The neural basis of the abnormal self‐referential processing and its impact on cognitive control in depressed patients

Persistent pondering over negative self‐related thoughts is a central feature of depressive psychopathology. In this study, we sought to investigate the neural correlates of abnormal negative self‐referential processing (SRP) in patients with Major Depressive Disorder and its impact on subsequent cognitive control‐related neuronal activation. We hypothesized aberrant activation dynamics during the period of negative and neutral SRP in the rostral anterior cingulate cortex (rACC) and in the amygdala in patients with major depressive disorder. Additionally, we assumed abnormal activation in the fronto‐cingulate network during Stroop task execution. 19 depressed patients and 20 healthy controls participated in the study. Using an event‐related functional magnetic resonance imaging (fMRI) design, negative, positive and neutral self‐referential statements were displayed for 6.5 s and followed by incongruent or congruent Stroop conditions. The data were analyzed with SPM8. In contrast to controls, patients exhibited no significant valence‐dependent rACC activation differences during SRP. A novel finding was the significant activation of the amygdala and the reward‐processing network during presentation of neutral self‐referential stimuli relative to baseline and to affective stimuli in patients. The fMRI analysis of the Stroop task revealed a reduced BOLD activation in the right fronto‐parietal network of patients in the incongruent condition after negative SRP only. Thus, the inflexible activation in the rACC may correspond to the inability of depressed patients to shift their attention away from negative self‐related stimuli. The accompanying negative affect and task‐irrelevant emotional processing may compete for neuronal resources with cognitive control processes and lead thereby to deficient cognitive performance associated with decreased fronto‐parietal activation. Hum Brain Mapp 36:2781–2794, 2015. © 2015 Wiley Periodicals, Inc.     

Enhanced rostral anterior cingulate cortex activation during cognitive control is related to orbitofrontal volume reduction in unipolar depression

Objective

In patients with major depressive disorder (MDD), enhanced activation of the rostral anterior cingulate cortex (rACC) during conflict resolution has been demonstrated with the use of functional magnetic resonance imaging (fMRI), which suggests dysregulation of the affective compartment of the ACC associated with error monitoring and cognitive control. Moreover, several previous studies have reported disrupted structural integrity in limbic brain areas and the orbitofrontal cortex in MDD. However, the relation between structural and functional alterations remains unclear. Therefore, the present study sought to investigate whether structural brain aberrations in terms of grey matter decreases directly in the medial frontal regions or in anatomically closely connected areas might be related to our previously reported functional alterations.

Methods

A sample of 16 female, drug-free patients with an acute episode of MDD and 16 healthy control subjects matched for age, sex and education were examined with structural high-resolution T₁-weighted MRI; fMRI images were obtained in the same session.

Results

Voxel-based morphometry (VBM) revealed grey matter decreases in the orbitofrontal and subgenual cortex, in the hippocampus-amygdala complex and in the middle frontal gyrus. The relative hyperactivation of the rACC in terms of inability to deactivate this region during the Stroop Color-Word Test showed an inverse correlation with grey matter reduction in the orbitofrontal cortex.

Conclusion

The present study provides strong evidence for an association between structural alterations in the orbitofrontal cortex and disturbed functional activation in the emotional compartment of the ACC in patients with MDD during cognitive control.Medical subject headings: magnetic resonance imaging, depressive disorder, depression     

Neural correlates of inhibitory deficits in depression

The present study used functional magnetic resonance imaging to examine neural correlates of inhibitory dysfunction in individuals diagnosed with major depressive disorder (MDD). Twelve MDD participants and 12 never-depressed controls completed the negative affective priming (NAP) task in the scanner. Results indicated that, in depressed participants, increased activation in the rostral anterior cingulate cortex (rACC) is associated with inhibition of negative, but not positive, words; in contrast, in nondepressed participants, inhibition of positive, but not negative, words is associated with increased activation in the rACC. These findings indicate that abnormalities in neural function, especially in the rACC, may underlie difficulties experienced by depressed individuals in inhibiting negative thoughts. These results underscore the importance of continuing to examine the relation between cognitive and neural functioning in depression in order to gain a broader and more integrative understanding of this disorder.     

Cognitive behavioral therapy for depression changes medial prefrontal and ventral anterior cingulate cortex activity associated with self-referential processing

Cognitive behavioral therapy (CBT), an effective treatment for depression, targets self-referential processing of emotional stimuli. We examined the effects of CBT on brain functioning during self-referential processing in depressive patients using functional magnetic resonance imaging (fMRI). Depressive patients (n = 23) and healthy participants (n = 15) underwent fMRI scans during a self-referential task using emotional trait words. The depressive patients had fMRI scans before and after completing a total of 12 weekly sessions of group CBT for depression, whereas the healthy participants underwent fMRI scans 12 weeks apart with no intervention. Before undergoing CBT, the depressive patients showed hyperactivity in the medial prefrontal cortex (MPFC) during self-referential processing of negative words. Following CBT, MPFC and ventral anterior cingulate cortex (vACC) activity during self-referential processing among depressive patients was increased for positive stimuli, whereas it was decreased for negative stimuli. Improvements in depressive symptoms were negatively correlated with vACC activity during self-referential processing of negative stimuli. These results suggest that CBT-related improvements in depressive symptoms are associated with changes in MPFC and vACC activation during self-referential processing of emotional stimuli.     

Working‐memory fMRI reveals cingulate hyperactivation in euthymic major depression

While cognitive impairments are well documented for the acute episode of major depressive disorder (MDD), less is known about cognitive functioning in the euthymic state. For working memory, dysfunctional activation of lateral prefrontal and cingulate cortex has been reported in the acute episode. This study investigates working‐memory function and its neurobiological correlate in euthymic MDD patients, particularly whether dysfunctional activation persists when depressive symptoms improve. We investigated 56 subjects with functional magnetic resonance imaging (fMRI) at 3 Tesla. To challenge working‐memory function, a classical verbal n‐back task (0‐, 1‐, and 2‐back) was used in 28 well‐characterized, euthymic, unipolar MDD patients and 28 healthy control subjects matched according to age, sex, and educational level. Data were analyzed using SPM5. In the absence of significant behavioral differences, we observed comparable overall patterns of brain activation in both groups. As expected, both groups showed stronger activation of the typical working‐memory network with increasing memory load. However, significant hyperactivation of the cingulate cortex was observed in euthymic patients, while lateral prefrontal activation was comparable between patients and controls. Working‐memory challenge in the euthymic state of MDD revealed a dissociation of lateral prefrontal and cingulate brain function. Cingulate function, which is important for both emotional and cognitive processing and their integration, is still abnormal when mood is restored. This could reflect a different speed of normalization in prefrontal and limbic cortices, persistent systematic changes in neuronal networks after an episode of MDD, or a compensatory mechanism to maintain working‐memory performance. Hum Brain Mapp, 2009. © 2008 Wiley‐Liss, Inc.     

Response conflict and frontocingulate dysfunction in unmedicated participants with major depression

Individuals with major depressive disorder (MDD) often exhibit impaired executive function, particularly in experimental tasks that involve response conflict and require adaptive behavioral adjustments. Prior research suggests that these deficits might be due to dysfunction within frontocingulate pathways implicated in response conflict monitoring and the recruitment of cognitive control. However, the temporal unfolding of conflict monitoring impairments in MDD remains poorly understood. To address this issue, we recorded 128-channel event-related potentials while 20 unmedicated participants with MDD and 20 demographically matched, healthy controls performed a Stroop task. Compared to healthy controls, MDD subjects showed larger Stroop interference effects and reduced N2 and N450 amplitudes. Source localization analyses at the time of maximal N450 activity revealed that MDD subjects had significantly reduced dorsal anterior cingulate cortex (dACC; Brodmann area 24/32) and left dorsolateral prefrontal cortex (Brodmann area 10/46) activation to incongruent relative to congruent trials. Consistent with the heterogeneous nature of depression, follow-up analyses revealed that depressed participants with the lowest level of conflict-related dACC activation 620 ms post-stimulus were characterized by the largest Stroop interference effects (relatively increased slowing and reduced accuracy for incongruent trials). Conversely, MDD participants with relatively stronger dACC recruitment did not differ from controls in terms of interference effects. These findings suggest that for some, but not all individuals, MDD is associated with impaired performance in trials involving competition among different response options, and reduced recruitment of frontocingulate pathways implicated in conflict monitoring and cognitive control.     

Piccolo genotype modulates neural correlates of emotion processing but not executive functioning

Major depressive disorder (MDD) is characterized by affective symptoms and cognitive impairments, which have been associated with changes in limbic and prefrontal activity as well as with monoaminergic neurotransmission. A genome-wide association study implicated the polymorphism rs2522833 in the piccolo (PCLO) gene—involved in monoaminergic neurotransmission—as a risk factor for MDD. However, the role of the PCLO risk allele in emotion processing and executive function or its effect on their neural substrate has never been studied. We used functional magnetic resonance imaging (fMRI) to investigate PCLO risk allele carriers vs noncarriers during an emotional face processing task and a visuospatial planning task in 159 current MDD patients and healthy controls. In PCLO risk allele carriers, we found increased activity in the left amygdala during processing of angry and sad faces compared with noncarriers, independent of psychopathological status. During processing of fearful faces, the PCLO risk allele was associated with increased amygdala activation in MDD patients only. During the visuospatial planning task, we found no genotype effect on performance or on BOLD signal in our predefined areas as a function of increasing task load. The PCLO risk allele was found to be specifically associated with altered emotion processing, but not with executive dysfunction. Moreover, the PCLO risk allele appears to modulate amygdala function during fearful facial processing in MDD and may constitute a possible link between genotype and susceptibility for depression via altered processing of fearful stimuli. The current results may therefore aid in better understanding underlying neurobiological mechanisms in MDD.     

Brain activation and pupil response during covert performance of the Stroop Color Word task.

Patterns of brain activation associated with covert performance of the Stroop Color-Word task were studied in young, healthy, adult volunteers using blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI). Comparisons of the incongruous Stroop condition were made with both color naming and word reading baselines. Areas of the left and right anterior cingulate, the right precuneus, and the left pars opercularis displayed larger BOLD signal responses during the incongruous Stroop condition than during baseline conditions. Activation of BOLD signals in these areas was highly repeatable. In a second experiment, pupil diameter was used to assess cognitive load in 7 individuals studied during overt and covert performance of both Stroop and color naming conditions. Cognitive load was similar in overt and covert response conditions. Results from the BOLD study indicate that brain regions participating in selective visual attention and in the selection of motor programs involved in speech were activated more by the Stroop task than by the baseline tasks. The neural substrate involved in the resolution of the perceptual and motor conflicts elicited by the Stroop Color-Word task does not appear to be a single brain region. Rather, a network of brain regions is implicated, with separate regions within this system supporting distinct functions.     

Activation of brainstem and midbrain nuclei during cognitive control in medicated patients with schizophrenia

Evidence suggests that cognitive control functions as well as the underlying brain network, anchored by the prefrontal cortex (PFC) and the dorsal anterior cingulate cortex (dACC), are dysfunctional in schizophrenia. Catecholamine producing midbrain and brainstem nuclei are densely connected with the PFC and dACC and exert profound contributions to cognitive control processes. Dysfunctions within the underlying neurotransmitter systems are considered to play a central role in the occurrence of various symptoms of schizophrenia. We sought to investigate the putatively abnormal activation pattern of the dopaminergic midbrain nuclei, that is, ventral tegmental area (VTA) and substantia nigra as well as that of the noradrenergic locus coeruleus (LC) in patients with schizophrenia during cognitive control. A total of 28 medicated patients and 27 healthy controls were investigated with the manual version of the Stroop task using event‐related fMRI. The main finding was a reduced BOLD activation in the VTA during both Stroop task conditions in patients in comparison to controls, which correlated significantly with the degree of negative symptoms. We further detected a comparable LC activation in in patients and healthy controls. However, in controls LC activation was significantly correlated with the Stroop interference time, which was not observed in patients. The finding of reduced VTA activation in schizophrenia patients lends further support to the assumed dysfunction of the DA system in schizophrenia. In addition, despite comparable LC activation, the nonsignificant correlation with the Stroop interference time might indicate altered LC functioning in schizophrenia and, thus, needs further investigations.     

Differential involvement of brainstem noradrenergic and midbrain dopaminergic nuclei in cognitive control

Several lines of evidence suggest that the lateral prefrontal cortex (PFC), the dorsal anterior cingulate cortex (dACC), the parietal cortex, and the thalamus are central cortical nodes in a network underlying cognitive control. However, the role of catecholamine producing midbrain and brainstem structures has rarely been addressed by functional magnetic resonance imaging (fMRI). We hypothesized differential activation patterns in the ventral tegmental area (VTA)/substantia nigra (SN) and locus coeruleus (LC) with respect to the degree of cognitive control during a Stroop task in healthy subjects. Forty‐five healthy subjects were investigated by the manual version of the Stroop task in an event‐related fMRI design. We observed significant BOLD activation of both the SN/VTA and LC during the Stroop interference condition (incongruent vs. congruent condition). LC, but not SN/VTA activation significantly correlated with the Stroop interference. Interestingly, a significant linear decrease in BOLD activation during the incongruent condition during the experiment was mainly observed in the fronto‐cingulo‐striatal network, but not in SN/VTA and LC. Using psychophysiological (PPI) analyses, a significant functional connectivity during cognitive control was observed between SN/VTA and the nigrostriatal/mesolimbic dopaminergic system. For the LC, distinct functional connectivity pattern was observed mainly to the dorsolateral and ventrolateral PFC. Both regions revealed significant functional connectivity to the dACC, parietal and occipital regions. Thus, we demonstrate for the first time that functional activation patterns in the SN/VTA and the LC are modulated by different demands of cognitive control. In addition, these nuclei exhibit distinguishable functional connectivity patterns to cortical brain networks. Hum Brain Mapp 37:2305–2318, 2016. © 2016 Wiley Periodicals, Inc.     

Neural correlates of the classic color and emotional stroop in women with abuse-related posttraumatic stress disorder.

BACKGROUND: The anterior cingulate and medial prefrontal cortex play an important role in the inhibition of responses, as measured by the Stroop task, as well as in emotional regulation. Dysfunction of the anterior cingulate/medial prefrontal cortex has been implicated in posttraumatic stress disorder (PTSD). The purpose of this study was to use the Stroop task as a probe of anterior cingulate function in PTSD. METHODS: Women with early childhood sexual abuse-related PTSD (n = 12) and women with abuse but without PTSD (n = 9) underwent positron emission tomographic measurement of cerebral blood flow during exposure to control, color Stroop, and emotional Stroop conditions. RESULTS: Women with abuse with PTSD (but not abused non-PTSD women) had a relative decrease in anterior cingulate blood flow during exposure to the emotional (but not color) classic Stroop task. During the color Stroop there were also relatively greater increases in blood flow in non-PTSD compared with PTSD women in right visual association cortex, cuneus, and right inferior parietal lobule. CONCLUSIONS: These findings add further evidence for dysfunction of a network of brain regions, including anterior cingulate and visual and parietal cortex, in abuse-related PTSD.     

In search of the depressive self: extended medial prefrontal network during self-referential processing in major depression

Major depression is associated with an excessive self-focus, a tendency to engage oneself in self-referential processing. The medial frontal gyrus (MFG) is central to self-referential processing. This study aimed to explore the neural bases of this excessive self-focus and to disambiguate the role of the MFG in the pathophysiology of major depression. We presented 15 depressed patients and 15 healthy subjects with personality traits during functional magnetic resonance imaging and asked them to judge whether each trait described them (‘self’ condition) or a generally desirable trait (‘general’ condition). Both patients and healthy subjects activated the MFG in ‘self’ vs ‘general’ condition. However, the activation of the dorsal part of the MFG and of the dorsolateral prefrontal cortex (DLPFC) in ‘self’ vs ‘general’ condition was unique to patients. Additionally, patients displayed an increased functional connectivity between the MFG, the dorsal anterior cingulate cortex and the DLPFC. These results provide evidence for an extended medial prefrontal network during self-referential processing in major depression, suggesting the involvement of a greater cognitive control.     

Depression,rumination and the default network

Major depressive disorder (MDD) has been characterized by excessive default-network activation and connectivity with the subgenual cingulate. These hyper-connectivities are often interpreted as reflecting rumination, where MDDs perseverate on negative, self-referential thoughts. However, the relationship between connectivity and rumination has not been established. Furthermore, previous research has not examined how connectivity with the subgenual cingulate differs when individuals are engaged in a task or not. The purpose of the present study was to examine connectivity of the default network specifically in the subgenual cingulate both on- and off-task, and to examine the relationship between connectivity and rumination. Analyses using a seed-based connectivity approach revealed that MDDs show more neural functional connectivity between the posterior-cingulate cortex and the subgenual-cingulate cortex than healthy individuals during rest periods, but not during task engagement. Importantly, these rest-period connectivities correlated with behavioral measures of rumination and brooding, but not reflection.     

Prefrontal hyperactivation during working memory task in untreated individuals with major depressive disorder

The prefrontal cortex, a part of the limbic-thalamic-cortical network, participates in regulation of mood, cognition and behavior and has been implicated in the pathophysiology of major depressive disorder (MDD). Many neuropsychological studies demonstrate impairment of working memory in patients with MDD. However, there are few functional neuroimaging studies of MDD patients during working memory processing, and most of the available ones included medicated patients or patients with both MDD and bipolar disorder. We used functional magnetic resonance imaging (fMRI) to measure prefrontal cortex function during working memory processing in untreated depressed patients with MDD. Fifteen untreated individuals with Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition recurrent MDD (mean age+/-s.d.=34.3+/-11.5 years) and 15 healthy comparison subjects (37.7+/-12.1 years) matched for age, sex and race were studied using a GE/Elscint 2T MR system. An echo-planar MRI sequence was used to acquire 24 axial slices. The n-back task (0-back, 1-back and 2-back) was used to elicit frontal cortex activation. Data were analyzed with a multiple regression analysis using the FSL-FEAT software. MDD patients showed significantly greater left dorsolateral cortex activation during the n-back task compared to the healthy controls (P<0.01), although task performance was similar in the two groups. Furthermore, the patients showed significant anterior cingulate cortex activation during the task, but the comparison subjects did not (P<0.01). This study provides in vivo imaging evidence of abnormal frontolimbic circuit function during working memory processing in individuals with MDD.     

Imbalance in subregional connectivity of the right temporoparietal junction in major depression

Major depressive disorder (MDD) involves impairment in cognitive and interpersonal functioning. The right temporoparietal junction (RTPJ) is a key brain region subserving cognitive‐attentional and social processes. Yet, findings on the involvement of the RTPJ in the pathophysiology of MDD have so far been controversial. Recent connectivity‐based parcellation data revealed a topofunctional dualism within the RTPJ, linking its anterior and posterior part (aRTPJ/pRTPJ) to antagonistic brain networks for attentional and social processing, respectively. Comparing functional resting‐state connectivity of the aRTPJ and pRTPJ in 72 MDD patients and 76 well‐matched healthy controls, we found a seed (aRTPJ/pRTPJ) × diagnosis (MDD/controls) interaction in functional connectivity for eight regions. Employing meta‐data from a large‐scale neuroimaging database, functional characterization of these regions exhibiting differentially altered connectivity with the aRTPJ/pRTPJ revealed associations with cognitive (dorsolateral prefrontal cortex, parahippocampus) and behavioral (posterior medial frontal cortex) control, visuospatial processing (dorsal visual cortex), reward (subgenual anterior cingulate cortex, medial orbitofrontal cortex, posterior cingulate cortex), as well as memory retrieval and social cognition (precuneus). These findings suggest that an imbalance in connectivity of subregions, rather than disturbed connectivity of the RTPJ as a whole, characterizes the connectional disruption of the RTPJ in MDD. This imbalance may account for key symptoms of MDD in cognitive, emotional, and social domains. Hum Brain Mapp 37:2931–2942, 2016. © 2016 Wiley Periodicals, Inc .     

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

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

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

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

Decreased prefrontal Myo-inositol in major depressive disorder.

BACKGROUND: Postmortem studies have shown robust prefrontal cortex glial losses and more subtle neuronal changes in major depressive disorder (MDD). Earlier proton magnetic resonance spectroscopy (1H-MRS) studies of the glial marker myo-inositol in MDD were subject to potential confounds. The primary hypothesis of this study was that MDD patients would show reduced prefrontal/anterior cingulate cortex levels of myo-inositol. METHODS: Thirteen nonmedicated moderate-severe MDD patients and 13 matched control subjects were studied (six male, seven female per group). Proton magnetic resonance spectroscopy stimulated echo acquisition mode spectra (3.0 T; echo time=168 msec; mixing time=28 msec; repetition time=3000 msec) were obtained from prefrontal/anterior cingulate cortex. Metabolite data were adjusted for tissue composition. RESULTS: Patients with MDD showed significantly lower myo-inositol/creatine ratios (.94+/-.23) than control subjects (1.32+/-.37) [F(1,23)=6.9; p=.016]. CONCLUSIONS: These data suggest a reduction of myo-inositol in prefrontal/anterior cingulate cortex in MDD, which could be a consequence of glial loss or altered glial metabolism. Additional in vivo studies of glial markers could add to the understanding of the pathophysiology of MDD.     

Never-depressed females with a family history of depression demonstrate affective bias

According to cognitive theories of depression, individuals susceptible to depression attend selectively to negative information. The purpose of the study was to examine if such an affective processing bias is present in never-depressed individuals with a family history of major depressive disorder (MDD). Formerly depressed female patients having at least one first-degree relative with a history of MDD (n=23), their never-depressed female siblings (n=21) and never-depressed female controls (n=21) performed a conventional and an emotional Stroop task using negative, positive and neutral words. A significant effect was found of group on negative processing bias; post hoc comparisons indicated that never-depressed siblings showed a larger negative processing bias than never-depressed controls. No significant differences were observed in positive bias or conventional interference between the three groups. Our findings suggest that never-depressed females with a family history of depression, like depressed patients, have more difficulties to inhibit negative material and to direct their attention towards task-specific material. This adds to the existing evidence that affective processing bias is a trait characteristic that contributes to the onset of depression and that could be a useful endophenotype for MDD.