Stimulation Of Prefrontal Cortex Research Articles

Characterising the contribution of auditory and somatosensory inputs to TMS-evoked potentials following stimulation of prefrontal, premotor and parietal cortex

Abstract Transcranial magnetic stimulation (TMS) results in a series of deflections in electroencephalography (EEG) recordings known as a TMS-evoked potential (TEP). However, it remains unclear whether these responses reflect neural activity resulting from transcranial stimulation of the cortex, the sensory experiences of TMS, or a combination of the two. Across three experiments (total n = 135), we recorded EEG activity following TMS to the dorsolateral prefrontal cortex, premotor cortex, and parietal cortex as well as a sensory control condition (stimulation of the shoulder or electrical stimulation of the scalp with a click sound). We found that TEPs showed a stereotypical frontocentral N100/P200 complex following TMS of all cortical sites and control conditions, regardless of TMS intensity or the type of sensory control. In contrast, earlier TEPs (<60 ms) showed site-specific characteristics which were largest at the site of stimulation, although TEP topographies were distorted in a subgroup of individuals due to residual TMS-evoked muscle artifact despite cleaning with independent component analysis. Self-reported sensory experiences differed across sites, with prefrontal stimulation resulting in stronger auditory (click sound perception) and somatosensory input (scalp muscle twitch, discomfort) than premotor or parietal stimulation, a pattern that was reflected in the amplitude of later (N100/P200), but not earlier (<60 ms) TEP peak amplitudes. Later TEPs were also larger in individuals who experienced stronger click sound perception and, to a lesser extent, TMS-evoked scalp muscle twitches. Increasing click sound perception by removing auditory masking increased N100/P200 amplitudes without altering earlier peaks, an effect which was more prominent at sites with more successful masking. Together, these findings suggest that the frontocentral N100/P200 complex primarily represents a generalised sensory response resulting from TMS-related auditory and somatosensory input when present. In contrast, early TEP peaks likely primarily reflect activity resulting from transcranial stimulation of the cortex when artifacts were adequately accounted for. The results have important implications for designing and interpreting TEP studies, especially when comparing TEPs between stimulation sites and participant groups showing differences in sensory experiences following TMS.

Functional Connectome Controllability in Patients with Mild Cognitive Impairment after Repetitive Transcranial Magnetic Stimulation of the Dorsolateral Prefrontal Cortex.

Background: Repetitive transcranial magnetic stimulation (rTMS) has shown therapeutic effects in neurological patients by inducing neural plasticity. In this pilot study, we analyzed the modifying effects of high-frequency (HF-)rTMS applied to the dorsolateral prefrontal cortex (DLPFC) of patients with mild cognitive impairment (MCI) using an advanced approach of functional connectome analysis based on network control theory (NCT). Methods: Using local-to-global functional parcellation, average and modal controllability (AC/MC) were estimated for DLPFC nodes of prefrontal-lateral control networks (R/LH_Cont_PFCl_3/4) from a resting-state fMRI series acquired at three time points (T0 = baseline, T1 = T0 + 4 weeks, T2 = T1 + 20 weeks) in MCI patients receiving regular daily sessions of 10 Hz HF-rTMS (n = 10, 68.00 ± 8.16 y, 4 males) or sham (n = 10, 63.80 ± 9.95 y, 5 males) stimulation, between T0 and T1. Longitudinal (group) effects on AC/MC were assessed with non-parametric statistics. Spearman correlations (ρ) of AC/MC vs. neuropsychological (RBANS) score %change (at T1, T2 vs. T0) were calculated. Results: AC median was reduced in MCI-rTMS, compared to the control group, for RH_Cont_PFCl_3/4 at T1 and T2 (vs. T0). In MCI-rTMS patients, for RH_Cont_PFCl_3, AC % change at T1 (vs. T0) was negatively correlated with semantic fluency (ρ = -0.7939, p = 0.045) and MC % change at T2 (vs. T0) was positively correlated with story memory (ρ = 0.7416, p = 0.045). Conclusions: HF-rTMS stimulation of DLFC nodes significantly affects the controllability of the functional connectome in MCI patients. Emerging correlations between AC/MC controllability and cognitive performance changes, immediately (T1 vs. T0) and six months (T2 vs. T0) after treatment, suggest NCT could help explain the HF-rTMS impact on prefrontal-lateral control network, monitoring induced neural plasticity effects in MCI patients.

Intermittent theta burst stimulation of the left dorsolateral prefrontal cortex has no additional effect on the efficacy of virtual reality exposure therapy for acrophobia. A randomized double-blind placebo-controlled study

Anxiety disorders are among the most common mental disorders. Treatment guidelines recommend pharmacotherapy and cognitive behavioral therapy as standard treatment. Although cognitive behavioral therapy is an effective therapeutic approach, not all patients benefit sufficiently from it. In recent years, non-invasive brain stimulation techniques, such as transcranial magnetic stimulation, have been investigated as promising adjuncts in the treatment of affective disorders. The aim of this study is to investigate whether a combination of intermittent theta burst stimulation (iTBS) and virtual reality exposure therapy leads to a significantly greater reduction in acrophobia than virtual reality exposure with sham stimulation. In this randomized double-blind placebo-controlled study, 43 participants with acrophobia received verum or sham iTBS over the left dorsolateral prefrontal cortex prior to two sessions of virtual reality exposure therapy. Stimulation of the left dorsolateral prefrontal cortex with iTBS was motivated by an experimental study showing a positive effect on extinction memory retention. Acrophobic symptoms were assessed using questionnaires and two behavioral approach tasks one week before, after treatment and six months after the second diagnostic session. The results showed that two sessions of virtual reality exposure therapy led to a significant reduction in acrophobic symptoms, with an overall remission rate of 79 %. However, there was no additional effect of iTBS of the left dorsolateral prefrontal cortex on the therapeutic effects. Further research is needed to determine how exactly a combination of transcranial magnetic stimulation and exposure therapy should be designed to enhance efficacy.

Interaction between BDNF Val66Met polymorphism and mismatch negativity for working memory capacity in schizophrenia

Both the brain-derived neurotrophic factor (BDNF) valine (Val)/methionine (Met) polymorphism and mismatch negativity (MMN) amplitude are reportedly linked to working memory impairments in schizophrenia. However, there is evident scarcity of research aimed at exploring the relationships among the three factors. In this secondary analysis of a randomized, controlled, double-blind trial, we investigated these relationships. The trial assessed the efficacy of transcranial direct current stimulation for enhancing working memory in clinically stable schizophrenia patients, who were randomly divided into three groups: dorsolateral prefrontal cortex stimulation, posterior parietal cortex stimulation, and sham stimulation groups. Transcranial direct current stimulation was administered concurrently with a working memory task over five days. We assessed the BDNF genotype, MMN amplitude, working memory capacity, and interference control subdomains. These assessments were conducted at baseline with 54 patients and followed up post-intervention with 48 patients. Compared to BDNF Met-carriers, Val homozygotes exhibited fewer positive and general symptoms and increased working memory capacity at baseline. A correlation between MMN amplitude and working memory capacity was noted only in BDNF Val homozygotes. The correlations were significantly different in the two BDNF genotype groups. Furthermore, in the intervention group that showed significant improvement in MMN amplitude, BDNF Val homozygotes exhibited greater enhancement in working memory capacity than Met-carriers. This study provides in vivo evidence for the interaction between MMN and BDNF Val/Met polymorphism for working memory capacity. As MMN has been considered a biomarker of N-methyl-D-aspartate receptor (NMDAR) function, these data shed light on the complex interactions between BDNF and NMDAR in terms of working memory in schizophrenia.

Dose-Dependent Target Engagement of a Clinical iTBS Protocol: An Interleaved TMS-fMRI Study in Healthy Subjects

BackgroundIntermittent theta burst stimulation (iTBS) of the dorsolateral prefrontal cortex (DLPFC) is widely applied as a therapeutic intervention in mental health; however, the understanding of its mechanisms is still incomplete. Prior magnetic resonance imaging studies have mainly used offline iTBS or short sequences in concurrent transcranial magnetic stimulation functional magnetic resonance imaging (fMRI). This study investigated a full 600-stimuli iTBS protocol using interleaved transcranial magnetic stimulation fMRI in comparison with 2 control conditions in healthy subjects. MethodsIn a crossover design, 18 participants underwent 3 sessions of interleaved iTBS-fMRI: 1) the left DLPFC at 40% resting motor threshold (rMT) intensity, 2) the left DLPFC at 80% rMT intensity, and 3) the left primary motor cortex (M1) at 80% rMT intensity. We compared immediate blood oxygen level–dependent (BOLD) responses during interleaved iTBS-fMRI across these conditions including correlations between individual fMRI BOLD activation and iTBS-induced electric field strength at the target sites. ResultsWhole-brain analysis showed increased activation in several regions following iTBS. Specifically, the left DLPFC, as well as the bilateral M1, anterior cingulate cortex, and insula, showed increased activation during 80% rMT left DLPFC stimulation. Increased BOLD activity in the left DLPFC was observed with neither 40% rMT left DLPFC stimulation nor left M1 80% rMT iTBS, whereas activation in other regions was found to overlap between conditions. Of note, BOLD activation and electric field intensities were only correlated for M1 stimulation and not for the DLPFC conditions. ConclusionsThe study showed dosage- and target-specific BOLD activation during interleaved transcranial magnetic stimulation fMRI with 600-stimuli iTBS in healthy individuals. Future studies may use our approach for demonstrating target engagement.

Beta and theta oscillations track effort and previous reward in the human basal ganglia and prefrontal cortex during decision making

Choosing whether to exert effort to obtain rewards is fundamental to human motivated behavior. However, the neural dynamics underlying the evaluation of reward and effort in humans is poorly understood. Here, we report an exploratory investigation into this with chronic intracranial recordings from the prefrontal cortex (PFC) and basal ganglia (BG; subthalamic nuclei and globus pallidus) in people with Parkinson's disease performing a decision-making task with offers that varied in levels of reward and physical effort required. This revealed dissociable neural signatures of reward and effort, with BG beta (12 to 20 Hz) oscillations tracking effort on a single-trial basis and PFC theta (4 to 7 Hz) signaling previous trial reward, with no effects of net subjective value. Stimulation of PFC increased overall acceptance of offers and sensitivity to reward while decreasing the impact of effort on choices. This work uncovers oscillatory mechanisms that guide fundamental decisions to exert effort for reward across BG and PFC, supports a causal role of PFC for such choices, and seeds hypotheses for future studies.

Female sex and age-based advantage of simulated electric field in TMS to the prefrontal cortex in schizophrenia and mood disorders

This study investigates computational models of electric field strength for transcranial magnetic stimulation (TMS) of the left dorsolateral prefrontal cortex (DLPFC) based on individual MRI data of patients with schizophrenia (SZ), major depressive disorder (MDD), bipolar disorder (BP), and healthy controls (HC). In addition, it explores the association of electric field intensities with age, gender and intracranial volume. The subjects were 23 SZ (12 male, mean age = 45.30), 24 MDD (16 male, mean age = 43.57), 23 BP (16 male, mean age = 39.29), 23 HC (13 male, mean age = 40.91). Based on individual MRI sequences, electric fields were computationally modeled by two independent investigators using SimNIBS ver. 2.1.1. There was no significant difference in electric field strength between the groups (HC vs SZ, HC vs MDD, HC vs BP, SZ vs MDD, SZ vs BP, MDD vs BP). Female subjects showed higher electric field intensities in widespread areas than males, and age was positively significantly associated with electric field strength in the left parahippocampal area as observed. Our results suggest differences in electric field strength of left DLPFC TMS for gender and age. It may open future avenues for individually modeling TMS based on structural MRI data.

The effects of electrical stimulation of ventromedial prefrontal cortex on skin sympathetic nerve activity.

Skin sympathetic nerve activity (SSNA) is primarily involved in thermoregulation and emotional expression; however, the brain regions involved in the generation of SSNA are not completely understood. In recent years, our laboratory has shown that blood-oxygen-level-dependent signal intensity in the ventromedial prefrontal cortex (vmPFC) and dorsolateral prefrontal cortex (dlPFC) are positively correlated with bursts of SSNA during emotional arousal and increases in signal intensity in the vmPFC occurring with increases in spontaneous bursts of SSNA even in the resting state. We have recently shown that unilateral transcranial alternating current stimulation (tACS) of the dlPFC causes modulation of SSNA but given that the current was delivered between electrodes over the dlPFC and the nasion, it is possible that the effects were due to current acting on the vmPFC. To test this, we delivered tACS to target the right vmPFC or dlPFC and nasion and recorded SSNA in 11 healthy participants by inserting a tungsten microelectrode into the right common peroneal nerve. The similarity in SSNA modulation between ipsilateral vmPFC and dlPFC suggests that the ipsilateral vmPFC, rather than the dlPFC, may be causing the modulation of SSNA during ipsilateral dlPFC stimulation.

Non-additive effects of electrical stimulation of the dorsolateral prefrontal cortex and the vestibular system on muscle sympathetic nerve activity in humans

Sinusoidal galvanic vestibular stimulation (sGVS) induces robust modulation of muscle sympathetic nerve activity (MSNA) alongside perceptions of side-to-side movement, sometimes with an accompanying feeling of nausea. We recently showed that transcranial alternating current stimulation (tACS) of the dorsolateral prefrontal cortex (dlPFC) also modulates MSNA, but does not generate any perceptions. Here, we tested the hypothesis that when the two stimuli are given concurrently, the modulation of MSNA would be additive. MSNA was recorded from 11 awake participants via a tungsten microelectrode inserted percutaneously into the right common peroneal nerve at the fibular head. Sinusoidal stimuli (± 2 mA, 0.08 Hz, 100 cycles) were applied in randomised order as follows: (i) tACS of the dlPFC at electroencephalogram (EEG) site F4 and referenced to the nasion; (ii) bilateral sGVS applied to the vestibular apparatuses via the mastoid processes; and (iii) tACS and sGVS together. Previously obtained data from 12 participants supplemented the data for stimulation protocols (i) and (ii). Cross-correlation analysis revealed that each stimulation protocol caused significant modulation of MSNA (modulation index (paired data): 35.2 ± 19.4% for sGVS; 27.8 ± 15.2% for tACS), but there were no additive effects when tACS and sGVS were delivered concurrently (32.1 ± 18.5%). This implies that the vestibulosympathetic reflexes are attenuated with concurrent dlPFC stimulation. These results suggest that the dlPFC is capable of blocking the processing of vestibular inputs through the brainstem and, hence, the generation of vestibulosympathetic reflexes.

The Effectiveness of Transcranial Direct Current Stimulation (tDCS) in Binge Eating Disorder (BED)-Review and Insight into the Mechanisms of Action.

Binge eating disorder (BED) is the most common eating disorder among those contributing to the development of obesity, and thus acts as a significant burden on the lives and health of patients. It is characterized by complex neurobiology, which includes changes in brain activity and neurotransmitter secretion. Existing treatments are moderately effective, and so the search for new therapies that are effective and safe is ongoing. This review examines the use of transcranial direct current stimulation (tDCS) in the treatment of binge eating disorder. Searches were conducted on the PubMed/Medline, Research Gate, and Cochrane databases. Six studies were found that matched the review topic. All of them used the anodal stimulation of the right dorsolateral prefrontal cortex (DLPFC) in BED patients. tDCS proved effective in reducing food cravings, the desire to binge eat, the number of binging episodes, and food intake. It also improved the outcomes of inhibitory control and the treatment of eating disorder psychopathology. The potential mechanisms of action of tDCS in BED are explained, limitations in current research are outlined, and recommendations for future research are provided. Preliminary evidence suggests that the anodal application of tDCS to the right DLPFC reduces the symptoms of BED. However, caution should be exercised in the broader use of tDCS in this context due to the small number of studies performed and the small number of patients included. Future studies should incorporate neuroimaging and neurophysiological measurements to elucidate the potential mechanisms of action of tDCS in BED.

Accelerated Theta Burst Transcranial Magnetic Stimulation for Refractory Depression in Autism Spectrum Disorder.

Major depressive disorder (MDD) disproportionately affects those living with autism spectrum disorder (ASD) and is associated with significant impairment and treatment recidivism. We studied the use of accelerated theta burst stimulation (ATBS) for the treatment of refractory MDD in ASD (3 treatments daily x 10 days). This prospective open-label 12-week trial included 10 subjects with a mean age of 21.5 years, randomized to receive unilateral or bilateral stimulation of the dorsolateral prefrontal cortex. One participant dropped out of the study due to intolerability. In both treatment arms, depressive symptoms, scored on the Hamilton Depression Rating Scale scores, diminished substantially. At 12 weeks post-treatment, full remission was sustained in 5 subjects and partial remission in 3 subjects. Treatment with ATBS, regardless of the site of stimulation, was associated with a significant, substantial, and sustained improvement in depressive symptomatology via the primary outcome measure, the Hamilton Depression Rating Scale. Additional secondary measures, including self-report depression scales, fluid cognition, and sleep quality, also showed significant improvement. No serious adverse events occurred during the study. Mild transient headaches were infrequently reported, which are expected side effects of ATBS. Overall, ATBS treatment was highly effective and well-tolerated in individuals with ASD and co-occurring MDD. The findings support the need for a larger, sham-controlled randomized controlled trial to further evaluate efficacy of ATBS in this population.

Stimulating prefrontal cortex facilitates training transfer by increasing representational overlap.

A recent hypothesis characterizes difficulties in multitasking as being the price humans pay for our ability to generalize learning across tasks. The mitigation of these costs through training has been associated with reduced overlap of constituent task representations within frontal, parietal, and subcortical regions. Transcranial direct current stimulation, which can modulate functional brain activity, has shown promise in generalizing performance gains when combined with multitasking training. However, the relationship between combined transcranial direct current stimulation and training protocols with task-associated representational overlap in the brain remains unexplored. Here, we paired prefrontal cortex transcranial direct current stimulation with multitasking training in 178 individuals and collected functional magnetic resonance imaging data pre- and post-training. We found that 1mA transcranial direct current stimulation applied to the prefrontal cortex paired with multitasking training enhanced training transfer to spatial attention, as assessed via a visual search task. Using machine learning to assess the overlap of neural activity related to the training task in task-relevant brain regions, we found that visual search gains were predicted by changes in classification accuracy in frontal, parietal, and cerebellar regions for participants that received left prefrontal cortex stimulation. These findings demonstrate that prefrontal cortex transcranial direct current stimulation may interact with training-related changes to task representations, facilitating the generalization of learning.

280. Acute Temporal Interference Stimulation of the Left Dorsolateral Prefrontal Cortex in Patients With Depression: First Results of a Double-Blind Controlled Study

280. Acute Temporal Interference Stimulation of the Left Dorsolateral Prefrontal Cortex in Patients With Depression: First Results of a Double-Blind Controlled Study

Effect of Inactivation of Prefrontal Cortex on Sleep-Wake States in Rat

There is a large body of literature to support subcortical regulation of sleep-wake states, but there have been limited studies to investigate the role of cortex in sleep-wake regulation. Previously, we have demonstrated that cholinergic stimulation of prefrontal cortex can reverse general anesthesia and promote wakefulness in unanesthetized rats, and there is emerging evidence to suggest that the prefrontal cortex might be a critical node in arousal state control. To better understand the direct role of prefrontal cortex in the regulation of sleep-wake states, we quantified the effect of prefrontal cortex inactivation, via local tetrodotoxin (156 μM) infusion, on sleep architecture. Under surgical isoflurane anesthesia, adult Sprague Dawley rats (n=7 male) were instrumented with electrodes to record electroencephalogram (EEG) from frontal and parietal cortices, and electromyogram (EMG) from dorsal nuchal muscles. In addition, a bilateral guide cannula was implanted aimed at the medial prefrontal cortex for tetrodotoxin infusion. After at least a week of post-surgical recovery and conditioning to the recording chambers, rats received bilateral microinjection (500 nL) of either 156 μM tetrodotoxin or 0.9% saline (vehicle control). The tetrodotoxin and 0.9% saline infusions were performed 30-minutes before the start of lights-OFF period (8:00 pm) after which EEG and EMG data were recorded for 24h across dark and light cycles. The EEG and EMG data were manually scored (SleepSign, Kissei Comtec Inc.) in 4-second intervals into wakefulness, slow-wave sleep, and rapid eye movement sleep, and then averaged in 3h bins across 24h recording period. A linear mixed model was used to compare the changes in percent time spent in each state, mean duration per episode for each state, and mean number of episodes for each state, between the vehicle control and tetrodotoxin-infusion sessions. Inactivation of prefrontal cortex via tetrodotoxin infusion produced long-lasting statistically significant increase in slow-wave sleep (p<0.05 for 0-3h, 4-6h, 7-9h, 10-12h, 13-15, 16-18, 22-24) and decrease in wakefulness (p<0.05 for 0-3h, 4-6h, 10-12h) and rapid eye movement sleep (p<0.05 for 7-9h, 10-12h, 13-15h). These data further support a causal contribution of prefrontal cortex in regulating arousal states. This work was supported by the National Institutes of Health (Bethesda, MD, USA) grant (R01 GM111293) to GAM and DP, and funding from the Department of Anesthesiology, University of Michigan Medical School, Ann Arbor. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Safety and efficacy of repetitive stimulation of the left dorsolateral prefrontal cortex using transcranial focused ultrasound in treatment-resistant depressed patients: A non-inferiority randomized controlled trial protocol

BackgroundAbout 30% of patients diagnosed with major depressive disorder fail with the mainstream pharmacological treatment. Patients who do not achieve clinical remission of symptoms, even with two different antidepressants, are classified with treatment-resistant depression (TDR). This condition imposes an additional burden with increased Disability Adjusted Life Years. Therefore, complementary treatments, such as neuromodulation, are necessary. The transcranial focused ultrasound (tFUS) has emerged in the past few years as a reliable method for non-invasive neuromodulation in humans and may help treat TRD. This study aims to propose a research protocol for a non-inferiority randomized clinical trial of TDR with tFUS. MethodsPatients with documented TRD will be screened upon entering the TRD outpatient clinic at UFMG (Brazil). One hundred patients without a clinical history of other psychiatric illness, anatomical abnormalities on magnetic resonance imaging (MRI), or treatment with electroconvulsive therapy will be invited to participate. Patients will be randomized (1:1) into two groups: 1) treatment with a previously established protocol of transcranial magnetic stimulation; and 2) treatment with a similar protocol using the stimulation. Besides regular consultations in the outpatient clinic, both groups will attend 7 protocolled spaced days of brain stimulation targeted at the left dorsolateral prefrontal cortex. They will also be submitted to 4 sessions of image studies (2 MRIs, 2 positron-emission tomography), 3 of neuropsychological assessments (at baseline, 1 week and 2 months after treatment), the Montgomery-Åsberg Depression Rating Scale to analyze the severity of depressive symptoms. DiscussionThis clinical trial intends to verify the safety and clinical efficacy of tFUS stimulation of the dorsolateral prefrontal cortex of patients with TRD, compared with a previously established neuromodulation method.

Role of Repetitive Transcranial Magnetic Stimulation in Treatment of Fibromyalgia: A Randomized Controlled Trial.

Fibromyalgia syndrome (FMS) is a chronic disease characterized by widespread, persistent musculoskeletal pain in association with impaired health-related quality of life. Repetitive transcranial magnetic stimulation (rTMS) is an emerging tool for the management of fibromyalgia. There is no standardized protocol of rTMS for the treatment of FMS, and both low- and high-frequency stimulation of the dorsolateral prefrontal cortex (DLPFC) are described in the literature with variable efficacy. The objective of this study was to determine the effectiveness of rTMS in people with fibromyalgia and compare the response of low- and high-frequency stimulation with sham stimulation. This study was a single-blinded, randomized, placebo-controlled trial. Ninety patients with the diagnosis of FMS were randomly allocated into one of the following three groups: low-frequency (1 Hz) group, high-frequency (10 Hz) group, and sham group. Pain, depression, anxiety, and quality of life were measured using the Numerical Pain Rating Scale (NPRS), Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression Rating Scale (HDRS), and Revised Fibromyalgia Impact Questionnaire (FIQR) immediately following treatment as well as at 1 and 3 months after treatment. The data was statistically analyzed using Statistical Package for the Social Sciences version 23 software. P value < 0.05 was considered statistically significant. Intergroup analysis revealed a significant improvement in NPRS, HAM-A, HDRS, and FIQR scores in both low- and high- frequency groups immediately following treatment and for 3 months after treatment. No significant difference in the efficacy of low- and high-frequency stimulation was noticed. rTMS is an effective mode of treatment in people with FMS. Both low and high frequencies of stimulation at DLPFC are equally effective in reducing pain and associated symptoms.

Transcranial Magnetic Stimulation of Dorsolateral Prefrontal Cortex in Treatment-Resistant Obsessive Compulsive Disorder: A Mini-Review

Introduction: Approximately two-thirds of patients with Obsessive-Compulsive Disorder (OCD) exhibit inadequate responses to current standard therapies. A previous meta-analysis has shown the potential benefit of repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (dlPFC) area in patients with OCD. However, the analysis also included patients who had not previously failed first-line treatments. This mini-review aims to explore the therapeutic effects of rTMS applied to the dlPFC area in patients with treatment-resistant OCD. Methods: We conducted a comprehensive search for randomized controlled trials (RCTs) and observational studies across various databases (PubMed, EMBASE, Ebsco, Web of Science, and Cochrane Central). Eligible studies encompassed rTMS administered to the dlPFC area in cases of treatment-resistant OCD. Studies that did not focus on using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) to assess the efficacy of rTMS were excluded. Quality assessments were conducted based on the Cochrane risk-of-bias tool. Results: Our review identified five RCTs involving 132 patients that met the established criteria. The application of high-frequency (HF) and low-frequency (LF) rTMS to the dlPFC region yielded controversial post-treatment Y-BOCS findings due to factors such as small sample sizes, short-term study durations, variations in rTMS protocols, and four studies exhibiting a high risk of bias. Discussion: The available data is constrained by a scarcity of high-quality, large-scale trials with extended follow-up periods and optimized protocols. Further research is warranted to establish the efficacy of rTMS administered to the dlPFC in this patient population.

Theta oscillations within right dorsolateral prefrontal cortex contribute differently to speech versus limb inhibition.

Evidence suggests that speech and limb movement inhibition are subserved by common neural mechanisms, particularly within the right prefrontal cortex. In a recent study, we found that cathodal stimulation of right dorsolateral prefrontal cortex (rDLPFC) differentially modulated P3 event-related potentials for speech versus limb inhibition. In the present study, we further analyzed these data to examine the effects of cathodal high-definition transcranial direct current stimulation (HD-tDCS) over rDLPFC on frontal theta - an oscillatory marker of cognitive control - in response to speech and limb inhibition, during a Go/No-Go task in 21 neurotypical adults. Electroencephalography data demonstrated that both speech and limb No-Go elicited prominent theta activity over right prefrontal electrodes, with stronger activity for speech compared to limb. Moreover, we found that cathodal stimulation significantly increased theta power over right prefrontal electrodes for speech versus limb No-Go. Source analysis revealed that cathodal, but not sham, stimulation increased theta activity within rDLPFC and bilateral premotor cortex for speech No-Go compared to limb movement inhibition. These findings complement our previous report and suggest (1) right prefrontal theta activity is an amodal oscillatory mechanism supporting speech and limb inhibition, (2) larger theta activity in prefrontal electrodes for speech versus limb following cathodal stimulation may reflect allocation of additional neural resources for a more complex motor task, such as speech compared to limb movement. These findings have translational implications for conditions such as Parkinson's disease, wherein both speech and limb movement are impaired.

Transcranial Direct Current Stimulation (tDCS) Ameliorates Stress-Induced Sleep Disruption via Activating Infralimbic-Ventrolateral Preoptic Projections.

Transcranial direct current stimulation (tDCS) is acknowledged for its non-invasive modulation of neuronal activity in psychiatric disorders. However, its application in insomnia research yields varied outcomes depending on different tDCS types and patient conditions. Our primary objective is to elucidate its efficiency and uncover the underlying mechanisms in insomnia treatment. We hypothesized that anodal prefrontal cortex stimulation activates glutamatergic projections from the infralimbic cortex (IL) to the ventrolateral preoptic area (VLPO) to promote sleep. After administering 0.06 mA of electrical currents for 8 min, our results indicate significant non-rapid eye movement (NREM) enhancement in naïve mice within the initial 3 h post-stimulation, persisting up to 16-24 h. In the insomnia group, tDCS enhanced NREM sleep bout numbers during acute stress response and improved NREM and REM sleep duration in subsequent acute insomnia. Sleep quality, assessed through NREM delta powers, remains unaffected. Interference of the IL-VLPO pathway, utilizing designer receptors exclusively activated by designer drugs (DREADDs) with the cre-DIO system, partially blocked tDCS's sleep improvement in stress-induced insomnia. This study elucidated that the activation of the IL-VLPO pathway mediates tDCS's effect on stress-induced insomnia. These findings support the understanding of tDCS effects on sleep disturbances, providing valuable insights for future research and clinical applications in sleep therapy.

Increasing striatal dopamine release through repeated bouts of theta burst transcranial magnetic stimulation of the left dorsolateral prefrontal cortex. A 18F-desmethoxyfallypride positron emission tomography study.

Transcranial Magnetic Stimulation (TMS) can modulate fronto-striatal connectivity in the human brain. Here Positron Emission Tomography (PET) and neuro-navigated TMS were combined to investigate the dynamics of the fronto-striatal connectivity in the human brain. Employing 18F-DesmethoxyFallypride (DMFP) - a Dopamine receptor-antagonist - the release of endogenous dopamine in the striatum in response to time-spaced repeated bouts of excitatory, intermittent theta burst stimulation (iTBS) of the Left-Dorsolateral Prefrontal Cortex (L-DLPFC) was measured. 23 healthy participants underwent two PET sessions, each one with four blocks of iTBS separated by 30 minutes: sham (control) and verum (90% of individual resting motor threshold). Receptor Binding Ratios were collected for sham and verum sessions across 37 time frames (about 130 minutes) in striatal sub-regions (Caudate nucleus and Putamen). Verum iTBS increased the dopamine release in striatal sub-regions, relative to sham iTBS. Dopamine levels in the verum session increased progressively across the time frames until frame number 28 (approximately 85 minutes after the start of the session and after three iTBS bouts) and then essentially remained unchanged until the end of the session. Results suggest that the short-timed iTBS protocol performed in time-spaced blocks can effectively induce a dynamic dose dependent increase in dopaminergic fronto-striatal connectivity. This scheme could provide an alternative to unpleasant and distressing, long stimulation protocols in experimental and therapeutic settings. Specifically, it was demonstrated that three repeated bouts of iTBS, spaced by short intervals, achieve larger effects than one single stimulation. This finding has implications for the planning of therapeutic interventions, for example, treatment of major depression.