[Potential Impact of Public Communication on Emergency Presentations due to Headache during the Covid-19 Pandemic]. / Epidemiologische Untersuchung zu möglichen Auswirkungen öffentlicher Kommunikation im Rahmen der COVID-19-Pandemie auf Notfallvorstellungen von Kopfschmerzpatient*innen.

Headache is a frequent presenting symptom in the emergency department. While most cases are of benign aetiology, it is crucially important to identify potentially dangerous underlying disorders. We hypothesized an increase in headache-related emergency presentations after venous thrombosis of cerebral sinuses had been identified as a rare side effect of vaccination with adenovirus vector-based Coronavirus-disease 2019 (COVID-19) vaccines and that information had been publicly communicated by the Paul Ehrlich Institute. Data from patients with the diagnosis of primary headache disorders or unspecified headache presenting to the Interdisciplinary Emergency Department of the University Medicine Mannheim were retrospectively analysed. Based on vaccination dashboard data published by the Federal Ministry of Health, calendar weeks 14-30 and 47-48, on the one hand, and 1-13 and 31-46, on the othe, were categorized into a variable "vaccination epoch" (14-30, 47-48: high vaccination activity if≥3 million weekly vaccinations in Germany; 1-13, 31-46: low vaccination activity if<3 million weekly vaccinations). The number of patients with headache was the dependent variable. A Poisson regression was performed to analyze whether the frequency of events, i. e., patient presentations, was a function of year (2019, 2021), epoch (high, low) and an interaction of year and epoch - the latter reflecting an impact of vaccination activity during the pandemic and expressed as incidence rate ratio. Compared to 2019, there was a more than 70% increase in presentations due to headache during periods of high vaccination activity in 2021 (p<0.001; 95% confidence interval 1.272-2.316), in 25% of presentations in 2021, patients considered their headache as vaccination-associated. Public communication and resulting nocebo effects may, among other factors, have contributed to our observation of increased numbers of emergency headache presentations, illustrating the impact of public distribution of medical information on practical aspects of emergency care during crises.

Cerebrospinal fluid-related tissue damage in multiple sclerosis patients with iron rim lesions.

BACKGROUND: In multiple sclerosis (MS), iron rim lesions (IRLs) are associated with pronounced tissue damage, higher disease severity and have been suggested as an imaging marker of chronic active inflammation behind the blood-brain barrier indicating progression. Furthermore, chronic intrathecal compartmentalized inflammation has been suggested to be a mediator of a cerebrospinal fluid (CSF)-related tissue damage. OBJECTIVE: To investigate CSF markers of intrathecal inflammation in patients with at least one IRL compared to patients without IRLs and to investigate tissue damage in lesions and normal-appearing white matter (NAWM) with proximity to CSF spaces. METHODS: A total of 102 patients (51 with at least 1 IRL and 51 age-/sex-matched patients without IRL) scanned with the same 3T magnetic resonance imaging (MRI) and having CSF analysis data were included. RESULTS: Patients with at least one IRL had higher disability scores, higher lesion volumes, lower brain volumes and a higher intrathecal immunoglobulin G (IgG) synthesis. Apparent diffusion coefficient (ADC) values in IRLs were higher compared to non-IRLs. We observed a negative linear correlation of ADC values in all tissue classes and distance to CSF, which was stronger in patients with high IgG quotients. CONCLUSION: IRLs are associated with higher intrathecal IgG synthesis. CSF-mediated intrathecal smouldering inflammation could explain a CSF-related gradient of tissue damage.

Impact of disease-modifying therapies on evolving tissue damage in iron rim multiple sclerosis lesions.

We investigated the impact of disease-modifying therapies (DMTs) on the evolving tissue damage in iron rim multiple sclerosis lesions using a novel post-processing magnetic resonance imaging (MRI) approach, the T1/T2 ratio. In this study, on baseline and 1-year follow-up, T1/T2 ratios of iron rim lesions (IRLs) in patients starting DMT (dimethyl fumarate, fingolimod, ocrelizumab) did not statistically differ compared to patients without DMT. At the second follow-up, T1/T2 ratios were significantly lower in IRLs in patients without DMT (p = 0.002), suggesting that DMTs have a beneficial delayed effect on lesion evolution and tissue matrix damage in IRLs.

Association of iron rim lesions with brain and cervical cord volume in relapsing multiple sclerosis.

OBJECTIVES: In multiple sclerosis (MS), iron rim lesions (IRLs) are indicators of chronic low-grade inflammation and ongoing tissue destruction. The aim of this study was to assess the relationship of IRLs with clinical measures and magnetic resonance imaging (MRI) markers, in particular brain and cervical cord volume. METHODS: Clinical and MRI parameters from 102 relapsing MS patients (no relapses for at least 6 months, no contrast-enhancing lesions) were included; follow-up data obtained after 12 months was available in 49 patients. IRLs were identified on susceptibility-weighted images (SWIs). In addition to standard brain and spinal cord MRI parameters, normalised cross-sectional area (nCSA) of the upper cervical cord was calculated. RESULTS: Thirty-eight patients had at least one IRL on SWI MRI. At baseline, patients with IRLs had higher EDSS scores, higher lesion loads (brain and spinal cord), and lower cortical grey matter volumes and a lower nCSA. At follow-up, brain atrophy rates were higher in patients with IRLs. IRLs correlated spatially with T1-hypointense lesions. CONCLUSIONS: Relapsing MS patients with IRLs showed more aggressive MRI disease characteristics in both the cross-sectional and longitudinal analyses. KEY POINTS: • Multiple sclerosis patients with iron rim lesions had higher EDSS scores, higher brain and spinal cord lesion loads, lower cortical grey matter volumes, and a lower normalised cross-sectional area of the upper cervical spinal cord. • Iron rim lesions are a new lesion descriptor obtained from susceptibility-weighted MRI. Our data suggests that further exploration of this lesion characteristic in regard to a poorer prognosis in multiple sclerosis patients is warranted.

Short-term brain atrophy evolution after initiation of immunotherapy in a real-world multiple sclerosis cohort.

BACKGROUND AND PURPOSE: In multiple sclerosis (MS), brain atrophy measurements have emerged as an important biomarker reflecting neurodegeneration and disability progression. However, due to several potential confounders, investigation of brain atrophy in clinical routine and even in controlled clinical studies can be challenging. The aim of this study was to investigate the short-term dynamics of brain atrophy development after initiation of disease-modifying therapy (DMT) in a "real-world setting." METHODS: In this retrospective study, we included MS patients starting DMT (natalizumab, fingolimod, dimethyl fumarate, or interferon-ß1a) or without DMT, availability of a baseline MRI, and two annual follow-up scans on the same MRI system. Two-timepoint percentage brain volume changes (PBVCs) were calculated. RESULTS: Fifty-five MS patients (12 patients starting DMT with natalizumab, 7 fingolimod, 14 dimethyl fumarate, 11 interferon-ß1a, and 11 patients without DMT) were included. We found the highest PBVCs in the first 12 months after initiation of natalizumab treatment. Furthermore, the PBVCs in our study were very much comparable to the results observed by other groups, as well as for fingolimod, dimethyl fumarate, and interferon-ß1a. CONCLUSION: We found PBVCs that are comparable to the results of previous studies, suggesting that brain atrophy, assessed on 3D MRI data sets acquired on the same 3T MRI, provides a robust MS biomarker.

Multiple sclerosis iron rim lesions are linked to impaired cervical spinal cord integrity using the T1/T2-weighted ratio.

BACKGROUND AND PURPOSE: In multiple sclerosis (MS), iron rim lesions (IRLs) are characterized by pronounced tissue matrix damage. The T1/T2-weighted (T1/T2w) ratio represents a postprocessing MRI approach to investigate tissue integrity, but studies investigating spinal cord pathology are missing until now. The aim of this study was to characterize tissue integrity using the T1/T2w ratio in lesions and the normal-appearing white and gray matter (NAWM, NAGM) in the spinal cord and brain in MS patients with and without brain IRLs. METHODS: Forty MS patients (20 patients with at least one brain IRL and 20 age- and sex-matched patients without IRLs) were included. Normalized cross-sectional area (nCSA) of the upper cervical cord was calculated in addition to T1/T2w values and standard brain and spinal cord MRI parameters. RESULTS: Patients with IRLs had higher disability scores, a smaller nCSA, and a higher cervical T2 lesion volume. T1/T2w values of brain IRLs were significantly lower compared to non-IRLs (p < .001). Furthermore, T1/T2w values of lesions were significantly lower compared to the NAGM and NAWM, both in the brain and the spinal cord (p < .05 for all comparisons). T1/T2w values of the NAGM and NAWM in the brain and spinal cord did not statistically differ between the IRL group and the non-IRL group. CONCLUSION: IRLs constitute an imaging marker of disease severity. T1/T2w ratio maps represent an interesting technique to capture diffuse tissue properties. Calculation of T1/T2w ratio maps of the spinal cord might provide additional insights into the pathophysiological processes of MS.

Exploring (peri-) lesional and structural connectivity tissue damage through T1/T2-weighted ratio in iron rim multiple sclerosis lesions.

OBJECTIVE: In multiple sclerosis (MS), iron rim lesions (IRLs) on magnetic resonance imaging (MRI) are associated with pronounced intralesional tissue damage. The aim of this study was to investigate (peri-)lesional and structural connectivity tissue damage in IRLs compared to non-IRLs. MATERIAL AND METHODS: MRI was acquired on a 3 T system. Tissue integrity was assessed using the T1/T2-weighted (T1/T2w) ratio. Furthermore, we assessed the impact on structural network connectivity accounting for differences in lesion volumes and T1/T2w values. RESULTS: Seventy-six patients (38 with at least one IRL and 38 age- and sex-matched patients without IRLs) were included. In the IRL-group, T1/T2w ratios of IRLs were significantly lower compared to non-IRLs (p < 0.05). When comparing the T1/T2w ratios in non-IRLs between the IRL-group and non-IRL group, there was no significant difference (p = 0.887). We observed a centrifugal decrease in microstructural damage from lesions to the perilesional white matter. In the IRL-group, T1/T2w ratios in the perilesional white matter 3-8 mm distant to the lesion were significantly lower in IRLs compared to non-IRLs. We found no significant differences in the amount of network disruption between both lesion types (p = 0.122). CONCLUSION: T1/T2w represents an interesting candidate to capture a pronounced intra- and perilesional tissue damage of IRLs. However, our preliminary results suggest that a pronounced tissue damage might not result in a higher disruption to structural connectivity networks in IRLs.

Spatial distribution of multiple sclerosis iron rim lesions and their impact on disability.

BACKGROUND: In multiple sclerosis (MS), iron rim lesions (IRLs) on magnetic resonance imaging (MRI) have been suggested as an imaging marker of disease progression. However, the exact mechanisms how they contribute to disability are yet not completely known. Strategic lesion location may be an important factor concerning the impact of focal lesions on clinical disability. Therefore, the aim of this study was to investigate the spatial distribution of IRLs compared to non-IRLs and their impact on disability. METHODS: We retrospectively identified 67 patients with at least one IRL on MRI and 67 age- and sex-matched patients without IRLs. We compared the spatial distribution of lesions between both groups and between IRLs and non-IRLs in patients with IRLs. Furthermore, we assessed the relationship between lesion localisation and disability on a voxel-by-voxel basis and investigated the impact on structural network disruptions. RESULTS: Patients with IRLs had higher disability scores (median Expanded Disability Status Scale score (range): 3.0 (0 - 8.5) versus 1.5 (0 - 6.5); p = 0.001; median pyramidal functional system score (range): 1.0 (0 - 5) versus 0 (0 - 4); p = 0.003), significantly lower brain volumes (mean normal-appearing grey matter volume: 749.66 ± 60.58 versus 785.83 ± 53.71 mL; mean normal-appearing white matter volume: 723.58 ± 60.13 versus 753.25 ± 69.61 mL; mean deep grey matter volume: 33.21 ± 4.19 versus 35.85 ± 4.89 mL; p < 0.05 for all comparisons) and a significantly higher total T2 lesion volume (mean: 9.96 ± 11.6 versus 4.31 ± 8.9 mL; p < 0.001). We found no neuroanatomical regions that were more often affected by IRLs. Furthermore, comparing the overall network disruption in the IRL group, IRLs caused less network disruption/mL lesion size compared to non-IRLs (1.54% / mL versus 2.0% / mL; p < 0.05). CONCLUSION: IRLs are associated with higher disability scores. However, our results suggest that a higher disability is not explained by the sheer topography of IRLs or their network disruption.

Hippocampal subfield involvement in patients with transient global amnesia.

BACKGROUND AND PURPOSE: Transient global amnesia (TGA) is a rare neurological disorder causing a transient disturbance of episodic long-term memory. Its etiology remains yet to be identified; the only consistently reported findings in patients with TGA are small hyperintense lesions in the hippocampus on diffusion-weighted magnetic resonance imaging (DWI). The aim of this study was to define whether these lesions are subfield specific, as suggested previously. METHODS: High-resolution multiplanar reformation T1 and DWI of the hippocampus were acquired in 25 patients after TGA with a total of 43 hippocampal lesions. Hippocampal subfields were determined using the FreeSurfer software and the location of the DWI lesions was transformed to the T1 images after data co-registration. Additionally, hippocampal subfield volumes in each patient were calculated and compared with that of 20 healthy controls. RESULTS: Hippocampal lesions were most frequently detected in the cornu ammonis area 1 (CA1) subfield (30.2%), the hippocampal tail (28.0%), and the subiculum (21.0%); however, lesions were also found in other subfields. There was no significant difference between patients and controls concerning the volumes of the hippocampal subfields. CONCLUSIONS: Contrasting previous assumptions, we found DWI hyperintense lesions not to be restricted to the CA1 subfield. The visualization of focal hippocampal lesions on diffusion imaging located to several different hippocampal subfields suggests a potential pathophysiology of TGA independent of microstructural hippocampal anatomy and subfield-specific vulnerability.

Sex-Specific Differences in Pre-Stroke Characteristics Reveal Vulnerability of Elderly Women.

While the sexually dimorphic character of ischemic stroke has been acknowledged along several dimensions, age-specific sex disparities regarding pre-stroke characteristics in particular have received comparatively little attention. This study aimed to identify age-dependent associations between sex and risk factors, premorbidity, and living situation in patients with ischemic stroke to foster the continuing development of dedicated preventative strategies. In a retrospective single-center study, data of patients with acute ischemic stroke (AIS) admitted to the Department of Neurology, University Hospital Mannheim, Germany, between June 2004−June 2020 were included; AIS frequency, vascular risk factors, premorbidity, living situation, and stroke etiology were analyzed across sexes and different age spectra. From a total of 11,003 patients included in the study, 44.1% were female. Women aged >70−≤90 years showed a pronounced increase in stroke frequency, lived alone significantly more frequently, and had a significantly higher degree of pre-stroke disability than men; however, only hypertension and atrial fibrillation were more prevalent in women in this age segment. The seventh and eighth decades are a critical time in which the pre-stroke risk profile changes resulting in an increase in stroke morbidity in women. This emphasizes the relevance of and need for an approach to stroke prevention that is both targeted and integrative.

MRI predictors for the conversion from contrast-enhancing to iron rim multiple sclerosis lesions.

BACKGROUND: In multiple sclerosis (MS), iron rim lesions (IRLs) are characterized by progressive tissue matrix damage. Therefore, early identification could represent an interesting target for therapeutic intervention to minimize evolving tissue damage. The aim of this study was to identify magnetic resonance imaging (MRI) parameters predicting the conversion from contrast-enhancing to IRLs. METHODS: We retrospective identified MS patients scanned on the same 3 T MRI system presenting at least one supratentorial contrast-enhancing lesion (CEL) and a second MRI including susceptibility-weighted images after at least 3 months. On baseline MRI, pattern of contrast-enhancement was categorized as "nodular" or "ring-like", apparent diffusion coefficient (ADC) maps were assessed for the presence of a peripheral hypointense rim. Lesion localization, quantitative volumes (ADC, lesion volume) and the presence of a central vein were assessed. RESULTS: Eighty-nine acute contrast-enhancing lesions in 54 MS patients were included. On follow-up, 16/89 (18%) initially CELs converted into IRLs. CELs that converted into IRLs were larger and demonstrated significantly more often a ring-like contrast-enhancement pattern and a peripheral hypointense rim on ADC maps. Logistic regression model including the covariables pattern of contrast-enhancement and presence of a hypointense rim on ADC maps showed the best predictive performance (area under the curve = 0.932). DISCUSSION: The combination of a ring-like contrast-enhancement pattern and a peripheral hypointense rim on ADC maps has the ability to predict the evolution from acute to IRLs. This could be of prognostic value and become a target for early therapeutic intervention to minimize the associated tissue damage.

Consistency of the "central vein sign" in chronic multiple sclerosis lesions.

BACKGROUND: In recent years, there has been an increasing interest in the central vein sign (CVS) as a new imaging marker and previous cross-sectional studies demonstrated that the CVS has the potential to discriminate multiple sclerosis (MS) lesions from non-MS lesions. The aim of this study was to investigate the consistency of the CVS in a longitudinal magnetic resonance imaging (MRI) data set. METHODS: 3T MRI datasets from seventy-one people with MS acquired at baseline and after 12 months-follow-up were analyzed. Chronic lesions were identified on fluid-attenuated inversion recovery (FLAIR) images. Co-registered susceptibility-weighted/FLAIR images were analyzed for the presence of a CVS at baseline and follow-up. RESULTS: A total of 183 chronic lesions were included in the final analysis. At baseline MRI, a CVS was detectable in 141/183 (77%) lesions. Overall, the CVS was consistent in 114/141 (81%) lesions (Cohen's kappa = 0.46, standard error = 0.07). CONCLUSION: The CVS is a rather stable feature in chronic MS lesions and therefore represents a robust imaging marker that could increase the specificity of MRI in MS.

Long-term dynamics of multiple sclerosis iron rim lesions.

BACKGROUND: Several studies have pointed out that seemingly chronic multiple sclerosis (MS) lesions may also be in inflammatory states. In pathological studies, up to 40% of chronic MS lesions are characterized as "chronic active" or "smoldering" lesions that are characterized by a rim of iron-laden proinflammatory macrophages/microglial cells at the lesion edge with low-grade continuous myelin breakdown. In vivo, these lesions can be visualized as "iron rim lesions" (IRLs) on susceptibility-weighted imaging (SWI). The aim of this study was to investigate the long-term dynamics of IRLs in vivo for a more detailed evolution of dynamic lesion volume changes occurring over time. METHODS: We retrospectively identified patients with MS who were followed for at least 36 months (up to 72 months) and underwent at least an annual MRI on the same 3 Tsystem. Using Voxel-Guided Morphometry (VGM) we investigated regional volume changes within lesions and correlated these findings with SWI for the presence of a characteristic hypointense lesion rim. To estimate tissue damage, apparent diffusion coefficient (ADC) values for every lesion at baseline and follow-up MRIs were determined. RESULTS: Forty-three patients were included in the study. Overall, we identified 302 supratentorial non-confluent MS lesions (52 persistent IRLs, nine transient IRLs, 228 non-IRLs and 13 acute contrast-enhancing lesions). During follow-up, persistent IRLs significantly enlarged, whereas non-IRLs showed a tendency to shrink. At baseline MRI, ADC values were significantly higher in persistent IRLs (1.23 × 10-3 mm/s2) compared to non-IRLs (1.01 × 10-3 mm/s2; p < 0.001), but not compared to transient IRLs (1.06 × 10-3 mm/s2; p = 0.15) and contrast-enhancing lesions (1.15 × 10-3 mm/s2; p = 1.0). During follow-up, ADC values significantly increased more often in persistent IRLs compared to all other lesion types (p < 0.0001). CONCLUSIONS: Our long-term data demonstrate that persistent IRLs enlarge during disease duration, whereas non-IRLs show a tendency to shrink. Furthermore, IRLs are associated with sustained tissue damage, supporting the notion that IRLs could represent a new imaging biomarker in MS.

IMI2-PainCare-BioPain-RCT1: study protocol for a randomized, double-blind, placebo-controlled, crossover, multi-center trial in healthy subjects to investigate the effects of lacosamide, pregabalin, and tapentadol on biomarkers of pain processing observed by peripheral nerve excitability testing (NET).

BACKGROUND: Few new drugs have been developed for chronic pain. Drug development is challenged by uncertainty about whether the drug engages the human target sufficiently to have a meaningful pharmacodynamic effect. IMI2-PainCare-BioPain-RCT1 is one of four similarly designed studies that aim to link different functional biomarkers of drug effects on the nociceptive system that could serve to accelerate the future development of analgesics. This study focusses on biomarkers derived from nerve excitability testing (NET) using threshold tracking of the peripheral nervous system. METHODS: This is a multisite single-dose, subject and assessor-blind, randomized, placebo-controlled, 4-period, 4-way crossover, pharmacodynamic (PD), and pharmacokinetic (PK) study in healthy subjects. Biomarkers derived from NET of large sensory and motor fibers and small sensory fibers using perception threshold tracking will be obtained before and three times after administration of three medications known to act on the nociceptive system (lacosamide, pregabalin, tapentadol) and placebo, given as a single oral dose with at least 1 week apart. Motor and sensory NET will be assessed on the right wrist in a non-sensitized normal condition while perception threshold tracking will be performed bilaterally on both non-sensitized and sensitized forearm skin. Cutaneous high-frequency electrical stimulation is used to induce hyperalgesia. Blood samples will be taken for pharmacokinetic purposes and pain ratings as well as predictive psychological traits will be collected. A sequentially rejective multiple testing approach will be used with overall alpha error of the primary analysis split across the two primary outcomes: strength-duration time constant (SDTC; a measure of passive membrane properties and nodal persistent Na+ conductance) of large sensory fibers and SDTC of large motor fibers comparing lacosamide and placebo. The key secondary endpoint is the SDTC measured in small sensory fibers. Remaining treatment arm effects on key NET outcomes and PK modelling are other prespecified secondary or exploratory analyses. DISCUSSION: Measurements of NET using threshold tracking protocols are sensitive to membrane potential at the site of stimulation. Sets of useful indices of axonal excitability collectively may provide insights into the mechanisms responsible for membrane polarization, ion channel function, and activity of ionic pumps during the process of impulse conduction. IMI2-PainCare-BioPain-RCT1 hypothesizes that NET can serve as biomarkers of target engagement of analgesic drugs in this compartment of the nociceptive system for future Phase 1 clinical trials. Phase 2 and 3 clinical trials could also benefit from these tools for patient stratification. TRIAL REGISTRATION: This trial was registered 25/06/2019 in EudraCT ( 2019-000942-36 ).

IMI2-PainCare-BioPain-RCT2 protocol: a randomized, double-blind, placebo-controlled, crossover, multicenter trial in healthy subjects to investigate the effects of lacosamide, pregabalin, and tapentadol on biomarkers of pain processing observed by non-invasive neurophysiological measurements of human spinal cord and brainstem activity.

BACKGROUND: IMI2-PainCare-BioPain-RCT2 is one of four similarly designed clinical studies aiming at profiling a set of functional biomarkers of drug effects on specific compartments of the nociceptive system that could serve to accelerate the future development of analgesics. IMI2-PainCare-BioPain-RCT2 will focus on human spinal cord and brainstem activity using biomarkers derived from non-invasive neurophysiological measurements. METHODS: This is a multisite, single-dose, double-blind, randomized, placebo-controlled, 4-period, 4-way crossover, pharmacodynamic (PD) and pharmacokinetic (PK) study in healthy subjects. Neurophysiological biomarkers of spinal and brainstem activity (the RIII flexion reflex, the N13 component of somatosensory evoked potentials (SEP) and the R2 component of the blink reflex) will be recorded before and at three distinct time points after administration of three medications known to act on the nociceptive system (lacosamide, pregabalin, tapentadol), and placebo, given as a single oral dose in separate study periods. Medication effects on neurophysiological measures will be assessed in a clinically relevant hyperalgesic condition (high-frequency electrical stimulation of the skin), and in a non-sensitized normal condition. Patient-reported outcome measures (pain ratings and predictive psychological traits) will also be collected; and blood samples will be taken for pharmacokinetic modelling. A sequentially rejective multiple testing approach will be used with overall alpha error of the primary analysis split between the two primary endpoints, namely the percentage amplitude changes of the RIII area and N13 amplitude under tapentadol. Remaining treatment arm effects on RIII, N13 and R2 recovery cycle are key secondary confirmatory analyses. Complex statistical analyses and PK-PD modelling are exploratory. DISCUSSION: The RIII component of the flexion reflex is a pure nociceptive spinal reflex widely used for investigating pain processing at the spinal level. It is sensitive to different experimental pain models and to the antinociceptive activity of drugs. The N13 is mediated by large myelinated non-nociceptive fibers and reflects segmental postsynaptic response of wide dynamic range dorsal horn neurons at the level of cervical spinal cord, and it could be therefore sensitive to the action of drugs specifically targeting the dorsal horn. The R2 reflex is mediated by large myelinated non-nociceptive fibers, its circuit consists of a polysynaptic chain lying in the reticular formation of the pons and medulla. The recovery cycle of R2 is widely used for assessing brainstem excitability. For these reasons, IMI2-PainCare-BioPain-RCT2 hypothesizes that spinal and brainstem neurophysiological measures can serve as biomarkers of target engagement of analgesic drugs for future Phase 1 clinical trials. Phase 2 and 3 clinical trials could also benefit from these tools for patient stratification. TRIAL REGISTRATION: This trial was registered on 02 February 2019 in EudraCT ( 2019-000755-14 ).

Quantitative MRI texture analysis in chronic active multiple sclerosis lesions.

OBJECTIVE: Recently, there has been an increasing interest in "chronic enlarging" or "chronic active" multiple sclerosis (MS) lesions that are associated with clinical disability. However, investigation of dynamic lesion volume changes requires longitudinal MRI data from two or more time points. The aim of this study was to investigate the application of texture analysis (TA) on baseline T1-weighted 3D magnetization-prepared rapid acquisition gradient-echo (MPRAGE) images to differentiate chronic active from chronic stable MS lesions. MATERIAL AND METHODS: To identify chronic active lesions as compared to non-enhancing stable lesions, two MPRAGE datasets acquired on a 3 T MRI at baseline and after 12 months follow-up were applied to the Voxel-Guided Morphometry (VGM) algorithm. TA was performed on the baseline MPRAGE images, 36 texture features were extracted for each lesion. RESULTS: Overall, 374 chronic MS lesions (155 chronic active and 219 chronic stable lesions) from 60 MS patients were included in the final analysis. Multiple texture features including "DISCRETIZED_HISTO_Energy", "GLCM_Energy", "GLCM_Contrast" and "GLCM_Dissimilarity" were significantly higher in chronic active as compared to chronic stable lesions. Partial least squares regression yielded an area under the curve of 0.7 to differentiate both lesion types. CONCLUSION: Our results suggest that multiple texture features extracted from MPRAGE images indicate higher intralesional heterogeneity, however they demonstrate only a fair accuracy to differentiate chronic active from chronic stable MS lesions.

Human surrogate models of central sensitization: A critical review and practical guide.

BACKGROUND: As in other fields of medicine, development of new medications for management of neuropathic pain has been difficult since preclinical rodent models do not necessarily translate to the clinics. Aside from ongoing pain with burning or shock-like qualities, neuropathic pain is often characterized by pain hypersensitivity (hyperalgesia and allodynia), most often towards mechanical stimuli, reflecting sensitization of neural transmission. DATA TREATMENT: We therefore performed a systematic literature review (PubMed-Medline, Cochrane, WoS, ClinicalTrials) and semi-quantitative meta-analysis of human pain models that aim to induce central sensitization, and generate hyperalgesia surrounding a real or simulated injury. RESULTS: From an initial set of 1569 reports, we identified and analysed 269 studies using more than a dozen human models of sensitization. Five of these models (intradermal or topical capsaicin, low- or high-frequency electrical stimulation, thermode-induced heat-injury) were found to reliably induce secondary hyperalgesia to pinprick and have been implemented in multiple laboratories. The ability of these models to induce dynamic mechanical allodynia was however substantially lower. The proportion of subjects who developed hypersensitivity was rarely provided, giving rise to significant reporting bias. In four of these models pharmacological profiles allowed to verify similarity to some clinical conditions, and therefore may inform basic research for new drug development. CONCLUSIONS: While there is no single "optimal" model of central sensitization, the range of validated and easy-to-use procedures in humans should be able to inform preclinical researchers on helpful potential biomarkers, thereby narrowing the translation gap between basic and clinical data. SIGNIFICANCE: Being able to mimic aspects of pathological pain directly in humans has a huge potential to understand pathophysiology and provide animal research with translatable biomarkers for drug development. One group of human surrogate models has proven to have excellent predictive validity: they respond to clinically active medications and do not respond to clinically inactive medications, including some that worked in animals but failed in the clinics. They should therefore inform basic research for new drug development.

IMI2-PainCare-BioPain-RCT3: a randomized, double-blind, placebo-controlled, crossover, multi-center trial in healthy subjects to investigate the effects of lacosamide, pregabalin, and tapentadol on biomarkers of pain processing observed by electroencephalography (EEG).

BACKGROUND: IMI2-PainCare-BioPain-RCT3 is one of four similarly designed clinical studies aiming at profiling a set of functional biomarkers of drug effects on the nociceptive system that could serve to accelerate the future development of analgesics, by providing a quantitative understanding between drug exposure and effects of the drug on nociceptive signal processing in human volunteers. IMI2-PainCare-BioPain-RCT3 will focus on biomarkers derived from non-invasive electroencephalographic (EEG) measures of brain activity. METHODS: This is a multisite single-dose, double-blind, randomized, placebo-controlled, 4-period, 4-way crossover, pharmacodynamic (PD) and pharmacokinetic (PK) study in healthy subjects. Biomarkers derived from scalp EEG measurements (laser-evoked brain potentials [LEPs], pinprick-evoked brain potentials [PEPs], resting EEG) will be obtained before and three times after administration of three medications known to act on the nociceptive system (lacosamide, pregabalin, tapentadol) and placebo, given as a single oral dose in separate study periods. Medication effects will be assessed concurrently in a non-sensitized normal condition and a clinically relevant hyperalgesic condition (high-frequency electrical stimulation of the skin). Patient-reported outcomes will also be collected. A sequentially rejective multiple testing approach will be used with overall alpha error of the primary analysis split between LEP and PEP under tapentadol. Remaining treatment arm effects on LEP or PEP or effects on EEG are key secondary confirmatory analyses. Complex statistical analyses and PK-PD modeling are exploratory. DISCUSSION: LEPs and PEPs are brain responses related to the selective activation of thermonociceptors and mechanonociceptors. Their amplitudes are dependent on the responsiveness of these nociceptors and the state of the pathways relaying nociceptive input at the level of the spinal cord and brain. The magnitude of resting EEG oscillations is sensitive to changes in brain network function, and some modulations of oscillation magnitude can relate to perceived pain intensity, variations in vigilance, and attentional states. These oscillations can also be affected by analgesic drugs acting on the central nervous system. For these reasons, IMI2-PainCare-BioPain-RCT3 hypothesizes that EEG-derived measures can serve as biomarkers of target engagement of analgesic drugs for future Phase 1 clinical trials. Phase 2 and 3 clinical trials could also benefit from these tools for patient stratification. TRIAL REGISTRATION: This trial was registered 25/06/2019 in EudraCT ( 2019%2D%2D001204-37 ).

Correlates and importance of neglect-like symptoms in complex regional pain syndrome.

Neglect-like symptoms (NLS) are frequently observed in complex regional pain syndrome (CRPS). The clinical meaning of NLS, however, is largely unknown. Therefore, this study sets out to assess the importance of NLS for patient outcome and to explore their clinical correlates. We assessed NLS in a group of 53 patients with CRPS and compared the results to 28 healthy volunteers. To define the origin of the NLS reports, we tested the subjective visual midline, performed a limb-laterality recognition test, and quantitative sensory testing. In addition, psychological and pain assessment scales were completed. Tests were analyzed with univariate and multivariate approaches. After 6 months, patients were reassessed and the influence of NLS on pain outcome was determined. Most patients reported NLS in the questionnaire, whereas subjective visual midline and limb-laterality recognition test in contrast to previous studies did not reveal perceptual disturbances. Neglect-like symptom scores were associated with pain and pain catastrophizing in acute CRPS and anxiety and thermal sensory loss in chronic CRPS. Furthermore, high NLS scores had a negative impact on pain outcome after 6 months. Our results indicate that NLS have a different meaning in acute and chronic CRPS and might be of prognostic value. Possibly, treatment should focus on reducing NLS.