Numerical human head modelling and investigation for precise tDCS applications

As a non-invasive and sub-convulsive functional stimulation technique, transcranial direct current stimulation (tDCS) generates a relatively weak current intensity and applies the moderate current to the brain to modulate the level of cortical excitability. This neuromodulatory technique has been extensively used as a potential clinical treatment for various neuropsychiatric conditions, ranging from depression, addition to schizophrenia and Parkinson’s disease. Recently, tDCS has also been researched as a promising alternative treatment to alleviate neuropathic pain of cancer patients. The focus of this project is to numerically investigate the precise applications of tDCS based on a series of high resolution realistic human head model using finite element methods. Specifically, the influence of brain shift caused by gravity was firstly pre-validated using real shaped human head model. After that, this study focuses on the investigation of tDCS applications on the brain cancer patients in order to treat their neuropsychiatric conditions and neuropathic pain caused by the brain tumors. Thirdly, the role of blood vessels in shaping the induced current distributions within the cortex during tDCS was thoroughly investigated and addressed. The outcomes of this project highlight the importance of head orientation during the clinical application of tDCS. The results also clear the safety concern in applying tDCS to the patients with brain cancer. In addition, this project provides positive supports on the introduction of brain blood vessels during the precise human head modelling for tDCS though considerable workload will be involved

Reduction of intratumoral brain perfusion by noninvasive transcranial electrical stimulation

Malignant brain neoplasms have a poor prognosis despite aggressive treatments. Animal models and evidence from human bodily tumors reveal that sustained reduction in tumor perfusion via electrical stimulation promotes tumor necrosis, therefore possibly representing a therapeutic option for patients with brain tumors. Here, we demonstrate that transcranial electrical stimulation (tES) allows to safely and noninvasively reduce intratumoral perfusion in humans. Selected patients with glioblastoma or metastasis underwent tES, while perfusion was assessed using magnetic resonance imaging. Multichannel tES was applied according to personalized biophysical modeling, to maximize the induced electrical field over the solid tumor mass. All patients completed the study and tolerated the procedure without adverse effects, with tES selectively reducing the perfusion of the solid tumor. Results potentially open the door to noninvasive therapeutic interventions in brain tumors based on stand-alone tES or its combination with other available therapies

Personalised, image-guided, noninvasive brain stimulation in gliomas : Rationale, challenges and opportunities

Malignant brain tumours are among the most aggressive human cancers, and despite intensive efforts made over the last decades, patients' survival has scarcely improved. Recently, high-grade gliomas (HGG) have been found to be electrically integrated with healthy brain tissue, a communication that facilitates tumour mitosis and invasion. This link to neuronal activity has provided new insights into HGG pathophysiology and opened prospects for therapeutic interventions based on electrical modulation of neural and synaptic activity in the proximity of tumour cells, which could potentially slow tumour growth. Noninvasive brain stimulation (NiBS), a group of techniques used in research and clinical settings to safely modulate brain activity and plasticity via electromagnetic or electrical stimulation, represents an appealing class of interventions to characterise and target the electrical properties of tumour-neuron interactions. Beyond neuronal activity, NiBS may also modulate function of a range of substrates and dynamics that locally interacts with HGG (e.g., vascular architecture, perfusion and blood-brain barrier permeability). Here we discuss emerging applications of NiBS in patients with brain tumours, covering potential mechanisms of action at both cellular, regional, network and whole-brain levels, also offering a conceptual roadmap for future research to prolong survival or promote wellbeing via personalised NiBS interventions

Self-administered transcranial direct current stimulation treatment of knee osteoarthritis alters pain-related fNIRS connectivity networks

Epub 2023 Mar 31Significance: Knee osteoarthritis (OA) is a disease that causes chronic pain in the elderly population. Currently, OA is mainly treated pharmacologically with analgesics, although research has shown that neuromodulation via transcranial direct current stimulation (tDCS) may be beneficial in reducing pain in clinical settings. However, no studies have reported the effects of home-based self-administered tDCS on functional brain networks in older adults with knee OA. Aim: We used functional near-infrared spectroscopy (fNIRS) to investigate the functional connectivity effects of tDCS on underlying pain processing mechanisms at the central nervous level in older adults with knee OA. Approach: Pain-related brain connectivity networks were extracted using fNIRS at baseline and for three consecutive weeks of treatment from 120 subjects randomly assigned to two groups undergoing active tDCS and sham tDCS. Results: Our results showed that the tDCS intervention significantly modulated pain-related connectivity correlation only in the group receiving active treatment. We also found that only the active treatment group showed a significantly reduced number and strength of functional connections evoked during nociception in the prefrontal cortex, primary motor (M1), and primary somatosensory (S1) cortices. To our knowledge, this is the first study in which the effect of tDCS on pain-related connectivity networks is investigated using fNIRS. Conclusions: fNIRS-based functional connectivity can be effectively used to investigate neural circuits of pain at the cortical level in association with nonpharmacological, self-administered tDCS treatment.S.M.H. and L.P. would like to acknowledge the support of the National Science Foundation (Grant Nos. CNS 1650536 and 2137255) and I/UCRC for Building Reliable Advances and Innovation in Neurotechnology. LP also acknowledges the U.S. Fulbright Scholar Program and the Fulbright Spain Commission for sponsoring his stay at the Basque Center on Cognition, Brain and Language. The research reported in this publication was supported by the National Institute of Nursing Research of the National Institutes of Health (Award No. R15NR018050)

Towards Individualized Transcranial Electric Stimulation Therapy through Computer Simulation

Transkranielle Elektrostimulation (tES) beschreibt eine Gruppe von Hirnstimulationstechniken, die einen schwachen elektrischen Strom über zwei nicht-invasiv am Kopf angebrachten Elektroden applizieren. Handelt es sich dabei um einen Gleichstrom, spricht man von transkranieller Gleichstromstimulation, auch tDCS abgekürzt. Die allgemeine Zielstellung aller Hirnstimulationstechniken ist Hirnfunktion durch ein Verstärken oder Dämpfen von Hirnaktivität zu beeinflussen. Unter den Stimulationstechniken wird die transkranielle Gleichstromstimulation als ein adjuvantes Werkzeug zur Unterstützung der mikroskopischen Reorganisation des Gehirnes in Folge von Lernprozessen und besonders der Rehabilitationstherapie nach einem Schlaganfall untersucht. Aktuelle Herausforderungen dieser Forschung sind eine hohe Variabilität im erreichten Stimulationseffekt zwischen den Probanden sowie ein unvollständiges Verständnis des Zusammenspiels der der Stimulation zugrundeliegenden Mechanismen. Als Schlüsselkomponente für das Verständnis der Stimulationsmechanismen wird das zwischen den Elektroden im Kopf des Probanden aufgebaute elektrische Feld erachtet. Einem grundlegenden Konzept folgend wird angenommen, dass Hirnareale, die einer größeren elektrischen Feldstärke ausgesetzt sind, ebenso einen höheren Stimulationseffekt erfahren. Damit kommt der Positionierung der Elektroden eine entscheidende Rolle für die Stimulation zu. Allerdings verteilt sich das elektrische Feld wegen des heterogenen elektrischen Leitfähigkeitsprofil des menschlichen Kopfes nicht uniform im Gehirn der Probanden. Außerdem ist das Verteilungsmuster auf Grund anatomischer Unterschiede zwischen den Probanden verschieden. Die triviale Abschätzung der Ausbreitung des elektrischen Feldes anhand der bloßen Position der Stimulationselektroden ist daher nicht ausreichend genau für eine zielgerichtete Stimulation. Computerbasierte, biophysikalische Simulationen der transkraniellen Elektrostimulation ermöglichen die individuelle Approximation des Verteilungsmusters des elektrischen Feldes in Probanden basierend auf deren medizinischen Bildgebungsdaten. Sie werden daher zunehmend verwendet, um tDCS-Anwendungen zu planen und verifizieren, und stellen ein wesentliches Hilfswerkzeug auf dem Weg zu individualisierter Schlaganfall-Rehabilitationstherapie dar. Softwaresysteme, die den dahinterstehenden individualisierten Verarbeitungsprozess erleichtern und für ein breites Feld an Forschern zugänglich machen, wurden in den vergangenen Jahren für den Anwendungsfall in gesunden Erwachsenen entwickelt. Jedoch bleibt die Simulation von Patienten mit krankhaftem Hirngewebe und strukturzerstörenden Läsionen eine nicht-triviale Aufgabe. Daher befasst sich das hier vorgestellte Projekt mit dem Aufbau und der praktischen Anwendung eines Arbeitsablaufes zur Simulation transkranieller Elektrostimulation. Dabei stand die Anforderung im Vordergrund medizinische Bildgebungsdaten insbesondere neurologischer Patienten mit krankhaft verändertem Hirngewebe verarbeiten zu können. Der grundlegende Arbeitsablauf zur Simulation wurde zunächst für gesunde Erwachsene entworfen und validiert. Dies umfasste die Zusammenstellung medizinischer Bildverarbeitungsalgorithmen zu einer umfangreichen Verarbeitungskette, um elektrisch relevante Strukturen in den Magnetresonanztomographiebildern des Kopfes und des Oberkörpers der Probanden zu identifizieren und zu extrahieren. Die identifizierten Strukturen mussten in Computermodelle überführt werden und das zugrundeliegende, physikalische Problem der elektrischen Volumenleitung in biologischen Geweben mit Hilfe numerischer Simulation gelöst werden. Im Verlauf des normalen Alterns ist das Gehirn strukturellen Veränderungen unterworfen, unter denen ein Verlust des Hirnvolumens sowie die Ausbildung mikroskopischer Veränderungen seiner Nervenfaserstruktur die Bedeutendsten sind. In einem zweiten Schritt wurde der Arbeitsablauf daher erweitert, um diese Phänomene des normalen Alterns zu berücksichtigen. Die vordergründige Herausforderung in diesem Teilprojekt war die biophysikalische Modellierung der veränderten Hirnmikrostruktur, da die resultierenden Veränderungen im Leitfähigkeitsprofil des Gehirns bisher noch nicht in der Literatur quantifiziert wurden. Die Erweiterung des Simulationsablauf zeichnete sich vorrangig dadurch aus, dass mit unsicheren elektrischen Leitfähigkeitswerten gearbeitet werden konnte. Damit war es möglich den Einfluss der ungenau bestimmbaren elektrischen Leitfähigkeit der verschiedenen biologischen Strukturen des menschlichen Kopfes auf das elektrische Feld zu ermitteln. In einer Simulationsstudie, in der Bilddaten von 88 Probanden einflossen, wurde die Auswirkung der veränderten Hirnfaserstruktur auf das elektrische Feld dann systematisch untersucht. Es wurde festgestellt, dass sich diese Gewebsveränderungen hochgradig lokal und im Allgemeinen gering auswirken. Schließlich wurden in einem dritten Schritt Simulationen für Schlaganfallpatienten durchgeführt. Ihre großen, strukturzerstörenden Läsionen wurden dabei mit einem höheren Detailgrad als in bisherigen Arbeiten modelliert und physikalisch abermals mit unsicheren Leitfähigkeiten gearbeitet, was zu unsicheren elektrischen Feldabschätzungen führte. Es wurden individuell berechnete elektrische Felddaten mit der Hirnaktivierung von 18 Patienten in Verbindung gesetzt, unter Berücksichtigung der inhärenten Unsicherheit in der Bestimmung der elektrischen Felder. Das Ziel war zu ergründen, ob die Hirnstimulation einen positiven Einfluss auf die Hirnaktivität der Patienten im Kontext von Rehabilitationstherapie ausüben und so die Neuorganisierung des Gehirns nach einem Schlaganfall unterstützen kann. Während ein schwacher Zusammenhang hergestellt werden konnte, sind weitere Untersuchungen nötig, um diese Frage abschließend zu klären.:Kurzfassung Abstract Contents 1 Overview 2 Anatomical structures in magnetic resonance images 2 Anatomical structures in magnetic resonance images 2.1 Neuroanatomy 2.2 Magnetic resonance imaging 2.3 Segmentation of MR images 2.4 Image morphology 2.5 Summary 3 Magnetic resonance image processing pipeline 3.1 Introduction to human body modeling 3.2 Description of the processing pipeline 3.3 Intermediate and final outcomes in two subjects 3.4 Discussion, limitations & future work 3.5 Conclusion 4 Numerical simulation of transcranial electric stimulation 4.1 Electrostatic foundations 4.2 Discretization of electrostatic quantities 4.3 The numeric solution process 4.4 Spatial discretization by volume meshing 4.5 Summary 5 Simulation workflow 5.1 Overview of tES simulation pipelines 5.2 My implementation of a tES simulation workflow 5.3 Verification & application examples 5.4 Discussion & Conclusion 6 Transcranial direct current stimulation in the aging brain 6.1 Handling age-related brain changes in tES simulations 6.2 Procedure of the simulation study 6.3 Results of the uncertainty analysis 6.4 Findings, limitations and discussion 7 Transcranial direct current stimulation in stroke patients 7.1 Bridging the gap between simulated electric fields and brain activation in stroke patients 7.2 Methodology for relating simulated electric fields to functional MRI data 7.3 Evaluation of the simulation study and correlation analysis 7.4 Discussion & Conclusion 8 Outlooks for simulations of transcranial electric stimulation List of Figures List of Tables Glossary of Neuroscience Terms Glossary of Technical Terms BibliographyTranscranial electric current stimulation (tES) denotes a group of brain stimulation techniques that apply a weak electric current over two or more non-invasively, head-mounted electrodes. When employing a direct-current, this method is denoted transcranial direct current stimulation (tDCS). The general aim of all tES techniques is the modulation of brain function by an up- or downregulation of brain activity. Among these, transcranial direct current stimulation is investigated as an adjuvant tool to promote processes of the microscopic reorganization of the brain as a consequence of learning and, more specifically, rehabilitation therapy after a stroke. Current challenges of this research are a high variability in the achieved stimulation effects across subjects and an incomplete understanding of the interplay between its underlying mechanisms. A key component to understanding the stimulation mechanism is considered the electric field, which is exerted by the electrodes and distributes in the subjects' heads. A principle concept assumes that brain areas exposed to a higher electric field strength likewise experience a higher stimulation. This attributes the positioning of the electrodes a decisive role for the stimulation. However, the electric field distributes non-uniformly across subjects' brains due to the heterogeneous electrical conductivity profile of the human head. Moreover, the distribution pattern is variable between subjects due to their individual anatomy. A trivial estimation of the distribution of the electric field solely based on the position of the stimulating electrodes is, therefore, not precise enough for a well-targeted stimulation. Computer-based biophysical simulations of transcranial electric stimulation enable the individual approximation of the distribution pattern of the electric field in subjects based on their medical imaging data. They are, thus, increasingly employed for the planning and verification of tDCS applications and constitute an essential tool on the way to individualized stroke rehabilitation therapy. Software pipelines facilitating the underlying individualized processing for a wide range of researchers have been developed for use in healthy adults over the past years, but, to date, the simulation of patients with abnormal brain tissue and structure disrupting lesions remains a non-trivial task. Therefore, the presented project was dedicated to establishing and practically applying a tES simulation workflow. The processing of medical imaging data of neurological patients with abnormal brain tissue was a central requirement in this process. The basic simulation workflow was first designed and validated for the simulation of healthy adults. This comprised compiling medical image processing algorithms into a comprehensive workflow to identify and extract electrically relevant physiological structures of the human head and upper torso from magnetic resonance images. The identified structures had to be converted to computational models. The underlying physical problem of electric volume conduction in biological tissue was solved by means of numeric simulation. Over the course of normal aging, the brain is subjected to structural alterations, among which a loss of brain volume and the development of microscopic alterations of its fiber structure are the most relevant. In a second step, the workflow was, thus, extended to incorporate these phenomena of normal aging. The main challenge in this subproject was the biophysical modeling of the altered brain microstructure as the resulting alterations to the conductivity profile of the brain were so far not quantified in the literature. Therefore, the augmentation of the workflow most notably included the modeling of uncertain electrical properties. With this, the influence of the uncertain electrical conductivity of the biological structures of the human head on the electric field could be assessed. In a simulation study, including imaging data of 88 subjects, the influence of the altered brain fiber structure on the electric field was then systematically investigated. These tissue alterations were found to exhibit a highly localized and generally low impact. Finally, in a third step, tDCS simulations of stroke patients were conducted. Their large, structure-disrupting lesions were modeled in a more detailed manner than in previous stroke simulation studies, and they were physically, again, modeled by uncertain electrical conductivity resulting in uncertain electric field estimates. Individually simulated electric fields were related to the brain activation of 18 patients, considering the inherently uncertain electric field estimations. The goal was to clarify whether the stimulation exerts a positive influence on brain function in the context of rehabilitation therapy supporting brain reorganization following a stroke. While a weak correlation could be established, further investigation will be necessary to answer that research question.:Kurzfassung Abstract Contents 1 Overview 2 Anatomical structures in magnetic resonance images 2 Anatomical structures in magnetic resonance images 2.1 Neuroanatomy 2.2 Magnetic resonance imaging 2.3 Segmentation of MR images 2.4 Image morphology 2.5 Summary 3 Magnetic resonance image processing pipeline 3.1 Introduction to human body modeling 3.2 Description of the processing pipeline 3.3 Intermediate and final outcomes in two subjects 3.4 Discussion, limitations & future work 3.5 Conclusion 4 Numerical simulation of transcranial electric stimulation 4.1 Electrostatic foundations 4.2 Discretization of electrostatic quantities 4.3 The numeric solution process 4.4 Spatial discretization by volume meshing 4.5 Summary 5 Simulation workflow 5.1 Overview of tES simulation pipelines 5.2 My implementation of a tES simulation workflow 5.3 Verification & application examples 5.4 Discussion & Conclusion 6 Transcranial direct current stimulation in the aging brain 6.1 Handling age-related brain changes in tES simulations 6.2 Procedure of the simulation study 6.3 Results of the uncertainty analysis 6.4 Findings, limitations and discussion 7 Transcranial direct current stimulation in stroke patients 7.1 Bridging the gap between simulated electric fields and brain activation in stroke patients 7.2 Methodology for relating simulated electric fields to functional MRI data 7.3 Evaluation of the simulation study and correlation analysis 7.4 Discussion & Conclusion 8 Outlooks for simulations of transcranial electric stimulation List of Figures List of Tables Glossary of Neuroscience Terms Glossary of Technical Terms Bibliograph

Human head temperature and electric field investigations under ECT

Electroconvulsive therapy (ECT) is a non-invasive technique used to treat psychiatric conditions. A high strength low frequency electrical stimulation is delivered through two electrodes. The aim of this work is to develop an ECT finite element human head model to investigate the electric field and the increase in temperature due to the electrical stimulation. The bio-heat transfer equation combined with Laplace equation and their initial and boundary conditions are used to define the physics of the models. Firstly, finite ele-ment spherical human head models are created in COMSOL Multiphysics and the behaviour of the thermal field due to ECT electrical stimulation is analysed. Hetero-geneity was considered and thermal anisotropy of the skull layer was applied to the finite element models. Secondly, a realistic human head model is created using magnetic resonance images (MRI). Similar physics is applied to define the thermal and electrical problems, and the anisotropic conductivity of the skull is considered. The realistic models contain anatomical features and realistic tissue conductive properties. Through these models we investigate the role of stimulation parameters such as: electrode montages, strength of stimulation, temperature behaviour, etc. Later on, another realistic human head model with a brain tumor is created and a diffusion tensor image is included. Based on this model the white matter anisotropy is considered and the effect on the electric field is analysed. The results show that high temperatures only occur on external areas of the head, such as scalp and fat. The thermal conductivity anisotropy is insignificant from a heat-transferring point of view. However, the electrical anisotropy does need to be included in order to get more accurate outcomes. If ECT was applied to a patient with a brain tumor, then factors such as tumor location, aggressiveness, electrode montage, etc would need to be considered. Further work can be undertaken through computational simulation to make personal ECT treatment feasible in clinical practice

Modern Developments in Transcranial Magnetic Stimulation (TMS) – Applications and Perspectives in Clinical Neuroscience

Transcranial magnetic stimulation (TMS) is being increasingly used in neuroscience and clinics. Modern advances include but are not limited to the combination of TMS with precise neuronavigation as well as the integration of TMS into a multimodal environment, e.g., by guiding the TMS application using complementary techniques such as functional magnetic resonance imaging (fMRI), electroencephalography (EEG), diffusion tensor imaging (DTI), or magnetoencephalography (MEG). Furthermore, the impact of stimulation can be identified and characterized by such multimodal approaches, helping to shed light on the basic neurophysiology and TMS effects in the human brain. Against this background, the aim of this Special Issue was to explore advancements in the field of TMS considering both investigations in healthy subjects as well as patients

Tinnitus – psychiatric comorbidity and treatment using transcranial magnetic stimulation (TMS)

Tinnitus is the perception of sound in the absence of any external noise. It severely impairs the quality of life in 1-2% of people. Tinnitus is frequently associated with depression, anxiety, and insomnia. The exact pathophysiology of tinnitus is still unclear. No curative therapy exists for chronic tinnitus, and treatment focuses on symptomatic relief. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique that is used for treating depression and neuropathic pain. The evidence of its efficacy for chronic tinnitus is still inconclusive, and the optimal treatment protocols are thus still obscure. This thesis aimed to further evaluate the use of rTMS for chronic tinnitus and investigate the psychiatric comorbidity of tinnitus patients. The first (open pilot) study utilized electric field (E-field) navigated rTMS for very severe chronic tinnitus with promising results. In the second (randomized placebo-controlled) study, the effects of 1-Hz E-field rTMS targeted according to the tinnitus pitch to the left auditory cortex were analyzed. Despite the significant improvements in tinnitus, active rTMS was not superior to the placebo, possibly due to large placebo-effect and wide inter-individual variation in treatment efficacy. The third study on parallel groups compared the effects of neuronavigated rTMS to nonnavigated rTMS (based on the 10-20 EEG localization system). Both groups benefitted from the treatment, but the method of coil localization was not a critical factor for treatment outcome. In the fourth study, current and lifetime DSM-IV diagnoses of Axis I (psychiatric disorders) and Axis II (personality disorders) were assessed in tinnitus patients using structured clinical interviews (SCID-I and -II). Tinnitus patients were prone to episodes of major depression, and they often had obsessive-compulsive personality features. Psychiatric disorders in this study seemed to be comorbid or predisposing conditions rather than the consequences of tinnitus.Tinnitus – psykiatrinen sairastavuus ja hoito transkraniaalisella magneettistimulaatiolla (TMS) Tinnituksen ääniaistimus syntyy ilman ulkoista äänilähdettä. Se heikentää vakavasti elämänlaatua 1-2%:lla ihmisistä. Tinnitus yhdistetään usein masennukseen, ahdistukseen ja unettomuuteen. Tinnituksen tarkka syntymekanismi on vielä epäselvä. Pitkäaikaiselle tinnitukselle ei ole parantavaa hoitoa, vaan hoidossa keskitytään oireiden lievittämiseen. Transkraniaalinen magneettistimulaatio sarjapulssein (rTMS) on kajoamaton aivojen toimintaa muokkaava menetelmä, jota käytetään masennuksen ja hermoperäisen kivun hoidossa. Sen teho pitkäaikaiseen tinnitukseen on vielä epävarmaa ja optimaaliset hoitoprotokollat ovat selvittämättä. Tämän väitöskirjan tavoitteena oli arvioida rTMS:n käyttöä pitkäaikaisen tinnituksen hoidossa ja lisäksi tutkia tinnituspotilaiden psykiatrista sairastavuutta. Ensimmäisessä osatyössä (avoin pilotti) käytettiin sähkökenttäohjattua (E-field) navigoivaa rTMS:a pitkäaikaiseen, erittäin vaikeaan tinnitukseen lupaavin tuloksin. Toisessa osatyössä (satunnaistettu lumekontrolloitu) arvioitiin tinnitusäänen korkeuden mukaan vasemmalle kuuloaivokuorelle suunnatun 1- Hz:n sähkökentän mukaan navigoidun rTMS:n vaikutuksia. Vaikka tinnitus helpottui merkittävästi, ei aktiivi-rTMS ollut lumehoitoa parempi, mahdollisesti johtuen suuresta lumevaikutuksesta ja laajasta yksilöiden välisestä vaihtelusta hoidon tehossa. Kolmannessa osatyössä verrattiin rinnakkaisryhmien välillä neuronavigoidun rTMS:n ja sokko rTMS:n (10-20 EEG-systeemiin perustuva paikannus) vaikutuksia. Molemmat ryhmät hyötyivät hoidosta, eikä kelan paikannusmenetelmä ollut ratkaiseva tekijä hoidon lopputuloksen kannalta. Neljännessä osatyössä nykyiset ja elämänaikaiset akselin I (psykiatriset häiriöt) ja akselin II (persoonallisuushäiriöt) DSM-IV diagnoosit määritettiin tinnituspotilailta käyttäen strukturoituja psykiatrisia haastatteluja (SCID-I ja -II). Tinnituspotilaat olivat alttiita vakaville masennusjaksoille ja heillä oli usein vaativan persoonallisuuden piirteitä. Psykiatriset häiriöt vaikuttivat olevan ennemmin samanaikaisia tai altistavia tiloja kuin tinnituksen seurauksena ilmaantuneita häiriöitä

Prediction and causal inference in the transition from acute to chronic low back pain

The overarching aim of this thesis was to enhance our understanding of the neurobiological risk factors associated with the transition from acute to chronic Low back pain (LBP). To achieve this aim, the Understanding persistent Pain Where it ResiDes (UPWaRD) study was conducted. In this thesis, six chapters describe the background, methods, and results of the UPWaRD study. Chapter 2 describes the protocol, published ‘a priori’ for developing a multivariable prediction model, including candidate predictors selected from the neurobiological (e.g. sensorimotor cortical excitability assessed by sensory and motor evoked potentials, Brain Derived Neurotrophic Factor [BDNF] genotype), psychological (e.g. depression and anxiety), symptom-related (e.g. LBP history) and demographic domains. Chapter 3 builds on the study protocol in the form of a cohort profile, describing baseline characteristics of 120 people experiencing an acute LBP episode and 57 pain-free control participants that form the UPWaRD cohort. Chapter 4 reports the results of the multivariable prediction model developed in 120 people experiencing acute LBP. To further understand the importance of these prognostic factors we developed a causal model of chronic LBP using directed acyclic graphs. The methodology and statistical analysis plan for drawing causal inferences, thus transparently reporting our causal assumptions, are reported in Chapter 5. Chapter 6 then provides the first evidence that low sensory cortex excitability during an acute LBP episode is a causal mechanism underpinning the development of chronic LBP. Finally, in Chapter 7, we report the results of a proteomic analysis, using hydrophobic interaction chromatography and electrospray ionization tandem mass spectrometry. Taken together this thesis makes an extensive and original contribution to our understanding of neurobiological risk factors involved in the transition from acute to chronic LBP. Not only is the inclusion of neurobiological prognostic factors in multivariable clinical prediction models a promising direction for future research that aims to identify people at high risk of poor outcome, but low sensory cortex excitability during acute LBP may be a promising causal mechanism that future treatments could target during acute LBP in the hope of expediting recovery and preventing the development of chronic LBP. Further, this thesis provides some of the earliest evidence to suggest sex-specific differential expression of proteins, measured from human serum, contributes to recovery status at three-month follow-up. This work provides foundational evidence for future research exploring strategies targeting distinct immune system processes in males and females that may interfere with the transition from acute to chronic LBP