Anti-neuroinflammatory microRNA-146a-5p as a potential biomarker for neuronavigation-guided rTMS therapy success in medication resistant depression disorder.

Treatment-resistant depression (TRD) is a challenging issue to address. Repetitive transcranial magnetic stimulation (rTMS) is commonly used but shows varying efficacy, necessitating a deeper understanding of depression physiology and rTMS mechanisms. Notably, an increasing amount of recent data has displayed the connection of TRD and its clinical outcome with chronic inflammatory processes. The current study included 19 TRD patients undergoing rTMS and 11 depressed patients responding to medication as a comparison group. We assessed therapeutic efficacy using MADRS, HAM-D-17, GAD-7, and PHQ-9 tests. Inflammatory markers, neurotrophins, and associated miRNAs were measured in patients blood serum before and during treatment. A control group of 18 healthy individuals provided baseline data. The results of our study showed significantly higher levels of pro-inflammatory interleukins-6 and - 8 in TRD patients compared to drug-responders, which also related to more severe symptoms before treatment. In addition, TRD patients, both before and during treatment, exhibited higher average blood serum concentrations of pro-inflammatory interleukin-18 and lower levels of anti-neuroinflammatory miR-146a-5p compared to healthy controls. We also observed that the expression of miR-16-5p, miR-93-5p, and especially miR-146a-5p correlated with clinical changes following rTMS. Our study confirmed that TRD patients possess a higher inflammatory status, while the anti-neuroinflammatory miR-146a-5p was demonstrated to have a considerable potential for predicting their rTMS treatment success.

Statistical Analysis of Graph-Theoretic Indices to Study EEG-TMS Connectivity in Patients With Depression.

AIM: The objective of this work was to demonstrate the usefulness of a novel statistical method to study the impact of transcranial magnetic stimulation (TMS) on brain connectivity in patients with depression using different stimulation protocols, i.e., 1 Hz repetitive TMS over the right dorsolateral prefrontal cortex (DLPFC) (protocol G1), 10 Hz repetitive TMS over the left DLPFC (G2), and intermittent theta burst stimulation (iTBS) consisting of three 50 Hz burst bundle repeated at 5 Hz frequency (G3). METHODS: Electroencephalography (EEG) connectivity analysis was performed using Directed Transfer Function (DTF) and a set of 21 indices based on graph theory. The statistical analysis of graph-theoretic indices consisted of a combination of the k-NN rule, the leave-one-out method, and a statistical test using a 2 × 2 contingency table. RESULTS: Our new statistical approach allowed for selection of the best set of graph-based indices derived from DTF, and for differentiation between conditions (i.e., before and after TMS) and between TMS protocols. The effects of TMS was found to differ based on frequency band. CONCLUSION: A set of four brain asymmetry measures were particularly useful to study protocol- and frequency-dependent effects of TMS on brain connectivity. SIGNIFICANCE: The new approach would allow for better evaluation of the therapeutic effects of TMS and choice of the most appropriate stimulation protocol.

Brain stimulation effects on serum BDNF, VEGF, and TNFα in treatment-resistant psychiatric disorders.

Resistance to pharmacological treatment poses a notable challenge for psychiatry. Such cases are usually treated with brain stimulation techniques, including repetitive transcranial magnetic stimulation (rTMS) and electroconvulsive therapy (ECT). Empirical evidence links treatment resistance to insufficient brain plasticity and chronic inflammation. Therefore, this study encompasses analysis of neurotrophic and inflammatory factors in psychiatric patients undergoing rTMS and ECT in order to refine the selection of patients and predict clinical outcomes. This study enrolled 25 drug-resistant depressive patients undergoing rTMS and 31 drug-resistant schizophrenia patients undergoing ECT. Clinical efficacy of brain stimulation therapies was gauged using MADRS and HAM-D scales in the depression group and PANSS scale in the schizophrenia group. Blood-derived BDNF, VEGF, and TNFα were analysed during the treatment course. For reference, 19 healthy control subjects were also enrolled. After statistical analysis, no significant differences were detected in BDNF, VEGF, and TNFα concentrations among healthy, depressive, and schizophrenic subject groups before the treatment. However, depressive patient treatment with rTMS has increased BDNF concentration, while schizophrenic patient treatment with ECT has lowered the concentration of TNFα. Our findings suggest that a lower initial TNFα concentration could be a marker for treatment success in depressed patients undergoing rTMS, whereas in schizophrenic patient group treated with ECT, a higher concentration of VEGF correlates to milder symptoms post-treatment, especially in the negative scale.

Migraine-linked characteristics of transcranial magnetic stimulation-induced phosphenes.

Transcranial magnetic stimulation is used to explore visual cortex hyperexcitability in migraine. We hypothesized that the phosphene threshold in subjects suffering from migraines with and without aura would be lower than in controls, and this phenomenon could be linked to higher pain and disability levels. We also implied that subjects with lower phosphene threshold could see more phosphenes of different colors and shapes. Our primary objective was to compare the phosphene threshold between migraine without aura, migraine with aura, and control groups and investigate which factors contribute to different phosphene parameters in migraineurs. Secondary objectives were to compare color, shape, and number of phosphenes between groups and assess pain and disability level correlation with the phosphene characteristics. Phosphene threshold in migraine without aura, migraine with aura, and control groups were 68 ± 9.5% vs. 75 ± 12%, vs. 80 ± 11%, respectively. Other phosphene parameters (number, color and shape) did not differ between groups. Average pain level during the attack did not correlate with phosphene threshold significantly, though the non-significant trend for negative correlation of migraine disability assessment scale score and a phosphene threshold has been found the higher was migraine disability assessment scale value, the lower was phosphene threshold (ß = -0.255; P = 0.139). Other variables: gender, age, migraine subtype, migraine duration and use of hormone contraceptives - were not related to the phosphene threshold value. Our study provides additional data on visual cortex hyperexcitability in migraineurs, regarding transcranial magnetic stimulation with a figure-of-eight coil. Visual cortex excitability might be linked to higher disability.

The use of MR­less MNI based neuronavigation for 10 Hz rTMS depression therapy: electrophysiological and clinical implications.

Repetitive transcranial magnetic stimulation (rTMS) is a popular and effective treatment for drug resistant depression. However, there is considerable variability in clinical outcomes, in previous studies and between patients. Because of high requirements for the use of fMRI based neuronavigation, many practitioners of rTMS still choose to use a standard 5 cm rule for rTMS coil placement which leads to large variations in which brain regions are being stimulated. We decided to test the possibilities of a MNI based MR­less neuronavigation system in rTMS depression treatment, by comparing the physiological effects and clinical outcomes of 3 distinct stimulation targets. Forty­six patients (thirty­three female, thirteen male) from the Republican Vilnius psychiatric hospital, all with drug resistant depressive disorder, participated in the study. All patients received high frequency (10 Hz) stimulation for 10 to 15 daily rTMS sessions. However, before the treatment they were randomly sorted into 3 groups according to stimulation target in MNI map: Group 1 received rTMS at point ­40; 48; 35; Group 2 received rTMS at point ­46; 45; 38; Group 3 received rTMS at point ­38; 44; 26. Electroencephalography (EEG) recordings and clinical tests were obtained the day before the rTMS course and after the last session. There were some notable differences in physiological changes between the groups, with the largest EEG band spectral power increases found in Group 1 patients and the lowest in Group 2 patients. There was a significantly larger decrease of the Hamilton Depression Rating Scale (HAM-D) scores in the Group 3 (66.94%) compared to Group 1 (57.52%) and Group 2 (56.02%). This suggests it is possible to achieve higher clinical efficacy and less physiological impact on the brain when using different targets in a neuronavigated MNI based MR­less rTMS system.

Subjective characteristics of TMS-induced phosphenes originating in human V1 and V2.

One way to study the neural correlates of visual consciousness is to localize the cortical areas whose stimulation generates subjective visual sensations, called phosphenes. While there is support for the view that the stimulation of several different visual areas in the occipital lobe may produce phosphenes, it is not clear what the contribution of each area is. Here, we studied the roles of the primary visual cortex (V1) and the adjacent area V2 in eliciting phosphenes by using functional magnetic resonance imaging-guided transcranial magnetic stimulation (TMS) combined with spherical modeling of the TMS-induced electric field. Reports of the subjective visual features of phosphenes were systematically collected and analyzed. We found that selective stimulation of V1 and V2 are equally capable of generating phosphenes, as demonstrated by comparable phosphene thresholds and similar characteristics of phosphene shape, color, and texture. However, the phosphenes induced by V1 stimulation were systematically perceived as brighter than the phosphenes induced by the stimulation of V2. Thus, these results suggest that V1 and V2 have a similar capability to produce conscious percepts. Nevertheless, V1 and V2 contribute differently to brightness: neural activation originating in V1 generates a more intense sensation of brightness than similar activation originating in V2.

Electrophysiological differences between high and low frequency rTMS protocols in depression treatment.

Repetitive transcranial magnetic stimulation (rTMS) is a rapidly expanding mean in drug resistant depression treatment. Yet, despite vast research in this field, exact neurophysiological mechanism of rTMS therapy still remains unclear. This results in difficulties choosing suitable rTMS parameters in advance and compromises thorough evaluation of efficacy after the treatment. In order to obtain more explicit assessment of rTMS therapy in the psychiatric field, we evaluated and compared the influence of two most widely used antidepressive rTMS protocols on EEG band power spectrum and relation to clinical test scores (MADRS, BDI, HAM-D17). Forty-five patients (12 male, 33 female, mean age 52.16 years) participated in the study. Twenty-three patients received high frequency (10 Hz) stimulation, the rest 22 were stimulated using low frequency (1 Hz) protocol. Both groups received 10 to 15 daily rTMS sessions. EEG recordings and clinical tests were obtained the day before rTMS course and same day after the last session. Majority (57.78%) of patients showed considerable improvement after the treatment. There were no notable differences in clinical test score drop between the two rTMS protocols. However, we found that different protocols resulted in significantly different electrophysiological changes. High frequency (10 Hz) rTMS resulted in widespread changes off EEG band power, including delta power increase on the left hemisphere and alpha power growth on the right. Theta power increase was also obtained in parietal-occipital areas. Low frequency (1 Hz) rTMS showed to have no major effect on basic EEG band power, however, we found a notable shift of frontal alpha power asymmetry towards the right hemisphere, which correlated with the clinical outcome. Our study results suggest that two widely used rTMS protocols strongly differ in their electrophysiological mechanisms. Low frequency stimulation finesse on frontal alpha power asymmetry shift, whereas high frequency protocol acts on wider electrophysiological changes in the brain.