Functional connectivity between prefrontal cortex and subgenual cingulate predicts antidepressant effects of ketamine.

Converging evidence suggests that a single sub-anesthetic dose of ketamine can produce strong and rapid antidepressant effects in patients that do not respond to standard treatment. Despite a considerable amount of research investigating ketamine's mechanisms of action, the exact neuronal targets conveying the antidepressant effects have not been identified yet. Preclinical studies suggest that molecular changes induced by ketamine bring forward large-scale network reconfigurations that might relate to ketamine's antidepressant properties. In this prospective two-site study we measured resting state fMRI in 24 depressed patients prior to, and 24 h after a single sub-anesthetic dose of ketamine. We analyzed functional connectivity (FC) at baseline and after ketamine and focused our analysis on baseline FC and FC changes directly linked to symptom reduction in order to identify neuronal targets that predict individual clinical responses to ketamine. Our results show that FC increases after ketamine between right lateral prefrontal cortex (PFC) and subgenual anterior cingulate cortex (sgACC) are positively linked to treatment response. Furthermore, low baseline FC between these regions predicts treatment outcome. We conclude that PFC-sgACC connectivity may represent a promising biomarker with both predictive and explanatory power.

Differential effects of rumination and distraction on ketamine induced modulation of resting state functional connectivity and reactivity of regions within the default-mode network.

Distraction and rumination are distinct response styles that determine how an individual deals with negative thoughts and feelings. Rumination is accompanied by an elevated self-focus, which is associated with increased resting state functional connectivity and decreased reactivity within the default mode network. Interestingly, the NMDA receptor antagonist ketamine reduces functional connectivity in this network, while its effects on blood oxygenation level-dependent (BOLD) responses during stimulus perception are not known. Ketamine might lead to a more variable processing of the external world with an attenuated self-focus by reducing the resting state connectivity. Here, we used an emotional picture-viewing task in combination with functional magnetic resonance imaging to test the hypothesis that a single ketamine administration to healthy subjects increases BOLD reactivity to negative stimuli. We found a region specific increase in BOLD reactivity in the pregenual anterior cingulate cortex and not in a posterior control region after ketamine compared with placebo administration. Moreover, a linear regression revealed that the increase in BOLD reactivity was more pronounced for subjects with a low ability to apply distraction during negative experiences. Our results implicate that ketamine attenuates a potentially pathological increased self-focus during negative experiences.

Amygdala-Hippocampal Connectivity Changes During Acute Psychosocial Stress: Joint Effect of Early Life Stress and Oxytocin.

Previous evidence shows that acute stress changes both amygdala activity and its connectivity with a distributed brain network. Early life stress (ELS), especially emotional abuse (EA), is associated with altered reactivity to psychosocial stress in adulthood and moderates or even reverses the stress-attenuating effect of oxytocin (OXT). The neural underpinnings of the interaction between ELS and OXT remain unclear, though. Therefore, we here investigate the joint effect of ELS and OXT on transient changes in amygdala-centered functional connectivity induced by acute psychosocial stress, using a double-blind, randomized, placebo-controlled, within-subject crossover design. Psychophysiological interaction analysis in the placebo session revealed stress-induced increases in functional connectivity between amygdala and medial prefrontal cortex, posterior cingulate cortex, putamen, caudate and thalamus. Regression analysis showed that EA was positively associated with stress-induced changes in connectivity between amygdala and hippocampus. Moreover, hierarchical linear regression showed that this positive association between EA and stress-induced amygdala-hippocampal connectivity was moderated after the administration of intranasal OXT. Amygdala-hippocampal connectivity in the OXT session correlated negatively with cortisol stress responses. Our findings suggest that altered amygdala-hippocampal functional connectivity during psychosocial stress may have a crucial role in the altered sensitivity to OXT effects in individuals who have experienced EA in their childhood.

Oxytocin improves mentalizing - pronounced effects for individuals with attenuated ability to empathize.

The ability to predict the behavior of others based on their mental states is crucial for social functioning. Previous studies have provided evidence for the role of Oxytocin (OXT) in enhancing the ability to mentalize. It has also been demonstrated that the effect of OXT seems to strongly depend on socio-cognitive skills with more pronounced effects in individuals with lower socio-cognitive skills. Although recent studies indicate that mentalizing is related to empathy, no study has yet examined whether the effects of OXT on mentalizing depend on the ability to empathize. 71 male participants participated in a double-blind, between-subjects, placebo-controlled experiment. The Reading the Mind in the Eye Test (RMET) was used to investigate mentalizing abilities. We analyzed the effect of OXT on easy and difficult items of the RMET depending on differential empathy scores of the participants as assessed with the Empathy Quotient (EQ). Our results showed that OXT improves mentalizing for difficult but not for easy items. We generally observed increased mentalizing accuracy in participants with higher empathy scores. Importantly, however, whereas the performance in participants with higher empathy scores was comparable in both OXT and placebo condition, OXT specifically enhanced mentalizing accuracy in participants with lower empathy scores. Our findings suggest that OXT enhances mentalizing abilities. However, we also demonstrate that not all participants benefited from OXT application. It seems that the effects of OXT strongly depend on baseline social-cognitive skills such as empathy.

The beneficial effect of oxytocin on avoidance-related facial emotion recognition depends on early life stress experience.

RATIONALE: Previous studies have shown that oxytocin (OXT) enhances social cognitive processes. It has also been demonstrated that OXT does not uniformly facilitate social cognition. The effects of OXT administration strongly depend on the exposure to stressful experiences in early life. Emotional facial recognition is crucial for social cognition. However, no study has yet examined how the effects of OXT on the ability to identify emotional faces are altered by early life stress (ELS) experiences. Given the role of OXT in modulating social motivational processes, we specifically aimed to investigate its effects on the recognition of approach- and avoidance-related facial emotions. METHODS: In a double-blind, between-subjects, placebo-controlled design, 82 male participants performed an emotion recognition task with faces taken from the "Karolinska Directed Emotional Faces" set. We clustered the six basic emotions along the dimensions approach (happy, surprise, anger) and avoidance (fear, sadness, disgust). ELS was assessed with the Childhood Trauma Questionnaire (CTQ). RESULTS: Our results showed that OXT improved the ability to recognize avoidance-related emotional faces as compared to approach-related emotional faces. Whereas the performance for avoidance-related emotions in participants with higher ELS scores was comparable in both OXT and placebo condition, OXT enhanced emotion recognition in participants with lower ELS scores. Independent of OXT administration, we observed increased emotion recognition for avoidance-related faces in participants with high ELS scores. CONCLUSIONS: Our findings suggest that the investigation of OXT on social recognition requires a broad approach that takes ELS experiences as well as motivational processes into account.

Early life stress modulates amygdala-prefrontal functional connectivity: implications for oxytocin effects.

Recent evidence suggests that early life stress (ELS) changes stress reactivity via reduced resting state functional connectivity (rs-FC) between amygdala and the prefrontal cortex. Oxytocin (OXT) modulates amygdala connectivity and attenuates responses to psychosocial stress, but its effect appears to be moderated by ELS. Here we first investigate the effect of ELS on amygdala-prefrontal rs-FC, and examine whether ELS-associated changes of rs-FC in this neural circuit predict its response to psychosocial stress. Secondly, we explore the joint effect of OXT and ELS on the amygdala-prefrontal circuit. Eighteen healthy young males participated in a resting-state fMRI study of OXT effects using a double-blind, randomized, placebo-controlled, within-subject crossover design. We measured the rs-FC to bilateral amygdalae and subsequently assessed changes of state anxiety and prefrontal responses to psychosocial stress. Multiple linear regressions showed that ELS, specifically emotional abuse, predicted reduced rs-FC between the right amygdala and pregenual anterior cingulate cortex (pgACC), which in turn predicted elevated state anxiety after psychosocial stress. In subjects with lower ELS scores, stronger pgACC-amygdala rs-FC predicted stronger pgACC deactivation during the psychosocial stress task, and this rest-task interaction was attenuated by OXT. In subjects with higher ELS scores however, the rest-task interaction was altered and OXT showed no significant effect. These findings highlight that ELS reduces pgACC-amygdala rs-FC and alters how rs-FC of this circuit predicts its stress responsiveness. Such changes in pgACC-amygdala functional dynamics may underlie the altered sensitivity to the effects of OXT after ELS.

Early life stress modulates oxytocin effects on limbic system during acute psychosocial stress.

Early life stress (ELS) is associated with altered stress responsivity, structural and functional brain changes and an increased risk for the development of psychopathological conditions in later life. Due to its behavioral and physiological effects, the neuropeptide oxytocin (OXT) is a useful tool to investigate stress responsivity, even though the neurobiological underpinnings of its effects are still unknown. Here we investigate the effects of OXT on cortisol stress response and neural activity during psychosocial stress. Using functional magnetic resonance imaging in healthy subjects with and without a history of ELS, we found attenuated hormonal reactivity and significantly reduced limbic deactivation after OXT administration in subjects without a history of ELS. Subjects who experienced ELS showed both blunted stress reactivity and limbic deactivation during stress. Furthermore, in these subjects OXT had opposite effects with increased hormonal reactivity and increased limbic deactivation. Our results might implicate that reduced limbic deactivation and hypothalamic-pituitary-adrenal axis responsivity during psychosocial stress are markers for biological resilience after ELS. Effects of OXT in subjects with a history of maltreatment could therefore be considered detrimental and suggest careful consideration of OXT administration in such individuals.

The association of interoceptive awareness and alexithymia with neurotransmitter concentrations in insula and anterior cingulate.

Alexithymia and increased interoceptive awareness have been associated with affective disorders as well as with altered insula and anterior cingulate cortex (ACC) function. Brain imaging studies have demonstrated an association between neurotransmitter function and affective disorders as well as personality traits. Here, we first examined the relationship between alexithymic facets as assessed with the Toronto Alexithymia Scale (TAS-20) and interoceptive awareness (assessed with the Body Perception Questionnaire) in 18 healthy subjects. Second, we investigated their association with glutamate and gamma-aminobutyric acid (GABA) concentrations in the left insula and the ACC using 3-Tesla proton magnetic resonance spectroscopy. Behaviorally, we found a close association between alexithymia and interoceptive awareness. Furthermore, glutamate levels in the left insula were positively associated with both alexithymia and awareness of autonomic nervous system reactivity, while GABA concentrations in ACC were selectively associated with alexithymia. Although preliminary, our results suggest that increased glutamate-mediated excitatory transmission-related to enhanced insula activity-reflects increased interoceptive awareness in alexithymia. Suppression of the unspecific emotional arousal evoked by increased awareness of bodily responses in alexithymics might thus be reflected in decreased neuronal activity mediated by increased GABA concentration in ACC.

[Electroconvulsive therapy as a "last resort" in the treatment of depression?]. / Elektrokonvulsionstherapie als Ultima Ratio in der Behandlung der Depression?

OBJECTIVE: The use of electroconvulsive therapy (ECT) in treatment-resistant depressed patients is supported by numerous international guidelines. This study aims to describe what type of patients are actually referred to treatment with ECT. METHODS: We included all patients referred to two main ECT-treatment centers in Switzerland during the period of August 2008 to February 2011. We collected data on the diagnosis, severity of illness, and the history of treatment. RESULTS: Most of the patients (n = 104) were referred after an average of 124 weeks of an index episode of unipolar depression. The patients were severely and chronically ill and had been treated on average for more than a decade. Eighty-three percent of the patients were referred for ECT treatment for the first time. CONCLUSIONS: The surveyed practice of referral does not concur with evidence-based guidelines for the use of ECT in the treatment of depression.

Effects of intranasal oxytocin prior to encoding and retrieval on recognition memory.

RATIONALE: The neuropeptide oxytocin (OXT) has been shown to modulate a variety of human social behaviors. However, little is known about its impact on emotional memory processing. Previous research demonstrated both memory-enhancing and memory-impairing oxytocinergic effects. METHODS: We investigated the influence of a single (prior to encoding) and a repeated (prior to encoding and retrieval) intranasal administration of OXT on recognition memory for stimuli taken from the International Affective Picture System. In addition, we assessed the interaction of emotion regulation during encoding and OXT-induced memory effects. In a double-blind, placebo-controlled design, 80 healthy young males performed an emotion regulation task followed by a surprising recognition memory task after 60 min. RESULTS: Results show that repeated OXT administration significantly improved memory certainty for negative social stimuli. Regarding the influence of emotion regulation, the promnestic effect of OXT was more pronounced when participants had been instructed to increase their negative emotions during encoding. CONCLUSIONS: Our findings indicate that OXT facilitates the processing of negative social stimuli during memory encoding and retrieval, possibly by enhancing the perception of aversive aspects in social situations.

Interoceptive awareness enhances neural activity during empathy.

Empathy is a multicomponent function that includes sensorimotor, affective, and cognitive components. Although especially the affective component may implicate interoception and interoceptive awareness, the impact of interoception on empathy has never been evaluated behaviorally or neurophysiologically. Here, we tested how a preceding period of interoceptive awareness impacts and modulates neural activity during subsequent empathy. We used functional magnetic resonance imaging (fMRI) and measured the sequential interaction between interoception and empathy using fMRI in 18 healthy subjects. We found that the preceding interoceptive awareness period significantly enhanced neural activity during empathy in bilateral anterior insula and various cortical midline regions. The enhancement of neural activity during empathy in both interoceptive and empathy networks by preceding interoceptive awareness suggests a close relationship between interoception and empathy; thereby, interoception seems to be implicated to yielding empathy.

[Catatonic dilemma in a schizoaffective patient with combined lithium-risperidone administration]. / Katatones Dilemma unter Kombinationsbehandlung mit Lithium und Risperidon.

OBJECTIVE: The case of a schizoaffective patient suffering from a malignant catatonic syndrome following combined lithium-risperidone therapy is explored. METHOD: A case report and relevant deliberations regarding pathophysiology of the catatonic dilemma are discussed. CONCLUSIONS: There are two critical transitions in the development of a malignant catatonic syndrome. Dopaminergic system and psychopharmacological factors are supposed to play a key role. However, other neurotransmitter systems and the individual predisposition must be considered.

[Automutilistic behaviour in female patients with affective disorders: investigation of personality structure and affect regulation by means of Operationalized Psychodynamic Diagnostics (OPD)]. / Automutilistisches Verhalten bei Patientinnen mit affektiven Störungen: Untersuchung der Persönlichkeitsstruktur und Affektregulation mittels Operationalisierter Psychodynamischer Diagnostik (OPD).

UNLABELLED: Automutilistic behaviour is frequently correlated with personality disorders and should be differentiated from suicidal behaviour during acute episodes of affective disorders. The aim of the study was to investigate psychotherapeutically and psychodynamically significant personality traits and affect regulation. The dimensions "relationship", "conflict" and "structure" were examined by means of Operationalized Psychodynamic Diagnostics. SAMPLE: 20 female patients with depression and automutilistic behaviour and 20 age-matched female subjects with a similar educational background, suffering from depression without automutilistic behaviour. RESULTS The female patients with depression and automutilistic behaviour could be differentiated from the control group in all categories in the OPD dimension "structure". They showed an "isolated" and "disclosed" self-image. This negative self-perception corresponded with a negative countertransference. There were no differences between the patients with automutilistic behaviour and the control group regarding the OPD dimension "conflict". Low and moderate levels of integration were prominently correlated with the autonomy-dependence conflict. CONCLUSION The results underline the significance of aspects of personality structure in automutilistic behaviour seen in female patients with depression. Operationalized Psychodynamic Diagnostics can reveal therapeutically relevant personality dimensions for empirical research.

[Neurotoxicity related to lithium-risperidon combination treatment in a patient with schizoaffective disorder]. / Neurotoxische Enzephalopathie unter Kombinationsbehandlung mit Lithium und Risperidon bei einer Patientin mit schizoaffektiver Störung.

OBJECTIVE: The case of a schizoaffective patient with a neurotoxic encephalopathy related to lithium-risperidon combination treatment is explored. METHOD: A case report and the relevant theoretical and clinical deliberations are described. CONCLUSIONS: Neurotoxicity related to lithium-risperidon combination treatment is the result of an interaction of different ethiopathogenetic mechanisms. The EEG is the most important diagnostic parameter.

[Self-esteem and partner relationships of patients with bipolar affective disorder: a study of the interval personality with the Giessen-test]. / Selbstwertgefühl und Partnerbeziehungen von Patienten mit bipolaren affektiven Störungen: Untersuchung zur Intervallpersönlichkeit mit dem Giessen-Test.

The self-concept and the partner relationships of patients with bipolar affective disorder in remission were investigated with the Giessen-Test (GT, Beckmann et al. ) comparing the bipolar patients with unipolar depressive patients, a control group of orthopedic patients and the standard sample of the Giessen-Test. The new dimensions "self-esteem" and "near-to-object" were developed by means of the Giessen-Test items. Self-esteem was significantly lower in bipolar patients in remission than in the controls. The bipolar patients also described themselves as "more distant to others" than the controls. Bipolar and unipolar-depressive patients had a similar self-concept and view of their partner relationships. The results underline the importance of the regulation of self-esteem and the interpersonal dimension in the long-term course of bipolar affective disorder. Therapeutic implications are discussed.

[In-patient hypnotherapeutic trauma exposure for posttraumatic stress disorder: a case report]. / Stationäre hypnotherapeutische Traumaexposition bei posttraumatischer Belastungsstörung: Ein Fallbericht.

This paper describes the treatment of a patient with the diagnoses of a borderline personality disorder and posttraumatic stress disorder (DSM-IV and ICD-10) within the setting of a psychiatric ward spezializing in depression. For purposes of controlled re-exposure to the patient's trauma, a hypnotherapeutic method was chosen. A significant reduction of symptoms, in particular the intrusions and the hyperarousal, was observed. Of great importance in the successful outcome of this case is the integration of hypnotherapy into a multi-dimensional treatment concept including group therapy, physical therapy and anxiety-reducing self-management therapy. This approach facilitated the development of trust and security in the patient required for the hypnotherapeutic intervention and minimized the splitting tendencies specific to borderline patients. Further discussion is centered on the difficulties arising in the context of an emergency ward setting with its high intensity atmosphere encompassing the danger of retraumatization of this special group of patients. Finally several aspects of the clinical implications of this method are addressed.