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.

Envelope Following Response to 440 Hz Carrier Chirp-Modulated Tones Show Clinically Relevant Changes in Schizophrenia.

The 40 Hz auditory steady-state response (ASSR) impairment is suggested as an electrophysiological biomarker of schizophrenia; however, existing data also points to the deficiency of low and high frequency ASSR responses. In order to obtain the full picture of potential impairment in schizophrenia, it is important to test responses at different frequencies. The current study aims to evaluate a wide frequency range (1-120 Hz) in response to brief low-frequency carrier chirp-modulated tones in a group of patients with schizophrenia. The EEG-derived envelope following responses (EFRs) were obtained in a group of male patients with schizophrenia (N = 18) and matched controls (N = 18). While subjects were watching silent movies, 440 Hz carrier chirp-modulated at 1-120 Hz tones were presented. Phase-locking index and evoked amplitude in response to stimulation were assessed and compared on point-to-point basis. The peak frequency of the low gamma response was estimated. Measures were correlated with psychopathology-positive, negative, total scores of the Positive and Negative Syndrome Scale (PANSS), and hallucination subscale scores. In comparison to controls, patients showed (1) reduced power of theta-beta (4-18 Hz) responses, (2) intact but slower low gamma (30-60 Hz), and (3) reduced high gamma (95-120 Hz) responses. No correlation survived the Bonferroni correction, but a sign of positive association between low gamma phase-locking and the prevalence of hallucinations, and a sign of negative association between high gamma phase-locking and the total PANSS scores were observed. Brain networks showed impaired capabilities to generate EFRs at different frequencies in schizophrenia; moreover, even when responses of patients did not significantly differ from controls on the group level, they still showed potentially clinically relevant variability.

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.

40Hz auditory steady-state response in schizophrenia: Sensitivity to stimulation type (clicks versus flutter amplitude-modulated tones).

Auditory steady-state response (ASSR) at 40Hz has been proposed as a potential biomarker for schizophrenia. The ASSR studies in patients have used click stimulation or amplitude-modulated tones. However, the sensitivity of 40Hz ASSRs to different stimulation types in the same group of patients has not been previously evaluated. Two stimulation types for ASSRs were tested in this study: (1) 40Hz clicks and (2) flutter-amplitude modulated tones. The mean phase-locking index, evoked amplitude and event-related spectral perturbation values were compared between schizophrenia patients (n=26) and healthy controls (n=20). Both stimulation types resulted in the observation of impaired phase-locking and power measures of late (200-500ms) 40Hz ASSR in patients compared to healthy controls. The early-latency (0-100ms) 40Hz ASSR part was diminished in the schizophrenia group in response to clicks only. The late-latency 40Hz ASSR parameters obtained through different stimulation types correlated in healthy subjects but not in patients. We conclude that flutter amplitude-modulated tone stimulation, due to its potential to reveal late-latency entrainment deficits, is suitable for use in clinical populations. Careful consideration of experimental stimulation settings can contribute to the interpretation of ASSR deficits and utilization as a potential biomarker.

Pathological Imitative Behavior and Response Preparation in Schizophrenia.

INTRODUCTION: Pathological imitative behavior (ehopraxia) is occasionally observed in schizophrenia patients. However, only a severe form of echopraxia can be detected with the help of a direct observation. Therefore, our goal was to study a latent form of pathological imitative behavior in this disorder, which is indicated by an increase of imitative tendencies. METHOD: In our study, 14 schizophrenia patients and 15 healthy subjects were employed in two tasks: (a) in an imitative task they had to copy a hand action seen on a screen; (b) in a counter-imitative task they had to make a different movement (which involves an inhibition of prepotent imitative tendency that is impaired in case of pathological imitative behavior). Imitative tendencies were assessed by an interference score - a difference between counter-imitative and imitative response parameters. We also studied a response preparation in both groups by employing precueing probabilistic information. RESULTS: Our results revealed that schizophrenia patients were able to employ probabilistic information to prepare properly not only the imitative, but also the counter-imitative responses, the same as the healthy subjects did. Nevertheless, we detected increased prepotent imitative tendencies in schizophrenia patients, what indicates the latent pathological imitative behavior in case of this disorder. CONCLUSIONS: The obtained results suggest that in the case of schizophrenia problems with pathological imitative behavior more likely occurred in executive rather than in the preparatory stage of response. Our findings can help to detect a latent echopraxia in schizophrenia patients that cannot be revealed by direct observation.

Response preparation and intra-individual reaction time variability in schizophrenia.

Background. It is important to prepare response in advance to increase the efficiency of its execution. The process of response preparation is usually studied using the precueing paradigm. In this paradigm subjects have to employ the preceding information about further imperative stimulus to perform proper response preparation, which shortens the reaction time of subsequent response execution. Previous studies detected the impairment of response preparation in schizophrenia only with the help of electroencephalographic parameters, but not with the assessing of reaction time. Therefore, in this study we attempted to find a behavioural parameter that could detect impairment in response preparation of schizophrenia patients. It was recently found that appropriate response preparation not only shortens the reaction time but also increases its stability, which is measured with the intra-individual reaction time variability. It was also revealed that response stability could better find cognitive dysfunction in some studies of schizophrenia disorder than classical behavioural parameters. Hence, the main goal of this study was to verify if intra-individual reaction time variability could detect the impairment of response preparation in schizophrenia patients. Materials and methods. In order to achieve the main purpose, we carried out a study with 14 schizophrenia patients and 14 control group subjects. We used precueing paradigm in our research, in which participants had to employ information about stimulus probability for the proper response preparation. Results. Our main result showed that despite the responses of schizophrenia patients were faster to the high-probability stimulus than to the low-probability one (F (1, 13) = 30.9, p < 0.001), intra-individual reaction time variability did not differ in this group between the responses to more and less probable stimuli (F (1, 13) = 0.64, p = 0.44). Conclusions. Results of the study suggest that people with schizophrenia were able to use precueing probabilistic information only to shorten their reaction time, but not to increase response stability. Therefore, it was found that intra-individual reaction time variability parameter could detect response preparation impairment in schizophrenia, and could be used in clinical purposes.

Intra-individual reaction time variability and response preparation: an EEG study.

To behave more efficiently the human brain must anticipate future events with different probabilities and prepare appropriate responses. Previous studies demonstrated that participants react faster to more probable stimuli. It has been shown that this effect in reaction time reduction is related to the response preparation process. However it is still unknown what the minimum difference in stimulus probabilities is that is sufficient to elicit response preparation as measured with the EEG. Intra-individual reaction time variability indicates the stability of an individual's response performance and provides useful information about cognitive functioning. It's use has become prevalent in recent clinical studies. In order to extend understanding of cognitive and neural mechanisms of response stability we hypothesized that intra-individual reaction time variability relates to the response preparation process. Specifically, we hypothesized that response preparation to more probable stimuli would result in not only faster reaction time but also in a reduction of response variability. To verify this hypothesis, we tested 14 healthy subjects using reaction time and EEG as dependent measures. Two different stimuli with probabilities of 33.3% and 66.6% were assigned to two counterbalanced responses. The results of our study showed that stimulus probabilities of 66.6% and 33.3% were sufficient to elicit response preparation. Our data also revealed that response preparation to more probable stimuli speeds RT and reduces RT variability.

Does brain ability to synchronize with 40 Hz auditory stimulation change with age?

Auditory steady-state responses (ASSRs) are widely applied to test brain ability to follow external stimulation and this appeared to be a promising method in neuropsychiatric disorders. Nevertheless, there is no established conclusion on the way aging affects phase-locking measures of ASSRs in healthy subjects. We aimed to identify the effects of aging on phaselocking measures of 40 Hz ASSR. The effect of aging was tested in a sample of 46 healthy male subjects (20-58 years old) during eyes open condition. Stimuli were 500 ms trains, consisting of 20 identical clicks (1.5 ms burst of white noise) delivered binaurally. Time-frequency analysis of the data was performed and phase-locking index, evoked amplitude and total intensity measures were extracted and decomposed by non-negative multi-way factorization. As shown by curve-fitting analyses, phase-locking index and evoked amplitudes were diminishing with age in the linear manner. This was also proven by ANOVA testing when sample was divided into age groups. No effect of age on the total intensity was found. The complexity of the factors modulating the 40 Hz ASSR is not entirely solved; nevertheless, the current results suggest that the ability to synchronize to high frequency external stimulation diminishes with age. This should be taken into account, particularly when ASSRs are used in clinical practice, comparing patients and healthy subjects.

Closed eyes condition increases auditory brain responses in schizophrenia.

The 40-Hz auditory steady-state responses (ASSRs) of 14 medicated schizophrenic patients were recorded in eyes-open and eyes-closed conditions as previously done in healthy volunteers. Patients show significantly increased precision of the evoked response with eyes closed, and a significant increase of broad-band noise activity when eyes are open.

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.

P50 potential-associated gamma band activity: modulation by distraction.

We aimed to evaluate the effect of changing attentional demands towards stimulation in healthy subjects on P50 potential-related high-frequency beta and gamma oscillatory responses, P50 and N100 peak amplitudes and their gating measures. There are no data showing effect of attention on P50 potential-related beta and gamma oscillatory responses and previous results of attention effects on P50 and N100 amplitudes and gating measures are inconclusive. Nevertheless the variation in the level of attention may be a source of variance in the recordings as well as it may provide additional information about the pathology under study. Nine healthy volunteers participated in the study. A standard paired stimuli auditory P50 potential paradigm was applied. Four stimulation conditions were selected: focused attention (stimuli pair counting), unfocused attention (sitting with open eyes), easy distraction (reading a magazine article), and difficult distraction (searching for Landolt rings with appropriate gap orientation). Time-frequency responses to both S1 and S2 were evaluated in slow beta (13-16 Hz, 45-175 ms window); fast beta (20-30 Hz, 45-105 ms window) and gamma (32-46 Hz, 45-65 ms window) ranges. P50 and N100 peak amplitudes in response to both S1 and S2 and their ratio were evaluated. The phase-locked P50 potential-associated gamma activity was attenuated during distraction tasks as compared to focused attention and an unfocused attention condition. The amplitudes and gating measures of P50 and N100 waves and beta activity were not sensitive to the competing distraction task performance. The use of a distraction task is not favorable when phase-locked gamma range activity is a key interest in auditory potential studies.

The level of arousal modulates P50 peak amplitude.

We aimed to evaluate the effect of arousal level in healthy subjects on P50 potential, as the variation in the level of arousal may be a source of variance in the recordings as well as it may provide additional information about the pathology under study. Eleven healthy volunteers participated in the study. A standard auditory P50 potential paradigm was applied. Two stimulation conditions were selected: eyes-open, i.e., high arousal level condition and eyes-closed, i.e., low arousal level condition. P50 component amplitudes in response to both the first (S1) and second stimulus (S2) of the pair, their ratio and difference were evaluated. P50 amplitude in response to S1 was significantly higher during the low arousal closed eyes condition as compared to high arousal open eyes condition. There was no P50 amplitude difference in response to S2 and no arousal effect on gating measures. This prompts for more careful evaluation of patients' arousal level when performing P50 studies and interpreting the results.

Distraction task rather than focal attention modulates gamma activity associated with auditory steady-state responses (ASSRs).

OBJECTIVE: To explore the modulation of auditory steady-state response (ASSR) by experimental tasks, differing in attentional focus and arousal level. METHODS: 20 Hz and 40 Hz click trains were used to elicit ASSRs. Experiment 1 consisted of two runs of closed eyes and two runs of open eyes. Experiment 2 consisted of six tasks: counting 20 Hz and 40 Hz stimuli, sitting with closed and open eyes, reading an article, and performing a search task. Phase locking factor, evoked amplitude and total intensity were decomposed by non-negative multi-way factorization. RESULTS: The total intensity of 40 Hz ASSR was enhanced during closed eyes condition in comparison to the open eyes condition. The evoked amplitude and phase locking factor of 40 Hz ASSR were attenuated during distraction, while there were no differences between attention to stimulation and no task. 20 Hz ASSR and 20 Hz ASSR-related 40 Hz activity were not modulated by the tasks. CONCLUSIONS: The phase-locked measures of 40 Hz ASSR are attenuated when attention to the stimulation is low, i.e. the subject is effortfully focused on the competitive "distraction" task performance. Lower arousal level increases the total intensity of 40 Hz ASSRs. SIGNIFICANCE: Improvements of the practical use of ASSRs are suggested: a careful monitoring for arousal fluctuations during ASSR recordings should be performed; when ASSRs are applied to investigate the ability to generate high frequency cortical activity a "distraction" task is not favorable.

The effects of 10 Hz repetitive transcranial magnetic stimulation on resting EEG power spectrum in healthy subjects.

10 Hz rTMS over the left prefrontal cortex may be useful in the treatment of depressive disorders. However, the effects of 10 Hz rTMS applied in potentially effective doses on electroencephalographic activity are not well studied. Using EEG, we aimed to investigate the neurobiological effects of the 10 Hz rTMS set of parameters currently used for depression treatment in a sample of healthy subjects. In 18 healthy subjects, either 10 Hz real rTMS or sham stimulation were given in a crossover design. Real rTMS stimulation was carried out with an intensity of 110% of motor threshold (MT) over the left dorsolateral prefrontal cortex. For the sham condition, the coil was angled over a parietotemporal position and the intensity was reduced to 90% of MT. EEG recordings were taken before and after a single rTMS session. EEG power spectrum was extracted using the complex demodulation method and changes in power were evaluated statistically. Real 10 Hz rTMS induced an overall increase in delta power. This increase prevailed throughout the sample, whereas effects on the power of the alpha, beta and theta EEG bands were highly variable. Sham stimulation had no substantial effects on the EEG power spectrum. Furthermore, no changes in EEG asymmetry were detected. Real 10 Hz rTMS applied at 2000 stimuli and 110% intensity may induce significant changes in resting EEG in healthy subjects.

Transcranial magnetic stimulation: the method and application.

Transcranial magnetic stimulation is a noninvasive method for stimulation of brain that is based on the ability of magnetic field to penetrate skull and brain meninges, subsequently inducing electric current in the brain tissues that produces neuronal depolarization and generation of action potentials. Moreover, transcranial magnetic stimulation has effects on neurochemical and synaptic processes in neurons. Due to its easy use and relatively fair side effects, nowadays, transcranial magnetic stimulation is widely used in neurosciences and medicine. The main areas of transcranial magnetic stimulation application are: 1) the investigation of cortical and spinal excitability, 2) the investigation of neuronal plasticity, 3) the investigation of neuronal connectivity, 4) functional mapping, and 5) the treatment of some neurological and psychiatric disorders. Transcranial magnetic stimulation alone or in combination with other noninvasive neuroimaging (PET--positron emission topography, MRI--magnetic resonance imaging) and neurofunctional (EEG--electroencephalography, ERP--event-related potentials, fMRI--functional magnetic resonance imaging) methods allows conducting research on brain functions. Thus, transcranial magnetic stimulation is suitable as a diagnostic tool in neurologic and neuropsychiatric brain research.

Does electroconvulsive therapy (ECT) affect cognitive components of auditory evoked P300?

Electroconvulsive therapy (ECT), as a treatment tool for psychiatric disorders, is believed to be safe and effective. Nevertheless, it has a negative impact on cognitive functioning, especially on memory, causing both retrograde and anterograde amnesia. However, ECT effects on more subtle stages of information processing are not studied enough. Event-related potentials, and especially P300, are thought to reflect physiology of cognition. Thus, we aimed to evaluate the effects of ECT treatment on parameters of endogenous components (N2, P3) of the P300 potential. Seventeen patients suffering from schizophrenia, schizoaffective disorder and recurrent depressive disorder participated at the study. After the course of ECT, significant increase of N2 amplitude in parietal midline region and prolongation of P3 latency in frontal midline region, of which the magnitude positively correlated with the number of ECT procedures, have been obtained.

Evaluation of new MMN parameters in schizophrenia.

ERPs could be helpful in the objectification of many psychological measures. In the last few decades one of the most commonly used ERPs has been the mismatch negativity (MMN) potential. It may be used to detect cognitive dysfunction in patients suffering from schizophrenia, dementia, depression, and can also be successfully applied in treatment monitoring. Nevertheless, changes of MMN parameters (prolongation of latency or reduction of amplitude) are not sufficiently specific to help to diagnose particular diseases. In this study we looked for more strict and specific MMN characteristics selective for schizophrenia. Fifteen healthy human subjects and twelve suffering from schizophrenia spectrum disorders were studied. Two new parameters were considered: the speed of ascending part of MMN slope (SAS) and the half area of the MMN wave. These two measures could differentiate the early stages of cognitive processing disturbances in schizophrenia spectrum disorders.