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- Study of neurophysiological responses associated with the application of magnetic fields to the brainPublication . Pinto, Nuno Filipe Cardoso; Patto, Maria da Assunção Morais e Cunha Vaz; Gama, Jorge Manuel dos ReisTranscranial magnetic stimulation (TMS) is a non-invasive diagnostic and therapeutic technique used to stimulate the brain in several neurological and psychiatric diseases, even though the main bases underlying its action are not fully understood. Theta Burst Stimulation (TBS), a patterned form of repetitive TMS, has been assuming particular importance due to its faster application. Research of TBS effects on some higher cortical functions such as cognition after stimulation of the prefrontal cortex (PFC), or its possible influence in some less studied cortical regions (as the temporal cortex) has been limited and revealed inconsistent results. One of the problems assessing the cognitive TBS after-effects relates to the use of multiple evaluation methods, with different sensitivities. In this matter, the use of neurophysiology studies such as the auditory P300, a cognitive evoked potential, may be of particular importance. To date, studies addressing the association between auditory P300 and TBS are scarce, and some contradictory results were found. The study of other higher cognitive domains such as creativity is even rarer, but it may be relevant given that part of the neural networks involved in creative processing are associated with the PFC. The effect of TMS over the PFC, studying the modulation of functions mediated by the autonomic nervous system has also been reported, but there is still a significant disagreement between the rare studies performed. So far, the extent of the modulatory effects associated with TBS at the sensory level is still poorly known, and research with TBS over the auditory cortex, despite showing some positive results, remains inconclusive, with some reports of sound hypersensitivity after sessions with higher intensity stimulation. It should also be noted that a significant part of the knowledge about the effects of TBS derives from studies in patients, with dysfunctional neuronal networks or hemispheric lesions, which add challenges to the search for scientific evidence in healthy individuals. Given the uncertainties that remain regarding the extent of the neuromodulatory effects of TBS, the primary objective of this thesis focused on increasing the scientific knowledge related to the use of TBS in the healthy brain. Therefore, we intended to study the neurophysiological responses (such as auditory P300), the functional responses (such as auditory thresholds), and the physiological responses (such as cerebral oximetry and blood pressure) associated with the application of TBS in the prefrontal and temporal cortices. All studies used a target population of healthy young adults, with an average age of approximately 23 years, and similar education. TBS was performed accordingly to the 600-pulse paradigm described by Huang et al. (continuous and intermittent). Sham-controlled, double-blind intervention protocols were used, with random distribution by the respective groups. The main objective of the study in chapter III was to evaluate the effect of TBS on the dorsolateral prefrontal cortex (DLPFC) of both cerebral hemispheres in cognitive processing. The objective was to assess if the auditory P300 would be influenced by the stimulation type. Results revealed that the mean P300 peak latency after TBS decreased only after leftward iTBS. A significant delay in P300 latency was originated from both right and left cTBS. Amplitude response did not change significantly. The results covered in chapter IV derived from the use of TBS on the left DLPFC, studying the possibility of a relationship between the post-TBS auditory P300 and the post-TBS neuropsychological tests: Trail Making Test (TMT) and the Stroop Test of Words and Colours. Results revealed that cTBS led to a delay of the P300, also significantly influencing the expected performance on Stroop C and Stroop Interference when compared to the groups submitted to iTBS and sham stimulation. No significant results were found in the TMT tests for any type of TBS stimulation. In Chapter V, we studied the cerebral oximetry using Near Infra-Red Spectroscopy, blood pressure, and heart rate, after applying TBS to the right and left DLPFC. We found a significant reduction in oximetry in the left frontal region after ipsilateral cTBS and a significant decrease in systolic blood pressure after cTBS to the right DLPFC. Chapter VI covered the evaluation of the effects of TBS over the left temporal cortex, specifically studying the auditory thresholds in the ear closest to the coil. Results showed no major side effects after iTBS, cTBS, or sham stimulation. It was also found that iTBS led to lower hearing thresholds, especially when comparing the iTBS and sham groups at 500Hz and between the iTBS and cTBS groups at 4000Hz. Chapter VII addresses a patent concerning the technique and possible use of iTBS as a method to influence creative processing. After iTBS over the right DLPFC, results of an adapted selection of the Torrance Tests of Creative Thinking suggest that divergent thinking, originality and fluency improved significantly compared to the sham group. An integrative analysis of the results shows that TBS seems to effectively influence the underlying cortical neurons and cortico-subcortical networks. The findings thus support the existence of a trans-synaptic effect advocated initially for the classic repetitive TMS, which after the publication of our research can continue to be extended with greater confidence to TBS protocols. Our results also support the most consensual theory about the modulatory effects of the two main forms of TBS – intermittent (excitatory) and continuous (inhibitory) – particularly on the prefrontal and temporal cortices. The effects of TBS seem to be intrinsically correlated with the hemispheric lateralization and this may be related to the specific functions or dominance of each hemisphere and the specific stimulated cortical regions. The combined results of this investigation also seem to suggest that the inhibition induced by cTBS seems more effective when compared to the excitatory effect of iTBS, which seemed stronger in the left hemisphere. After all our research with TBS in more than one cortical region, we can infer that this is a safe technique, with rare and incipient side effects. The encouraging results after using iTBS in the auditory cortex opens new perspectives regarding future implementations of the technique and should be replicated in patients, particularly with mild sensorineural hearing loss, in order to assess whether this stimulation protocol can be a valid therapeutic technique in these cases. We also conclude that the techniques used to study TBS-related effects, as the P300 or the NIRS, can be very useful in the future, as an attempt to identify the effectiveness of the therapeutic use of TBS protocols, possibly allowing to adapt and modify the idealized interventions, leading to a personalized patient intervention. Our findings provide relevant information, necessary to increase the technical and scientific credibility required for achieving a more comprehensive and reliable clinical use of TBS. This is crucial at a time when transcranial magnetic stimulation use as an off-label therapy for numerous neurological and psychiatric diseases grows unregulated, and the patient best interests must be defended.