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.

Six-Week Supplementation with Creatine in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Magnetic Resonance Spectroscopy Feasibility Study at 3 Tesla.

BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic medical condition with no specific pharmacological treatment. Creatine, a nutrient essential for maintaining energy homeostasis in the cells, is a candidate for interventions in ME/CFS. METHODS: Fourteen participants with ME/CFS received supplementation with 16 g creatine monohydrate for 6 weeks. Before starting creatine and on the last day of treatment, participants underwent brain magnetic resonance spectroscopy (MRS) scanning of the pregenual anterior cingulate cortex (pgACC) and dorsolateral prefrontal cortex (DLPFC), followed by symptom, cognition, and hand-grip strength assessments. RESULTS: Eleven participants completed the study. Creatine treatment increased creatine concentration in both the pgACC and DLPFC (p = 0.004 and 0.012, respectively), decreased fatigue and reaction time (RT) on congruent and incongruent trials of the Stroop test (p = 0.036 and 0.014, respectively), and increased hand-grip strength (p = 0.0004). There was a positive correlation between increases in pgACC creatine and changes in RT on Stroop congruent and incongruent trials (p = 0.048 and p = 0.022, respectively). Creatine was well tolerated, and none of the participants stopped treatment. CONCLUSION: Creatine supplementation over six weeks in ME/CFS patients increased brain creatine and improved fatigue and some aspects of cognition. Despite its methodological limitations, this study encourages placebo-controlled investigations of creatine treatment in ME/CFS.

Activities of the dorsolateral and medial prefrontal cortices during oral function training with cognitive training elements: a NIRS study.

BACKGROUND: Cognitive function plays a crucial role in human life, and its maintenance and improvement are essential in both young and older adults. Since cognitive decline can be associated with oral function decline, preventing the decline in both cognitive and oral functions is an urgent social issue. Several training methods to improve each function have been proposed. Previous studies have indicated that greater brain activity during training is associated with increased benefits for cognitive function. Although adding cognitive function elements to oral function training may promote the activation of brain activity during oral function training, the effects have not been validated. The main purpose of this study is to develop a novel training program that combines oral function training with cognitive training, which is expected to activate key brain regions involved in oral and cognitive functions, such as the left dorsolateral prefrontal cortex (DLPFC) and right medial prefrontal cortex (mPFC). METHODS: Four types of training programs combining oral and cognitive training: PaTaKaRa × calculation, lip exercise × N-back, tongue exercise × inhibition, and tongue exercise × memory, were developed. Each program had seven levels of difficulty [level 0 (no cognitive load) and level 6 (maximum difficulty)]. Twelve healthy young adults participated in the study and were instructed to perform all four programs. Brain activity in the left DLPFC and right mPFC were measured during each training session using two-channel near-infrared spectroscopy (NIRS). RESULTS: No significant brain activity was observed during training at level 0. Brain activity in the left DLPFC was significantly increased at levels 1 and 2 and in the left DLPFC and right mPFC at level 6 during PaTaKaRa × calculation training. Brain activity in the left DLPFC was significantly increased at level 6 during tongue exercise × inhibition training. Brain activity in the left DLPFC and right mPFC was significantly increased at level 6 during lip exercise × N-back training. CONCLUSION: Oral function training did not significantly increase brain activity; nevertheless, oral function with cognitive training stimulated brain activity in the prefrontal cortex. TRIAL REGISTRATION: UMIN-CTR. ID: UMIN000039678. date: 06/03/2020.

Neural Function Desynchronisation in Left and Right Dorsolateral Prefrontal Cortices During Virtual Reality Earthquake Video Viewing.

During natural disasters such as earthquakes, individuals are required to evacuate calmly amidst significant emotional distress, presenting a considerable challenge. Very few studies have measured emotional responses during disasters, and the emotional responses and brain activity during natural disasters are poorly understood. Therefore, this study aimed to investigate emotional responses during an earthquake using immersive virtual reality (VR), focusing on changes in neural connectivity in the left and right dorsolateral prefrontal cortices (DLPFCs). We measured changes in total haemoglobin concentration (Δtotal-Hb) using 2-channel near infrared spectroscopy (NIRS) while 24 healthy young adults viewed earthquake and neutral videos through a head-mounted display (HMD). Spearman's correlation analysis was applied to the time variation in Δtotal-Hb in the left and right DLPFCs, independently for seismic or neutral video conditions. The findings revealed a negative correlation between the left and right total haemoglobin concentration changes during the earthquake video (ρ = -0.53). Conversely, individuals exposed to the neutral video exhibited a positive correlation (ρ = 0.75). The present steady-state analysis suggests that emotional changes induced by virtual earthquake videos disturbed steady-state neural synchronisation between the left and right DLPFCs.

Cell Type-Specific Profiles and Developmental Trajectories of Transcriptomes in Primate Prefrontal Layer 3 Pyramidal Neurons: Implications for Schizophrenia.

OBJECTIVE: In schizophrenia, impaired working memory is associated with transcriptome alterations in layer 3 pyramidal neurons (L3PNs) in the dorsolateral prefrontal cortex (DLPFC). Distinct subtypes of L3PNs that send axonal projections to the DLPFC in the opposite hemisphere (callosal projection [CP] neurons) or the parietal cortex in the same hemisphere (ipsilateral projection [IP] neurons) play critical roles in working memory. However, how the transcriptomes of these L3PN subtypes might shift during late postnatal development when working memory impairments emerge in individuals later diagnosed with schizophrenia is not known. The aim of this study was to characterize and compare the transcriptome profiles of CP and IP L3PNs across developmental transitions from prepuberty to adulthood in macaque monkeys. METHODS: The authors used retrograde labeling to identify CP and IP L3PNs in the DLPFC of prepubertal, postpubertal, and adult macaque monkeys, and used laser microdissection to capture these neurons for RNA sequencing. RESULTS: At all three ages, CP and IP L3PNs had distinct transcriptomes, with the number of genes differentially expressed between neuronal subtypes increasing with age. For IP L3PNs, age-related shifts in gene expression were most prominent between prepubertal and postpubertal animals, whereas for CP L3PNs such shifts were most prominent between postpubertal and adult animals. CONCLUSIONS: These findings demonstrate the presence of cell type-specific profiles and developmental trajectories of the transcriptomes of PPC-projecting IP and DLPFC-projecting CP L3PNs in monkey DLPFC. The evidence that IP L3PNs reach a mature transcriptome earlier than CP L3PNs suggests that these two subtypes differentially contribute to the maturation of working memory performance across late postnatal development and that they may be differentially vulnerable to the disease process of schizophrenia at specific stages of postnatal development.

Divergent gene expression patterns in alcohol and opioid use disorders lead to consistent alterations in functional networks within the dorsolateral prefrontal cortex.

Substance Use Disorders (SUDs) manifest as persistent drug-seeking behavior despite adverse consequences, with Alcohol Use Disorder (AUD) and Opioid Use Disorder (OUD) representing prevalent forms associated with significant mortality rates and economic burdens. The co-occurrence of AUD and OUD is common, necessitating a deeper comprehension of their intricate interactions. While the causal link between these disorders remains elusive, shared genetic factors are hypothesized. Leveraging public datasets, we employed genomic and transcriptomic analyses to explore conserved and distinct molecular pathways within the dorsolateral prefrontal cortex associated with AUD and OUD. Our findings unveil modest transcriptomic overlap at the gene level between the two disorders but substantial convergence on shared biological pathways. Notably, these pathways predominantly involve inflammatory processes, synaptic plasticity, and key intracellular signaling regulators. Integration of transcriptomic data with the latest genome-wide association studies (GWAS) for problematic alcohol use (PAU) and OUD not only corroborated our transcriptomic findings but also confirmed the limited shared heritability between the disorders. Overall, our study indicates that while alcohol and opioids induce diverse transcriptional alterations at the gene level, they converge on select biological pathways, offering promising avenues for novel therapeutic targets aimed at addressing both disorders simultaneously.

Dorsolateral prefrontal cortex to ipsilateral primary motor cortex intercortical interactions during inhibitory control enhance response inhibition in open-skill athletes.

Numerous studies have reported that long-term sports training can affect inhibitory control and induce brain functional alterations. However, the influence of environmental dynamics in sports training on inter-cortical connectivity has not been well studied. In the current study, we used twin-coil transcranial magnetic stimulation to investigate the functional connectivity between dorsolateral prefrontal cortex (DLPFC) and ipsilateral primary motor cortex (M1) during proactive and reactive inhibition in participants with sports skills in dynamic environment (open-skill experts), stable environment (closed-skill experts), and no sports skills (controls). Using a modified stop signal task, proactive inhibition was measured by the response delay effect (RDE), and reactive inhibition was measured by the stop-signal reaction time (SSRT). Intra-hemispheric DLPFC-M1 interactions and single pulse motor-evoked potentials (MEPs) were measured during the task. A stronger inhibitory effect of the DLPFC over M1 was observed during early reactive control stages compared to baseline levels. In addition, this inhibitory effect was pronounced when comparing open-skill experts to non-athlete controls, a relationship that was significantly correlated with superior reactive control performance. Furthermore, DLPFC to M1 influencing direction shifted from late proactive control to reactive control. Behavioral results also demonstrated enhanced proactive control abilities in open-skill experts relative to controls. Such enhancement may be due to the combination of environmental complexity and physical fitness in long-term skill training.

Exploring potential working mechanisms of accelerated HF-rTMS in refractory major depression with a focus on locus coeruleus connectivity.

BACKGROUND: This study investigates the effects of accelerated high-frequency repetitive transcranial magnetic stimulation (aHF-rTMS), applied to the left dorsolateral prefrontal cortex (DLPFC), on locus coeruleus (LC) functional connectivity in the treatment of refractory medication-resistant major depression (MRD). METHODS: We studied 12 antidepressant-free refractory MRD patients, focusing on how aHF-rTMS affects the LC, a central component of the brain's noradrenergic system and key to mood regulation and stress response. RESULTS: A stronger decrease in LC functional connectivity following aHF-rTMS treatment resulted in better clinical improvement. We observed such LC functional connectivity decreases with several brain regions, including the superior frontal gyrus, precentral gyrus, middle occipital gyrus, and cerebellum. Moreover, our exploratory analyses hint at a possible role for E-field modeling in forecasting clinical outcomes. Additional analyses suggest potential genetic and dopaminergic factors influencing changes in LC functional connectivity in relation to clinical response. CONCLUSIONS: The findings of this study underscore the pivotal role of the LC in orchestrating higher cognitive functions through its extensive connections with the prefrontal cortices, facilitating decision-making, influencing attention, and addressing depressive rumination. Additionally, the observed enhancement in LC-(posterior) cerebellar connectivity not only highlights the cerebellum's role in moderating clinical outcomes through noradrenergic system modulation but also suggests its potential as a predictive marker for aHF-rTMS efficacy. These results reveal new insights into the neural mechanisms of refractory depression and suggest therapeutic targets for enhancing noradrenergic activity, thereby addressing both cognitive and psychomotor symptoms associated with the disorder.

Differing effectiveness of transcranial random noise stimulation and transcranial direct current stimulation for enhancing working memory in healthy individuals: a randomized controlled trial.

BACKGROUND: Transcranial direct current stimulation (tDCS) applied to the left dorsolateral prefrontal cortex (DLPFC) is a promising technique for enhancing working memory (WM) performance in healthy and psychiatric populations. However, limited information is available about the effectiveness of transcranial random noise stimulation (tRNS) applied to the left DLPFC on WM. This study investigated the effectiveness of tRNS on WM compared with that of tDCS, which has established functional evidence. METHODS: This randomized, double-blind, sham-controlled trial enrolled 120 healthy right-handed adults who were randomly allocated to four stimulation groups: tRNS + direct current (DC) offset, tRNS, tDCS, or sham. Each stimulus was placed over the left DLPFC and had a current intensity of 2 mA applied for 20 min during the dual n-back task. The dual n-back task was repeated thrice: pre-stimulation, during stimulation, and post-stimulation. The d-prime scores, and response times were calculated as the main outcome measures. A linear mixed model was created to identify the main effects and interactions between the groups and times, with the group and time as fixed effects, and baseline performance and the subject as a covariate and random effect, respectively. The relationships between the benefit of each stimulus and baseline WM performance were also examined. RESULTS: For the d-prime score during stimulation, the tRNS group significantly performed better than the sham group at online assessment (ß = 0.310, p = 0.001). In the relationships between the benefit of each stimulus and baseline WM performance, the tRNS group had significantly larger negative line slopes than the sham group for the d-prime score (ß = -0.233, p = 0.038). CONCLUSIONS: tRNS applied to the left DLPFC significantly improved WM performance and generated greater benefits for healthy individuals with lower WM performance. These findings highlight the potential utility of tRNS for enhancing WM performance in individuals with lower WM performance and contribute evidence for clinical application to patients with cognitive decline. TRIAL REGISTRATION: This study was registered in the University Hospital Medical Information Network Clinical Trial Registry in Japan (UMIN000047365) on April 1, 2022; https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000054021 .

Depicting Primate-Like Granular Dorsolateral Prefrontal Cortex in the Chinese Tree Shrew.

It remains unknown whether the Chinese tree shrew, regarded as the closest sister of primate, has evolved a dorsolateral prefrontal cortex (dlPFC) comparable with primates that is characterized by a fourth layer (L4) enriched with granular cells and reciprocal connections with the mediodorsal nucleus (MD). Here, we reported that following AAV-hSyn-EGFP expression in the MD neurons, the fluorescence micro-optical sectioning tomography revealed their projection trajectories and targeted brain areas, such as the hippocampus, the corpus striatum, and the dlPFC. Cre-dependent transsynaptic viral tracing identified the MD projection terminals that targeted the L4 of the dlPFC, in which the presence of granular cells was confirmed via cytoarchitectural studies by using the Nissl, Golgi, and vGlut2 stainings. Additionally, the L5/6 of the dlPFC projected back to the MD. These results suggest that the tree shrew has evolved a primate-like dlPFC which can serve as an alternative for studying cognition-related functions of the dlPFC.

Meta-learning of human motor adaptation via the dorsal premotor cortex.

Meta-learning enables us to learn how to learn the same or similar tasks more efficiently. Decision-making literature theorizes that a prefrontal network, including the orbitofrontal and anterior cingulate cortices, underlies meta-learning of decision making by reinforcement learning. Recently, computationally similar meta-learning has been theorized and empirically demonstrated in motor adaptation. However, it remains unclear whether meta-learning of motor adaptation also relies on a prefrontal network. Considering hierarchical information flow from the prefrontal to motor cortices, this study explores whether meta-learning is processed in the dorsolateral prefrontal cortex (DLPFC) or in the dorsal premotor cortex (PMd), which is situated upstream of the primary motor cortex, but downstream of the DLPFC. Transcranial magnetic stimulation (TMS) was delivered to either PMd or DLPFC during a motor meta-learning task, in which human participants were trained to regulate the rate and retention of motor adaptation to maximize rewards. While motor adaptation itself was intact, TMS to PMd, but not DLPFC, attenuated meta-learning, impairing the ability to regulate motor adaptation to maximize rewards. Further analyses revealed that TMS to PMd attenuated meta-learning of memory retention. These results suggest that meta-learning of motor adaptation relies more on the premotor area than on a prefrontal network. Thus, while PMd is traditionally viewed as crucial for planning motor actions, this study suggests that PMd is also crucial for meta-learning of motor adaptation, processing goal-directed planning of how long motor memory should be retained to fit the long-term goal of motor adaptation.

A causal role of the right dorsolateral prefrontal cortex in random exploration.

Decision to explore new options with uncertain outcomes or exploit familiar options with known outcomes is a fundamental challenge that the brain faces in almost all real-life decisions. Previous studies have shown that humans use two main explorative strategies to negotiate this explore-exploit tradeoff. Exploring for the sake of information is called directed exploration, and exploration driven by behavioral variability is known as random exploration. While previous neuroimaging studies have shown different neural correlates for these explorative strategies, including right frontopolar cortex (FPC), right dorsolateral prefrontal cortex (DLPFC), and dorsal anterior cingulate cortex (dACC), there is still a lack of causal evidence for most of these brain regions. Here, we focused on the right DLPFC, which was previously supported to be involved in exploration. Using the continuous theta burst stimulation (cTBS) and Horizon task on twenty-five healthy right-handed adult participants, we showed that inhibiting rDLPFC did not change directed exploration but selectively reduced random exploration, by increasing reward sensitivity over the average reward of each option. This suggests a causal role for rDLPFC in random exploration, and further supports dissociable neural implementations for these two explorative strategies.

Cortical activation during the verbal fluency task for obstructive sleep apnea patients with depressive symptoms: A multi-channel fNIRS study.

STUDY OBJECTIVE: The aim of our study was to elucidate differences in brain activity patterns among obstructive sleep apnea (OSA) patients, OSA patients with depressive symptoms, and healthy controls (HCs). We also investigated the relationship between brain function and depression in OSA patients. METHODS: A total of 95 subjects were included in the study, including 34 OSA patients without depressive symptoms, 31 OSA patients with depressive symptoms, and 30 HCs. The 53-channel functional near-infrared spectroscopy (fNIRS) was used to monitor the concentration of oxy-hemoglobin (Oxy-Hb) in the brain, whereas the participants performed the verbal fluency task, and the degree of depression was scored using the 17-item Hamilton Rating Scale for Depression (HAMD-17). Hierarchical regression models were conducted to analyze the association of fNIRS features with depressive symptom. RESULTS: The Oxy-Hb changes of the three groups were significantly different in Channels 25 (H = 9.878, p = .007) and 43 (H = 6.957, p = .031). Inter-group comparisons showed that the Oxy-Hb change of Channel 25 (located in the dorsolateral prefrontal cortex [DLPFC]) in OSA group was less than that in HC group (p = .006), and the Oxy-Hb change of Channel 43 (located in the right frontal polar region) in OSA group with depression was less than that in OSA group (p = .025). Spearman's test showed that there was a significant negative correlation between HAMD-17 scores and mean Oxy-Hb changes in Channel 43 (r = -.319, p < .05) in the OSA patients. Using hierarchical regression, Oxy-Hb changes in Channel 43 accounted for a significant proportion of the variation in outcome variables, even when accounting for other polysomnography features. CONCLUSIONS: Changes in the hemodynamic response of DLPFC may be a potential mechanism of executive dysfunction in OSA patients. And the right frontal polar region may be significant in assessing depressive symptoms in patients with OSA.

Modulation of High-Frequency rTMS on Reward Circuitry in Individuals with Nicotine Dependence: A Preliminary fMRI Study.

Although previous studies have shown that repetitive transcranial magnetic stimulation (rTMS) can ameliorate addictive behaviors and cravings, the underlying neural mechanisms remain unclear. This study aimed to investigate the effect of high-frequency rTMS with the left dorsolateral prefrontal cortex (L-DLPFC) as a target region on smoking addiction in nicotine-dependent individuals by detecting the change of spontaneous brain activity in the reward circuitry. We recruited 17 nicotine-dependence participants, who completed 10 sessions of 10 Hz rTMS over a 2-week period and underwent evaluation of several dependence-related scales, and resting-state fMRI scan before and after the treatment. Functional connectivity (FC) analysis was conducted with reward-related brain regions as seeds, including ventral tegmental area, bilateral nucleus accumbens (NAc), bilateral DLPFC, and bilateral amygdala. We found that, after the treatment, individuals showed reduced nicotine dependence, alleviated tobacco withdrawal symptoms, and diminished smoking cravings. The right NAc showed increased FC with right fusiform gyrus, inferior temporal gyrus (ITG), calcarine fissure and surrounding cortex, superior occipital gyrus (SOG), lingual gyrus, and bilateral cuneus. No significant FC changes were observed in other seed regions. Moreover, the changes in FC between the right NAc and the right ITG as well as SOG before and after rTMS were negatively correlated with changes in smoking scale scores. Our findings suggest that high-frequency L-DLPFC-rTMS reduces nicotine dependence and improves tobacco withdrawal symptoms, and the dysfunctional connectivity in reward circuitry may be the underlying neural mechanism for nicotine addiction and its therapeutic target.

Impact of Electric Field Magnitude in the Left Dorsolateral Prefrontal Cortex on Changes in Intrinsic Functional Connectivity Using Transcranial Direct Current Stimulation: A Randomized Crossover Study.

This study investigated whether the electric field magnitude (E-field) delivered to the left dorsolateral prefrontal cortex (L-DLPFC) changes resting-state brain activity and the L-DLPFC resting-state functional connectivity (rsFC), given the variability in tDCS response and lack of understanding of how rsFC changes. Twenty-one healthy participants received either 2 mA anodal or sham tDCS targeting the L-DLPFC for 10 min. Brain imaging was conducted before and after stimulation. The fractional amplitude of low-frequency fluctuation (fALFF), reflecting resting brain activity, and the L-DLPFC rsFC were analyzed to investigate the main effect of tDCS, main effect of time, and interaction effects. The E-field was estimated by modeling tDCS-induced individual electric fields and correlated with fALFF and L-DLPFC rsFC. Anodal tDCS increased fALFF in the left rostral middle frontal area and decreased fALFF in the midline frontal area (FWE p < 0.050), whereas sham induced no changes. Overall rsFC decreased after sham (positive and negative connectivity, p = 0.001 and 0.020, respectively), with modest and nonsignificant changes after anodal tDCS (p = 0.063 and 0.069, respectively). No significant differences in local rsFC were observed among the conditions. Correlations were observed between the E-field and rsFC changes in the L-DLPFC (r = 0.385, p = 0.115), left inferior parietal area (r = 0.495, p = 0.037), and right lateral visual area (r = 0.683, p = 0.002). Single-session tDCS induced resting brain activity changes and may help maintain overall rsFC. The E-field in the L-DLPFC is associated with rsFC changes in both proximal and distally connected brain regions to the L-DLPFC.

Dynamic layer-specific processing in the prefrontal cortex during working memory.

The dorsolateral prefrontal cortex (dlPFC) is reliably engaged in working memory (WM) and comprises different cytoarchitectonic layers, yet their functional role in human WM is unclear. Here, participants completed a delayed-match-to-sample task while undergoing functional magnetic resonance imaging (fMRI) at ultra-high resolution. We examine layer-specific activity to manipulations in WM load and motor response. Superficial layers exhibit a preferential response to WM load during the delay and retrieval periods of a WM task, indicating a lamina-specific activation of the frontoparietal network. Multivariate patterns encoding WM load in the superficial layer dynamically change across the three periods of the task. Last, superficial and deep layers are non-differentially involved in the motor response, challenging earlier findings of a preferential deep layer activation. Taken together, our results provide new insights into the functional laminar circuitry of the dlPFC during WM and support a dynamic account of dlPFC coding.

Cortical mechanisms of across-ear speech integration investigated using functional near-infrared spectroscopy (fNIRS).

This study aimed to investigate integration of alternating speech, a stimulus which classically produces a V-shaped speech intelligibility function with minimum at 2-6 Hz in typical-hearing (TH) listeners. We further studied how degraded speech impacts intelligibility across alternating rates (2, 4, 8, and 32 Hz) using vocoded speech, either in the right ear or bilaterally, to simulate single-sided deafness with a cochlear implant (SSD-CI) and bilateral CIs (BiCI), respectively. To assess potential cortical signatures of across-ear integration, we recorded activity in the bilateral auditory cortices (AC) and dorsolateral prefrontal cortices (DLPFC) during the task using functional near-infrared spectroscopy (fNIRS). For speech intelligibility, the V-shaped function was reproduced only in the BiCI condition; TH (with ceiling scores) and SSD-CI conditions had significantly higher scores across all alternating rates compared to the BiCI condition. For fNIRS, the AC and DLPFC exhibited significantly different activity across alternating rates in the TH condition, with altered activity patterns in both regions in the SSD-CI and BiCI conditions. Our results suggest that degraded speech inputs in one or both ears impact across-ear integration and that different listening strategies were employed for speech integration manifested as differences in cortical activity across conditions.

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.

Analgesia of noninvasive electrical stimulation of the dorsolateral prefrontal cortex: A systematic review and meta-analysis.

OBJECTIVE: The dorsolateral prefrontal cortex (DLPFC) is implicated in pain modulation, suggesting its potential as a therapeutic target for pain relief. However, studies on transcranial electrical stimulation (tES) over the DLPFC yielded diverse results, likely due to differences in stimulation protocols or pain assessment methods. This study aims to evaluate the analgesic effects of DLPFC-tES using a meta-analytical approach. METHODS: A meta-analysis of 29 studies involving 785 participants was conducted. The effects of genuine and sham DLPFC-tES on pain perception were examined in healthy individuals and patients with clinical pain. Subgroup analyses explored the impact of stimulation parameters and pain modalities. RESULTS: DLPFC-tES did not significantly affect pain outcomes in healthy populations but showed promise in reducing pain-intensity ratings in patients with clinical pain (Hedges' g = -0.78, 95% CI = [-1.33, -0.24], p = 0.005). Electrode placement significantly influenced the analgesic effect, with better results observed when the anode was at F3 and the cathode at F4. CONCLUSIONS: DLPFC-tES holds potential as a cost-effective pain management option, particularly for clinical populations. Optimizing electrode placement, especially with an symmetrical configuration, may enhance therapeutic efficacy. These findings underscore the promise of DLPFC-tES for alleviating perceived pain intensity in clinical settings, emphasizing the importance of electrode placement optimization.