Amygdala response to self-critical stimuli and symptom improvement in psychotherapy for depression.

BACKGROUND: Cognitive-behavioural therapy is efficacious in the treatment of major depressive disorder but response rates are still far from satisfactory. AIMS: To better understand brain responses to individualised emotional stimuli and their association with outcome, to enhance treatment. METHOD: Functional magnetic resonance imaging data were collected prior to individual psychotherapy. Differences in brain activity during passive viewing of individualised self-critical material in 23 unmedicated out-patients with depression and 28 healthy controls were assessed. The associations between brain activity, cognitive and emotional change, and outcome were analysed in 21 patients. RESULTS: Patients showed enhanced activity in the amygdala and ventral striatum compared with the control group. Non-response to therapy was associated with enhanced activity in the right amygdala compared with those who responded, and activity in this region was negatively associated with outcome. Emotional but not cognitive changes mediated this association. CONCLUSIONS: Amygdala hyperactivity may lessen symptom improvement in psychotherapy for depression through attenuating emotional skill acquisition.

Sleep deprivation increases dorsal nexus connectivity to the dorsolateral prefrontal cortex in humans.

In many patients with major depressive disorder, sleep deprivation, or wake therapy, induces an immediate but often transient antidepressant response. It is known from brain imaging studies that changes in anterior cingulate and dorsolateral prefrontal cortex activity correlate with a relief of depression symptoms. Recently, resting-state functional magnetic resonance imaging revealed that brain network connectivity via the dorsal nexus (DN), a cortical area in the dorsomedial prefrontal cortex, is dramatically increased in depressed patients. To investigate whether an alteration in DN connectivity could provide a biomarker of therapy response and to determine brain mechanisms of action underlying sleep deprivations antidepressant effects, we examined its influence on resting state default mode network and DN connectivity in healthy humans. Our findings show that sleep deprivation reduced functional connectivity between posterior cingulate cortex and bilateral anterior cingulate cortex (Brodmann area 32), and enhanced connectivity between DN and distinct areas in right dorsolateral prefrontal cortex (Brodmann area 10). These findings are consistent with resolution of dysfunctional brain network connectivity changes observed in depression and suggest changes in prefrontal connectivity with the DN as a brain mechanism of antidepressant therapy action.

Valence and agency influence striatal response to feedback in patients with major depressive disorder.

BACKGROUND: Reduced sensitivity to positive feedback is common in patients with major depressive disorder (MDD). However, findings regarding negative feedback are ambiguous, with both exaggerated and blunted responses being reported. The ventral striatum (VS) plays a major role in processing valenced feedback, and previous imaging studies have shown that the locus of controls (self agency v. external agency) over the outcome influences VS response to feedback. We investigated whether attributing the outcome to one's own action or to an external agent influences feedback processing in patients with MDD. We hypothesized that depressed participants would be less sensitive to the feedback attribution reflected by an altered VS response to self-attributed gains and losses. METHODS: Using functional MRI and a motion prediction task, we investigated the neural responses to self-attributed (SA) and externally attributed (EA) monetary gains and losses in unmedicated patients with MDD and healthy controls. RESULTS: We included 21 patients and 25 controls in our study. Consistent with our prediction, healthy controls showed a VS response influenced by feedback valence and attribution, whereas in depressed patients striatal activity was modulated by valence but was insensitive to attribution. This attribution insensitivity led to an altered ventral putamen response for SA - EA losses in patients with MDD compared with healthy controls. LIMITATIONS: Depressed patients with comorbid anxiety disorder were included. CONCLUSION: These results suggest an altered assignment of motivational salience to SA losses in patients with MDD. Altered striatal response to SA negative events may reinforce the belief of not being in control of negative outcomes contributing to a cycle of learned helplessness.

Functional lateralization of the anterior insula during feedback processing.

Effective adaptive behavior rests on an appropriate understanding of how much responsibility we have over outcomes in the environment. This attribution of agency to ourselves or to an external event influences our behavioral and affective response to the outcomes. Despite its special importance to understanding human motivation and affect, the neural mechanisms involved in self-attributed rewards and punishments remain unclear. Previous evidence implicates the anterior insula (AI) in evaluating the consequences of our own actions. However, it is unclear if the AI has a general role in feedback evaluation (positive and negative) or plays a specific role during error processing. Using functional magnetic resonance imaging and a motion prediction task, we investigate neural responses to self- and externally attributed monetary gains and losses. We found that attribution effects vary according to the valence of feedback: significant valence × attribution interactions in the right AI, the anterior cingulate cortex (ACC), the midbrain, and the right ventral putamen. Self-attributed losses were associated with increased activity in the midbrain, the ACC and the right AI, and negative BOLD response in the ventral putamen. However, higher BOLD activity to self-attributed feedback (losses and gains) was observed in the left AI, the thalamus, and the cerebellar vermis. These results suggest a functional lateralization of the AI. The right AI, together with the midbrain and the ACC, is mainly involved in processing the salience of the outcome, whereas the left is part of a cerebello-thalamic-cortical pathway involved in cognitive control processes important for subsequent behavioral adaptations.

Cerebellar and cortico-striatal-midbrain contributions to reward-cognition processes and apathy within the psychosis continuum.

Negative symptoms in the psychosis continuum are linked to impairments in reward processing and cognitive function. Processes at the interface of reward processing and cognition and their relation to negative symptoms remain little studied, despite evidence suggestive of integration in mechanisms and neural circuitry. Here, we investigated brain activation during reward-dependent modulation of working memory (WM) and their relationship to negative symptoms in subclinical and early stages of the psychosis continuum. We included 27 persons with high schizotypal personality traits and 23 patients with first episode psychosis as well as 27 healthy controls. Participants underwent functional magnetic resonance imaging while performing an established 2-back WM task with two reward levels (5 CHF vs. no reward), which allowed us to assess common reward-cognition regions through whole-brain conjunction analyses and to investigate relations with clinical scores of negative symptoms. As expected for behavior, reward facilitated performance while cognitive load diminished it. At the neural level, the conjunction of high reward and high cognitive load contrasts across the psychosis continuum showed increased hemodynamic activity in the thalamus and the cerebellar vermis. During high cognitive load, more severe apathy but not diminished expression in the psychosis continuum was associated with reduced activity in right lateral orbitofrontal cortex, midbrain, posterior vermal cerebellum, caudate and lateral parietal cortex. Our results suggest that hypoactivity in the cerebellar vermis and the cortical-striatal-midbrain-circuitry in the psychosis continuum relates to apathy possibly via impaired flexible cognitive resource allocation for effective goal pursuit.

Aberrant striatal coupling with default mode and central executive network relates to self-reported avolition and anhedonia in schizophrenia.

BACKGROUND: Avolition and anhedonia are common symptoms in schizophrenia and are related to poor long-term prognosis. There is evidence for aberrant cortico-striatal function and connectivity as neural substrate of avolition and anhedonia. However, it remains unclear how both relate to shared or distinct striatal coupling with large-scale intrinsic networks. Using resting state functional magnetic resonance imaging (rs-fMRI) this study investigated the association of large-scale cortico-striatal functional connectivity with self-reported and clinician-rated avolition and anhedonia in subjects with schizophrenia. METHODS: Seventeen subjects with schizophrenia (SZ) and 28 healthy controls (HC) underwent rs-fMRI. Using Independent Component Analysis (ICA), we assessed Independent Components (ICs) reflecting intrinsic connectivity networks (ICNs), intra intrinsic functional connectivity within the ICs (intra-iFC), and intrinsic functional connectivity between different ICs (inter-iFC). Avolition and anhedonia were assessed using the Self Evaluation Scale for Negative Symptoms and the Brief Negative Symptom Scale. RESULTS: ICA revealed three striatal components and six cortical ICNs. Both self-rated avolition and anhedonia correlated with increased inter-iFC between the caudate and posterior Default Mode Network (pDMN) and between the caudate and Central Executive Network (CEN). In contrast, clinician-rated avolition and anhedonia were not correlated with cortico-striatal connectivity. Group comparison revealed trend-wise decreased inter-iFC between the caudate and Salience Network (SN) in schizophrenia patients compared to HC. DISCUSSION: Self-rated, but not clinician-rated, avolition and anhedonia was associated with aberrant striatal coupling with the default mode and the central executive network. These findings suggest that self-reported and clinician-rated scores might capture different aspects of motivational and hedonic deficits in schizophrenia and therefore relate to different cortico-striatal functional abnormalities.

The potential impact of biochemical mediators on telomere attrition in major depressive disorder and implications for future study designs: A narrative review.

BACKGROUND: Major depressive disorder (MDD) has been proposed to represent a "disease of premature aging", which is associated with certain biomarkers of cellular ageing and numerous other age-related diseases. Over the last decade, telomere length (TL) arose as a surrogate for cellular aging. Recent data suggests that TL might be reduced in patients with MDD, however, results are still inconclusive. This might be explained by the lack of assessment of potential biochemical mediators that are directly associated with telomere shortening and frequently observed in patients with MDD. METHODS: A narrative review was performed. The PubMed database was searched for relevant studies. RESULTS: We identified four major mediators, which are recurrently reported in patients with MDD and are associated with reduced TL: inflammation/oxidative stress, dysregulation of the hypothalamic-pituitary-adrenal axis, metabolic dysbalance including insulin resistance, and decreased brain-derived neurotrophic factor. These mediators are also mutually associated and were not systematically assessed in current studies investigating TL and MDD, which might explain inconclusive findings across current literature. Finally, we discuss possible ways to assess those mediators and potential implications of such approaches for future research. LIMITATIONS: The majority of identified studies had cross-sectional designs and used heterogeneous methods to assess TL and associated relevant biochemical mediators. CONCLUSIONS: A better understanding of the complex interactions between biochemical mediators, somatic comorbidities and shortened telomeres in patients with MDD might further specify the pathophysiology-based conceptualization and, based on that, personalized treatment of MDD.

Anterior cingulate volume predicts response to psychotherapy and functional connectivity with the inferior parietal cortex in major depressive disorder.

In major depressive disorder (MDD), the anterior cingulate cortex (ACC) has been associated with clinical outcome as well as with antidepressant treatment response. Nonetheless, the association between individual differences in ACC structure and function and the response to cognitive behavioral therapy (CBT) is still unexplored. For this aim, twenty-five unmedicated patients with MDD were scanned with structural and resting state functional magnetic resonance imaging before the beginning of CBT treatment. ACC morphometry was correlated with clinical changes following psychotherapy. Furthermore, whole-brain resting state functional connectivity with the ACC was correlated with clinical measures. Greater volume in the left subgenual (subACC), the right pregenual (preACC), and the bilateral supragenual (supACC) predicted depressive symptoms improvement after CBT. Greater subACC volume was related to stronger functional connectivity with the inferior parietal cortex and dorsolateral prefrontal cortex. Stronger subACC-inferior parietal cortex connectivity correlated with greater adaptive rumination. Greater preACC volume was associated with stronger functional connectivity with the inferior parietal cortex and ventrolateral prefrontal cortex. In contrast, greater right supACC volume was related to lower functional connectivity with the inferior parietal cortex. These results suggest that ACC volume and its functional connectivity with the fronto-parietal cortex are associated with CBT response in MDD, and this may be mediated by adaptive forms of rumination. Our findings support the role of the subACC as a potential predictor for CBT response.

Resting state brain network function in major depression - Depression symptomatology, antidepressant treatment effects, future research.

The alterations of functional connectivity brain networks in major depressive disorder (MDD) have been subject of a large number of studies. Using different methodologies and focusing on diverse aspects of the disease, research shows heterogeneous results lacking integration. Disrupted network connectivity has been found in core MDD networks like the default mode network (DMN), the central executive network (CEN), and the salience network, but also in cerebellar and thalamic circuitries. Here we review literature published on resting state brain network function in MDD focusing on methodology, and clinical characteristics including symptomatology and antidepressant treatment related findings. There are relatively few investigations concerning the qualitative aspects of symptomatology of MDD, whereas most studies associate quantitative aspects with distinct resting state functional connectivity alterations. Such depression severity associated alterations are found in the DMN, frontal, cerebellar and thalamic brain regions as well as the insula and the subgenual anterior cingulate cortex. Similarly, different therapeutical options in MDD and their effects on brain function showed patchy results. Herein, pharmaceutical treatments reveal functional connectivity alterations throughout multiple brain regions notably the DMN, fronto-limbic, and parieto-temporal regions. Psychotherapeutical interventions show significant functional connectivity alterations in fronto-limbic networks, whereas electroconvulsive therapy and repetitive transcranial magnetic stimulation result in alterations of the subgenual anterior cingulate cortex, the DMN, the CEN and the dorsal lateral prefrontal cortex. While it appears clear that functional connectivity alterations are associated with the pathophysiology and treatment of MDD, future research should also generate a common strategy for data acquisition and analysis, as a least common denominator, to set the basis for comparability across studies and implementation of functional connectivity as a scientifically and clinically useful biomarker.

Altered dynamics of brain connectivity in major depressive disorder at-rest and during task performance.

Major depressive disorder (MDD) has been associated with alterations in several functional brain networks. Previous studies investigating brain networks in MDD during the performance of a task have yielded inconsistent results with the function of the brain at rest. In this study, we used functional magnetic resonance imaging at rest and during a goal-directed task to investigate dynamics of functional connectivity in 19 unmedicated patients with MDD and 19 healthy controls across both experimental paradigms. Patients had spatial differences in the default mode network (DMN), in the executive network (EN), and in the dorsal attention network (DAN) compared to controls at rest and during task performance. In patients the amplitude of the low frequency (LFO) oscillations was reduced in the motor and in the DAN networks during both paradigms. There was a diagnosis by paradigm interaction on the LFOs amplitude of the salience network, with increased amplitude change between task and rest in patients relative to controls. Our findings suggest that the function of several networks could be intrinsically affected in MDD and this could be viable phenotype for the investigation on the neurobiological mechanisms of this disorder and its treatment.

Funicular myelosis in a butcher: it was the cream cans.

Background. Funicular myelosis is a known consequence of exposure to nitrous oxide. Nevertheless, there are only a few clinical trials assessing its long-term effects and there is no literature about the role of nutritional vitamin B12 supplementation in the context of nitrous oxide abuse. Case Descriptions. We diagnosed funicular myelosis in a young butcher, who consumed high amounts of meat regularly. Since the diagnostic process did not reveal any metabolic causes, reinterrogation of the patient uncovered recreational abuse of nitrous oxide out of whipped cream can gas cartridges. After stopping abuse and supplementation of vitamin B12, the patient recovered almost completely. Conclusions. In our case, even high nutritional vitamin B12 uptake could not compensate the noxious effects of nitrous oxide. Since there are emerging reports of increasing misuse, this should be considered in the diagnostic and therapeutic care of patients with nitrous oxide abuse. Furthermore, our case emphasizes that patients with vitamin B12 deficiency should be assessed for nitrous oxide abuse.

Prefrontal thinning affects functional connectivity and regional homogeneity of the anterior cingulate cortex in depression.

Major depressive disorder (MDD) is associated with structural and functional alterations in the prefrontal cortex (PFC) and anterior cingulate cortex (ACC). Enhanced ACC activity at rest (measured using various imaging methodologies) is found in treatment-responsive patients and is hypothesized to bolster treatment response by fostering adaptive rumination. However, whether structural changes influence functional coupling between fronto-cingulate regions and ACC regional homogeneity (ReHo) and whether these functional changes are related to levels of adaptive rumination and treatment response is still unclear. Cortical thickness and ReHo maps were calculated in 21 unmedicated depressed patients and 35 healthy controls. Regions with reduced cortical thickness defined the seeds for the subsequent functional connectivity (FC) analyses. Patients completed the Response Style Questionnaire, which provided a measure of adaptive rumination associated with better response to psychotherapy. Compared with controls, depressed patients showed thinning of the right anterior PFC, increased prefrontal connectivity with the supragenual ACC (suACC), and higher ReHo in the suACC. The suACC clusters of increased ReHo and FC spatially overlapped. In depressed patients, suACC ReHo scores positively correlated with PFC thickness and with FC strength. Moreover, stronger fronto-cingulate connectivity was related to higher levels of adaptive rumination. Greater suACC ReHo and connectivity with the right anterior PFC seem to foster adaptive forms of self-referential processing associated with better response to psychotherapy, whereas prefrontal thinning impairs the ability of depressed patients to engage the suACC during a major depressive episode. Bolstering the function of the suACC may represent a potential target for treatment.

Neural representation and clinically relevant moderators of individualised self-criticism in healthy subjects.

Many people routinely criticise themselves. While self-criticism is largely unproblematic for most individuals, depressed patients exhibit excessive self-critical thinking, which leads to strong negative affects. We used functional magnetic resonance imaging in healthy subjects (N = 20) to investigate neural correlates and possible psychological moderators of self-critical processing. Stimuli consisted of individually selected adjectives of personally negative content and were contrasted with neutral and negative non-self-referential adjectives. We found that confrontation with self-critical material yielded neural activity in regions involved in emotions (anterior insula/hippocampus-amygdala formation) and in anterior and posterior cortical midline structures, which are associated with self-referential and autobiographical memory processing. Furthermore, contrasts revealed an extended network of bilateral frontal brain areas. We suggest that the co-activation of superior and inferior lateral frontal brain regions reflects the recruitment of a frontal top-down pathway, representing cognitive reappraisal strategies for dealing with evoked negative affects. In addition, activation of right superior frontal areas was positively associated with neuroticism and negatively associated with cognitive reappraisal. Although these findings may not be specific to negative stimuli, they support a role for clinically relevant personality traits in successful regulation of emotion during confrontation with self-critical material.