Martin Tik

Towards understanding rTMS mechanism of action: Stimulation of the DLPFC causes network-specific increase in functional connectivity

&NA; Transcranial magnetic stimulation (TMS) is a powerful non‐invasive technique for the modulation of brain activity. While the precise mechanism of action is still unknown, TMS is applied in cognitive neuroscience to establish causal relationships between stimulation and subsequent changes in cerebral function and behavioral outcome. In addition, TMS is an FDA‐approved therapeutic agent in psychiatric disorders, especially major depression. Successful repetitive TMS in such disorders is usually applied over the left dorso‐lateral prefrontal cortex (DLPFC) and treatment response mechanism was therefore supposed to be based on modulations in functional networks, particularly the meso‐cortico‐limbic reward circuit. However, mechanistic evidence for the direct effects of rTMS over DLPFC is sparse. Here we show the specificity and temporal evolution of rTMS effects by comparing connectivity changes within 20 common independent components in a sham‐controlled study. Using an unbiased whole‐brain resting‐state network (RSN) approach, we successfully demonstrate that stimulation of left DLPFC modulates anterior cingulate cortex (ACC) connectivity in one specific meso‐cortico‐limbic network, while all other networks are neither influenced by rTMS nor by sham treatment. The results of this study show that the neural correlates of TMS treatment response are also traceable in DLPFC stimulation of healthy brains and therefore represent direct effects of the stimulation procedure. HighlightsSham controlled assessment of connectivity changes pre and post rTMS in 60 subjects.Unbiased analysis approach based on 20 common resting state networks (fcon1000).DLPFC rTMS increases connectivity between ACC and specific, fronto‐parietal network.

Default mode network deactivation during emotion processing predicts early antidepressant response

Several previous functional magnetic resonance imaging (fMRI) studies have demonstrated the predictive value of brain activity during emotion processing for antidepressant response, with a focus on clinical outcome after 6–8 weeks. However, longitudinal studies emphasize the paramount importance of early symptom improvement for the course of disease in major depressive disorder (MDD). We therefore aimed to assess whether neural activity during the emotion discrimination task (EDT) predicts early antidepressant effects, and how these predictive measures relate to more sustained response. Twenty-three MDD patients were investigated once with ultrahigh-field 7T fMRI and the EDT. Following fMRI, patients received Escitalopram in a flexible dose schema and were assessed with the Hamilton Depression Rating Scale (HAMD) before, and after 2 and 4 weeks of treatment. Deactivation of the precuneus and posterior cingulate cortex (PCC) during the EDT predicted change in HAMD scores after 2 weeks of treatment. Baseline EDT activity was not predictive of HAMD change after 4 weeks of treatment. The precuneus and PCC are integral components of the default mode network (DMN). We show that patients who exhibit stronger DMN suppression during emotion processing are more likely to show antidepressant response after 2 weeks. This is, to our knowledge, the first study to show that DMN activity predicts early antidepressant effects. However, DMN deactivation did not predict response at 4 weeks, suggesting that our finding is representative of early, likely treatment-related, yet unspecific symptom improvement. Regardless, early effects may be harnessed for optimization of treatment regimens and patient care.

Unsmoothed functional MRI of the human amygdala and bed nucleus of the stria terminalis during processing of emotional faces.

ABSTRACT Functional neuroimaging of the human amygdala has been of great interest to uncover the neural underpinnings of emotions, mood, motivation, social cognition, and decision making, as well as their dysfunction in psychiatric disorders. Yet, several factors limit in vivo imaging of amygdalar function, most importantly its location deep within the temporal lobe adjacent to air‐filled cavities that cause magnetic field inhomogeneities entailing signal dropouts. Additionally, the amygdala and the extended amygdalar region consist of several substructures, which have been assigned different functions and have important implications for functional and effective connectivity studies. Here we show that high‐resolution ultra‐high field fMRI at 7 T can be used to overcome these fundamental challenges for acquisition and can meet some of the demands posed by the complex neuroanatomy and ‐physiology in this region. Utilizing the inherently high SNR, we use an optimized preprocessing and data analysis strategy to demonstrate that imaging of the (extended) amygdala is highly reliable and robust. Using unsmoothed single‐subject data allowed us to differentiate brain activation during processing of emotional faces in the central and basolateral amygdala and, for the first time, in the bed nucleus of the stria terminalis (BNST), which is critically involved in the neural mechanisms of anxiety and threat monitoring. We also provide a quantitative assessment of single subject sensitivity, which is relevant for connectivity studies that rely on time course extraction of functionally‐defined volumes of interest. HIGHLIGHTS7 Tesla functional MRI of emotional face discrimination task in 38 healthy subjects.Unsmoothed single‐subject data applicable for whole‐brain group analysis.Differentiation of activation in central and basolateral amygdala.Significant effects in bed nucleus of stria terminalis, a key region for anxiety.Robust effects also on single‐subject level, relevant for connectivity analyses.

Ultra‐high‐field fMRI insights on insight: Neural correlates of the Aha!‐moment

Finding creative solutions to difficult problems is a fundamental aspect of human culture and a skill highly needed. However, the exact neural processes underlying creative problem solving remain unclear. Insightful problem solving tasks were shown to be a valid method for investigating one subcomponent of creativity: the Aha!‐moment. Finding insightful solutions during a remote associates task (RAT) was found to elicit specific cortical activity changes. Considering the strong affective components of Aha!‐moments, as manifested in the subjectively experienced feeling of relief following the sudden emergence of the solution of the problem without any conscious forewarning, we hypothesized the subcortical dopaminergic reward network to be critically engaged during Aha. To investigate those subcortical contributions to insight, we employed ultra‐high‐field 7 T fMRI during a German Version of the RAT. During this task, subjects were exposed to word triplets and instructed to find a solution word being associated with all the three given words. They were supposed to press a button as soon as they felt confident about their solution without further revision, allowing us to capture the exact event of Aha!‐moment. Besides the finding on cortical involvement of the left anterior middle temporal gyrus (aMTG), here we showed for the first time robust subcortical activity changes related to insightful problem solving in the bilateral thalamus, hippocampus, and the dopaminergic midbrain comprising ventral tegmental area (VTA), nucleus accumbens (NAcc), and caudate nucleus. These results shed new light on the affective neural mechanisms underlying insightful problem solving.

High-sensitivity TMS/fMRI of the Human Motor Cortex Using a Dedicated Multichannel MR Coil

Purpose To validate a novel setup for concurrent TMS/fMRI in the human motor cortex based on a dedicated, ultra‐thin, multichannel receive MR coil positioned between scalp and TMS system providing greatly enhanced sensitivity compared to the standard birdcage coil setting. Methods A combined TMS/fMRI design was applied over the primary motor cortex based on 1 Hz stimulation with stimulation levels of 80%, 90%, 100%, and 110% of the individual active motor threshold, respectively. Due to the use of a multichannel receive coil we were able to use multiband‐accelerated (MB=2) EPI sequences for the acquisition of functional images. Data were analysed with SPM12 and BOLD‐weighted signal intensity time courses were extracted in each subject from two local maxima (individual functional finger tapping localiser, fixed MNI coordinate of the hand knob) next to the hand area of the primary motor cortex (M1) and from the global maximum. Results We report excellent image quality without noticeable signal dropouts or image distortions. Parameter estimates in the three peak voxels showed monotonically ascending activation levels over increasing stimulation intensities. Across all subjects, mean BOLD signal changes for 80%, 90%, 100%, 110% of the individual active motor threshold were 0.43%, 0.63%, 1.01%, 2.01% next to the individual functional finger tapping maximum, 0.73%, 0.91%, 1.34%, 2.21% next to the MNI‐defined hand knob and 0.88%, 1.09%, 1.65%, 2.77% for the global maximum, respectively. Conclusion Our results show that the new setup for concurrent TMS/fMRI experiments using a dedicated MR coil array allows for high‐sensitivity fMRI particularly at the site of stimulation. Contrary to the standard birdcage approach, the results also demonstrate that the new coil can be successfully used for multiband‐accelerated EPI acquisition. The gain in flexibility due to the new coil can be easily combined with neuronavigation within the MR scanner to allow for accurate targeting in TMS/fMRI experiments.

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

Abstract 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. HighlightsEffects of sex hormone treatment on white matter microstructure was investigated.Female‐to‐male and Male‐to‐female transgender people and controls were included.Androgenization reduced mean diffusivity and increased fractional anisotropy.Feminization increased mean diffusivity and reduced fractional anisotropy.

Neurobiological differences in mental rotation and instrument interpretation in airline pilots.

Airline pilots and similar professions require reliable spatial cognition abilities, such as mental imagery of static and moving three-dimensional objects in space. A well-known task to investigate these skills is the Shepard and Metzler mental rotation task (SMT), which is also frequently used during pre-assessment of pilot candidates. Despite the intuitive relationship between real-life spatial cognition and SMT, several studies have challenged its predictive value. Here we report on a novel instrument interpretation task (IIT) based on a realistic attitude indicator used in modern aircrafts that was designed to bridge the gap between the abstract SMT and a cockpit environment. We investigated 18 professional airline pilots using fMRI. No significant correlation was found between SMT and IIT task accuracies. Contrasting both tasks revealed higher activation in the fusiform gyrus, angular gyrus, and medial precuneus for IIT, whereas SMT elicited significantly stronger activation in pre- and supplementary motor areas, as well as lateral precuneus and superior parietal lobe. Our results show that SMT skills per se are not sufficient to predict task accuracy during (close to) real-life instrument interpretation. While there is a substantial overlap of activation across the task conditions, we found that there are important differences between instrument interpretation and non-aviation based mental rotation.

Artificial scotoma estimation based on population receptive field mapping

ABSTRACT Population receptive field (pRF) mapping based on functional magnetic resonance imaging (fMRI) is an ideal method for obtaining detailed retinotopic information. One particularly promising application of pRF mapping is the estimation and quantification of visual field effects, for example scotomata in patients suffering from macular dysfunction or degeneration (MD) or hemianopic defects in patients with intracranial dysfunction. However, pRF mapping performance is influenced by a number of factors including spatial and temporal resolution, distribution of dural venous sinuses and patient performance. This study addresses the ability of current pRF methodology to assess the size of simulated scotomata in healthy individuals. The data demonstrate that central scotomata down to a radius of 2.35° (4.7° diameter) visual angle can be reliably estimated in single subjects using high spatial resolution protocols and multi‐channel receive array coils. HighlightsCentral scotomata size assessment by population Receptive Field (pRF) mapping using fMRI.Scotomata size can be reliably estimated down to radius of 2.35° in single subjects.The method could complement microperimetry examinations in patients suffering from macular dysfunction.

Imaging the neuroplastic effects of ketamine with VBM and the necessity of placebo control

ABSTRACT In the last years a plethora of studies have investigated morphological changes induced by behavioural or pharmacological interventions using structural T1‐weighted MRI and voxel‐based morphometry (VBM). Ketamine is thought to exert its antidepressant action by restoring neuroplasticity. In order to test for acute impact of a single ketamine infusion on grey matter volume we performed a placebo‐controlled, double‐blind investigation in healthy volunteers using VBM. 28 healthy individuals underwent two MRI sessions within a timeframe of 2 weeks, each consisting of two structural T1‐weighted MRIs within a single session, one before and one 45 min after infusion of S‐ketamine (bolus of 0.11 mg/kg, followed by an maintenance infusion of 0.12 mg/kg) or placebo (0.9% NaCl infusion) using a crossover design. In the repeated‐measures ANOVA with time (post‐infusion/pre‐infusion) and medication (placebo/ketamine) as factors, no significant effect of interaction and no effect of medication was found (FWE‐corrected). Importantly, further post‐hoc t‐tests revealed a strong “decrease” of grey matter both in the placebo and the ketamine condition over time. This effect was evident mainly in frontal and temporal regions bilaterally with t‐values ranging from 4.95 to 5.31 (FWE‐corrected at p<0.05 voxel level). The vulnerabilities of VBM have been repeatedly demonstrated, with reports of influence of blood flow, tissue water and direct effects of pharmacological compounds on the MRI signal. Here again, we highlight that the relationship between intervention and VBM results is apparently subject to a number of physiological influences, which are partly unknown. Future studies focusing on the effects of ketamine on grey matter should try to integrate known influential factors such as blood flow into analysis. Furthermore, the results of this study highlight the importance of a carefully performed placebo condition in pharmacological fMRI studies. HIGHLIGHTSThe study aimed to evaluate the effects of ketamine on brain structure using VBM.No effects of ketamine using a double‐blind, placebo‐controlled, cross‐over design.Drug‐unspecific strong “decrease” of grey matter over time.VBM results are influenced by a parameters independent of “real” changes of brain structure.Study highlights the importance of placebo condition in pharmacological MRI studies.

Correction to: The pulvinar nucleus and antidepressant treatment: dynamic modeling of antidepressant response and remission with ultra-high field functional MRI

The author list was presented as last name, first name. The names should have been listed as:Christoph Kraus, Manfred Klöbl, Martin Tik, Bastian Auer, Thomas Vanicek, Nicole Geissberger, Daniela M. Pfabigan, Andreas Hahn, Michael Woletz, Katharina Paul, Arkadiusz Komorowski, Siegfried Kasper, Christian Windischberger, Claus Lamm, Rupert Lanzenberger.