Modeling transcranial magnetic stimulation from the induced electric fields to the membrane potentials along tractography-based white matter fiber tracts

Objective. Transcranial magnetic stimulation (TMS) is a promising non-invasive tool for modulating the brain activity. Despite the widespread therapeutic and diagnostic use of TMS in neurology and psychiatry, its observed response remains hard to predict, limiting its further development and applications. Although the stimulation intensity is always maximum at the cortical surface near the coil, experiments reveal that TMS can affect deeper brain regions as well. Approach. The explanation of this spread might be found in the white matter fiber tracts, connecting cortical and subcortical structures. When applying an electric field on neurons, their membrane potential is altered. If this change is significant, more likely near the TMS coil, action potentials might be initiated and propagated along the fiber tracts towards deeper regions. In order to understand and apply TMS more effectively, it is important to capture and account for this interaction as accurately as possible. Therefore, we compute, next to the induced electric fields in the brain, the spatial distribution of the membrane potentials along the fiber tracts and its temporal dynamics. Main results. This paper introduces a computational TMS model in which electromagnetism and neurophysiology are combined. Realistic geometry and tissue anisotropy are included using magnetic resonance imaging and targeted white matter fiber tracts are traced using tractography based on diffusion tensor imaging. The position and orientation of the coil can directly be retrieved from the neuronavigation system. Incorporating these features warrants both patient- and case-specific results. Significance. The presented model gives insight in the activity propagation through the brain and can therefore explain the observed clinical responses to TMS and their inter- and/or intra-subject variability. We aspire to advance towards an accurate, flexible and personalized TMS model that helps to understand stimulation in the connected brain and to target more focused and deeper brain regions

Combined rTMS/fMRI studies: An overlooked resource in animal models

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique, which has brain network-level effects in healthy individuals and is also used to treat many neurological and psychiatric conditions in which brain connectivity is believed to be abnormal. Despite the fact that rTMS is being used in a clinical setting and animal studies are increasingly identifying potential cellular and molecular mechanisms, little is known about how these mechanisms relate to clinical changes. This knowledge gap is amplified by non-overlapping approaches used in preclinical and clinical rTMS studies: preclinical studies are mostly invasive, using cellular and molecular approaches, while clinical studies are non-invasive, including functional magnetic resonance imaging (fMRI), TMS electroencephalography (EEG), positron emission tomography (PET), and behavioral measures. A non-invasive method is therefore needed in rodents to link our understanding of cellular and molecular changes to functional connectivity changes that are clinically relevant. fMRI is the technique of choice for examining both short and long term functional connectivity changes in large-scale networks and is becoming increasingly popular in animal research because of its high translatability, but, to date, there have been no reports of animal rTMS studies using this technique. This review summarizes the main studies combining different rTMS protocols with fMRI in humans, in both healthy and patient populations, providing a foundation for the design of equivalent studies in animals. We discuss the challenges of combining these two methods in animals and highlight considerations important for acquiring clinically-relevant information from combined rTMS/fMRI studies in animals. We believe that combining rTMS and fMRI in animal models will generate new knowledge in the following ways: functional connectivity changes can be explored in greater detail through complementary invasive procedures, clarifying mechanism and improving the therapeutic application of rTMS, as well as improving interpretation of fMRI data. And, in a more general context, a robust comparative approach will refine the use of animal models of specific neuropsychiatric conditions

Altered paired associative stimulation-induced plasticity in NMDAR encephalitis

Objective: To determine whether neurophysiological mechanisms indicating cortical excitability, long-term potentiation (LTP)-like plasticity, GABAergic and glutamatergic function are altered in patients with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis and whether they can be helpful as markers of diagnostic assessment, disease progression, and potentially therapy response. Methods: Neurophysiological characterizations of patients with NMDAR encephalitis (n = 34, mean age: 28 ± 11 years; 30 females) and age/gender-matched healthy controls (n = 27, 28.5 ± 10 years; 25 females) were performed using transcranial magnetic stimulation-derived protocols including resting motor threshold, recruitment curve, intracortical facilitation, short intracortical inhibition, and cortical silent period. Paired associative stimulation (PAS) was applied to assess LTP-like mechanisms which are mediated through NMDAR. Moreover, resting state functional connectivity was determined using functional magnetic resonance imaging. Results: PAS-induced plasticity differed significantly between groups (P = 0.0056). Cortical excitability, as assessed via motor-evoked potentials after PAS, decreased in patients, whereas it increased in controls indicating malfunctioning of NMDAR in encephalitis patients. Lower PAS-induced plasticity significantly correlated with the modified Rankin Scale (mRS) (r = −0.41; P = 0.0031) and was correlated with lower functional connectivity within the motor network in NMDAR encephalitis patients (P < 0.001, uncorrected). Other neurophysiological parameters were not significantly different between groups. Follow-up assessments were available in six patients and demonstrated parallel improvement of PAS-induced plasticity and mRS. Interpretation: Assessment of PAS-induced plasticity may help to determine NMDAR dysfunction and disease severity in NMDAR encephalitis, and might even aid as a sensitive, noninvasive, and well-tolerated “electrophysiological biomarker” to monitor therapy response in the future.Clinical Trial Registration: ClinicalTrials.gov: Identifier: NCT0186557

The role of the cerebellum in social and non-social action sequences : a preliminary LF-rTMS study

An increasing number of studies demonstrated the involvement of the cerebellum in (social) sequence processing. The current preliminary study is the first to investigate the causal involvement of the cerebellum in sequence generation, using low-frequency repetitive transcranial magnetic stimulation (LF-rTMS). By targeting the posterior cerebellum, we hypothesized that the induced neuro-excitability modulation would lead to altered performance on a Picture and Story sequencing task, which involve the generation of the correct chronological order of various social and non-social stories depicted in cartoons or sentences. Our results indicate that participants receiving LF-rTMS over the cerebellum, as compared to sham participants, showed a stronger learning effect from pre to post stimulation for both tasks and for all types of sequences (i.e. mechanical, social scripts, false belief, true belief). No differences between sequence types were observed. Our results suggest a positive effect of LF-rTMS on sequence generation. We conclude that the cerebellum is causally involved in the generation of sequences of social and nonsocial events. Our discussion focuses on recommendations for future studies

Distal Functional Connectivity of Known and Emerging Cortical Targets for Therapeutic Noninvasive Stimulation.

Noninvasive stimulation is an emerging modality for the treatment of psychiatric disorders, including addiction. A crucial element in effective cortical target selection is its distal influence. We approached this question by examining resting-state functional connectivity patterns in known and potential stimulation targets in 145 healthy adults. We compared connectivity patterns with distant regions of particular relevance in the development and maintenance of addiction. We used stringent Bonferroni-correction for multiple comparisons. We show how the anterior insula, dorsal anterior cingulate, and ventromedial prefrontal cortex had opposing functional connectivity with striatum compared to the dorsomedial prefrontal cortex. However, the dorsolateral prefrontal cortex, the currently preferred target, and the presupplementary motor area had strongest negative connections to amygdala and hippocampus. Our findings highlight differential and opposing influences as a function of cortical site, underscoring the relevance of careful cortical target selection dependent on the desired effect on subcortical structures. We show the relevance of dorsal anterior cingulate and ventromedial prefrontal cortex as emerging cortical targets, and further emphasize the anterior insula as a potential promising target in addiction treatment, given its strong connections to ventral striatum, putamen, and substantia nigra

Accelerated rTMS : a potential treatment to alleviate refractory depression

Three decades of clinical research on repetitive transcranial magnetic stimulation (rTMS) has yielded one clear treatment indication in psychiatry for major depression disorder (MDD). Although the clinical response equals the standard treatment algorithms, the effect sizes on the beneficial outcome remain rather modest. Over the last couple of years, to improve the efficacy in resistant depression, two new avenues have been developed: personalization and intensifying rTMS treatment. For the latter, we retrospectively compared accelerated high-frequency rTMS (arTMS) with accelerated intermittent theta burst stimulation (aiTBS) in the refractory depressed state. Although the clinical efficacy was not significantly different between both protocols, our observations substantiate the potential of the accelerated stimulation to shorten the treatment duration from the depressed state to the response state. Any time gain from the depressed state to the recovered state is in the patients' interest

Operculo-Insular and Anterior Cingulate Plasticity Induced by Transcranial Magnetic Stimulation in the Human Motor Cortex: A Dynamic Casual Modelling Study

The ability to induce neuroplasticity with non-invasive brain stimulation techniques offers a unique opportunity to examine the human brain systems involved in pain modulation. In experimental and clinical settings, the primary motor cortex (M1) is commonly targeted to alleviate pain, but its mechanism of action remains unclear. Using dynamic causal modelling (DCM) and Bayesian model selection (BMS), we tested seven competing hypotheses about how TMS modulates the directed influences (or effective connectivity) between M1 and three distinct cortical areas of the medial and lateral pain systems, including the insular (INS), anterior cingulate cortex (ACC), and parietal operculum (PO). The dataset included a novel fMRI acquisition collected synchronously with M1 stimulation during rest and while performing a simple hand motor task. DCM and BMS showed a clear preference for the fully connected model in which all cortical areas receive input directly from M1, with facilitation of the connections INS®M1, PO®M1, and ACC®M1, plus increased inhibition of their reciprocal connections. An additional DCM analysis comparing the reduced models only corresponding to networks with a sparser connectivity within the full model, showed that M1 input into the INS is the second-best model of plasticity following TMS manipulations. The results reported here provide a starting point forinvestigating whether pathway-specific targeting involving M1«INS improves analgesic response beyond conventional targeting. We eagerly await future empirical data and models that tests this hypothesis