Cortical Thickness Estimations of FreeSurfer and the CAT12 Toolbox in Patients with Alzheimer's Disease and Healthy Controls.

BACKGROUND AND PURPOSE: Automated cortical thickness (CT) measurements are often used to assess gray matter changes in the healthy and diseased human brain. The FreeSurfer software is frequently applied for this type of analysis. The computational anatomy toolbox (CAT12) for SPM, which offers a fast and easy-to-use alternative approach, was recently made available. METHODS: In this study, we compared region of interest (ROI)-wise CT estimations of the surface-based FreeSurfer 6 (FS6) software and the volume-based CAT12 toolbox for SPM using 44 elderly healthy female control subjects (HC). In addition, these 44 HCs from the cross-sectional analysis and 34 age- and sex-matched patients with Alzheimer's disease (AD) were used to assess the potential of detecting group differences for each method. Finally, a test-retest analysis was conducted using 19 HC subjects. All data were taken from the OASIS database and MRI scans were recorded at 1.5 Tesla. RESULTS: A strong correlation was observed between both methods in terms of ROI mean CT estimates (R2 = .83). However, CAT12 delivered significantly higher CT estimations in 32 of the 34 ROIs, indicating a systematic difference between both approaches. Furthermore, both methods were able to reliably detect atrophic brain areas in AD subjects, with the highest decreases in temporal areas. Finally, FS6 as well as CAT12 showed excellent test-retest variability scores. CONCLUSION: Although CT estimations were systematically higher for CAT12, this study provides evidence that this new toolbox delivers accurate and robust CT estimates and can be considered a fast and reliable alternative to FreeSurfer.

Effects of testosterone treatment on hypothalamic neuroplasticity in female-to-male transgender individuals.

Diffusion-weighted imaging (DWI) is used to measure gray matter tissue density and white matter fiber organization/directionality. Recent studies show that DWI also allows for assessing neuroplastic adaptations in the human hypothalamus. To this end, we investigated a potential influence of testosterone replacement therapy on hypothalamic microstructure in female-to-male (FtM) transgender individuals. 25 FtMs were measured at baseline, 4 weeks, and 4 months past treatment start and compared to 25 female and male controls. Our results show androgenization-related reductions in mean diffusivity in the lateral hypothalamus. Significant reductions were observed unilaterally after 1 month and bilaterally after 4 months of testosterone treatment. Moreover, treatment induced increases in free androgen index and bioavailable testosterone were significantly associated with the magnitude of reductions in mean diffusivity. These findings imply microstructural plasticity and potentially related changes in neural activity by testosterone in the adult human hypothalamus and suggest that testosterone replacement therapy in FtMs changes hypothalamic microstructure towards male proportions.

Task-relevant brain networks identified with simultaneous PET/MR imaging of metabolism and connectivity.

Except for task-specific functional MRI, the vast majority of imaging studies assessed human brain function at resting conditions. However, tracking task-specific neuronal activity yields important insight how the brain responds to stimulation. We specifically investigated changes in glucose metabolism, functional connectivity and white matter microstructure during task performance using several recent methodological advancements. Opening the eyes and right finger tapping had elicited an increased glucose metabolism in primary visual and motor cortices, respectively. Furthermore, a decreased metabolism was observed in the regions of the default mode network, which allowed absolute quantification of commonly described deactivations during cognitive tasks. These brain regions showed widespread task-specific changes in functional connectivity, which stretched beyond their primary resting-state networks and presumably reflected the level of recruitment of certain brain regions for each task. Finally, the corresponding white matter fiber pathways exhibited changes in axial and radial diffusivity during the tasks, which were regionally distinctive for certain tract groups. These results highlight that even simple task performance leads to substantial changes of entire brain networks. Exploiting the complementary nature of the different imaging modalities may reveal novel insights how the brain processes external stimuli and which networks are involved in certain tasks.

Effects of sex hormone treatment on white matter microstructure in individuals with gender dysphoria.

Sex steroid hormones such as estradiol and testosterone are known to have organizing, as well as activating effects on neural tissue in animals and humans. This study investigated the effects of transgender hormone replacement therapy on white matter microstructure using diffusion tensor imaging. Female-to-male and male-to-female transgender participants were measured at baseline, four weeks and four months past treatment start and compared to female and male controls. We observed androgenization-related reductions in mean diffusivity and increases in fractional anisotropy. We also observed feminization-related increases in mean diffusivity and reductions in fractional anisotropy. In both transgender participants and controls, hormonal fluctuations were correlated with changes in white matter microstructure. Although the present study does not preclude regression to the mean as a potential contributing factor, the results indicate that sex hormones are - at least in part - responsible for white matter variability in the human brain. Studies investigating the effects of sex hormones on adult human brain structure may be an important route for greater understanding of the psychological differences between females and males.

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.

Subcortical gray matter changes in transgender subjects after long-term cross-sex hormone administration.

Sex-steroid hormones are primarily involved in sexual differentiation and development and are thought to underlie processes related to cognition and emotion. However, divergent results have been reported concerning the effects of hormone administration on brain structure including side effects like brain atrophy and dementia. Cross-sex hormone therapy in transgender subjects offers a unique model for studying the effects of sex hormones on the living human brain. In this study, 25 Female-to-Male (FtM) and 14 Male-to-Female (MtF) subjects underwent MRI examinations at baseline and after a period of at least 4-months of continuous cross-sex hormone administration. While MtFs received estradiol and anti-androgens, FtM subjects underwent high-dose testosterone treatment. The longitudinal processing stream of the FreeSurfer software suite was used for the automated assessment and delineation of brain volumes to assess the structural changes over the treatment period of cross-sex hormone administration. Most prominent results were found for MtFs receiving estradiol and anti-androgens in the form of significant decreases in the hippocampal region. Further analysis revealed that these decreases were reflected by increases in the ventricles. Additionally, changes in progesterone levels correlated with changes in gray matter structures in MtF subjects. In line with prior studies, our results indicate hormonal influences on subcortical structures related to memory and emotional processing. Additionally, this study adds valuable knowledge that progesterone may play an important role in this process.

Testosterone affects language areas of the adult human brain.

Although the sex steroid hormone testosterone is integrally involved in the development of language processing, ethical considerations mostly limit investigations to single hormone administrations. To circumvent this issue we assessed the influence of continuous high-dose hormone application in adult female-to-male transsexuals. Subjects underwent magnetic resonance imaging before and after 4 weeks of testosterone treatment, with each scan including structural, diffusion weighted and functional imaging. Voxel-based morphometry analysis showed decreased gray matter volume with increasing levels of bioavailable testosterone exclusively in Broca's and Wernicke's areas. Particularly, this may link known sex differences in language performance to the influence of testosterone on relevant brain regions. Using probabilistic tractography, we further observed that longitudinal changes in testosterone negatively predicted changes in mean diffusivity of the corresponding structural connection passing through the extreme capsule. Considering a related increase in myelin staining in rodents, this potentially reflects a strengthening of the fiber tract particularly involved in language comprehension. Finally, functional images at resting-state were evaluated, showing increased functional connectivity between the two brain regions with increasing testosterone levels. These findings suggest testosterone-dependent neuroplastic adaptations in adulthood within language-specific brain regions and connections. Importantly, deteriorations in gray matter volume seem to be compensated by enhancement of corresponding structural and functional connectivity. Hum Brain Mapp 37:1738-1748, 2016. © 2016 Wiley Periodicals, Inc.

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.

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.

Individual diversity of functional brain network economy.

On average, brain network economy represents a trade-off between communication efficiency, robustness, and connection cost, although an analogous understanding on an individual level is largely missing. Evaluating resting-state networks of 42 healthy participants with seven Tesla functional magnetic resonance imaging and graph theory revealed that not even half of all possible connections were common across subjects. The strongest similarities among individuals were observed for interhemispheric and/or short-range connections, which may relate to the essential feature of the human brain to develop specialized systems within each hemisphere. Despite this marked variability in individual network architecture, all subjects exhibited equal small-world properties. Furthermore, interdependency between four major network economy metrics was observed across healthy individuals. The characteristic path length was associated with the clustering coefficient (peak correlation r=0.93), the response to network attacks (r=-0.97), and the physical connection cost in three-dimensional space (r=-0.62). On the other hand, clustering was negatively related to attack response (r=-0.75) and connection cost (r=-0.59). Finally, increased connection cost was associated with better response to attacks (r=0.65). This indicates that functional brain networks with high global information transfer also exhibit strong network resilience. However, it seems that these advantages come at the cost of decreased local communication efficiency and increased physical connection cost. Except for wiring length, the results were replicated on a subsample at three Tesla (n=20). These findings highlight the finely tuned interrelationships between different parameters of brain network economy. Moreover, the understanding of the individual diversity of functional brain network economy may provide further insights in the vulnerability to mental and neurological disorders.

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.

Emotional fronto-cingulate cortex activation and brain derived neurotrophic factor polymorphism in premenstrual dysphoric disorder.

Premenstrual dysphoric disorder (PMDD) is the prototypical sex-specific disorder in which symptom onset and offset require a particular hormonal milieu and for which there is moderate heritability. The present study investigated brain emotion processing in PMDD and healthy controls, as well as functional polymorphisms in two candidate genes for PMDD, the serotonin transporter (5-HTT) and brain derived neurotrophic factor (BDNF). The 5-HTT linked polymorphic region (5-HTTLPR) and BDNF Val66Met polymorphisms were genotyped in 31 patients with PMDD and 31 healthy controls. A subset of 16 patients and 15 controls participated in two functional magnetic resonance imaging-sessions performing an emotion processing task; once in the mid-follicular, and once in the late luteal phase which corresponds with maximum severity of mood symptoms. Genotypes were not directly associated with PMDD. A main effect of group was found in the whole brain analysis, with patients having lower activation of the pre-genual anterior cingulate and ventro-medial prefrontal cortex, independent of menstrual cycle phase. Post-hoc functional ROI analyses in the fronto-cingulate cluster showed no effect of 5-HTTLPR genotype but a genotype-by-group-by-phase interaction effect of BDNF Val66Met. Women with PMDD who were carriers of the Met-allele had lower fronto-cingulate cortex activation in the luteal phase compared to Met-allele carrying controls. The results provide suggestive evidence of impaired emotion-induced fronto-cingulate cortex activation in PMDD patients. Although limited by a small sample, the potential influence of BDNF Val66Met in PMDD is in line with preclinical findings.

Gray matter and intrinsic network changes in the posterior cingulate cortex after selective serotonin reuptake inhibitor intake.

Preclinical studies have demonstrated that serotonin (5-HT) challenge changes neuronal circuitries and microarchitecture. However, evidence in human subjects is missing. Pharmacologic magnetic resonance imaging (phMRI) applying selective 5-HT reuptake inhibitors (SSRIs) and high-resolution structural and functional brain assessment is able to demonstrate the impact of 5-HT challenge on neuronal network morphology and functional activity. To determine how SSRIs induce changes in gray matter and neuronal activity, we conducted a longitudinal study using citalopram and escitalopram. Seventeen healthy subjects completed a structural and functional phMRI study with randomized, cross-over, placebo-controlled, double-blind design. Significant gray matter increases were observed (among other regions) in the posterior cingulate cortex (PCC) and the ventral precuneus after SSRI intake of 10days, while decreases were observed within the pre- and postcentral gyri (all P<0.05, family-wise error [FWE] corrected). Furthermore, enhanced resting functional connectivity (rFC) within the ventral precuneus and PCC was associated with gray matter increases in the PCC (all FWE Pcorr<0.05). Corroborating these results, whole-brain connectivity density, measuring the brain's functional network hubs, was significantly increased after SSRI-intake in the ventral precuneus and PCC (all FWE Pcorr<0.05). Short-term administration of SSRIs changes gray matter structures, consistent with previous work reporting enhancement of neuroplasticity by serotonergic neurotransmission. Furthermore, increased gray matter in the PCC is associated with increased functional connectivity in one of the brain's metabolically most active regions. Our novel findings provide convergent evidence for dynamic alterations of brain structure and function associated with SSRI pharmacotherapy.

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.