Impact of disabilities in activities of daily living on opioid use for chronic pain in older adults: an exploratory secondary analysis from ELSI-Brazil.

OBJECTIVES: Problematic use of opioids by older adults is associated with adverse effects and has become a public health crisis worldwide. Ageing-related disabilities in activities of daily living (ADL) could promote unnecessary use of opioids in this population. This study evaluates the association between ADL disability and opioid consumption in Brazilian older adults. STUDY DESIGN: Study design- cross-sectional secondary data analysis of the second wave of the Brazil Longitudinal Study of Ageing (ELSI-Brazil). METHODS: Data from the second wave of the Brazil Longitudinal Study of Ageing (ELSI-Brazil) were used. Older adults with chronic pain were included. ADL disability was measured using the Katz Index. The primary outcome was opioid consumption for chronic pain. The primary association was explored using logistic regression models adjusting for predetermined confounders. Sensitivity analyses evaluating model performance were done by calibrating and validating the model using randomly split equal sets. RESULTS: In those who reported presence of chronic pain (n = 2865), the prevalence of opioid use was 29% (95% CI:23.1%-35.6%). In adjusted models, participants with moderate and severe ADL disability had 1.6 (95% CI:1.13-2.32; P = 0.009) and 3.8 (95% CI: 1.80-7.90; P < 0.001) times higher odds of opioid consumption compared to no disability, respectively. Being female, alcohol consumption, higher pain intensity, history of dementia, fractures, and presence of ≥2 comorbidities were significantly associated with increased opioid use (P < 0.05). CONCLUSION: Nearly one-third of the Brazilian elderly population experiencing chronic pain reported using opioids. The functional decline during the process of ageing appears to be a risk factor for pain intolerance and opioid use. Multidisciplinary approaches to detect early ADL disabilities and improve mobility and access to assistive technologies need to be established to prevent opioid overuse and addiction in elderly populations.

Factors influencing clinical trial participation of women with fibromyalgia across the United States: a cross-sectional survey.

Although fibromyalgia is a widespread chronic pain condition where 90 percent of patients are women, they are underrepresented in Randomized Clinical Trials (RCTs). We aim to describe the willingness to participate, assess different factors, and explore the impact of sociodemographic and clinical characteristics on perceived barriers to trial participation. This is a cross-sectional survey targeting women with fibromyalgia. Univariate and multivariate logistic regression were performed. Of the 436 women with fibromyalgia, 56 percent were very likely to participate in RCTs. Minorities expressed less interest than non-minorities, while higher pain scores, previous participation, and younger patients reported a higher interest. Barriers significantly associated with a reduced willingness were: the participant's perception (side effects, distance, potential negative impact), the center (reputation), the trial protocol (number of visits, placebo), and trial awareness by their physician. In a multivariate analysis, older age, low education, lower income, and higher pain scores were associated with perceived barriers to RCT participation. Despite the high interest to participate, factors such as side effects, the center's distance, number of visits, placebo treatments, and the institution's reputation must be considered in clinical trials for women with fibromyalgia.

Non-invasive brain stimulation for fine motor improvement after stroke: a meta-analysis.

The aim of this study was to determine whether non-invasive brain stimulation (NIBS) techniques improve fine motor performance in stroke. We searched PubMed, EMBASE, Web of Science, SciELO and OpenGrey for randomized clinical trials on NIBS for fine motor performance in stroke patients and healthy participants. We computed Hedges' g for active and sham groups, pooled data as random-effects models and performed sensitivity analysis on chronicity, montage, frequency of stimulation and risk of bias. Twenty-nine studies (351 patients and 152 healthy subjects) were reviewed. Effect sizes in stroke populations for transcranial direct current stimulation and repeated transcranial magnetic stimulation were 0.31 [95% confidence interval (CI), 0.08-0.55; P = 0.010; Tau2 , 0.09; I2 , 34%; Q, 18.23; P = 0.110] and 0.46 (95% CI, 0.00-0.92; P = 0.05; Tau2 , 0.38; I2 , 67%; Q, 30.45; P = 0.007). The effect size of non-dominant healthy hemisphere transcranial direct current stimulation on non-dominant hand function was 1.25 (95% CI, 0.09-2.41; P = 0.04; Tau2 , 1.26; I2 , 93%; Q, 40.27; P < 0.001). Our results show that NIBS is associated with gains in fine motor performance in chronic stroke patients and healthy subjects. This supports the effects of NIBS on motor learning and encourages investigation to optimize their effects in clinical and research settings.

Repeated transcranial direct current stimulation reduces food craving in Wistar rats.

It has been suggested that food craving-an intense desire to consume a specific food (particularly foods high in sugar and fat)-can lead to obesity. This behavior has also been associated with abuse of other substances, such as drugs. Both drugs and food cause dependence by acting on brain circuitry involved in reward, motivation, and decision-making processes. The dorsolateral prefrontal cortex (DLPFC) can be activated following evocation and is implicated in alterations in food behavior and craving. Transcranial direct current stimulation (tDCS), a noninvasive brain stimulation technique capable of modulates brain activity significantly, has emerged as a promising treatment to inhibit craving. This technique is considered safe and inexpensive; however, there is scant research using animal models. Such studies could help elucidate the behavioral and molecular mechanisms of eating disorders, including food craving. The aim of our study was to evaluate palatable food consumption in rats receiving tDCS treatment (anode right/cathode left). Eighteen adult male Wistar rats were randomized by weight and divided into three groups (n = 6/group): control, with no stimulation; sham, receiving daily 30 s tDCS (500 µA) sessions for 8 consecutive days; and tDCS, receiving daily 20 min tDCS (500 µA) sessions for 8 consecutive days. All rats were evaluated for locomotor activity and anxiety-like behavior. A palatable food consumption test was performed at baseline and on treatment completion (24 h after the last tDCS session) under fasting and feeding conditions and showed that tDCS decreased food craving, thus corroborating human studies. This result confirms the important role of the prefrontal cortex in food behavior, which can be modulated by noninvasive brain stimulation.

Association of acute pancreatitis or high level of serum pancreatic enzymes in patients with acute spinal cord injury: a prospective study.

BACKGROUND: Spinal cord injuries has increased together with urban violence and show a high rates of incidence. Besides the onus to patient and society, it can also cause other serious complications to victims. Acute pancreatitis has an important impact on this disease and has been underdiagnosed in several patients. OBJECTIVES: The aim of this study was investigate the association of acute pancreatitis in acute spinal cord injuries. The secondary aim was to propose an investigation protocol to early diagnose and prevent it. METHODS: A prospective observational study was conducted in 78 patients who presented acute spinal cord injury (SCI) at our emergency department, confirmed by clinical and imaging examination, in according to the American Spinal Injury Association (ASIA) Classification. Exclusion criteria were chronic or associate diseases in spinal cord, pancreatic direct trauma, alcoholism and chronic pancreatic disease. RESULTS: The association of acute pancreatitis in patients with SCI was 11.53%. The occurrence of pancreatitis or high levels of serum pancreatic enzymes in patients with ASIA A was 41.7% and only 4.17% in patients with ASIA E. In all, 55.2% of patients who presented pancreatitis or high levels of serum pancreatic enzymes had cervical level of SCI and 34.5% had thoracic level. Adynamic ileus was observed in 68.96% of this group. CONCLUSION: We concluded that, in acute spinal cord injuries, the occurrence of acute pancreatitis or high serum levels of pancreatic enzymes are more frequent in patients with ASIA A Classification, cervical/thoracic level of spinal injury and adynamic ileus.

Structural and functional motor cortex asymmetry in unilateral lower limb amputation with phantom limb pain.

OBJECTIVE: The role of motor cortex reorganization in the development and maintenance of phantom limb pain (PLP) is still unclear. This study aims to evaluate neurophysiological and structural motor cortex asymmetry in patients with PLP and its relationship with pain intensity. METHODS: Cross-sectional analysis of an ongoing randomized-controlled trial. We evaluated the motor cortex asymmetry through two techniques: i) changes in cortical excitability indexed by transcranial magnetic stimulation (motor evoked potential, paired-pulse paradigms and cortical mapping), and ii) voxel-wise grey matter asymmetry analysis by brain magnetic resonance imaging. RESULTS: We included 62 unilateral traumatic lower limb amputees with a mean PLP of 5.9 (SD = 1.79). We found, in the affected hemisphere, an anterior shift of the hand area center of gravity (23 mm, 95% CI 6 to 38, p = 0.005) and a disorganized and widespread representation. Regarding voxel-wise grey matter asymmetry analysis, data from 21 participants show a loss of grey matter volume in the motor area of the affected hemisphere. This asymmetry seems negatively associated with time since amputation. For TMS data, only the ICF ratio is negatively correlated with PLP intensity (r = -0.25, p = 0.04). CONCLUSION: There is an asymmetrical reorganization of the motor cortex in patients with PLP, characterized by a disorganized, widespread, and shifted hand cortical representation and a loss in grey matter volume in the affected hemisphere. This reorganization seems to reduce across time since amputation. However, it is not associated with pain intensity. SIGNIFICANCE: These findings are significant to understand the role of the motor cortex reorganization in patients with PLP, showing that the pain intensity may be related with other neurophysiological factors, not just cortical reorganization.

Cortical plasticity in phantom limb pain: A fMRI study on the neural correlates of behavioral clinical manifestations.

The neural mechanism of phantom limb pain (PLP) is related to the intense brain reorganization process implicating plasticity after deafferentation mostly in sensorimotor system. There is a limited understanding of the association between the sensorimotor system and PLP. We used a novel task-based functional magnetic resonance imaging (fMRI) approach to (1) assess neural activation within a-priori selected regions-of-interested (motor cortex [M1], somatosensory cortex [S1], and visual cortex [V1]), (2) quantify the cortical representation shift in the affected M1, and (3) correlate these changes with baseline clinical characteristics. In a sample of 18 participants, we found a significantly increased activity in M1 and S1 as well as a shift in motor cortex representation that was not related to PLP intensity. In an exploratory analyses (not corrected for multiple comparisons), they were directly correlated with time since amputation; and there was an association between increased activity in M1 with a lack of itching sensation and V1 activation was negatively correlated with PLP. Longer periods of amputation lead to compensatory changes in sensory-motor areas; and itching seems to be a protective marker for less signal changes. We confirmed that PLP intensity is not associated with signal changes in M1 and S1 but in V1.

Temporal cortex direct current stimulation enhances performance on a visual recognition memory task in Alzheimer disease.

Several studies have reported that transcranial direct current stimulation (tDCS), a non-invasive method of neuromodulation, enhances some aspects of working memory in healthy and Parkinson disease subjects. The aim of this study was to investigate the impact of anodal tDCS on recognition memory, working memory and selective attention in Alzheimer disease (AD). Ten patients with diagnosis of AD received three sessions of anodal tDCS (left dorsolateral prefrontal cortex, left temporal cortex and sham stimulation) with an intensity of 2 mA for 30 min. Sessions were performed in different days in a randomised order. The following tests were assessed during stimulation: Stroop, Digit Span and a Visual Recognition Memory task (VRM). The results showed a significant effect of stimulation condition on VRM (p = 0.0085), and post hoc analysis showed an improvement after temporal (p = 0.01) and prefrontal (p = 0.01) tDCS as compared with sham stimulation. There were no significant changes in attention as indexed by Stroop task performance. As far as is known, this is the first trial showing that tDCS can enhance a component of recognition memory. The potential mechanisms of action and the implications of these results are discussed.

Modulatory effects of anodal transcranial direct current stimulation on perception and pain thresholds in healthy volunteers.

BACKGROUND AND PURPOSE: We aimed to evaluate whether transcranial direct current stimulation (tDCS) is effective in modulating sensory and pain perception thresholds in healthy subjects as to further explore mechanisms of tDCS in pain relief. METHODS: Twenty healthy subjects received stimulation with tDCS under four different conditions of stimulation: anodal tDCS of the primary motor cortex (M1), dorsolateral prefrontal cortex (DLPFC), occipital cortex (V1), and sham tDCS. The order of conditions was randomized and counterbalanced across subjects. Perception threshold and pain threshold to peripheral electrical stimulation of the right index finger were evaluated by a blinded rater. RESULTS: The results showed a significant effect of the interaction time versus stimulation condition for perception (P = 0.046) and pain threshold (P = 0.015). Post hoc comparisons revealed that anodal stimulation of M1 increased both perception (P < 0.001, threshold increase of 6.5%) and pain (P = 0.001, threshold increase of 8.3%) thresholds significantly, whilst stimulation of the DLPFC increased pain threshold only (P = 0.046, threshold increase of 10.0%). There were no significant effects for occipital or sham stimulation. CONCLUSIONS: These results show that both M1 and DLFPC anodal tDCS can be used to modulate pain thresholds in healthy subjects; thus, the mechanism of tDCS in modulating pain involves pathways that are independent of abnormal pain-related neural activity.

Transcranial direct current stimulation (tDCS) prevents chronic stress-induced hyperalgesia in rats.

BACKGROUND: Chronic stress (CS) is associated with a decrease in pain threshold caused by the changes in neural pain circuits. It can be associated to glucocorticoid imbalance with alterations in neural circuitry. Inhibition of stress-induced pain-related neural changes by using techniques that safely induce neuroplasticity such as transcranial direct current stimulation (tDCS) may prevent hyperalgesia triggered by CS. OBJECTIVE: This study aimed to verify the effect of tDCS performed prior to CS exposure on nociceptive response. METHODS: Thirty-two rats were distributed in the following groups: control; stress; sham-tDCS + stress; and tDCS + stress. Bicephalic active tDCS was performed for 8 consecutive days before the CS exposure. The pain threshold was evaluated using a hot plate and tail flick latency (TFL) tests. RESULTS: The tDCS exposure increased the pain threshold on stressed rats. CONCLUSION: The data obtained indicate that the treatment with bicephalic active tDCS before chronic stress exposure prevents stress-induced hyperalgesia.

Supraspinal inputs reduce corticomotor excitability during passive movement: evidence from a pure sensory stroke.

Corticomotor excitability is reduced during rhythmic passive movement compared to rest, but it is not known whether the mechanism is purely segmental or includes a supraspinal pathway. To determine how interruption of sensory projections at a supraspinal level affects corticomotor excitability during passive movement, we measured the amplitude of motor evoked potential (MEP) during 1 Hz cyclic index finger movements in a patient with a brainstem and thalamus lesion that resulted in a pure sensory stroke. Measurements of MEP amplitude and proprioception were made 14 and 64 days post-stroke. In the first study, when subjective position sense was reduced for the index finger, MEP amplitude was significantly increased during passive movement compared to rest (4.6+/-0.2 SEM mV vs. 4.0+/-0.2 mV; p=0.0281). However in the second study, when position sense had returned to normal, MEP amplitude was significantly reduced during movement compared to rest (6.2+/-0.3 mV vs. 6.6+/-0.1 mV; p=0.0224). These observations provide evidence that supraspinal sensory pathways are involved in reducing corticomotor excitability during rhythmic passive movement.

Low intensity transcranial electric stimulation: Safety, ethical, legal regulatory and application guidelines.

Low intensity transcranial electrical stimulation (TES) in humans, encompassing transcranial direct current (tDCS), transcutaneous spinal Direct Current Stimulation (tsDCS), transcranial alternating current (tACS), and transcranial random noise (tRNS) stimulation or their combinations, appears to be safe. No serious adverse events (SAEs) have been reported so far in over 18,000 sessions administered to healthy subjects, neurological and psychiatric patients, as summarized here. Moderate adverse events (AEs), as defined by the necessity to intervene, are rare, and include skin burns with tDCS due to suboptimal electrode-skin contact. Very rarely mania or hypomania was induced in patients with depression (11 documented cases), yet a causal relationship is difficult to prove because of the low incidence rate and limited numbers of subjects in controlled trials. Mild AEs (MAEs) include headache and fatigue following stimulation as well as prickling and burning sensations occurring during tDCS at peak-to-baseline intensities of 1-2mA and during tACS at higher peak-to-peak intensities above 2mA. The prevalence of published AEs is different in studies specifically assessing AEs vs. those not assessing them, being higher in the former. AEs are frequently reported by individuals receiving placebo stimulation. The profile of AEs in terms of frequency, magnitude and type is comparable in healthy and clinical populations, and this is also the case for more vulnerable populations, such as children, elderly persons, or pregnant women. Combined interventions (e.g., co-application of drugs, electrophysiological measurements, neuroimaging) were not associated with further safety issues. Safety is established for low-intensity 'conventional' TES defined as <4mA, up to 60min duration per day. Animal studies and modeling evidence indicate that brain injury could occur at predicted current densities in the brain of 6.3-13A/m2 that are over an order of magnitude above those produced by tDCS in humans. Using AC stimulation fewer AEs were reported compared to DC. In specific paradigms with amplitudes of up to 10mA, frequencies in the kHz range appear to be safe. In this paper we provide structured interviews and recommend their use in future controlled studies, in particular when trying to extend the parameters applied. We also discuss recent regulatory issues, reporting practices and ethical issues. These recommendations achieved consensus in a meeting, which took place in Göttingen, Germany, on September 6-7, 2016 and were refined thereafter by email correspondence.

Transient tinnitus suppression induced by repetitive transcranial magnetic stimulation and transcranial direct current stimulation.

Modulation of activity in the left temporoparietal area (LTA) by 10 Hz repetitive transcranial magnetic stimulation (rTMS) results in a transient reduction of tinnitus. We aimed to replicate these results and test whether transcranial direct current stimulation (tDCS) of LTA could yield similar effect. Patients with tinnitus underwent six different types of stimulation in a random order: 10-Hz rTMS of LTA, 10-Hz rTMS of mesial parietal cortex, sham rTMS, anodal tDCS of LTA, cathodal tDCS of LTA and sham tDCS. A non-parametric analysis of variance showed a significant main effect of type of stimulation (P = 0.002) and post hoc tests showed that 10-Hz rTMS and anodal tDCS of LTA resulted in a significant reduction of tinnitus. These effects were short lasting. These results replicate the findings of the previous study and, in addition, show preliminary evidence that anodal tDCS of LTA induces a similar transient tinnitus reduction as high-frequency rTMS.

A technical guide to tDCS, and related non-invasive brain stimulation tools.

Transcranial electrical stimulation (tES), including transcranial direct and alternating current stimulation (tDCS, tACS) are non-invasive brain stimulation techniques increasingly used for modulation of central nervous system excitability in humans. Here we address methodological issues required for tES application. This review covers technical aspects of tES, as well as applications like exploration of brain physiology, modelling approaches, tES in cognitive neurosciences, and interventional approaches. It aims to help the reader to appropriately design and conduct studies involving these brain stimulation techniques, understand limitations and avoid shortcomings, which might hamper the scientific rigor and potential applications in the clinical domain.

Cumulative effects of transcranial direct current stimulation on EEG oscillations and attention/working memory during subacute neurorehabilitation of traumatic brain injury.

OBJECTIVE: To investigate in a randomized, double-blind design, cumulative effects of anodal tDCS on EEG oscillations and neuropsychological tests among patients with traumatic brain injury (TBI) undergoing subacute neurorehabilitation. METHODS: Twenty-six patients were randomly assigned to active (n=13) or sham (n=13) tDCS groups. EEGs were recorded at 6 different time points, assessing both immediate and cumulative effects of tDCS on EEG oscillations. Twenty minute sessions of 1mA anodal stimulation to the left dorsolateral prefrontal cortex (F3, cathode placed at right supraorbital site, Fp2), were provided on 10 consecutive days. Neuropsychological tests were administered before and after the series of tDCS sessions. RESULTS: Theta was significantly reduced for active tDCS patients following the first tDCS session. Delta decreased and alpha increased, both significantly, for the active tDCS group after 10 consecutive tDCS sessions. No significant changes were seen for sham group. Decreases in delta were significantly correlated with improved performance on neuropsychological tests for the active tDCS group to far greater degree than for the sham group. Participants in the active tDCS group who had excess slow EEG activity in their initial recordings showed greater improvement on neuropsychological tests than other groups. CONCLUSION: Results suggest that 10 anodal tDCS sessions may beneficially modulate regulation of cortical excitability for patients with TBI. SIGNIFICANCE: EEG-guided tDCS warrants further investigation as a potential intervention for TBI during subacute neurorehabilitation.

Regulatory Considerations for the Clinical and Research Use of Transcranial Direct Current Stimulation (tDCS): review and recommendations from an expert panel.

The field of transcranial electrical stimulation (tES) has experienced significant growth in the past 15 years. One of the tES techniques leading this increased interest is transcranial direct current stimulation (tDCS). Significant research efforts have been devoted to determining the clinical potential of tDCS in humans. Despite the promising results obtained with tDCS in basic and clinical neuroscience, further progress has been impeded by a lack of clarity on international regulatory pathways. We therefore convened a group of research and clinician experts on tDCS to review the research and clinical use of tDCS. In this report, we review the regulatory status of tDCS, and we summarize the results according to research, off-label and compassionate use of tDCS in the following countries: Australia, Brazil, France, Germany, India, Iran, Italy, Portugal, South Korea, Taiwan and United States. Research use, off label treatment and compassionate use of tDCS are employed in most of the countries reviewed in this study. It is critical that a global or local effort is organized to pursue definite evidence to either approve and regulate or restrict the use of tDCS in clinical practice on the basis of adequate randomized controlled treatment trials.

Interactions between transcranial direct current stimulation (tDCS) and pharmacological interventions in the Major Depressive Episode: findings from a naturalistic study.

BACKGROUND: Transcranial direct current stimulation (tDCS) is a non-invasive, neuromodulatory technique with an emerging role for treating major depression. OBJECTIVE: To investigate the interactions between tDCS and drug therapy in unipolar and bipolar depressed patients who were refractory for at least one pharmacological treatment. METHODS: This was a naturalistic study using data from 54 female and 28 male patients (mean age of 54 years) that consecutively visited our psychiatric unit. They received active tDCS (five consecutive days, 2mA, anodal stimulation over the left and cathodal over the right dorsolateral prefrontal cortex, twice a day, 20minutes). The outcome variable (mood) was evaluated using the Beck Depression Inventory (BDI) and the Hamilton Depression Rating Scale (HDRS). Predictor variables were age, gender, disorder and pharmacological treatment (seven dummy variables). We performed univariate and multivariate analyses as to identify predictors associated to the outcome. RESULTS: After 5 days of treatment, BDI and HDRS scores decreased significantly (29%±36%, 18%±9%, respectively, P<0.01 for both). Benzodiazepine use was independently associated with a worse outcome in both univariate (ß=4.92, P<0.01) and multivariate (ß=5.8, P<0.01) analyses; whereas use of dual-reuptake inhibitors positively changed tDCS effects in the multivariate model (ß=-4.7, P=0.02). A similar trend was observed for tricyclics (ß=-4, P=0.06) but not for antipsychotics, non-benzodiazepine anticonvulsants and other drugs. CONCLUSION: tDCS over the DLPFC acutely improved depressive symptoms. Besides the inherent limitations of our naturalistic design, our results suggest that tDCS effects might vary according to prior pharmacological treatment, notably benzodiazepines and some antidepressant classes. This issue should be further explored in controlled studies.