Human Studies

Topographic organisation is a hallmark of vertebrate cortex architecture, characterised by ordered projections of the body's sensory surfaces onto brain systems. High-resolution functional magnetic resonance imaging (fMRI) has proven itself as a valuable tool to investigate the cortical landscape and its (mal-)adaptive plasticity with respect to various body part representations, in particular extremities such as the hand and fingers. Less is known, however, about the cortical representation of the human back. We therefore validated a novel, MRI-compatible method of mapping cortical representations of sensory afferents of the back, using vibrotactile stimulation at varying frequencies and paraspinal locations, in conjunction with fMRI. We expected high-frequency stimulation to be associated with differential neuronal activity in the primary somatosensory cortex (S1) compared with low-frequency stimulation and that somatosensory representations would differ across the thoracolumbar axis. We found significant differences between neural representations of high-frequency and low-frequency stimulation and between representations of thoracic and lumbar paraspinal locations, in several bilateral S1 sub-regions, and in regions of the primary motor cortex (M1). High-frequency stimulation preferentially activated Brodmann Area (BA) regions BA3a and BA4p, whereas low-frequency stimulation was more encoded in BA3b and BA4a. Moreover, we found clear topographic differences in S1 for representations of the upper and lower back during high-frequency stimulation. We present the first neurobiological validation of a method for establishing detailed cortical maps of the human back, which might serve as a novel tool to evaluate the pathological significance of neuroplastic changes in clinical conditions such as chronic low back pain.

Erenumab, a fully human monoclonal antibody that targets the calcitonin gene-related peptide receptor, has demonstrated efficacy and safety in the prevention of episodic and chronic migraine. There exists an unmet need to establish the safety of erenumab in older individuals, in view of existing multiple comorbidities, polypharmacy, and age-related physiological changes. This pooled analysis of five large migraine-prevention studies examined the safety of erenumab stratified across age groups, particularly in older populations.

The aim of the current study was to determine whether tension-type headache (TTH) and migraine with or without aura have altered anterior and posterior circulation compared with normal volunteers as assessed by Transcranial Doppler (TCD) ultrasonography. The study included 24 patients with chronic TTH and 37 patients with migraine (16 with aura and 21 without aura) classified according to the diagnostic criteria of the International Headache Society 2018. They were compared with a control group of 50 age- and sex-matched healthy volunteers. Each participant was examined with TCD ultrasonography of the middle, anterior and posterior cerebral and vertebral arteries (MCA, ACA, PCA, and VA) at rest. Patients in the TTH group had a significantly lower peak systolic velocity (PSV) and mean flow velocity (MFV) in the MCA compared with controls, whereas EDV and MFV in the ACA were significantly higher in the migraine without aura group than controls. Within the 3 groups of patients, the TTH group had significantly lower PSV in the MCA and PCA than the group of migraine with aura. In addition, the TTH group had significantly lower PSV and MFV in the MCA and a lower EDV in the VA than migraine patients without aura. In conclusion, the possibility of cerebrovascular changes is confirmed in the present study in both TTH and migraine without aura. The former has a low MFV in the MCA whereas the latter has a high MFV in the ACA.

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5-2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillbirth. Whilst rare mutations affecting hepatobiliary transporters contribute to the aetiology of ICP, the role of common genetic variation in ICP has not been systematically characterised to date. Here, we perform genome-wide association studies (GWAS) and meta-analyses for ICP across three studies including 1138 cases and 153,642 controls. Eleven loci achieve genome-wide significance and have been further investigated and fine-mapped using functional genomics approaches. Our results pinpoint common sequence variation in liver-enriched genes and liver-specific cis-regulatory elements as contributing mechanisms to ICP susceptibility.

Chronic pain is a complex disease with high prevalence rates, and many individuals who are affected do not receive adequate treatment. As a complement to conventional therapies, eHealth interventions could provide many benefits to a multimodal treatment approach for patients with chronic pain, whereby future use is associated with the acceptance of these interventions.

Existing equipment for quantitative sensory testing is generally expensive and not easily applicable in a clinical setting thus simple bed-side devices are warranted. Pressure hyperalgesia is a common finding in patients with musculoskeletal pain and an experimental model is delayed-onset muscle soreness (DOMS). DOMS is characterised by muscle hyperalgesia and some studies report facilitation of temporal summation of pain. This study aimed to detect DOMS induced muscle hyperalgesia and temporal summation of pain using a newly developed bed-side quantitative sensory testing device to deliver standardised pressure.

The thermal grill illusion of pain (TGIP) is a paradoxical burning pain sensation elicited by the simultaneous application of innocuous cutaneous warm and cold stimuli with a thermode ('thermal grill') consisting of interlaced heated and cooled bars. Its neurophysiological mechanisms are unclear, but TGIP may have some mechanisms in common with pathological pain, including central sensitization in particular, through the involvement of N-methyl-D-aspartate (NMDA) receptors. However, few studies have investigated TGIP in chronic pain patients and its clinical relevance is uncertain. We hypothesized that the TGIP would be increased in comparison with controls in patients with fibromyalgia or irritable bowel syndrome (IBS), which are regarded as typical "nociplastic" primary pain syndromes related to changes in central pain processing. We compared the sensations elicited by a large range of combinations of temperature differentials between the warm and cold bars of a thermal grill applied to the hand between patients with fibromyalgia (n = 30) or IBS (n= 30) and controls (n = 30). The percentage of TGIP responses, and the intensity and unpleasantness of TGIP were significantly greater in patients than controls. Furthermore, positive correlations were found between TGIP intensity and clinical pain intensity, and between TGIP intensity and the cold pain threshold measured on the hand. These results are consistent with our working hypothesis of shared mechanisms between TGIP and clinical pain mechanisms in patients with nociplastic chronic pain syndromes and suggest that TGIP might represent a clinical marker of central sensitization in these patients.

Current research indicates that spinal cord stimulation (SCS) has a positive short-term impact on outcomes such as quality of life, pain, and productivity in patients with chronic neuropathic pain. However, there is a need for studies on larger population samples. This study utilized data from Swedish national registers to analyze change and predictors of sick leave and disability pension two years before and after SCS treatment. Patients with SCS implanted between 2006-2017, and a reference group consisting of 5 individuals matched to each SCS patient without replacement with respect to age, sex, and region of residence, were included. A difference-in-difference approach was used to compare the average change (two years after treatment versus two years before treatment) in net disability days and indirect cost related to disability days for the SCS group, compared to the average change for the reference group. The results showed that SCS treatment in Sweden is associated with a decrease of 21 disability days and consequent decrease in indirect cost of €3,372 in working age patients. Large work loss prior to index date was also demonstrated (average 214 days one year prior), indicating a significant burden on the patient, employers, and the society at large. The number of disability days varied considerably depending on age, sex, socioeconomic variables, and comorbidities, however, the effect of SCS appeared to have little association with patient characteristics. This economic benefit needs to be considered, as well as the clinical outcome, when evaluating the full societal value of SCS.