Deficient GABABergic and glutamatergic excitability in the motor cortex of patients with long-COVID and cognitive impairment.

OBJECTIVE: Attention, working memory and executive processing have been reported to be consistently impaired in Neuro-Long coronavirus disease (COVID). On the hypothesis of abnormal cortical excitability, we investigated the functional state of inhibitory and excitatory cortical regulatory circuits by single "paired-pulse" transcranial magnetic stimulation (ppTMS) and Short-latency Afferent Inhibition (SAI). METHODS: We compared clinical and neurophysiological data of 18 Long COVID patients complaining of persistent cognitive impairment with 16 Healthy control (HC) subjects. Cognitive status was evaluated by means of the Montreal Cognitive Assessment (MoCA) and a neuropsychological evaluation of the executive function domain; fatigue was scored by the Fatigue Severity Scale (FSS). Resting motor threshold (RMT), the amplitude of the motor evoked potential (MEP), Short Intra-cortical Inhibition (SICI), Intra-cortical Facilitation (ICF), Long-interval Intracortical Inhibition (LICI) and Short-afferent inhibition (SAI) were investigated over the motor (M1) cortex. RESULTS: MoCA corrected scores were significantly different between the two groups (p = 0.023). The majority of the patients' performed sub-optimally in the neuropsychological assessment of the executive functions. The majority (77.80%) of the patients reported high levels of perceived fatigue in the FSS. RMT, MEPs, SICI and SAI were not significantly different between the two groups. On the other hand, Long COVID patients showed a reduced amount of inhibition in LICI (p = 0.003) and a significant reduction in ICF (p < 0.001). CONCLUSIONS: Neuro-Long COVID patients performing sub-optimally in the executive functions showed a reduction of LICI related to GABAb inhibition and a reduction of ICF related to glutamatergic regulation. No alteration in cholinergic circuits was found. SIGNIFICANCE: These findings can help to better understand the neurophysiological characteristics of Neuro-Long COVID, and in particular, motor cortex regulation in people with "brain fog".

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.

A 30-Year-Old Woman with an 8-Week History of Anxiety, Depression, Insomnia, and Mild Cognitive Impairment Following COVID-19 Who Responded to Accelerated Bilateral Theta-Burst Transcranial Magnetic Stimulation Over the Prefrontal Cortex.

BACKGROUND This report is of a 30-year-old woman with an 8-week history of anxiety, depression, insomnia, and mild cognitive impairment following COVID-19 infection, who responded to accelerated bilateral theta-burst transcranial magnetic stimulation (TBS) over the prefrontal cortex. CASE REPORT A previously healthy 30-year-old woman visited our psychiatric clinic for symptoms including anxiety, depression, insomnia, and brain fog (mild cognitive impairment) for more than 8 weeks after being diagnosed with COVID-19 on May 9, 2022. Continuous TBS of the right dorsolateral prefrontal cortex (DLPFC), followed by intermittent TBS of the left DLPFC, was performed twice daily over 5 days for a total of 10 sessions. The Beck Depression Inventory (BDI), Hamilton Depression Rating Scale (HAMD), Beck Anxiety Inventory (BAI), Pittsburgh Sleep Quality Index (PSQI), and subsets of the Wechsler Memory Scale (WMS)-Third Edition were administered at baseline and at the end of treatment. After 10 sessions of treatment, her BAI, BDI, HAMD, PSQI, WMS-Logical Memory, WMS-Faces, WMS-Verbal Paired Associates, and WMS-Family Pictures scores had improved from 4, 18, 10, 14, 8, 10, 12, and 8, respectively, to 0, 7, 1, 10, 15, 15, 15, and 10, respectively. CONCLUSIONS Accelerated TBS over the bilateral DLPFC may ameliorate long-COVID-associated neuropsychiatric symptoms. Additional trials are warranted to evaluate the effect of neuropsychiatric symptoms following COVID-19.

Real world research on transcranial magnetic stimulation treatment strategies for neuropsychiatric symptoms with long-COVID in Japan.

The number of patients suffering from long-COVID is currently increasing rapidly, even after the acute symptoms of COVID-19 have improved. The objective of this study was to investigate the effects of a pilot transcranial magnetic stimulation (TMS) treatment on neuropsychiatric symptoms caused by long-COVID. In this study, we examined the efficacy of the TMS treatment protocol, which has been established to be effective in refractory depression, by applying it to patients who sought TMS treatment for neuropsychiatric symptoms caused by long-COVID at TMS clinics in Tokyo, Japan in the context of the real world TMS registry study in Japan. Of the 23 patients (13 females) with long-COVID included in this case series, the main neuropsychiatric symptoms were chronic fatigue (n = 12) and cognitive dysfunction (n = 11), but most patients also showed mild depressive symptoms. The mean score on the Montgomery-Åsberg Depression Rating Scale before TMS treatment was 21.2, which improved to 9.8 after treatment. Similarly, the score on the Performance Status, which assesses the degree of fatigue, improved from 5.4 to 4.2, and the score on the Perceived Deficits Questionnaire-Depression 5-item, which reflects cognitive function, improved from 10.0 to 6.3. Although a few patients complained of pain at the stimulation site during the TMS as a side effect, there were no serious adverse events. Despite the limitations of this open-label pilot study, the TMS protocol implemented in this study may have beneficial effects on neuropsychiatric symptoms caused by long-COVID, including depressive symptoms, chronic fatigue, and cognitive impairment. These preliminary findings warrant further validation in randomized controlled trials.

The therapeutic potential of non-invasive brain stimulation for the treatment of Long-COVID-related cognitive fatigue.

Following an acute COVID-19 infection, a large number of patients experience persisting symptoms for more than four weeks, a condition now classified as Long-COVID syndrome. Interestingly, the likelihood and severity of Long-COVID symptoms do not appear to be related to the severity of the acute COVID-19 infection. Fatigue is amongst the most common and debilitating symptoms of Long-COVID. Other symptomes include dyspnoea, chest pain, olfactory disturbances, and brain fog. Fatigue is also frequently reported in many other neurological diseases, affecting a broad range of everyday activities. However, despite its clinical significance, limited progress has been made in understanding its causes and developing effective treatment options. Non-invasive brain stimulation (NIBS) methods offer the unique opportunity to modulate fatigue-related maladaptive neuronal activity. Recent data show promising results of NIBS applications over frontoparietal regions to reduce fatigue symptoms. In this current paper, we review recent data on Long-COVID and Long-COVID-related fatigue (LCOF), with a special focus on cognitive fatigue. We further present widely used NIBS methods, such as transcranial direct current stimulation, transcranial alternating current stimulation, and transcutaneous vagus nerve stimulation and propose their use as possible therapeutic strategies to alleviate individual pathomechanisms of LCOF. Since NIBS methods are safe and well-tolerated, they have the potential to enhance the quality of life in a broad group of patients.

Genetic Algorithm for TMS Coil Position Optimization in Stroke Treatment.

Transcranial magnetic stimulation (TMS), a non-invasive technique to stimulate human brain, has been widely used in stroke treatment for its capability of regulating synaptic plasticity and promoting cortical functional reconstruction. As shown in previous studies, the high electric field (E-field) intensity around the lesion helps in the recovery of brain function, thus the spatial location and angle of coil truly matter for the significant correlation with therapeutic effect of TMS. But, the error caused by coil placement in current clinical setting is still non-negligible and a more precise coil positioning method needs to be proposed. In this study, two kinds of real brain stroke models of ischemic stroke and hemorrhagic stroke were established by inserting relative lesions into three human head models. A coil position optimization algorithm, based on the genetic algorithm (GA), was developed to search the spatial location and rotation angle of the coil in four 4 × 4 cm search domains around the lesion. It maximized the average intensity of the E-field in the voxel of interest (VOI). In this way, maximum 17.48% higher E-field intensity than that of clinical TMS stimulation was obtained. Besides, our method also shows the potential to avoid unnecessary exposure to the non-target regions. The proposed algorithm was verified to provide an optimal position after nine iterations and displayed good robustness for coil location optimization between different stroke models. To conclude, the optimized spatial location and rotation angle of the coil for TMS stroke treatment could be obtained through our algorithm, reducing the intensity and duration of human electromagnetic exposure and presenting a significant therapeutic potential of TMS for stroke.

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.

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.

The Effect of Repetitive Transcranial Magnetic Stimulation on Suicidal Ideation in Treatment-Resistant Depression: A Meta-Analysis.

Objective: To quantitatively synthesize the literature on the effects of repetitive transcranial magnetic stimulation (rTMS) on suicidal ideation (SI) in patients with treatment-resistant depression.Data Sources: A literature search was conducted using PubMed, SCOPUS, Ovid, MEDLINE, Embase, and Web of Science from inception to January 11, 2021, for the keywords repetitive transcranial magnetic stimulation, suicidal ideation, suicidality, treatment-resistant depression, refractory depression, transcranial magnetic stimulation, and brain stimulation.Study Selection: A total of 16 publications were eligible for inclusion. Studies were included that investigated the effects of rTMS in adolescents and/or adults 16 years or older diagnosed with unipolar or bipolar depression with suicidal ideation data before and after rTMS intervention.Data Extraction: Data were extracted and managed using Covidence. Extracted data included authors, publication year, country of origin, study design, patient demographics, primary diagnosis, comorbidities, mean age, outcome assessment instruments, detailed stimulation parameters, sham control procedures, and any serious adverse events related to SI.Results: A quantitative analysis of effect size using Hedges g was calculated for both randomized controlled trials and all other uncontrolled trials. We found a decrease in SI scores in randomized controlled trials (g = 0.158, 95% confidence interval [CI] = -0.078 to 0.393, P = .191), although the effect was not significant. There was a significant decrease in suicidal ideation scores for uncontrolled trials (g = 0.692, 95% CI = 0.463 to 0.922, P < .001).Conclusions: Our findings suggest that rTMS may be an effective treatment for SI in individuals with treatment-resistant depression, although further investigation is warranted.

Intermittent theta burst stimulation over the parietal cortex has a significant neural effect on working memory.

The crucial role of the parietal cortex in working memory (WM) storage has been identified by fMRI studies. However, it remains unknown whether repeated parietal intermittent theta-burst stimulation (iTBS) can improve WM. In this within-subject randomized controlled study, under the guidance of fMRI-identified parietal activation in the left hemisphere, 22 healthy adults received real and sham iTBS sessions (five consecutive days, 600 pulses per day for each session) with an interval of 9 months between the two sessions. Electroencephalography signals of each subject before and after both iTBS sessions were collected during a change detection task. Changes in contralateral delay activity (CDA) and K-score were then calculated to reflect neural and behavioral WM improvement. Repeated-measures ANOVA suggested that real iTBS increased CDA more than the sham one (p = .011 for iTBS effect). Further analysis showed that this effect was more significant in the left hemisphere than in the right hemisphere (p = .029 for the hemisphere-by-iTBS interaction effect). Pearson correlation analyses showed significant correlations for two conditions between CDA changes in the left hemisphere and K score changes (ps <.05). In terms of the behavioral results, significant K score changes after real iTBS were observed for two conditions, but a repeated-measures ANOVA showed a nonsignificant main effect of iTBS (p = .826). These results indicate that the current iTBS protocol is a promising way to improve WM capability based on the neural indicator (CDA) but further optimization is needed to produce a behavioral effect.

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.

The role of repetitive transcranial magnetic stimulation (rTMS) in the treatment of behavioral addictions: Two case reports and review of the literature.

BACKGROUND: Several behaviors, besides consumption of psychoactive substances, produce short-term reward that may lead to persistent aberrant behavior despite adverse consequences. Growing evidence suggests that these behaviors warrant consideration as nonsubstance or "behavioral" addictions, such as pathological gambling, internet gaming disorder and internet addiction. CASE PRESENTATION: Here, we report two cases of behavioral addictions (BA), compulsive sexual behavior disorder for online porn use and internet gaming disorder. A 57-years-old male referred a loss of control over his online pornography use, started 15 years before, while a 21-years-old male university student reported an excessive online gaming activity undermining his academic productivity and social life. Both patients underwent a high-frequency repetitive transcranial magnetic stimulation (rTMS) protocol over the left dorsolateral prefrontal cortex (l-DLPFC) in a multidisciplinary therapeutic setting. A decrease of addictive symptoms and an improvement of executive control were observed in both cases. DISCUSSION: Starting from these clinical observations, we provide a systematic review of the literature suggesting that BAs share similar neurobiological mechanisms to those underlying substance use disorders (SUD). Moreover, we discuss whether neurocircuit-based interventions, such as rTMS, might represent a potential effective treatment for BAs.

The Impact of COVID-19 on Brain Stimulation Therapy.

Among the far-reaching effects of the COVID-19 pandemic has been restricted access to safe and effective forms of psychiatric treatment. Focusing on electroconvulsive therapy and transcranial magnetic stimulation, we review the pandemic's impact on brain stimulation therapy by asking 3 fundamental questions-Where have we been? How are we doing? And where are we going?

Two rTMS sessions per week: a practical approach for treating major depressive disorder.

INTRODUCTION: Depression is one of the leading causes of disability in the world, and a disease that contributes greatly to the global burden of disease. Repetitive transcranial magnetic stimulation (rTMS) has proven to be a well-tolerated, effective treatment for depression. The present study was designed to evaluate the efficacy of an rTMS treatment scheme with a fewer number of sessions per week. METHODS: In total 91 adult university students with major depressive disorder (MDD). This was a double-blind, randomized clinical trial in which 15 sessions of rTMS were given to each one of two treatment groups made up of adults with active MDD. One treatment group received two sessions per week, the other received five. The study protocol included their respective sham rTMS groups. The patients who received active rTMS also participated in a follow-up procedure that consisted of two sessions of active rTMS per month for three more months. RESULTS: Measurements by the Hamilton Rating Scale for Depression (HAMD) showed that the groups which received active rTMS had higher percentages of antidepressant response at 96 and 95.5% for five and two sessions/week, respectively, compared to the sham rTMS groups: 27.3 and 4.5% for five and two sessions/week, respectively. Observations at the end of the 3-month follow-up phase showed that the improvements in HAMD scores were maintained in both groups. CONCLUSION: This study contributes to demonstrating that rTMS with a more practical schedule of two sessions/week is an effective antidepressant treatment that could be considered the first choice for managing symptoms of depression.