Introduction:
Chronic Pain (CP) presents a complex and prevalent issue that significantly affects individuals and society. Exploring the complexities of CP involves analyzing Functional Connectivity (FC), a process that identifies how different brain regions communicate across distances. Magnetoencephalography (MEG) is particularly effective for FC analysis, offering advantages over Electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) due to its superior temporal resolution. Most studies on FC in CP have focused on resting-state analyses, leaving a gap in research on connectivity responses to noxious stimuli in CP.

Study aim:
The overarching goal of my exploring study is to investigate FC differences in response to noxious stimuli between individuals with CP and Healthy Controls (HCs) across different frequency bands, using MEG. This encompasses the comparison of FC patterns within pain-related brain regions between these two groups, the analysis of their response to a noxious stimulus, and the synthesis of these findings to identify potential differences in how the two groups respond to noxious stimuli.

Methods:
The study involved 17 individuals with CP and 17 HCs, each undergoing MEG sessions within a conditioned pain modulation (CPM) paradigm. During each CPM block, 22 noxious stimuli were applied to the right tibial nerve. FC was computed between pain-processing regions using phase and amplitude-based metrics in different frequency bands. Connectivity patterns were compared between the groups using a non-parametric permutation test. Connectivity was also evaluated on a time-scale to observe potential changes in the FC in response to the stimulus. These results were taken together to observe potential differences in the groups in response to the stimulus.

Results:
In comparing FC patterns across the entire epoch between the HC and CP groups, there is a predominant observation of increased FC in the CP group relative to the HC group. The insula and Dorsolateral Prefrontal Cortex (DLPFC) emerged as central hubs, and these alterations were most prominent in the beta (13-29 Hz) and gamma-low bands (30-45 Hz). An increase in FC in the mean response over all scout pairs and both groups was observed immediately following the stimulus, particularly in the theta band (5-7 Hz). Additionally, in investigating the specific hypothesis that there may be distinct FC responses to noxious stimuli between the HC and CP group, the findings indicate subtle differences rather than clear, pronounced patterns, with findings in the theta, alpha and gamma-low bands.

Conclusion:
My study explored FC differences in response to noxious stimuli between individuals with CP and HCs across different frequency bands, using MEG. Higher FC was predominantly observed in the CP group, suggesting more interconnected pain-processing networks. Key regions demonstrating this increased FC included the insula and the DLPFC, suggesting an altered insula-DLPFC network potentially influenced by underlying physiological factors of the CP group. Specifically examining differences in FC response to the noxious stimulus between the HC and the CP group yielded in subtle differences rather than clear, distinct patterns. This study stands out as the first using MEG to identify FC in CP in response to noxious stimuli. Future research should focus on refining connectivity as a biomarker for treatment follow-up and potential outcome predictor.

Background
Spasticity is a condition that affects patients who have sustained an upper motor neuron lesion. Such lesions include for example cerebral palsy (CP), of which 35% is affected by spasticity, and stroke, of which 90% is affected by spasticity. Pharmacological therapy often involves the prescription of oral baclofen. However, due to the difficulty of medication in crossing the blood-brain barrier, high dosages of oral baclofen are required to achieve the desired therapeutic effect, which in turn leads to an increase of the incidence of negative side-effects. For patients with severe spasticity, the intrathecal baclofen (ITB) pump is indicated for more effective drug delivery. To monitor the efficacy of the treatment and quantify the level of spasticity, the Modified Ashworth Scale (MAS) is employed. Nevertheless, the moderate inter- and intra-rater reliability indicates that the subjectivity of the approach represents a potential limitation. Therefore, a more objective approach is required. Surface electromyography (sEMG) can measure direct muscle activity and is an objective and non-invasive approach. Yet, there is no research available on sEMG measurements to assess the change in muscle activity as a result of ITB treatment.

Objective
The primary objective of this exploratory study is to assess the effect of intrathecal baclofen on lower limb muscle activity using sEMG. The secondary objectives are assessing the correlation between the sEMG feature values and MAS scores, and between the sEMG feature values and Patient's Global Impression of Change (PGIC) scores.

Method
sEMG measurements were performed during standard assessment of the MAS on patients receiving an ITB single shot trial (SS) and/or pump implantation. The following features were analyzed: (1) Root Mean Square (RMS), (2) Peak Amplitude Value (PAV), (3) Median Frequency, and (4) Co-Contraction (CCR). A comparative analysis was conducted to assess the change in mean feature value of each individual muscle between pre- and post-treatment for the purpose of study aim 1. The Spearman's rank correlation coefficient was calculated in order to assess the relationship between changes in feature values and changes in MAS scores. Furthermore, the Spearman's rank correlation coefficient was calculated to assess the relationship between the changes in most effective feature and the PGIC scores.

Results
A total of twelve patients were included in the study, diagnosed with a variety of conditions including spinal cord injury (SCI), multiple sclerosis (MS), traumatic brain injury (TBI) and CP. Following ITB treatment, the RMS demonstrated a statistically significant decrease for three out of eight muscles: the left semitendinosus (p = 0.020), the right rectus femoris (p = 0.025) and the right tibialis anterior (p = 0.002). The PAV presented a decrease in 3-8 out of 10 patients following SS baclofen treatment. The changes in median frequency exhibited considerable variability between patients following ITB treatment. The CCR decreased in six out of ten patients for the left leg following SS baclofen treatment. A significant correlation was observed between the change in MAS scores and change in RMS in the medial gastrocnemius (p = 0.027) and the change in median frequency in the semitendinosus (p = 0.002). A low correlation was observed between the change in RMS and the PGIC score.

Conclusion
In conclusion, this study demonstrates the potential of sEMG features, such as RMS, in assessing the impact of ITB treatment on muscle activity. Future work could validate these findings by increasing the sample size and improving certain methodological aspects.

Introduction: The positioning of spinal cord stimulation (SCS) leads in the epidural space to deliver therapy for chronic pain currently relies on intraoperative feedback from the patient. This feedback is not always reliable due to sedation, discomfort, and prone positioning of the patient. Excluding the need for patient feedback by performing objective intraoperative measurements to guide lead placement could be possible using the recording capabilities of closed loop SCS leads.
Objective: Assess the feasibility of performing intraoperative evoked compound action potential (ECAP) measurements in the spinal cord using stimulation on the dorsal root ganglion (DRG) corresponding to the painful area of the patient to guide SCS lead placement.
Methods: Intraoperative measurements were performed during placement of the SCS leads. The L3, L4 or L5 DRG was stimulated with a RF-needle and a recording electrode on the lead measured the neural activity in the dorsal column. The reference electrode was either on a subdermal needle or on one of the electrodes on the lead. The DRG was stimulated with a frequency of 10 Hz, a pulse width of 300 μs and a biphasic pulse type with negative polarity. By increasing the stimulation amplitude until ECAPs are visible, the activation threshold was determined, and by recording on different electrodes on the lead, propagation of the signal was validated. All data gathered during the measurements was processed and analyzed in MATLAB, and conduction velocities were calculated.
Results: We included eight patients, and in two out of eight patients it was possible to measure ECAPs in the epidural space when stimulating on the DRG. A measured signal was deemed an ECAP if certain characteristics were met. The morphology should match that of an ECAP. Also, an increase in the stimulation amplitude on the DRG should lead to a linear increase in the ECAP amplitude. Lastly, an ECAP propagates along the dorsal column. In many patients, the stimulation on the DRG did not activate enough fibers to create an ECAP that was measurable in the epidural space.
Discussion: There is no clear common denominator in the patients or stimulation parameters in the measurements where ECAPs were successfully measured in the epidural space, making specific improvements to the measurement protocol difficult. Age, gender or medication use seemed unrelated to whether the measurements succeeded. The experimental set-up could be improved by validating the distance between RF-needle and the DRG. Also, the use of sedation allows for an increased stimulation amplitude use, which could increase the amount of fibers activated to elicit an ECAP.
Conclusion: Stimulating the DRG with a RF-needle can lead to measurable ECAPs in the dorsal column, which could help guide lead placement without the need for feedback. However, the measurement protocol as it is now does not produce predictable results and should be improved if to continue with this study. Also, the need for this intraoperative procedure should be reevaluated since experienced surgeons estimate the lead localization quite accurately. In combination with 12 electrode leads covering 3 vertebrae, the rest of the coverage overlap can often be achieved during postoperative programming of the stimulation.

Introduction
Chronic pain is an increasing problem in terms of prevalence and disease-related costs. Due to its complexity, it is difficult to treat. Spinal cord stimulation (SCS) is a neurostimulation therapy with a relatively good success rate for patients with severe, intractable chronic pain. The mechanisms of action (MOAs) of SCS are considered to rely on spinal and supraspinal mechanisms. It has been suggested that newer SCS paradigms, such as burst SCS, may act through different MOAs than the traditional tonic SCS paradigm. Tonic and burst SCS are both postulated to act on the lateral pain pathway, which is associated with the location and character of a stimulus, whereas burst SCS is postulated to additionally act on the medial pain pathway, which is associated with the emotional/attentional processing of a stimulus. Somatosensory evoked responses (SERs) can be used to evaluate the processing of somatosensory stimuli and may aid in the unraveling of the MOAs of SCS.

Aim
The aim of this thesis is to assess how burst and tonic SCS affect the supraspinal SERs elicited by non-painful transcutaneous electrical stimulation of the tibial nerve as well as of the median nerve. The two distinct SERs are evaluated using magnetoencephalography (MEG).

Methods
26 chronic pain patients treated with SCS underwent MEG sessions after receiving tonic and burst SCS for one week. Four of these patients additionally underwent a MEG session before SCS treatment. During each session, approximately 200 non-painful electrical stimuli were applied to the median nerve as well as to the tibial nerve to elicit SERs. The SERs were compared in various cortical and subcortical regions of interest (ROIs). The following comparisons were made: 1) SERs in chronic pain patients before SCS implantation versus SERs in the same individuals during SCS, 2) SERs elicited by tibial nerve stimulation versus SERs elicited by median nerve stimulation, 3) SERs during tonic SCS versus SERs during burst SCS, and 4) the SERs in four case studies of two good and two poor responders to the tonic and/or burst SCS paradigms.

Results
22 patients were included for analysis. The number of patients varied among comparisons to facilitate within-patient comparisons. The results suggested an inhibitory effect of SCS on the SER elicited by tibial nerve stimulation, whereas the amplitude of the SER elicited by median nerve stimulation tended to increase during SCS. For both the SERs elicited by tibial nerve and by median nerve stimulation, the SER amplitudes were predominantly higher during burst SCS compared to tonic SCS. Differences in SER amplitude that were observed in the case studies did not correlate with pain relief.

Conclusion
The results suggested a spinal MOA of SCS on the SER, however, supraspinal MOAs likely play a role as well. The results did not suggest that burst SCS additionally acts on the emotional/attentional processing compared to tonic SCS. No evidence was found to support a correlation between the effect of SCS on the SER and the effect of SCS on the pain, underscoring the complexity of the relationship between somatosensory processing and pain perception in the context of SCS.

Introduction: Spinal Cord Stimulation (SCS) is a successful last-resort treatment for chronic pain patients, although its exact mechanisms of action (MOAs) still need to be unraveled. The MOAs of SCS partly rely on spinal mechanisms (gate control theory) and supraspinal mechanisms likely play a role as well. Pain processing involves a complex network of cortical structures and can be modulated. Conditioned pain modulation (CPM) is a measure to describe the modulation of pain perception. CPM relies on the 'pain inhibits pain' theory, where a nociceptive test stimulus (TS) is modulated by applying a nociceptive conditioning stimulus (CS). CPM is often less efficient in chronic pain patients, but this might be improved by effective SCS.
Objective: The aim of this thesis is to assess how effective SCS affects the supraspinal mechanisms of pain modulation in chronic pain patients. The supraspinal mechanisms are evaluated using magnetoencephalography (MEG) to assess the cortical response to TS before, during and after CPM in chronic pain patients treated with SCS.

Methods: Chronic pain patients treated with SCS underwent MEG sessions after receiving tonic and burst SCS for one week. Each session consisted of three CPM blocks: before, during and after CPM. During each CPM block 22 TS were administered accompanied by CS during CPM, after each block the subject reported a subjective pain rating of TS (and CS). The cortical response to TS, measured using MEG, was analyzed in the time and time-frequency (TF) domain using Brainstorm and Matlab software. TF decomposition was computed in several pain related regions of interest using complex Morlet wavelets. We examined how CPM affected event related spectral perturbations, induced by TS, in the alpha (8-12 Hz) and beta (13-30 Hz) frequency ranges. The average cortical response during tonic and burst SCS was evaluated in all subjects, and separately in the five clearest SCS responders (effective) and the five clearest SCS non-responders (non-effective).
Results: 17 subjects were included. On average a decrease in subjective pain ratings of TS was observed during CPM. In the time domain, TS evoked activity in areas related to the sensory-discriminative aspect of pain. In the TF domain, TS induced event related desynchronization (ERD) followed by event related synchronization (ERS) in the alpha and beta frequency ranges in the bilateral sensorimotor cortices. During CPM the power of beta ERS was significantly decreased during burst SCS. A trend was observed towards a decrease in power of beta ERS for the effective burst SCS group, whereas no decrease was observed for the non-effective burst, effective tonic and non-effective tonic SCS groups.
Conclusion: The results suggest that on average, effective burst SCS decreases the power of beta ERS during CPM, this decrease indicates successful modulation of pain. Therefore, I suggest that effective burst SCS is capable of improving the supraspinal mechanisms of pain modulation, whereas effective tonic SCS is not capable of doing so. This suggestion indicates a partially different MOA for tonic and burst SCS. Future studies containing larger group sizes should validate these findings.

Background: Complex regional pain syndrome (CRPS) is a clinical disorder characterized by continuous, disproportionate pain and sensory, vasomotor, sudomotor and motor trophic changes. CRPS patients have a heterogeneous clinical picture caused by multiple underlying pathophysiology mechanisms including inflammation, vasomotor disturbances and central nervous system (CNS) dysregulation. Spinal cord stimulation (SCS) is believed to target multiple CRPS mechanisms by stimulating the dorsal column in the spinal cord. Closed-loop SCS is a recently developed form of SCS in which the stimulation intensity adapts to the patient's position, continuously stimulating the same amount of fibers in the dorsal column. This constant perceived stimulation intensity may benefit CRPS patients who are generally hypersensitive.

Objectives: To better understand the effects SCS has on the CRPS mechanisms, my research focuses on quantifying changes in vasomotor disturbances due to conventional SCS treatment using thermographic image analysis. In addition, exploratory analysis is performed in patients treated with closed-loop SCS to evaluate its effects on CRPS mechanisms.

Method: Various histogram features indicating temperature intensity were selected based on histogram distributions of the thermographic images. These features were then extracted from the affected and unaffected extremities of each image. The histogram features of patients with and without vasomotor improvement were compared based on the change in differences between affected and unaffected extremities after 3 months of SCS. The change between improved or not improved was then determined for different characteristics of the patients, such as affected extremity and CRPS type. It was hypothesized that with improved vasomotor symptoms, the affected and unaffected extremities would become more similar and thus the difference would become smaller.
For evaluation of the effects of closed-loop SCS on CPRS mechanisms, measurements were conducted before implantation and up to 6 months of follow-up. Measurements include thermographic images, CRPS severity score (CSS), Condition Pain Modulation (CPM), Temporal Summation (TS) and determination of sIL-2R levels using blood samples. In addition, conventional SCS was compared to closed-loop SCS, with patients randomized to receive both settings during the follow-up for two months.

Results: The following histogram features were selected: mean, median, minimum, maximum, peak, skewness, kurtosis, and quartile range. Based on 28 patients, for patients with improved vasomotor symptoms a decrease in difference was observed for histogram features mean, median, minimum, peak and quartile range. Furthermore, statistically significant differences were found in patients with vasomotor symptoms at baseline compared to patients without vasomotor symptoms for the mean (p=0.026), median (p=0.046), minimum (p=0.008), and quartile range (p=0.016). For patients with a cold CRPS type, statistically significant different feature values were observed between patients with and without vasomotor improvement in maximum (p=0.024), peak (p=0.016), and quartile range (p=0.027), with a decrease of histogram feature values. No statistically significant differences were found between the affected upper or lower extremities...

Background: Spinal cord stimulation (SCS) is a last resort therapy for chronic pain syndromes, of which the exact mechanisms of action remain unknown. Although often effective, not all patients have sufficient pain reduction after implantation. Objective: Analyse the acute effects of tonic and burst SCS on spectral features in the whole brain and in specific brain regions using magnetoencephalography (MEG). Methods: Resting state MEG recordings of seventeen patients with SCS set to a cyclic stimulation program were analysed. Spectral analysis was done by computing power spectrum densities and calculating the ratio between different frequency bands. Time frequency decompositions were then computed to image the spectral changes over time. Results: I showed a shift of power to the 7-10 Hz range during tonic and burst stimulation ON, and that burst stimulation modulated the regions involved in the medial pathway more than tonic stimulation did. I also hypothesised that burst stimulation has a lingering effect on the neuronal activity after it is switched OFF. Lastly, I showed that alpha power decreased at the moment the stimulation switched ON or OFF. Conclusion: Although most findings were not statistically significant, the results were similar to the results of studies with patients who had longer exposure to SCS. There is still room for improvement in SCS treatment, and MEG analysis of acute modulation can help to gain more insight in its working mechanisms.