Accelerated HF-rTMS in treatment-resistant unipolar depression: Insights from subgenual anterior cingulate functional connectivity

Objectives. Intensified repetitive transcranial magnetic stimulation (rTMS) applied to the left dorsolateral prefrontal cortex (DLPFC) may result in fast clinical responses in treatment resistant depression (TRD). In these kinds of patients, subgenual anterior cingulate cortex (sgACC) functional connectivity (FC) seems to be consistently disturbed. So far, no de novo data on the relationship between sgACC FC changes and clinical efficacy of accelerated rTMS were available. Methods. Twenty unipolar TRD patients, all at least stage III treatment resistant, were recruited in a randomized sham-controlled crossover high-frequency (HF)-rTMS treatment study. Resting-state (rs) functional MRI scans were collected at baseline and at the end of treatment. Results. HF-rTMS responders showed significantly stronger resting-state functional connectivity (rsFC) anti-correlation between the sgACC and parts of the left superior medial prefrontal cortex. After successful treatment an inverted relative strength of the anti-correlations was observed in the perigenual prefrontal cortex (pgPFC). No effects on sgACC rsFC were observed in non-responders. Conclusions. Strong rsFC anti-correlation between the sgACC and parts of the left prefrontal cortex could be indicative of a beneficial outcome. Accelerated HF-rTMS treatment designs have the potential to acutely adjust deregulated sgACC neuronal networks in TRD patients.     

Adolescents' depressive symptoms moderate neural responses to their mothers' positive behavior

The way that parents express their emotions during interactions with their adolescent children is important for adolescent adjustment, and predicts adolescent emotional problems such as depression. In the current study, we assessed whether adolescent depressive symptoms were associated with neural activity during exposure to their mother's affective behavior. Thirty adolescents (18 females, mean age 17.35, s.d. 0.43) participated in an fMRI task that used digitized video segments of their own mother's, as well as an unfamiliar mother's affective behavior as stimuli. Exposure to one's own (compared to an unfamiliar) mother's positive (compared to neutral) behavior was associated with activation in the anterior and posterior cingulate, precuneus and ventrolateral prefrontal cortex. In contrast, exposure to positive behavior across own and an unfamiliar mother (controlling for neutral behavior) was associated with superior temporal sulcus, occipital pole, amygdala and striatum activity. Adolescent depressive symptoms were associated with reduced rostral anterior cingulate activity during exposure to one's own (compared to an unfamiliar) mother's positive behavior, and reduced striatal activity during exposure to positive behavior in general. This study represents an important step in furthering our understanding of the neural basis of affective processing in adolescents. Further, the results support a disruption of reward function in depression.     

Individual differences in neural responses to social rejection: the joint effect of self-esteem and attentional control

Individuals with low self-esteem have been found to react more negatively to signs of interpersonal rejection than those with high self-esteem. However, previous research has found that individual differences in attentional control can attenuate negative reactions to social rejection among vulnerable, low self-esteem individuals. The current fMRI study sought to elucidate the neurobiological substrate of this buffering effect. We hypothesized and found that while looking at scenes of social rejection (vs negative scenes) low self-esteem high attentional control individuals engaged the rostral anterior cingulate cortex (rACC), an area of the brain associated with emotional control, more than their low self-esteem low attentional control peers. Furthermore, we found that low self-esteem high attentional control individuals evaluated social rejection as less arousing and less rejecting in a separate behavioral task. Importantly, activation in the rACC fully mediated the relationship between the interaction of self-esteem and attentional control and emotional evaluations, suggesting that the rACC activation underlies the buffering effects of attentional control. Results are discussed in terms of individual differences in emotional vulnerability and protection and by highlighting the role of rACC in emotion regulation.     

Inflammatory bowel disease: perspectives from cingulate cortex in the first brain

The article by Agostini et al. (2013) in this issue of Neurogastroenterology and Motility evaluated patients with Crohn’s disease (CD) for volumetric changes throughout the brain. They observed decreased gray matter volumes in dorsolateral prefrontal cortex and anterior midcingulate cortex (aMCC) and disease duration was negatively correlated with volumes in subgenual anterior cingulate (sACC), posterior MCC (pMCC), ventral posterior cingulate (vPCC), and parahippocampal cortices. As all patients were in remission and suffered from ongoing abdominal pain, this study provides a critical link between forebrain changes and abdominal pain experience independent of active disease and drug treatment. The aMCC has a role in feedback‐mediated decision making and there are specific cognitive tasks that differentiate aMCC and pMCC that can be used to evaluate defects in CD. The sACC is an important area as it has impaired functions in major depression. As depressive symptoms are a feature in a subset of patients with active inflammatory diseases including IBD, treatment targeting this subregion should prove efficacious. Finally, vPCC has a role in ongoing self‐monitoring of the personal relevance of sensory stimuli including visceral signals via sACC. This pathway may be interrupted by vPCC atrophy in CD. Cingulate atrophy in CD leads to targeting chronic pain and psychiatric symptoms via cingulate‐mediated therapies. These include psychotherapy, guided imagery and relaxation training, analgesic dosages of morphine or antidepressants, and hypnosis. Thus, a new generation of novel treatments may emerge from drug and non‐traditional therapies for CD in this formative area of research.     

Parsing neural mechanisms of social and physical risk identifications

Psychometric studies of risk perception have categorized personal risks into social and physical domains. To investigate whether and how the human brain differentiates social and physical risks, we scanned human adults using functional magnetic resonance imaging when they identified potential risks involved in social and physical behaviors. We found that the identification of risky behaviors in both domains induced increased activations in the anterior medial prefrontal cortex (MPFC, BA9/10)/ventral anterior cingulate (ACC) and posterior cingulate (PCC) relative to identification of safe behaviors. However, social risks induced stronger anterior MPFC activation whereas physical risks were associated with stronger ventral ACC activity. In addition, anterior MPFC activity was negatively correlated with the rating scores of the degree of social risk whereas PCC activity was positively correlated with the rating scores of the degree of physical risk. Relative to an autobiographical control task, the social risk identification task induced stronger sustained activity in the left supplementary motor area/dorsal ACC and increased transient activity in bilateral posterior insula. The physical risk identification task, however, resulted in stronger sustained activity in the right cuneus/precuneus and increased transient activation in bilateral amygdala. Our results indicate the existence of distinct neural mechanisms underlying social and physical risk identifications and provide neural bases for the psychometric categorization of risks into different domains.     

Empathic neural responses to others' pain are modulated by emotional contexts

Recent brain imaging studies indicate that empathy for pain relies upon both the affective and/or the sensorimotor nodes of the pain matrix, and empathic neural responses are modulated by stimulus reality, personal experience, and affective link with others. The current work investigated whether and how empathic neural responses are modulated by emotional contexts in which painful stimulations are perceived. Using functional magnetic resonance imaging (fMRI), we first showed that perceiving a painful stimulation (needle penetration) applied to a face with neutral expression induced activation in the anterior cingulate cortex (ACC) relative to nonpainful stimulation (Q‐tip touch). However, when observation of the painful stimuli delivered to a neutral face was intermixed with observation of painful or happy faces, the ACC activity decreased while the activity in the face area of the secondary somatosensory cortex increased to the painful stimulation. Moreover, the secondary somatosensory activity associated with the painful stimulation decreased when the painful stimulation was applied to faces with happy and painful expressions. The findings suggest that observing painful stimuli in an emotional context weakens affective responses but increases sensory responses to perceived pain and implies possible interactions between the affective and sensory components of the pain matrix during empathy for pain. Hum Brain Mapp 2009. © 2009 Wiley‐Liss, Inc.     

Associations between maternal negative affect and adolescent's neural response to peer evaluation

Parenting is often implicated as a potential source of individual differences in youths’ emotional information processing. The present study examined whether parental affect is related to an important aspect of adolescent emotional development, response to peer evaluation. Specifically, we examined relations between maternal negative affect, observed during parent–adolescent discussion of an adolescent-nominated concern with which s/he wants parental support, and adolescent neural responses to peer evaluation in 40 emotionally healthy and depressed adolescents. We focused on a network of ventral brain regions involved in affective processing of social information: the amygdala, anterior insula, nucleus accumbens, and subgenual anterior cingulate, as well as the ventrolateral prefrontal cortex. Maternal negative affect was not associated with adolescent neural response to peer rejection. However, longer durations of maternal negative affect were associated with decreased responsivity to peer acceptance in the amygdala, left anterior insula, subgenual anterior cingulate, and left nucleus accumbens. These findings provide some of the first evidence that maternal negative affect is associated with adolescents’ neural processing of social rewards. Findings also suggest that maternal negative affect could contribute to alterations in affective processing, specifically, dampening the saliency and/or reward of peer interactions during adolescence.     

Perceiving rejection by others: Relationship between rejection sensitivity and the spontaneous neuronal activity of the brain

Rejection sensitivity (RS) can be defined as the disposition of a person to anxiously expect, readily perceive, and intensely react to rejection. Individuals with high RS are likely to suffer from mental disorders. The association between individual differences in RS and spontaneous neuronal activity at resting state has not yet been investigated. In this study, resting state data were used to investigate the relationship between RS and spontaneous neuronal activity in a large sample of healthy men (137) and women (172). The participants completed the rejection sensitivity questionnaire and underwent resting-state magnetic resonance imaging scan. Multiple regression analysis was conducted to examine the correlation between the regional amplitude of low-frequency fluctuations (ALFF) and rejection sensitivity scores adjusted for age and sex. Results showed that the ALFF value in the subgenual anterior cingulate cortex (sgACC) was positively associated with RS. Furthermore, functional connectivity with the middle frontal gyrus was negatively correlated with RS when sgACC was used as the seed region. These findings suggest that the spontaneous neuronal activity of sgACC and its functional connectivity with the lateral prefrontal cortex which are involved in experiencing social exclusion and regulating negative emotions are associated with individual differences in RS.     

Anterior cingulate dysfunction in geriatric depression

BACKGROUND: Although several brain abnormalities have been identified in geriatric depression, their relationship to the pathophysiological mechanisms leading to the development and perpetuation of this syndrome remain unclear. METHODS: This paper reviews findings on the anterior cingulate cortex (ACC) function and on the relationship of ACC abnormalities to the clinical presentation and the course of geriatric depression in order to elucidate the pathophysiological role of ACC in this disorder. RESULTS: The ACC is responsible for conflict detection and emotional evaluation of error and is connected to brain structures that regulate mood, emotional valence of thought and autonomic and visceral responses, which are functions disturbed in depression. Geriatric depression often is accompanied by abnormalities in some executive functions and has a clinical presentation consistent with ACC abnormalities. Indices of ACC dysfunction are associated with adverse outcomes of geriatric depression. CONCLUSIONS: Converging findings suggest that at least some ACC functions are abnormal in depression and these abnormalities are pathophysiologically meaningful. Indices of ACC dysfunction may be used to identify subgroups of depressed elderly patients with distinct illness course and treatment needs and serve as the theoretical background for novel treatment development.     

Attenuated prefrontal activation during a verbal fluency task in remitted major depression

The aim of the present study was to investigate whether a functional abnormality in the left prefrontal cortex observed in patients with major depression performing a verbal fluency task is present after remission of depression. Functional magnetic resonance imaging was used to study changes in cerebral blood oxygenation in eight remitted patients with major depression and 10 healthy control subjects during a verbal fluency task. Compared to the control subjects, the patients had a reduced response in the left prefrontal cortex (middle frontal gyrus, Brodmann area 10). These findings suggest the presence of dysfunction in the left prefrontal cortex during remission in major depression.     

The role of the subgenual anterior cingulate cortex in dorsomedial prefrontal–amygdala neural circuitry during positive‐social emotion regulation

Positive‐social emotions mediate one's cognitive performance, mood, well‐being, and social bonds, and represent a critical variable within therapeutic settings. It has been shown that the upregulation of positive emotions in social situations is associated with increased top‐down signals that stem from the prefrontal cortices (PFC) which modulate bottom‐up emotional responses in the amygdala. However, it remains unclear if positive‐social emotion upregulation of the amygdala occurs directly through the dorsomedial PFC (dmPFC) or indirectly linking the bilateral amygdala with the dmPFC via the subgenual anterior cingulate cortex (sgACC), an area which typically serves as a gatekeeper between cognitive and emotion networks. We performed functional MRI (fMRI) experiments with and without effortful positive‐social emotion upregulation to demonstrate the functional architecture of a network involving the amygdala, the dmPFC, and the sgACC. We found that effortful positive‐social emotion upregulation was associated with an increase in top‐down connectivity from the dmPFC on the amygdala via both direct and indirect connections with the sgACC. Conversely, we found that emotion processes without effortful regulation increased network modulation by the sgACC and amygdala. We also found that more anxious individuals with a greater tendency to suppress emotions and intrusive thoughts, were likely to display decreased amygdala, dmPFC, and sgACC activity and stronger connectivity strength from the sgACC onto the left amygdala during effortful emotion upregulation. Analyzed brain network suggests a more general role of the sgACC in cognitive control and sheds light on neurobiological informed treatment interventions.     

Volumetric reduction in left subgenual prefrontal cortex in early onset depression.

BACKGROUND: Subgenual prefrontal cortex (SGPFC) volume reduction has been reported in middle age adults with major depression (MD) or bipolar affective disorder. In this study, the authors test the hypothesis that SGPFC reduction is present in adolescent onset MD, and examine differences in the magnitude of reduction in younger versus older women. METHODS: Subgenual prefrontal cortex volume was measured from T1 weighted MR images in (1) 30 young women with early onset MD versus eight age-matched controls, and (2) 18 middle aged women with recurrent MD versus nine age-matched controls. RESULTS: Left SGPFC volume was reduced in adolescent and middle aged females with depression. The magnitude of the difference between depressed and control groups (average 19% difference) was similar in younger and older women. CONCLUSIONS: Left subgenual cingulate volume reductions are present in young women with adolescent onset MD.     

Separate neural systems for behavioral change and for emotional responses to failure during behavioral inhibition

To analyze the involvement of different brain regions in behavioral inhibition and impulsiveness, differences in activation were investigated in fMRI data from a response inhibition task, the stop‐signal task, in 1709 participants. First, areas activated more in stop‐success (SS) than stop‐failure (SF) included the lateral orbitofrontal cortex (OFC) extending into the inferior frontal gyrus (ventrolateral prefrontal cortex, BA 47/12), and the dorsolateral prefrontal cortex (DLPFC). Second, the anterior cingulate and anterior insula (AI) were activated more on failure trials, specifically in SF versus SS. The interaction between brain region and SS versus SF activations was significant (P = 5.6 * 10^?8). The results provide new evidence from this “big data” investigation consistent with the hypotheses that the lateral OFC is involved in the stop‐related processing that inhibits the action; that the DLPFC is involved in attentional processes that influence task performance; and that the AI and anterior cingulate are involved in emotional processes when failure occurs. The investigation thus emphasizes the role of the human lateral OFC BA 47/12 in changing behavior, and inhibiting behavior when necessary. A very similar area in BA47/12 is involved in changing behavior when an expected reward is not obtained, and has been shown to have high functional connectivity in depression. Hum Brain Mapp 38:3527–3537, 2017 . © 2017 Wiley Periodicals, Inc.     

Unlike adults,children and adolescents show predominantly increased neural activation to social exclusion by members of the opposite gender

The effects of group membership on brain responses to social exclusion have been investigated in adults, revealing greater anterior cingulate responses to exclusion by members of one’s in-group (e.g., same-gender). However, social exclusion is a critical aspect of peer relations in youth and reaches heightened salience during adolescence, a time when social anxiety disorders are also emergent. While the behavioral and neural correlates of social exclusion in adolescence have been extensively explored, the effects of group membership on peer rejection are less clear. The current study used functional magnetic resonance imaging (fMRI) to investigate the differential neural correlates of being excluded by peers of one’s same- versus opposite-gender during an online ball-toss game. Participants were a group of typically developing children and adolescents (7–17 years). As predicted, anterior cingulate cortex showed a main effect of social exclusion versus fair play. However, unlike a previous adult study, this region did not show increased activation to same-gender exclusion. Instead, several regions differentiating same- versus opposite-gender exclusion were exclusively more sensitive to exclusion by one’s opposite gender. These results are discussed in the context of adolescent socio-emotional development.     

Age-related changes to the neural correlates of social evaluation

Recent work suggests the existence of a specialized neural system underlying social processing that may be relatively spared with age, unlike pervasive aging-related decline occurring in many cognitive domains. We investigated how neural mechanisms underlying social evaluation are engaged with age, and how age-related changes to socioemotional goals affect recruitment of regions within this network. In a functional MRI study, 15 young and 15 older adults formed behavior-based impressions of individuals. They also responded to a prompt that was interpersonally meaningful, social but interpersonally irrelevant, or non-social. Both age groups engaged regions implicated in mentalizing and impression formation when making social relative to non-social evaluations, including dorsal and ventral medial prefrontal cortices, precuneus, and temporoparietal junction. Older adults had increased activation over young in right temporal pole when making social relative to non-social evaluations, suggesting reliance on past experiences when evaluating others. Young adults had greater activation than old in posterior cingulate gyrus when making interpersonally irrelevant, compared to interpersonally meaningful, evaluations, potentially reflecting enhanced valuation of this information. The findings demonstrate the age-related preservation of the neural correlates underlying social evaluation, and suggest that functioning in these regions might be mediated by age-related changes in socioemotional goals.     

Antipsychotic effect of electroconvulsive therapy is related to normalization of subgenual cingulate theta activity in psychotic depression

OBJECTIVE: Electroconvulsive therapy (ECT) is one of the most effective options available for treating depressive and psychotic symptoms in a variety of disorders. While the exact mechanism of ECT is unclear, it is known to increase metabolism and blood flow specifically in the anterior cingulate cortex (ACC). The ACC is a cortical generator of theta rhythms, which are abnormal in patients with depression and psychotic disorders. Since patients with psychotic depression are known to respond particularly robustly to ECT, we investigated whether the therapeutic effect of ECT in this population was related to normalization of abnormal theta activity in the ACC. METHOD: We obtained 19-lead electroencephalography (EEG) data from 17 participants with psychotic depression before and 2-3 weeks after a full course of ECT. EEG data was analyzed with quantitative measures and low-resolution electromagnetic tomography (LORETA) compared to an age-adjusted normative database. RESULTS: Quantitative EEG analyses revealed that theta band (4-7 Hz) activity was the only frequency band that changed with ECT. LORETA analyses revealed that the primary site of theta activity change was within the subgenual ACC (Brodmann area 25). There was a positive association between increased subgenual ACC theta activity and decreased psychotic symptoms. The degree of low theta activity in the subgenual ACC prior to ECT predicted the antipsychotic response of ECT. CONCLUSIONS: The antipsychotic effect of ECT is related to normalization of subgenual ACC theta hypoactivity.     

Neural responses to negative feedback are related to negative emotionality in healthy adults

Prior neuroimaging and electrophysiological evidence suggests that potentiated responses in the anterior cingulate cortex (ACC), particularly the rostral ACC, may contribute to abnormal responses to negative feedback in individuals with elevated negative affect and depressive symptoms. The feedback-related negativity (FRN) represents an electrophysiological index of ACC-related activation in response to performance feedback. The purpose of the present study was to examine the FRN and underlying ACC activation using low resolution electromagnetic tomography source estimation techniques in relation to negative emotionality (a composite index including negative affect and subclinical depressive symptoms). To this end, 29 healthy adults performed a monetary incentive delay task while 128-channel event-related potentials were recorded. We found that enhanced FRNs and increased rostral ACC activation in response to negative-but not positive-feedback was related to greater negative emotionality. These results indicate that individual differences in negative emotionality-a putative risk factor for emotional disorders-modulate ACC-related processes critically implicated in assessing the motivational impact and/or salience of environmental feedback.