Multi-Target and Multi-Session Transcranial Direct Current Stimulation in Patients With Prolonged Disorders of Consciousness: A Controlled Study

Objectives: To investigate the effect of multi-session transcranial direct current stimulation (tDCS) over the prefrontal area, left dorsolateral prefrontal cortex (DLPFC), and bilateral fronto-temporo-parietal cortices (FTPCs) in patients with prolonged disorders of consciousness (DOC) and to examine the altered cortical interconnections using non-linear electroencephalography (EEG).Methods: In this open-label controlled study, conventional treatments were implemented in both the control and tDCS groups, together with 80 tDCS sessions only in the tDCS group. The order of tDCS targets was as follows: prefrontal area, left FTPC, right FTPC, and left DLPFC. The Coma Recovery Scale-Revised (CRS-R) and non-linear EEG index were evaluated before and after the treatment. Additionally, the modified Glasgow Outcome Scale (mGOS) was used as a follow-up evaluation at 12 months after the disease onset.Results: The CRS-R improved significantly in both groups after the treatment. However, the CRS-R and mGOS were more significantly improved in the tDCS group than in the control group. Among the cross approximate entropy (C-ApEn) indices, the local CA-PA and CA-FA under the affected painful stimulus condition and all local and remote indices of the unaffected side under the unaffected painful stimulus condition were significantly higher in the tDCS group than in the control group. Multivariate logistic regression analysis revealed that group and type were the main relevant factors based on mGOS improvement. Multivariate linear regression analysis revealed that group, CA-FA, and CU-MTU were the main relevant factors based on CRS-R improvement under the affected painful stimulus conditions, whereas only CU-MTU and CU-FPU were relevant under the unaffected painful stimulus condition.Conclusion: Multi-target and multi-session tDCS could improve the cortical connections between the primary sensorimotor and frontal cortices of the affected hemisphere and the prefrontal-parietal and temporo-parietal associative cortical networks of the unaffected hemisphere. Thus, this tDCS protocol may be used as an add-on treatment for prolonged DOC.

Offset analgesia and onset hyperalgesia with different stimulus ranges

ABSTRACTOffset analgesia (OA), a large reduction in pain following a brief increase in intensity of an otherwise stable painful stimulus, has been established by a large body of research. But the opposite effect, onset hyperalgesia (OH), a disproportional hyperalgesic response following a briefly decreased intensity of a painful stimulus, has only been investigated in one previous study. The aim of this study was to induce OA and OH in healthy participants and explore the effects of different stimulus ranges on OA and OH. A total of 62 participants were tested in two identical experiments. OA and OH conditions included two different temperature deviations (±1°C/±2°C) from baseline and were compared to a constant temperature (control). OA was successfully elicited in three out of four conditions. A dose-response relationship was demonstrated between the increase of temperature and the resulting hypoalgesic response. OH was only elicited in one out of four conditions (OH2°C in experiment 1). Exploratory analysis showed that OA and OH responses were only weakly correlated. The asymmetry between pain responses following a brief temperature increase and decrease could be seen as evidence for different mechanisms involved in the pain responses to increasing and decreasing temperature. This asymmetry may also be explained by high temperatures in OA condition (+1°C/+2°C above baseline) that could be seen as salient “learning signals”, which augment the response to following changes in temperature.

What goes up must come down: insights from studies on descending controls acting on spinal pain processing

Descending controls link higher processing of noxious signals to modulation of spinal cord responses to their noxious inputs. It has become possible to study one key inhibitory system in animals and humans using one painful stimulus to attenuate another distant response and so eliciting diffuse noxious inhibitory controls (DNIC) or the human counterpart, conditioned pain modulation (CPM). Here, we discuss the neuronal pathways in both species, their pharmacology and examine changes in descending controls with a focus on osteoarthritis. We will also discuss the opposing descending facilitatory system. Strong parallels between DNIC and CPM emphasize the possibility of forward and reverse translation.

Muscle stretching – the potential role of endogenous pain inhibitory modulation on stretch tolerance

Background and aims The effect of stretching on joint range of motion is well documented and is primarily related to changes in the tolerance to stretch, but the mechanisms underlying this change are still largely unknown. The aim of this study was to investigate the influence of a remote, painful stimulus on stretch tolerance. Methods Thirty-four healthy male subjects were recruited and randomly assigned to an experimental pain group (n=17) or a control group (n=17). Passive knee extension range of motion, the activity of hamstring muscles and passive resistive torque were measured with subjects in a seated position. Three consecutive measures were performed with a 5-min interval between. A static stretch protocol was utilized in both groups to examine the effect of stretching and differences in stretch tolerance between groups. Following this, the pain-group performed a cold pressor test which is known to engage the endogenous pain inhibitory system after which measurements were repeated. Results A significant increase in knee extension range of motion was found in the pain group compared with controls (ANCOVA: p<0.05). No difference was found in muscle activity or passive resistive torque between groups (ANCOVA p>0.091). Conclusions Passive knee extension range of motion following stretching increased when following a distant, painful stimulus, potentially engaging the endogenous pain inhibitory systems. Current findings indicate a link between increased tolerance to stretch and endogenous pain inhibition. Implications The current findings may have implications for clinical practice as they indicate that a distant painful stimulus can influence range of motion in healthy individuals. This implies that the modulation of pain has significance for the efficacy of stretching which is important knowledge when prescribing stretching as part of rehabilitation.

Chapter 3. Mechanisms of changes in dynamic complexity of EEG patterns underlying correction of psychogenic pain in anxiety-phobic states

The third chapter explains the mechanisms for correcting anxiety-phobic states. For this, the changes occurring in the EEG patterns during the presentation of a painful stimulus and in the process of eliminating the pain sensation using the psychorelaxation technique in healthy individuals are considered; and these changes are compared with changes in EEG patterns during patients’ feelings of psychogenic pain and during its removal using psycho-relaxation techniques. It has been shown that the mechanisms underlying the correction of psychogenic pain in anxiety-phobic states are associated with changes in the dynamics of successive EEG values and the degree of their multifractality. With successful correction in the process of psychorelaxation in persons with anxiety-phobic disorders, there is a transition to the values of multifractal parameters characteristic for healthy people.

Comparison of pre-emptive butorphanol or metamizole with ketamine +medetomidine and s-ketamine + medetomidine anaesthesia in improving intraoperative analgesia in mice

In accordance with the ‘refinement’ component of the 3Rs, the primary aim of this study was to investigate and compare ketamine + medetomidine (KM) and s-ketamine + medetomidine (SKM) anaesthetic protocols in C57BL/6J mice (both sexes). We sought to determine whether s-ketamine could provide adequate surgical tolerance at a 50% dose relative to that of ketamine racemate and whether antagonism of medetomidine could be initiated 15 min earlier. The second aim was to investigate the potential improvement in analgesia for both anaesthetic protocols by adding butorphanol or metamizole. Analgesia was tested via the pedal withdrawal reaction (PWR) to a painful stimulus. During anaesthesia, respiratory frequency, pulse oximetry, body temperature and PWR were monitored. Among the 16 mice in each group, the PWR was lost in all the KM + metamizole (35:56 ± 6:07 min), KM + butorphanol (43:45 ± 2:14 min) and SKM + butorphanol (24:03 ± 5:50 min) mice, 15 of the non-premedicated KM (37:00 ± 8:11 min) mice, and 9 of the pure SKM (20:00 ± 4:19 min) mice; the latter group increased to 11 mice (17:16 ± 5:10 min) with premedication of metamizole. In contrast to the racemic combination, s-ketamine at the dose used here did not lead to sufficient loss of the PWR. However, earlier partial antagonism of SKM resulted in a slightly shorter and qualitatively better recovery than later partial antagonism of SKM. The addition of metamizole or butorphanol to KM or SKM anaesthesia positively influences the analgesic quality. However, when butorphanol is added, controlled ventilation may be necessary, especially for male mice.

Observing painful events in others leads to a temporally extended general response facilitation in the self

Excitability in the motor cortex is modulated when we observe other people receiving a painful stimulus (Avenanti et al., 2005). However, the task dependency of this modulation is not well understood, as different paradigms have yielded seemingly different results. Previous neurophysiological work employing transcranial magnetic stimulation (TMS) suggests that watching another person’s hand being pierced by a needle leads to a muscle specific inhibition, assessed via motor evoked potentials. Results from previous behavioural studies suggest that overt behavioural responses are facilitated due to pain observation (Morrison et al., 2007a; 2007b). There are several paradigmatic differences both between typical TMS studies and behavioural studies, and within behavioural studies themselves, that limit our overall understanding of how pain observation affects the motor system. In the current study, we combine elements of typical TMS experimental designs in a behavioural assessment of how pain observation affects overt behavioural responding. Specifically, we examined the muscle specificity, timing, and direction of modulation of motor responses due to pain observation. To assess muscle specificity, we employed pain and non-pain videos from previous TMS studies in a Go/No-Go task in which participants responded by either pressing a key with their index finger or with their foot. To assess timing, we examined response times for Go signals presented at 0ms or 500ms after the video. Results indicate that observation of another individual receiving a painful stimulus leads to a non-effector specific, temporally extended response facilitation (e.g., finger and foot facilitation present at 0ms and 500ms delays), compared to observation of non-pain videos. This behavioural facilitation effect differs from the typical motor inhibition seen in TMS studies, and we argue that the effects of pain observation on the motor system are state-dependent, with different states induced via task instructions. We discuss our results in light of previous work on motor responses to pain observation.