Hypothalamic volume in pedophilia with or without child sexual offense.

The hypothalamus regulates sexual behavior and is simultaneously associated with aggression and violence. Consequently, this brain region is relevant in research of pedophilia and child sexual offenses (CSO). The distinction between these two phenomena is of great importance and was the object of consideration of this study. We analyzed exclusively men, including 73 pedophilic offenders who committed CSO, an equal number of people with pedophilia but without such offenses, and 133 non-pedophilic, non-offending subjects who formed the control group. All data were collected in a multicenter in vivo study and analyzed using a semi-automated segmentation algorithm for 3-Tesla magnetic resonance images. Men with pedophilia who committed CSO on average had a 47 mm3 smaller hypothalamus per side than people without committed CSO. This effect was driven by both the group of non-offending people with pedophilia and the control group. By contrast, the exploratory comparison of pedophilic persons without CSO with the control group showed no significant difference. The present study demonstrates a deviant hypothalamic structure as a neurobiological correlate of CSO in pedophiles, but not in people with pedophilia who have not committed CSO. Thus, it strengthens the argument to distinguish between sexual offending and paraphilic sexual preferences.

Trait anxiety is related to Nx4's efficacy on stress-induced changes in amygdala-centered resting state functional connectivity: a placebo-controlled cross-over trial in mildly to moderately stressed healthy volunteers.

BACKGROUND: The multicomponent drug Neurexan (Nx4) was shown to reduce the neural stress network activation. We now investigated its effects on stress-induced resting state functional connectivity (RSFC) in dependence of trait anxiety (TA), an acknowledged vulnerability factor for stress-induced psychopathologies. METHODS: Nx4 was tested in a randomized placebo-controlled crossover trial. Resting state fMRI scans were performed before and after a psychosocial stress task and exploratively analyzed for amygdala centered RSFC. Effects of Nx4 on stress-induced RSFC changes were evaluated and correlated to TA levels. A subgroup analysis based on TA scores was performed. RESULTS: Multiple linear regression analysis revealed a significant correlation between TA and Nx4 effect on stress-induced RSFC changes between right amygdala and pregenual anterior cingulate cortex (pgACC) and ventro-medial prefrontal cortex (vmPFC). For participants with above average TA, a significant amelioration of the stress-induced RSFC changes was observed. CONCLUSIONS: The data add evidence to the hypothesis that Nx4's clinical efficacy is based on a dampened activation of the neural stress network, with a greater neural response in subjects with anxious personality traits. Further studies assessing clinically relevant outcome measures in parallel to fMRI are encouraged to evaluate the real-world benefit of Nx4. Trial registration NCT02602275.

Nx4 Modulated Resting-State Functional Connectivity Between Amygdala and Prefrontal Cortex in a Placebo-Controlled, Crossover Trial.

Background: The basic functional organization of the resting brain, assessed as resting-state functional connectivity (rsFC), can be affected by previous stress experience and it represents the basis on which subsequent stress experience develops. Notably, the rsFC between the amygdala and the cortical regions associated with emotion regulation and anxiety are affected during stress. The multicomponent drug Neurexan® (Nx4) has previously demonstrated a reduction in amygdala activation in an emotional face matching task and it ameliorated stress-related symptoms. We, thus, investigated the effect of Nx4 on rsFC of the amygdala before stress induction compared with baseline in mildly to moderately stressed participants. Methods: In a randomized, placebo-controlled, double-blind, crossover trial 39 participants received a single dose of placebo or Nx4. Resting-state functional magnetic resonance imaging scans were performed pre-dose and 40 to 60 min post-dose, before any stress induction. First, highly connected functional hubs were identified by global functional connectivity density (gFCD) analysis. Second, by using a seed-based approach, rsFC maps of the left centromedial amygdala (CeMA) were created. The effect of Nx4 on both was evaluated. Results: The medial prefrontal cortex was identified as a relevant functional hub affected by Nx4 in an explorative whole brain gFCD analysis. Using the seed-based approach, we then demonstrated that Nx4 significantly enhanced the negative connectivity between the left CeMA and two cortical regions: the dorsolateral and medial prefrontal cortices. Conclusions: In a resting-state condition, Nx4 reduced the prefrontal cortex gFCD and strengthened the functional coupling between the amygdala and the prefrontal cortex that is relevant for emotion regulation and the stress response. Further studies should elaborate whether this mechanism represents enhanced regulatory control of the amygdala at rest and, consequently, to a diminished susceptibility to stress. ClinicalTrials.gov ID: NCT02602275.

Subcortical shape alterations in major depressive disorder: Findings from the ENIGMA major depressive disorder working group.

Alterations in regional subcortical brain volumes have been investigated as part of the efforts of an international consortium, ENIGMA, to identify reliable neural correlates of major depressive disorder (MDD). Given that subcortical structures are comprised of distinct subfields, we sought to build significantly from prior work by precisely mapping localized MDD-related differences in subcortical regions using shape analysis. In this meta-analysis of subcortical shape from the ENIGMA-MDD working group, we compared 1,781 patients with MDD and 2,953 healthy controls (CTL) on individual measures of shape metrics (thickness and surface area) on the surface of seven bilateral subcortical structures: nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen, and thalamus. Harmonized data processing and statistical analyses were conducted locally at each site, and findings were aggregated by meta-analysis. Relative to CTL, patients with adolescent-onset MDD (≤ 21 years) had lower thickness and surface area of the subiculum, cornu ammonis (CA) 1 of the hippocampus and basolateral amygdala (Cohen's d = -0.164 to -0.180). Relative to first-episode MDD, recurrent MDD patients had lower thickness and surface area in the CA1 of the hippocampus and the basolateral amygdala (Cohen's d = -0.173 to -0.184). Our results suggest that previously reported MDD-associated volumetric differences may be localized to specific subfields of these structures that have been shown to be sensitive to the effects of stress, with important implications for mapping treatments to patients based on specific neural targets and key clinical features.

Non-invasive vagus nerve stimulation boosts mood recovery after effort exertion.

BACKGROUND: Mood plays an important role in our life which is illustrated by the disruptive impact of aberrant mood states in depression. Although vagus nerve stimulation (VNS) has been shown to improve symptoms of depression, the exact mechanism is still elusive, and it is an open question whether non-invasive VNS could be used to swiftly and robustly improve mood. METHODS: Here, we investigated the effect of left- and right-sided transcutaneous auricular VNS (taVNS) v. a sham control condition on mood after the exertion of physical and cognitive effort in 82 healthy participants (randomized cross-over design) using linear mixed-effects and hierarchical Bayesian analyses of mood ratings. RESULTS: We found that 90 min of either left-sided or right-sided taVNS improved positive mood [b = 5.11, 95% credible interval, CI (1.39-9.01), 9.6% improvement relative to the mood intercept, BF10 = 7.69, pLME = 0.017], yet only during the post-stimulation phase. Moreover, lower baseline scores of positive mood were associated with greater taVNS-induced improvements in motivation [r = -0.42, 95% CI (-0.58 to -0.21), BF10 = 249]. CONCLUSIONS: We conclude that taVNS boosts mood after a prolonged period of effort exertion with concurrent stimulation and that acute motivational effects of taVNS are partly dependent on initial mood states. Collectively, our results show that taVNS may help quickly improve affect after a mood challenge, potentially by modulating interoceptive signals contributing to the reappraisal of effortful behavior. This suggests that taVNS could be a useful add-on to current behavioral therapies.

Localized Prediction of Glutamate from Whole-Brain Functional Connectivity of the Pregenual Anterior Cingulate Cortex.

Local measures of neurotransmitters provide crucial insights into neurobiological changes underlying altered functional connectivity in psychiatric disorders. However, noninvasive neuroimaging techniques such as magnetic resonance spectroscopy (MRS) may cover anatomically and functionally distinct areas, such as p32 and p24 of the pregenual anterior cingulate cortex (pgACC). Here, we aimed to overcome this low spatial specificity of MRS by predicting local glutamate and GABA based on functional characteristics and neuroanatomy in a sample of 88 human participants (35 females), using complementary machine learning approaches. Functional connectivity profiles of pgACC area p32 predicted pgACC glutamate better than chance (R2 = 0.324) and explained more variance compared with area p24 using both elastic net and partial least-squares regression. In contrast, GABA could not be robustly predicted. To summarize, machine learning helps exploit the high resolution of fMRI to improve the interpretation of local neurometabolism. Our augmented multimodal imaging analysis can deliver novel insights into neurobiology by using complementary information.SIGNIFICANCE STATEMENT Magnetic resonance spectroscopy (MRS) measures local glutamate and GABA noninvasively. However, conventional MRS requires large voxels compared with fMRI, because of its inherently low signal-to-noise ratio. Consequently, a single MRS voxel may cover areas with distinct cytoarchitecture. In the largest multimodal 7 tesla machine learning study to date, we overcome this limitation by capitalizing on the spatial resolution of fMRI to predict local neurotransmitters in the PFC. Critically, we found that prefrontal glutamate could be robustly and exclusively predicted from the functional connectivity fingerprint of one of two anatomically and functionally defined areas that form the pregenual anterior cingulate cortex. Our approach provides greater spatial specificity on neurotransmitter levels, potentially improving the understanding of altered functional connectivity in mental disorders.

fMRI Revealed Reduced Amygdala Activation after Nx4 in Mildly to Moderately Stressed Healthy Volunteers in a Randomized, Placebo-Controlled, Cross-Over Trial.

Social stress contributes to major societal health burdens, such as anxiety disorders and nervousness. Nx4 has been found to modulate stress responses. We investigated whether dampening of such responses is associated with neuronal correlates in brain regions involved in stress and anxiety. In a randomized, placebo-controlled, double-blind, cross-over trial, 39 healthy males took a single dose (three tablets) of either placebo or Nx4, 40 to 60 minutes before an fMRI scan session. We here report on drug effects on amygdala responses during a face-matching task, which was performed during a complex test battery further including resting-state brain connectivity and a social stress experiment. The first of the Primary Outcomes, defined in a hierarchical order, concerned reduced amygdala effects after intake of verum compared to placebo. We found a statistically significant reduction in differential activations in the left amygdala for the contrast negative faces versus forms during verum versus placebo condition. Our results indicate that effects of Nx4 can be monitored in the brain. Previously noted effects on stress responses may thus be modulated by affective brain regions including the amygdala.

In vivo anatomical mapping of human locus coeruleus functional connectivity at 3 T MRI.

The locus coeruleus (LC) is involved in numerous crucial brain functions and several disorders like depression and Alzheimer's disease. Recently, the LC resting-state functional connectivity (rs-fc) has been investigated in functional MRI by calculating the blood oxygen level-dependent (BOLD) response extracted using Montreal Neurological Institute (MNI) space masks. To corroborate these results, we aimed to investigate the LC rs-fc at native space by improving the identification of the LC location using a neuromelanin sensitive sequence. Twenty-five healthy male participants (mean age 24.8 ± 4.2) were examined in a Siemens MAGNETOM Prisma 3 T MRT applying a neuromelanin sensitive T1TSE sequence and functional MRI. We compared the rs-fc of LC calculated by a MNI-based approach with extraction of the BOLD signal at the exact individual location of the LC after applying CompCor and field map correction. As a measure of advance, a marked increase of regional homogeneity (ReHo) of time series within LC could be achieved with the subject-specific approach. Furthermore, the methods differed in the rs-fc to the right temporoparietal junction, which showed stronger connectivity to the LC in the MNI-based method. Nevertheless, both methods comparably revealed LC rs-fc to multiple brain regions including ACC, bilateral thalamus, and cerebellum. Our results are relevant for further research assessing and interpreting LC function, especially in patient populations examined at 3 T MRI.

Non-invasive stimulation of vagal afferents reduces gastric frequency.

Metabolic feedback between the gut and the brain relayed via the vagus nerve contributes to energy homeostasis. We investigated in healthy adults whether non-invasive stimulation of vagal afferents impacts energy homeostasis via efferent effects on metabolism or digestion. In a randomized crossover design, we applied transcutaneous auricular vagus nerve stimulation (taVNS) while recording efferent metabolic effects using simultaneous electrogastrography (EGG) and indirect calorimetry. We found that taVNS reduced gastric myoelectric frequency (p = .008), but did not alter resting energy expenditure. We conclude that stimulating vagal afferents induces gastric slowing via vagal efferents without acutely affecting net energy expenditure at rest. Collectively, this highlights the potential of taVNS to modulate digestion by activating the dorsal vagal complex. Thus, taVNS-induced changes in gastric frequency are an important peripheral marker of brain stimulation effects.

Alterations in Brain Structure and Amplitude of Low-frequency after 8 weeks of Mindfulness Meditation Training in Meditation-Naïve Subjects.

Increasing neuroimaging evidence suggests that mindfulness meditation expertise is related to different functional and structural configurations of the default mode network (DMN), the salience network (SN) and the executive network at rest. However, longitudinal studies observing resting network plasticity effects in brains of novices who started to practice meditation are scarce and generally related to one dimension, such as structural or functional effects. The purpose of this study was to investigate structural and functional brain network changes (e.g. DMN) after 40 days of mindfulness meditation training in novices and set these in the context of potentially altered depression symptomatology and anxiety. We found overlapping structural and functional effects in precuneus, a posterior DMN region, where cortical thickness increased and low-frequency amplitudes (ALFF) decreased, while decreased ALFF in left precuneus/posterior cingulate cortex correlates with the reduction of (CES-D) depression scores. In conclusion, regional overlapping of structural and functional changes in precuneus may capture different components of the complex changes of mindfulness meditation training.

2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis.

BACKGROUND: Thyrotoxicosis has multiple etiologies, manifestations, and potential therapies. Appropriate treatment requires an accurate diagnosis and is influenced by coexisting medical conditions and patient preference. This document describes evidence-based clinical guidelines for the management of thyrotoxicosis that would be useful to generalist and subspecialty physicians and others providing care for patients with this condition. METHODS: The American Thyroid Association (ATA) previously cosponsored guidelines for the management of thyrotoxicosis that were published in 2011. Considerable new literature has been published since then, and the ATA felt updated evidence-based guidelines were needed. The association assembled a task force of expert clinicians who authored this report. They examined relevant literature using a systematic PubMed search supplemented with additional published materials. An evidence-based medicine approach that incorporated the knowledge and experience of the panel was used to update the 2011 text and recommendations. The strength of the recommendations and the quality of evidence supporting them were rated according to the approach recommended by the Grading of Recommendations, Assessment, Development, and Evaluation Group. RESULTS: Clinical topics addressed include the initial evaluation and management of thyrotoxicosis; management of Graves' hyperthyroidism using radioactive iodine, antithyroid drugs, or surgery; management of toxic multinodular goiter or toxic adenoma using radioactive iodine or surgery; Graves' disease in children, adolescents, or pregnant patients; subclinical hyperthyroidism; hyperthyroidism in patients with Graves' orbitopathy; and management of other miscellaneous causes of thyrotoxicosis. New paradigms since publication of the 2011 guidelines are presented for the evaluation of the etiology of thyrotoxicosis, the management of Graves' hyperthyroidism with antithyroid drugs, the management of pregnant hyperthyroid patients, and the preparation of patients for thyroid surgery. The sections on less common causes of thyrotoxicosis have been expanded. CONCLUSIONS: One hundred twenty-four evidence-based recommendations were developed to aid in the care of patients with thyrotoxicosis and to share what the task force believes is current, rational, and optimal medical practice.

Upregulation of Key Molecules for Targeted Imaging and Therapy.

Targeted diagnosis and therapy enable precise tumor detection and treatment. Successful examples for precise tumor targeting are diagnostic and therapeutic radioligands. However, patients with tumors expressing low levels of the relevant molecular targets are deemed ineligible for such targeted approaches. METHODS: We performed a screen for drugs that upregulate the somatostatin receptor subtype 2 (sstr2). Then, we characterized the effects of these drugs on transcriptional, translational, and functional levels in vitro and in vivo. RESULTS: We identified 9 drugs that act as epigenetic modifiers, including the inhibitor of DNA methyltransferase decitabine as well as the inhibitors of histone deacetylase tacedinaline and romidepsin. In vitro, these drugs upregulated sstr2 on transcriptional, translational, and functional levels in a time- and dose-dependent manner. Thereby, their combinations revealed synergistic effects. In vivo, drug-based sstr2 upregulation improved the tumor-to-background and tumor-to-kidney ratios, which are the key determinants of successful sstr2-targeted imaging and radiopeptide therapy. CONCLUSION: We present an approach that uses epigenetic modifiers to improve sstr2 targeting in vitro and in vivo. Translation of this method into the clinic may potentially convert patients ineligible for targeted imaging and therapy to eligible candidates.

State and Training Effects of Mindfulness Meditation on Brain Networks Reflect Neuronal Mechanisms of Its Antidepressant Effect.

The topic of investigating how mindfulness meditation training can have antidepressant effects via plastic changes in both resting state and meditation state brain activity is important in the rapidly emerging field of neuroplasticity. In the present study, we used a longitudinal design investigating resting state fMRI both before and after 40 days of meditation training in 13 novices. After training, we compared differences in network connectivity between rest and meditation using common resting state functional connectivity methods. Interregional methods were paired with local measures such as Regional Homogeneity. As expected, significant differences in functional connectivity both between states (rest versus meditation) and between time points (before versus after training) were observed. During meditation, the internal consistency in the precuneus and the temporoparietal junction increased, while the internal consistency of frontal brain regions decreased. A follow-up analysis of regional connectivity of the dorsal anterior cingulate cortex further revealed reduced connectivity with anterior insula during meditation. After meditation training, reduced resting state functional connectivity between the pregenual anterior cingulate and dorsal medical prefrontal cortex was observed. Most importantly, significantly reduced depression/anxiety scores were observed after training. Hence, these findings suggest that mindfulness meditation might be of therapeutic use by inducing plasticity related network changes altering the neuronal basis of affective disorders such as depression.

Brain parcellation choice affects disease-related topology differences increasingly from global to local network levels.

Network-based analyses of deviant brain function have become extremely popular in psychiatric neuroimaging. Underpinning brain network analyses is the selection of appropriate regions of interest (ROIs). Although ROI selection is fundamental in network analysis, its impact on detecting disease effects remains unclear. We investigated the impact of parcellation choice when comparing results from different studies. We investigated the effects of anatomical (AAL) and literature-based (Dosenbach) parcellation schemes on comparability of group differences in 35 female patients with anorexia nervosa and 35 age- and sex-matched healthy controls. Global and local network properties, including network-based statistics (NBS), were assessed on resting state functional magnetic resonance imaging data obtained at 3T. Parcellation schemes were comparably consistent on global network properties, while NBS and local metrics differed in location, but not metric type. Location of local metric alterations varied for AAL (parietal and cingulate cortices) versus Dosenbach (insula, thalamus) parcellation approaches. However, consistency was observed for the occipital cortex. Patient-specific global network properties can be robustly observed using different parcellation schemes, while graph metrics characterizing impairments of individual nodes vary considerably. Therefore, the impact of parcellation choice on specific group differences varies depending on the level of network organization.

Dynamic disconnection of the supplementary motor area after processing of dismissive biographic narratives.

INTRODUCTION: To understand the interplay between affective social information processing and its influence on mental states we investigated changes in functional connectivity (FC) patterns after audio exposure to emotional biographic narratives. METHODS: While lying in the 7T MR scanner, 23 male participants listened to narratives of early childhood experiences of three persons, each having either a secure, dismissing, or preoccupied attachment representation. Directly after having listened to each of the prototypical narratives, participants underwent a 10-minute resting-state fMRI scan. To study changes in FC patterns between experimental conditions, three post-task conditions were compared to a baseline condition. Specific local alterations, as well as differences in connectivity patterns between distributed brain regions, were quantified using Network-based statistics (NBS) and graph metrics. RESULTS: Using NBS, a nine-region subnetwork showing reduced FC after having listened to the dismissing narrative was identified. Of this subnetwork, only the left Supplementary Motor Area (SMA) exhibited a decrease in the nodal graph metrics degree and strength exclusively after listening to the dismissing narrative. No other region showed post-task changes in nodal metrics. A post hoc analysis of dynamic characteristics of FC of the left SMA showed a significant decrease in the dismissing condition when compared with the other conditions in the first three minutes of the scan, but faded away in the two subsequent intervals the differences. CONCLUSIONS: Nodal metrics and NBS converge on reduced connectivity measures exclusively in left SMA in the dismissing condition, which may specifically reflect ongoing network changes underlying prolonged emotional reactivity to attachment-related processing.

Reduced functional connectivity in the thalamo-insular subnetwork in patients with acute anorexia nervosa.

The neural underpinnings of anorexia nervosa (AN) are poorly understood. Results from existing functional brain imaging studies using disorder-relevant food- or body-stimuli have been heterogeneous and may be biased due to varying compliance or strategies of the participants. In this study, resting state functional connectivity imaging was used. To explore the distributed nature and complexity of brain function we characterized network patterns in patients with acute AN. Thirty-five unmedicated female acute AN patients and 35 closely matched healthy female participants underwent resting state functional magnetic resonance imaging. We used a network-based statistic (NBS) approach [Zalesky et al., 2010a] to identify differences between groups by isolating a network of interconnected nodes with a deviant connectivity pattern. Group comparison revealed a subnetwork of connections with decreased connectivity including the amygdala, thalamus, fusiform gyrus, putamen and the posterior insula as the central hub in the patient group. Results were not driven by changes in intranodal or global connectivity. No network could be identified where AN patients had increased coupling. Given the known involvement of the identified thalamo-insular subnetwork in interoception, decreased connectivity in AN patients in these nodes might reflect changes in the propagation of sensations that alert the organism to urgent homeostatic imbalances and pain-processes that are known to be severely disturbed in AN and might explain the striking discrepancy between patient's actual and perceived internal body state.

Disease severity is correlated to tract specific changes of fractional anisotropy in MD and CM thalamus--a DTI study in major depressive disorder.

BACKGROUND: Depression is commonly conceptualized as corticolimbic dysregulation. Due to insufficient studies in normal aged populations especially subcortical sources of disconnection are unclear in contrast to potentially general parietal white matter (WM) deficits. This may be due to important influences of variable patient characteristics, most importantly episode severity. Especially thalamic disconnections have been functionally revealed, however, their structural correlates have not been distinctly investigated for its highly diverse subnuclei. METHODS: We compared 20 major depressive disorder (MDD) patients with mixed Hamilton depression rating scale (HAMD) severity to matched controls in fractional anisotropy (FA) derived from diffusion tensor imaging (DTI). Robust acquisition of 4 repetitions restricted to twelve directions, also to match the same parameters used by Eckert et al. (2011) who described a preferential architecture of centromedian (CM) and mediodorsal (MD) thalamic connections. Second to whole brain analysis, we tested for group differences within the preferred structural network of these two nuclei using a tract of interest (TOI) approach. RESULTS: Significant FA deficits in a whole brain analysis were only found in right parietal WM (p<0.05, corrected). Effects of severity were found for increasing thalamic FA. Post hoc analysis revealed this effect to be restricted to CM specific tracts. In contrast, we found MD to dorsolateral prefrontal cortex (DLPFC) tracts to be decreased in FA. Unspecific decreases between MD and CM towards amygdala were paralleled by primary amygdala FA reductions. LIMITATIONS: Specificity of the TOI approach and heterogenous sample. CONCLUSIONS: Robust parietal FA reductions, controlled for age effects were found in MDD. Further we revealed subcortical disease state dependency of FA in thalamic tracts, specific to predescribed preferential connections.

High resolution fMRI of subcortical regions during visual erotic stimulation at 7 T.

OBJECT: Involvement of distinct subcortical structures during sexual arousal was shown in animals and functional imaging studies gave coarse evidence for a similar organisation in humans. In contrast to previous imaging studies at lower field strengths, we tried to investigate activation in distinguishable subcortical structures at high spatial resolution during a short stimulating paradigm to further account for potential effects of attenuation or adaptation. MATERIALS AND METHODS: Seven healthy subjects were investigated using functional magnetic resonance imaging (fMRI) on a 7 T scanner. High resolution EPI images of 1.4 x 1.4 mm2 inplane resolution were acquired in a single functional session of 13.6 minutes. During the session erotic and non-erotic pictures were presented in an event-related design. RESULTS: In the unsmoothed data with preserved high spatial resolution significant effects were detected in relevant structures, including anterior caudate and mediodorsal thalamus. These effects were restricted to subcortical target structures and their anatomical boundaries. CONCLUSION: This study demonstrates that fMRI at high fields provides an ideal tool to investigate functional anatomy of subcortical structures. Due to an increased signal-to-noise ratio, functional scans of short duration can be acquired at high resolution without the need for further spatial smoothing.