Let me in: The neural correlates of inclusion motivation in loneliness.

BACKGROUND: While it is well-established that humans possess an innate need for social belonging, the neural mechanisms underlying motivation for connection are still largely unknown. We propose that inclusion motivation - measured through the effort that individuals are willing to invest to be included in social interactions - may serve as one of the basic building blocks of social behavior and may change in lonely individuals. METHODS: Following the screening of 303 participants, we scanned 30 low- and 28 high-loneliness individuals with functional magnetic resonance imaging while they performed the Active Inclusion Task (AIT). The AIT assesses the participants' levels of effort invested in influencing their inclusion during classic Cyberball conditions of fair play and exclusion. RESULTS: High- compared to low-loneliness individuals showed higher urgency for inclusion, specifically during fair play, which correlated with higher activity in the right thalamus. Furthermore, in high-loneliness individuals, we found increased functional connectivity between the thalamus and the temporoparietal junction, putamen, and insula. LIMITATIONS: Participants interacted with computerized avatars, reducing ecological validity. Additionally, although increasing inclusion in the task required action, the physical demand was not high. Additional limitations are discussed. CONCLUSIONS: Inclusion motivation in loneliness is heightened during fair but not exclusionary interactions, and is linked to activity in brain regions implicated in appetitive behavior and social cognition. The findings indicate that lonely individuals may view threat in inclusionary interactions, prompting them to take action to regain connection. This suggests that inclusion motivation may help explain social difficulties in loneliness.

[Oxytocin in schizophrenia : Evidence for an etiological and therapeutic relevance of the social neuromodulator]. / Oxytocin bei Schizophrenie : Evidenz für eine ätiologische und therapeutische Relevanz des sozialen Neuromodulators.

Neurobiological results from animal models as well as biochemical and genetic findings in patients indicate that the oxytocin (OT) system may be dysfunctional in schizophrenia. On this pathogenetic basis transnasally administered OT (tnOT) could be an innovative treatment option for schizophrenia. Experimental data from animal studies are also suggestive of a particular effectiveness in treatment-resistant schizophrenia. To date, clinical data on tnOT treatment of schizophrenia patients does not unequivocally support a general therapeutic effect on the psychopathology but suggests positive effects on higher integrated social cognitive performance, such as empathy and mentalization. In particular, tnOT augmentation of a social cognitive skills training resulted in a marked and lasting treatment effect; however, numerous person- and context-dependent variables can potentially moderate individual effects of OT and may even reverse effects in certain constellations. Most clinical studies so far have not systematically accounted and controlled for these factors with the probable result of larger variance of recorded treatment effects and lower likelihood of ascertaining positive effectiveness. Furthermore, there is still a gap of knowledge on dose response relations and central nervous system (CNS) permeation in man following tnOT administration. This review aims to give a concise overview on the evidence for the etiological relevance of the neurohormone OT and its treatment potential in schizophrenia.

Effects of ketamine on brain function during response inhibition.

INTRODUCTION: The uncompetitive N-methyl-D-aspartate (NMDA) receptor (NMDAR) antagonist ketamine has been proposed to model symptoms of psychosis. Inhibitory deficits in the schizophrenia spectrum have been reliably reported using the antisaccade task. Interestingly, although similar antisaccade deficits have been reported following ketamine in non-human primates, ketamine-induced deficits have not been observed in healthy human volunteers. METHODS: To investigate the effects of ketamine on brain function during an antisaccade task, we conducted a double-blind, placebo-controlled, within-subjects study on n = 15 healthy males. We measured the blood oxygen level dependent (BOLD) response and eye movements during a mixed antisaccade/prosaccade task while participants received a subanesthetic dose of intravenous ketamine (target plasma level 100 ng/ml) on one occasion and placebo on the other occasion. RESULTS: While ketamine significantly increased self-ratings of psychosis-like experiences, it did not induce antisaccade or prosaccade performance deficits. At the level of BOLD, we observed an interaction between treatment and task condition in somatosensory cortex, suggesting recruitment of additional neural resources in the antisaccade condition under NMDAR blockage. DISCUSSION: Given the robust evidence of antisaccade deficits in schizophrenia spectrum populations, the current findings suggest that ketamine may not mimic all features of psychosis at the dose used in this study. Our findings underline the importance of a more detailed research to further understand and define effects of NMDAR hypofunction on human brain function and behavior, with a view to applying ketamine administration as a model system of psychosis. Future studies with varying doses will be of importance in this context.

[New insights into the neuroscience of human altruism]. / Neue Einblicke in die Psychobiologie altruistischer Entscheidungen.

Numerous honorary initiatives for humanitarian aid towards refugees illustrate the high prevalence of altruistic behavior in the population. In medicine, an exquisite example of a human propensity for altruism is organ donation. Current perspectives on the neurobiology of altruism suggest that it is deeply rooted in the motivational architecture of the social brain. This is reflected by the social evolution of cooperation and parochialism, both of which are modulated by the evolutionarily conserved peptide hormone oxytocin. From a psychiatric perspective, altruism varies along a dimensional spectrum, with pathological hyperaltruism resulting in unexpected harm for oneself and others.

Effects of ketamine on brain function during smooth pursuit eye movements.

The uncompetitive NMDA receptor antagonist ketamine has been proposed to model symptoms of psychosis. Smooth pursuit eye movements (SPEM) are an established biomarker of schizophrenia. SPEM performance has been shown to be impaired in the schizophrenia spectrum and during ketamine administration in healthy volunteers. However, the neural mechanisms mediating SPEM impairments during ketamine administration are unknown. In a counter-balanced, placebo-controlled, double-blind, within-subjects design, 27 healthy participants received intravenous racemic ketamine (100 ng/mL target plasma concentration) on one of two assessment days and placebo (intravenous saline) on the other. Participants performed a block-design SPEM task during functional magnetic resonance imaging (fMRI) at 3 Tesla field strength. Self-ratings of psychosis-like experiences were obtained using the Psychotomimetic States Inventory (PSI). Ketamine administration induced psychosis-like symptoms, during ketamine infusion, participants showed increased ratings on the PSI dimensions cognitive disorganization, delusional thinking, perceptual distortion and mania. Ketamine led to robust deficits in SPEM performance, which were accompanied by reduced blood oxygen level dependent (BOLD) signal in the SPEM network including primary visual cortex, area V5 and the right frontal eye field (FEF), compared to placebo. A measure of connectivity with V5 and FEF as seed regions, however, was not significantly affected by ketamine. These results are similar to the deviations found in schizophrenia patients. Our findings support the role of glutamate dysfunction in impaired smooth pursuit performance and the use of ketamine as a pharmacological model of psychosis, especially when combined with oculomotor biomarkers. Hum Brain Mapp 37:4047-4060, 2016. © 2016 Wiley Periodicals, Inc.

[Experimental and therapeutic neuromodulation of emotion and social cognition with non-invasive brain stimulation]. / Experimentelle und therapeutische Neuromodulation von Emotion und sozialer Kognition mit nichtinvasiver Hirnstimulation.

Transcranial magnetic stimulation (TMS) is not only a highly elegant method for basic neuroscientific research that employs transient lesions to explore the relationship between brain structure and function but in a clinical context it is also a very promising approach to augmentation therapy in middle to severe grade depressive episodes. This overview illustrates the methodological basis of TMS and illuminates its neuromodulatory potential with reference to findings from recent studies on emotion regulation and social cognition. Against this empirical background, it becomes clear that preclinical studies on healthy participants are extremely important to develop innovative stimulation protocols and define functionally relevant target regions to be tested in clinical studies for therapeutic efficacy. Finally, the perspectives and limitations of functionally guided, individualized TMS neuronavigation will be explored based on task-independent connectivity and task-dependent activity measurements.

Magnetic seizure therapy in treatment-resistant depression: clinical, neuropsychological and metabolic effects.

BACKGROUND: Magnetic seizure therapy (MST), despite being in an early phase of clinical research, has been demonstrated to be associated with antidepressant efficacy. However, safety, tolerability and efficacy data in connection with functional brain activity from larger samples are lacking. The aim of this study was to determine clinical and cognitive effects of MST and the influence of MST on regional brain glucose metabolism. METHOD: Twenty-six patients suffering from treatment-resistant depression (TRD) underwent MST. Ten patients underwent a randomized trial and 16 patients an open-label study design. The primary outcome criterion was the severity of depressive symptoms assessed with the Hamilton Depression Rating Scale (HAMD). Depressive symptoms, tolerability and cognitive safety, along with social functioning and quality of life parameters, were assessed using various rating scales. A clinical follow-up visit 6 months following the completion of a course of MST and [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) scans of 12 patients were analysed. RESULTS: A significant response to MST was demonstrated by 69% of the patient sample, with 46% meeting remission criteria. Anxiety ratings were significantly reduced in responders and their quality of life was improved. Half of the responders relapsed within 6 months. No cognitive side-effects were observed. FDG-PET scans showed a metabolic increase in the frontal cortex bilaterally and a decrease in the left striatum. CONCLUSIONS: Robust antidepressant and anti-anxiety efficacy of MST was demonstrated, and found to be associated with localized metabolic changes in brain areas that are strongly implicated in depression. Thus, MST presents an effective, well-tolerated and safe treatment option for patients unable to respond to other forms of therapy for depression.

[Oxytocin: evidence for a therapeutic potential of the social neuromodulator]. / Oxytozin: Evidenz für ein therapeutisches Potenzial des sozialen Neuromodulators.

Only few substances have achieved such a great prominence in recent years as the hypothalamic neuropeptide oxytocin, which is also widely known as the love hormone. Oxytocin is a potent neuromodulator which can improve social cognitive functions including empathy, trust, cooperation and social learning. However, oxytocin can also promote negative social behavior and increase poor memory and feelings of fear in social situations. Positive data from initial clinical trials give rise to the hope that oxytocin will prove to be a substance which is suitable for targeted treatment of poor social-cognitive behavior in neuropsychiatric diseases. This review article summarizes the most important recent preclinical and clinical human studies and discusses the findings presented with respect to current concepts of personal and contextual influences.

Noradrenergic-glucocorticoid modulation of emotional memory encoding in the human hippocampus.

BACKGROUND: Current rodent models emphasize the joint action of the stress mediators noradrenaline (NE) and cortisol (CORT) in conferring a memory advantage of emotional over neutral stimuli. METHOD: Using a pharmacological strategy of tackling this stress-related mechanism to enhance human episodic (autobiographical) memory, we measured amygdala-hippocampal responses during encoding of emotional and neutral stimuli with functional magnetic resonance imaging in 51 healthy subjects under four pharmacological conditions in a double-blind parallel group design: (i) placebo; (ii) the NE-reuptake inhibitor reboxetine (4 mg); (iii) hydrocortisone (synthetic CORT) (30 mg); or (iv) both agents in combination. RESULTS: Differential drug effects were found in the left hippocampus, whereas hydrocortisone alone selectively decreased hippocampal responses to emotional relative to neutral stimuli, reboxetine potentiated hippocampal responses to these stimuli. Importantly, the inhibitory influence of hydrocortisone was reversed by co-administration of reboxetine. CONCLUSIONS: Our results imply that stress levels of CORT alone attenuate hippocampal responses to emotional stimuli, an effect possibly related to a regulatory negative feedback loop. However, when simultaneously elevated to stress levels, NE and CORT act together to synergistically enhance hippocampal activity during encoding of emotional stimuli, a mechanism that may turn maladaptive under circumstances of traumatic stress.

Human amygdala reactivity is diminished by the ß-noradrenergic antagonist propranolol.

BACKGROUND: Animal models of anxiety disorders emphasize the crucial role of locus ceruleus-noradrenergic (norepinephrine, NE) signaling, the basolateral amygdala (BLA) and their interactions in the expression of anxiety-like behavioral responses to stress. Despite clinical evidence for the efficacy of a ß-noradrenergic receptor blockade with propranolol in the alleviation of anxiety symptoms and the secondary prevention of post traumatic stress disorder, preclinical evidence for a ß-noradrenergic modulation of BLA activity in humans is missing. METHOD: We combined functional magnetic resonance imaging in healthy volunteers with probabilistic mapping of intra-amygdalar responses to fearful, neutral and happy facial expressions to test the hypothesis that a ß-noradrenergic receptor blockade with propranolol would inactivate the BLA. RESULTS: Consistent with our a priori hypothesis, propranolol diminished BLA responses to facial expressions, independent of their emotional valence. The absence of activity changes in probabilistically defined visual control regions underscores the specific action of propranolol in the BLA. CONCLUSIONS: Our findings provide the missing link between the anxiolytic potential of propranolol and the biological basis of ß-noradrenergic activation in the human BLA as a key target for the pharmacological inhibition of anxiety neurocircuitry. Moreover, our findings add to emerging evidence that NE modulates both the reactivity (sensitivity) and the operating characteristics (specificity) of the BLA via ß-noradrenergic receptors.

Interrelated neuropsychological and anatomical evidence of hippocampal pathology in the at-risk mental state.

BACKGROUND: Verbal learning and memory deficits are frequent among patients with schizophrenia and correlate with reduced magnetic resonance imaging (MRI) volumes of the hippocampus in these patients. A crucial question is the extent to which interrelated structural-functional deficits of the hippocampus reflect a vulnerability to schizophrenia, as opposed to the disorder per se. METHOD: We combined brain structural measures and the Rey Auditory Verbal Learning Test (RAVLT) to assess hippocampal structure and function in 36 never-medicated individuals suspected to be in early (EPS) or late prodromal states (LPS) of schizophrenia relative to 30 healthy controls. RESULTS: Group comparisons revealed bilaterally reduced MRI hippocampal volumes in both EPS and LPS subjects. In LPS subjects but not in EPS subjects, these reductions were correlated with poorer performance in RAVLT delayed recall. CONCLUSIONS: Our findings suggest progressive and interrelated structural-functional pathology of the hippocampus, as prodromal symptoms and behaviours accumulate, and the level of risk for psychosis increases. Given the inverse correlation of learning and memory deficits with social and vocational functioning in established schizophrenia, our findings substantiate the rationale for developing preventive treatment strategies that maintain cognitive capacities in the at-risk mental state.

Acute S-ketamine application does not alter cerebral [18F]altanserin binding: a pilot PET study in humans.

Modeling short-term psychotic states with subanaesthetic doses of ketamine provides substantial experimental evidence in support of the glutamate hypothesis of schizophrenia. Ketamine exerts its pharmacological effects both directly via interactions with glutamate receptors and indirectly by stimulating presynaptic release of endogenous serotonin (5-HT). The aim of this feasibility study was to examine whether acute ketamine-induced 5-HT release interferes with the binding of the 5-HT(2A) receptor (5-HT(2A)R) radioligand [(18)F]altanserin and positron emission tomography (PET). Two subjects treated with ketamine and one subject treated with placebo underwent [(18)F]altanserin PET at distribution equilibrium conditions. Robust physiological, psychopathological and cognitive effects were present at ketamine plasma concentrations exceeding 100 microg/l during >70 min. Notwithstanding, we observed stable radioligand binding (changes +/-95% CI of -1.0 +/- 1.6% and +4.1 +/- 1.8% versus -1.2 +/- 2.6%) in large cortical regions presenting high basal uptake of both, [(18)F]altanserin and ketamine. Marginal decreases of 4% of radioligand binding were observed in the frontal lobe, and 8% in a posteriorily specified frontomesial subregion. This finding is not compatible with a specific radioligand displacement from 5-HT(2A)R which should occur proportionally throughout the whole brain. Instead, the spatial pattern of these minor reductions was congruent with ketamine-induced increases in cerebral blood flow observed in a previous study using [(15)O]butanol PET. This may caused by accelerated clearance of unspecifically bound [(18)F]altanserin from cerebral tissue with increased perfusion. In conclusion, this study suggests that [(18)F]altanserin PET is not sensitive to acute neurotransmitter fluctuations under ketamine. Advantageously, the stability of [(18)F]altanserin PET towards acute influences is a prerequisite for its future use to detect sub-acute and chronic effects of ketamine.

Magnetoencephalography (MEG) determined temporal modulation of visual and auditory sensory processing in the context of classical conditioning to faces.

Using magnetoencephalography (MEG), we determined the time course of sensory-evoked modulations during differential aversive conditioning to faces, with an aversive noise event (UCS). Conditioning was associated with the development of a differential event-related waveform peaking at approximately 150 ms. Source analysis indicated the localization of this modulation to ventral occipital regions. In the auditory domain, a modulation of auditory-evoked responses to a probe sound was evident in a late component emerging at approximately 180 ms over sensors in fronto-temporal regions. The findings indicate the time course in processing sensory stimuli can be altered on the basis of their acquired value.

An emotion-induced retrograde amnesia in humans is amygdala- and beta-adrenergic-dependent.

The influence of emotion on human memory is associated with two contradictory effects in the form of either emotion-induced enhancements or decrements in memory. In a series of experiments involving single word presentation, we show that enhanced memory for emotional words is strongly coupled to decrements in memory for items preceding the emotional stimulus, an effect that is more pronounced in women. These memory effects would appear to depend on a common neurobiological substrate, in that enhancements and decrements are reversed by propranolol, a beta-adrenergic antagonist, and abolished by selective bilateral amygdala damage. Thus, our findings suggest that amygdala-dependent beta-adrenergic modulation of episodic encoding has costs as well as benefits.

Abnormalities of grey and white matter [11C]flumazenil binding in temporal lobe epilepsy with normal MRI.

In 20% of potential surgical candidates with refractory epilepsy, current optimal MRI does not identify the cause. GABA is the principal inhibitory neurotransmitter in the brain, and GABA(A) receptors are expressed by most neurones. [(11)C]Flumazenil (FMZ) PET images the majority of GABA(A) receptor subtypes. We investigated abnormalities of FMZ binding in grey and white matter in 18 patients with refractory temporal lobe epilepsy (TLE) and normal quantitative MRI. Parametric images of FMZ volume of distribution (FMZ-V(d)) were calculated. Twenty-one healthy controls were scanned for comparison. Statistical parametric mapping (SPM99) was used to localize significant changes in FMZ-V(d) in individual patients and between groups, specifically including the entire white matter in all subjects through explicit masking. Sixteen of 18 patients showed single or multiple abnormalities of FMZ-V(d). Six had hippocampal decreases of FMZ-V(d). Eleven patients showed increased FMZ-V(d) in the temporal lobe white matter (TLWM). Outside the mesial temporal structures, seven showed multiple areas of increase or decrease and only one a single area of decrease. In seven of the 16 patients with abnormalities, findings were concordant with EEG and clinical data, enabling further presurgical evaluation. Group findings were: (i) decreased FMZ-V(d) in the ipsilateral (Z = 3.01) and contralateral (Z = 2.56) hippocampus; (ii) increased FMZ-V(d) in the ipsilateral (Z = 3.71) and contralateral TLWM (two clusters, Z = 3.11 and 2.79); and (iii) increased FMZ-V(d) in the ipsilateral frontal lobe white matter between the superior and medial frontal gyrus (Z = 3.80) with similar changes contralaterally (Z = 4.87). No changes were found in the thalamus and basal ganglia. Region-of-interest analyses indicated an average increase in FMZ binding of 16% in the TLWM ipsilateral to the epileptic focus. PET findings were corroborated by invasive EEG or pathology in five cases. FMZ-PET, analysed by SPM with explicit masking, was sensitive in patients with normal MRI, and hippocampal abnormalities were detected in a third of these patients. Furthermore, increases in FMZ binding in TLWM, indicating microdysgenesis, were detected in the majority of these patients and may represent the structural basis of their epilepsy.