Publications by authors named "Felipe Fregni"

520 Publications

Publisher Correction: The mapping of cortical activation by near-infrared spectroscopy might be a biomarker related to the severity of fibromyalgia symptoms.

Sci Rep 2021 Oct 22;11(1):21257. Epub 2021 Oct 22.

Post‑Graduation Program in Medical Sciences, School of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.

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http://dx.doi.org/10.1038/s41598-021-99824-6DOI Listing
October 2021

Electroencephalography Signatures for Conditioned Pain Modulation and Pain Perception in Non-Specific Chronic Low Back Pain-an Exploratory Study.

Pain Med 2021 Oct 11. Epub 2021 Oct 11.

Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Charlestown, MA, USA.

: Conditioned pain modulation (CPM) can discriminate between healthy and chronic pain patients. However, its relationship with neurophysiological pain mechanisms is poorly understood. Brain oscillations measured by electroencephalography (EEG) might help gain insight into this complex relationship.

Objective: To investigate the relationship between CPM response and self-reported pain intensity in non-specific chronic low back pain (NSCLBP) and explore respective EEG signatures associated to these mechanisms.

Design: Cross-sectional analysis. Participants: Thirty NSCLBP patients participated.

Methods: Self-reported low back pain, questionnaires, mood scales, CPM (static and dynamic quantitative sensory tests), and resting surface EEG data were collected and analyzed. Linear regression models were used for statistical analysis.

Results: CPM was not significantly correlated with self-reported pain intensity scores. Relative power of EEG in the beta and high beta bands as recorded from the frontal, central, and parietal cortical areas were significantly associated with CPM. EEG relative power at delta and theta bands as recorded from the central area were significantly correlated with self-reported pain intensity scores while controlling for self-reported depression.

Conclusions: Faster EEG frequencies recorded from pain perception areas may provide a signature of a potential cortical compensation caused by chronic pain states. Slower EEG frequencies may have a critical role in abnormal pain processing.
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http://dx.doi.org/10.1093/pm/pnab293DOI Listing
October 2021

Transcranial direct current stimulation combined with robotic training in incomplete spinal cord injury: a randomized, sham-controlled clinical trial.

Spinal Cord Ser Cases 2021 Sep 27;7(1):87. Epub 2021 Sep 27.

Neuromodulation Center, Spaulding Rehabilitation Hospital, Harvard Medical School, Boston, MA, USA.

Study Design: A randomized, sham-controlled clinical trial.

Objective: To test the effects of tDCS, combined with robotic training, on gait disability in SCI. Our hypothesis was that participants who received active tDCS would experience greater walking gains, as indexed by the WISCI-II, than those who received sham tDCS.

Setting: University of São Paulo, Brazil.

Methods: This randomized, double-blind study comprised 43 participants with incomplete SCI who underwent 30 sessions of active (n = 21) or sham (n = 22) tDCS (20 min, 2 mA) before every Lokomat session of 30 min (3 times a week over 12 weeks or 5 times a week over 6 weeks). The main outcome was the improvement in WISCI-II. Participants were assessed at baseline, after 15 and 30 sessions of Lokomat, and after three months of treatment.

Results: There was a significant difference in the percentage of participants that improved in WISCI-II at the 30-session, compared with baseline: 33.3% in the sham group and 70.0% in the active group (p = 0.046; OR: 3.7; 95% CI: 1.0-13.5). At the follow-up, the improvement compared with baseline in the sham group was 35.0% vs. 68.4% for the active group (p = 0.046; OR: 3.7; 95% CI: 1.0-13.5). There was no significant difference at the 15-session.

Conclusion: Thirty sessions of active tDCS is associated with a significant improvement in walking, compared to sham. Moreover, 15 sessions had no significant effect. The improvement in WISCI-II can be related to different aspects of motor learning, including motor recovery and compensation.
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http://dx.doi.org/10.1038/s41394-021-00448-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8476486PMC
September 2021

Addressing the critical role of gender identity and sex in the planning, analysis, and conduct of clinical trials.

Princ Pract Clin Res 2021 Jul 25;7(2):59-62. Epub 2021 Aug 25.

-Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard Medical School, 96-13th Street, Charlestown, Boston, MA, USA.

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http://dx.doi.org/10.21801/ppcrj.2021.72.7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8443128PMC
July 2021

Central Post-Stroke Pain: An Integrative Review of Somatotopic Damage, Clinical Symptoms, and Neurophysiological Measures.

Front Neurol 2021 18;12:678198. Epub 2021 Aug 18.

Graduate Program in Medical Sciences, School of Medicine, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.

The physiopathology of central post-stroke pain (CPSP) is poorly understood, which may contribute to the limitations of diagnostic and therapeutic advancements. Thus, the current systematic review was conducted to examine, from an integrated perspective, the cortical neurophysiological changes observed transcranial magnetic stimulation (TMS), focusing on the structural damage, and clinical symptoms in patients with CPSP. The literature review included the databases EMBASE, PubMed, and ScienceDirect using the following search terms by MeSH or Entree descriptors: [("Cerebral Stroke") AND ("Pain" OR "Transcranial Magnetic Stimulation") AND ("Transcranial Magnetic Stimulation")] (through September 29, 2020). A total of 297 articles related to CPSP were identified. Of these, only four quantitatively recorded cortical measurements. We found four studies with different methodologies and results of the TMS measures. According to the National Institutes of Health (NIH) guidelines, two studies had low methodological quality and the other two studies had satisfactory methodological quality. The four studies compared the motor threshold (MT) of the stroke-affected hemisphere with the unaffected hemisphere or with healthy controls. Two studies assessed other cortical excitability measures, such as cortical silent period (CSP), short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF). The main limitations in the interpretation of the results were the heterogeneity in parameter measurements, unknown cortical excitability measures as potential prognostic markers, the lack of a control group without pain, and the absence of consistent and validated diagnosis criteria. Despite the limited number of studies that prevented us from conducting a meta-analysis, the dataset of this systematic review provides evidence to improve the understanding of CPSP physiopathology. Additionally, these studies support the construction of a framework for diagnosis and will help improve the methodological quality of future research in somatosensory sequelae following stroke. Furthermore, they offer a way to integrate dysfunctional neuroplasticity markers that are indirectly assessed by neurophysiological measures with their correlated clinical symptoms.
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http://dx.doi.org/10.3389/fneur.2021.678198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416310PMC
August 2021

Deficit of Inhibition as a Marker of Neuroplasticity (DEFINE Study) in Rehabilitation: A Longitudinal Cohort Study Protocol.

Front Neurol 2021 9;12:695406. Epub 2021 Aug 9.

Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation Hospital, Boston, MA, United States.

Brain plasticity is an intrinsic property of the nervous system, which is modified during its lifetime. This is one mechanism of recuperation after injuries with an important role in rehabilitation. Evidence suggests that injuries in the nervous system disturb the stability between inhibition and excitability essential for the recuperation process of neuroplasticity. However, the mechanisms involved in this balance are not completely understood and, besides the advancement in the field, the knowledge has had a low impact on the rehabilitation practice. Therefore, the understanding of the relationship between biomarkers and functional disability may help to optimize and individualize treatments and build consistent studies in the future. This cohort study, the deficit of inhibition as a marker of neuroplasticity study, will follow four groups (stroke, spinal cord injury, limb amputation, and osteoarthritis) to understand the neuroplasticity mechanisms involved in motor rehabilitation. We will recruit 500 subjects (including 100 age- and sex-matched controls). A battery of neurophysiological assessments, transcranial magnetic stimulation, electroencephalography, functional near-infrared spectroscopy, and magnetic resonance imaging, is going to be used to assess plasticity on the motor cortex before and after rehabilitation. One of the main hypotheses in this cohort is that the level of intracortical inhibition is related to functional deficits. We expect to develop a better understanding of the neuroplasticity mechanisms involved in the rehabilitation, and we expect to build neurophysiological "transdiagnostic" biomarkers, especially the markers of inhibition, which will have great relevance in the scientific and therapeutic improvement in rehabilitation. The relationship between neurophysiological and clinical outcomes will be analyzed using linear and logistic regression models. By evaluating the reliability of electroencephalography, functional near-infrared spectroscopy, transcranial magnetic stimulation, and magnetic resonance imaging measures as possible biomarkers for neurologic rehabilitation in different neurologic disorders, this study will aid in the understanding of brain plasticity mechanisms in rehabilitation, allowing more effective approaches and screening methods to take place.
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http://dx.doi.org/10.3389/fneur.2021.695406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380986PMC
August 2021

Robot-Assisted Therapy and Constraint-Induced Movement Therapy for Motor Recovery in Stroke: Results From a Randomized Clinical Trial.

Front Neurorobot 2021 21;15:684019. Epub 2021 Jul 21.

Physiatry, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil.

Stroke is one of the leading causes of adult disability, and up to 80% of stroke survivors undergo upper extremity motor dysfunction. Constraint-Induced Movement Therapy (CIMT) and Robot-Assisted Therapy (RT) are used for upper limb stroke rehabilitation. Although CIMT and RT are different techniques, both are beneficial; however, their results must be compared. The objective is to establish the difference between RT and CIMT after a rehabilitation program for chronic stroke patients. This is a randomized clinical trial, registered at ClinicalTrials.gov (ID number NCT02700061), in which patients with stroke received sessions of RT or CIMT protocol, combined with a conventional rehabilitation program for 12 weeks. The primary outcome was measured by Wolf Motor Function Test (WMFT) and Fugl-Meyer Assessment-Upper Limb (FMA-UL). Activities of daily living were also assessed. Fifty one patients with mild to moderate upper limb impairment were enrolled in this trial, 25 women and 26 men, mean age of 60,02 years old (SD 14,48), with 6 to 36 months after stroke onset. Function significantly improved regardless of the treatment group. However, no statistical difference was found between both groups as -values of the median change of function measured by WMFT and FMA were 0.293 and 0.187, respectively. This study showed that Robotic Therapy (RT) was not different from Constraint-Induced Movement Therapy (CIMT) regardless of the analyzed variables. There was an overall upper limb function, motor recovery, functionality, and activities of daily living improvement regardless of the interventions. At last, the combination of both techniques should be considered in future studies.
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http://dx.doi.org/10.3389/fnbot.2021.684019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8335542PMC
July 2021

Repetitive Transcranial Magnetic Stimulation (rTMS) Reverses the Long-term Memory Impairment and the Decrease of Hippocampal Interleukin-10 Levels, both Induced by Neuropathic Pain in Rats.

Neuroscience 2021 09 3;472:51-59. Epub 2021 Aug 3.

Programa de Pós-Graduação em Ciências Biológicas: Farmacologia e Terapêutica - Instituto de Ciências Básicas da Saúde - Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil; Laboratório de Farmacologia da Dor e Neuromodulação: Investigações Pré-Clínicas - Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil; Programa de Pós-Graduação em Medicina: Ciências Médicas - Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil. Electronic address:

Neuropathic pain (NP) is characterized by the presence of spontaneous pain, allodynia and hyperalgesia. Repetitive transcranial magnetic stimulation (rTMS) is one of neuromodulatory techniques that induces satisfactory NP relief, including that from refractory pain patients. The objective of this study was to evaluate rTMS treatment over long term memory (LTM) and hippocampal BDNF and IL-10 levels in rats submitted to a NP model. A total of 81 adult (60-days old) male Wistar rats were randomly allocated to one of the following 9 experimental groups: control, control + sham rTMS, control + rTMS, sham neuropathic pain, sham neuropathic pain + sham rTMS, sham neuropathic pain + rTMS, neuropathic pain (NP), neuropathic pain + sham rTMS and neuropathic pain + rTMS. Fourteen days after the surgery for chronic constriction injury (CCI) of the sciatic nerve, NP establishment was accomplished. Then, rats were treated with daily 5-minute sessions of rTMS for eight consecutive days. LTM was assessed by the object recognition test (ORT) twenty-four hours after the end of rTMS treatment. Biochemical assays (BDNF and IL-10 levels) were performed in hippocampus tissue homogenates. rTMS treatment reversed the reduction of the discrimination index in the ORT and the hippocampal IL-10 levels in NP rats. This result shows that rTMS reverses the impairment LTM and the increase in the hippocampal IL-10 levels, both induced by NP. Moreover, it appears to be a safe non-pharmacological therapeutic tool since it did not alter LTM and neurochemical parameters in naive animals.
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http://dx.doi.org/10.1016/j.neuroscience.2021.07.030DOI Listing
September 2021

The mapping of cortical activation by near-infrared spectroscopy might be a biomarker related to the severity of fibromyalgia symptoms.

Sci Rep 2021 08 3;11(1):15754. Epub 2021 Aug 3.

Post-Graduation Program in Medical Sciences, School of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.

The delta value of oxyhemoglobin (Δ-HbO) determined by functional near-infrared spectroscopy at prefrontal cortex (PFC) and motor cortex (MC) based on primary (25 °C) and secondary (5 °C) thermal stimuli presented a larger peak latency at left MC in fibromyalgia than in controls. The difference between HbO concentration 15 s after the thermal stimuli ending and HbO concentration before the thermal stimuli onset (Δ-HbO*) at left PFC increased 47.82% in fibromyalgia and 76.66% in controls. This value had satisfactory discriminatory properties to differentiate cortical activation in fibromyalgia versus controls. A receiver operator characteristics (ROC) analysis showed the Δ-HbO* cutoffs of - 0.175 at left PFC and - 0.205 at right PFC offer sensitivity and specificity of at least 80% in screening fibromyalgia from controls. In fibromyalgia, a ROC analysis showed that these cutoffs could discriminate those with higher disability due to pain and more severe central sensitization symptoms (CSS). The ROC with the best discriminatory profile was the CSS score with the Δ-HbO* at left PFC (area under the curve = 0.82, 95% confidence interval = 0.61-100). These results indicate that cortical activation based on Δ-HbO* at left PFC might be a sensitive marker to identify fibromyalgia subjects with more severe clinical symptoms.
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http://dx.doi.org/10.1038/s41598-021-94456-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8333354PMC
August 2021

Barriers and facilitators for clinical trial participation of underrepresented and non-underrepresented fibromyalgia patients: A cross-sectional internet survey.

Heliyon 2021 Jul 5;7(7):e07475. Epub 2021 Jul 5.

Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Background: There is a need of well-powered randomized clinical trials in fibromyalgia. However, challenges for recruitment are presented. This study aims to describe and assess the perception of barriers and facilitators and the associated factors for the participation of underrepresented and non-underrepresented fibromyalgia patients.

Methods: We performed an online survey through REDCap (Research Electronic Data Capture) targeting fibromyalgia patients from April 7 to July 3, 2020 during the COVID-19 stay home mandate and it was restricted to the United States of America. We described and compared the survey characteristics between underrepresented and non-underrepresented participants, and we performed logistic regression models to assess the associated factors with clinical trial participation.

Results: In total, 481 completed the survey including 168 underrepresented fibromyalgia patients. Only (1) 11.09 % reported previous participation in clinical trials and the significant perceived barriers were investigator-related (lack of friendliness of research staff and the opportunity to receive the results) and center-related (privacy and confidentiality policies, and the institution's reputation); (2) the participation rate and perceived barriers and facilitators were similar between underrepresented and non-underrepresented patients; and was positively associated with low income, higher age, and clinical trial awareness from their physician; and negatively associated with the perception of investigator-related barriers; and (4) for the underrepresented population, the presence of emotional support.

Conclusion: Our findings suggest low rates of participation, regardless of underrepresented population status. Strategies as involving their physician as liaison to increase the awareness of clinical trials, as well as improving patient-researcher communication should be considered in this population.
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http://dx.doi.org/10.1016/j.heliyon.2021.e07475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278426PMC
July 2021

Neuroplasticity and non-invasive brain stimulation in the developing brain.

Prog Brain Res 2021 3;264:57-89. Epub 2021 Jun 3.

Department of Neuroscience and Mental Health, Faculdade de Medicina da Bahia, Universidade Federal da Bahia, Salvador, Brazil.

The brain is a dynamic organ whose growth and organization varies according to each subject's life experiences. Through adaptations in gene expression and the release of neurotrophins and neurotransmitters, these experiences induce a process of cellular realignment and neural network reorganization, which consolidate what is called neuroplasticity. However, despite the brain's resilience and dynamism, neuroplasticity is maximized during the first years of life, when the developing brain is more sensitive to structural reorganization and the repair of damaged neurons. This review presents an overview of non-invasive brain stimulation (NIBS) techniques that have increasingly been a focus for experimental research and the development of therapeutic methods involving neuroplasticity, especially Transcranial Magnetic Stimulation (TMS) and Transcranial Direct Current Stimulation (tDCS). Due to its safety risk profile and extensive tolerability, several trials have demonstrated the benefits of NIBS as a feasible experimental alternative for the treatment of brain and mind disorders in children and adolescents. However, little is known about the late impact of neuroplasticity-inducing tools on the developing brain, and there are concerns about aberrant plasticity. There are also ethical considerations when performing interventions in the pediatric population. This article will therefore review these aspects and also obstacles related to the premature application of NIBS, given the limited evidence available concerning the extent to which these methods interfere with the developing brain.
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http://dx.doi.org/10.1016/bs.pbr.2021.04.003DOI Listing
June 2021

Bimodal transcranial direct current stimulation reduces alcohol consumption and induces long-term neurochemical changes in rats with neuropathic pain.

Neurosci Lett 2021 08 7;759:136014. Epub 2021 Jun 7.

Laboratory of Pain Pharmacology and Neuromodulation: Preclinical Investigations - Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil; Postgraduate Program in Medical Sciences, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Postgraduate Program in Biological Sciences: Pharmacology and Therapeutics, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Laboratoryof Neuromodulation, Department of Physical Medicine & Rehabilitation, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard University, Boston, MA, USA. Electronic address:

This study aimed to evaluate the effects of repeated bimodal transcranial direct current stimulation (tDCS) on alcohol consumption and immunohistological and neurochemical parameters in nerve-injured rats. Forty-eight adult male Wistar rats were distributed into six groups: control, neuropathic pain (NP) + sham-tDCS, NP + alcohol + sham-tDCS, alcohol + sham-tDCS, alcohol + tDCS, and NP + alcohol + tDCS. NP is induced by chronic sciatic nerve constriction (CCI). The rats were exposed to a 10% alcohol solution by voluntary consumption for 14 days. From the 16th day after surgery, bimodal tDCS was applied for 20 min/day for 8 days. Brain structures were collected to evaluate the number of neuropeptide Y (NPY)-positive neurons, neurites, and argyrophilic grains by immunohistochemistry, and brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), interleukin (IL)-6, and IL-10 by ELISA. Nerve-injured rats showed a progressive increase in alcohol consumption compared to the non-injured rats. In addition, there was a reduction in voluntary alcohol consumption over time induced by tDCS. Alcohol exposure, chronic pain, and tDCS treatment modulated the central NPY immunoreactivity. tDCS increased the cerebellar levels of IL-6 and IL-10, and CCI and/or tDCS reduced striatal BDNF levels. The current data suggest that tDCS could be a promising non-pharmacological adjuvant to treat patients with chronic pain who use alcohol to relieve their symptoms.
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http://dx.doi.org/10.1016/j.neulet.2021.136014DOI Listing
August 2021

Effects of Combined and Alone Transcranial Motor Cortex Stimulation and Mirror Therapy in Phantom Limb Pain: A Randomized Factorial Trial.

Neurorehabil Neural Repair 2021 Aug 1;35(8):704-716. Epub 2021 Jun 1.

Spaulding Rehabilitation Hospital, Harvard Medical School, Boston, MA, USA.

Phantom limb pain (PLP) is a frequent complication in amputees, which is often refractory to treatments. We aim to assess in a factorial trial the effects of transcranial direct current stimulation (tDCS) and mirror therapy (MT) in patients with traumatic lower limb amputation; and whether the motor cortex plasticity changes drive these results. In this large randomized, blinded, 2-site, sham-controlled, 2 × 2 factorial trial, 112 participants with traumatic lower limb amputation were randomized into treatment groups. The interventions were active or covered MT for 4 weeks (20 sessions, 15 minutes each) combined with 2 weeks of either active or sham tDCS (10 sessions, 20 minutes each) applied to the contralateral primary motor cortex. The primary outcome was PLP changes on the visual analogue scale at the end of interventions (4 weeks). Motor cortex excitability and cortical mapping were assessed by transcranial magnetic stimulation (TMS). We found no interaction between tDCS and MT groups ( = 1.90, = .13). In the adjusted models, there was a main effect of active tDCS compared to sham tDCS (beta coefficient = -0.99, = .04) on phantom pain. The overall effect size was 1.19 (95% confidence interval: 0.90, 1.47). No changes in depression and anxiety were found. TDCS intervention was associated with increased intracortical inhibition (coefficient = 0.96, = .02) and facilitation (coefficient = 2.03, = .03) as well as a posterolateral shift of the center of gravity in the affected hemisphere. MT induced no motor cortex plasticity changes assessed by TMS. These findings indicate that transcranial motor cortex stimulation might be an affordable and beneficial PLP treatment modality.
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http://dx.doi.org/10.1177/15459683211017509DOI Listing
August 2021

Mapping of predictors of the disengagement of the descending inhibitory pain modulation system in fibromyalgia: an exploratory study.

Br J Pain 2021 May 30;15(2):221-233. Epub 2020 May 30.

Graduate Program in Medical Science, School of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.

Background: The main symptoms of fibromyalgia comprise diffuse pain, disability, depressive symptoms, catastrophizing, sleep disruption and fatigue, associated with dysfunction of the descending pain-modulating system (DPMS).

Objectives: We aimed to identify patterns of main symptoms of fibromyalgia and neuroplasticity biomarkers (i.e. brain-derived neurotrophic factor (BDNF) and S100B protein) in non-responders to the conditioned pain modulation task (CPM-task) induced by immersion of hand in cold water (0-1°C). Furthermore, we evaluated if these patterns predict responsiveness to CPM-task.

Methods: This cross-sectional study included 117 women with fibromyalgia (( = 60) non-responders and ( = 57) responders), with age ranging from 30 to 65 years old. We analysed changes in numerical pain scale (NPS-10) during the CPM-task using a standardized protocol.

Results: A hierarchical multivariate logistic regression analysis was used to construct a propensity score-adjusted index to identify non-responders compared to responders to CPM-task. The following variables were retained in the models: analgesic use four or more times per week, heat pain threshold (HPT), poor sleep quality, pain catastrophizing, serum levels of BDNF, number of psychiatric diagnoses and the impact of symptoms of fibromyalgia on quality of life. Receiver operator characteristics (ROC) analysis showed non-responders can be discriminated from responders by a composite index of more frequent symptoms of fibromyalgia and neuroplasticity markers (area under the curve (AUC) = 0.83, sensitivity = 100% and specificity = 98%).

Conclusion: Patterns of fibromyalgia symptoms and neuroplasticity markers may be helpful to predict responsiveness to the CPM-task which might help personalize treatment and thereby contribute to the care of patients with fibromyalgia.
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http://dx.doi.org/10.1177/2049463720920760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138619PMC
May 2021

Specific Electroencephalographic Signatures for Pain and Descending Pain Inhibitory System in Spinal Cord Injury.

Pain Med 2021 May 5. Epub 2021 May 5.

Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Objectives: The pain related to Spinal Cord Injury (SCI) is difficult to treat and it is associated with significant morbidity. One aspect to improve therapeutics is to explore markers of pain and its correlates in SCI.

Methods: In this cross-sectional neurophysiological analysis of a randomized, double-blind controlled trial, thirty-nine patients with SCI were included. We analyzed conditioned pain modulation (CPM) efficiency as the index of the descending pain inhibitory system, EEG variables, and clinical pain levels as measured by the Visual Analogue Scale. Regression analyses were performed to assess the relationship among EEG variables, pain levels, and CPM.

Results: We included 39 SCI patients, 74% reported SCI-related pain. We found that (1)less alpha and beta power are related to pain presence, (2)less alpha and beta power are associated with higher pain levels among patients with pain, (3)patients with pain have decreased peak alpha-theta frequency compared to no-pain group, (4)more relative theta power are related to the presence of low CPM efficiency, (5)higher relative theta power is associated with lower CPM efficiency.

Conclusions: Our results confirm and provide additional data on the relationship between decreased alpha and beta frequencies and higher pain levels. One important finding, though, was a specific and different EEG signature for the descending inhibitory pain system, as we showed that increased theta EEG power is related to decreased CPM efficiency; suggesting that, although low CPM efficiency plays a major role in pain in these participants, it does seem to be associated with a specific oscillatory brain rhythm different from clinical pain. These findings have significant implications for future research on EEG-based biomarkers of pain in post-SCI and new interventions as neurofeedback to manage pain in this population.
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http://dx.doi.org/10.1093/pm/pnab124DOI Listing
May 2021

Electroencephalography as a Biomarker for Functional Recovery in Spinal Cord Injury Patients.

Front Hum Neurosci 2021 9;15:548558. Epub 2021 Apr 9.

Neuromodulation Center, Spaulding Rehabilitation Hospital, Harvard Medical School, Boston, MA, United States.

Background: Functional changes after spinal cord injury (SCI) are related to changes in cortical plasticity. These changes can be measured with electroencephalography (EEG) and has potential to be used as a clinical biomarker.

Method: In this longitudinal study participants underwent a total of 30 sessions of robotic-assisted gait training (RAGT) over a course of 6 weeks. The duration of each session was 30 min. Resting state EEG was recorded before and after 30-session rehabilitation therapy. To measure gait, we used the Walking Index for Spinal Cord Injury Scale, 10-Meter- Walking Test, Timed-Up-and-Go, and 6-Min-Walking Test. Balance was measured using Berg Balance Scale.

Results: Fifteen participants with incomplete SCI who had AIS C or D injuries based on American Spinal Cord Injury Association Impairment Scale classification were included in this study. Mean age was 35.7 years (range 17-51) and the mean time since injury was 17.08 (range 4-37) months. All participants showed clinical improvement with the rehabilitation program. EEG data revealed that high beta EEG activity in the central area had a negative correlation with gait ( = 0.049; β coefficient: -0.351; and adj- : 0.23) and balance ( = 0.043; β coefficient: -0.158; and adj- :0.24) measured at baseline, in a way that greater high beta EEG power was related to worse clinical function at baseline. Moreover, improvement in gait and balance had negative correlations with the change in alpha/theta ratio in the parietal area (Gait: = 0.049; β coefficient: -0.351; adj- : 0.23; Balance: = 0.043; β coefficient: -0.158; and adj- : 0.24).

Conclusion: In SCI, functional impairment and subsequent improvement following rehabilitation therapy with RAGT correlated with the change in cortical activity measured by EEG. Our results suggest that EEG alpha/theta ratio may be a potential surrogate marker of functional improvement during rehabilitation. Future studies are necessary to improve and validate these findings as a neurophysiological biomarker for SCI rehabilitation.
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http://dx.doi.org/10.3389/fnhum.2021.548558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062968PMC
April 2021

The effects of direct current stimulation and random noise stimulation on attention networks.

Sci Rep 2021 03 18;11(1):6201. Epub 2021 Mar 18.

I2P-Portucalense Institute for Psychology, Portucalense University, Porto, Portugal.

Attention is a complex cognitive process that selects specific stimuli for further processing. Previous research suggested the existence of three attentional networks: alerting, orienting and executive. However, one important topic is how to enhance the efficiency of attentional networks. In this context, understanding how this system behaves under two different modulatory conditions, namely transcranial direct current stimulation (tDCS) and transcranial Random Noise Stimulation (tRNS), will provide important insights towards the understanding of the attention network system. Twenty-seven healthy students took part on a randomized single-blinded crossover study, testing the effects that involved three modalities of unilateral stimulation (tRNS, anodal tDCS, and sham) over the DLPFC, during the performance of the attention network test (ANT) in three different conditions: standard, speed and accuracy. Results showed that tRNS was able to increase attention during more complex situations, namely by increasing alerting and decreasing conflict effect in the executive network. Under the Speed condition, tRNS increased efficiency of the alerting network, as well as under the more demanding conflict network, tRNS overall increased the performance when comparing to sham. No statistical significant effects of tDCS were observed. These results are compatible with the attention requiring the synchronization of pre-existing networks, rather the reinforcement or creation of new pathways.
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http://dx.doi.org/10.1038/s41598-021-85749-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973424PMC
March 2021

rTMS induces analgesia and modulates neuroinflammation and neuroplasticity in neuropathic pain model rats.

Brain Res 2021 07 15;1762:147427. Epub 2021 Mar 15.

Programa de Pós-Graduação em Ciências Biológicas: Farmacologia e Terapêutica - Instituto de Ciências Básicas da Saúde - Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil; Laboratório de Farmacologia da Dor e Neuromodulação: Investigações Pré-clínicas - Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil; Programa de Pós-Graduação em Medicina: Ciências Médicas - Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil. Electronic address:

Neuropathic pain (NP) is related to the presence of hyperalgesia, allodynia, and spontaneous pain, affecting 7%-10% of the general population. Repetitive transcranial magnetic stimulation (rTMS) is applied for NP relief, especially in patients with refractory pain. As NP response to existing treatments is often insufficient, we aimed to evaluate rTMS treatment on the nociceptive response of rats submitted to an NP model and its effect on pro-and anti-neuroinflammatory cytokine and neurotrophin levels. A total of 106 adult male Wistar rats (60 days old) were divided into nine experimental groups: control, control + sham rTMS, control + rTMS, sham NP, sham neuropathic pain + sham rTMS, sham neuropathic pain + rTMS, NP, neuropathic pain + sham rTMS, and neuropathic pain + rTMS. NP establishment was achieved 14 days after the surgery to establish chronic constriction injury (CCI) of the sciatic nerve. Rats were treated with 5 min daily sessions of rTMS for eight consecutive days. Nociceptive behavior was assessed using von Frey and hot plate tests at baseline, after NP establishment, and post-treatment. Biochemical assays to assess the levels of brain-derived neurotrophic factor (BDNF), tumor necrosis factor-alpha (TNF-α), and interleukin (IL)-10, were performed in the prefrontal cortex (PFC) and spinal cord tissue homogenates. rTMS treatment promoted a partial reversal of mechanical allodynia and total reversal of thermal hyperalgesia induced by CCI. Moreover, rTMS increased the levels of BDNF, TNF-α, and IL-10 in the PFC. rTMS may be a promising tool for the treatment of NP. The alterations induced by rTMS on neurochemical parameters may have contributed to the analgesic effect presented.
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http://dx.doi.org/10.1016/j.brainres.2021.147427DOI Listing
July 2021

IMPORTANCE trial: a provisional study-design of a single-center, phase II, double-blinded, placebo-controlled, randomized, 4-week study to compare the efficacy and safety of intranasal esketamine in chronic opioid refractory pain.

F1000Res 2021 22;10:42. Epub 2021 Jan 22.

PPCR Program, ECPE, Harvard T.H. Chan School of Public Health, Boston, USA.

 Cancer is the second leading cause of death globally. Up to 86% of advanced cancer patients experience significant pain, while 10-20% live in chronic pain. Besides, increasing prescription of opioids resulted in 33,000 deaths in the US in 2015. Both reduce patients' functional status and quality of life. While cancer survival rates are increasing, therapeutic options for chronic opioid refractory pain are still limited. Esketamine is the s-enantiomer of ketamine, with superior analgesic effect and less psychotomimetic side effects. Intranasal esketamine was approved by the FDA for treatment-resistant depression. However, its use in chronic cancer pain has never been tested. Therefore, we propose a phase II, randomized, placebo-controlled trial to evaluate the efficacy and safety of intranasal esketamine in chronic opioid refractory cancer pain. We will recruit 120 subjects with chronic opioid refractory pain, defined as pain lasting more than 3 months despite optimal therapy with high dose opioids (>60 mg morphine equivalent dose/day) and optimal adjuvant therapy. Subjects will be randomized into two groups: intranasal esketamine (56mg) and placebo. Treatment will be administered twice a week for four consecutive weeks. The primary outcome is defined as reduction in the Numeric Pain Rating Scale (NPRS) after first application. Secondary outcomes include NPRS reduction after four weeks, the number of daily morphine rescue doses, functional status and satisfaction, and depression. This study may extend therapeutic options in patients with chronic pain, thus improving their quality of life and reducing opioid use. Clinical Trials.gov, NCT04666623. Registered on 14 December 2020.
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http://dx.doi.org/10.12688/f1000research.27809.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885290PMC
June 2021

Motor cortex transcranial direct current stimulation effects on knee osteoarthritis pain in elderly subjects with dysfunctional descending pain inhibitory system: A randomized controlled trial.

Brain Stimul 2021 May-Jun;14(3):477-487. Epub 2021 Mar 5.

Department of Evidence-Based Medicine, Brazilian Cochrane Centre, Federal University of São Paulo, São Paulo, SP, Brazil; Department of Rheumatology, Santo Amaro University, São Paulo, SP, Brazil. Electronic address:

Background: Although evidence has indicated a positive effect of transcranial direct current stimulation (tDCS) on reducing pain, few studies have focused on the elderly population with knee osteoarthritis (KOA).

Objective: To evaluate whether tDCS reduces KOA pain in elderly individuals with a dysfunctional descending pain inhibitory system (DPIS).

Methods: In a double-blind trial, individuals ≥ 60 years with KOA pain and a dysfunctional DPIS, we randomly assigned patients to receive 15 daily sessions of 2 mA tDCS over the primary motor cortex (anode) and contralateral supraorbital area (cathode) (M1-SO) for 20 min or sham tDCS. Change in pain perception indexed by the Brief Pain Inventory (BPI) at the end of intervention was the primary outcome. Secondary outcomes included: disability, quantitative sensory testing, pain pressure threshold and conditioned pain modulation (CPM). Subjects were followed-up for 2 months.

Results: Of the 104 enrolled subjects, with mean (SD) age of 73.9 (8.01) years and 88 (84.6%) female, 102 finished the trial. In the intention-to-treat analysis, the active tDCS group had a significantly greater reduction in BPI compared to the sham group (difference, 1.59; 95% CI, 0.95 to 2.23; P < 0.001; Cohen's d, 0.58); and, also a significantly greater improvement in CPM-pressure in the knee (P = 0.01) and CPM-pain in the hand (P = 0.01). These effects were not sustained at follow-up. The intervention was well tolerated, with no severe adverse effects.

Conclusion: M1-SO tDCS is associated with a moderate effect size in reducing pain in elderly patients with KOA after 15 daily sessions of stimulation. This intervention has also shown to modulate the DPIS.
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http://dx.doi.org/10.1016/j.brs.2021.02.018DOI Listing
March 2021

Understanding intracortical excitability in phantom limb pain: A multivariate analysis from a multicenter randomized clinical trial.

Neurophysiol Clin 2021 Mar 26;51(2):161-173. Epub 2021 Feb 26.

Neuromodulation and Clinical Research Learning Center, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Charlestown, MA, USA; Harvard Medical School, Boston, MA, USA; Harvard T. H. Chan School of Public Health, Boston, MA, USA.

Objectives: To explore associations of intracortical excitability with clinical characteristics in a large sample of subjects with phantom limb pain (PLP).

Methods: Ancillary study using baseline and longitudinal data from a large multicenter randomized trial that investigated the effects of non-invasive brain stimulation combined with sensorimotor training on PLP. Multivariate regression modeling analyses were used to investigate the association of intracortical excitability, measured by percentages of intracortical inhibition (ICI) and facilitation (ICF) with clinical variables.

Results: Ninety-eight subjects were included. Phantom sensation of itching was positively associated with ICI changes and at baseline in the affected hemisphere (contralateral to PLP). However, in the non-affected hemisphere (ipsilateral to PLP), the phantom sensation of warmth and PLP intensity were negatively associated with ICI (both models). For the ICF, PLP intensity (baseline model only) and age (longitudinal model) were negatively associated, while time since amputation and amputation level (both for longitudinal model only) were positively associated in the affected hemisphere. Additionally, use of antidepressants led to lower ICF in the non-affected hemisphere for the baseline model while higher amputation level also led to less changes in the ICF.

Conclusion: Results revealed clear associations of clinical variables and cortical excitability in a large chronic pain sample. ICI and ICF changes appear not to be mainly explained by PLP intensity. Instead, other variables associated with duration of neuroplasticity changes (such as age and duration of amputation) and compensatory mechanisms (such as itching and phantom limb sensation) seem to be more important in explaining these variables.
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http://dx.doi.org/10.1016/j.neucli.2020.12.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8402325PMC
March 2021

Reply to Moman and Hooten.

Pain 2021 03;162(3):986

Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Boston, MA, United States.

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http://dx.doi.org/10.1097/j.pain.0000000000002158DOI Listing
March 2021

tDCS and exercise improve anxiety-like behavior and locomotion in chronic pain rats via modulation of neurotrophins and inflammatory mediators.

Behav Brain Res 2021 04 9;404:113173. Epub 2021 Feb 9.

Laboratório de Farmacologia da Dor e Neuromodulação: Investigações Pré-Clínicas, Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre, 90035-007 Porto Alegre, Brazil; Programa de Pós-Graduação em Ciências Biológicas: Fisiologia, Instituto de Ciências Básicas da Saúde, (ICBS), Universidade Federal do Rio Grande do Sul (UFRGS), 90050-170 Porto Alegre, Brazil; Programa de Pós-Graduação em Medicina: Ciências Médicas, Universidade Federal do Rio Grande do Sul, 90035-003 Porto Alegre, Brazil; Programa de Pós-Graduação em Ciências Biológicas: Farmacologia e Terapêutica, Universidade Federal Rio Grande do Sul, 90050-170 Porto Alegre, Brazil. Electronic address:

Anxiety disorders cause distress and are commonly found to be comorbid with chronic pain. Both are difficult-to-treat conditions for which alternative treatment options are being pursued. This study aimed to evaluate the effects of transcranial direct current stimulation (tDCS), treadmill exercise, or both, on anxiety-like behavior and associated growth factors and inflammatory markers in the hippocampus and sciatic nerve of rats with neuropathic pain. Male Wistar rats (n = 216) were subjected to sham-surgery or sciatic nerve constriction for pain induction. Fourteen days following neuropathic pain establishment, either bimodal tDCS, treadmill exercise, or a combination of both was used for 20 min a day for 8 consecutive days. The elevated plus-maze test was used to assess anxiety-like behavior and locomotor activity during the early (24 h) or late (7 days) phase after the end of treatment. BDNF, TNF-ɑ, and IL-10 levels in the hippocampus, and BDNF, NGF, and IL-10 levels in the sciatic nerve were assessed 48 h or 7 days after the end of treatment. Rats from the pain groups developed an anxiety-like state. Both tDCS and treadmill exercise provided ethological and neurochemical alterations induced by pain in the early and/or late phase, and a modest synergic effect between tDCS and exercise was observed. These results indicate that non-invasive neuromodulatory approaches can attenuate both anxiety-like status and locomotor activity and alter the biochemical profile in the hippocampus and sciatic nerve of rats with neuropathic pain and that combined interventions may be considered as a treatment option.
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http://dx.doi.org/10.1016/j.bbr.2021.113173DOI Listing
April 2021

Exercise-induced pain threshold modulation in healthy subjects: a systematic review and meta-analysis.

Princ Pract Clin Res 2020 Sep 16;6(3):11-28. Epub 2020 Sep 16.

Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Boston, USA.

Background: The use of exercise is a potential treatment option to modulate pain (exercise-induced hypoalgesia). The pain threshold (PT) response is a measure of pain sensitivity that may be a useful marker to assess the effect of physical exercise on pain modulation.

Aim: The aim of this systematic review and meta-analysis is to evaluate the PT response to exercise in healthy subjects.

Methods: We searched in MEDLINE, EMBASE, Web of Science, Lilacs, and Scopus using a search strategy with the following search terms: "exercise" OR "physical activity" AND "Pain Threshold" from inception to December 2nd, 2019. As criteria for inclusion of appropriate studies: randomized controlled trials or quasi-experimental studies that enrolled healthy subjects; performed an exercise intervention; assessed PT. Hedge's effect sizes of PT response and their 95% confidence intervals were calculated, and random-effects meta-analyses were performed.

Results: For the final analysis, thirty-six studies were included (n=1326). From this we found a significant and homogenous increase in PT in healthy subjects (ES=0.19, 95% CI= 0.11 to 0.27, I2=7.5%). According to subgroup analysis the effect was higher in studies: with women (ES=0.36); performing strength exercise (ES=0.34), and with moderate intensity (ES=0.27), and no differences by age were found. Confirmed by the meta-regression analysis.

Conclusion: This meta-analysis provides evidence of small to moderate effects of exercise on PT in healthy subjects, being even higher for moderate strength exercise and in women. These results support the idea of modulation of the endogenous pain system due to exercise and highlight the need of clinical translation to chronic pain population.
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http://dx.doi.org/10.21801/ppcrj.2020.63.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785086PMC
September 2020

Risk factors of pain, physical function, and health-related quality of life in elderly people with knee osteoarthritis: A cross-sectional study.

Heliyon 2020 Dec 19;6(12):e05723. Epub 2020 Dec 19.

Laboratory of Neuromodulation, Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Data on the precise mechanisms of the complex interactions of factors related to clinical impact of knee osteoarthritis (KOA) in the elderly population remain limited. To find predictors that explain pain intensity, physical function, and quality of life in elderly KOA subjects, we performed a cross-sectional analysis of the baseline data from a randomized trial. The trial included 104 subjects (aged ≥60) with KOA pain and dysfunctional endogenous pain-inhibitory system activity assessed by conditioned pain modulation (CPM). Three multiple linear regression models were performed to understand the independent predictors of Brief Pain Inventory (BPI), WOMAC function subscale (WOMACFunc), and SF-12 physical subscale (SF12-PCS). Model 1 showed that BPI pain score was predicted by low CPM response, high von-Frey light touch threshold, worse radiological severity as indexed by Kellgren-Lawrence grade (KL), high von-Frey punctate pain intensity and high levels of anxiety (adjusted R2 = 27.1%, F (6,95) = 7.27, P < 0.0001). In model 2, von-Frey light touch threshold, KL, depressive symptoms indexed by Beck Depression Inventory (BDI), level of sleepiness and pain pressure threshold were risk factors for SF12-PCS (adjusted R2 = 31.9%, F (5,96) = 10.5, P < 0.0001). Finally, model 3 showed that WOMACFunc was predicted by BDI, KL and BPI (adjusted R2 = 41%, F (3,98) = 24.42, P < 0.0001). Our data provides an interesting framework to understand the predictors of KOA pain in the elderly and highlights how its related outcomes are affected by disease-specific factors, somatosensory dysfunction and emotional factors.
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http://dx.doi.org/10.1016/j.heliyon.2020.e05723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758370PMC
December 2020

Transcranial direct current stimulation for fatigue in patients with Sjogren's syndrome: A randomized, double-blind pilot study.

Brain Stimul 2021 Jan-Feb;14(1):141-151. Epub 2020 Dec 17.

Rheumatologist. Discipline of Emergency and Evidence-Based Medicine, EPM - UNIFESP, São Paulo, SP, Brazil.

Background: Transcranial direct-current stimulation (tDCS) has shown promise to decrease fatigue. However, it has never been examined in primary Sjogren Syndrome (pSS).

Objective: To assess the effect of a tDCS protocol on fatigue in patients with pSS.

Methods: This is a parallel, double-blind pilot study (NCT04119128). Women aged 18-65 years, with pSS, on stable pharmacological therapy, with complaints of fatigue for at least three months, and with scores >5 on Fatigue Severity Scale (FSS) were included. We randomized 36 participants to receive five consecutive or sham tDCS sessions, with an intensity of 2 mA, for 20 min/day.

Results: After five tDCS sessions, fatigue severity assessed by the FSS (primary outcome) demonstrated a mean group difference of -0.85 [95% confidence interval (CI) -1.57, -0.13; effect size 0.80] favouring the active group. The active group presented significantly greater reductions in fatigue as measured by the EULAR Sjögren's Syndrome Patient Reported Index after five tDCS sessions [mean group difference: 1.40; 95%CI -2.33, -0.48; effect size 1.04]. Although there were no between-group differences in the secondary outcomes of sleep, mood and anxiety, within-group comparisons evidenced a small but significant difference in the active group for pain and sleep. There were no significant cortisol changes. All reported adverse events were mild and transitory.

Conclusion: tDCS seems to be safe and reduce fatigue in pSS. A differential effect on pain and sleep may underlie its effects. Further studies are needed to optimise tDCS treatment strategies in pSS.
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http://dx.doi.org/10.1016/j.brs.2020.12.004DOI Listing
October 2021

EEG modulation by different transcranial direct current stimulation (tDCS) montages: a randomized double-blind sham-control mechanistic pilot trial in healthy participants.

Expert Rev Med Devices 2021 Jan 21;18(1):107-120. Epub 2020 Dec 21.

Neuromodulation Center, Spaulding Rehabilitation Hospital, Department of Physical Medicine and Rehabilitation, Harvard Medical School, Boston, MA, United States.

: Based on our Phantom study on transcranial direct current stimulation (tDCS), we hypothesized that EEG band power and field confinement would be greater following left dorsolateral prefrontal cortex (DLPFC - F3) tDCS using circular vs. rectangular electrodes.: Double-blind-randomized trial comparing tDCS with anode over left DLPFC (groups: rectangular electrodes, circular electrodes, sham) and 2 active subgroup references (right shoulder vs. right DLPFC).: Twenty-four randomized participants were assessed. We indeed found higher average EEG power spectral density (PSD) across bands for circular vs. rectangular electrodes, largely confined to F3 and there was a significant increase at AF3 for low alpha (p = 0.037). Significant differences included: increased PSD in low beta (p = 0.024) and theta bands (p = 0.021) at F3, and in theta (p = 0.036) at FC5 for the right DLPFC vs. shoulder with no coherence changes. We found PSD differences between active vs. sham tDCS at Fz for alpha (p = 0.043), delta (p = 0.036), high delta (p = 0.030); and at FC1 for alpha (p = 0.031), with coherence differences for F3-Fz in beta (p = 0.044), theta (p = 0.044), delta (p = 0.037) and high delta (p = 0.009).: This pilot study despite low statistical power given its small sample size shows that active left DLPFC tDCS modulates EEG frontocentrally and suggests that electrode shapes/reference locations affect its neurophysiological effects, such as increased low alpha power at AF3 using circular vs. rectangular electrodes. Further research with more participants is warranted.
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http://dx.doi.org/10.1080/17434440.2021.1860018DOI Listing
January 2021

A review of burn symptoms and potential novel neural targets for non-invasive brain stimulation for treatment of burn sequelae.

Burns 2021 05 20;47(3):525-537. Epub 2020 Jun 20.

Spaulding Rehabilitation Hospital, Harvard Medical School, Boston, MA, United States. Electronic address:

Burn survivors experience myriad associated symptoms such as pain, pruritus, fatigue, impaired motor strength, post-traumatic stress, depression, anxiety, and sleep disturbance. Many of these symptoms are common and remain chronic, despite current standard of care. One potential novel intervention to target these post burn symptoms is transcranial direct current stimulation (tDCS). tDCS is a non-invasive brain stimulation (NIBS) technique that modulates neural excitability of a specific target or neural network. The aim of this work is to review the neural circuits of the aforementioned clinical sequelae associated with burn injuries and to provide a scientific rationale for specific NIBS targets that can potentially treat these conditions. We ran a systematic review, following the PRISMA statement, of tDCS effects on burn symptoms. Only three studies matched our criteria. One was a feasibility study assessing cortical plasticity in chronic neuropathic pain following burn injury, one looked at the effects of tDCS to reduce pain anxiety during burn wound care, and one assessed the effects of tDCS to manage pain and pruritus in burn survivors. Current literature on NIBS in burn remains limited, only a few trials have been conducted. Based on our review and results in other populations suffering from similar symptoms as patients with burn injuries, three main areas were selected: the prefrontal region, the parietal area and the motor cortex. Based on the importance of the prefrontal cortex in the emotional component of pain and its implication in various psychosocial symptoms, targeting this region may represent the most promising target. Our review of the neural circuitry involved in post burn symptoms and suggested targeted areas for stimulation provide a spring board for future study initiatives.
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http://dx.doi.org/10.1016/j.burns.2020.06.005DOI Listing
May 2021

Transcranial Direct Current Stimulation as an Add-on Treatment to Cognitive-Behavior Therapy in First Episode Drug-Naïve Major Depression Patients: The ESAP Study Protocol.

Front Psychiatry 2020 3;11:563058. Epub 2020 Nov 3.

Department of Physical Medicine and Rehabilitation, Spaulding Neuromodulation Center, Spaulding Rehabilitation Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.

Major Depressive Disorder (MDD) affects more than 264 million people worldwide. Current treatments include the use of psychotherapy and/or drugs, however ~30% of patients either do not respond to these treatments, or do not tolerate the side effects associated to the use of pharmacological interventions. Thus, it is important to study non-pharmacological interventions targeting mechanisms not directly involved with the regulation of neurotransmitters. Several studies demonstrated that transcranial Direct Current Stimulation (tDCS) can be effective for symptoms relief in MDD. However, tDCS seems to have a better effect when used as an add-on treatment to other interventions. This is a study protocol for a parallel, randomized, triple-blind, sham-controlled clinical trial in which a total of 90 drug-naïve, first-episode MDD patients (45 per arm) will be randomized to one of two groups to receive a 6-weeks of CBT combined with either active or sham tDCS to the dorsolateral prefrontal cortex (DLPFC). The primary outcome will depressive symptoms improvement as assessed by the Montgomery-Asberg Depression Rating Scale (MADRS) at 6-weeks. The secondary aim is to test whether CBT combined with tDCS can engage the proposed mechanistic target of restoring the prefrontal imbalance and connectivity through the bilateral modulation of the DLPFC, as assessed by changes over resting-state and emotional task eliciting EEG. This study evaluates the synergetic clinical effects of CBT and tDCS in the first episode, drug-naïve, patients with MDD. First episode MDD patients provide an interesting opportunity, as their brains were not changed by the pharmacological treatments, by the time course, or by the recurrence of MDD episodes (and other comorbidities). This study is registered with the United States National Library of Medicine Clinical Trials Registry (NCT03548545). Registered June 7, 2018, clinicaltrials.gov/ct2/show/NCT03548545. Protocol Version 1.
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http://dx.doi.org/10.3389/fpsyt.2020.563058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669750PMC
November 2020

Age as a Mediator of tDCS Effects on Pain: An Integrative Systematic Review and Meta-Analysis.

Front Hum Neurosci 2020 28;14:568306. Epub 2020 Oct 28.

Graduate Program in Medical Sciences, School of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.

The transcranial direct current stimulation (tDCS) is a neuromodulatory technique with the potential to decrease pain scores and to improve chronic pain treatment. Although age is an essential factor that might impact the tDCS effect, most studies are solely conducted in adults. Therefore, the age limitation presents a critical research gap in this field and can be shown by only a handful of studies that have included other age groups. To examine the evidence upon the tDCS effect on pain scores on children, adolescents, or elderly, and indirectly, to infer the age-dependent impact on tDCS effects, we conducted a systematic review and meta-analysis. A systematic review searching the following databases: PubMed, EMBASE, and Science Direct using the following search terms adapted according to MeSh or Entree: [("Adolescent" OR "Children" OR "Elderly") AND ("tDCS") AND ("Pain" OR "Pain threshold") AND ("dorsolateral prefrontal cortex" OR "Motor cortex)] up to April 20th, 2020. We retrieved 228 articles, 13 were included in the systematic review, and five studies with elderly subjects that had their outcomes assessed by pain score or pain threshold were included in the meta-analysis. For the analysis of pain score, 96 individuals received active stimulation, and we found a favorable effect for active tDCS to reduce pain score compared to sham ( = 0.002). The standardized difference was -0.76 (CI 95% = -1.24 to -0.28). For the pain threshold, the analysis showed no significant difference between active and sham tDCS. We reviewed two studies with adolescents: one study using anodal tDCS over the prefrontal cortex reported a reduction in pain scores. However, the second study reported an increase in pain sensitivity for the dorsolateral prefrontal cortex (DLPFC) stimulation. Our findings suggest tDCS may reduce pain levels in the elderly group. Nevertheless, the small number of studies included in this review-and the considerable heterogeneity for clinical conditions and protocols of stimulation present-limits the support of tDCS use for pain treatment in elderly people. Larger studies on the tDCS effect on pain are needed to be conducted in elderly and adolescents, also evaluating different montages and electrical current intensity.
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http://dx.doi.org/10.3389/fnhum.2020.568306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654216PMC
October 2020
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