Effects of Psychotherapy on Glutamatergic Neurotransmission.

INTRODUCTION: Psychodynamic psychotherapy is an effective and widely used treatment for major depressive disorder (MDD); however, little is known about neurobiological changes associated with induced symptom improvement. METHODS: Proton magnetic resonance spectroscopy with a two-dimensional J-resolved sequence served to test the relationship between glutamate (Glu) and glutamine (Gln) levels, measured separately in pregenual anterior cingulate cortex (pgACC) and the anterior midcingulate cortex (aMCC) as a control region, with change in depression symptoms after 6 months of weekly psychodynamic psychotherapy sessions in MDD patients. Depressed (N = 45) and healthy (N = 30) subjects participated in a baseline proton magnetic resonance spectroscopy measurement and a subgroup of MDD subjects (N = 21) then received once-a-week psychodynamic psychotherapy and participated in a second proton magnetic resonance spectroscopy measurement after 6 months. Change in depression symptoms was assessed using the Hamilton Depression Rating Scale (HAMD). RESULTS: Higher pretreatment pgACC Gln concentrations in MDD patients compared to healthy controls were associated with symptom severity. Patients and controls did not differ regarding Gln levels in aMCC nor regarding Glu levels in both regions. The association of pgACC Gln concentration and severity of depressive symptoms was reversed after 6 months of psychotherapy in MDD subjects. Regarding Gln in aMCC as well as Glu in both regions, there were no significant associations with improvement of depressive symptoms in the course of psychotherapy. DISCUSSION: Findings indicate specific regional effects of psychodynamic psychotherapy on glutamatergic neurotransmission and thereby highlight the key role of the pgACC in both depression pathophysiology and recovery.

Anticipating control over aversive stimuli is mediated by the medial prefrontal cortex: An fMRI study with healthy adults.

The anticipation of control over aversive events in life is relevant for our mental health. Insights on the underlying neural mechanisms remain limited. We developed a new functional magnetic resonance imaging (fMRI) task that uses auditory stimuli to explore the neural correlates of (1) the anticipation of control over aversion and (2) the processing of aversion. In a sample of 25 healthy adults, we observed increased neural activation in the medial prefrontal cortex (ventromedial prefrontal cortex and rostral anterior cingulate cortex), other brain areas relevant for reward anticipation (ventral striatum, brainstem [ventral tegmental area], midcingulate cortex), and the posterior cingulate cortex when they anticipated control over aversion compared with anticipating no control (1). The processing of aversive sounds compared to neutral sounds (2) was associated with increased neural activation in the bilateral posterior insula. Our findings provide evidence for the important role of medial prefrontal regions in control anticipation and highlight the relevance of conceiving the neural mechanisms involved within a reward-based framework.

Effects of ketamine on cognition-emotion interaction in the brain.

Cognition-emotion interaction in the brain can be investigated by incorporating stimuli with emotional content into cognitive tasks. Emotional stimuli in the context of a working memory (WM) task yield increased activation in WM-related lateral prefrontal regions, whereas cognitive effort enhances deactivation in emotion-related cortical midline regions. N-methyl-d-aspartate glutamate receptors (NMDA-Rs) are critically involved in WM, and NMDA-R antagonists, such as ketamine, accordingly affect WM but also have a profound impact on emotional processing, as underscored by the rapid reduction of depressive symptoms after administration of a single dose of ketamine. The effect of ketamine on both cognitive and emotional processing therefore makes it a useful tool to further explore cognition-emotion interaction in the brain. Twenty-three healthy subjects were administered ketamine to investigate whether its effects on WM performance and brain reactivity depend on emotional content or emotional valence of stimuli. Furthermore, we aimed at investigating how ketamine affects the integration of emotion and WM processes in emotion-related cortical midline regions and WM-related lateral prefrontal regions. Results show that ketamine modulates cognition-emotion interaction in the brain by inducing lateralized and valence-specific effects in emotion-related cortical midline regions, WM-related lateral prefrontal regions and insula. In emotion-related cortical midline regions ketamine abolishes enhancement of deactivation normally observed during cognitive effort, while in the right DLPFC and the left insula the previously described pattern of increased activation due to emotional content is abrogated exclusively for negative stimuli. Our data therefore shows a specific effect of ketamine on cognition-emotion interaction in the brain and indicates that its effect on amelioration of negative biases in MDD patients might be related to less interference of cognitive processing by negative emotional content.

Ketamine administration reduces amygdalo-hippocampal reactivity to emotional stimulation.

Increased amygdala reactivity might lead to negative bias during emotional processing that can be reversed by antidepressant drug treatment. However, little is known on how N-methyl-d-aspartate (NMDA) receptor antagonism with ketamine as a novel antidepressant drug target might modulate amygdala reactivity to emotional stimulation. Using functional magnetic resonance imaging (fMRI) and resting-state fMRI (rsfMRI), we assessed amygdalo-hippocampal reactivity at baseline and during pharmacological stimulation with ketamine (intravenous bolus of 0.12 mg/kg, followed by a continuous infusion of 0.25 mg/kg/h) in 23 healthy subjects that were presented with stimuli from the International Affective Picture System (IAPS). We found that ketamine reduced neural reactivity in the bilateral amygdalo-hippocampal complex during emotional stimulation. Reduced amygdala reactivity to negative pictures was correlated to resting-state connectivity to the pregenual anterior cingulate cortex. Interestingly, subjects experienced intensity of psychedelic alterations of consciousness during ketamine infusion predicted the reduction in neural responsivity to negative but not to positive or neutral stimuli. Our findings suggest that the pharmacological modulation of glutamate-responsive cerebral circuits, which is associated with a shift in emotional bias and a reduction of amygdalo-hippocampal reactivity to emotional stimuli, represents an early biomechanism to restore parts of the disrupted neurobehavioral homeostasis in MDD patients. Hum Brain Mapp 37:1941-1952, 2016. © 2016 Wiley Periodicals, Inc.

Determinants of cerebral hemodynamics during the Trail Making Test in schizophrenia.

Patients with schizophrenia show deficits in cognitive functioning, and studies on cerebral hemodynamics have revealed aberrant patterns of mean cerebral blood flow velocity (MFV), an equivalent of cerebral blood flow (CBF). Therefore, we carried out a controlled study that assessed MFV in schizophrenia during a well-known neuropsychological task, the Trail Making Test (TMT). We measured MFV in the middle cerebral arteries using functional transcranial Doppler sonography in 15 schizophrenia patients and 15 healthy subjects. In comparison to healthy subjects, patients performed poorer on the TMT-A and the TMT-B, and there was increased cerebral blood flow velocity during the TMT-B. A comparison of subgroups of patients and controls matched in performance on the TMT-B revealed that these patients still showed significantly increased cerebral blood flow velocity. Increased MFV in schizophrenia suggests specific alterations of cerebral hemodynamics during the Trail Making Test, Part B, which are not detectable during visuomotor activity, and which are independent of performance. These findings emphasize the pathophysiological importance of cognitive functioning in schizophrenia, but cast doubts whether performance in this particular test plays a relevant role for CBF abnormalities in schizophrenia.

Gender and rapid alterations of hemispheric dominance during planning.

BACKGROUND: Mental planning and carrying out a plan provoke specific cerebral hemodynamic responses. Gender aspects of hemispheric laterality using rapid cerebral hemodynamics have not been reported. METHOD: Here, we applied functional transcranial Doppler sonography to examine lateralization of cerebral hemodynamics of the middle cerebral arteries of 28 subjects (14 women and 14 men) performing a standard planning task. There were easy and difficult problems, and mental planning without motor activity was separated from movement execution. RESULTS: Difficult mental planning elicited lateralization to the right hemisphere after 2 or more seconds, a feature that was not observed during movement execution. In females, there was a dominance to the left hemisphere during movement execution. Optimized problem solving yielded an increased laterality change to the right during mental planning. CONCLUSIONS: Gender-related hemispheric dominance appears to be condition-dependent, and change of laterality to the right may play a role in optimized performance. Results are of relevance when considering laterality from a perspective of performance enhancement of higher cognitive functions, and also of psychiatric disorders with cognitive dysfunctions and abnormal lateralization patterns such as schizophrenia.

Sustained cognitive impairments after clinical recovery of severe depression.

Neuropsychological impairment is prominent in patients with depression, but it is unclear whether deficits persist after clinical response. This study aimed to investigate neuropsychological functions in the course of the illness. Depressive patients were investigated in the acute state and after clinical response using an extensive neuropsychological test battery. After clinical response, there was only a partial improvement in learning and memory and there were no changes regarding working memory, executive functions, and attention. Transient impairments in visual learning and memory suggest a depression-related state effect. The continuing deficits in attention, working memory, and executive function might be considered a trait marker.

Predicting non-response to multimodal day clinic treatment in severely impaired depressed patients: a machine learning approach.

A considerable number of depressed patients do not respond to treatment. Accurate prediction of non-response to routine clinical care may help in treatment planning and improve results. A longitudinal sample of N = 239 depressed patients was assessed at admission to multi-modal day clinic treatment, after six weeks, and at discharge. First, patient's treatment response was modelled by identifying longitudinal trajectories using the Hamilton Depression Rating Scale (HDRS-17). Then, individual items of the HDRS-17 at admission as well as individual patient characteristics were entered as predictors of response/non-response trajectories into the binary classification model (eXtremeGradient Boosting; XGBoost). The model was evaluated on a hold-out set and explained in human-interpretable form by SHapley Additive explanation (SHAP) values. The prediction model yielded a multi-class AUC = 0.80 in the hold-out set. The predictive power for the binary classification yielded an AUC = 0.83 (sensitivity = .80, specificity = .77). Most relevant predictors for non-response were insomnia symptoms, younger age, anxiety symptoms, depressed mood, being unemployed, suicidal ideation and somatic symptoms of depressive disorder. Non-responders to routine treatment for depression can be identified and screened for potential next-generation treatments. Such predictors may help personalize treatment and improve treatment response.

Gender characteristics of cerebral hemodynamics during complex cognitive functioning.

Functional Transcranial Doppler sonography (fTCD) has been applied to assess peak mean cerebral blood flow velocity (MFV) with a high temporal resolution during cognitive activation. Yet, little attention has been devoted to gender-related alterations of MFV, including spectral analysis. In healthy subjects, fTCD was used to investigate a series of cerebral hemodynamic parameters in the middle cerebral arteries (MCA) during the Trail Making Tests (TMT), a means of selective attention and complex cognitive functioning. In females, there was a frequency peak at 0.375 Hz in both MCA, and we observed a dynamic shift in hemispheric dominance during that condition. Further, after the start phase, there was an MFV decline during complex functioning for the entire sample. These novel results suggest condition-specific features of cerebral hemodynamics in females, and it adds to the notion that gender is a fundamental confounder of brain physiology.

GABA concentrations in the human anterior cingulate cortex predict negative BOLD responses in fMRI.

The human anterior cingulate cortex (ACC) is part of the default-mode network that shows predominant negative blood oxygen level-dependent (BOLD) responses in functional magnetic resonance imaging (fMRI). We combined fMRI during emotional processing and resting-state magnetic resonance spectroscopy measurements and observed that the concentration of GABA in the ACC specifically correlated with the amount of negative BOLD responses in the very same region. Our findings show that default-mode network negative BOLD responses during emotions are mediated by GABA.

Differential Alterations in Resting State Functional Connectivity Associated with Depressive Symptoms and Early Life Adversity.

Depression and early life adversity (ELA) are associated with aberrant resting state functional connectivity (FC) of the default mode (DMN), salience (SN), and central executive networks (CEN). However, the specific and differential associations of depression and ELA with FC of these networks remain unclear. Applying a dimensional approach, here we analyzed associations of FC between major nodes of the DMN, SN, and CEN with severity of depressive symptoms and ELA defined as childhood abuse and neglect in a sample of 83 healthy and depressed subjects. Depressive symptoms were linked to increased FC within the SN and decreased FC of the SN with the DMN and CEN. Childhood abuse was associated with increased FC within the SN, whereas childhood neglect was associated with decreased FC within the SN and increased FC between the SN and the DMN. Our study thus provides evidence for differential associations of depressive symptoms and ELA with resting state FC and contributes to a clarification of previously contradictory findings. Specific FC abnormalities may underlie specific cognitive and emotional impairments. Future research should link specific clinical symptoms resulting from ELA to FC patterns thereby characterizing depression subtypes with specific neurobiological signatures.

Sex differences in depressive symptoms and their networks in a treatment-seeking population - a cross-sectional study.

BACKGROUND: The higher prevalence of major depressive disorder (MDD) in females relative to males is well-established. Some authors have posited this difference arises to divergent symptom profiles in females vs. males. However, empirical tests of this hypothesis have yielded equivocal results. Here, we investigate sex differences in MDD of individual symptoms and symptom networks in a treatment-seeking sample. METHODS: We assessed depressive symptoms using Hamilton Depression Rating Scale (HDRS-17) in 590 treatment-seeking adults with MDD (300 females). We examined group differences in symptom endorsement. We investigated symptom networks and estimated Gaussian Graphical Models. Finally, we compared the female and male networks using the Network Comparison Test. RESULTS: Females scored significantly higher in psychological anxiety (p <0.001; rB = -0.155), somatic anxiety (p = .001; rB = -0.150) and feelings of guilt (p = .002; rB = -0.139). Male and female patients did not differ in depression sum scores. There were no sex differences in network structure or global strength. LIMITATIONS: Our study was sufficiently powered to detect only medium sized symptom differences. The generalizability of our study is limited to clinical samples and further studies are needed to investigate if findings also translate to outpatient samples. CONCLUSION: Females reported elevated anxiety symptoms and guilt. Clinicians should assess these symptom differences and tailor treatment to individual symptom profiles. No differences between sexes emerged in MDD network structures, indicating that features may be more similar than previously assumed. Sex differences in psychopathological features of MDD are important for future research and personalized treatment.

The awareness of the scared - context dependent influence of oxytocin on brain function.

Oxytocin is both a hormone and a neurotransmitter and has been originally recognized for its role in childbirth and lactation. Later, it became widely known as a "cuddle hormone" that induces trusting behavior towards strangers and reduces social stress and anxiety. Several studies showed that oxytocin influences empathic behavior and has prosocial effects. The anterior cingulate cortex and the anterior insula are brain regions that are active when humans observe fear in others. Therefore, the aim of this study was to investigate whether oxytocin administration affects activity in these regions depending on whether a threat is directed at another person (empathy) compared to when the threat is directed at the subject itself (fear). Our findings demonstrate increased anterior cingulate cortex activation after oxytocin administration in the fear, but not in the empathy condition. Furthermore, oxytocin administration was associated with deceased anterior insula activity in the empathy condition. However, our findings do not support the idea that oxytocin generally augments activity in brain regions associated with empathy. Thereby this study supports current research questioning that oxytocin has exclusively prosocial effects on human behavior. Rather, the effect of oxytocin depends on various contextual (e.g. presence of a familiar person) and interindividual (e.g. sex, mental disorder) factors. Therefore, to consider oxytocin an empathy inducing hormone is an oversimplification and future research should focus on factors moderating oxytocin effects.

Increased self-focus in major depressive disorder is related to neural abnormalities in subcortical-cortical midline structures.

Patients with major depressive disorder (MDD) often show a tendency to strongly introspect and reflect upon their self, which has been described as increased self-focus. Although subcortical-cortical midline structures have been associated with reflection and introspection of oneself in healthy subjects, the neural correlates of the abnormally increased attribution of negative emotions to oneself, i.e. negative self-attribution, as hallmark of the increased self-focus in MDD remain unclear. The aim of the study was, therefore, to investigate the neural correlates during judgment of self-relatedness of positive and negative emotional stimuli thereby testing for emotional self-attribution. Using fMRI, we investigated 27 acute MDD patients and compared them with 25 healthy subjects employing a paradigm that focused on judgment of self-relatedness when compared with mere perception of the very same emotional stimuli. Behaviourally, patients with MDD showed significantly higher degrees of self-relatedness of specifically negative emotional stimuli when compared with healthy subjects. Neurally, patients with MDD showed significantly lower signal intensities in various subcortical and cortical midline regions like the dorsomedial prefrontal cortex (DMPFC), supragenual anterior cingulate cortex, precuneus, ventral striatum (VS), and the dorsomedial thalamus (DMT). Signal changes in the DMPFC correlated with depression severity and hopelessness whereas those in the VS and the DMT were related to judgment of self-relatedness of negative emotional stimuli. In conclusion, we present first evidence that the abnormally increased negative self-attribution as hallmark of the increased self-focus in MDD might be mediated by altered neural activity in subcortical-cortical midline structures.

Rapid cerebral hemodynamic modulation during set shifting: evidence of time-locked associations with cognitive control in females.

Set shifting provokes specific alterations of cerebral hemodynamics in basal cerebral arteries. However, no gender differences have been reported. In the following functional transcranial Doppler study, we introduced cerebral hemodynamic modulation to the aspects of set shifting during Wisconsin Card Sorting Test (WCST). Twenty-one subjects underwent the WCST during insonation of the middle cerebral arteries. We examined gender effects on task performance and cerebral hemodynamic modulation. Further, we investigated the linkage between performance and cerebral hemodynamic modulation. In females, maximum positive modulation was restricted to the behaviorally relevant time point of set shifting, and there were time-locked associations between mental slowing during set shifting and rapid cerebral hemodynamic modulation exclusively in females. This study provides evidence of gender-related cerebral hemodynamic modulation during set shifting, and we detected time-locked brain-behavior relationship during cognitive control in females.

Deliberate self-harm in female patients with affective disorders: investigation of personality structure and affect regulation by means of operationalized psychodynamic diagnostics.

This study investigated psychodynamically relevant dimensions in female depressive patients with and without deliberate self-harm (DSH). DSH is often observed in depressive patients and frequently shows a correlation with personality disorders. Forty female depressive patients with and without DSH were investigated after recovery from acute depressive pathology by means of "operationalized psychodynamic diagnostics" (OPD). Patients with DSH had a significantly lower level of integration in the OPD dimension "structure," and their "interpersonal relationships" showed dysfunctional interaction patterns. They also had a significantly higher rate of personality disorders. These results underline the significance of aspects of personality structure in female depressive patients with DSH, and enable a deeper understanding of their dysfunctional defense strategies, the connections with underlying disturbed affect regulation, and vicious circles in the therapeutic transference-countertransference relationship. OPD has been shown to be a useful tool for empirical research into therapeutically relevant dimensions of personality.

Neuropsychodynamic Approach to Depression: Integrating Resting State Dysfunctions of the Brain and Disturbed Self-Related Processes.

A mechanism-based approach was developed focusing on the psychodynamic, psychological and neuronal mechanisms in healthy and depressed persons. In this integrative concept of depression, the self is a core dimension in depression. It is attributed to negative emotions (e.g., failure, guilt). The increased inward focus in depression is connected with a decreased environmental focus. The development of neuropsychodynamic hypotheses of the altered self-reference is based on the investigation of the emotional-cognitive interaction in depressed patients. It may be hypothesized that the increased negative self-attributions-as typical characteristics of an increased self-focus in depression-may result from altered neuronal activity in subcortical-cortical midline structures in the brain, especially from hyperactivity in the cortical-subcortical midline regions and hypoactivity in the lateral regions. The increased resting state activity in depression is especially associated with an increased resting state activity in the default mode network (DMN) and a dysbalance between DMN and executive network (EN) activity. Possible therapeutic consequences of the neuropsychodynamic approach to depression involve the necessary emotional attunement in psychotherapy of depressed patients and the adequate timing of therapeutic interventions. The hypotheses which have been developed in the context of the neuropsychodynamic model of depression may be used for more specific psychotherapeutic interventions, aiming at specific mechanisms of compensation and defence, which are related to the increased resting state activity and the disturbed resting state-stimulus-interaction.

One look is worth a thousand words: New picture stimuli of interpersonal situations.

This paper introduces a picture system that can be used in functional imaging experiments exploring interpersonal relations. This is important for psychotherapy research to understand the neural basis of psychological treatment effects. Pictures have many advantages for the design of functional imaging experiments, but no picture system illustrating interpersonal behavior patterns is, to date, available. We therefore developed, on the basis of a validated card-sorting test, the Interpersonal Relations Picture System. In summary, 43 pictures with 2 or more stick figures in different social situations and 9 control pictures were composed. To test the relation between each picture and the appropriate description, two successive online surveys, including 1058 and 675 individuals respectively, were conducted. Using two question types, the grade expressiveness of each picture was assessed. In total, 24 pictures and 6 control pictures met our criteria for sufficient strength and consistency with the appropriate description. Both measures are correlated with each other in all pictures illustrating interpersonal behavior, but not in the control pictures. Relations to other stimulus types and the applicability of the new picture system in functional neuroimaging methods are discussed. It is concluded that the new system will be helpful in studying the profound effect of relational change in psychotherapy.

Rapid cerebral hemodynamic modulation during mental planning and movement execution: evidence of time-locked relationship with complex behavior.

OBJECTIVE: Although there is evidence of specific associations between neuronal activity and early cerebral blood flow (CBF), little is known on a logical furtherance of this linkage, namely the association between early measures of cerebral hemodynamics and complex behavior. The present study examined the linkage between hemodynamic modulation in basal cerebral arteries and performance in a non-routine planning task by means of functional transcranial Doppler sonography (fTCD). METHODS: The Stockings of Cambridge (SOC) was employed as planning paradigm. The middle and anterior cerebral arteries (MCA/ACA) were bilaterally insonated. Statistical methods comprised uni- and multivariate analyses of variance and multiple linear regression analyses. RESULTS: Taking advantage of the excellent temporal resolution of fTCD, early cerebral hemodynamic modulation of the left MCA markedly predicted task accuracy. Pronounced early blood flow increase during planning and early decrease during movement execution were associated with better performance. No such blood flow modulations were observed in worse performers. CONCLUSIONS: Early cerebral hemodynamic modulation in the left MCA proved to be a valuable neurophysiological marker that showed a great overlap with task accuracy during non-routine planning. SIGNIFICANCE: These results support the notion that a high temporal resolution in functional monitoring is a favorable strategy to disentangle relevant neurophysiological correlates of higher cognitive functioning.

Voluntary vs. involuntary hospital admission in acute mania of bipolar disorder: results from the Swiss sample of the EMBLEM study.

BACKGROUND: Patients with acute mania in bipolar disorder require pharmacological treatment to reduce symptoms. In addition, it is recognised that admission status is a clinically relevant aspect of bipolar disorder. There is, however, a lack of published data assessing the association of admission status with clinical or functional outcomes. The European-Mania-in-Bipolar-Longitudinal-Evaluation-of-Medication (EMBLEM) study has been designed to describe outcomes associated with medication therapies. Baseline data from this study are now available and we used these data to examine the characteristics of patients with acute mania in the Swiss EMBLEM cohort who were admitted involuntary and voluntary, respectively, and their functional and clinical status. METHODS: Ninety-five patients with an acutely manic or mixed episode of bipolar disorder were included in the Swiss cohort of the study. Patients' history, psychosocial functioning, clinical measures of mania and depression, pharmacological and compliance variables were assessed. Statistical methods comprised univariate analyses of variance and logistic regression analyses to elucidate associations between variables of interest. RESULTS: Patients with involuntary hospital admission (n = 55) were more aggressive and had less insight. They had a more frequent history of substance abuse and were less likely to take anticonvulsants or lithium. Furthermore, these patients showed lower compliance, which also guided physicians' decision on pharmacotherapy. LIMITATION: The EMBLEM study had an observational and non-interventional design; therefore it was not possible to compare treatment groups by means of stringent between-group analyses. However, a main target of this study was to gather clinically relevant information on outcomes of acute mania associated with currently available medication therapies. CONCLUSIONS: Involuntary admission status was significantly associated with clinical status, especially aggression and also compliance. Admission status in bipolar patients plays a clinically important role.