Publications by authors named "Laura Tiemann"

26 Publications

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Dynamics of brain function in patients with chronic pain assessed by microstate analysis of resting-state electroencephalography.

Pain 2021 Apr 8. Epub 2021 Apr 8.

Department of Neurology, School of Medicine, Technical University of Munich (TUM), Munich, Germany TUM-Neuroimaging Center, School of Medicine, TUM, Munich, Germany Center for Interdisciplinary Pain Medicine, School of Medicine, TUM, Munich, Germany.

Abstract: Chronic pain is a highly prevalent and severely disabling disease that is associated with substantial changes of brain function. Such changes have mostly been observed when analyzing static measures of resting-state brain activity. However, brain activity varies over time, and it is increasingly recognized that the temporal dynamics of brain activity provide behaviorally relevant information in different neuropsychiatric disorders. Here, we therefore investigated whether the temporal dynamics of brain function are altered in chronic pain. To this end, we applied microstate analysis to eyes-open and eyes-closed resting-state electroencephalography data of 101 patients suffering from chronic pain and 88 age- and sex-matched healthy controls. Microstate analysis describes electroencephalography activity as a sequence of a limited number of topographies termed microstates that remain stable for tens of milliseconds. Our results revealed that sequences of 5 microstates, labelled with the letters A to E, consistently described resting-state brain activity in both groups in the eyes-closed condition. Bayesian analysis of the temporal characteristics of microstates revealed that microstate D has a less predominant role in patients than in controls. As microstate D has previously been related to attentional networks and functions, these abnormalities might relate to dysfunctional attentional processes in chronic pain. Subgroup analyses replicated microstate D changes in patients with chronic back pain, while patients with chronic widespread pain did not show microstates alterations. Together, these findings add to the understanding of the pathophysiology of chronic pain and point to changes of brain dynamics specific to certain types of chronic pain.
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http://dx.doi.org/10.1097/j.pain.0000000000002281DOI Listing
April 2021

Modulating Brain Rhythms of Pain Using Transcranial Alternating Current Stimulation (tACS) - A Sham-Controlled Study in Healthy Human Participants.

J Pain 2021 Jun 11. Epub 2021 Jun 11.

Department of Neurology, School of Medicine, Technical University of Munich (TUM), Munich, Germany; TUM-Neuroimaging Center, School of Medicine, TUM, Munich, Germany; Center for Interdisciplinary Pain Medicine, School of Medicine, TUM, Munich, Germany. Electronic address:

Chronic pain is a major health care problem. A better mechanistic understanding and new treatment approaches are urgently needed. In the brain, pain has been associated with neural oscillations at alpha and gamma frequencies, which can be targeted using transcranial alternating current stimulation (tACS). Thus, we investigated the potential of tACS to modulate pain and pain-related autonomic activity in an experimental model of chronic pain in 29 healthy participants. In 6 recording sessions, participants completed a tonic heat pain paradigm and simultaneously received tACS over prefrontal or somatosensory cortices at alpha or gamma frequencies or sham tACS. Concurrently, pain ratings and autonomic responses were collected. Using the present setup, tACS did not modulate pain or autonomic responses. Bayesian statistics confirmed a lack of tACS effects in most conditions. The only exception was alpha tACS over somatosensory cortex where evidence was inconclusive. Taken together, we did not find significant tACS effects on tonic experimental pain in healthy humans. Based on our present and previous findings, further studies might apply refined stimulation protocols targeting somatosensory alpha oscillations. TRIAL REGISTRATION: The study protocol was pre-registered at ClinicalTrials.gov (NCT03805854). PERSPECTIVE: Modulating brain oscillations is a promising approach for the treatment of pain. We therefore applied transcranial alternating current stimulation (tACS) to modulate experimental pain in healthy participants. However, tACS did not modulate pain, autonomic responses, or EEG oscillations. These findings help to shape future tACS studies for the treatment of pain.
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http://dx.doi.org/10.1016/j.jpain.2021.03.150DOI Listing
June 2021

Exploring Dynamic Connectivity Biomarkers of Neuropsychiatric Disorders.

Trends Cogn Sci 2021 05 12;25(5):336-338. Epub 2021 Mar 12.

Department of Neurology and TUM-Neuroimaging Center, School of Medicine, Technical University of Munich, Munich, Germany.

A recent study by Lee et al. showed that a dynamic functional connectivity pattern induced by tonic experimental pain might serve as a biomarker of chronic pain. The study illustrates key topics in translational neuroscience: the differentiation of biomarker functions, the multimodal integration of biomarkers, and the functional relevance of dynamic connectivity.
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http://dx.doi.org/10.1016/j.tics.2021.03.005DOI Listing
May 2021

Infantile Hemangioma: A Review of Current Pharmacotherapy Treatment and Practice Pearls.

J Pediatr Pharmacol Ther 2020 ;25(7):586-599

Infantile hemangioma (IH) is the most common vascular tumor of infancy, affecting as many as 5% to 10% of all infants. The exact cause is unclear, but specific risk factors, such as low birth weight, prematurity, female sex, white race, and family history are associated with IH development. Most IHs are benign and self-resolving, but a small subset of patients with IHs are at risk of severe or life-threatening outcomes. Systemic and topical β-blockers are effective and safe for use in pediatric patients and considered first-line treatment for both complicated and uncomplicated IHs. Recently published guidelines provide a thorough review of IH and management. This article focuses on IH pharmacotherapy and provides practice pearls to support health care providers in IH medication management.
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http://dx.doi.org/10.5863/1551-6776-25.7.586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541030PMC
January 2020

Cognitive impairment in early MS: contribution of white matter lesions, deep grey matter atrophy, and cortical atrophy.

J Neurol 2020 Aug 23;267(8):2307-2318. Epub 2020 Apr 23.

Department of Neurology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Ismaninger Str. 22, 81541, Munich, Germany.

Background: Cognitive impairment (CI) is a frequent and debilitating symptom in MS. To better understand the neural bases of CI in MS, this magnetic resonance imaging (MRI) study aimed to identify and quantify related structural brain changes and to investigate their relation to each other.

Methods: We studied 51 patients with CI and 391 patients with cognitive preservation (CP). We analyzed three-dimensional T1-weighted and FLAIR scans at 3 Tesla. We determined mean cortical thickness as well as volumes of cortical grey matter (GM), deep GM including thalamus, cerebellar cortex, white matter, corpus callosum, and white matter lesions (WML). We also analyzed GM across the whole brain by voxel-wise and surface-based techniques.

Results: Mean disease duration was 5 years. Comparing MS patients with CI and CP, we found higher volumes of WML, lower volumes of deep and cortical GM structures, and lower volumes of the corpus callosum (all corrected p values < 0.05). Effect sizes were largest for WML and thalamic volume (standardized ß values 0.25 and - 0.25). By logistic regression analysis including both WML and thalamic volume, we found a significant effect only for WML volume. Inclusion of the interaction term of WML and thalamic volume increased the model fit and revealed a highly significant interaction of WML and thalamic volume. Moreover, voxel-wise and surface-based comparisons of MS patients with CI and CP showed regional atrophy of both deep and cortical GM independent of WML volume and overall disability, but effect sizes were lower.

Conclusion: Although several mechanisms contribute to CI already in the early stage of MS, WML seem to be the main driver with thalamic atrophy primarily intensifying this effect.
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http://dx.doi.org/10.1007/s00415-020-09841-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359155PMC
August 2020

Longitudinal prevalence and determinants of pain in multiple sclerosis: results from the German National Multiple Sclerosis Cohort study.

Pain 2020 04;161(4):787-796

Department of Neurology, Technical University of Munich (TUM), School of Medicine, Munich, Germany.

Pain is frequent in multiple sclerosis (MS) and includes different types, with neuropathic pain (NP) being most closely related to MS pathology. However, prevalence estimates vary largely, and causal relationships between pain and biopsychosocial factors in MS are largely unknown. Longitudinal studies might help to clarify the prevalence and determinants of pain in MS. To this end, we analyzed data from 410 patients with newly diagnosed clinically isolated syndrome or relapsing-remitting MS participating in the prospective multicenter German National MS Cohort Study (NationMS) at baseline and after 4 years. Pain was assessed by self-report using the PainDETECT Questionnaire. Neuropsychiatric assessment included tests for fatigue, depression, and cognition. In addition, sociodemographic and clinical data were obtained. Prevalence of pain of any type was 40% and 36% at baseline and after 4 years, respectively, whereas prevalence of NP was 2% and 5%. Pain of any type and NP were both strongly linked to fatigue, depression, and disability. This link was even stronger after 4 years than at baseline. Moreover, changes in pain, depression, and fatigue were highly correlated without any of these symptoms preceding the others. Taken together, pain of any type seems to be much more frequent than NP in early nonprogressive MS. Moreover, the close relationship between pain, fatigue, and depression in MS should be considered for treatment decisions and future research on a possible common pathophysiology.
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http://dx.doi.org/10.1097/j.pain.0000000000001767DOI Listing
April 2020

Neural oscillations and connectivity characterizing the state of tonic experimental pain in humans.

Hum Brain Mapp 2020 01 9;41(1):17-29. Epub 2019 Sep 9.

Department of Neurology and TUM-Neuroimaging Center, TUM School of Medicine, Technical University of Munich, Munich, Germany.

Pain is a complex phenomenon that is served by neural oscillations and connectivity involving different brain areas and frequencies. Here, we aimed to systematically and comprehensively assess the pattern of neural oscillations and connectivity characterizing the state of tonic experimental pain in humans. To this end, we applied 10-min heat pain stimuli consecutively to the right and left hand of 39 healthy participants and recorded electroencephalography. We systematically analyzed global and local measures of oscillatory brain activity, connectivity, and graph theory-based network measures during tonic pain and compared them to a nonpainful control condition. Local measures showed suppressions of oscillatory activity at alpha frequencies together with stronger connectivity at alpha and beta frequencies in sensorimotor areas during tonic pain. Furthermore, sensorimotor areas contralateral to stimulation showed significantly increased connectivity to a common area in the medial prefrontal cortex at alpha frequencies. Together, these observations indicate that the state of tonic experimental pain is associated with a sensorimotor-prefrontal network connected at alpha frequencies. These findings represent a step further toward understanding the brain mechanisms underlying long-lasting pain states in health and disease.
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http://dx.doi.org/10.1002/hbm.24784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267966PMC
January 2020

Brain dysfunction in chronic pain patients assessed by resting-state electroencephalography.

Pain 2019 12;160(12):2751-2765

Department of Neurology, School of Medicine, Technical University of Munich, Munich, Germany.

Chronic pain is a common and severely disabling disease whose treatment is often unsatisfactory. Insights into the brain mechanisms of chronic pain promise to advance the understanding of the underlying pathophysiology and might help to develop disease markers and novel treatments. Here, we systematically exploited the potential of electroencephalography to determine abnormalities of brain function during the resting state in chronic pain. To this end, we performed state-of-the-art analyses of oscillatory brain activity, brain connectivity, and brain networks in 101 patients of either sex suffering from chronic pain. The results show that global and local measures of brain activity did not differ between chronic pain patients and a healthy control group. However, we observed significantly increased connectivity at theta (4-8 Hz) and gamma (>60 Hz) frequencies in frontal brain areas as well as global network reorganization at gamma frequencies in chronic pain patients. Furthermore, a machine learning algorithm could differentiate between patients and healthy controls with an above-chance accuracy of 57%, mostly based on frontal connectivity. These results suggest that increased theta and gamma synchrony in frontal brain areas are involved in the pathophysiology of chronic pain. Although substantial challenges concerning the reproducibility of the findings and the accuracy, specificity, and validity of potential electroencephalography-based disease markers remain to be overcome, our study indicates that abnormal frontal synchrony at theta and gamma frequencies might be promising targets for noninvasive brain stimulation and/or neurofeedback approaches.
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http://dx.doi.org/10.1097/j.pain.0000000000001666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195856PMC
December 2019

Perceptual and motor responses directly and indirectly mediate the effects of noxious stimuli on autonomic responses.

Pain 2019 12;160(12):2811-2818

Department of Neurology, TUM-Neuroimaging Center, School of Medicine, Technical University of Munich, Munich, Germany.

Autonomic responses are an essential component of pain. They serve its adaptive function by regulating homeostasis and providing resources for protective and recuperative responses to noxious stimuli. To be adaptive and flexible, autonomic responses are not only determined by noxious stimulus characteristics, but likely also shaped by perceptual and motor responses to noxious stimuli. However, it is not fully known how noxious stimulus characteristics, perceptual responses, and motor responses interact in shaping autonomic responses. To address this question, we collected perceptual, motor, and autonomic responses to brief noxious laser stimuli of different intensities in 47 healthy human participants. Multilevel 2-path mediation analyses revealed that perceptual, but not motor responses mediated the translation of noxious stimuli into autonomic responses. Multilevel 3-path mediation analyses further specified that motor responses indirectly related to autonomic responses through their close association with perceptual responses. These findings confirm that autonomic responses are not only a reflexive reaction to noxious stimuli, but directly and indirectly shaped by perceptual and motor responses, respectively. These effects of motor and perceptual processes on autonomic responses likely allow for the integration of contextual processes into protective and regulatory autonomic responses, aiding adaptive and flexible coping with threat.
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http://dx.doi.org/10.1097/j.pain.0000000000001661DOI Listing
December 2019

Motor Responses to Noxious Stimuli Shape Pain Perception in Chronic Pain Patients.

eNeuro 2018 Sep-Oct;5(5). Epub 2018 Nov 29.

Department of Neurology, Technische Universität München, Munich 81675, Germany.

Pain serves vital protective functions, which crucially depend on appropriate motor responses to noxious stimuli. Such responses not only depend on but can themselves shape the perception of pain. In chronic pain, perception is often decoupled from noxious stimuli and motor responses are no longer protective, which suggests that the relationships between noxious stimuli, pain perception, and behavior might be changed. We here performed a simple experiment to quantitatively assess the relationships between noxious stimuli, perception and behavior in 22 chronic pain patients and 22 age-matched healthy human participants. Brief noxious and tactile stimuli were applied to the participants' hands and participants performed speeded motor responses and provided perceptual ratings of the stimuli. Multi-level moderated mediation analyses assessed the relationships between stimulus intensity, perceptual ratings and reaction times for both stimulus types. The results revealed a significantly stronger involvement of motor responses in the translation of noxious stimuli into perception than in the translation of tactile stimuli into perception. This significant influence of motor responses on pain perception was found for both chronic pain patients and healthy participants. Thus, stimulus-perception-behavior relationships appear to be at least partially preserved in chronic pain patients and motor-related as well as behavioral interventions might harness these functional relationships to modulate pain perception.
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http://dx.doi.org/10.1523/ENEURO.0290-18.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354784PMC
April 2019

Distinct patterns of brain activity mediate perceptual and motor and autonomic responses to noxious stimuli.

Nat Commun 2018 10 26;9(1):4487. Epub 2018 Oct 26.

Department of Neurology and TUM-Neuroimaging Center, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany.

Pain is a complex phenomenon involving perceptual, motor, and autonomic responses, but how the brain translates noxious stimuli into these different dimensions of pain is unclear. Here, we assessed perceptual, motor, and autonomic responses to brief noxious heat stimuli and recorded brain activity using electroencephalography (EEG) in humans. Multilevel mediation analysis reveals that each pain dimension is subserved by a distinct pattern of EEG responses and, conversely, that each EEG response differentially contributes to the different dimensions of pain. In particular, the translation of noxious stimuli into autonomic and motor responses involved the earliest N1 wave, whereas pain perception was mediated by later N2 and P2 waves. Gamma oscillations mediated motor responses rather than pain perception. These findings represent progress towards a mechanistic understanding of the brain processes translating noxious stimuli into pain and suggest that perceptual, motor, and autonomic dimensions of pain are partially independent rather than serial processes.
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http://dx.doi.org/10.1038/s41467-018-06875-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6203833PMC
October 2018

Prefrontal gamma oscillations reflect ongoing pain intensity in chronic back pain patients.

Hum Brain Mapp 2019 01 10;40(1):293-305. Epub 2018 Sep 10.

Department of Neurology, Technische Universität München, Munich, Germany.

Chronic pain is a major health care issue characterized by ongoing pain and a variety of sensory, cognitive, and affective abnormalities. The neural basis of chronic pain is still not completely understood. Previous work has implicated prefrontal brain areas in chronic pain. Furthermore, prefrontal neuronal oscillations at gamma frequencies (60-90 Hz) have been shown to reflect the perceived intensity of longer lasting experimental pain in healthy human participants. In contrast, noxious stimulus intensity has been related to alpha (8-13 Hz) and beta (14-29 Hz) oscillations in sensorimotor areas. However, it is not fully understood how the intensity of ongoing pain as the key symptom of chronic pain is represented in the human brain. Here, we asked 31 chronic back pain patients to continuously rate their ongoing pain while simultaneously recording electroencephalography (EEG). Time-frequency analyses revealed a positive association between ongoing pain intensity and prefrontal beta and gamma oscillations. No association was found between pain and alpha or beta oscillations in sensorimotor areas. These findings indicate that ongoing pain as the key symptom of chronic pain is reflected by neuronal oscillations implicated in the subjective perception of longer lasting pain rather than by neuronal oscillations related to the processing of objective nociceptive input. The findings, thus, support a dissociation of pain intensity from nociceptive processing in chronic back pain patients. Furthermore, although possible confounds by muscle activity have to be taken into account, they might be useful for defining a neurophysiological marker of ongoing pain in the human brain.
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http://dx.doi.org/10.1002/hbm.24373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585682PMC
January 2019

Influence of pain on motor preparation in the human brain.

J Neurophysiol 2017 10 2;118(4):2267-2274. Epub 2017 Aug 2.

Department of Neurology and TUM-Neuroimaging Center, Technische Universität München, Munich, Germany

The protective function of pain depends on appropriate motor responses to avoid injury and promote recovery. The preparation and execution of motor responses is thus an essential part of pain. However, it is not yet fully understood how pain and motor processes interact in the brain. Here we used electroencephalography to investigate the effects of pain on motor preparation in the human brain. Twenty healthy human participants performed a motor task in which they performed button presses to stop increasingly painful thermal stimuli when they became intolerable. In another condition, participants performed button presses without concurrent stimulation. The results show that the amplitudes of preparatory event-related desynchronizations at alpha and beta frequencies did not differ between conditions. In contrast, the amplitude of the preparatory readiness potential was reduced when a button press was performed to stop a painful stimulus compared with a button press without concomitant pain. A control experiment with nonpainful thermal stimuli showed a similar reduction of the readiness potential when a button press was performed to stop a nonpainful thermal stimulus. Together, these findings indicate that painful and nonpainful thermal stimuli can similarly influence motor preparation in the human brain. Pain-specific effects on motor preparation in the human brain remain to be demonstrated. Pain is inherently linked to motor processes, but the interactions between pain and motor processes in the human brain are not yet fully understood. Using electroencephalography, we show that pain reduces movement-preparatory brain activity. Further results indicate that this effect is not pain specific but independent of the modality of stimulation.
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http://dx.doi.org/10.1152/jn.00489.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5626884PMC
October 2017

Autonomic responses to tonic pain are more closely related to stimulus intensity than to pain intensity.

Pain 2017 Nov;158(11):2129-2136

Department of Neurology, TUM-Neuroimaging Center, Technische Universität München, Munich, Germany.

Pain serves the protection of the body by translating noxious stimulus information into a subjective percept and protective responses. Such protective responses rely on autonomic responses that allocate energy resources to protective functions. However, the precise relationship between objective stimulus intensity, subjective pain intensity, autonomic responses, and brain activity is not fully clear yet. Here, we addressed this question by continuously recording pain ratings, skin conductance, heart rate, and electroencephalography during tonic noxious heat stimulation of the hand in 39 healthy human subjects. The results confirmed that pain intensity dissociates from stimulus intensity during 10 minutes of noxious stimulation. Furthermore, skin conductance measures were significantly related to stimulus intensity but not to pain intensity. Correspondingly, skin conductance measures were significantly related to alpha and beta oscillations in contralateral sensorimotor cortex, which have been shown to encode stimulus intensity rather than pain intensity. No significant relationships were found between heart rate and stimulus intensity or pain intensity. The findings were consistent for stimulation of the left and the right hands. These results suggest that sympathetic autonomic responses to noxious stimuli in part directly result from nociceptive rather than from perceptual processes. Beyond, these observations support concepts of pain and emotions in which sensory, motor, and autonomic components are partially independent processes that together shape emotional and painful experiences.
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http://dx.doi.org/10.1097/j.pain.0000000000001010DOI Listing
November 2017

Behavioral responses to noxious stimuli shape the perception of pain.

Sci Rep 2017 03 9;7:44083. Epub 2017 Mar 9.

Department of Neurology and TUM-Neuroimaging Center, Technische Universität München, 81675 Munich, Germany.

Pain serves vital protective functions. To fulfill these functions, a noxious stimulus might induce a percept which, in turn, induces a behavioral response. Here, we investigated an alternative view in which behavioral responses do not exclusively depend on but themselves shape perception. We tested this hypothesis in an experiment in which healthy human subjects performed a reaction time task and provided perceptual ratings of noxious and tactile stimuli. A multi-level moderated mediation analysis revealed that behavioral responses are significantly involved in the translation of a stimulus into perception. This involvement was significantly stronger for noxious than for tactile stimuli. These findings show that the influence of behavioral responses on perception is particularly strong for pain which likely reflects the utmost relevance of behavioral responses to protect the body. These observations parallel recent concepts of emotions and entail implications for the understanding and treatment of pain.
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http://dx.doi.org/10.1038/srep44083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5343499PMC
March 2017

Brain oscillations differentially encode noxious stimulus intensity and pain intensity.

Neuroimage 2017 03 7;148:141-147. Epub 2017 Jan 7.

Department of Neurology and TUM-Neuroimaging Center, Technische Universität München, 81675 Munich, Germany. Electronic address:

Noxious stimuli induce physiological processes which commonly translate into pain. However, under certain conditions, pain intensity can substantially dissociate from stimulus intensity, e.g. during longer-lasting pain in chronic pain syndromes. How stimulus intensity and pain intensity are differentially represented in the human brain is, however, not yet fully understood. We therefore used electroencephalography (EEG) to investigate the cerebral representation of noxious stimulus intensity and pain intensity during 10min of painful heat stimulation in 39 healthy human participants. Time courses of objective stimulus intensity and subjective pain ratings indicated a dissociation of both measures. EEG data showed that stimulus intensity was encoded by decreases of neuronal oscillations at alpha and beta frequencies in sensorimotor areas. In contrast, pain intensity was encoded by gamma oscillations in the medial prefrontal cortex. Contrasting right versus left hand stimulation revealed that the encoding of stimulus intensity in contralateral sensorimotor areas depended on the stimulation side. In contrast, a conjunction analysis of right and left hand stimulation revealed that the encoding of pain in the medial prefrontal cortex was independent of the side of stimulation. Thus, the translation of noxious stimulus intensity into pain is associated with a change from a spatially specific representation of stimulus intensity by alpha and beta oscillations in sensorimotor areas to a spatially independent representation of pain by gamma oscillations in brain areas related to cognitive and affective-motivational processes. These findings extend the understanding of the brain mechanisms of nociception and pain and their dissociations during longer-lasting pain as a key symptom of chronic pain syndromes.
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http://dx.doi.org/10.1016/j.neuroimage.2017.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5349759PMC
March 2017

Prevalence of neuropathic pain in early multiple sclerosis.

Mult Scler 2016 08 19;22(9):1224-30. Epub 2015 Oct 19.

Department of Neurology, Technische Universität München, Germany

Background: Pain is considered a frequent symptom in multiple sclerosis. Neuropathic pain is the type of pain most closely related to the pathology of multiple sclerosis and its prevalence estimates vary largely.

Objective: We prospectively assessed the prevalence of neuropathic pain in patients with early multiple sclerosis and investigated the association of neuropathic pain with other clinical parameters.

Methods: A total of 377 outpatients with multiple sclerosis at an early disease stage were included in this prospective study. Mean disease duration was 4.2 years, mean Expanded Disability Status Scale (EDSS) score was 1.6, 96.8% of patients were classified as having relapsing-remitting multiple sclerosis. Neuropathic pain was assessed using the PainDETECT questionnaire (PDQ). Depression, fatigue and cognition were assessed using the Beck Depression Inventory (BDI), the Fatigue Scale for Motor and Cognitive Functions (FSMC) and the Paced Auditory Serial Addition Test.

Results: PDQ scores indicative of neuropathic pain were found in 4.2% of patients. Regression analysis revealed EDSS, BDI and FMSC scores as strongest predictors of PDQ scores.

Conclusions: Neuropathic pain appears to be less frequent in early multiple sclerosis than expected and is significantly associated with disability, depression and fatigue. The assessment and therapy of pain in multiple sclerosis should thus take into account neuropsychiatric symptoms already at early disease stages.
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http://dx.doi.org/10.1177/1352458515613643DOI Listing
August 2016

Prefrontal Gamma Oscillations Encode Tonic Pain in Humans.

Cereb Cortex 2015 Nov 8;25(11):4407-14. Epub 2015 Mar 8.

Department of Neurology, Technische Universität München, 81675 Munich, Germany TUM - Neuroimaging Center, Technische Universität München, 81675 Munich, Germany.

Under physiological conditions, momentary pain serves vital protective functions. Ongoing pain in chronic pain states, on the other hand, is a pathological condition that causes widespread suffering and whose treatment remains unsatisfactory. The brain mechanisms of ongoing pain are largely unknown. In this study, we applied tonic painful heat stimuli of varying degree to healthy human subjects, obtained continuous pain ratings, and recorded electroencephalograms to relate ongoing pain to brain activity. Our results reveal that the subjective perception of tonic pain is selectively encoded by gamma oscillations in the medial prefrontal cortex. We further observed that the encoding of subjective pain intensity experienced by the participants differs fundamentally from that of objective stimulus intensity and from that of brief pain stimuli. These observations point to a role for gamma oscillations in the medial prefrontal cortex in ongoing, tonic pain and thereby extend current concepts of the brain mechanisms of pain to the clinically relevant state of ongoing pain. Furthermore, our approach might help to identify a brain marker of ongoing pain, which may prove useful for the diagnosis and therapy of chronic pain.
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http://dx.doi.org/10.1093/cercor/bhv043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4816790PMC
November 2015

Differential neurophysiological correlates of bottom-up and top-down modulations of pain.

Pain 2015 Feb;156(2):289-296

Department of Neurology, Technische Universität München, Munich, Germany TUM-Neuroimaging Center, Technische Universität München, Munich, Germany Department of Neurology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

The perception of pain is highly variable. It depends on bottom-up-mediated factors like stimulus intensity and top-down-mediated factors like expectations. In the brain, pain is associated with a complex pattern of neuronal responses including evoked potentials and induced responses at alpha and gamma frequencies. Although they all covary with stimulus intensity and pain perception, responses at gamma frequencies can be particularly closely related to the perception of pain. It is, however, unclear whether this association holds true across all types of pain modulation. Here, we used electroencephalography to directly compare bottom-up- and top-down-mediated modulations of pain, which were implemented by changes in stimulus intensity and placebo analgesia, respectively. The results show that stimulus intensity modulated pain-evoked potentials and pain-induced alpha and gamma responses. In contrast, placebo analgesia was associated with changes of evoked potentials, but not of alpha and gamma responses. These findings reveal that pain-related neuronal responses are differentially sensitive to bottom-up and top-down modulations of pain, indicating that they provide complementary information about pain perception. The results further show that pain-induced gamma oscillations do not invariably encode pain perception but may rather represent a marker of sensory processing whose influence on pain perception varies with behavioral context.
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http://dx.doi.org/10.1097/01.j.pain.0000460309.94442.44DOI Listing
February 2015

Dopamine precursor depletion influences pain affect rather than pain sensation.

PLoS One 2014 23;9(4):e96167. Epub 2014 Apr 23.

Department of Neurology, Technische Universität München, Munich, Germany; TUM-Neuroimaging Center, Technische Universität München, Munich, Germany.

Pain is a multidimensional experience, which includes sensory, cognitive, and affective aspects. Converging lines of evidence indicate that dopaminergic neurotransmission plays an important role in human pain perception. However, the precise effects of dopamine on different aspects of pain perception remain to be elucidated. To address this question, we experimentally decreased dopaminergic neurotransmission in 22 healthy human subjects using Acute Phenylalanine and Tyrosine Depletion (APTD). During APTD and a control condition we applied brief painful laser stimuli to the hand, assessed different aspects of pain perception, and recorded electroencephalographic responses. APTD-induced decreases of cerebral dopaminergic activity did not influence sensory aspects of pain perception. In contrast, APTD yielded increases of pain unpleasantness. The increases of unpleasantness ratings positively correlated with effectiveness of APTD. Our finding of an influence of dopaminergic neurotransmission on affective but not sensory aspects of phasic pain suggests that analgesic effects of dopamine might be mediated by indirect effects on pain affect rather than by direct effects on ascending nociceptive signals. These findings contribute to our understanding of the complex relationship between dopamine and pain perception, which may play a role in various clinical pain states.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0096167PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3997524PMC
June 2015

γ Oscillations are involved in the sensorimotor transformation of pain.

J Neurophysiol 2012 Aug 23;108(4):1025-31. Epub 2012 May 23.

Department of Neurology, Technische Universität München, Munich, Germany.

Pain signals threat and initiates motor responses to avoid harm. The transformation of pain into a motor response is thus an essential part of pain. Here, we investigated the neural mechanisms subserving the sensorimotor transformation of pain at the cortical level by using electroencephalography. In a simple reaction time experiment, brief painful stimuli were delivered to the left hand of healthy human subjects who responded with button presses of the right hand. The results show that the simple reaction time task was associated with neuronal responses at delta/theta, alpha/beta, and gamma frequencies. The analysis of the relationship between neuronal activity and response speed revealed that gamma oscillations, which were temporally coupled to the painful stimuli, but not temporally coupled to the motor response, predicted reaction times. Lateralization of gamma oscillations indicates that they originate from motor areas rather than from sensory areas. We conclude that gamma oscillations are involved in the sensorimotor transformation of pain whose efficiency they reflect. We hypothesize that the relationship between stimulus-locked gamma oscillations and reaction times reflects a direct thalamo-motor route of nociceptive information that is central to the biological function of pain.
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http://dx.doi.org/10.1152/jn.00186.2012DOI Listing
August 2012

Behavioral and neuronal investigations of hypervigilance in patients with fibromyalgia syndrome.

PLoS One 2012 11;7(4):e35068. Epub 2012 Apr 11.

Department of Neurology, Technische Universität München, Munich, Germany.

Painful stimuli are of utmost behavioral relevance and thereby affect attentional resources. In health, variable effects of pain on attention have been observed, indicating alerting as well as distracting effects of pain. In the human brain, these effects are closely related to modulations of neuronal gamma oscillations. As hypervigilance as an abnormal increase of attention to external stimuli has been implicated in chronic pain states, we assumed both attentional performance and pain-induced gamma oscillations to be altered in patients with fibromyalgia syndrome (FMS). We recorded electroencephalography from healthy subjects (n = 22) and patients with FMS (n = 19) during an attention demanding visual reaction time task. In 50% of the trials we applied painful laser stimuli. The results of self-assessment questionnaires confirm that patients with FMS consider themselves hypervigilant towards pain as compared to healthy controls. However, the experimental findings indicate that the effects of painful stimuli on attentional performance and neuronal gamma oscillations do not differ between patients and healthy subjects. We further found a significant correlation between the pain-induced modulation of visual gamma oscillations and the pain-induced modulation of reaction times. This relationship did not differ between groups either. These findings confirm a close relationship between gamma oscillations and the variable attentional effects of pain, which appear to be comparable in health and disease. Thus, our results do not provide evidence for a behavioral or neuronal manifestation of hypervigilance in patients with FMS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0035068PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3324411PMC
August 2012

Decoding an individual's sensitivity to pain from the multivariate analysis of EEG data.

Cereb Cortex 2012 May 17;22(5):1118-23. Epub 2011 Jul 17.

Department of Neurology, Technische Universität München, Ismaninger Strasse 22, 81675 Munich, Germany.

The perception of pain is characterized by its tremendous intra- and interindividual variability. Different individuals perceive the very same painful event largely differently. Here, we aimed to predict the individual pain sensitivity from brain activity. We repeatedly applied identical painful stimuli to healthy human subjects and recorded brain activity by using electroencephalography (EEG). We applied a multivariate pattern analysis to the time-frequency transformed single-trial EEG responses. Our results show that a classifier trained on a group of healthy individuals can predict another individual's pain sensitivity with an accuracy of 83%. Classification accuracy depended on pain-evoked responses at about 8 Hz and pain-induced gamma oscillations at about 80 Hz. These results reveal that the temporal-spectral pattern of pain-related neuronal responses provides valuable information about the perception of pain. Beyond, our approach may help to establish an objective neuronal marker of pain sensitivity which can potentially be recorded from a single EEG electrode.
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http://dx.doi.org/10.1093/cercor/bhr186DOI Listing
May 2012

Neurophysiological coding of traits and states in the perception of pain.

Cereb Cortex 2011 Oct 4;21(10):2408-14. Epub 2011 Mar 4.

Department of Neurology, Technische Universität München, 81675 Munich, Germany.

Perception is not a simple reflection of sensory information but varies within and between individuals. This applies particularly to the perception of pain, which, in the brain, is associated with neuronal responses at different frequencies. Here, we show how these different neuronal responses subserve interindividual and intraindividual variations in the perception of identical painful stimuli. A time-frequency analysis of single trial electroencephalographic data indicates that pain-related responses in the theta frequency range but not at higher gamma frequencies code for interindividual variations in the perception of pain. In contrast, both pain-related theta and gamma responses provide different and complementary information on intraindividual variations in the pain experience. We conclude that theta responses reflect rather constant physiological and psychological traits of the individual, whereas gamma responses relate to short-term modulations of the individual's state. These findings reveal how neuronal responses at different frequencies differentially contribute to the translation of sensory information into a subjective percept.
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http://dx.doi.org/10.1093/cercor/bhr027DOI Listing
October 2011

Gamma oscillations as a neuronal correlate of the attentional effects of pain.

Pain 2010 Aug 16;150(2):302-308. Epub 2010 Jun 16.

Department of Neurology, Technische Universität München, 81675 Munich, Germany Centre for Cognitive Neuroimaging, Department of Psychology, University of Glasgow, G12 8QB Glasgow, UK.

Successful behavior requires the attentional selection and preferred processing of behaviorally relevant sensory information. Painful stimuli are of utmost behavioral relevance and can therefore involuntarily affect attentional resources and interfere with ongoing behavior. However, the neuronal mechanisms which subserve the involuntary attentional effects of pain are largely unknown yet. Here, we therefore investigated the neuronal mechanisms of the attentional effects of pain by using electroencephalography during a visual attention task with the concurrent presentation of painful stimuli. Our results confirm that painful and visual stimuli induce gamma oscillations over central and occipital areas, respectively. Pain-induced gamma oscillations were correlated with pain-induced changes in visual gamma oscillations. Behaviorally, we observed variable effects of pain on visual reaction times, yielding an increase of reaction times for some subjects, as well as a decrease of reaction times for others. Most importantly, however, these changes in visual task performance were significantly related to pain-induced changes of visual gamma oscillations. These findings demonstrate that the variable attentional effects of pain are closely related to changes in neuronal gamma oscillations in the human brain. In the hypervigilant state of chronic pain, maladaptive changes in the attentional effects of pain may be associated with abnormal changes in neuronal gamma oscillations. Our findings may thus contribute to the understanding of the neuronal substrates of pain in health and may open a new window towards the understanding of pathological alterations of the pain experience in chronic pain syndromes.
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http://dx.doi.org/10.1016/j.pain.2010.05.014DOI Listing
August 2010

Neuropsychological sequelae of carotid angioplasty with stent placement: correlation with ischemic lesions in diffusion weighted imaging.

PLoS One 2009 Sep 10;4(9):e7001. Epub 2009 Sep 10.

Neurologische Klinik und Poliklinik der Technischen Universität München, Munich, Germany.

Background And Purpose: Few studies investigated the neuropsychological outcome after carotid angioplasty with stent placement (CAS), yielding partially inconsistent results. The present investigation evaluated the effect of CAS in patients with high-grade stenosis and assessed the predictive value of ischemic lesion number for postinterventional cognitive deterioration.

Methods: 22 patients were tested neuropsychologically before and six weeks after CAS. Cerebral ischemic changes were assessed with diffusion weighted imaging (DWI) prior to and after angioplasty.

Results: Pre- to postinterventional cognitive performance improved significantly in terms of verbal memory (t = -2.30; p<0.05), whereas significant deterioration was noted regarding verbal memory span (t = 2.31; p<0.05). 8 (36%) persons conformed to the criteria of cognitive improvement. 6 patients (27%) were postinterventionally classified as having deficits. Analysis yielded no statistically significant correlations between lesion quantity and cognitive change.

Conclusion: Both improvement and deterioration of cognitive functioning was observed in our collective of patients, leaving the neuropsychological outcome after percutaneous transluminal angioplasty unpredictable in individual cases. The presence of acute ischemic lesions on DWI was found to be not tightly associated with cognitive dysfunction after CAS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0007001PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734991PMC
September 2009
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