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BACKGROUND: Cortico-cortical evoked potentials (CCEP) are becoming popular to infer brain connectivity and cortical excitability in implanted refractory epilepsy patients. Our goal was to transfer this methodology to the freely moving rodent. NEW METHOD: CCEP were recorded on freely moving Sprague-Dawley rats, from cortical and subcortical areas using depth electrodes. Electrical stimulation was applied using 1 ms biphasic current pulse, cathodic first, at a frequency of 0.5 Hz, with intensities ranging from 0.2 to 0.8 mA. Data were then processed in a similar fashion to human clinical studies, which included epoch selection, artefact correction and smart averaging. RESULTS: For a large range of tested intensities, we recorded CCEPs with very good signal to noise ratio and reproducibility between animals, without any behavioral modification. The CCEP were composed of different components according to recorded and stimulated sites, similarly to human recordings. COMPARISON WITH EXISTING METHODS: We minimally adapted a clinically-motivated methodology to a freely moving rodent model to achieve high translational relevance of future preclinical studies. CONCLUSIONS: Our results indicate that the CCEP methodology can be applied to freely moving rodents and transferred to preclinical research. This will be of interest to address various neuroscientific questions, in physiological and pathological conditions.

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The objective of this work was to study the impact of repetitive Transcranial Magnetic Stimulation (rTMS) on the EEG connectivity evaluated by indices based on graph theory, derived from Directed Transfer Function (DTF), in patients with major depressive disorder (MDD) or with bipolar disorder (BD). The results showed the importance of beta and gamma rhythms. The indices density, degree and clustering coefficient increased in MDD responders in beta and gamma bands after rTMS. Interestingly, the density and the degree changed in theta band in both groups of nonresponders (decreased in MDD nonresponders but increased in BD nonresponders). Moreover, both indices of integration (the characteristic path length and the global efficiency) as well as the clustering coefficient increased in BD nonresponders for gamma band. In BD responders, the activity increased in the frontal lobe, mainly in the left hemisphere, while in MDD responders in the central posterior part of brain. The fronto-posterior asymmetry decreased in both groups of responders in delta and beta bands. Changes in inter-hemispheric asymmetry were found only in BD nonresponders in all bands, except gamma band. Comparison between groups showed that the degree increased in delta band independently on disease (BD, MDD). These preliminary results showed that the DTF may be a useful marker allowing for evaluation of effectiveness of the rTMS therapy as well for group differentiation between MDD and BD considering separately groups of responders and nonresponders. However, further investigation should be performed over larger groups of patients to confirmed our findings.

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Aim: The aim of this work was to study the neurophysiological effect of repetitive transcranial magnetic stimulation (rTMS) applied to the left dorsolateral prefrontal cortex (DLPFC) in 8 patients with major depression disorder (MDD) and 10 patients with bipolar disorder (BP), considering separately responders and non-responders to rTMS therapy in each of both groups. Methods: The Higuchi's Fractal Dimension (FD) was analyzed from 64-channels EEG signals in five physiological frequency bands and every channel separately. Changes of FD were analyzed before and after 1st, 10th, and 20th session of rTMS. Results: Some differences in response to the rTMS therapy was found across individual groups. In MDD responders, FD decreased in all bands after longer stimulation (20th session). Whereas, in BP non-responders, FD decreased after 1st session in all bands as well as after 10th session in lower frequencies (delta and theta). In MDD non-responders and BP responders FD increased at the beginning of the therapy (1st and 10th session, respectively), but the final FD value did not changed in comparison to the initial FD value, except the FD decrease for theta band in BP responders. Comparison between groups showed a higher FD in MDD responders than in MDD non-responders in every band before as well as after stimulation. In contrast to MDD patients, FD was lower in BP responders than in BP non-responders in higher frequency bands (alpha, beta, and gamma) in both conditions as well as in lower frequency bands (delta and theta) after stimulation. Comparing both groups of responders, FD was lower in MDD than in BP in every band, except alpha. In case of non-responders, FD was higher in BP than in MDD in all bands in both conditions. Conclusion: The results showed that FD may be useful marker for evaluation of the rTMS effectiveness and the therapy progress as well as for group differentiation between MDD and BP or between responders and non-responders. The changes of FD under the influence of rTMS allow to unambiguously conclude whether the effect of stimulation is positive or negative as well as allow to evaluate an optimal time of rTMS.

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Aim: The main objective of this work was to study the impact of repetitive Transcranial Magnetic Stimulation (rTMS) treatment on brain activity in 8 patients with major depressive disorder (MDD) and 10 patients with bipolar disorder (BP). Changes due to rTMS stimulation of the left dorsolateral prefrontal cortex (DLPFC) were investigated considering separately responders and non-responders to therapy in each of both groups. The aim of the research is to determine whether non-responders differ from responders suffered from both diseases, as well as if any change occurred due to rTMS across consecutive rTMS sessions. Methods: The graph-theory-based connectivity analysis of non-linearity measure of phase interdependencies-Phase Locking Value (PLV)-was examined from EEG data. The approximately 15-min EEG recordings from each of participants were recorded before and after 1st, 10th, and 20th session, respectively. PLV calculated from data was analyzed using principal graph theory indices (strength and degree) within five physiological frequency bands and in individual channels separately. The impact of rTMS on the EEG connectivity in every group of patients evaluated by PLV was assessed. Results: Each of four groups reacted differently to rTMS treatment. The strength and degree of PLV increased in gamma band in both groups of responders. Moreover, an increase of indices in beta band for BP-responders was observed. While, in MDD-non-responders the indices decreased in gamma band and increased in beta band. Moreover, the index strength was lower in alpha band for BP- non-responders. The rTMS stimulation caused topographically specific changes, i.e., the increase of the activity in the left DLPFC as well as in other brain regions such as right parieto-occipital areas. Conclusions: The analysis of PLV allowed for evaluation of the rTMS impact on the EEG activity in each group of patients. The changes of PLV under stimulation might be a good indicator of response to depression treatment permitting to improve the effectiveness of therapy.

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Working memory (WM) can be defined as the ability to maintain and process physically absent information for a short period of time. This vital cognitive function has been related to cholinergic neuromodulation and, in independent work, to theta (4-8Hz) and alpha (9-14Hz) band oscillations. However, the relationship between both aspects remains unclear. To fill this apparent gap, we used electroencephalography (EEG) and a within-subject design in healthy humans who either received the acetylcholinesterase inhibitor galantamine (8mg) or a placebo before they performed a Sternberg WM paradigm. Here, sequences of sample images were memorized for a delay of 5s in three different load conditions (two, four or six items). On the next day, long-term memory (LTM) for the images was tested according to a remember/know paradigm. As a main finding, we can show that both theta and alpha oscillations scale during WM maintenance as a function of WM load; this resembles the typical performance decrease. Importantly, cholinergic stimulation via galantamine administration slowed down retrieval speed during WM and reduced associated alpha but not theta power, suggesting a functional relationship between alpha oscillations and WM performance. At LTM, this pattern was accompanied by impaired familiarity based recognition. These findings show that stimulating the healthy cholinergic system impairs WM and subsequent recognition, which is in line with the notion of a quadratic relationship between acetylcholine levels and cognitive functions. Moreover, our data provide empirical evidence for a specific role of alpha oscillations in acetylcholine dependent WM and associated LTM formation.

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BACKGROUND: Major depressive disorder (MDD) and bipolar disorder (BP) are two different types of mood disorders, sometimes difficult to distinguish from their depressive symptoms, and for which repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (DLPFC) has been proposed to treat refractory patients. Here we studied whether the electroencephalogram (EEG) at rest could be used to predict the therapeutic response to left DLPFC 10 Hz rTMS, and to which extent BP and MDD patients show similar correlation between the clinical response and the cortical networks at rest. METHODS: Eight MDD (6 females) and 10 BP patients (6 females) were included. The rTMS therapy consisted of 10 to 20 neuronavigated sessions, with 2000 pulses continuously applied at 120% motor threshold for each session. RTMS sessions at the beginning, middle and end of the therapy were performed while recording EEG signals. EEG spectral power was partitioned using the common physiological frequency bands and was statistically analysed at the scalp level and after cortical source reconstruction. RESULTS: We found significantly higher power in theta and beta bands in BP patients than in MDD patients, mainly localised in the prefrontal cortex. In addition, responders showed higher power in delta and theta bands in parietal regions and weaker frontal alpha power, when compared to non-responders. DISCUSSION: These preliminary findings on a small cohort suggest that pre-treatment EEG oscillatory patterns may have some predictive value regarding rTMS therapy, both for MDD and BP disorders.

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Repetitive transcranial magnetic stimulation (rTMS) modulates brain activity in different ways according to the stimulation parameters. Although the after-effects of rTMS over motor cortex are well documented in healthy individuals, less is known about the stimulation of dorso-lateral prefrontal cortex (DLPFC). Here, we studied in 20 healthy subjects how cortical oscillations are modulated by four different active rTMS protocols (1Hz, 10Hz, continuous and intermittent theta bursts - cTBS and iTBS) of the left DLPFC, and by a sham protocol used as a control condition, by comparing the spectral power of pre- and post-rTMS electroencephalographic (EEG) recordings of 15min duration. EEG spectrum was estimated with the fast Fourier transform (FFT) and partitioned using the common physiological frequency bands: delta (1-4Hz), theta (3.5-7Hz), alpha (7.5-13Hz), low beta (14-22Hz), high beta (22-30Hz) and gamma (30-45Hz). Statistical analyses of EEG changes induced by rTMS were computed with Statistical Parametric Mapping (SPM) for EEG, in every frequency band, at the scalp level and at the cortex level. We found for every active protocol a significant decrease of delta and theta power on left prefrontal electrodes, mainly localised in the left DLPFC. In higher frequency bands (beta and gamma), the decrease of power in the DLPFC was also observed contralaterally. Protocol-specific amplitude effects were found in the prefrontal cortex bilaterally in all frequency bands, but also in parietal and temporal regions in low EEG frequencies. In high frequencies, EEG power in the prefrontal cortex increased after rTMS for 10Hz and iTBS protocols, but this effect did not survive the comparison to Sham responses. Because large delta and theta activity is usually associated with cortical inhibition, observed rTMS-induced EEG changes in low frequencies suggest that rTMS of DLPFC transiently decreases local cortical inhibition. Importantly, local responses take place in association with other unknown mechanisms that modulate inter-hemispheric connectivity between homologous regions, resulting in the increase or decrease of fast activity in each prefrontal lobe, depending on the stimulation protocol. Only decreases of fast activity following active rTMS could be detected as significant when compared to Sham stimulation.

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