The role of dorsolateral prefrontal cortex on placebo effect of regulating social pain: A TMS study

Under the influence of the novel coronavirus epidemic, some negative social events, such as separation of family or friends and home isolation have increased. These events can cause negative emotion experiences similar to physical pain, thus they are called social pain. Placebo effect refers to the positive response to the inert treatment with no specific therapeutic properties, which has been shown to be one of the effective ways to alleviate social pain. Studies have shown that the dorsolateral prefrontal cortex (DLPFC) plays a key role in placebo effect. Therefore, this study aimed to explore whether activating DLPFC by using transcranial magnetic stimulation (TMS) could improve the ability of placebo effects to regulate social pain. Besides, we also combined neuroimaging and neuromodulation techniques to provide bidirectional evidence for the role of the DLPFC on placebo effects. We recruited a total of 100 participants to finish the task of negative emotional rating of the social exclusion images. Among them, 50 participants were stimulated by TMS at the right DLPFC (rDLPFC), while the others were assigned to the sham group. This study contained two independent variables. The between-subject variable was TMS group (rDLPFC-activated group or sham group) and the within-subject variable was placebo type (no-placebo and placebo). All participants received nasal spray in two blocks. In the no-placebo condition, participants were instructed that they would receive a saline nasal spray which helped to improve physiological readings;in placebo block, participants were told to administrate an intranasal fluoxetine spray (saline nasal spray in fact) that could reduce unpleasantness within 10 minutes. To strengthen the expectation of intranasal fluoxetine, participants viewed a professional introduction to fluoxetine's clinical and academic usage including downregulating negative emotion, such as fear, anxiety, and disgust. Participants who received the placebo block first would be reminded that fluoxetine's effect was over before the next block to reduce the carry-over for the following block. Self-reported negative emotional and electroencephalogram data were recorded. There was a significant two-way interaction of TMS group and placebo type. Results showed that compared with the sham group, participants in the rDLPFC-activated group reported less negative emotional feeling and had a lower amplitude of the late positive potential (LPP) in placebo condition, a component that reflects the emotional intensity, suggesting that activating rDLPFC can improve the ability of placebo effect to regulate social pain. The above finding suggested that activating DLPFC can improve the placebo effect of regulating negative emotion. Moreover, this study is the first attempt to investigate the enhancement of placebo effects by using TMS on emotion regulation. The findings not only support the critical role of DLPFC on placebo effect using neuroimaging and neuromodulation techniques, but also provide a potential brain target for treating emotional regulation deficits in patients with psychiatric disorders. © 2023 WANG Mei.

Transcranial and Transcutaneous Stimulation for Pain: What Have We Learned From the COVID-19 Pandemic Shutdown?

BACKGROUND: Transcranial magnetic stimulation (TMS) and transcutaneous magnetic stimulation (tMS) offer a novel noninvasive treatment option for chronic pain. While the recent COVID-19 pandemic caused by the SARS-CoV-2 virus resulted in a temporary interruption of the treatments for patients, it provided an excellent opportunity to assess the long-term sustainability of the treatment, and the feasibility of resuming the treatments after a brief period of interruption as no such data are available in current literature. METHODS: First, a list of patients whose pain/headache conditions have been stably controlled with either treatment for at least 6 months prior to the 3-month pandemic-related shutdown was generated. Those who returned for treatments after the shutdown were identified and their underlying pain diagnoses, pre- and posttreatment Mechanical Visual Analog Scale (M-VAS) pain scores, 3-item Pain, Enjoyment, and General Activity (PEG-3), and Patient Health Questionnaire-9 scores were assessed in 3 phases: Phase I (P1) consisted of a 6-month pre-COVID-19 period in which pain conditions were stably managed with either treatment modality; Phase II (P2) consisted of the first treatment visit period immediately after COVID-19 shutdown; and Phase III (P3) consisted of a 3-4 month post-COVID-19 shutdown period patients received up to 3 sessions of either treatment modality after the P2 treatment. RESULTS: For pre- and posttreatment M-VAS pain scores, mixed-effect analyses for both treatment groups demonstrated significant (P < 0.01) time interactions across all phases. For pretreatment M-VAS pain scores, TMS (n = 27) between-phase analyses indicated a significant (F = 13.572, P = 0.002) increase from 37.7 ± 27.6 at P1 to 49.6 ± 25.9 at P2, which then decreased significantly (F = 12.752, P = 0.001) back to an average score of 37.1 ± 24.7 at P3. Similarly, tMS (n = 25) between-phase analyses indicated the mean pretreatment pain score (mean ± standard deviation [SD]) increased significantly (F = 13.383, P = 0.003) from 34.9 ± 25.1 at P1 to 56.3 ± 27.0 at P2, which then decreased significantly (F = 5.464, P = 0.027) back to an average score of 41.9 ± 26.4 at P3. For posttreatment pain scores, the TMS group between-phase analysis indicated the mean posttreatment pain score (mean ± SD) increased significantly (F = 14.206, P = 0.002) from 25.6 ± 22.9 at P1 to 36.2 ± 23.4 at P2, which then significantly decreased (F = 16.063, P < 0.001) back to an average score of 23.2 ± 21.3 at P3. The tMS group between-phase analysis indicates a significant (F = 8.324, P = 0.012) interaction between P1 and P2 only with the mean posttreatment pain score (mean ± SD) increased from 24.9 ± 25.7 at P1 to 36.9 ± 26.7 at P2. The combined PEG-3 score between-phase analyses demonstrated similar significant (P < 0.001) changes across the phases in both treatment groups. CONCLUSIONS: Both TMS and tMS treatment interruptions resulted in an increase of pain/headache severity and interference of quality of life and functions. However, the pain/headache symptoms, patients' quality of life, or function can quickly be improved once the maintenance treatments were restarted.

Moving to accelerated protocols of tDCS in schizophrenic catatonia: A case report

This is a case report of a 74-year-old woman with catatonic schizophrenia who was treated with transcranial Direct Current Stimulation (tDCS) in place of electroconvulsive therapy (ECT) during the Covid-19 pandemic that impacted access to ECT facilities. In 2021, the exceptional number of patients infected with SARS-Cov-2 led the French public hospital system to adjust its organization, temporarily redirecting anesthetists from ECT departments to ICUs. Our patient, who was hospitalized via the emergency department, presented schizophrenia with catatonic features. Due to the pandemic, ECT, which is considered the gold standard treatment for this condition, was not available. Therefore, tDCS, a neuromodulation technique that doesn't require general anesthesia, was recommended for this patient, and was delivered at the relatively (compared to standard protocols) accelerated rate of five sessions a day, five days a week. This protocol was chosen as accelerated rTMS had been shown to be effective against depression in recent trials (Cole et al. 2021), and one study had also reported this exact protocol as effective and harmless for a patient with schizophrenia (Mondino et al. 2021). The Bush-Francis Catatonia Rating Scale (BFCRS) was used to evaluate the severity of the catatonia. After 49 sessions, the clinical response was meaningful, with a BFCRS score of 16, compared to 36 at baseline. We then moved to five sessions a day, three days a week, and then two days a week. After 80 sessions, we noted the complete disappearance of catatonia (BFCRS = 6). This case provides evidence for the feasibility and tolerability of accelerated tDCS for patients with catatonia. Accelerated tDCS represents a potential alternative to ECT in the treatment of catatonia, and needs further randomized clinical studies to confirm its efficacy. Research Category and Technology and Methods Clinical Research: 9. Transcranial Direct Current Stimulation (tDCS) Keywords: tdcs, catatonia, covid-19, ECTCopyright © 2023

If you build it, will they come? Acceptability, feasibility, and uptake of TMS-based treatment for pediatric Tourette Syndrome

Background: Transcranial magnetic stimulation (TMS) treatment holds promise for pediatric neurological and psychiatric illnesses, but little is known about the acceptability, feasibility, and uptake of experimental TMS intervention in pediatric populations. The current study aimed to identify successful recruitment strategies and participation barriers in the CBIT+TMS Trial, an ongoing clinical trial testing TMS augmentation of behavior therapy for Tourette Syndrome in 12-21 year olds. Method(s): Participation involves 10 daily treatment sessions over two weeks plus pre/post neuroimaging and clinical assessments through 3-month follow-up. Recruitment data from November 2020 - August 2022 were examined for recruitment status, recruitment source, and reason for ineligibility or non-participation. Result(s): N = 171 individuals expressed interest in participation. Of these, 53% declined or passively declined participation, 45% completed phone screening, 19% were deemed ineligible, and 18% enrolled. The most successful recruitment strategies were community flyering, sharing information through a patient support organization, and provider referrals. The most commonly stated reasons for declining participation were related to time commitment and the need to travel to in-person appointments. Notably, participation was greatest during summer months. All enrolled participants have been retained through follow-up visits. Conclusion(s): TMS treatment is of interest to youth and parents in the TS community. As a comparison, a prior TS therapy trial screened =6 youth/month across three sites (Piacentini et al., 2010), whereas our single site is screening =4 youth/month. Stated reasons for declining participation related to schedule and travel feasibility rather than concerns about TMS. This recruitment period overlapped with the COVID-19 pandemic, which likely heightened these particular barriers. Future pediatric TMS research should include efforts to maximize efficacy within protocol schedules that are feasible for youth. Continued examination of factors contributing to pediatric TMS interest and uptake can help inform developmentally sensitive intervention and clinical trial protocols. Research Category and Technology and Methods Clinical Research: 10. Transcranial Magnetic Stimulation (TMS) Keywords: Tourette, Clinical Trial, Pediatric, FeasibilityCopyright © 2023

Combination of tps and tms in a patient with post covid-19 depression

Abstract In the case of a 76 year old patient with moderate depression and anxiosomatic symptoms the treatment was initiated with TMS. After 30 sessions, anxiety improved in the subjective perception around 30% but not the depressive mood. By changing the method to TPS, after 3 sessions the mood improved significantly and after the 6th session we effectuated a nearly complete and lasting remission of depressive symptoms with additionally slightly improved anxiosomatic symtoms.This may be the first reference of potentially synergistic effects of TPS and TMS in depressed patients and also the first description of treating a non-demented depressed patient with tps. Research Category and Technology and Methods Clinical Research: 10. Transcranial Magnetic Stimulation (TMS) Keywords: TPS, TMS, depression, combinationCopyright © 2023

Case report: Dysphagia after COVID-19 infection in a stroke patient-Is neurostimulation a potential management?

A 90-year-old man with stroke was weaned from tube feeding 4 months after stroke onset. However, he had a coronavirus disease 2019 (COVID-19) infection after 2 months and suffered from drastically worsened oropharyngeal dysphagia that required a reinsertion of the nasogastric tube. A videofluoroscopic swallowing study revealed poor bolus oral transit, significantly delayed swallowing reflex, reduced pharyngeal movements, and insufficient cough response. Repetitive transcranial magnetic stimulation and neuromuscular electrical stimulation were applied, in addition to conventional swallowing training. The feeding tube was removed after 20 treatment sessions. Clinicians should be aware of the risk of dysphagia after COVID-19 infection in patients with underlying neurological diseases. The management of post-COVID-19 dysphagia has not yet been fully established. Repetitive transcranial electrical stimulation combined with neuromuscular electrical stimulation may be used as an auxiliary intervention in specific cases.

Co-ultramicronized palmitoylethanolamide/luteolin normalizes GABAB-ergic activity and cortical plasticity in long COVID-19 syndrome.

OBJECTIVE: Transcranial magnetic stimulation (TMS) studies showed that patients with cognitive dysfunction and fatigue after COVID-19 exhibit impaired cortical GABAB-ergic activity, as revealed by reduced long-interval intracortical inhibition (LICI). Aim of this study was to test the effects of co-ultramicronized palmitoylethanolamide/luteolin (PEA-LUT), an endocannabinoid-like mediator able to enhance GABA-ergic transmission and to reduce neuroinflammation, on LICI. METHODS: Thirty-nine patients (26 females, mean age 49.9 ± 11.4 years, mean time from infection 296.7 ± 112.3 days) suffering from persistent cognitive difficulties and fatigue after mild COVID-19 were randomly assigned to receive either PEA-LUT 700 mg + 70 mg or PLACEBO, administered orally bid for eight weeks. The day before (PRE) and at the end of the treatment (POST), they underwent TMS protocols to assess LICI. We further evaluate short-latency afferent inhibition (SAI) and long-term potentiation (LTP)-like cortical plasticity. RESULTS: Patients treated with PEA-LUT but not with PLACEBO showed a significant increase of LICI and LTP-like cortical plasticity. SAI remained unaffected. CONCLUSIONS: Eight weeks of treatment with PEA-LUT restore GABAB activity and cortical plasticity in long Covid patients. SIGNIFICANCE: This study confirms altered physiology of the motor cortex in long COVID-19 syndrome and indicates PEA-LUT as a candidate for the treatment of this post-viral condition.

Transcranial Magnetic Stimulation for Long-Term Smoking Cessation: Preliminary Examination of Delay Discounting as a Therapeutic Target and the Effects of Intensity and Duration.

Background: Repetitive transcranial magnetic stimulation (rTMS) is a novel treatment for smoking cessation and delay discounting rate is novel therapeutic target. Research to determine optimal therapeutic targets and dosing parameters for long-term smoking cessation is needed. Due to potential biases and confounds introduced by the COVID-19 pandemic, we report preliminary results from an ongoing study among participants who reached study end prior to the pandemic. Methods: In a 3 × 2 randomized factorial design, participants (n = 23) received 900 pulses of 20 Hz rTMS to the left dorsolateral prefrontal cortex (PFC) in one of three Durations (8, 12, or 16 days of stimulation) and two Intensities (1 or 2 sessions per day). We examined direction and magnitude of the effect sizes on latency to relapse, 6-month point-prevalence abstinence rates, research burden, and delay discounting rates. Results: A large effect size was found for Duration and a medium for Intensity for latency to relapse. Increasing Duration increased the odds of abstinence 7-8-fold while increasing Intensity doubled the odds of abstinence. A large effect size was found for Duration, a small for Intensity for delay discounting rate. Increasing Duration and Intensity had a small effect on participant burden. Conclusion: Findings provide preliminary support for delay discounting as a therapeutic target and for increasing Duration and Intensity to achieve larger effect sizes for long-term smoking cessation and will provide a pre-pandemic comparison for data collected during the pandemic. Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [NCT03865472].

The BISTIM study: first RCT comparing dual ovarian stimulation on the same cycle (duostim) vs 2 conventional ovarianstimulations in poor ovarian responders undergoing IVF

Study question: Is the number of cumulated oocytes with dual ovarian stimulation on the same cycle (duostim) higher compared to 2 consecutive antagonist cycles in poor responders? Summary answer: Considering the number of total and mature oocytes collected in poor ovarian responders, there is no benefit of duostim vs two consecutive antagonist cycles. What is known already: Several waves of follicular development exist on the same cycle. Recent studies have shown the ability to obtain oocytes with equivalent quality in the luteal phase, even after a previous ovarian stimulation in the follicular phase. During stimulation, smaller follicles are recruited and sensitized, which may increase the selection of follicles available on the second stimulation. In poor ovarian responders (POR) this potentialization may have a great interest, as 2 stimulations on the same cycle could give a higher number of oocytes compared to two conventional stimulations. However, these preliminary data need to be confirmed with a randomized controlled trial. Study design, size, duration: This is a multicenter, open-labeled randomized control trial (2018, september-2021, march). The primary objective was to demonstrate that two ovarian stimulations within the same cycle (first in the follicular phase, followed by a second in the luteal phase) lead to the retrevial of 1.5 more oocytes than the cumulative number of oocytes from two consecutive conventional stimulation, in POR women. According to this hypothesis, 44 patients were needed in each group. Participants/materials, setting, methods: 88 POR women, defined with Bologna criteria (AFC≤5 and/or AMH≤1.2ng/ml and ≤3 oocytes if previous IVF) were randomized, 44 in duostim group (D) and 44 in conventional group (C). Fertistart Kit®300IU/day with antagonist protocol was used except in luteal phase stimulation of group D. In group D, oocytes were pooled and inseminated after the second retrieval, with freeze all embryos. Fresh transfer was performed in group C. The analysis is presented in intention to treat. Main results and the role of chance: There was no difference between the groups regarding demographics, ovarian reserve markers (AFC, AMH) and stimulation parameters. The mean number of cumulated oocytes retrieved with 2 ovarian stimulation was not statistically different in group D and C, respectively 5.0+/-3.4 and 4.6+/-3.4 (p=0.56). The mean number of cumulated mature oocytes was not statistically different, 3.7+/-3.3 in group D vs 3.1+/-3.0 in group C (p=0.38). The mean number of embryos was significantly lower in the group D, 0.8+/-1.3 vs group C 1.6+/-1.3 (p<0.01). There was no statistical difference of the mean number of oocytes retrieved per cycle in cycle 1 vs cycle 2 in both group D and C. The delay, between the first and the second day 1 of stimulation was statistically different in group D 14.4 days (10-19) vs group C 90.6 (28-232). The ongoing pregnancy rate in group D 17.9% (7/39) was not statistically different with group C 29.3% (12/41), (p=0.23). And the mean time to ongoing pregnancy tends to be longer in group D (144 days) vs group C (115 days) but was not statistically different (p=0.21). Limitations, reasons for caution: The RCT was impacted by Covid pandemia and stop of IVF activities for 10 weeks. Delays were recalculated to exclude this period, however one women in group D cannot have the luteal stimulation. We also faced unexpected good ovarian responses and pregnancies after the first oocyte pick-up in group C. Wider implications of the findings: In routine practice, the benefit of duostim in patients with POR is not confirmed. Firstly, because there is no potentialization on the number of oocyte retrieved in luteal phase after follicular phase stimulation. Secondly, because the freeze all strategy avoids a pregnancy with fresh embryo transfer after the first cycle.

Fibromyalgia syndrome: year in review

The aim of this review is to describe the most recent findings concerning the diagnosis, aetiopathogenesis and treatment of fibromyalgia syndrome (FM) that were published between January 2021 and January 2022 and appearing on PubMed database. Year 2021 saw the publication of many papers which tried to estimate the big COVID-19 impact on FM patient's lives, both from a physical and a mental point of view (1-3). Moreover, more and more attention has been put on juvenile fibromyalgia, which is surging as a distinct clinical entity which needs prompt diagnosis (4), and, as the adult counterpart, if it is comorbid with a rheumatic disease, it increases the perception of disease activity with respect to physician's evaluation. The most important publications last year were centered on the aetiopathogenesis of FM. One of the things that has to be kept in mind is the extreme importance of trauma in the life of these individuals. An interesting metaanalysis by Kaleycheva et al. (5) comprising nineteen studies confirms that there is a significant association between stressor exposure and adult FM, with the strongest associations observed for physical abuse (physical abuse (OR 3.23, 95% confidence interval 1.99-5.23) and total abuse (3.06, 1.71-5.46);intermediate for sexual abuse (2.65, 1.85-3.79) and smaller for medical trauma (1.80, 1.19-2.71), other lifetime stressors (1.70, 1.31-2.20), and emotional abuse (1.52, 1.27-1.81)). In addition, an autoantibody-centered theory is now developing. The most important recent study in this perspective comes from a study by Goebel et al. published on Journal of Clinical Investigation (6). Researchers found that mice treated with IgG from FM patients displayed increased sensitivity to noxious mechanical and cold stimulation, and nociceptive fibers in skin-nerve preparations from mice treated with FM IgG displayed an increased responsiveness to cold and mechanical stimulation. From the therapeutic point of view, few studies worth mentioning focused on the pharmacological treatment of FM;in particular, well-conducted clinical trials were about ketamine and low-dose naltrexone (7, 8). Most of 2021 studies focused on neurostimulation in FM patients, in particular on repetitive transcranial magnetic stimulation (rTMS) or direct current stimulation (DCS) (9, 10 etc.).

EMERGING NON-INVASIVE NEUROPLASTIC-TARGETING THERAPIES FOR SUBSTANCE USE DISORDER TREATMENT

Context: America is in the midst of a substance use disorder (SUD) epidemic, which has only worsened in the current COVID-19 pandemic. SUD is a public health crisis that affects an ever-increasing proportion of the population and is extraordinarily difficult to treat. Misused substances induce neuroplastic changes that not only predispose individuals to relapse but also persist after completing treatment recommendations. Objective: To establish the phenomenon of neuroplasticity in relation to SUD and summarize non-invasive neuroplastic therapies designed to return the brain to its pre-dependency state. Methods: On October 29, 2019, the search term “neuroplasticity addiction” was entered into PubMed. Articles were selected based on description of neuroplastic changes occurring in SUD and treatment modalities that foster neuroplastic improvements for SUD treatment. Results: 1241 articles were excluded based on irrelevance to the specific topic, language or redundancy. 41 articles met inclusion criteria, with 18 illustrating neuroplastic effects induced by SUD and 23 describing therapeutic interventions. Conclusions: SUD induces neuroplastic changes that predispose an individual to relapse and persist after completing SUD recommendations. Transcranial magnetic stimulation, environmental enrichment and exercise are shown to affect altered brain composition and reduce SUD-related negative behavior, while motor training appears to block neurophysiological changes normally caused by substance use. This illustrates that therapies targeting neuroplastic changes reduce adverse behaviors in those with SUD. The implementation of these modalities with current standard-of-care treatment may increase treatment success. Additional research into these modalities and their potential to enhance current treatments is warranted.

EEG Evoked Potentials to Repetitive Transcranial Magnetic Stimulation in Normal Volunteers: Inhibitory TMS EEG Evoked Potentials.

The impact of repetitive magnetic stimulation (rTMS) on cortex varies with stimulation parameters, so it would be useful to develop a biomarker to rapidly judge effects on cortical activity, including regions other than motor cortex. This study evaluated rTMS-evoked EEG potentials (TEP) after 1 Hz of motor cortex stimulation. New features are controls for baseline amplitude and comparison to control groups of sham stimulation. We delivered 200 test pulses at 0.20 Hz before and after 1500 treatment pulses at 1 Hz. Sequences comprised AAA = active stimulation with the same coil for test-treat-test phases (n = 22); PPP = realistic placebo coil stimulation for all three phases (n = 10); and APA = active coil stimulation for tests and placebo coil stimulation for treatment (n = 15). Signal processing displayed the evoked EEG waveforms, and peaks were measured by software. ANCOVA was used to measure differences in TEP peak amplitudes in post-rTMS trials while controlling for pre-rTMS TEP peak amplitude. Post hoc analysis showed reduced P60 amplitude in the active (AAA) rTMS group versus the placebo (APA) group. The N100 peak showed a treatment effect compared to the placebo groups, but no pairwise post hoc differences. N40 showed a trend toward increase. Changes were seen in widespread EEG leads, mostly ipsilaterally. TMS-evoked EEG potentials showed reduction of the P60 peak and increase of the N100 peak, both possibly reflecting increased slow inhibition after 1 Hz of rTMS. TMS-EEG may be a useful biomarker to assay brain excitability at a seizure focus and elsewhere, but individual responses are highly variable, and the difficulty of distinguishing merged peaks complicates interpretation.

When Two Is Better Than One: A Pilot Study on Transcranial Magnetic Stimulation Plus Muscle Vibration in Treating Chronic Pelvic Pain in Women.

Chronic pelvic pain syndrome (CPPS) affects about 4-16% of adult women, and about one-third of them require medical assistance due to severe symptoms. Repetitive transcranial magnetic stimulation (rTMS) over the supplementary motor area (SMA) has been shown to manage pain in refractory CPPS. Focal muscle vibration (FMV) has also been reported to relieve pelvic pain. The objective of this study was to assess the feasibility and effect of rTMS coupled with FMV to reduce pain in seven adult women with refractory CPPS. This pilot, open-labeled, prospective trial examined treatment by 5 Hz rTMS over SMA and 150 Hz FMV over the perineum, suprapubic, and sacrococcygeal areas, with one daily session for five consecutive days for three weeks. We assessed tolerance and subjective pain changes (as per visual analog scale, VAS) until one month post-treatment, with a primary endpoint at day 7. No patients experienced serious adverse effects or a significant increase in pain. Six out of seven patients experienced a VAS improvement of at least 10% at T7; three of these individuals experienced a VAS improvement of more than 30%. Overall, we found a significant VAS reduction of 15 points (95% CI 8.4-21.6) at T7 (t = 6.3, p = 0.001; ES = 2.3 (1.1-3.9)). Three of the women who demonstrated a significant VAS reduction at T7 retained such VAS improvement at T30. VAS decreased by six points (95% CI 1.3-10.7) at T30 (t = 3.1, p = 0.02; ES = 1.5 (0.2-2.6)). This coupled approach seems promising for pain management in adult women with refractory CPPS and paves the way for future randomized controlled trials.

Altered motor cortex physiology and dysexecutive syndrome in patients with fatigue and cognitive difficulties after mild COVID-19.

BACKGROUND AND PURPOSE: Fatigue and cognitive difficulties are reported as the most frequently persistent symptoms in patients after mild SARS-CoV-2 infection. An extensive neurophysiological and neuropsychological assessment of such patients was performed focusing on motor cortex physiology and executive cognitive functions. METHODS: Sixty-seven patients complaining of fatigue and/or cognitive difficulties after resolution of mild SARS-CoV-2 infection were enrolled together with 22 healthy controls (HCs). Persistent clinical symptoms were investigated by means of a 16-item questionnaire. Fatigue, exertion, cognitive difficulties, mood and 'well-being' were evaluated through self-administered tools. Utilizing transcranial magnetic stimulation of the primary motor cortex (M1) resting motor threshold, motor evoked potential amplitude, cortical silent period duration, short-interval intracortical inhibition, intracortical facilitation, long-interval intracortical inhibition and short-latency afferent inhibition were evaluated. Global cognition and executive functions were assessed with screening tests. Attention was measured with computerized tasks. RESULTS: Post COVID-19 patients reported a mean of 4.9 persistent symptoms, high levels of fatigue, exertion, cognitive difficulties, low levels of well-being and reduced mental well-being. Compared to HCs, patients presented higher resting motor thresholds, lower motor evoked potential amplitudes and longer cortical silent periods, concurring with reduced M1 excitability. Long-interval intracortical inhibition and short-latency afferent inhibition were also impaired, indicating altered GABAB -ergic and cholinergic neurotransmission. Short-interval intracortical inhibition and intracortical facilitation were not affected. Patients also showed poorer global cognition and executive functions compared to HCs and a clear impairment in sustained and executive attention. CONCLUSIONS: Patients with fatigue and cognitive difficulties following mild COVID-19 present altered excitability and neurotransmission within M1 and deficits in executive functions and attention.

Connectivity-Guided Theta Burst Transcranial Magnetic Stimulation Versus Repetitive Transcranial Magnetic Stimulation for Treatment-Resistant Moderate to Severe Depression: Magnetic Resonance Imaging Protocol and SARS-CoV-2-Induced Changes for a Randomized Double-blind Controlled Trial.

BACKGROUND: Depression is a substantial health and economic burden. In approximately one-third of patients, depression is resistant to first-line treatment; therefore, it is essential to find alternative treatments. Transcranial magnetic stimulation (TMS) is a neuromodulatory treatment involving the application of magnetic pulses to the brain that is approved in the United Kingdom and the United States in treatment-resistant depression. This trial aims to compare the clinical effectiveness, cost-effectiveness, and mechanism of action of standard treatment repetitive TMS (rTMS) targeted at the F3 electroencephalogram site with a newer treatment-a type of TMS called theta burst stimulation (TBS) targeted based on measures of functional brain connectivity. This protocol outlines brain imaging acquisition and analysis for the Brain Imaging Guided Transcranial Magnetic Stimulation in Depression (BRIGhTMIND) study trial that is used to create personalized TMS targets and answer the proposed mechanistic hypotheses. OBJECTIVE: The aims of the imaging arm of the BRIGhTMIND study are to identify functional and neurochemical brain signatures indexing the treatment mechanisms of rTMS and connectivity-guided intermittent theta burst TMS and to identify imaging-based markers predicting response to treatment. METHODS: The study is a randomized double-blind controlled trial with 1:1 allocation to either 20 sessions of TBS or standard rTMS. Multimodal magnetic resonance imaging (MRI) is acquired for each participant at baseline (before TMS treatment) with T1-weighted and task-free functional MRI during rest used to estimate TMS targets. For participants enrolled in the mechanistic substudy, additional diffusion-weighted sequences are acquired at baseline and at posttreatment follow-up 16 weeks after treatment randomization. Core data sets of T1-weighted and task-free functional MRI during rest are acquired for all participants and are used to estimate TMS targets. Additional sequences of arterial spin labeling, magnetic resonance spectroscopy, and diffusion-weighted images are acquired depending on the recruitment site for mechanistic evaluation. Standard rTMS treatment is targeted at the F3 electrode site over the left dorsolateral prefrontal cortex, whereas TBS treatment is guided using the coordinate of peak effective connectivity from the right anterior insula to the left dorsolateral prefrontal cortex. Both treatment targets benefit from the level of MRI guidance, but only TBS is provided with precision targeting based on functional brain connectivity. RESULTS: Recruitment began in January 2019 and is ongoing. Data collection is expected to continue until January 2023. CONCLUSIONS: This trial will determine the impact of precision MRI guidance on rTMS treatment and assess the neural mechanisms underlying this treatment in treatment-resistant depressed patients. TRIAL REGISTRATION: ISRCTN Registry ISRCTN19674644; https://www.isrctn.com/ISRCTN19674644. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/31925.

Facilitation of Motor Evoked Potentials in Response to a Modified 30 Hz Intermittent Theta-Burst Stimulation Protocol in Healthy Adults.

Theta-burst stimulation (TBS) is a form of repetitive transcranial magnetic stimulation (rTMS) developed to induce neuroplasticity. TBS usually consists of 50 Hz bursts at 5 Hz intervals. It can facilitate motor evoked potentials (MEPs) when applied intermittently, although this effect can vary between individuals. Here, we sought to determine whether a modified version of intermittent TBS (iTBS) consisting of 30 Hz bursts repeated at 6 Hz intervals would lead to lasting MEP facilitation. We also investigated whether recruitment of early and late indirect waves (I-waves) would predict individual responses to 30 Hz iTBS. Participants (n = 19) underwent single-pulse TMS to assess MEP amplitude at baseline and variations in MEP latency in response to anterior-posterior, posterior-anterior, and latero-medial stimulation. Then, 30 Hz iTBS was administered, and MEP amplitude was reassessed at 5-, 20- and 45-min. Post iTBS, most participants (13/19) exhibited MEP facilitation, with significant effects detected at 20- and 45-min. Contrary to previous evidence, recruitment of early I-waves predicted facilitation to 30 Hz iTBS. These observations suggest that 30 Hz/6 Hz iTBS is effective in inducing lasting facilitation in corticospinal excitability and may offer an alternative to the standard 50 Hz/5 Hz protocol.

Network-based rTMS to modulate working memory: The difficult choice of effective parameters for online interventions.

BACKGROUND: Online repetitive transcranialmagnetic stimulation (rTMS) has been shown to modulate working memory (WM) performance in a site-specific manner, with behavioral improvements due to stimulation of the dorsolateral prefrontal cortex (DLPFC), and impairment from stimulation to the lateral parietal cortex (LPC). Neurobehavioral studies have demonstrated that subprocesses of WM allowing for the maintenance and manipulation of information in the mind involve unique cortical networks. Despite promising evidence of modulatory effects of rTMS on WM, no studies have yet demonstrated distinct modulatory control of these two subprocesses. The current study therefore sought to explore this possibility through site-specific stimulation during an online task invoking both skills. METHODS: Twenty-nine subjects completed a 4-day protocol, in which active or sham 5Hz rTMS was applied over the DLPFC and LPC in separate blocks of trials while participants performed tasks that required either maintenance alone, or both maintenance and manipulation (alphabetization) of information. Stimulation targets were defined individually based on fMRI activation and structural network properties. Stimulation amplitude was adjusted using electric field modeling to equate induced current in the target region across participants. RESULTS: Despite the use of advanced techniques, no significant differences or interactions between active and sham stimulation were found. Exploratory analyses testing stimulation amplitude, fMRI activation, and modal controllability showed nonsignificant but interesting trends with rTMS effects. CONCLUSION: While this study did not reveal any significant behavioral changes in WM, the results may point to parameters that contribute to positive effects, such as stimulation amplitude and functional activation.