The maintenance of complex visual scenes in working memory may require activation of working memory manipulation circuits in the dlPFC: a preliminary report.

Past research has shown that the bilateral dorsolateral prefrontal cortices (dlPFC) are implicated in both emotional processing as well as cognitive processing,1,2,3 in addition to working memory4, 5. Exactly how these disparate processes interact with one another within the dlPFC is less understood. To explore this, we designed a task that looked at working memory performance during fMRI under both emotional and non-emotional conditions, and tested it in this preliminary report. Participants were asked to complete three tasks (letters, neutral images, emotional images) of the Sternberg Sorting Task under one of two trial conditions (sort or maintain). Regions of interest consisted of the left and right dlPFC as defined by brain masks based on NeuroSynth6. Results showed a significant main effect of the 'sort' condition on reaction speed for all three trial types, as well as a main effect of task type (letters) on accuracy. In addition, a significant interaction was found between trial type (sort) and task type (letters), but not for either of the picture tasks. Although preliminary, these results reveal a discrepancy between BOLD signal and behavioral data, with no significant difference in BOLD activity during image trials being displayed, despite longer response times for every condition. While these initial results show that the dlPFC is implicated in non-emotional cognitive processing, more research is needed to explain the lack of BOLD activation seen here for similar emotionally valanced tasks, possibly indicating involvement of other brain networks.

Impact of high-frequency rTMS combined with pharmacotherapy on the left dorsolateral prefrontal cortex in treating major depressive disorder: A real-world study.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) combined with pharmacotherapy is a promising treatment method for depression. However, its treatment mechanism needs further research. METHODS: This study recruited 38 healthy individuals (HC) and 52 patients with severe depression (MDD) and divided patients into two treatment groups: the rTMS combined antidepressant (rTMS+ADP) group and the single antidepressant (ADP) group. We used functional magnetic resonance imaging to calculate the fractional amplitude of low-frequency fluctuations (fALFF) in the left dorsolateral prefrontal cortex (DLPFC) to investigate the functional change after treatment. RESULT: The fALFF in the left DLPFC was significantly lower in the MDD group than that in the HC group (p < 0.05). In addition, fALFF values of the left DLPFC negatively correlated with HAMD-24 scores (r = -0.294, p = 0.005). After treatment, both MDD groups showed a significant decrease in HAMD-24 scores, with a response rate of 88.89 % and a remission rate of 62.96 % in the rTMS+ADP group, compared to 64 % response and 56 % remission rates in the ADP group. The fALFF values in patients' left DLPFC significantly reduced in the rTMS+ADP group (p < 0.05), but not in the ADP group. LIMITATIONS: Our study only focused on the treatment effect in the left DLPFC, without exploring the other brain regions or networks. CONCLUSIONS: This study emphasizes the significance of the left DLPFC in MDD treatment. However, combined left DLPFC rTMS with ADP causes deviation from the normal resting brain function of the left DLPFC, indicating that future research should explore targeted treatment methods to normalize the left DLPFC.

The impact of anger on intertemporal decision-making in individuals with internet addiction: an fNIRS study.

Intertemporal decision-making is the choice between an immediate smaller reward (SS) and a delayed larger reward (LL). Intertemporal decision-making depends on the interaction of the cognitive and emotional systems, and the latter is particularly vital. According to the Appraisal Tendency Frame (ATF) theory, anger influences intertemporal decision-making by increasing an individual's sense of certainty and control. This study examined whether anger affects intertemporal decision-making in individuals with internet addiction (IA) in this manner and investigated its neural mechanisms. Nineteen individuals with IA and 20 healthy controls were recruited. All subjects performed the Monetary choice task under anger and neutral emotions while functional near-infrared spectroscopy (fNIRS) equipment simultaneously recorded the hemodynamics in the prefrontal cortex (PFC). Individuals with IA showed a more considerable delay discount and lower brain activations in the orbitofrontal cortex (OFC) and left dorsolateral prefrontal cortex (L-dlPFC) compared to HC. Moreover, individuals with IA made more LL choices in the angry condition than in the neutral emotion, yet there was no difference in HC. The brain activation in L-dlPFC of individuals with IA tends to increase in the angry condition compared to the neutral condition. These findings revealed that impairment of intertemporal decision-making in individuals with individuals with IA might be related to the dysfunction of OFC and L-dlPFC. Our work also provided initial footing for the applicability of the appraisal tendency frame theory to individuals with IA, and L-dlPFC might play a role in the effects of anger on intertemporal decision-making.

iTBS reveals the roles of domain-general cognitive control and language-specific brain regions during word formation rule learning.

Repeated exposure to word forms and meanings improves lexical knowledge acquisition. However, the roles of domain-general and language-specific brain regions during this process remain unclear. To investigate this, we applied intermittent theta burst stimulation over the domain-general (group left dorsolateral prefrontal cortex) and domain-specific (Group L IFG) brain regions, with a control group receiving sham intermittent theta burst stimulation. Intermittent theta burst stimulation effects were subsequently assessed in functional magnetic resonance imaging using an artificial word learning task which consisted of 3 learning phases. A generalized psychophysiological interaction analysis explored the whole brain functional connectivity, while dynamic causal modeling estimated causal interactions in specific brain regions modulated by intermittent theta burst stimulation during repeated exposure. Compared to sham stimulation, active intermittent theta burst stimulation improved word learning performance and reduced activation of the left insula in learning phase 2. Active intermittent theta burst stimulation over the domain-general region increased whole-brain functional connectivity and modulated effective connectivity between brain regions during repeated exposure. This effect was not observed when active intermittent theta burst stimulation was applied to the language-specific region. These findings suggest that the domain-general region plays a crucial role in word formation rule learning, with intermittent theta burst stimulation enhancing whole-brain connectivity and facilitating efficient information exchange between key brain regions during new word learning.

Repetitive Transcranial Magnetic Stimulation of the Dorsolateral Prefrontal Cortex for Phantom Limb Pain.

BACKGROUND: Phantom limb pain (PLP) is a prevalent and distressing occurrence in 60-80% of individuals who have undergone amputations. Recent research underscores the significance of maladaptive cortical plasticity in the genesis of PLP, emphasizing the importance of targeting cortical areas for therapeutic interventions. Repetitive transcranial magnetic stimulation (rTMS), a noninvasive tool for cortical stimulation, demonstrates effectiveness in treating various chronic pain conditions of neuropathic origin. Nevertheless, there exists a limited body of research investigating the application of rTMS as a therapeutic intervention specifically for managing PLP. Notably, the dorsolateral prefrontal cortex (DLPFC) plays a crucial role in central pain processing, suggesting its potential as a key therapeutic target in PLP treatment. There is a lack of adequate data regarding the effectiveness of DLPFC-targeting rTMS in alleviating the pain experienced by PLP patients. OBJECTIVE: In this study, our aim was to investigate the impact of 10 sessions of DLPFC-targeting rTMS on the pain status of individuals experiencing PLP. STUDY DESIGN: Randomized controlled trial. SETTING: Traumatic amputees reporting to the tertiary care center with PLP. METHODS: The study was approved by the Institute Ethics Committee (IECPG-299/27.04.2022) and registered in the Clinical Trials Registry of India (CTRI/2022/07/043938). Nineteen patients suffering from PLP were recruited and randomized into real or sham rTMS groups. In the real rTMS group, patients received 10 sessions of rTMS at the DLPFC contralateral to the amputation site. The rTMS, administered at 90% of the resting motor threshold (RMT), was delivered as 8 trains of 150 pulses per train at the rate of one Hz and an inter-train interval of 60 seconds. The total number of pulses per session was 1,200. The sham group received 10 sessions of sham rTMS through the perpendicular placement of an rTMS coil over the DLPFC. These sessions lasted for the same duration and included the same sounds as the real group but involved no active stimulation. The patients' pain status was evaluated using the Visual Analog Scale (VAS) at baseline, at the end of each session of real or sham rTMS and at the 15th, 30th, and 60th day after the the completion of real or sham therapy. RESULTS: A significant decrease in VAS scores was noted after 10 sessions of real rTMS that targeted the DLPFC, in contrast to the sham rTMS group. The real rTMS group's reduction in VAS scores also persisted during the follow-up. LIMITATIONS: A few patients had to drop out due to physical restrictions and financial constraints. Consequently, only a small number of individuals were able to complete the study protocol successfully. CONCLUSION: A regimen of 10 sessions of real rTMS of the DLPFC was associated with significant pain relief in patients with PLP, and the effects were sustained for 2 months. Therefore, the present study shows that rTMS of the DLPFC has potential as an effective therapeutic intervention for sustained pain relief in PLP patients.

Revisiting the effects of rTMS over the dorsolateral prefrontal cortex on pain: An updated systematic review and meta-analysis.

BACKGROUND: Our previous study synthesized the analgesic effects of repetitive Transcranial Magnetic Stimulation (rTMS) over the dorsolateral prefrontal cortex (DLPFC) trials up to 2019. There has been a significant increase in pain trials in the past few years, along with methodological variabilities such as sample size, stimulation intensity, and rTMS paradigms. OBJECTIVES/METHODS: This study therefore updated the effects of DLPFC-rTMS on chronic pain and quantified the impact of methodological differences across studies. RESULTS: A total of 36 studies were included. Among them, 26 studies were clinical trials (update = 9, 307/711 patients), and 10 (update = 1, 34/249 participants) were provoked pain studies. The updated meta-analysis does not support an effect on neuropathic pain after including the additional trials (pshort-term = 0.20, pmid-term = 0.50). However, there is medium-to-large analgesic effect in migraine trials extending up to six weeks follow-up (SMDmid-term = -0.80, SMDlong-term = -0.51), that was not previously reported. Methodological differences wthine the studies were considered. DLPFC-rTMS also induces potential improvement in the emotional aspects of pain (SMDshort-term = -0.28). CONCLUSIONS: The updated systematic meta-analysis continues to support analgesic effects for chronic pain overall. However, the updated results no longer support DLPFC-rTMS for pain relief in neuropathic pain, and do supports DLPFC-rTMS in the management of migraine. There is also evidence for DLPFC-rTMS to improve emotional aspects of pain.

Cortico-striatal white-matter connectivity underlies the ability to exert goal-directed control.

The balance between goal-directed and habitual control has been proposed to determine the flexibility of instrumental behaviour, in both humans and animals. This view is supported by neuroscientific studies that have implicated dissociable neural pathways in the ability to flexibly adjust behaviour when outcome values change. A previous Diffusion Tensor Imaging study provided preliminary evidence that flexible instrumental performance depends on the strength of parallel cortico-striatal white-matter pathways previously implicated in goal-directed and habitual control. Specifically, estimated white-matter strength between caudate and ventromedial prefrontal cortex correlated positively with behavioural flexibility, and posterior putamen-premotor cortex connectivity correlated negatively, in line with the notion that these pathways compete for control. However, the sample size of the original study was limited, and so far, there have been no attempts to replicate these findings. In the present study, we aimed to conceptually replicate these findings by testing a large sample of 205 young adults to relate cortico-striatal connectivity to performance on the slips-of-action task. In short, we found only positive neural correlates of goal-directed performance, including striatal connectivity (caudate and anterior putamen) with the dorsolateral prefrontal cortex. However, we failed to provide converging evidence for the existence of a neural habit system that puts limits on the capacity for flexible, goal-directed action. We discuss the implications of our findings for dual-process theories of instrumental action.

Validation of the number of pulses required for TMS-EEG in the prefrontal cortex considering test feasibility.

BACKGROUND: Transcranial magnetic stimulation (TMS) combined with electroencephalography (EEG), TMS-EEG, is a useful neuroscientific tool for the assessment of neurophysiology in the human cerebral cortex. Theoretically, TMS-EEG data is expected to have a better data quality as the number of stimulation pulses increases. However, since TMS-EEG testing is a modality that is examined on human subjects, the burden on the subject and tolerability of the test must also be carefully considered. METHOD: In this study, we aimed to determine the number of stimulation pulses that satisfy the reliability and validity of data quality in single-pulse TMS (spTMS) for the dorsolateral prefrontal cortex (DLPFC). TMS-EEG data for (1) 40-pulse, (2) 80-pulse, (3) 160-pulse, and (4) 240-pulse conditions were extracted from spTMS experimental data for the left DLPFC of 20 healthy subjects, and the similarities between TMS-evoked potentials (TEP) and oscillations across the conditions were evaluated. RESULTS: As a result, (2) 80-pulse and (3) 160-pulse conditions showed highly equivalent to the benchmark condition of (4) 240-pulse condition. However, (1) 40-pulse condition showed only weak to moderate equivalence to the (4) 240-pulse condition. Thus, in the DLPFC TMS-EEG experiment, 80 pulses of stimulations was found to be a reasonable enough number of pulses to extract reliable TEPs, compared to 160 or 240 pulses. CONCLUSIONS: This is the first substantial study to examine the appropriate number of stimulus pulses that are reasonable and feasible for TMS-EEG testing of the DLPFC.

Prefrontal oscillatory slowing in early-course schizophrenia is associated with worse cognitive performance and negative symptoms: a TMS-EEG study.

BACKGROUND: Abnormalities in dorsolateral prefrontal cortex (DLPFC) oscillations are neurophysiological signatures of schizophrenia thought to underlie its cognitive deficits. Transcranial magnetic stimulation with electroencephalography (TMS-EEG) provides a measure of cortical oscillations unaffected by sensory relay functionality and/or patients' level of engagement, which are important confounding factors in schizophrenia. Previous TMS-EEG work showed reduced fast, gamma-range oscillations and a slowing of the main DLPFC oscillatory frequency, or natural frequency, in chronic schizophrenia. However, it is unclear whether this DLPFC natural frequency slowing is present in early-course schizophrenia (EC-SCZ) and is associated with symptom severity and cognitive dysfunction. METHODS: We applied TMS-EEG to the left DLPFC in 30 EC-SCZ and 28 healthy control (HC) subjects. Goal-directed working memory performance was assessed using the "AX" Continuous Performance Task (AX-CPT). The EEG frequency with the highest cumulative power at the stimulation site, or natural frequency, was extracted. We also calculated the local Relative Spectral Power (RSP) as the average power in each frequency band divided by the broadband power. RESULTS: Compared to HC, EC-SCZ had reduced DLPFC natural frequency (p=0.0000002, Cohen's d=-2.32) and higher DLPFC beta-range RSP (p=0.0003, Cohen's d=0.77). In EC-SCZ, the DLPFC natural frequency was inversely associated with negative symptoms. Across all participants, the beta-band RSP negatively correlated with the AX-CPT performance. CONCLUSIONS: A DLPFC oscillatory slowing is an early pathophysiological biomarker of schizophrenia that is associated with its symptom severity and cognitive impairments. Future work should assess whether non-invasive neurostimulation can ameliorate prefrontal oscillatory deficits and related clinical functions in EC-SCZ.

The neural structures of theory of mind are valence-sensitive: evidence from three tDCS studies.

Several cortical structures are involved in theory of mind (ToM), including the dorsolateral prefrontal cortex (dlPFC), the ventromedial prefrontal cortex (vmPFC), and the right temporo- parietal junction (rTPJ). We investigated the role of these regions in mind reading with respect to the valence of mental states. Sixty-five healthy adult participants were recruited and received transcranial direct current stimulation (tDCS) (1.5 mA, 20 min) with one week interval in three separate studies. The stimulation conditions were anodal tDCS over the dlPFC coupled with cathodal tDCS over the vmPFC, reversed stimulation conditions, and sham in the first study, and anodal tDCS over the vmPFC, or dlPFC, and sham stimulation, with an extracranial return electrode in the second and third study. During stimulation, participants underwent the reading mind from eyes/voice tests (RMET or RMVT) in each stimulation condition. Anodal left dlPFC/cathodal right vmPFC stimulation increased the accuracy of negative mental state attributions, anodal rTPJ decreased the accuracy of negative and neutral mental state attributions, and decreased the reaction time of positive mental state attributions. Our results imply that the neural correlates of ToM are valence-sensitive.

The impact of transcranial direct current stimulation combined with interim testing on spatial route learning in patients with schizophrenia.

BACKGROUND: Cognitive deficits in patients with schizophrenia have drawn widespread attention. Transcranial direct current stimulation (tDCS) can modulate cognitive processes by altering neuronal excitability. Previous studies have found that interim testing can enhance spatial route learning and memory in patients with schizophrenia. However, there has been limited research on the combined effects of these two methods on spatial route learning in these patients. OBJECTIVE: To investigate whether the combination of tDCS and interim testing can effectively contribute to the maintenance of spatial route memory in patients with schizophrenia. The study involved conducting route learning using interim testing after anodal tDCS treatment on the left dorsolateral prefrontal cortex (L-DLPFC). METHODS: Ninety-two patients with schizophrenia were recruited and divided into groups receiving anodal, sham, or no stimulation. The anodal group received L-DLPFC tDCS treatment 10 times over 5 days (twice daily for 20 min). After treatment, spatial route learning was assessed in interim testing. Correct recall rates of landmark positions and proactive interference from prior learning were compared among the groups. RESULTS: Regardless of stimulation type, the interim testing group outperformed the relearning group. Additionally, recall scores were higher following anodal stimulation, indicating the efficacy of tDCS. CONCLUSIONS: Both tDCS and interim testing independently enhance the ability to learn new information in spatial route learning for patients with schizophrenia, indicating that tDCS of the left DLPFC significantly improves memory in these patients.

Dysregulated Transcript Expression but Not Function of the Glutamate Transporter EAAT2 in the Dorsolateral Prefrontal Cortex in Schizophrenia.

BACKGROUND: Schizophrenia (SCZ) is a serious mental illness with complex pathology, including abnormalities in the glutamate system. Glutamate is rapidly removed from the synapse by excitatory amino acid transporters (EAATs). Changes in the expression and localization of the primary glutamate transporter EAAT2 are found in the brain in central nervous system (CNS) disorders including SCZ. We hypothesize that neuronal expression and function of EAAT2 are increased in the frontal cortex in subjects diagnosed with SCZ. STUDY DESIGN: EAAT2 protein expression and glutamate transporter function were assayed in synaptosome preparations from the dorsolateral prefrontal cortex (DLPFC) of SCZ subjects and age- and sex-matched nonpsychiatrically ill controls. EAAT2 splice variant transcript expression was assayed in enriched populations of neurons and astrocytes from the DLPFC. Pathway analysis of publicly available transcriptomic datasets was carried out to identify biological changes associated with EAAT2 perturbation in different cell types. RESULTS: We found no significant changes in EAAT2 protein expression or glutamate uptake in the DLPFC in SCZ subjects compared with controls (n = 10/group). Transcript expression of EAAT2 and signaling molecules associated with EAAT2b trafficking (CaMKIIa and DLG1) were significantly altered in enriched populations of astrocytes and pyramidal neurons (P < .05) in SCZ (n = 16/group). These changes were not associated with antipsychotic medications. Pathway analysis also identified cell-type-specific enrichment of biological pathways associated with perturbation of astrocyte (immune pathways) and neuronal (metabolic pathways) EAAT2 expression. CONCLUSIONS: Overall, these data support the growing body of evidence for the role of dysregulation of the glutamate system in the pathophysiology of SCZ.

Real-time optimization to enhance noninvasive cortical excitability assessment in the human dorsolateral prefrontal cortex.

Objective: We currently lack a robust noninvasive method to measure prefrontal excitability in humans. Concurrent TMS and EEG in the prefrontal cortex is usually confounded by artifacts. Here we asked if real-time optimization could reduce artifacts and enhance a TMS-EEG measure of left prefrontal excitability. Methods: This closed-loop optimization procedure adjusts left dlPFC TMS coil location, angle, and intensity in real-time based on the EEG response to TMS. Our outcome measure was the left prefrontal early (20-60 ms) and local TMS-evoked potential (EL-TEP). Results: In 18 healthy participants, this optimization of coil angle and brain target significantly reduced artifacts by 63% and, when combined with an increase in intensity, increased EL-TEP magnitude by 75% compared to a non-optimized approach. Conclusions: Real-time optimization of TMS parameters during dlPFC stimulation can enhance the EL-TEP. Significance: Enhancing our ability to measure prefrontal excitability is important for monitoring pathological states and treatment response.

Repetitive Transcranial Magnetic Stimulation in Fibromyalgia: Exploring the Necessity of Neuronavigation for Targeting New Brain Regions.

Fibromyalgia and osteoarthritis are among the most prevalent rheumatic conditions worldwide. Nonpharmacological interventions have gained scientific endorsements as the preferred initial treatments before resorting to pharmacological modalities. Repetitive transcranial magnetic stimulation (rTMS) is among the most widely researched neuromodulation techniques, though it has not yet been officially recommended for fibromyalgia. This review aims to summarize the current evidence supporting rTMS for treating various fibromyalgia symptoms. Recent findings: High-frequency rTMS directed at the primary motor cortex (M1) has the strongest support in the literature for reducing pain intensity, with new research examining its long-term effectiveness. Nonetheless, some individuals may not respond to M1-targeted rTMS, and symptoms beyond pain can be prominent. Ongoing research aims to improve the efficacy of rTMS by exploring new brain targets, using innovative stimulation parameters, incorporating neuronavigation, and better identifying patients likely to benefit from this treatment. Summary: Noninvasive brain stimulation with rTMS over M1 is a well-tolerated treatment that can improve chronic pain and overall quality of life in fibromyalgia patients. However, the data are highly heterogeneous, with a limited level of evidence, posing a significant challenge to the inclusion of rTMS in official treatment guidelines. Research is ongoing to enhance its effectiveness, with future perspectives exploring its impact by targeting additional areas of the brain such as the medial prefrontal cortex, anterior cingulate cortex, and inferior parietal lobe, as well as selecting the right patients who could benefit from this treatment.

Mechanisms of Action of TMS in the Treatment of Depression.

Transcranial magnetic stimulation (TMS) is entering increasingly widespread use in treating depression. The most common stimulation target, in the dorsolateral prefrontal cortex (DLPFC), emerged from early neuroimaging studies in depression. Recently, more rigorous casual methods have revealed whole-brain target networks and anti-networks based on the effects of focal brain lesions and focal brain stimulation on depression symptoms. Symptom improvement during therapeutic DLPFC-TMS appears to involve directional changes in signaling between the DLPFC, subgenual and dorsal anterior cingulate cortex, and salience-network regions. However, different networks may be involved in the therapeutic mechanisms for other TMS targets in depression, such as dorsomedial prefrontal cortex or orbitofrontal cortex. The durability of therapeutic effects for TMS involves synaptic neuroplasticity, and specifically may depend upon dopamine acting at the D1 receptor family, as well as NMDA-receptor-dependent synaptic plasticity mechanisms. Although TMS protocols are classically considered 'excitatory' or 'inhibitory', the actual effects in individuals appear quite variable, and might be better understood at the level of populations of synapses rather than individual synapses. Synaptic meta-plasticity may provide a built-in protective mechanism to avoid runaway facilitation or inhibition during treatment, and may account for the relatively small number of patients who worsen rather than improve with TMS. From an ethological perspective, the antidepressant effects of TMS may involve promoting a whole-brain attractor state associated with foraging/hunting behaviors, centered on the rostrolateral periaqueductal gray and salience network, and suppressing an attractor state associated with passive threat defense, centered on the ventrolateral periaqueductal gray and default-mode network.

Mapping cortical excitability in the human dorsolateral prefrontal cortex.

BACKGROUND: Transcranial magnetic stimulation (TMS) to the dorsolateral prefrontal cortex (dlPFC) is an effective treatment for depression, but the neural effects after TMS remains unclear. TMS paired with electroencephalography (TMS-EEG) can causally probe these neural effects. Nonetheless, variability in single pulse TMS-evoked potentials (TEPs) across dlPFC subregions, and potential artifact induced by muscle activation, necessitate detailed mapping for accurate treatment monitoring. OBJECTIVE: To characterize early TEPs anatomically and temporally (20-50 ms) close to the TMS pulse (EL-TEPs), as well as associated muscle artifacts (<20 ms), across the dlPFC. We hypothesized that TMS location and angle influence EL-TEPs, and specifically that conditions with larger muscle artifact may exhibit lower observed EL-TEPs due to over-rejection during preprocessing. Additionally, we sought to determine an optimal group-level TMS target and angle, while investigating the potential benefits of a personalized approach. METHODS: In 16 healthy participants, we applied single-pulse TMS to six targets within the dlPFC at two coil angles and measured EEG responses. RESULTS: Stimulation location significantly influenced observed EL-TEPs, with posterior and medial targets yielding larger EL-TEPs. Regions with high EL-TEP amplitude had less muscle artifact, and vice versa. The best group-level target yielded 102% larger EL-TEP responses compared to other dlPFC targets. Optimal dlPFC target differed across subjects, suggesting that a personalized targeting approach might boost the EL-TEP by an additional 36%. SIGNIFICANCE: EL-TEPs can be probed without significant muscle-related confounds in posterior-medial regions of the dlPFC. The identification of an optimal group-level target and the potential for further refinement through personalized targeting hold significant implications for optimizing depression treatment protocols.

Asynchronous Involvement of VLPFC and DLPFC During Negative Emotion Processing: An Online Transcranial Magnetic Stimulation Study.

The ventrolateral prefrontal cortex (VLPFC) and dorsolateral prefrontal cortex (DLPFC) have been found to play important roles in negative emotion processing. However, the specific time window of their involvement remains unknown. This study addressed this issue in three experiments using single-pulse transcranial magnetic stimulation (TMS). We found that TMS applied over the VLPFC at 400 ms after negative emotional exposure significantly enhanced negative feelings compared to the vertex condition. Furthermore, TMS applied over the DLPFC at both 0 ms and 600 ms after negative emotional exposure also resulted in deteriorated negative feelings. These findings provide potential evidence for the VLPFC-dependent semantic processing (∼400 ms) and the DLPFC-dependent attentional and cognitive control (∼0/600 ms) in negative emotion processing. The asynchronous involvement of these frontal cortices not only deepens our understanding of the neural mechanisms underlying negative emotion processing but also provides valuable temporal parameters for neurostimulation therapy targeting patients with mood disorders.

Targeting the left DLPFC and right VLPFC in unmarried romantic relationship breakup (love trauma syndrome) with intensified electrical stimulation: A randomized, single-blind, parallel-group, sham-controlled study.

BACKGROUND: Ending a romantic relationship is one of the most painful losses an adult experience. Neuroimaging studies suggest that there is a neuropsychological link between breakup experiences and bereaved individuals, and that specific prefrontal regions are involved. The aim of this study was to determine whether enhancement of left DLPFC and right VLPFC activity with a novel intensified anodal transcranial direct current stimulation protocol reduces core symptoms of love trauma syndrome (LTS) and improves treatment-related variables. METHODS: In this randomized, sham-controlled, single-blind parallel trial, we assessed the efficacy of an intensified anodal stimulation protocol (20 min, twice-daily sessions with 20 min intervals, 5 consecutive days) with two montages (left DLPFC vs right VLPFC) to reduce love trauma symptoms. 36 participants with love trauma syndrome were randomized in three tDCS condition (left DLPFC, right VLPFC, sham stimulation). LTS symptoms, treatment-related outcome variables (depressive state, anxiety, emotion regulation, positive and negative affect), and cognitive functions were assessed before, right after, and one month after intervention. RESULTS: Both DLPFC and VLPFC protocols significantly reduced LTS symptoms, and improved depressive state and anxiety after the intervention, as compared to the sham group. The improving effect of the DLPFC protocol on love trauma syndrome was significantly larger than that of the VLPFC protocol. For emotion regulation and positive and negative affect, improved regulation of emotions and positive affect and reduced negative affect were revealed after intervention in the two real stimulation conditions compared to the sham. For cognitive functions, no significant difference was observed between the groups, but again a positive effect of intervention within groups in the real stimulation conditions (DLPFC and VLPFC) was found for most components of the cognitive tasks. CONCLUSIONS: Enhancement of left DLPFC and right VLPFC activity with intensified stimulation improves LTS symptoms and treatment-related variables. For LTS symptoms, DLPFC stimulation was more efficient than VLPFC stimulation., For the other variables, no significant difference was observed between these two stimulation groups. These promising results require replication in larger trials.

Prolonged intermittent theta burst stimulation targeting the left prefrontal cortex and cerebellum does not affect executive functions in healthy individuals.

Repetitive transcranial magnetic stimulation (rTMS) for alleviating negative symptoms and cognitive dysfunction in schizophrenia commonly targets the left dorsolateral prefrontal cortex (LDLPFC). However, the therapeutic effectiveness of rTMS at this site remains inconclusive and increasingly, studies are focusing on cerebellar rTMS. Recently, prolonged intermittent theta-burst stimulation (iTBS) has emerged as a rapid-acting form of rTMS with promising clinical benefits. This study explored the cognitive and neurophysiological effects of prolonged iTBS administered to the LDLPFC and cerebellum in a healthy cohort. 50 healthy participants took part in a cross-over study and received prolonged (1800 pulses) iTBS targeting the LDLPFC, cerebellar vermis, and sham iTBS. Mixed effects repeated measures models examined cognitive and event-related potentials (ERPs) from 2-back (P300, N200) and Stroop (N200, N450) tasks after stimulation. Exploratory non-parametric cluster-based permutation tests compared ERPs between conditions. There were no significant differences between conditions for behavioural and ERP outcomes on the 2-back and Stroop tasks. Exploratory cluster-based permutation tests of ERPs did not identify any significant differences between conditions. We did not find evidence that a single session of prolonged iTBS administered to either the LDLPFC or cerebellum could cause any cognitive or ERP changes compared to sham in a healthy sample.

A comparative study of the dorsolateral prefrontal cortex targeting approaches for transcranial magnetic stimulation treatment: Insights from the healthy control data.

Repetitive transcranial magnetic stimulation (rTMS) to the left dorsolateral prefrontal cortex (DLPFC) is an established treatment for medication-resistant depression. Several targeting methods for the left DLPFC have been proposed including identification with resting-state functional magnetic resonance imaging (rs-fMRI) neuronavigation, stimulus coordinates based on structural MRI, or electroencephalography (EEG) F3 site by Beam F3 method. To date, neuroanatomical and neurofunctional differences among those approaches have not been investigated on healthy subjects, which are structurally and functionally unaffected by psychiatric disorders. This study aimed to compare the mean location, its dispersion, and its functional connectivity with the subgenual cingulate cortex (SGC), which is known to be associated with the therapeutic outcome in depression, of various approaches to target the DLPFC in healthy subjects. Fifty-seven healthy subjects underwent MRI scans to identify the stimulation site based on their resting-state functional connectivity and were measured their head size for targeting with Beam F3 method. In addition, we included two fixed stimulus coordinates over the DLPFC in the analysis, as recommended in previous studies. From the results, the rs-fMRI method had, as expected, more dispersed target sites across subjects and the greatest anticorrelation with the SGC, reflecting the known fact that personalized neuronavigation yields the greatest antidepressant effect. In contrast, the targets located by the other methods were relatively close together with less dispersion, and did not differ in anticorrelation with the SGC, implying their limitation of the therapeutic efficacy and possible interchangeability of them.