Brain imaging of chronic pain

Acute pain has substantial survival value because of its protective function in the everyday environment. Instead, chronic pain lacks survival and adaptive function, causes great amount of individual suffering, and consumes the resources of the society due to the treatment costs and loss of production. The treatment of chronic pain has remained challenging because of inadequate understanding of mechanisms working at different levels of the nervous system in the development, modulation, and maintenance of chronic pain. Especially in unclear chronic pain conditions the treatment may be suboptimal because it can not be targeted to the underlying mechanisms. Noninvasive neuroimaging techniques have greatly contributed to our understanding of brain activity associated with pain in healthy individuals. Many previous studies, focusing on brain activations to acute experimental pain in healthy individuals, have consistently demonstrated a widely-distributed network of brain regions that participate in the processing of acute pain. The aim of the present thesis was to employ non-invasive brain imaging to better understand the brain mechanisms in patients suffering from chronic pain. In Study I, we used magnetoencephalography (MEG) to measure cortical responses to painful laser stimulation in healthy individuals for optimization of the stimulus parameters for patient studies. In Studies II and III, we monitored with MEG the cortical processing of touch and acute pain in patients with complex regional pain syndrome (CRPS). We found persisting plastic changes in the hand representation area of the primary somatosensory (SI) cortex, suggesting that chronic pain causes cortical reorganization. Responses in the posterior parietal cortex to both tactile and painful laser stimulation were attenuated, which could be associated with neglect-like symptoms of the patients. The primary motor cortex reactivity to acute pain was reduced in patients who had stronger spontaneous pain and weaker grip strength in the painful hand. The tight coupling between spontaneous pain and motor dysfunction supports the idea that motor rehabilitation is important in CRPS. In Studies IV and V we used MEG and functional magnetic resonance imaging (fMRI) to investigate the central processing of touch and acute pain in patients who suffered from recurrent herpes simplex virus infections and from chronic widespread pain in one side of the body. With MEG, we found plastic changes in the SI cortex, suggesting that many different types of chronic pain may be associated with similar cortical reorganization. With fMRI, we found functional and morphological changes in the central pain circuitry, as an indication of central contribution for the pain. These results show that chronic pain is associated with morphological and functional changes in the brain, and that such changes can be measured with functional imaging.Akuutti kipu toimii terveellä ihmisellä elämää ylläpitäväna varoitussignaalina, joka syntyy vahingollisen ärsykkeen vaikutuksesta. Kivun muuttuessa krooniseksi se menettää normaalin varoitusfunktionsa, eikä enää edesauta selviytymistä. Krooninen kipu aiheuttaa yksilötasolla suurta kärsimystä ja huonontaa elämänlaatua, ja sen yhteiskunnalliset ja taloudelliset vaikutukset ovat mittavat hoitokulujen ja työkyvyttömyyden vuoksi. Kaikentyyppisessä kroonisessa kivussa keskushermostolliset mekanismit osallistuvat kivun kehittymiseen, säätelyyn ja ylläpitoon. Toistaiseksi näitä mekanismeja on ymmärretty huonosti, joten kroonisen kivun tehokas hoito on vaikeaa. Erityisesti silloin kun kroonisen kivun syntymekanismia ei tunneta, diagnostiikka, hoito ja kuntoutus ovat erityisen haasteellisia. Uudet aivokuvantamismenetelmät kuten magnetoenkefalografia (MEG) ja toiminnallinen magneettikuvaus (fMRI), joilla kipuun liittyviä aivoaktivaatioita voidaan havaita hyvällä aika- ja paikkatarkkuudella ovat tuoneet runsaasti tietoa akuutin kivun keskushermostollisesta käsittelystä terveillä ihmisillä. Tämän väitöskirjan tarkoituksena oli näitä menetelmiä käyttäen tutkia krooniseen kipuun liittyviä aivomekanismeja kahdella potilasryhmällä, jotka kärsivät kroonisesta kivusta. Tutkimuksiin osallistui kahdeksan monimuotoisesta paikallisesta kipuoireyhtymästä (CRPS) kärsivää potilasta, joilla krooninen kipu paikantui toiseen yläraajaan, sekä kahdeksan potilasta, jotka kärsivät toistuviin virusinfektioihin liittyvästä koko toisen kehonpuoliskon käsittävästä kroonisesta kiputilasta. Kipupotilaitten aivoaktivaatiota verrattiin terveiden verrokkihenkilöiden vastaaviin aivoaktivaatioihin. Tutkimuksissamme selvitimme ensin MEG:llä terveiden koehenkilöiden aivokuorivasteita kivuliaille lasersärsykkeille optimoidaksemme mittausparametreja ennen siirtymistämme varsinaisiin potilasmittauksiin. Seuraavaksi tarkastelimme MEG:llä CRPS-potilaiden aivokuorivasteita kosketukseen ja akuuttiin kipuun, sekä mittasimme liikeaivokuoren reaktiivisuutta akuuttiin kipuun. Osoitimme että käden edustustalue primaarilla tuntoaivokuorella (SI) oli kutistunut, viitaten siihen että krooninen kipu voi muovata aivoja ja jättää niihin pysyvät jäljet. Liikeaivokuori reagoi akuuttiin kipuun sitä huonommin, mitä voimakkaammasta kivusta potilaat kärsivät ja mitä huonompi puristusvoima kädessä oli. On mahdollista että potilaitten krooninen kipu johtaa liikeaivokuoren huonontuneeseen toimintaan ja sen välityksellä puristusvoiman heikkouteen. Lopulta käytimme MEG:tä ja fMRI:tä tutkiaksemme kosketuksen ja kivun käsittelyä potilailla, jotka kärsivät toistuviin virusinfektioihin liittyvästä kroonisesta kivusta. Havaitsimme käden edustusalueen kutistumisen SI:lla, viitaten siihen että useasta eri syystä johtuva krooninen kipu voi jättää samanlaiset jäljet aivoihin. fMRI:llä löysimme sekä toiminnallisia että rakenteellisia muutoksia aivojen kivunkäsittelyalueilla. Nämä muutokset viittaavat siihen että toistuviin virusinfektioihin liittyvillä keskushermostollisilla mekanismeilla voi olla osuutta kroonisen kivun kehittymisessä näillä potilailla. Tutkimuksen tulokset osoittavat, että krooniseen kipuun liittyy sekä rakenteellisia että toiminnallisia muutoksia aivoissa, ja että tällaiset muutokset ovat mitattavissa moderneilla aivokuvantamismenetelmillä

A Functional MRI Study of Happy and Sad Emotions in Music with and without Lyrics

Musical emotions, such as happiness and sadness, have been investigated using instrumental music devoid of linguistic content. However, pop and rock, the most common musical genres, utilize lyrics for conveying emotions. Using participants’ self-selected musical excerpts, we studied their behavior and brain responses to elucidate how lyrics interact with musical emotion processing, as reflected by emotion recognition and activation of limbic areas involved in affective experience. We extracted samples from subjects’ selections of sad and happy pieces and sorted them according to the presence of lyrics. Acoustic feature analysis showed that music with lyrics differed from music without lyrics in spectral centroid, a feature related to perceptual brightness, whereas sad music with lyrics did not diverge from happy music without lyrics, indicating the role of other factors in emotion classification. Behavioral ratings revealed that happy music without lyrics induced stronger positive emotions than happy music with lyrics. We also acquired functional magnetic resonance imaging data while subjects performed affective tasks regarding the music. First, using ecological and acoustically variable stimuli, we broadened previous findings about the brain processing of musical emotions and of songs versus instrumental music. Additionally, contrasts between sad music with versus without lyrics recruited the parahippocampal gyrus, the amygdala, the claustrum, the putamen, the precentral gyrus, the medial and inferior frontal gyri (including Broca’s area), and the auditory cortex, while the reverse contrast produced no activations. Happy music without lyrics activated structures of the limbic system and the right pars opercularis of the inferior frontal gyrus, whereas auditory regions alone responded to happy music with lyrics. These findings point to the role of acoustic cues for the experience of happiness in music and to the importance of lyrics for sad musical emotions

A functional MRI study of happy and sad emotions in music with and without lyrics

Musical emotions,such as happiness and sadness,have been investigated using instrumental music devoid of linguistic content. However, pop and rock, the most common musical genres, utilize lyrics for conveying emotions. Using participants’ self-selected musical excerpts, we studied their behavior and brain responses to elucidate how lyrics interact with musical emotion processing, as reflected by emotion recognition and activation of limbic areas involved in affective experience. We extracted samples from subjects’ selections of sad and happy pieces and sorted them according to the presence of lyrics. Acoustic feature analysis showed that music with lyrics differed from music without lyrics in spectral centroid, a feature related toperceptual brightness,whereassadmusicwithlyricsdidnotdivergefromhappymusicwithoutlyrics,indicatingtheroleofotherfactorsinemotionclassification.Behavioralratingsrevealedthathappymusicwithoutlyricsinducedstrongerpositiveemotionsthanhappymusicwithlyrics.Wealsoacquiredfunctionalmagneticres-onanceimagingdatawhilesubjectsperformedaffectivetasksregardingthemusic.First,usingecologicalandacousticallyvariablestimuli,webroadenedpreviousfindingsaboutthebrainprocessingofmusicalemotionsandofsongsversusinstrumentalmusic.Addition-ally,contrastsbetweensadmusicwithversuswithoutlyricsrecruitedtheparahippocampalgyrus,theamygdala,theclaustrum,theputamen,theprecentralgyrus,themedialandinfe-riorfrontalgyri(includingBroca’sarea),andtheauditorycortex,whilethereversecontrastproducednoactivations.Happymusicwithoutlyricsactivatedstructuresofthelimbicsys-temandtherightparsopercularisoftheinferiorfrontalgyrus,whereasauditoryregionsalonerespondedtohappymusicwithlyrics.Thesefindingspointtotheroleofacousticcuesfortheexperienceofhappinessinmusicandtotheimportanceoflyricsforsadmusicalemotions

Real-Life Experience on Directional Deep Brain Stimulation in Patients with Advanced Parkinson's Disease

Directional deep brain stimulation (dDBS) is preferred by patients with advanced Parkinson's disease (PD) and by programming neurologists. However, real-life data of dDBS use is still scarce. We reviewed the clinical data of 53 PD patients with dDBS to 18 months of follow-up. Directional stimulation was favored in 70.5% of dDBS leads, and single segment activation (SSA) was used in 60% of dDBS leads. Current with SSA was significantly lower than with other stimulation types. During the 6-month follow-up, a 44% improvement in the Unified Parkinson's Disease Rating Scale (UPDRS-III) points and a 43% decline in the levodopa equivalent daily dosage (LEDD) was observed. After 18 months of follow-up, a 35% LEDD decrease was still noted. The Hoehn and Yahr (H&Y) stages and scores on item no 30 "postural stability" in UPDRS-III remained lower throughout the follow-up compared to baseline. Additionally, dDBS relieved non-motor symptoms during the 6 months of follow-up. Patients with bilateral SSA had similar clinical outcomes to those with other stimulation types. Directional stimulation appears to effectively reduce both motor and non-motor symptoms in advanced PD with minimal adverse effects in real-life clinical care.Peer reviewe

Real-Life Experience on Directional Deep Brain Stimulation in Patients with Advanced Parkinson’s Disease

Directional deep brain stimulation (dDBS) is preferred by patients with advanced Parkinson’s disease (PD) and by programming neurologists. However, real-life data of dDBS use is still scarce. We reviewed the clinical data of 53 PD patients with dDBS to 18 months of follow-up. Directional stimulation was favored in 70.5% of dDBS leads, and single segment activation (SSA) was used in 60% of dDBS leads. Current with SSA was significantly lower than with other stimulation types. During the 6-month follow-up, a 44% improvement in the Unified Parkinson’s Disease Rating Scale (UPDRS-III) points and a 43% decline in the levodopa equivalent daily dosage (LEDD) was observed. After 18 months of follow-up, a 35% LEDD decrease was still noted. The Hoehn and Yahr (H&Y) stages and scores on item no 30 “postural stability” in UPDRS-III remained lower throughout the follow-up compared to baseline. Additionally, dDBS relieved non-motor symptoms during the 6 months of follow-up. Patients with bilateral SSA had similar clinical outcomes to those with other stimulation types. Directional stimulation appears to effectively reduce both motor and non-motor symptoms in advanced PD with minimal adverse effects in real-life clinical care

Kromatiinin rakennemuutosten vaikutus HSV-1 – kapsidien sijaintiin tumassa

Tyypin 1 Herpes Simplex –virus on maailmanlaajuisesti levinnyt yleinen virus. Se leviää yleisimmin limakalvokontaktissa ja voi aiheuttaa huuliherpeksen. Virus aiheuttaa lyyttisen infektion epiteelisoluissa. Infektio voi myöhemmin levitä myös aluetta hermottaviin hermosoluihin, joissa se aiheuttaa latentin infektion. Virus replikoituu isäntäsolun tumassa, jossa tapahtuu myös uusien kapsidien kokoaminen. Isäntäsolun perimä on pakattu tumaan pieneen tilavuuteen kromatiiniksi, jonka rakenne vaikuttaa siihen, miten viruskapsidit pääsevät liikkumaan tumassa. Herpesinfektio aiheuttaa isäntäsolun tuman rakenteissa muutoksia, joihin kuuluu replikaatioalueiden laajeneminen, kromatiinin pakkautuminen tuman reunoille sekä tuman koon kasvaminen. Tumassa kapsidit liikkuvat diffuusion avulla pääasiassa kromatiinin välitiloissa ja poistuvat kuroutumalla sisempään tumakalvoon. Tässä tutkielmassa pyrimme selvittämään, vaikuttaako isäntäsolun tuman kromatiinin rakenteen muuntelu siihen, miten tyypin 1 Herpes Simplex -viruskapsidit sijoittuvat tumassa. Tämän selvittämiseksi Vero-solulinjan solujen kromatiinia kondensoitiin tai dekondensoitiin, ja solut infektoitiin viruksilla. Näytesolut immunoleimattiin ja kuvattiin konfokaalimikroskoopilla. Kuvista havaittiin, että viruskapsidit pääsivät dekondensoitujen solujen kromatiinin sekaan paremmin kuin kondensoitujen. Kuitenkaan kapsidijakaumissa ei näkynyt merkittävää eroa. Kapsidijakauma oli samankaltainen lähes koko mittausalueella, mikä poikkesi odotetusta.Type 1 Herpes Simplex virus (HSV-1) is a common globally spread virus. It is transmitted most commonly by direct mucous membrane contact and it can be a cause of cold sores. The virus causes a lytic infection in epithelial cells. The infection can later spread to nerve cells innervating the area where it causes a latent infection. Replication of the virus takes place inside the nucleus of a host cell where also progeny capsids are assembled. The genome of a host cell is packed in the nucleus into a smaller volume as chromatin and its structure affects how the capsids move in the nucleus. Herpes infection leads to structural changes in the host cell’s nucleus including chromatin marginalization to nucleus’s periphery and expansion of the nucleus and viral replication compartment. In the nucleus capsids move by diffusion mainly in interchromatin spaces and egress by budding into the inner nuclear membrane. In this study our goal was to examine if the changes in host cell’s chromatin structure affects the localization of the type 1 Herpes Simplex virus capsids in the nucleus. This was studied by condensing or decondensing the chromatin structure of infected Vero cells. Sample cells were immunolabeled and imaged using confocal microscopy. Image data analyses showed that the viral capsids had better access into the chromatin in the decondensed cells than in the condensed cells. However, no significant difference was seen in the capsid distributions. The capsid distribution was similar over almost the entire measuring range which differed from the expected

A functional MRI study of happy and sad emotions in music with and without lyrics

Musical emotions,such as happiness and sadness,have been investigated using instrumental music devoid of linguistic content. However, pop and rock, the most common musical genres, utilize lyrics for conveying emotions. Using participants’ self-selected musical excerpts, we studied their behavior and brain responses to elucidate how lyrics interact with musical emotion processing, as reflected by emotion recognition and activation of limbic areas involved in affective experience. We extracted samples from subjects’ selections of sad and happy pieces and sorted them according to the presence of lyrics. Acoustic feature analysis showed that music with lyrics differed from music without lyrics in spectral centroid, a feature related toperceptual brightness,whereassadmusicwithlyricsdidnotdivergefromhappymusicwithoutlyrics,indicatingtheroleofotherfactorsinemotionclassification.Behavioralratingsrevealedthathappymusicwithoutlyricsinducedstrongerpositiveemotionsthanhappymusicwithlyrics.Wealsoacquiredfunctionalmagneticres-onanceimagingdatawhilesubjectsperformedaffectivetasksregardingthemusic.First,usingecologicalandacousticallyvariablestimuli,webroadenedpreviousfindingsaboutthebrainprocessingofmusicalemotionsandofsongsversusinstrumentalmusic.Addition-ally,contrastsbetweensadmusicwithversuswithoutlyricsrecruitedtheparahippocampalgyrus,theamygdala,theclaustrum,theputamen,theprecentralgyrus,themedialandinfe-riorfrontalgyri(includingBroca’sarea),andtheauditorycortex,whilethereversecontrastproducednoactivations.Happymusicwithoutlyricsactivatedstructuresofthelimbicsys-temandtherightparsopercularisoftheinferiorfrontalgyrus,whereasauditoryregionsalonerespondedtohappymusicwithlyrics.Thesefindingspointtotheroleofacousticcuesfortheexperienceofhappinessinmusicandtotheimportanceoflyricsforsadmusicalemotions

A functional MRI study of happy and sad emotions in music with and without lyrics

Musical emotions,such as happiness and sadness,have been investigated using instrumental music devoid of linguistic content. However, pop and rock, the most common musical genres, utilize lyrics for conveying emotions. Using participants’ self-selected musical excerpts, we studied their behavior and brain responses to elucidate how lyrics interact with musical emotion processing, as reflected by emotion recognition and activation of limbic areas involved in affective experience. We extracted samples from subjects’ selections of sad and happy pieces and sorted them according to the presence of lyrics. Acoustic feature analysis showed that music with lyrics differed from music without lyrics in spectral centroid, a feature related toperceptual brightness,whereassadmusicwithlyricsdidnotdivergefromhappymusicwithoutlyrics,indicatingtheroleofotherfactorsinemotionclassification.Behavioralratingsrevealedthathappymusicwithoutlyricsinducedstrongerpositiveemotionsthanhappymusicwithlyrics.Wealsoacquiredfunctionalmagneticres-onanceimagingdatawhilesubjectsperformedaffectivetasksregardingthemusic.First,usingecologicalandacousticallyvariablestimuli,webroadenedpreviousfindingsaboutthebrainprocessingofmusicalemotionsandofsongsversusinstrumentalmusic.Addition-ally,contrastsbetweensadmusicwithversuswithoutlyricsrecruitedtheparahippocampalgyrus,theamygdala,theclaustrum,theputamen,theprecentralgyrus,themedialandinfe-riorfrontalgyri(includingBroca’sarea),andtheauditorycortex,whilethereversecontrastproducednoactivations.Happymusicwithoutlyricsactivatedstructuresofthelimbicsys-temandtherightparsopercularisoftheinferiorfrontalgyrus,whereasauditoryregionsalonerespondedtohappymusicwithlyrics.Thesefindingspointtotheroleofacousticcuesfortheexperienceofhappinessinmusicandtotheimportanceoflyricsforsadmusicalemotions

Kirurgisesti asennettujen selkäydinstimulaattorien poistoleikkausten komplikaatiot ja altistavat tekijät

Selkäydinstimulaatio on tehokas hoitokeino konservatiiviselle hoidolle resistenttiin krooniseen kipuun. Tästä huolimatta, jopa 38% kaikista selkäydinstimulaattoreista joudutaan poistamaan, ja vaikka selkäydinstimulaattorin asennukseen liittyvät riskit ovat hyvin tiedossa, poistoleikkausten komplikaatioista ei ole juurikaan julkaisuja saatavilla. Meidän tavoitteena oli dokumentoida selkäydinstimulaattorien poistoon liittyvät riskit, sekä riskeille altistavat tekijät. Tutkimuksessa tarkasteltiin retrospektiivisesti HUS Neurokirurgialla 2/2005 – 10/2020 välillä kirurgisesti asennettujen selkäydinstimulaattorin poistoleikkauksien tuloksia ja potilaiden ominaisuuksia. Tällä aikavälillä 131 poistoleikkausta toteutettiin 106:lla potilaalla. Komplikaatioriski todettiin olevan 18.3% (24:n leikkauksen aikana). Vakavia komplikaatioita esiintyi viiden leikkauksen aikana (3.8%). Pysyvää neurologista haittaa ei dokumentoitu. Tupakointi altisti potilaat komplikaatioille (p = 0.023). Keskimäärin potilaat jotka kärsivät komplikaation viettivät päivän pidempään sairaalahoidossa (p = 0.011). Potilaat, jotka läpikävivät toistuvat (kolmesta viiteen) poistoleikkaukset kärsivät huomattavasti enemmän komplikaatioista, kuin potilaat jotka läpikävivät poistoleikkauksen vain yhden tai kaksi kertaa (15.4% VS 62.5%, p = .005). Näin ollen voidaan todeta, että selkäydinstimulaattorin poisto on suhteellisen turvallinen toimenpide. Vaikkakin vakavia komplikaatioita todettiin, ne pystyttiin hoitamaan tehokkaasti. Toistuvia poistoleikkauksia tulee harkita vakavasti, sillä tutkimusdatamme perusteella ne näyttävät lisäävän komplikaatioiden riskiä.Background and objective: Spinal cord stimulation (SCS) is an effective treatment for chronic pain that does not respond to conservative treatment. Nonetheless, up to 38% of all implanted SCS electrodes are explanted, and while the risks involved in the surgical implantation of SCS paddle electrodes are well documented, there is scarce information about SCS explantations and their associated complications. We aimed to document the complication rate in SCS paddle electrode explantations and identify predisposing factors. Methods: We retrospectively reviewed the outcomes and the characteristics of all patients who underwent explantation of surgically implanted SCS paddle electrodes at the Helsinki University Hospital Department of Neurosurgery between February 2005 and October 2020. Results: 131 explantations were performed on 106 patients. The complication rate was 18.3% (24 operations). Major complications occurred during five operations (3.8%). No permanent neurological deficits were recorded. Smoking predisposed patients to postoperative complications (p = .023). On average, patients who suffered complications required a day longer hospitalisation (p = .011). Patients who had repeated explantations (three or more) suffered significantly more complications than patients who had only one or two operations (15.4% VS 62.5%, p = .005). Conclusion: Our results suggest that the explantation of the SCS paddle electrode is a relatively safe surgical procedure. Even though severe complications occurred, they were successfully managed. Repeated explantations should be treated cautiously as they seem to increase the complication rate considerably. Running Title: Explantation of SCS Paddle Electrodes Keywords: Complications, electrode explantation, electrode removal, paddle electrode, spinal cord stimulatio