Background Transcranial Magnetic Stimulation (TMS) can affect episodic memory, one of the main cognitive hallmarks of aging, but the mechanisms of action remain unclear. Objectives To evaluate the behavioral and functional impact of excitatory TMS in a group of healthy elders. Methods We applied a paradigm of repetitive TMS -intermittent theta-burst stimulation- over left inferior frontal gyrus in healthy elders (n=24) and evaluated its impact on the performance of an episodic memory task with two levels of processing and the associated brain activity as captured by a pre and post fMRI scans. Results In the post-TMS fMRI we found TMS-related activity increases in left prefrontal and cerebellum-occipital areas specifically during deep encoding but not during shallow encoding or at rest. Furthermore, we found a task-dependent change in connectivity during the encoding task between cerebellum-occipital areas and the TMS-targeted left inferior frontal region. This connectivity change correlated with the TMS effects over brain networks. Conclusions The results suggest that the aged brain responds to brain stimulation in a state-dependent manner as engaged by different tasks components and that TMS effect is related to inter-individual connectivity changes measures. These findings reveal fundamental insights into brain network dynamics in aging and the capacity to probe them with combined behavioral and stimulation approaches.

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Transcranial magnetic stimulation (TMS) can interfere with cognitive processes, such as transiently impairing memory. As part of a multi-center European project, we investigated the adaptability and reproducibility of a previously published TMS memory interfering protocol in two centers using EEG or fMRI scenarios. Participants were invited to attend three experimental sessions on different days, with sham repetitive TMS (rTMS) applied on day 1 and real rTMS on days 2 and 3. Sixty-eight healthy young men were included. On each experimental day, volunteers were instructed to remember visual pictures while receiving neuronavigated rTMS trains (20 Hz, 900 ms) during picture encoding at the left dorsolateral prefrontal cortex (L-DLPFC) and the vertex. Mixed ANOVA model analyses were performed. rTMS to the L-DLPFC significantly disrupted recognition memory on experimental day 2. No differences were found between centers or between fMRI and EEG recordings. Subjects with lower baseline memory performances were more susceptible to TMS disruption. No stability of TMS-induced memory interference could be demonstrated on day 3. Our data suggests that adapted cognitive rTMS protocols can be implemented in multi-center studies incorporating standardized experimental procedures. However, our center and modality effects analyses lacked sufficient statistical power, hence highlighting the need to conduct further studies with larger samples. In addition, inter and intra-subject variability in response to TMS might limit its application in crossover or longitudinal studies.

The BDNF Val66Met gene polymorphism is a relevant factor explaining inter-individual differences to TMS responses in studies of the motor system. However, whether this variant also contributes to TMS-induced memory effects, as well as their underlying brain mechanisms, remains unexplored. In this investigation, we applied rTMS during encoding of a visual memory task either over the left frontal cortex (LFC; experimental condition) or the cranial vertex (control condition). Subsequently, individuals underwent a recognition memory phase during a functional MRI acquisition. We included 43 young volunteers and classified them as 19 Met allele carriers and 24 as Val/Val individuals. The results revealed that rTMS delivered over LFC compared to vertex stimulation resulted in reduced memory performance only amongst Val/Val allele carriers. This genetic group also exhibited greater fMRI brain activity during memory recognition, mainly over frontal regions, which was positively associated with cognitive performance. We concluded that BDNF Val66Met gene polymorphism, known to exert a significant effect on neuroplasticity, modulates the impact of rTMS both at the cognitive as well as at the associated brain networks expression levels. This data provides new insights on the brain mechanisms explaining cognitive inter-individual differences to TMS, and may inform future, more individually-tailored rTMS interventions.

The frequency-following response (FFR) is an auditory evoked potential (AEP) that follows the periodic characteristics of a sound. Despite being a widely studied biosignal in auditory neuroscience, the neural underpinnings of the FFR are still unclear. Traditionally, FFR was associated with subcortical activity, but recent evidence suggested cortical contributions which may be dependent on the stimulus frequency. We combined electroencephalography (EEG) with an inhibitory transcranial magnetic stimulation protocol, the continuous theta burst stimulation (cTBS), to disentangle the cortical contribution to the FFR elicited to stimuli of high and low frequency. We recorded FFR to the syllable /ba/ at two fundamental frequencies (Low: 113 Hz; High: 317 Hz) in healthy participants. FFR, cortical potentials, and auditory brainstem response (ABR) were recorded before and after real and sham cTBS in the right primary auditory cortex. Results showed that cTBS did not produce a significant change in the FFR recorded, in any of the frequencies. No effect was observed in the ABR and cortical potentials, despite the latter known contributions from the auditory cortex. Possible reasons behind the negative results include compensatory mechanisms from the non-targeted areas, intraindividual variability of the cTBS effectiveness, and the particular location of our target area, the primary auditory cortex.

Transcranial Magnetic Stimulation (TMS) was proposed as a neurophysiological tool almost three decades ago. It now encompasses a very wide range of applications including clinical research and the treatment of psychiatric, neurologic and medical conditions such as depression, schizophrenia, addictions, post-traumatic stress disorders, pain, migraine, stroke, Alzheimer's disease, autism, multiple sclerosis and Parkinson's disease. By inducing electrical brain responses through the administration of magnetic pulses, TMS is in a unique position to painlessly modulate cortical regions and offers good spatial resolution and excellent temporal resolution, particularly when applied using single pulses. However, despite the impressive number of papers describing the use of TMS to modulate cognitive functions, the mechanisms underlying the behavioral changes observed after stimulation have not been fully identified. Here we present a review of the ability of TMS to transiently compromise brain function in humans. The primary aim was to investigate its capacity for use as a 'cognitive challenge model' in human pharmacological studies. The data reviewed include findings on executive function, attention and episodic memory. For each cognitive process, the convergent and divergent results are discussed in terms of paradigm differences and in order to define the optimal methodology for obtaining the desired effects.

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