Ketamine-dependent neuronal activation in healthy volunteers.

Over the last years, a number of studies have been conducted to clarify the neurobiological correlates of ketamine application. However, comprehensive information regarding the influence of ketamine on cortical activity is still lacking. Using resting-state functional MRI and integrating pharmacokinetic information, a double-blind, randomized, placebo-controlled, crossover study was performed to determine the effects of ketamine on neuronal activation. During a 55 min resting-state fMRI scan, esketamine (Ketanest S®) was administered intravenously to 35 healthy volunteers. Neural activation as indicated by the BOLD signal using the pharmacokinetic curve of ketamine plasma levels as a regressor was computed. Compared with placebo, ketamine-dependent increases of neural activation were observed in the midcingulate cortex, the dorsal part of the anterior cingulate cortex, the insula bilaterally, and the thalamus (t values ranging between 5.95-9.78, p < 0.05; FWE-corrected). A significant decrease of neural activation in the ketamine condition compared to placebo was found in a cluster within the subgenual/subcallosal part of the anterior cingulate cortex, the orbitofrontal cortex and the gyrus rectus (t = 7.81, p < 0.05, FWE-corrected). Using an approach combining pharmacological and fMRI data, important information about the neurobiological correlates of the clinical antidepressant effects of ketamine could be revealed.

Comparison of continuously acquired resting state and extracted analogues from active tasks.

Functional connectivity analysis of brain networks has become an important tool for investigation of human brain function. Although functional connectivity computations are usually based on resting-state data, the application to task-specific fMRI has received growing attention. Three major methods for extraction of resting-state data from task-related signal have been proposed (1) usage of unmanipulated task data for functional connectivity; (2) regression against task effects, subsequently using the residuals; and (3) concatenation of baseline blocks located in-between task blocks. Despite widespread application in current research, consensus on which method best resembles resting-state seems to be missing. We, therefore, evaluated these techniques in a sample of 26 healthy controls measured at 7 Tesla. In addition to continuous resting-state, two different task paradigms were assessed (emotion discrimination and right finger-tapping) and five well-described networks were analyzed (default mode, thalamus, cuneus, sensorimotor, and auditory). Investigating the similarity to continuous resting-state (Dice, Intraclass correlation coefficient (ICC), R(2) ) showed that regression against task effects yields functional connectivity networks most alike to resting-state. However, all methods exhibited significant differences when compared to continuous resting-state and similarity metrics were lower than test-retest of two resting-state scans. Omitting global signal regression did not change these findings. Visually, the networks are highly similar, but through further investigation marked differences can be found. Therefore, our data does not support referring to resting-state when extracting signals from task designs, although functional connectivity computed from task-specific data may indeed yield interesting information.

Ketamine-Induced Modulation of the Thalamo-Cortical Network in Healthy Volunteers As a Model for Schizophrenia.

BACKGROUND: Schizophrenia has been associated with disturbances of thalamic functioning. In light of recent evidence suggesting a significant impact of the glutamatergic system on key symptoms of schizophrenia, we assessed whether modulation of the glutamatergic system via blockage of the N-methyl-D-aspartate (NMDA)-receptor might lead to changes of thalamic functional connectivity. METHODS: Based on the ketamine model of psychosis, we investigated changes in cortico-thalamic functional connectivity by intravenous ketamine challenge during a 55-minute resting-state scan. Thirty healthy volunteers were measured with pharmacological functional magnetic resonance imaging using a double-blind, randomized, placebo-controlled, crossover design. RESULTS: Functional connectivity analysis revealed significant ketamine-specific changes within the thalamus hub network, more precisely, an increase of cortico-thalamic connectivity of the somatosensory and temporal cortex. CONCLUSIONS: Our results indicate that changes of thalamic functioning as described for schizophrenia can be partly mimicked by NMDA-receptor blockage. This adds substantial knowledge about the neurobiological mechanisms underlying the profound changes of perception and behavior during the application of NMDA-receptor antagonists.

Voxel-based morphometry at ultra-high fields. a comparison of 7T and 3T MRI data.

Recent technological progress enables MRI recordings at ultra-high fields of 7 T and above leading to brain images of higher resolution and increased signal-to-noise ratio. Despite these benefits, imaging at 7 T exhibits distinct challenges due to B1 field inhomogeneities, causing decreased image quality and problems in data analysis. Although several strategies have been proposed, a systematic investigation of bias-corrected 7 T data for voxel-based morphometry (VBM) is still missing and it is an ongoing matter of debate if VBM at 7 T can be carried out properly. Here, an optimized VBM study was conducted, evaluating the impact of field strength (3T vs. 7 T) and pulse sequence (MPRAGE vs. MP2RAGE) on gray matter volume (GMV) estimates. More specifically, twenty-two participants were measured under the conditions 3T MPRAGE, 7 T MPRAGE and 7 T MP2RAGE. Due to the fact that 7 T MPRAGE data exhibited strong intensity inhomogeneities, an alternative preprocessing pipeline was proposed and applied for that data. VBM analysis revealed higher GMV estimates for 7 T predominantly in superior cortical areas, caudate nucleus, cingulate cortex and the hippocampus. On the other hand, 3T yielded higher estimates especially in inferior cortical areas of the brain, cerebellum, thalamus and putamen compared to 7 T. Besides minor exceptions, these results were observed for 7 T MPRAGE as well for the 7 T MP2RAGE measurements. Results gained in the inferior parts of the brain should be taken with caution, as native GM segmentations displayed misclassifications in these regions for both 7 T sequences. This was supported by the test-retest measurements showing highest variability in these inferior regions of the brain for 7 T and also for the advanced MP2RAGE sequence. Hence, our data support the use of 7 T MRI for VBM analysis in cortical areas, but direct comparison between field strengths and sequences requires careful assessment. Similarly, analysis of the inferior cortical regions, cerebellum and subcortical regions still remains challenging at 7 T even if the advanced MP2RAGE sequence is used.

Structural Connectivity Networks of Transgender People.

Although previous investigations of transsexual people have focused on regional brain alterations, evaluations on a network level, especially those structural in nature, are largely missing. Therefore, we investigated the structural connectome of 23 female-to-male (FtM) and 21 male-to-female (MtF) transgender patients before hormone therapy as compared with 25 female and 25 male healthy controls. Graph theoretical analysis of whole-brain probabilistic tractography networks (adjusted for differences in intracranial volume) showed decreased hemispheric connectivity ratios of subcortical/limbic areas for both transgender groups. Subsequent analysis revealed that this finding was driven by increased interhemispheric lobar connectivity weights (LCWs) in MtF transsexuals and decreased intrahemispheric LCWs in FtM patients. This was further reflected on a regional level, where the MtF group showed mostly increased local efficiencies and FtM patients decreased values. Importantly, these parameters separated each patient group from the remaining subjects for the majority of significant findings. This work complements previously established regional alterations with important findings of structural connectivity. Specifically, our data suggest that network parameters may reflect unique characteristics of transgender patients, whereas local physiological aspects have been shown to represent the transition from the biological sex to the actual gender identity.

Uncertainty during pain anticipation: the adaptive value of preparatory processes.

OBJECTIVES: Anticipatory processes prepare the organism for upcoming experiences. The aim of this study was to investigate neural responses related to anticipation and processing of painful stimuli occurring with different levels of uncertainty. EXPERIMENTAL DESIGN: Twenty-five participants (13 females) took part in an electroencephalography and functional magnetic resonance imaging (fMRI) experiment at separate times. A visual cue announced the occurrence of an electrical painful or nonpainful stimulus, delivered with certainty or uncertainty (50% chance), at some point during the following 15 s. PRINCIPAL OBSERVATIONS: During the first 2 s of the anticipation phase, a strong effect of uncertainty was reflected in a pronounced frontal stimulus-preceding negativity (SPN) and increased fMRI activation in higher visual processing areas. In the last 2 s before stimulus delivery, we observed stimulus-specific preparatory processes indicated by a centroparietal SPN and posterior insula activation that was most pronounced for the certain pain condition. Uncertain anticipation was associated with attentional control processes. During stimulation, the results revealed that unexpected painful stimuli produced the strongest activation in the affective pain processing network and a more pronounced offset-P2. CONCLUSIONS: Our results reflect that during early anticipation uncertainty is strongly associated with affective mechanisms and seems to be a more salient event compared to certain anticipation. During the last 2 s before stimulation, attentional control mechanisms are initiated related to the increased salience of uncertainty. Furthermore, stimulus-specific preparatory mechanisms during certain anticipation also shaped the response to stimulation, underlining the adaptive value of stimulus-targeted preparatory activity which is less likely when facing an uncertain event.

Disrupted effective connectivity between the amygdala and orbitofrontal cortex in social anxiety disorder during emotion discrimination revealed by dynamic causal modeling for FMRI.

Social anxiety disorder (SAD) is characterized by over-reactivity of fear-related circuits in social or performance situations and associated with marked social impairment. We used dynamic causal modeling (DCM), a method to evaluate effective connectivity, to test our hypothesis that SAD patients would exhibit dysfunctions in the amygdala-prefrontal emotion regulation network. Thirteen unmedicated SAD patients and 13 matched healthy controls performed a series of facial emotion and object discrimination tasks while undergoing fMRI. The emotion-processing network was identified by a task-related contrast and motivated the selection of the right amygdala, OFC, and DLPFC for DCM analysis. Bayesian model averaging for DCM revealed abnormal connectivity between the OFC and the amygdala in SAD patients. In healthy controls, this network represents a negative feedback loop. In patients, however, positive connectivity from OFC to amygdala was observed, indicating an excitatory connection. As we did not observe a group difference of the modulatory influence of the FACE condition on the OFC to amygdala connection, we assume a context-independent reduction of prefrontal control over amygdalar activation in SAD patients. Using DCM, it was possible to highlight not only the neuronal dysfunction of isolated brain regions, but also the dysbalance of a distributed functional network.

White matter microstructure in transsexuals and controls investigated by diffusion tensor imaging.

Biological causes underpinning the well known gender dimorphisms in human behavior, cognition, and emotion have received increased attention in recent years. The advent of diffusion-weighted magnetic resonance imaging has permitted the investigation of the white matter microstructure in unprecedented detail. Here, we aimed to study the potential influences of biological sex, gender identity, sex hormones, and sexual orientation on white matter microstructure by investigating transsexuals and healthy controls using diffusion tensor imaging (DTI). Twenty-three female-to-male (FtM) and 21 male-to-female (MtF) transsexuals, as well as 23 female (FC) and 22 male (MC) controls underwent DTI at 3 tesla. Fractional anisotropy, axial, radial, and mean diffusivity were calculated using tract-based spatial statistics (TBSS) and fiber tractography. Results showed widespread significant differences in mean diffusivity between groups in almost all white matter tracts. FCs had highest mean diffusivities, followed by FtM transsexuals with lower values, MtF transsexuals with further reduced values, and MCs with lowest values. Investigating axial and radial diffusivities showed that a transition in axial diffusivity accounted for mean diffusivity results. No significant differences in fractional anisotropy maps were found between groups. Plasma testosterone levels were strongly correlated with mean, axial, and radial diffusivities. However, controlling for individual estradiol, testosterone, or progesterone plasma levels or for subjects' sexual orientation did not change group differences. Our data harmonize with the hypothesis that fiber tract development is influenced by the hormonal environment during late prenatal and early postnatal brain development.

Stability of low-frequency fluctuation amplitudes in prolonged resting-state fMRI.

The (fractional) amplitudes of low-frequency fluctuations (f)ALFF are popular measures for the magnitude of low-frequency oscillations in resting-state fMRI (R-fMRI) data. Both measures can be directly derived from the spectral power of R-fMRI time courses. Numerous studies suggest that ALFF and fALFF might be used as biomarkers for a variety of diseases including schizophrenia, major depressive disorder, and obsessive-compulsive disorder. However, the temporal stability of (f)ALFF values, which is of great importance for the application of (f)ALFF both as a biomarker and scaling parameter, has not been studied in detail yet. Here, we quantify the temporal stability, robustness and reproducibility of both ALFF and fALFF maps obtained from R-fMRI data by performing statistical analyses over 55 minute resting-state scans which included a period of NaCl infusion. We also examine the differences of using either raw or standardised (f)ALFF maps. Our analyses show that no significant changes of (f)ALFF values over the 55minute period occur for both raw and standardised (f)ALFF maps. In addition, we demonstrate that raw (f)ALFF maps across subjects are correlated with head motion as quantified via frame-wise displacement, whereas no such correlation is present in standardised (f)ALFF maps. In conclusion, the results of our study show that both ALFF and fALFF qualify as potential biomarkers due to their high temporal stability.

P300 amplitude variation is related to ventral striatum BOLD response during gain and loss anticipation: an EEG and fMRI experiment.

The anticipation of favourable or unfavourable events is a key component in our daily life. However, the temporal dynamics of anticipation processes in relation to brain activation are still not fully understood. A modified version of the monetary incentive delay task was administered during separate functional magnetic resonance imaging (fMRI) and electroencephalogram (EEG) sessions in the same 25 participants to assess anticipatory processes with a multi-modal neuroimaging set-up. During fMRI, gain and loss anticipation were both associated with heightened activation in ventral striatum and reward-related areas. EEG revealed most pronounced P300 amplitudes for gain anticipation, whereas CNV amplitudes distinguished neutral from gain and loss anticipation. Importantly, P300, but not CNV amplitudes, were correlated to neural activation in the ventral striatum for both gain and loss anticipation. Larger P300 amplitudes indicated higher ventral striatum blood oxygen level dependent (BOLD) response. Early stimulus evaluation processes indexed by EEG seem to be positively related to higher activation levels in the ventral striatum, indexed by fMRI, which are usually associated with reward processing. The current results, however, point towards a more general motivational mechanism processing salient stimuli during anticipation.

Comparing neural response to painful electrical stimulation with functional MRI at 3 and 7 T.

Progressing from 3T to 7 T functional MRI enables marked improvements of human brain imaging in vivo. Although direct comparisons demonstrated advantages concerning blood oxygen level dependent (BOLD) signal response and spatial specificity, these mostly focused on single brain regions with rather simple tasks. Considering that physiological noise also increases with higher field strength, it is not entirely clear whether the advantages of 7T translate equally to the entire brain during tasks which elicit more complex neuronal processing. Therefore, we investigated the difference between 3T and 7 T in response to transcutaneous electrical painful and non-painful stimulation in 22 healthy subjects. For painful stimuli vs. baseline, stronger activations were observed at 7 T in several brain regions including the insula and supplementary motor area, but not the secondary somatosensory cortex (p<0.05 FWE-corrected). Contrasting painful vs. non-painful stimulation limited the differences between the field strengths to the periaqueductal gray (PAG, p<0.001 uncorrected) due to a similar signal increase at 7 T for both the target and specific control condition in most brain regions. This regional specificity obtained for the PAG at higher field strengths was confirmed by an additional spatial normalization strategy optimized for the brainstem. Here, robust BOLD responses were obtained in the dorsal PAG at 7 T (p<0.05 FWE-corrected), whereas at 3T activation was completely missing for the contrast against non-painful stimuli. To summarize, our findings support previously reported benefits obtained at ultra-high field strengths also for complex activation patterns elicited by painful electrical stimulation. However, this advantage depends on the region and even more on the contrast of interest. The greatest gain at 7 T was observed within the small brainstem region of the PAG, where the increased field strength offered marked improvement for the localization of activation foci with high spatial specificity.