Basal ganglia function in parkinsonism and dystonia

Parkinsonism and dystonia are movement disorders linked with abnormal function of the basal ganglia. The most common cause of parkinsonism, Parkinson’s disease (PD), is caused by loss of dopaminergic neurons in the nigrostriatal tract, leading to dopamine depletion in the striatum. The pathophysiology in dystonia is largely unknown, although a major role of the basal ganglia has been suspected. Both syndromes can be treated with deep brain stimulation (DBS) in specific targets in the basal ganglia. The aim of this thesis was to study the function of the basal ganglia in parkinsonism and dystonia using single-photon emission computed tomography (SPECT) and positron emission tomography (PET). The work in this thesis was broadly divided into two sets of experiments. The basal ganglia function of patients with PD, non-degenerative parkinsonism and healthy controls were evaluated using dopamine transporter (DAT) imaging. In the other experiment, basal ganglia function in dystonia was investigated in patients with cervical dystonia undergoing globus pallidus interna (GPi) DBS using 18F-fluoro-deoxyglucose-positron emission tomography (FDG-PET). The results of this thesis showed that DAT binding does not predict the number of preserved neurons in the striatum in PD. Moreover, patients with a non-degenerative condition seemed to have higher DAT binding compared to healthy controls. Bupropion, even with a recommended wash-out time, caused clearly abnormal DAT binding in a patient without a neurodegenerative disorder affecting the dopamine system. In cervical dystonia, GPi-DBS increased glucose metabolism at the stimulation site and in other basal ganglia structures as well as in the primary sensorimotor cortex. Metabolic changes in the cortical regions, including the primary sensorimotor cortex and the supplementary motor area (SMA), correlated with acute and long-term therapeutic benefits, respectively. The symptoms returned gradually to the preoperative level after cessation of treatment. The results of this thesis indicate that DAT imaging reflects dopamine function of the striatum rather than neuron count. Moreover, DAT binding is affected by several factors that should be controlled for in both clinical work and in research settings. The findings also suggest that dystonia involves brain regions outside the basal ganglia, which may play a critical role in motor symptoms of dystonia and contribute to slow neuroplastic changes associated with DBS.Tyvitumakkeiden toiminta parkinsonismissa ja dystoniassa Parkinsonismi ja dystonia ovat neurologisia liikehäiriösairauksia, jotka yhdistetään tyvitumakkeiden eli aivojen liikehäiriökeskuksen toimintahäiriöihin. Yleisimmässä parkinsonismissa, Parkinsonin taudissa, aivojen striatumin ja mustatumakkeen dopamiinisolut tuhoutuvat. Dystonian etiologia on sen sijaan edelleen epäselvä, mutta sen on epäilty johtuvan tyvitumakkeiden poikkeavasta toiminnasta. Molempien sairauksien vaikeita muotoja voidaan hoitaa tyvitumakealueelle kohdennettavalla syväaivostimulaattorilla. Tässä tutkimuksessa tyvitumakkeiden toimintaa tutkittiin isotooppikuvantamisella parkinsonismissa ja dystoniassa. Väitöskirjassa tutkittiin Parkinsonin tautia sairastavia henkilöitä, oireisia ja dopamiinitoiminnaltaan terveitä henkilöitä sekä terveitä ja oireettomia henkilöitä dopamiinitransportterikuvantamisella. Lisäksi syväaivostimulaatiohoitoa saavia dystoniapotilaita tutkittiin aivojen sokeriaineenvaihduntaa kuvaavalla PET-tutkimuksella. Tulokset osoittivat, että aivojen dopamiinitransportterisitoutuminen ei ennusta säilyneiden hermosolujen määrää. Sitoutumisarvot saattavat myös olla korkeampia dopamiinitoiminnallaan terveillä, mutta oireisilla potilailla kuin terveillä ja oireettomilla henkilöillä. Lisäksi bupropion saattaa aiheuttaa virheellisiä tuloksia dopamiinikuvantamiseen. Syväaivostimulaattori lisää dystoniapotilalla aivojen sokeriaineenvaihduntaa stimulaatiokohdassa ja lisäksi viereisissä rakenteissa tyvitumakealueella sekä aivokuorella tunto- ja liikeaivokuorella. Oirekuvan nopea korjaantuminen korreloi aineenvaihdunnan lisääntymiseen tunto- ja liikeaivokuorella ja pitkäaikainen hoitovaste lisääntymiseen suplementaarisella motorisella aivokuorella. Oirekuvan hitaampaa palautumista kahden vuorokauden hoitotauon aikana ennusti nuori ikä. Tulokset osoittavat, että tyvitumakkeiden dopamiinikuvantamisessa tulosten tulkinta kliinisessä työssä ja tutkimuksessa ei ole johtopäätösten kannalta yksiselitteistä ja tulee tehdä mahdolliset virhelähteet huomioiden. Dystoniassa myös tyvitumakkeen ulkopuoliset aivoalueet saattavat olla tärkeitä oirekuvan synnyssä sekä hoitovasteen kehittymisessä syväaivostimulaatiohoidossa

Understanding brand relationships with OTC pharmaceutical products and corporate brand experienced by the consumers: Case Orion Oyj

Objectives The purpose of this thesis was to study consumer-brand relationships of OTC products and pharmaceutical corporate brand. The practical aim was to determine whether the corporate brand should be utilized in product marketing and to what extent. As branding of drugs is a rising trend and something not yet properly understood, this study will provide both practical and theoretical implications that are novel, regarding the research conducted in this field is extremely limited. Methodology Six in-depth interviews were conducted by following existential-phenomenological methodology, which is a means of conducting qualitative research. The interviewees were chosen based on their lifestyles and demographic qualities were left in a diminished part. In terms of some participants, second interviews were conducted in order to discover more information. The empirical analysis was built around consumer profiles of five respondents. The purpose was to explain their consumption by life values, personal history, and involved persons in addition to study what type of brand relationships there exist. Moreover, trust formation and brand relationship typology were central themes of the analysis. Results The results of the study indicate that consumers share deep emotions and long relationships with OTC brands that are frequently regarded to solely provide rational and functional benefits. The strong relationships not only have been already developed in childhood, but also have increased price tolerance and affected trust. The relationships with OTC products evolve during time and are based on both emotional and functional attributes. Despite experiencing Orion rather distant, the consumers valued its trustworthiness and quality of being domestic. These are attributes that should be used in the future when constructing a strong corporate brand and differentiating from other companies in this market characterized by low growth and increasing competition. Only after efficient corporate brand building is it justified to attach it in the product marketing, as currently the brand is not strong enough to separate Orion's products from others. This is especially important as the consumer behaviour is rapidly changing in addition to the evolving sales environment and legislation. Moreover, there was a need to exercise more influential branding strategies in terms of memorable brand name development, more personalized advertising, and as a whole, investing in marketing and branding rather than simply in sales and R&D, which regarding the current market situation is not sufficient

Dystonian patofysiologia ja hoito

Dystonia on krooninen neurologinen liikehäiriösairaus, johon liittyy lisääntyneen lihasten aktiivisuuden aiheuttamia tahdosta riippumattomia, vääntäviä tai nykiviä liikkeitä ja pysyviä virheasentoja. Oireet voivat alkaa lapsuudessa tai aikuisiässä ja painottua paikallisesti yksittäiselle kehon alueelle (fokaalinen ja segmentaalinen dystonia) tai esiintyä laaja-alaisesti kehon eri lihaksissa (hemidystonia, multifokaalinen ja yleistynyt dystonia). Aikuisiässä alkanut dystonia on useimmiten etiologialtaan idiopaattinen, mutta dystonia voi kehittyä myös esimerkiksi keskushermostovaurion seurauksena. Dystonian neurobiologista mekanismia ei toistaiseksi tunneta, mutta sen ajatellaan olevan aivojen laaja-alainen sensoristen ja motoristen hermoverkostojen toimintahäiriö. Aikuisiän dystonian diagnoosi on kliininen ja kuuluu neurologian erikoisalalle. Dystonian hoito on oireenmukaista ja hoitovaihtoehtoja ovat botuliiniruiskeet, lääkehoito ja syväaivostimulaatio.</p

Neurobiological effects of deep brain stimulation: A systematic review of molecular brain imaging studies

Deep brain stimulation (DBS) is an established treatment for several brain disorders, including Parkinson's disease, essential tremor, dystonia and epilepsy, and an emerging therapeutic tool in many other neurological and psychiatric disorders. The therapeutic efficacy of DBS is dependent on the stimulation target, but its mechanisms of action are still relatively poorly understood. Investigating these mechanisms is challenging, partly because the stimulation devices and electrodes have limited the use of functional MRI in these patients. Molecular brain imaging techniques, such as positron emission tomography (PET) and single photon emission tomography (SPET), offer a unique opportunity to characterize the whole brain effects of DBS. Here, we investigated the direct effects of DBS by systematically reviewing studies performing an `on' vs `off' contrast during PET or SPET imaging. We identified 62 studies (56 PET and 6 SPET studies; 531 subjects). Approximately half of the studies focused on cerebral blood flow or glucose metabolism in patients Parkinson's disease undergoing subthalamic DBS (25 studies, n = 289), therefore Activation Likelihood Estimation analysis was performed on these studies. Across disorders and stimulation targets, DBS was associated with a robust local increase in ligand uptake at the stimulation site and target-specific remote network effects. Subthalamic nucleus stimulation in Parkinson's disease showed a specific pattern of changes in the motor circuit, including increased ligand uptake in the basal ganglia, and decreased ligand uptake in the primary motor cortex, supplementary motor area and cerebellum. However, there was only a handful of studies investigating other brain disorder and stimulation site combinations (1-3 studies each), or specific neurotransmitter systems, preventing definitive conclusions of the detailed molecular effects of the stimulation in these cases.</p

Bupropion Causes Misdiagnosis in Brain Dopamine Transporter Imaging for Parkinsonism

Objective: The objective of this study was to report long-lasting effects of bupropion on brain dopamine transporter (DAT) in a patient with depression and parkinsonism. Methods: The patient was a 52-year old man who had been treated with 150 mg/d of bupropion for depression. The patient developed cognitive problems, bradykinesia, and reduced stride length for which he was scanned with [123I]FP-CIT single photon emission computed tomography after the recommended 1-week discontinuation of bupropion. Levodopa treatment trial was initiated without a response. Eleven months later, the patient was scanned for a second time after a 1-month stoppage of bupropion. Results: The first scan was abnormal with left putamen specific binding ratio of 1.99 (SDs from the reference value mean, −2.40), right putamen of 2.27 (SD, −1.84), left caudate of 2.33 (SD, −2.26), and right caudate of 2.29 (SD, −2.18). The second scan (after 1-month discontinuation) was normal, and specific binding ratios had increased from 5.2% to 31.7% in all striatal regions as compared with the first scan. Brain magnetic resonance imaging and [18F]fluorodeoxyglucose positron emission tomography imaging were normal, and there was no levodopa response or other features supporting neurodegenerative parkinsonism. Conclusions: Bupropion has previously generally been discontinued 1 week prior DAT imaging, which meets the recommended, albeit arbitrary, time interval of 5 plasma clearance half-lives before the scan. One-week discontinuation of bupropion before DAT imaging may be insufficiently short. Our case shows that longer medication washout and rescan may be needed when there is contradiction between the imaging result and clinical outcome in patients with medications affecting DAT binding</p

Reappearance of Symptoms after GPi-DBS Discontinuation in Cervical Dystonia

Background: Deep brain stimulation of the globus pallidus interna (GPi-DBS) is a highly efficacious treatment for cervical dystonia. Typically, the treatment response is delayed, appearing and increasing even months after implantation. However, it is not known how fast the symptoms reappear and whether there is a long-term therapeutic effect after the stimulation is discontinued.Objectives: To study symptom reappearance after switching GPi-DBS off in cervical dystonia.Methods: Twelve patients with bilateral GPi-DBS were included in the study. The Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) was evaluated during the study with DBS stimulation on, after switching the stimulation off and 2 days after the stimulation was switched off. Presurgical symptom severity and best postsurgical response were extracted from the hospital records.Results: At the time of the investigation, GPi-DBS was associated with 67 (SD 39)% symptom improvement of presurgical symptoms severity (P = 0.001). Symptom improvement decreased to 27 (53)% (P = 0.046) (n = 12) acutely after switching the stimulation off and was further reduced to 4 (56)% 2 days after discontinuation (P = 0.01) (n = 11), reaching the presurgical level (P = 0.42). In descriptive analyses, older age was associated with faster worsening of symptoms (P < 0.05). Presurgical symptoms severity, stimulation parameters or magnitude of treatment response did not predict symptom worsening. All but one patient tolerated 2 days DBS switched off.Conclusions: The results provide novel information about the time frame and severity of symptom worsening after discontinuing GPi-DBS in cervical dystonia. Symptoms partially reappear immediately after discontinuing GPi-DBS and full presurgical symptom severity is reached within 2 days

No Link Between Striatal Dopaminergic Axons and Dopamine Transporter Imagingin Parkinson’s Disease

Background:Brain dopamine transporter binding hasbeen considered a possible biomarker for nigrostriataldegeneration in PD.Objective:To investigate whether dopamine trans-porter binding is associated with the number of dopa-minergic neurites in the putamen.Methods:Tyrosine hydroxylase–positive nervefiberswere counted from postmortem putamen sections takenfrom 14 parkinsonism patients who had been scannedwith dopamine transporter single-photon emission com-puted tomography antemortem. Fiber counts were cor-related with putamen dopamine transporter binding andSN neuron counts.Results:The putamen dopamine transporter specificbinding ratio did not correlate with the putamen tyrosinehydroxylase–positive axon counts (r = 0.00;P= 1.0; PDpatients: r = 0.07;P= 0.86). The nigra neuron counts had a positive correlation with the putamen tyrosinehydroxylase–positive axon counts.Conclusions:Striatal dopamine transporter imagingdoes not associate with axonal nor somal loss of thenigrostriatal neurons in PD. It may reflect dopaminergicactivity rather than number of surviving neurons or theirstriatal projection axons.</p

Sex correction improves the accuracy of clinical dopamine transporter imaging

Background In clinical diagnostic imaging, dopamine transporter (DAT) SPECT scans are commonly evaluated using automated semiquantitative analysis software. Age correction is routinely implemented, but usually no sex correction of DAT binding is performed. Since there are sex differences in presynaptic dopaminergic function, we investigated the effect of DAT sex correction in a sample of healthy volunteers who underwent brain [I-123]-FP-CIT SPECT. Methods Forty healthy elderly individuals (21 men and 19 women) underwent brain [I-123]-FP-CIT SPECT, and each subject was examined clinically for motor and non-motor parkinsonian symptoms and signs. Regional specific DAT binding ratios (SBR = [ROI-occ]/occ) were calculated using age correction, and the results were compared to those in normal databases with and without sex correction. The level of regional abnormality was set at 2 standard deviations below the mean values of the reference databases. Results In the analysis without sex correction, compared to the mean ratio of the reference database, ten healthy individuals (8 men and 2 women) had abnormally low DAT binding ratios, and four individuals (3 men and 1 woman) had borderline low DAT binding ratios in at least one striatal region. When sex correction was implemented, the ratio of one individual was abnormal, and the ratio of one individual was borderline (both males). There were no clinically significant differences in motor or non-motor symptoms between healthy volunteers with abnormal and normal binding. Conclusions A considerable number of elderly healthy male subjects can be interpreted to be dopaminergically abnormal if no sex correction of DAT binding is performed. Sex differences in striatal dopaminergic function should be taken into account when DAT imaging is used to assist clinical diagnostics in patients with suspected neurological disorders.</p

Diagnostic accuracy of glabellar tap sign for Parkinson's disease

Glabellar tap or reflex (GR) is an old bedside clinical test used in the diagnostics of Parkinson's disease (PD), but its diagnostic value is unclear. This study examines the diagnostic validity and reliability of GR in PD in relation to brain dopaminergic activity. GR was performed on 161 patients with PD, 47 patients with essential tremor (ET) and 40 healthy controls immediately prior to dopamine transporter (DAT) [I-123]FP-CIT SPECT scanning. The binding ratios were investigated with consideration of the GR result (normal/abnormal). In addition, the consistency of the GR was investigated with 89 patients after a mean follow-up of 2.2 years. PD and ET patients had higher GR scores than healthy controls (p 0.36). Over follow-up, the GR changed from abnormal to normal in 20% of PD patients despite the presence of clinically typical disease. The sensitivity and specificity of GR for differentiating PD from ET were 78.3% and 36.2%, respectively. Although GR has been used by clinicians in the diagnostics of PD, it does not separate PD from ET. It also shows considerable inconsistency over time, and abnormal GR has no relationship with dopamine loss. Its usefulness should be tested for other clinical diagnostic purposes.Peer reviewe

Diagnostic value of micrographia in Parkinson's disease : a study with [I-123]FP-CIT SPECT

Micrographia is a common symptom of Parkinson's disease (PD), and it may precede other motor symptoms. Despite the high prevalence of micrographia in PD, its neurobiological mechanisms are not known. Given that levodopa may alleviate consistent micrographia and that nondopaminergic essential tremor (ET) is not associated with micrographia, micrographia could possibly be used as an ancillary diagnostic method that reflects nigrostriatal dopamine function. We evaluated the usefulness of micrographia as a simple one-sentence writing test in differentiating PD from ET. A total of 146 PD patients, 42 ET patients and 38 healthy controls provided writing samples and were scanned with brain [I-123]FP-CIT dopamine transporter (DAT) SPECT imaging with ROI-based and voxelwise analyses. The diagnostic accuracy of micrographia was evaluated and compared to that of DAT binding. Compared to ET and healthy controls, PD patients showed micrographia (consistent, 25.6% smaller area of handwriting sample in PD compared to ET, p = 0.002, and 27.2% smaller area of handwriting compared to healthy controls, p = 0.004). PD patients showed 133% more severe progressive micrographia compared with ET patients (median b = - 0.14 in PD, b = - 0.06 in ET, p = 0.021). In early unmedicated cognitively normal patients, consistent micrographia showed 71.2% specificity and 87.5% sensitivity in PD versus ET differentiation, but micrographia had no correlation with striatal or extrastriatal [I-123]FP-CIT binding in patients with PD. The one-sentence micrographia test shows moderately good accuracy in PD versus ET differentiation. The severity of micrographia has no relationship with DAT binding, suggesting nondopaminergic mechanism of micrographia in PD. ClinicalTrials.gov identifier: NCT02650843 (NMDAT study).Peer reviewe