Mental imagery-induced attention modulates pain perception and cortical excitability.

BACKGROUND: Mental imagery is a powerful method of altering brain activity and behavioral outcomes, such as performance of cognition and motor skills. Further, attention and distraction can modulate pain-related neuronal networks and the perception of pain. This exploratory study examined the effects of mental imagery-induced attention on pressure pain threshold and cortical plasticity using transcranial magnetic stimulation (TMS). This blinded, randomized, and parallel-design trial comprised 30 healthy right-handed male subjects. Exploratory statistical analyses were performed using ANOVA and t-tests for pain and TMS assessments. Pearson's correlation was used to analyze the association between changes in pain threshold and cortical excitability. RESULTS: In the analysis of pain outcomes, there was no significant interaction effect on pain between group versus time. In an exploratory analysis, we only observed a significant effect of group for the targeted left hand (ANOVA with pain threshold as the dependent variable and time and group as independent variables). Although there was only a within-group effect of mental imagery on pain, further analyses showed a significant positive correlation of changes in pain threshold and cortical excitability (motor-evoked potentials via TMS). CONCLUSIONS: Mental imagery has a minor effect on pain modulation in healthy subjects. Its effects appear to differ compared with chronic pain, leading to a small decrease in pain threshold. Assessments of cortical excitability confirmed that these effects are related to the modulation of pain-related cortical circuits. These exploratory findings suggest that neuronal plasticity is influenced by pain and that the mental imagery effects on pain depend on the state of central sensitization.

Inflammatory bowel disease (IBD)-like disease in a case of a 33-year old man with glycogenosis 1b.

BACKGROUND: Inflammatory bowel disease (IBD)-like conditions in glycogen storage disease (GSD) type Ib have been predominantly described in children. Signs and symptoms of GSD type Ib are hypoglycemia, pancytopenia and hepatosplenomegaly. Based on few published cases, there is evidence that granulocyte-colony stimulating factor (G-CSF) in patients with glycogenosis-related pancytopenia might ameliorate the IBD-like disease through leukocyte increase. CASE PRESENTATION: Here we firstly describe a case of an adult 33-year-old Caucasian male patient with GSD type Ib accompanied with IBD-like disease with persistent pancytopenia despite moderate-dose G-CSF treatment. Recent vomiting and abdominal discomfort were due to a high-grade stenosis in the transverse colon. A dose increase of the G-CSF successfully normalized his leukocyte count. However, the stenosis worsened and surgical therapy was needed. CONCLUSION: We suggest that symptomatic patients with GSD type Ib should undergo endoscopic examination in order to detect IBD-like disease and to initiate early treatment.

Analgesic effects of noninvasive brain stimulation in rodent animal models: a systematic review of translational findings.

OBJECTIVES: Noninvasive brain stimulation (NIBS) interventions have demonstrated promising results in the clinical treatment of pain, according to several preliminary trials, although the results have been mixed. The limitations of clinical research on NIBS are the insufficient understanding of its mechanisms of action, a lack of adequate safety data, and several disparities with regard to stimulation parameters, which have hindered the generalizability of such studies. Thus, experimental animal research that allows the use of more invasive interventions and creates additional control of independent variables and confounders is desirable. To this end, we systematically reviewed animal studies investigating the analgesic effects of NIBS. In addition, we also explored the investigation of NIBS in animal models of stroke as to compare these findings with NIBS animal pain research. METHODS: Of 1916 articles that were found initially, we identified 15 studies (stroke and pain studies) per our eligibility criteria that used NIBS methods, such as transcranial direct current stimulation, paired associative stimulation, transcranial magnetic stimulation, and transcranial electrostimulation. We extracted the main outcomes on stroke and pain, as well as the methods and electrical parameters of each technique. RESULTS: NIBS techniques are effective in alleviating pain. Similar beneficial clinical effects are observed in stroke. The main insights from these animal studies are the following: 1) combination of NIBS with analgesic drugs has a synergistic effect; 2) effects are dependent on the parameters of stimulation, and in fact, not necessarily the strongest stimulation parameter (i.e., the largest intensity of stimulation) is associated with the largest benefit; 3) pain studies show an overall good quality as indexed by Animals in Research: Reporting In Vivo Experiments guidelines of the reporting of animal experiments, but insufficient with regard to the reporting of safety data for brain stimulation; 4) these studies suggest that NIBS techniques have a primary effect on synaptic plasticity, but they also suggest other mechanisms of action such as via neurovascular modulation. CONCLUSIONS: We found a limited number of animal studies for both pain and stroke NIBS experimental research. There is a lack of safety data in animal studies in these two topics and results from these studies have not been yet fully tested and translated to human research. We discuss the challenges and limitations of translating experimental animal research on NIBS into clinical studies.

A systematic review on reporting and assessment of adverse effects associated with transcranial direct current stimulation.

Transcranial direct current stimulation (tDCS) is a non-invasive method of brain stimulation that has been intensively investigated in clinical and cognitive neuroscience. Although the general impression is that tDCS is a safe technique with mild and transient adverse effects (AEs), human data on safety and tolerability are largely provided from single-session studies in healthy volunteers. In addition the frequency of AEs and its relationship with clinical variables is unknown. With the aim of assessing tDCS safety in different conditions and study designs, we performed a systematic review and meta-analysis of tDCS clinical trials. We assessed Medline and other databases and reference lists from retrieved articles, searching for articles from 1998 (first trial with contemporary tDCS parameters) to August 2010. Animal studies, review articles and studies assessing other neuromodulatory techniques were excluded. According to our eligibility criteria, 209 studies (from 172 articles) were identified. One hundred and seventeen studies (56%) mentioned AEs in the report. Of these studies, 74 (63%) reported at least one AE and only eight studies quantified AEs systematically. In the subsample reporting AEs, the most common were, for active vs. sham tDCS group, itching (39.3% vs. 32.9%, p>0.05), tingling (22.2% vs. 18.3%, p>0.05), headache (14.8% vs. 16.2%, p>0.05), burning sensation (8.7% vs. 10%, p>0.05) and discomfort (10.4% vs. 13.4%, p>0.05). Meta-analytical techniques could be applied in only eight studies for itching, but no definite results could be obtained due to between-study heterogeneity and low number of studies. Our results suggested that some AEs such as itching and tingling were more frequent in the tDCS active group, although this was not statistically significant. Although results suggest that tDCS is associated with mild AEs only, we identified a selective reporting bias for reporting, assessing and publishing AEs of tDCS that hinders further conclusions. Based on our findings, we propose a revised adverse effects questionnaire to be applied in tDCS studies in order to improve systematic reporting of tDCS-related AEs.

Transcranial direct current stimulation in inflammatory bowel disease patients modifies resting-state functional connectivity: A RCT.

BACKGROUND: Chronic pain is known to be associated with functional and structural changes in the brain. Inflammatory bowel disease (IBD) presents with chronic abdominal pain in almost 35% of all patients. This study investigates structural and functional changes in magnetic resonance imaging (MRI) after transcranial direct current stimulation (tDCS) applied to ameliorate pain in IBD. METHODS: This phase-III, placebo-controlled, randomized study included 36 patients with IBD and chronic pain. MRI scans were performed before and following tDCS, which was applied for 5 days. RESULTS/CONCLUSION: For the first time, this study revealed an association of changes in resting-state functional MRI and pain reduction in IBD. There was a significant increase in functional connectivity after active tDCS within the visual medial and the right frontoparietal network being connected with the amygdala, the insula, and the primary somatosensory cortex indicating central pain mechanisms in IBD. Moreover, tDCS offers a novel therapeutic strategy for abdominal pain.

Altered paired associative stimulation-induced plasticity in NMDAR encephalitis.

OBJECTIVE: To determine whether neurophysiological mechanisms indicating cortical excitability, long-term potentiation (LTP)-like plasticity, GABAergic and glutamatergic function are altered in patients with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis and whether they can be helpful as markers of diagnostic assessment, disease progression, and potentially therapy response. METHODS: Neurophysiological characterizations of patients with NMDAR encephalitis (n = 34, mean age: 28 ± 11 years; 30 females) and age/gender-matched healthy controls (n = 27, 28.5 ± 10 years; 25 females) were performed using transcranial magnetic stimulation-derived protocols including resting motor threshold, recruitment curve, intracortical facilitation, short intracortical inhibition, and cortical silent period. Paired associative stimulation (PAS) was applied to assess LTP-like mechanisms which are mediated through NMDAR. Moreover, resting state functional connectivity was determined using functional magnetic resonance imaging. RESULTS: PAS-induced plasticity differed significantly between groups (P = 0.0056). Cortical excitability, as assessed via motor-evoked potentials after PAS, decreased in patients, whereas it increased in controls indicating malfunctioning of NMDAR in encephalitis patients. Lower PAS-induced plasticity significantly correlated with the modified Rankin Scale (mRS) (r = -0.41; P = 0.0031) and was correlated with lower functional connectivity within the motor network in NMDAR encephalitis patients (P < 0.001, uncorrected). Other neurophysiological parameters were not significantly different between groups. Follow-up assessments were available in six patients and demonstrated parallel improvement of PAS-induced plasticity and mRS. INTERPRETATION: Assessment of PAS-induced plasticity may help to determine NMDAR dysfunction and disease severity in NMDAR encephalitis, and might even aid as a sensitive, noninvasive, and well-tolerated "electrophysiological biomarker" to monitor therapy response in the future. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: Identifier: NCT01865578.

Movement observation-induced modulation of pain perception and motor cortex excitability.

OBJECTIVE: The observation of movements increases primary motor cortex (M1) excitability. This exploratory study examined the effects of movement observation on pressure pain threshold (PPT) and transcranial magnetic stimulation (TMS)-indexed corticospinal excitability bilaterally. METHODS: Thirty healthy right-handed subjects were randomized to a left hand-movement observation task or a control task. Statistical analyses were performed using ANOVA models and t-tests. Results were not corrected for multiple comparisons. Quantitative sensory assessments were measured in both hands, while M1 excitability has only been tested for the right (non-dominant) M1 corresponding to the observed left hand movements. RESULTS: Analysis of pain and cortical silent period (CSP) outcomes demonstrated a significant interaction between task (hand-movement group) versus control group and time (pre-/postintervention). PPT increased in the left hand (moving hand in the task) and declined significantly in the contralateral hand (still hand) in the movement-observation-task-group, whereas PTT in the control group remained unchanged. CSP was significantly shorter in the movement-observation group indicating decreased intracortical inhibition (results uncorrected for multiple comparisons). CONCLUSIONS: The observation of hand-movements led to a side-specific reduction in pain perception and a decrease in intracortical inhibition. SIGNIFICANCE: These exploratory findings support the notion that M1 is a robust modulator of pain-related neural networks. This effect might be mediated through modulation of the GABAergic system and appears to differ from what is observed in chronic pain.

Specific CD4+ T-Cell Reactivity and Cytokine Release in Different Clinical Presentations of Leptospirosis.

Clinical manifestations of leptospirosis are highly variable: from asymptomatic to severe and potentially fatal. The outcome of the disease is usually determined in the immunological phase, beginning in the second week of symptoms. The underlying mechanisms, predictive factors, and individual immune responses that contribute to clinical variations are not well understood. The aim of this study was to determine the specifics of CD4(+) T-cell reactivity and cytokine release after stimulation with leptospiral antigens in patients with leptospirosis of different disease severities (patients with mild and severe symptoms) and in control subjects (with and without proven exposure to Leptospira). Whole-blood specimens were stimulated with Leptospira antigens in vitro. Subsequently, intracellular staining of cytokines was performed, and flow cytometry was used to assess the expression of CD40 ligand (CD40L) and the production of gamma interferon (IFN-γ), interleukin-10 (IL-10), IL-2, and tumor necrosis factor alpha (TNF-α) by CD4(+) T cells. The production of inflammatory cytokines such as TNF-α by CD4(+) T cells after stimulation with leptospiral antigens was highest in patients with severe disease. In contrast, the ratio of IL-10 production to TNF-α production was higher in exposed subjects than in patients with mild and severe disease. Levels of proinflammatory cytokines such as TNF-α may be useful markers of the severity of the immunological phase of leptospirosis. IL-10 production by T cells after antigen-specific stimulation may indicate a more successful downregulation of the inflammatory response and may contribute to an asymptomatic course of the disease.

Combination of transcranial direct current stimulation and methylphenidate in subacute stroke.

Noninvasive transcranial direct current stimulation (tDCS) and methylphenidate (MP) are associated with motor recovery after stroke. Based on the potentially complementary mechanisms of these interventions, we examined whether there is an interactive effect between MP and tDCS. In this preliminary study, we randomized subacute stroke subjects to receive tDCS alone, MP alone or combination of tDCS and MP. A blinded rater measured safety, hand function, and cortical excitability before and after treatment. None of the treatments caused any major or severe adverse effects or induced significant differences in cortical excitability. Analysis of variance of gain score, as measured by Purdue pegboard test, showed a significant between-group difference (F(2,6)=12.167, p=0.008). Post hoc analysis showed that the combination treatment effected greater Purdue pegboard gain scores than tDCS alone (p=0.017) or MP alone (p=0.01). Our preliminary data with nine subjects shows an interesting dissociation between motor function improvement and lack of motor corticospinal plasticity changes as indexed by transcranial magnetic stimulation in subacute stroke subjects.

Technique and considerations in the use of 4x1 ring high-definition transcranial direct current stimulation (HD-tDCS).

High-definition transcranial direct current stimulation (HD-tDCS) has recently been developed as a noninvasive brain stimulation approach that increases the accuracy of current delivery to the brain by using arrays of smaller "high-definition" electrodes, instead of the larger pad-electrodes of conventional tDCS. Targeting is achieved by energizing electrodes placed in predetermined configurations. One of these is the 4x1-ring configuration. In this approach, a center ring electrode (anode or cathode) overlying the target cortical region is surrounded by four return electrodes, which help circumscribe the area of stimulation. Delivery of 4x1-ring HD-tDCS is capable of inducing significant neurophysiological and clinical effects in both healthy subjects and patients. Furthermore, its tolerability is supported by studies using intensities as high as 2.0 milliamperes for up to twenty minutes. Even though 4x1 HD-tDCS is simple to perform, correct electrode positioning is important in order to accurately stimulate target cortical regions and exert its neuromodulatory effects. The use of electrodes and hardware that have specifically been tested for HD-tDCS is critical for safety and tolerability. Given that most published studies on 4x1 HD-tDCS have targeted the primary motor cortex (M1), particularly for pain-related outcomes, the purpose of this article is to systematically describe its use for M1 stimulation, as well as the considerations to be taken for safe and effective stimulation. However, the methods outlined here can be adapted for other HD-tDCS configurations and cortical targets.

Effects of sensory behavioral tasks on pain threshold and cortical excitability.

BACKGROUND/OBJECTIVE: Transcutaneous electrical stimulation has been proven to modulate nervous system activity, leading to changes in pain perception, via the peripheral sensory system, in a bottom up approach. We tested whether different sensory behavioral tasks induce significant effects in pain processing and whether these changes correlate with cortical plasticity. METHODOLOGY/PRINCIPAL FINDINGS: This randomized parallel designed experiment included forty healthy right-handed males. Three different somatosensory tasks, including learning tasks with and without visual feedback and simple somatosensory input, were tested on pressure pain threshold and motor cortex excitability using transcranial magnetic stimulation (TMS). Sensory tasks induced hand-specific pain modulation effects. They increased pain thresholds of the left hand (which was the target to the sensory tasks) and decreased them in the right hand. TMS showed that somatosensory input decreased cortical excitability, as indexed by reduced MEP amplitudes and increased SICI. Although somatosensory tasks similarly altered pain thresholds and cortical excitability, there was no significant correlation between these variables and only the visual feedback task showed significant somatosensory learning. CONCLUSIONS/SIGNIFICANCE: Lack of correlation between cortical excitability and pain thresholds and lack of differential effects across tasks, but significant changes in pain thresholds suggest that analgesic effects of somatosensory tasks are not primarily associated with motor cortical neural mechanisms, thus, suggesting that subcortical neural circuits and/or spinal cord are involved with the observed effects. Identifying the neural mechanisms of somatosensory stimulation on pain may open novel possibilities for combining different targeted therapies for pain control.

The relationship between cortical excitability and pain catastrophizing in myofascial pain.

UNLABELLED: Pain catastrophizing regularly occurs in chronic pain patients. It has been suggested that pain catastrophizing is a stable, person-based construct. These findings highlight the importance of investigating catastrophizing in conceptualizing specific approaches for pain management. One important area of investigation is the mechanism underlying pain catastrophizing. Therefore, this study explored the relationship between a neurophysiological marker of cortical excitability, as assessed by transcranial magnetic stimulation, and catastrophizing, as assessed by the Brazilian Portuguese Pain Catastrophizing Scale, in patients with chronic myofascial pain syndrome. The Pain Catastrophizing Scale is a robust questionnaire used to examine rumination, magnification and helplessness that are associated with the experience of pain. We include 24 women with myofascial pain syndrome. The Brazilian Portuguese Pain Catastrophizing Scale and cortical excitability were assessed. Functional and behavioral aspects of pain were evaluated with a version of the Profile of Chronic Pain scale and by multiple pain measurements (eg, pain intensity, pressure pain threshold, and other quantitative sensory measurements). Intracortical facilitation was found to be significantly associated with pain catastrophizing (ß = .63, P = .001). Our results did not suggest that these findings were influenced by other factors, such as age or medication use. Furthermore, short intracortical inhibition showed a significant association with pressure pain threshold (ß = .44, P = .04). This study elaborates on previous findings indicating a relationship between cortical excitability and catastrophizing. The present findings suggest that glutamatergic activity may be associated with mechanisms underlying pain catastrophizing; thus, the results highlight the need to further investigate the neurophysiological mechanisms associated with pain and catastrophizing. PERSPECTIVE: This study highlights the relationship between cortical excitability and catastrophizing. Cortical measures may illuminate how catastrophizing responses may be related to neurophysiological mechanisms associated with chronic pain.

Neurobiological effects of transcranial direct current stimulation: a review.

Transcranial Direct Current Stimulation (tDCS) is a non-invasive brain stimulation technique that is affordable and easy to operate compared to other neuromodulation techniques. Anodal stimulation increases cortical excitability, while the cathodal stimulation decreases it. Although tDCS is a promising treatment approach for chronic pain as well as for neuropsychiatric diseases and other neurological disorders, several complex neurobiological mechanisms that are not well understood are involved in its effect. The purpose of this systematic review is to summarize the current knowledge regarding the neurobiological mechanisms involved in the effects of tDCS. The initial search resulted in 171 articles. After applying inclusion and exclusion criteria, we screened 32 full-text articles to extract findings about the neurobiology of tDCS effects including investigation of cortical excitability parameters. Overall, these findings show that tDCS involves a cascade of events at the cellular and molecular levels. Moreover, tDCS is associated with glutamatergic, GABAergic, dopaminergic, serotonergic, and cholinergic activity modulation. Though these studies provide important advancements toward the understanding of mechanisms underlying tDCS effects, further studies are needed to integrate these mechanisms as to optimize clinical development of tDCS.

Electrode positioning and montage in transcranial direct current stimulation.

Transcranial direct current stimulation (tDCS) is a technique that has been intensively investigated in the past decade as this method offers a non-invasive and safe alternative to change cortical excitability. The effects of one session of tDCS can last for several minutes, and its effects depend on polarity of stimulation, such as that cathodal stimulation induces a decrease in cortical excitability, and anodal stimulation induces an increase in cortical excitability that may last beyond the duration of stimulation. These effects have been explored in cognitive neuroscience and also clinically in a variety of neuropsychiatric disorders--especially when applied over several consecutive sessions. One area that has been attracting attention of neuroscientists and clinicians is the use of tDCS for modulation of pain-related neural networks. Modulation of two main cortical areas in pain research has been explored: primary motor cortex and dorsolateral prefrontal cortex. Due to the critical role of electrode montage, in this article, we show different alternatives for electrode placement for tDCS clinical trials on pain; discussing advantages and disadvantages of each method of stimulation.