Excitability regulation in the dorsomedial prefrontal cortex during sustained instructed fear responses: a TMS-EEG study

Abstract

Threat detection is essential for protecting individuals from adverse situations, in which a network of amygdala, limbic regions and dorsomedial prefrontal cortex (dmPFC) regions are involved in fear processing. Excitability regulation in the dmPFC might be crucial for fear processing, while abnormal patterns could lead to mental illness. Notwithstanding, non-invasive paradigms to measure excitability regulation during fear processing in humans are missing. To address this challenge we adapted an approach for excitability characterization, combining electroencephalography (EEG) and transcranial magnetic stimulation (TMS) over the dmPFC during an instructed fear paradigm, to dynamically dissect its role in fear processing. Event-related (ERP) and TMS-evoked potentials (TEP) were analyzed to trace dmPFC excitability. We further linked the excitability regulation patterns to individual MRI-derived gray matter structural integrity of the fear network. Increased cortical excitability was demonstrated to threat (T) processing in comparison to no-threat (NT), reflected by increased amplitude of evoked potentials. Furthermore, TMS at dmPFC enhanced the evoked responses during T processing, while the structural integrity of the dmPFC and amygdala predicted the excitability regulation patterns to fear processing. The dmPFC takes a special role during fear processing by dynamically regulating excitability. The applied paradigm can be used to non-invasively track response abnormalities to threat stimuli in healthy subjects or patients with mental disorders.

Cortical Excitability Dynamics During Fear Processing

“…Previous studies showed increased cortical excitability to fear stimuli after verbal instruction of the CS+/US contingency (Bublatzky and Schupp, 2012; Weymar et al, 2013; Meyer et al, 2015; Gonzalez-Escamilla et al, 2018a). The current results from GMFP analyses also show increased cortical excitability during processing of fearful stimuli compared to neutral stimuli.…”

“…In such paradigms, the participants are explicitly informed that a conditioned stimulus (CS+) will be repeatedly paired with an aversive unconditioned stimulus (US), while a second conditioned stimulus will always be safe (CS-) (Mechias et al, 2010; Mertens et al, 2018). These fear responses are well associated with subjective and peripheral psycho-physiological measures, in terms of skin conductance, heart rate acceleration and self-reported fear ratings (Gonzalez-Escamilla et al, 2018a).…”

“…In a previous study, we analyzed the TMS-evoked potentials (TEP) measured with EEG and TMS over the right dmPFC during an instructed fear paradigm (Gonzalez-Escamilla et al, 2018a). We showed that TMS over dmPFC led to increased evoked cortical excitability at a specific time window during CS+ relative to CS-, measured by TMS-EEG potentials amplitudes and latencies.…”

Integrating TMS, EEG, and MRI as an Approach for Studying Brain Connectivity

“…The coil is positioned using the individual coordinates and monitored during the whole recording through a neuronavigation system. The anatomical landmarks used in neurophysiological measurements involved both anterior and posterior regions, that is, prefrontal and parieto-occipital cortices (Gonzalez-Escamilla and others 2018; Mattavelli and others 2019; Schauer and others 2016; Vernet and others 2015).…”

Exciting Complexity: The Role of Motor Circuit Elements in ALS Pathophysiology

“…et al, 2013). To probe the excitability of neurons in humans, more indirect measures are typically employed, such as a combination of transcranial magnetic stimulation (TMS) together with electroencephalography (EEG) (Miniussi et al, 2012;Hill et al, 2016;Gonzalez-Escamilla et al, 2018) or for the motor system TMS stimulation of the motor cortex and simultaneous recording of the motorevoked potential (MEP) of the respective innervated muscle. The actual activity of neurons (that is the frequency of APs) hinges on a number of factors, including the intrinsic excitability of a neuron, strength of individual synapses, as well as on the quantity and timing of excitatory synaptic input and its regulation by inhibition, a phenomenon called excitation-inhibition (E/I) BOX 1 | Definitions of neuronal hyperexcitability and hyperactivity.…”