Repetitive transcranial magnetic stimulation over dorsolateral prefrontal cortex modulates value-based learning during sequential decision-making

Adaptive behavior in daily life often requires the ability to acquire and represent sequential contingencies between actions and the associated outcomes. Although accumulating evidence implicates the role of dorsolateral prefrontal cortex (dlPFC) in complex value-based learning and decision-making, direct evidence for involvements of this region in integrating information across sequential decision states is still scarce. Using a 3-stage deterministic Markov decision task, here we applied offline, inhibitory low-frequency 1-Hz repetitive transcranial magnetic stimulation (rTMS) over the left dlPFC in young male adults (n = 31, mean age = 23.8 years, SD = 2.5 years) in a within-subject cross-over design to study the roles of this region in influencing value-based sequential decision-making. In two separate sessions, each participant received 1-Hz rTMS stimulation either over the left dlPFC or over the vertex. The results showed that transiently inhibiting the left dlPFC impaired choice accuracy, particularly in situations in which the acquisition of sequential transitions between decision states and temporally lagged action-outcome contingencies played a greater role. Estimating parameters of a diffusion model from behavioral choices, we found that the diffusion drift rate, which reflects the efficiency of information integration, was attenuated by the stimulation. Moreover, the effects of rTMS interacted with session: individuals who could not efficiently integrate information across sequential states in the first session due to disrupted dlPFC function also could not catch up in performance during the second session with those individuals who could learn sequential transitions with intact dlPFC function in the first session. Taken together, our findings suggest that the left dlPFC is crucially involved in the acquisition of complex sequential relations and in the potential of such learning

Transcranial Alternating Current Stimulation Increases Risk-Taking Behavior in the Balloon Analog Risk Task

The process of evaluating risks and benefits involves a complex neural network that includes the dorsolateral prefrontal cortex (DLPFC). It has been proposed that in conflict and reward situations, theta-band (4–8 Hz) oscillatory activity in the frontal cortex may reflect an electrophysiological mechanism for coordinating neural networks monitoring behavior, as well as facilitating task-specific adaptive changes. The goal of the present study was to investigate the hypothesis that theta-band oscillatory balance between right and left frontal and prefrontal regions, with a predominance role to the right hemisphere (RH), is crucial for regulatory control during decision-making under risk. In order to explore this hypothesis, we used transcranial alternating current stimulation, a novel technique that provides the opportunity to explore the functional role of neuronal oscillatory activities and to establish a causal link between specific oscillations and functional lateralization in risky decision-making situations. For this aim, healthy participants were randomly allocated to one of three stimulation groups (LH stimulation/RH stimulation/Sham stimulation), with active AC stimulation delivered in a frequency-dependent manner (at 6.5 Hz; 1 mA peak-to-peak). During the AC stimulation, participants performed the Balloon Analog Risk Task. This experiment revealed that participants receiving LH stimulation displayed riskier decision-making style compared to sham and RH stimulation groups. However, there was no difference in decision-making behaviors between sham and RH stimulation groups. The current study extends the notion that DLPFC activity is critical for adaptive decision-making in the context of risk-taking and emphasis the role of theta-band oscillatory activity during risky decision-making situations

A gut feeling:Noninvasive brain stimulation, gut microbiota and decision-making under risk

The majority of our daily choices include some degree of risk. This dissertation comprises a series of studies that investigate risk-taking behavior through the lens of decision neuroscience, exploring its neural processing from the brain to the gut. The first part includes studies using transcranial alternating current stimulation (tACS) and electroencephalography (EEG) to investigate the role of frontal theta-band activity in the modulation of risk-taking behavior. Part 2 explores the specific roles of the right DLPFC (rDLPFC) and the ventromedial prefrontal cortex (VMPFC) in this type of behavior and demonstrates that both areas are involved in valuation processing and the modulation of risk-taking behavior, reinforcing evidence of a strong functional interplay (Hare et al., 2009; Schiller et al., 2014). Finally, in part 3, the neural basis of risk-taking behavior was explored by looking beyond the central nervous system. The gut microbiota can influence various cognitive processes via the gut-brain axis (GBA). This study explores the effects of a probiotics manipulation on participants’ risk-taking behavior and intertemporal choices. The results show that probiotics led to a relative reduction in risk-taking behavior and increased likelihood of opting for delayed gratification, with reduced discount rates and lower risk proneness. In conclusion, this dissertation provides novel insights into the neural mechanisms underlying risk-taking behavior, both within the central nervous system and including the gut-brain axis as a potential key actor

Addiction: Brain and Cognitive Stimulation for Better Cognitive Control and Far Beyond

Addiction behaviors are characterized by conditioned responses responsible for craving and automatic actions as well as disturbances within the supervisory network, one of the key elements of which is the inhibition of prepotent response. Interventions such as brain stimulation and cognitive training targeting this imbalanced system can potentially be a positive adjunct to treatment as usual. The relevance of several invasive and noninvasive brain stimulation techniques in the context of addiction as well as several cognitive training protocols is reviewed. By reducing cue-induced craving and modifying the pattern of action, memory associations, and attention biases, these interventions produced significant but still limited clinical effects. A new refined definition of response inhibition, including automatic inhibition of response and a more consistent approach to cue exposure capitalizing on the phase of reconsolidation of pre-activated emotional memories, all associated with brain and cognitive stimulation, opens new avenues for clinical research

No evidence that prefrontal HD-tDCS influences cue-induced food craving.

This study investigated whether the application of high definition transcranial DC stimulation (HD-tDCS) to the dorsolateral prefrontal cortex reduces cue-induced food craving when combined with food-specific inhibitory control training. Using a within-subjects design, participants (N = 55) received both active and sham HD-tDCS across 2 sessions while completing a Go/No-Go task in which foods were either associated with response inhibition or response execution. Food craving was measured pre and post stimulation using a standardized questionnaire as well as desire to eat ratings for foods associated with both response inhibition and response execution in the training task. Results revealed no effect of HD-tDCS on reducing state food craving or desire to eat. Due to the COVID-19 pandemic, we were unable to achieve our maximum preplanned sample size or our minimum desired Bayesian evidence strength across all a priori hypotheses; however 6 of the 7 hypotheses converged with moderate or stronger evidence in favor of the null hypothesis over the alternative hypothesis. We discuss the importance of individual differences and provide recommendations for future studies with an emphasis on the importance of cognitive interventions

The Impact of Non-Invasive Brain Stimulation on Motor Cortex Excitability and Cognition in Chronic Lower Back Pain

This thesis was a placebo controlled, randomised control trial that examined the impact of transcranial direct current stimulation on motor cortex excitability and cognitive function in people with chronic lower back pain. This thesis aimed to examine the potential for non-invasive brain stimulation as a therapeutic technique in the management of chronic lower back pain

THETA BURST BRAIN STIMULATION IN PAINFUL DIABETIC NEUROPATHY PATIENTS: INVESTIGATING NEURAL MECHANISMS

Chronic pain (CP) is a significant contributor to disability and disease burden globally. In 2019, approximately 50.2 million adults (20.4% of the US population) experienced chronic pain, contributing to $560-635 billion in direct medical costs. In addition, the worldwide prevalence of diabetes mellitus has reached epidemic proportions and is set to increase to 629 million by 2045. Almost 50% of patients with diabetes present with diabetic neuropathy (DN), and one in five patients with diabetes presents with painful DN (pDN) which is the most common cause of neuropathic pain (NP) in the US. Symptomatic treatment is the mainstay of management for pDN due to the paucity of disease-modifying therapies targeting the irreversible nerve damage from DN. Noninvasive brain stimulation using transcranial magnetic stimulation (TMS) has been utilized as a therapeutic tool in patients with neuropsychiatric disorders, and has only been used in CP patients for research purposes. Previous studies have consistently reported the analgesic effects of high frequency repetitive TMS (HF-rTMS) via stimulation of the primary motor cortex (M1) in patients with NP. Another cortical target that has been studied using rTMS is the Dorsolateral Prefrontal Cortex (DLPFC). More recently, rTMS paradigms such as theta burst stimulation (TBS) have been developed that require less stimulation time (1-4 minutes) and lower stimulation intensities than conventional HF-rTMS protocols. TBS can be provided using either the intermittent or continuous paradigms. A prolonged form of continuous TBS (pcTBS) produces facilitatory and analgesic effects similar to HF-rTMS. No study has examined the analgesic effects of pcTBS targeted at the M1 and DLPFC brain regions in pDN patients, and concomitantly evaluated neural mechanisms of pain perception. Therefore, the central aim of this dissertation is to examine the effectiveness of pcTBS as an intervention in pDN patients by targeting the M1 and DLPFC regions of the brain, and to investigate the neural mechanisms that may explain the changes in pain perception. Therefore, Study 1 (Chapter 3) examined the efficacy of pcTBS targeted at the M1 and DLPFC brain regions as an intervention in pDN patients with a single session, prospective, single-blind, sham-controlled, randomized clinical trial. Study 2 (Chapter 4) investigated the neural mechanisms that could potentially explain the effects of pcTBS targeted at the M1 and DLPFC brain regions on pain perception in patients with pDN; (a) psychophysical mechanisms that comprise of the descending and ascending endogenous pain modulatory systems (b) neurophysiological mechanisms of corticospinal excitability, and (c) intracortical inhibition measures linked to GABA activity. The main findings from this dissertation are that pcTBS targeted at M1 or DLPFC may constitute an effective analgesic treatment for pDN and neurophysiological mechanisms related to corticospinal excitability and neurochemical mechanisms linked to intracortical inhibition may explain the analgesic response to pcTBS stimulation at the M1 and DLPFC brain regions in patients with pDN. Chapter 2 presents a review of the literature on brain derived neurotrophic factor (BDNF), focusing on its role as a biomarker, its mechanism of action in NP, and a critical analysis of the quantification of BDNF in serum and plasma