Publications by authors named "Henrik Heitmann"

10 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

Fatigue, depression, and pain in multiple sclerosis: How neuroinflammation translates into dysfunctional reward processing and anhedonic symptoms.

Mult Scler 2020 Nov 12:1352458520972279. Epub 2020 Nov 12.

Department of Neurology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany/TUM-Neuroimaging Center, School of Medicine, Technical University of Munich, Munich, Germany.

Fatigue, depression, and pain affect the majority of multiple sclerosis (MS) patients, which causes a substantial burden to patients and society. The pathophysiology of these symptoms is not entirely clear, and current treatments are only partially effective. Clinically, these symptoms share signs of anhedonia, such as reduced motivation and a lack of positive affect. In the brain, they are associated with overlapping structural and functional alterations in areas involved in reward processing. Moreover, neuroinflammation has been shown to directly impede monoaminergic neurotransmission that plays a key role in reward processing. Here, we review recent neuroimaging and neuroimmunological findings, which indicate that dysfunctional reward processing might represent a shared functional mechanism fostering the symptom cluster of fatigue, depression, and pain in MS. We propose a framework that integrates these findings with a focus on monoaminergic neurotransmission and discuss its therapeutic implications, limitations, and perspectives.
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http://dx.doi.org/10.1177/1352458520972279DOI Listing
November 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

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

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

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

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
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