Neural signature of error processing in major depression.

The clinical presentation of major depression (MD) is heterogenous and comprises various affective and cognitive symptoms including an increased sensitivity to errors. Various electrophysiological but only few functional magnetic resonance imaging (fMRI) studies investigated neural error processing in MD with inconsistent findings. Thus, reliable evidence regarding neural signatures of error processing in patients with current MD is limited despite its potential relevance as viable neurobiological marker of psychopathology. We therefore investigated a sample of 16 young adult female patients with current MD and 17 healthy controls (HC). During fMRI, we used an established Erikson-flanker Go/NoGo-paradigm and focused on neural alterations during errors of commission. In the absence of significant differences in rates of errors of commission in MD compared to HC, we observed significantly (p < 0.05, FWE-corrected on cluster level) enhanced neural activations of the dorsal anterior cingulate cortex (dACC) and the pre-supplementary motor area (pre-SMA) in MD relative to HC and thus, in brain regions consistently associated to neural error processing and corresponding behavioral adjustments. Considering comparable task performance, in particular similar commission error rates in MD and HC, our results support the evidence regarding an enhanced responsivity of neural error detection mechanisms in MD as a potential neural signature of increased negative feedback sensitivity as one of the core psychopathological features of this disorder.

Differential neural processing of unpleasant sensory stimulation in patients with major depression.

An altered processing of negative salient stimuli has been suggested to play a central role in the pathophysiology of major depression (MD). Besides negative affective and social stimuli, physical pain as a subtype of negative sensory stimulation has been investigated in this context. However, the few neuroimaging studies on unpleasant sensory stimulation or pain processing in MD report heterogeneous findings. Here, we investigated 47 young females, 22 with MD and 25 healthy controls (HC) using fMRI (3.0 T). Four levels of increasingly unpleasant electrical stimulation were applied. Ratings of stimulus intensity were assessed by a visual analogue scale. fMRI-data were analyzed using a 2 × 4 ANOVA. Behavioral results revealed no group differences regarding accuracy of unpleasant stimulation level ratings and sensitivity to stimulation. Regarding neural activation related to increasing levels of unpleasant stimulation, we observed increasing activation of brain regions related to the pain and salient stimulus processing corresponding to increasingly unpleasant stimulation in controls. This modulation was significantly smaller in MD compared to controls, particularly in the dorsal anterior cingulate cortex, the somatosensory cortex, and the posterior insula. Overall, brain regions associated with the processing of unpleasant sensory stimulation, but also associated with the salience network, were highly reactive but less modulated in female patients with MD. These results support and extent findings on altered processing of salience and of negative sensory stimuli even of a non-painful quality in female patients with MD.

Neural Signatures of Social Inclusion in Borderline Personality Disorder Versus Non-suicidal Self-injury.

Borderline personality disorder (BPD) is characterized by interpersonal disturbances and dysfunctional behavior such as non-suicidal self-injury (NSSI). We recently observed neural alterations in BPD during social inclusion by enhanced activations within the dorsomedial prefrontal cortex (dmPFC) and the posterior cingulate cortex (PCC). To examine the specificity of these neural alterations, we now investigated participants with NSSI but without BPD and compared them to BPD and healthy controls (HC). Considering the association between NSSI and BPD, we further examined neural commonalities during social inclusion. Fifteen females diagnosed with BPD, 16 with NSSI and 17 HC were investigated by fMRI and the cyberball paradigm, focusing on social inclusion (p < 0.05; FWE on cluster-level). To examine neural commonalities between BPD and NSSI compared to HC, we computed a conjunction analysis on neural activations under social inclusion. Significant increases in neural activation were observed in BPD within the dmPFC under social inclusion compared to NSSI and HC, whereas neural activations within the PCC did not differ between BPD and NSSI. The conjunction analysis revealed a common neurofunctional increase within the pregenual anterior cingulate cortex and the anterior insula in both, BPD and NSSI. We provide a further evidence regarding a disorder-specific neural reactivity within the dmPFC during social inclusion in BPD, whereas PCC activations may represent an unspecific neural alteration in BPD when compared to NSSI. In contrast, both clinical groups revealed a common neural increase within the salience network that may support the assumptions of a developmental continuum between these two psychiatric conditions.

Adolescent depression and brain development: evidence from voxel-based morphometry

Background: Investigating adolescents and young adults may provide a unique opportunity to understand developmental aspects of the neurobiology of depression. During adolescence, a considerable physiologic reorganization of both grey and white matter of the brain takes place, and it has been suggested that differences in grey-matter volumes during adolescence may reflect different maturational processes. Methods: We investigated grey-matter volumes in a comparatively large sample (n = 103) of adolescents and young adults (aged 12 to 27 years), 60 of them with a diagnosis of current depression. Results: Replicating previous studies, we found a clear wholebrain effect of age: the older the participants, the lower their global grey-matter volumes, particularly in the paracingulate and prefrontal cortices. Contrasting depressed and healthy youth in a whole-brain approach, we found greater grey-matter volumes in the dorsolateral prefrontal cortex of those with depression. Furthermore, a region-of-interest analysis indicated lower grey-matter volumes in the hippocampus in participants with depression compared with healthy controls. Limitations: The present study was limited because of a skewed sex distribution, its cross-sectional design and the fact that some participants were taking an antidepressant. Conclusion: During adolescence, restructuring of the brain is characterized by marked decreases in prefrontal grey-matter volumes, interpreted as a correlate of brain maturation. Findings of greater volumes in the prefrontal cortex, particularly in younger adolescents with depression, may suggest that these participants were more prone to delayed brain maturation or increased neuroplasticity. This finding may represent a risk factor for depression or constitute an effect of developing depression.

Neural Correlates of Social Inclusion in Borderline Personality Disorder.

Humans engage in social interactions and have a fundamental need and motivation to establish and maintain social connections. Neuroimaging studies particularly focused on the neural substrates of social exclusion in healthy subjects (HC), borderline personality disorder (BPD), and major depression (MD). However, there is evidence regarding neural alterations also during social inclusion in BPD that we intended to elucidate in our study. Considering that patients with BPD often have comorbid MD, we investigated patients with BPD, and comorbid MD, patients with MD without BPD, and a sample of HC. By investigating these two clinical samples within one study design, we attempted to disentangle potential confounds arising by psychiatric disorder or medication and to relate neural alterations under social inclusion specifically to BPD. We investigated 48 females (15 BPD and MD, 16 MD, and 17 HC) aged between 18 and 40 years by fMRI (3T), using the established cyberball paradigm with social exclusion, inclusion, and passive watching conditions. Significant group-by-condition interaction effects (p < 0.05, FWE-corrected on cluster level) were observed within the dorsolateral (dlPFC) and dorsomedial prefrontal cortex (dmPFC), the temporo-parietal junction (TPJ), the posterior cingulate cortex (PCC), and the precuneus. Comparisons of estimated neural activations revealed that significant interaction effects were related to a relative increase in neural activations during social inclusion in BPD. In detail, we observed a significant increase in differential (social inclusion vs. passive watching) neural activation within the dmPFC and the PCC in BPD compared to both, MD and HC. However, significant interaction effects within the dlPFC and the TPJ could not specifically be linked to BPD considering that they did not differ significantly between the two clinical groups in post-hoc comparisons. Our study supports previous results on effects of social and inclusion in BPD, and provides further evidence regarding disorder specific neural alterations in BPD for brain regions associated with self-referential and mentalizing processes during social inclusion.

Somatosensory Stimulus Intensity Encoding in Borderline Personality Disorder.

Borderline Personality Disorder (BPD) is clinically characterized by emotional instability, interpersonal disturbances and dysfunctional behavior such as non-suicidal self-injury (NSSI). During NSSI, patients with BPD typically report analgesic or hypoalgesic phenomena, and pain perception and pain processing in BPD have been repeatedly investigated. Most of the studies so far focused on affective-motivational and cognitive-evaluative neural components of pain within categorial study designs. By contrast, rather basic somatosensory aspects such as neural intensity-encoding of somatosensory stimuli were not examined in further details. Thus, we investigated patients with BPD and healthy controls (HC) by functional magnetic resonance imaging (fMRI) during an unpleasant sensory stimulation task with parametrically increasing stimulus intensities. 15 females diagnosed with BPD and 15 HCs were investigated with fMRI during four individually adjusted levels of electrical stimulus intensities. Ratings of stimulus intensity were assessed by button presses during fMRI. fMRI-data were analyzed by analyses of variances (ANOVA) at a statistical threshold of p < 0.05 FWE-corrected on cluster level. Subjective ratings of stimulus intensities were alike between BPD and HC, and intensity levels identified with equal accuracy. Significant intensity-encoding neural activations were observed within the primary and secondary somtasensory cortex, the posterior insula, the posterior midcingulate cortex (pMCC) and the supplementary motor area (SMA) in both, HC and BPD. Notably, there were no significant between-groups differences in intensity-encoding neural activations, even at lowered significance thresholds. Present results suggest a similar neural somatosensory stimulus intensity encoding in BPD as previously observed on a behavioral level. The alterations in neural affective-motivational or cognitive-evaluative components reported so far may be restricted to pain rather than unpleasant stimulus processing and were absent in our study.

Differential Neural Processing of Social Exclusion and Inclusion in Adolescents with Non-Suicidal Self-Injury and Young Adults with Borderline Personality Disorder.

INTRODUCTION: Non-suicidal self-injury (NSSI) is a symptom of borderline personality disorder (BPD). However, NSSI often occurs independently of BPD. Altered neural processing of social exclusion has been shown in adolescents with NSSI and adults with BPD with additional alterations during social inclusion in BPD patients. Aims of this study were to investigate differences in neural processing of social inclusion and exclusion situations between adolescents with NSSI and young adults with BPD and NSSI. METHODS: Using fMRI, neural processing of positive and negative social situations (paradigm: "Cyberball") was explored. Participants were 14 adolescents with NSSI, but without BPD (Mage = 15.4; SD = 1.9), 15 adults with BPD and NSSI (Mage = 23.3; SD = 4.1), as well as 15 healthy adolescents (Mage = 14.5; SD = 1.7), and 16 healthy adults (Mage = 23.2; SD = 4.4). RESULTS: Behavioral results showed enhanced feelings of social exclusion in both patient groups as compared to healthy controls but only the NSSI group showed enhanced activation during social exclusion versus inclusion compared to the other groups. While both NSSI and BPD groups showed enhanced activation in the ventral anterior cingulate cortex during social exclusion as compared to their age-matched controls, enhanced activation during social inclusion as compared to a passive watching condition was mainly observed in the BPD group in the dorsolateral and dorsomedial prefrontal cortex, and the anterior insula. DISCUSSION: While neural processing of social exclusion was pronounced in adolescents with NSSI, BPD patients also showed increased activity in a per se positive social situation. These results might point toward a higher responsiveness to social exclusion in adolescents with NSSI, which might then develop into a generalized increased sensitivity to all kinds of social situations in adults with BPD.

Glucocorticoid receptor variants in childhood attention-deficit/hyperactivity disorder and comorbid psychiatric disorders.

Stress results in a variety of neuroendocrine, immune and behavioral responses and represents a risk factor for many disorders. Following exposure to stress, glucocorticoids are secreted from the adrenal cortex and act via the ligand-activated glucocorticoid receptor (GR). Several polymorphisms of the GR-encoding gene NR3C1 have been described and functionally investigated. However, the impact of these variants on complex diseases such as Attention-Deficit/Hyperactivity Disorder (ADHD) is still unclear. In this study, 251 children with ADHD, 19 affected and 35 unaffected siblings, and their parents were included in a family-based association study assessing seven common variants of NR3C1 (TthIIII_rs10052957; NR3C1-I_rs10482605; ER22/23EK_rs6189/rs6190; N363S_rs56149945; BclI_rs41423247; GR-9beta_rs6198). A four-marker haplotype (TthIIII-NR3C1-I-ER22/23EK) was nominally associated with ADHD. In addition, in index children with ADHD, associations with comorbid disorders, inattentive and hyperactive-impulsive symptoms were explored. N363S minor allele carriers were more likely to show comorbid conduct disorder (CD). In our study, NR3C1 variants moderately affected ADHD and had a significant effect on comorbid CD. Therefore, NR3C1 as an important gene of the hypothalamic-pituitary-adrenal axis seems to be particularly relevant for the pathophysiology of ADHD combined with comorbid CD. For a deeper understanding, investigations in larger samples of healthy, ADHD and CD individuals are warranted.

Differential neural processing of social exclusion in adolescents with non-suicidal self-injury: An fMRI study.

Non-suicidal self-injury (NSSI) is highly prevalent in adolescence and has been suggested as an autonomous diagnosis in the Diagnostic and Statistical Manual (DSM-5). Social rejection is as potential risk-factor for NSSI and depression in adolescence. Objectives of this study were to identify differences in neural processing of social rejection in depressed adolescents with and without co-morbid NSSI and healthy controls. Participants were 28 depressed adolescents (14 with co-morbid NSSI, 79% females) and 15 healthy controls, with an average age of 15.2 years (SD=1.8). Social exclusion was implemented using the Cyberball paradigm 'Cyberball' during functional magnetic resonance imaging (fMRI). All participants reported feelings of social exclusion after fMRI scanning. Investigating the effects of NSSI, we found that depressed adolescents with NSSI showed relatively enhanced activation of the medial prefrontal cortex (mPFC) and the ventrolateral prefrontal cortex (vlPFC) compared to depressed adolescents without NSSI and also compared to healthy controls. Results point towards divergent processing of social exclusion in depressed adolescents with NSSI as compared to adolescents with mere depression in brain regions previously related to the processing of social exclusion. This finding of distinct neurophysiological responses may stimulate further research on individual treatment approaches.

Differential neural processing of unpleasant haptic sensations in somatic and affective partitions of the insula in non-suicidal self-injury (NSSI).

Altered perception and neural processing of pain have been observed during non-suicidal self-injury (NSSI). Evidence suggests that this phenomenon could be associated with the affective rather than the somatosensory dimension of pain. Sub-partitions of the insula have been suggested to process these different aspects differentially. In the present study, activation within the posterior, middle, and anterior partitions of the insula upon unpleasant electric stimulation was compared between subjects with a history of NSSI and healthy controls. Using functional magnetic resonance imaging (fMRI), we investigated a sample of 30 subjects, 14 of them with a lifetime history of NSSI. Unpleasant electric stimulation to the dorsum of the non-dominant hand was performed at four levels of increasing intensity. Significantly increasing posterior insula activation, which is likely to reflect the somatosensory aspects of unpleasant haptic sensations, was found upon parametrically increasing electric stimulation in both groups. By contrast, activation of the anterior insula, rather related to the more affective aspects of distressing stimuli, was significantly modulated only in the control group, but not in subjects with NSSI. These findings may support present hypotheses of altered processing of the more affective aspects of unpleasant or distressing experiences in NSSI, as a putatively relevant factor for understanding the etiology of this behavior.

A brief cognitive-behavioural group therapy programme for the treatment of depression in adolescent outpatients: a pilot study.

BACKGROUND: The goal of this pilot study was to examine the feasibility and clinical outcomes of a brief (6-session) group therapy programme in adolescent outpatients with depression. The programme had previously been assessed in in-patients, with positive results. METHODS: A total of 15 outpatients aged 13 to 18 years took part in the programme between October 2010 and May 2011, in 3 separate groups of 4-6 participants each. The outcomes measured were feasibility of the programme, as assessed by attendance rate, user feedback, fidelity of implementation, and response to treatment, as assessed by pre- and post-intervention measurement of depressive symptoms, quality of life, and suicidal ideation. RESULTS: The programme demonstrated good feasibility, with a mean attendance rate of 5.33 out of 6 sessions, a mean rating by participants on overall satisfaction with the programme of 7.21 out of 10 (SD = 1.89), and a 93% concurrence between the contents of the sessions and the contents of the treatment manual. Compared to baseline scores, depressive symptoms at follow-up test were significantly reduced, as assessed by the Children's Depression Rating Scale Revised (F(1, 12) = 11.76, p < .01) and the Beck Depression Inventory Revision (F(1, 32) = 11.19, p < .01); quality of life improved, as assessed by the Inventory of Quality of Life (F(1, 31) = 5.27, p < .05); and suicidal ideation was reduced. No significant changes were seen on the measures of the Parent Rating Scale for Depression and the Clinical Global Impression scale. CONCLUSIONS: Based on the results of this pilot study, it is feasible to further assess this brief outpatient treatment programme in a randomized controlled trial without further modifications.

It's all about money: oral contraception alters neural reward processing.

Mating preferences in phases of the natural menstrual cycle with a low probability to conceive have been associated with lower interest in characteristics promising genetic benefits but increased search for safety and future security. We hypothesized that this effect would also be evident under oral contraception and may therefore alter neural processing of monetary rewards as a proxy for potential safety. Our aim was to assess the activation of reward-related brain areas using a monetary incentive task in women with functional MRI (fMRI). We compared fMRI activation of 12 young women taking oral contraceptives with 12 women with a natural hormonal cycle in their follicular phase during the expectation of monetary rewards. Women under hormonal contraception who have already shown decreased anterior insula activation upon erotic stimulation in a previous study of the same sample now showed enhanced activation during monetary reward expectation in the anterior insula/inferior lateral prefrontal cortex (t=2.84; P<0.05) relative to young normal cycling women in the follicular phase. Our finding supports the notion that the switch in mating preferences related to different hormonal states in women is mirrored by a switch in the stimulus-dependent excitability of reward-related brain regions. Beyond highlighting hormonal effects on reward processing, our data underline the importance of monitoring hormonal states in fMRI research in women.