients with schizophrenia, schizophrenia patients in remission, and healthy volunteers. Online subject performance was measured by utilizing a clustered fMRI acquisition sequence that allowed overt verbal responses to be made in the relative absence of scanner noise. RESULTS: Patients with schizophrenia showed less activation than the healthy comparison subjects in the anterior cingulate and the inferior frontal and right middle frontal cortices, independent of psychotic state and task demand. Acutely psychotic patients showed less activation than the healthy comparison subjects, but these differences were less marked than the differences between the patients in remission and the healthy comparison subjects. Acutely psychotic patients had less activation than the comparison subjects in the anterior cingulate but no significant difference in lateral prefrontal activation. Increasing task demand led to greater anterior cingulate and middle frontal activation in patients with active psychosis than in patients in remission. CONCLUSIONS: Schizophrenia is associated with impaired prefrontal function, but its manifestation depends on the severity of psychotic symptoms and the level of task difficulty.     

Expecting unpleasant stimuli--an fMRI study

Expecting forthcoming events and preparing adequate responses are important cognitive functions that help the individual to deal with the environment. The emotional valence of an event is decisive for the resulting action. Revealing the underlying mechanisms may help to understand the dysfunctional information processing in depression and anxiety that are associated with negative expectation of the future. We were interested in selective brain activity during the expectation of unpleasant visual stimuli. Twelve healthy female subjects were biased to expect and then perceive emotionally unpleasant, pleasant or neutral stimuli during functional magnetic resonance imaging. Expecting unpleasant stimuli relative to expecting pleasant and neutral stimuli resulted in activation of mainly cingulate cortex, insula, prefrontal areas, thalamus, hypothalamus and striatum. While certain areas were also active during subsequent presentation of the emotional stimuli, distinct regions of the anterior cingulate gyrus and the thalamus were solely active during expectation of the unpleasant stimuli. The identified areas may reflect a network for internal adaptation and preparation processes in order to react adequately to expected unpleasant events. They are known as well to be altered in depression. Disorders of this network may be relevant for psychiatric disorders such as depression.     

Disrupted theory of mind network processing in response to idea of reference evocation in schizophrenia

Park IH, Ku J, Lee H, Kim SY, Kim SI, Yoon KJ, Kim J‐J. Disrupted theory of mind network processing in response to idea of reference evocation in schizophrenia. Objective: This study examined the neural pathophysiology of the theory of mind network by eliciting self‐referential processing during an idea of reference evocating situation in patients with schizophrenia. Method: Functional MRI was conducted on 14 schizophrenic in‐patients with the idea of reference and 15 healthy participants while viewing video vignettes of referential conversations, non‐referential conversations or no conversations between two people, which were filmed at varying distances of 1, 5 or 10 m. Results: The patient group did not show normal patterns of superior temporal sulcus activation to conversational context, and reciprocal deactivation and activation of the ventromedial and dorsomedial prefrontal cortex to referential conversational context. Instead, the patient group showed overall greater ventromedial prefrontal activities across different conversational contexts and inverse correlation between superior temporal sulcus activity and delusional severity. Differential activations of the temporal pole and its posterior extension to varying distances were observed in the control group but not in the patient group. Conclusion: The present study demonstrates that theory of mind‐related responses of the medial prefrontal‐superior temporal network are attenuated during the self‐referential processing in patients with schizophrenia and that these abnormalities may be related to the formation of their referential or persecutory delusion.     

The neural substrates of affective processing toward positive and negative affective pictures in patients with major depressive disorder

Previous studies examining neural responses to emotional stimuli in individuals with major depressive disorder (MDD) have indicated increased responses within the left amygdala to sad faces, and increased activity within the visual cortex and striatum to expressions of happiness. Using functional magnetic resonance imaging (fMRI), the current study measured neural responses to neutral, positive and negative pictures of the International Affective Picture System in 15 healthy individuals and 15 patients with MDD. Depressed individuals demonstrated lower activity in the right hippocampus and the right insula to negative affective pictures, whereas they showed lower activity in the right anterior cingulate cortex and the left insula to positive pictures. However, within the MDD group, the severity of depression correlated with the activity of the left amygdala, bilateral inferior orbitofrontal areas, and the left insula to negative pictures, whereas there were no clear indications of association between specific cerebral regions and positive pictures. Our findings indicate that preferential decreases in the left amygdala in response to negative pictures might be involved in the processing of emotional stimuli in depressed individuals. Also, these findings suggest that the bilateral inferior orbitofrontal cortices and left amygdala may be preferentially recruited in MDD patients, but not in healthy individuals.