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Transcranial direct current stimulation (tDCS) is a form of non-invasive brain stimulation which has gained widespread interest in neurology and psychology, both as a clinical and research tool. While it has been explored as a treatment for numerous disorders and as a potential means to improve function, there is still too little empirical evidence regarding its efficacy. So far, it is only considered effective as a treatment for depression. In schizophrenia, the tDCS montage of anodal stimulation over the dorsolateral prefrontal cortex (DLPFC) and cathodal stimulation over the temporo parietal cortex (TPC) has been proposed as treatment for auditory verbal hallucinations (AVH). This montage is based on the hypofrontal/hypertemporal model in schizophrenia, which says that the DLPFC is hypoactive and therefore has reduced control over the hyperactive TPC, which causes AVH. By placing the anode over the DLPFC, which usually has an excitatory effect, activity in the DLPFC is expected to be boosted; and by placing the usually inhibitory cathode over the TPC activity is expected to be reduced. However, whether the idea that underlies the tDCS treatment is true, namely that tDCS reverses the hypertemporal/hypofrontal activity pattern, has not been studied sufficiently. In general, it is unclear what the underlying mechanisms of tDCS treatment of AVH are. Moreover, since the discovery of the tDCS treatment for AVH, the findings regarding whether it is effective have been inconsistent (Brunelin et al., 2012). Whether the hypofrontal/hypertemporal model and the hypothesized underlying mechanism of the treatment is correct has not been studied sufficiently. Therefore, the main goal of the thesis was to study the underlying mechanisms of tDCS with multimodal neuroimaging, including functional magnetic resonance imaging (fMRI), magnetic resonance spectroscopy (MRS), functional connectivity and structural imaging in both a healthy population (paper II) and a population of people with severe AVH within a randomized controlled trial (paper III). In addition, clinical measures and a behavioral task were included to examine whether the treatment reduces AVH. To study the electric field of tDCS, simulation was performed in the specific montages of the studies. In paper I, the opportunity arose to research, if tDCS works in a specific type of epilepsy caused by mitochondrial disease, specifically a DNA polymerase-gamma (POLG) gene mutation. A previous case study (Ng et al., 2018) raised hopes that tDCS could alleviate symptoms in such POLG patients. Paper I studied the effects of tDCS using electroencephalography and electromyography. The results showed, however, that tDCS treatment at 2mA did not lead to a statistically or clinically significant reduction of myoclonus jerking or epilepsy spikes in the 15-year old POLG patient. In paper II, tDCS did not induce any changes in functional activity in the DLPFC or TPC and there was only a trend for higher glutamate levels (as approximated by Glx = glutamate+glutamine) in both DLPFC and TPC. Neither finding is in line with the hypertemporal/hypofrontal model. Moreover, we found that simulation of tDCS showed peak electric field strength between the electrodes (Broca’s areas), not as hypothesized directly under the electrodes. In paper III, there was a small decrease in AVH after tDCS treatment. However, this decrease only emerged in self-reports from patients but not examinations by professional clinicians and was hard to distinguish from placebo effect. None of the neuroimaging data (rs-fMRI, MRS, structural MRI nor task-related fMRI) showed significant effects for the DLPFC or TPC. Taken together, this thesis gives an overview of tDCS treatment in neurological and psychiatric disorders based on a single case study, a healthy control population and a patient population of schizophrenia/psychosis. It was shown that tDCS does not always relieve epilepsy symptoms in POLG disease cases. With only two case studies on the subject, much more research is needed if and in which cases of POLG disease tDCS can be effective. Paper II tested the hypofrontal/hypertemporal model indirectly and paper III directly tested the notion that underlies the tDCS treatment, namely that this activity pattern could be reversed with tDCS, with multimodal neuroimaging. The results showed that tDCS reduces AVH to a certain degree. In conclusion, the findings from both paper II and III argue against the notion that the tDCS treatment reverses the hypofrontal/hypertemporal activity pattern that is believed to underlie AVH. Our data indicated that the Broca’s area should be investigated, as the peak intensity of the stimulation lies there when DLPFC and TPC are stimulated. In addition, future research should investigate the differences between tDCS responders and non-responders, preferably in a multimodal manner similar to paper II and III, as it is a crucial approach to investigate underlying neuronal mechanisms. Doktorgradsavhandling

Supplemental material, Jonauskaite_Supplemental_Method_and_Figs._S1-S5_rev for Universal Patterns in Color-Emotion Associations Are Further Shaped by Linguistic and Geographic Proximity by Domicele Jonauskaite, Ahmad Abu-Akel, Nele Dael, Daniel Oberfeld, Ahmed M. Abdel-Khalek, Abdulrahman S. Al-Rasheed, Jean-Philippe Antonietti, Victoria Bogushevskaya, Amer Chamseddine, Eka Chkonia, Violeta Corona, Eduardo Fonseca-Pedrero, Yulia A. Griber, Gina Grimshaw, Aya Ahmed Hasan, Jelena Havelka, Marco Hirnstein, Bodil S. A. Karlsson, Eric Laurent, Marjaana Lindeman, Lynn Marquardt, Philip Mefoh, Marietta Papadatou-Pastou, Alicia Pérez-Albéniz, Niloufar Pouyan, Maya Roinishvili, Lyudmyla Romanyuk, Alejandro Salgado Montejo, Yann Schrag, Aygun Sultanova, Mari Uusküla, Suvi Vainio, Grażyna Wąsowicz, Sunčica Zdravković, Meng Zhang and Christine Mohr in Psychological Science

Supplemental material, Jonauskaite_OpenPracticesDisclosure_rev for Universal Patterns in Color-Emotion Associations Are Further Shaped by Linguistic and Geographic Proximity by Domicele Jonauskaite, Ahmad Abu-Akel, Nele Dael, Daniel Oberfeld, Ahmed M. Abdel-Khalek, Abdulrahman S. Al-Rasheed, Jean-Philippe Antonietti, Victoria Bogushevskaya, Amer Chamseddine, Eka Chkonia, Violeta Corona, Eduardo Fonseca-Pedrero, Yulia A. Griber, Gina Grimshaw, Aya Ahmed Hasan, Jelena Havelka, Marco Hirnstein, Bodil S. A. Karlsson, Eric Laurent, Marjaana Lindeman, Lynn Marquardt, Philip Mefoh, Marietta Papadatou-Pastou, Alicia Pérez-Albéniz, Niloufar Pouyan, Maya Roinishvili, Lyudmyla Romanyuk, Alejandro Salgado Montejo, Yann Schrag, Aygun Sultanova, Mari Uusküla, Suvi Vainio, Grażyna Wąsowicz, Sunčica Zdravković, Meng Zhang and Christine Mohr in Psychological Science

Background Transcranial direct current stimulation (tDCS) is a brain stimulation method which is growing in popularity in both research and clinical settings, especially as a treatment of auditory verbal hallucinations (AVH) in patients with schizophrenia. However, the underlying neural mechanisms of this tDCS treatment are poorly understood. Current AVH models propose that AVH arise from hyperactivation in the left temporo parietal (LTPC), causing AVH, and from hypoactivation in the left dorsolateral prefrontal cortex (LDLPFC), leading to diminished control over AVH. We aimed to “mimic” this hyper-/hypoactivation pattern in healthy individuals with tDCS by placing the excitatory anode above the LTPC and the inhibitory cathode over the LDLPFC and then to study the effects of tDCS on these brain areas. Previous studies examined either brain activation, neurochemistry, or behavior, with other electrode montages, but few looked at those aspects together. The present study therefore examined tDCS effects with fMRI (functional magnetic resonance imaging), MR spectroscopy, behavioral tasks and simulation of the electric field in a multimodal approach. We hypothesized that tDCS would (a) lead to similar behavioral deficits in healthy individuals as in schizophrenia patients and (b) induce changes in the stimulated areas on neurotransmitter and functional activation level. Methods Thirty-two healthy participants (18 males, mean age=26 yrs) were tested twice, ca. one week apart, with either real or sham (control) 2mA tDCS for 20 min while in a GE 750, 3T MRI scanner. The order of real/sham stimulation was counterbalanced in a double-blind design. During fMRI, participants completed a dichotic listening task in a block design, in order to measure behavior and brain activation changes. Before and after fMRI/tDCS, MR spectroscopy was carried out in two voxels placed under the electrodes. The data was analyzed with repeated measures ANOVAs. After data-collection, the structural T1 sequence was used to simulate the electric field of tDCS stimulation. Results Glx (Glutamate and glutamine combined) showed a trend (F(1,31)=3.35, p=.077, η2p=.098) to increase after tDCS stimulation compared to before, however this was not electrode specific. Neither fMRI, nor the dichotic listening task (all F≤1.64, p≥.203, η2p≤.052) showed any stimulation specific differences between real and sham stimulation. The tDCS simulation revealed large individual differences in the electric field induced. Discussion In the present study, tDCS seemed to have little effect on the measured brain parameters and little validation for the AVH model was found. The mechanisms of tDCS and how it affects the underlying brain tissue are poorly understood and seem to be affected by different stimulation parameters like stimulation duration, current strength and electrode montage. To use tDCS most effectively in schizophrenia research and treatment of auditory hallucinations, it should be validated with a multitude of methods, similar to the approach described here.

Background We used transcranial direct current stimulation (tDCS) in a non-clinical population to simulate a model of tDCS-treatment for auditory verbal hallucinations (AVH) in schizophrenia. In tDCS, a low current is induced via two electrodes attached to the scalp. The anode and cathode typically up- and downregulate neuronal activity, respectively. It was suggested that AVH arise due to two main neuronal pathways: hyper-activity in the language areas in the temporo-parietal cortex and hypo-activity of the cognitive control areas in the dorsolateral prefrontal cortex. Accordingly, it was further hypothesized that by reducing activity in the temporo-parietal cortex through cathodal tDCS and simultaneously increasing neuronal activity in the dorsolateral prefrontal cortex with anodal tDCS, AVH could be reduced. Patients with schizophrenia, particularly those with AVH show additionally deficits on language and cognitive control tasks, which are known to draw on temporo-parietal and dorsolateral prefrontal cortex regions, respectively. In order to test the model we thus reversed the electrode montage in non-clinical participants and tested whether they would show similar deficits as schizophrenia patients. In addition, the healthy participants underwent magnetic resonance spectroscopy (MRS) to test whether, in accordance with the model, glutamate levels increase under the anode, and decrease under the cathode area. Methods Eighteen participants were recruited in a convenience sample (7 male/ 11 female) with a mean age of 26 years. They were tested twice with a mean interval of 8 days. In one session they received real 2mA tDCS for 20 min, while in an MRI scanner (GE 750, 3T). The other session was a sham stimulation control. The order of real/sham stimulation was counterbalanced and stimulation was double-blind. In each session, MRS was measured using a PRESS sequence (TE=35ms, 1500ms) before and after stimulation. MRS data were acquired from two voxels, one in the left dorsolateral prefrontal cortex (22ml) and one in the left temporo parietal cortex (25ml), right underneath anode and cathode electrodes, respectively. MRS data were analyzed using LCModel software; water-scaled estimates for glutamate and glutamine combined (Glx) are reported herein, with N-Acetylaspartate (NAA) and creatine (Cre) inspected to ensure stability of the Glx measure. Glx levels were subjected to a 2x2x2 ANOVA with the within-participant factors Stimulation (real vs sham), Stimulation area (dorsolateral prefrontal cortex versus temporo-parietal cortex), and Time (Pre and Post stimulation). Results Two datasets where excluded from analysis due to poor spectral quality. As expected, NAA (F1,16=.809, p=.382) and Cre (F1,16=.005, p=.944) did not show significant changes. There was a trend for Glx to be higher during real as compared to sham stimulation (main effect Stimulation F1,16=3.867, p=.067) and for Glx to be higher after than before stimulation (main effect Time F1,16=1.396, p=.078). Discussion Glx was increased during real compared to sham tDCS, and before compared to after stimulation. This could indicate that tDCS overall changes neuronal firing thresholds. However, we did not observe the expected three-way interaction of reduced glutamate levels in the dorsolateral prefrontal cortex and increased glutamate levels in the temporo-parietal cortex. This could be due to the relatively small sample. However, the present data analysis is preliminary and we aim to report findings for a larger dataset.

Introduction: Adults with attention-deficit/hyperactivity disorder (ADHD) are examined by electroencephalography (EEG). EEG is a non-invasive method to measure brain activity indirectly, by measuring voltage changes on the scalp. This thesis focuses on EEG signals from relaxed resting, recorded with closed eyes. 8-12Hz alpha is the predominant signal and is analyzed, and we hypothesize that Alpha power is lower and more variable in ADHD. ADHD is a common childhood onset mental disorder (prevalence of about 3-7 % of school children) with symptoms of inattentiveness, impulsivity and hyperactivity. Between 50 – 70 % of patients continue to have symptoms in adulthood. Numerous behavioural studies showed that participants with ADHD have slower response times (RT) compared with control participants. In EEG/event related potentials (ERP) studies, the most consistent EEG findings have been an increased theta/beta ratio. Methods: EEG recordings were performed in three different conditions, during resting state, Flanker task and Oddball task on 59 participants, equally distributed between ADHD patients and controls . The EEG data were analyzed in MATLAB® with EEGLAB by Independent component analysis (ICA) which separates multichannel data and projects it into a source space. The source time series were transformed into power spectra by fast Fourier transform (FFT). The alpha peak was analyzed and correlated with the behavioural data. T-tests were performed in Statistica® for most analyses. Results: Behavioural results showed significant longer maximum RT and slightly lower accuracy for incompatible trials in participants with ADHD. Further, we found trend-significant post error slowing (PES) in participants with ADHD. EEG results showed a marginally but significantly lower parietal alpha frequency in ADHD participants while power did not show significant differences. Significant correlations between EEG and flanker behaviour were found positive for right occipital region between alpha frequency and incompatible RT and incompatible error RT in controls. In the oddball task in the frontal region alpha frequency and RT correlated positively in controls. In the central region incompatible RT and alpha power related negatively in controls. The only correlation for ADHD was negativ , in the central region compatible RT and alpha frequency correlated. Discussion: Overall, there were only few and small differences in the resting EEG between normally developed adults and adults with ADHD. The paucity of significant differences might indicate recruitment bias, the participants that manage to meet and finish the scheduled experiments might belong to a high functioning group of ADHD cases in this study. Conclusion: RT slowing, as found in most studies, was not replicated here, similar with Woltering et.al. (Steven Woltering, Jung, Liu, & Tannock, 2012) Less PES in ADHD was not as obvious as expected from the literature, where the majority of studies find less PES. Alpha power decrease was not found either. More research is needed on ADHD to develop robust EEG markers. Future analyses of behavioral and EEG data from Oddball and Flanker might help understand the questions on the underlying biology of adults with ADHD. Master i Medisinsk biologi MAMD-MEDBI BMED395