Transcranial magnetic stimulation over the right temporoparietal junction influences the sense of agency in healthy humans.

Background: The sense of agency is an important aspect of motor control. Impaired sense of agency has been linked to several medical conditions, including schizophrenia and functional neurological disorders. A complex brain network subserves the sense of agency, and the right temporoparietal junction is one of its main nodes. In this paper, we tested whether transcranial magnetic stimulation over the right temporoparietal junction elicited behavioural changes in the sense of agency. Methods: In experiment 1, 15 healthy participants performed a behavioural task during functional MRI, with the goal of localizing the area relevant for the sense of agency in the right temporoparietal junction. In the task, the movement of a cursor (controlled by the participants) was artificially manipulated, and the sense of agency was either diminished (turbulence) or enhanced (magic). In experiment 2, we applied transcranial magnetic stimulation in 20 healthy participants in a sham-controlled, crossover trial with excitatory, inhibitory or sham (vertex) stimulation. We measured the summary agency score, an indicator of the sense of agency (lower values correspond to diminished sense of agency). Results: Experiment 1 revealed a peak of activation during agency manipulation in the right temporoparietal junction (Montreal Neurological Institute coordinates x, y, z: 68, -26, 34). Experiment 2 showed that inhibition of the right temporoparietal junction significantly reduced the summary agency score in both turbulence (from -14.4 ± 11.4% to -22.5 ± 8.9%), and magic (from -0.7 ± 5.8% to -4.4 ± 4.4%). Limitations: We found no excitatory effects, possibly because of a ceiling effect (because healthy participants have a normal sense of agency) or noneffectiveness of the excitatory protocol. Conclusion: Our experiments showed that the network subserving the sense of agency was amenable to neuromodulation in healthy participants. This sets the ground for further research in patients with impaired sense of agency. Clinical trial identification: DRKS00012992 (German clinical trials registry).

Rumination related activity in brain networks mediating attentional switching in euthymic bipolar patients.

INTRODUCTION: Mood disorder patients have a tendency to be more internally oriented, with difficulties in switching attentional focus, which might result in the generation of negative thoughts, such as rumination. The present study explored self-referential neural activity correlating with rumination tendency and attentional switching capacity in bipolar disorder. METHODS: Twenty euthymic bipolar patients and twenty matched healthy controls underwent a novel introspection task of switching between internally and externally focused attention during a word processing task, while their brain activity was assessed using functional MRI. RESULTS: During internal focus, higher activity in self-related regions (mPFC, PCC) was found in euthymic bipolar patients as compared to controls, verifying the hypothesis of exaggerated recruitment of self-referential processes in bipolar subjects. Switching from internal to external focus revealed higher parahippocampal activity in patients as compared to controls, additionally more pronounced when switching away from negative as compared to positive self-referential information. Furthermore, rumination traits correlated with activity in PCC, subgenual and pregenual ACC, and bilateral anterior insula during repetition of internal focus, specifically when evaluating negative words. Finally, we used ACC subregions that correlated with tendency to ruminate as seeds for a whole brain connectivity analysis. Patients showed stronger connectivity between sgACC (seed), pgACC, dPFC, and anterior insula during internal focus, whereas pgACC (seed) was more strongly connected to parahippocampal gyrus when switching from internal to external focus. CONCLUSIONS: These findings reveal an overactive rumination-related network whose activity is enhanced by negative information in euthymic bipolar patients, which could possibly contribute to impaired switching of thoughts away from internal attention.

Abnormal postural behavior in patients with functional movement disorders during exposure to stress.

BACKGROUND: Patients affected by functional (psychogenic) movement disorders (FMD) have abnormal processing of stress responses. However, little is known about the influence of this abnormal stress processing on automatic motor defense behavior, such as freeze response. Our aim was thus to investigate stress-induced postural motor responses in FMD. METHODS: Nine FMD patients and thirteen healthy controls were engaged in the Trier Social Stress Test, while we measured the movement of their body by means of accelerometers and gyroscopes attached to the thorax. Standard deviation of thorax acceleration, reflecting the variability of movement amplitude (body sway), was compared across groups over time in a 2 × 2 ANOVA design. Higuchi's fractal dimension (HFD), reflecting the complexity of movement pattern over time, was also analyzed. Salivary cortisol and α-amylase samples were collected before and after the experiment, as stress biomarkers. Pearson's correlation coefficients were calculated between these biomarkers and movement parameters. RESULTS: A significant interaction effect was found, showing that healthy controls reduced their thorax sway over time during exposure to stress (from 0.027 ± 0.010 m/s2 to 0.023 ± 0.008 m/s2, effect size of Cohen's d = 0.95), whereas patients with FMD did not. This change in body sway in controls over time negatively correlated with salivary cortisol values (ρ = -0.67, p = 0.012). A significant group effect revealed that FMD patients had an overall larger body sway (0.038 ± 0.013 m/s2) compared to controls (0.025 ± 0.009 m/s2 - effect size of Cohen's d = 1.29) and a lower HFD (1.602 ± 0.071) than controls (1.710 ± 0.078 - Cohen's d = 1.43). CONCLUSIONS: Patients with FMD failed to show a reduction of body sway over time, i.e., freeze response observed in the controls, thus suggesting an impairment in the automatic defense behavior. Moreover, our analysis found a lower complexity of movement (HFD) in FMD, which deserves future research in order to verify whether this could represent a characteristic trait of the disorder.

Antidepressive effects of targeting ELK-1 signal transduction.

Depression, a devastating psychiatric disorder, is a leading cause of disability worldwide. Current antidepressants address specific symptoms of the disease, but there is vast room for improvement 1 . In this respect, new compounds that act beyond classical antidepressants to target signal transduction pathways governing synaptic plasticity and cellular resilience are highly warranted2-4. The extracellular signal-regulated kinase (ERK) pathway is implicated in mood regulation5-7, but its pleiotropic functions and lack of target specificity prohibit optimal drug development. Here, we identified the transcription factor ELK-1, an ERK downstream partner 8 , as a specific signaling module in the pathophysiology and treatment of depression that can be targeted independently of ERK. ELK1 mRNA was upregulated in postmortem hippocampal tissues from depressed suicides; in blood samples from depressed individuals, failure to reduce ELK1 expression was associated with resistance to treatment. In mice, hippocampal ELK-1 overexpression per se produced depressive behaviors; conversely, the selective inhibition of ELK-1 activation prevented depression-like molecular, plasticity and behavioral states induced by stress. Our work stresses the importance of target selectivity for a successful approach for signal-transduction-based antidepressants, singles out ELK-1 as a depression-relevant transducer downstream of ERK and brings proof-of-concept evidence for the druggability of ELK-1.