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  • 1. Adams, Hieab H. H.
    et al.
    Hibar, Derrek P.
    Chouraki, Vincent
    Stein, Jason L.
    Nyquist, Paul A.
    Renteria, Miguel E.
    Trompet, Stella
    Arias-Vasquez, Alejandro
    Seshadri, Sudha
    Desrivieres, Sylvane
    Beecham, Ashley H.
    Jahanshad, Neda
    Wittfeld, Katharine
    Van der Lee, Sven J.
    Abramovic, Lucija
    Alhusaini, Saud
    Amin, Najaf
    Andersson, Micael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Arfanakis, Konstantinos
    Aribisala, Benjamin S.
    Armstrong, Nicola J.
    Athanasiu, Lavinia
    Axelsson, Tomas
    Beiser, Alexa
    Bernard, Manon
    Bis, Joshua C.
    Blanken, Laura M. E.
    Blanton, Susan H.
    Bohlken, Marc M.
    Boks, Marco P.
    Bralten, Janita
    Brickman, Adam M.
    Carmichael, Owen
    Chakravarty, M. Mallar
    Chauhan, Ganesh
    Chen, Qiang
    Ching, Christopher R. K.
    Cuellar-Partida, Gabriel
    Den Braber, Anouk
    Doan, Nhat Trung
    Ehrlich, Stefan
    Filippi, Irina
    Ge, Tian
    Giddaluru, Sudheer
    Goldman, Aaron L.
    Gottesman, Rebecca F.
    Greven, Corina U.
    Grimm, Oliver
    Griswold, Michael E.
    Guadalupe, Tulio
    Hass, Johanna
    Haukvik, Unn K.
    Hilal, Saima
    Hofer, Edith
    Hoehn, David
    Holmes, Avram J.
    Hoogman, Martine
    Janowitz, Deborah
    Jia, Tianye
    Kasperaviciute, Dalia
    Kim, Sungeun
    Klein, Marieke
    Kraemer, Bernd
    Lee, Phil H.
    Liao, Jiemin
    Liewald, David C. M.
    Lopez, Lorna M.
    Luciano, Michelle
    Macare, Christine
    Marquand, Andre
    Matarin, Mar
    Mather, Karen A.
    Mattheisen, Manuel
    Mazoyer, Bernard
    Mckay, David R.
    McWhirter, Rebekah
    Milaneschi, Yuri
    Mirza-Schreiber, Nazanin
    Muetzel, Ryan L.
    Maniega, Susana Munoz
    Nho, Kwangsik
    Nugent, Allison C.
    Loohuis, Loes M. Olde
    Oosterlaan, Jaap
    Papmeyer, Martina
    Pappa, Irene
    Pirpamer, Lukas
    Pudas, Sara
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Puetz, Benno
    Rajan, Kumar B.
    Ramasamy, Adaikalavan
    Richards, Jennifer S.
    Risacher, Shannon L.
    Roiz-Santianez, Roberto
    Rommelse, Nanda
    Rose, Emma J.
    Royle, Natalie A.
    Rundek, Tatjana
    Saemann, Philipp G.
    Satizabal, Claudia L.
    Schmaal, Lianne
    Schork, Andrew J.
    Shen, Li
    Shin, Jean
    Shumskaya, Elena
    Smith, Albert V.
    Sprooten, Emma
    Strike, Lachlan T.
    Teumer, Alexander
    Thomson, Russell
    Tordesillas-Gutierrez, Diana
    Toro, Roberto
    Trabzuni, Daniah
    Vaidya, Dhananjay
    Van der Grond, Jeroen
    Van der Meer, Dennis
    Van Donkelaar, Marjolein M. J.
    Van Eijk, Kristel R.
    Van Erp, Theo G. M.
    Van Rooij, Daan
    Walton, Esther
    Westlye, Lars T.
    Whelan, Christopher D.
    Windham, Beverly G.
    Winkler, Anderson M.
    Woldehawariat, Girma
    Wolf, Christiane
    Wolfers, Thomas
    Xu, Bing
    Yanek, Lisa R.
    Yang, Jingyun
    Zijdenbos, Alex
    Zwiers, Marcel P.
    Agartz, Ingrid
    Aggarwal, Neelum T.
    Almasy, Laura
    Ames, David
    Amouyel, Philippe
    Andreassen, Ole A.
    Arepalli, Sampath
    Assareh, Amelia A.
    Barral, Sandra
    Bastin, Mark E.
    Becker, Diane M.
    Becker, James T.
    Bennett, David A.
    Blangero, John
    van Bokhoven, Hans
    Boomsma, Dorret I.
    Brodaty, Henry
    Brouwer, Rachel M.
    Brunner, Han G.
    Buckner, Randy L.
    Buitelaar, Jan K.
    Bulayeva, Kazima B.
    Cahn, Wiepke
    Calhoun, Vince D.
    Cannon, Dara M.
    Cavalleri, Gianpiero L.
    Chen, Christopher
    Cheng, Ching -Yu
    Cichon, Sven
    Cookson, Mark R.
    Corvin, Aiden
    Crespo-Facorro, Benedicto
    Curran, Joanne E.
    Czisch, Michael
    Dale, Anders M.
    Davies, Gareth E.
    De Geus, Eco J. C.
    De Jager, Philip L.
    de Zubicaray, Greig I.
    Delanty, Norman
    Depondt, Chantal
    DeStefano, Anita L.
    Dillman, Allissa
    Djurovic, Srdjan
    Donohoe, Gary
    Drevets, Wayne C.
    Duggirala, Ravi
    Dyer, Thomas D.
    Erk, Susanne
    Espeseth, Thomas
    Evans, Denis A.
    Fedko, Iryna
    Fernandez, Guillen
    Ferrucci, Luigi
    Fisher, Simon E.
    Fleischman, Debra A.
    Ford, Ian
    Foroud, Tatiana M.
    Fox, Peter T.
    Francks, Clyde
    Fukunaga, Masaki
    Gibbs, J. Raphael
    Glahn, David C.
    Gollub, Randy L.
    Goring, Harald H. H.
    Grabe, Hans J.
    Green, Robert C.
    Gruber, Oliver
    Gudnason, Vilmundur
    Guelfi, Sebastian
    Hansell, Narelle K.
    Hardy, John
    Hartman, Catharina A.
    Hashimoto, Ryota
    Hegenscheid, Katrin
    Heinz, Andreas
    Le Hellard, Stephanie
    Hernandez, Dena G.
    Heslenfeld, Dirk J.
    Ho, Beng-Choon
    Hoekstra, Pieter J.
    Hoffmann, Wolfgang
    Hofman, Albert
    Holsboer, Florian
    Homuth, Georg
    Hosten, Norbert
    Hottenga, Jouke-Jan
    Pol, Hilleke E. Hulshoff
    Ikeda, Masashi
    Ikram, M. Kamran
    Jack, Clifford R., Jr.
    Jenldnson, Mark
    Johnson, Robert
    Jonsson, Erik G.
    Jukema, J. Wouter
    Kahn, Rene S.
    Kanai, Ryota
    Kloszewska, Iwona
    Knopman, David S.
    Kochunov, Peter
    Kwok, John B.
    Lawrie, Stephen M.
    Lemaitre, Herve
    Liu, Xinmin
    Longo, Dan L.
    Longstreth, W. T., Jr.
    Lopez, Oscar L.
    Lovestone, Simon
    Martinez, Oliver
    Martinot, Jean-Luc
    Mattay, Venkata S.
    McDonald, Colm
    McIntosh, Andrew M.
    McMahon, Katie L.
    McMahon, Francis J.
    Mecocci, Patrizia
    Melle, Ingrid
    Meyer-Lindenberg, Andreas
    Mohnke, Sebastian
    Montgomery, Grant W.
    Morris, Derek W.
    Mosley, Thomas H.
    Muhleisen, Thomas W.
    Mueller-Myhsok, Bertram
    Nalls, Michael A.
    Nauck, Matthias
    Nichols, Thomas E.
    Niessen, Wiro J.
    Noethen, Markus M.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Ohi, Kazutaka
    Olvera, Rene L.
    Ophoff, Roel A.
    Pandolfo, Massimo
    Paus, Tomas
    Pausova, Zdenka
    Penninx, Brenda W. J. H.
    Pike, G. Bruce
    Potkin, Steven G.
    Psaty, Bruce M.
    Reppermund, Simone
    Rietschel, Marcella
    Roffman, Joshua L.
    Romanczuk-Seiferth, Nina
    Rotter, Jerome I.
    Ryten, Mina
    Sacco, Ralph L.
    Sachdev, Perminder S.
    Saykin, Andrew J.
    Schmidt, Reinhold
    Schofield, Peter R.
    Sigurdsson, Sigurdur
    Simmons, Andy
    Singleton, Andrew
    Sisodiya, Sanjay M.
    Smith, Colin
    Smoller, Jordan W.
    Soininen, Hindu.
    Srikanth, Velandai
    Steen, Vidar M.
    Stott, David J.
    Sussmann, Jessika E.
    Thalamuthu, Anbupalam
    Tiemeier, Henning
    Toga, Arthur W.
    Traynor, Bryan J.
    Troncoso, Juan
    Turner, Jessica A.
    Tzourio, Christophe
    Uitterlinden, Andre G.
    Hernandez, Maria C. Valdes
    Van der Brug, Marcel
    Van der Lugt, Aad
    Van der Wee, Nic J. A.
    Van Duijn, Cornelia M.
    Van Haren, Neeltje E. M.
    Van't Ent, Dennis
    Van Tol, Marie Jose
    Vardarajan, Badri N.
    Veltman, Dick J.
    Vernooij, Meike W.
    Voelzke, Henry
    Walter, Henrik
    Wardlaw, Joanna M.
    Wassink, Thomas H.
    Weale, Michael E.
    Weinberger, Daniel R.
    Weiner, Michael W.
    Wen, Wei
    Westman, Eric
    White, Tonya
    Wong, Tien Y.
    Wright, Clinton B.
    Zielke, H. Ronald
    Zonderman, Alan B.
    Deary, Ian J.
    DeCarli, Charles
    Schmidt, Helena
    Martin, Nicholas G.
    De Craen, Anton J. M.
    Wright, Margaret J.
    Launer, Lenore J.
    Schumann, Gunter
    Fornage, Myriam
    Franke, Barbara
    Debette, Stephanie
    Medland, Sarah E.
    Ikram, M. Arfan
    Thompson, Paul M.
    Novel genetic loci underlying human intracranial volume identified through genome-wide association2016In: Nature Neuroscience, ISSN 1097-6256, E-ISSN 1546-1726, Vol. 19, no 12, p. 1569-1582Article in journal (Refereed)
    Abstract [en]

    Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (rho(genetic) = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (N-combined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.

  • 2.
    af Bjerkén, Sara
    Umeå University, Faculty of Medicine, Integrative Medical Biology.
    On dopamine neurons: nerve fiber outgrowth and L-DOPA effects2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Parkinson’s disease is a disorder mainly characterized by progressive degeneration of dopamine producing neurons in the substantia nigra of the midbrain. The most commonly used treatment strategy is to pharmacologically restore the lost function by the administration of the dopaminergic precursor L-DOPA. Another treatment strategy is to replace the degenerated neurons with immature fetal ventral mesencephalic tissue, or ultimately stem cell-derived tissue. Grafting trials have, however, revealed poor reinnervation capacity of the grafts, leaving much of the striata dopamine-denervated. An additional drawback is the upcoming of dyskinesia (involuntary movements), a phenomenon also observed during L-DOPA treatment of Parkinson’s disease patients. Attempts to characterize nerve fiber formation from dopamine neurons have demonstrated that the nerve fibers are formed in two morphologically diverse outgrowth patterns, one early outgrowth seen in the absence of astrocytes and one later appearing outgrowth seen in co-existence with astrocytes.

    The overall objective of this thesis has been to study the dopaminergic outgrowth including guidance of nerve fiber formation, and to look into the mechanisms of L-DOPA-induced dyskinesia. The first paper in this thesis characterizes the different outgrowth patterns described above and their relation to different glial cells. The study demonstrated the two different outgrowth patterns to be a general phenomenon, applying not only to dopamine neurons. Attempts of characterization revealed no difference of origin in terms of dopaminergic subpopulations, i.e. A9 or A10, between the outgrowth patterns. Furthermore, the “roller-drum” technique was found optimal for studying the dual outgrowth sequences.

    The second and the third paper also utilized the “roller-drum” technique in order to promote both patterns of neuronal fiber formation. The effects of glial cell line-derived neurotrophic factor (GDNF) on the formation of dopamine nerve fibers, was investigated. Cultures prepared from gdnf knockout mice revealed that dopaminergic neurons survive and form nerve fiber outgrowth in the absence of GDNF. The dopaminergic nerve fibers exhibited an outgrowth pattern consistent with that previous observed in rat. GDNF was found to exert effect on the glial-associated outgrowth whereas the non-glial-associated was not affected. Astrocytic proliferation was inhibited using cytosine β-D-arabinofuranoside, resulting in reduced glial-associated outgrowth. The non-glial-associated dopaminergic outgrowth was on the other hand promoted, and was retained over longer time in culture. Furthermore, the non-glial-associated nerve fibers were found to target the fetal frontal cortex. Different developmental stages were shown to promote and affect the outgrowths differently. Taken together, these data indicate and state the importance of astrocytes and growth factors for neuronal nerve fiber formation and guidance. It also stresses the importance of fetal donor age at the time for transplantation.

    The fourth and fifth studies focus on L-DOPA dynamics and utilize in vivo chronoamperometry. In study four, 6-OHDA dopamine-depleted rats were exposed to chronic L-DOPA treatment and then rated as dyskinetic or non-dyskinetic. The electrochemical recordings demonstrated reduced KCl-evoked release in the intact striatum after chronic L-DOPA treatment. Time for maximal dopamine concentration after L-DOPA administration was found to be shorter in dyskinetic animals than in non-dyskinetic animals. The serotonergic nerve fiber content in the striatum was evaluated and brains from dyskinetic animals were found to exhibit significantly higher nerve fiber density compared to non-dyskinetic animals. Furthermore, the mechanisms behind the conversion of L-DOPA to dopamine in 6-OHDA dopamine-depleted rats were studied. Local administration of L-DOPA in the striatum increased the KCl-evoked dopamine release in the intact striatum. Acute application of L-DOPA resulted sometimes in a rapid conversion to dopamine, probably without vesicle packaging. This type of direct conversion is presumably occurring in non-neuronal tissue. Furthermore, KCl-evoked dopamine releases were present upon local application of L-DOPA in the dopamine-depleted striatum, suggesting that the conversion to dopamine took place elsewhere, than in dopaminergic nerve fibers. In conclusion, these studies state the importance of astrocytes for neuronal nerve fiber formation and elucidate the complexity of L-DOPA conversion in the brain.

  • 3.
    af Bjerkén, Sara
    et al.
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Histology and Cell Biology.
    Boger, Heather A
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Histology and Cell Biology.
    Nelson, Matthew
    Hoffer, Barry J
    Granholm, Ann-Charlotte
    Strömberg, Ingrid
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Histology and Cell Biology.
    Effects of glial cell line-derived neurotrophic factor deletion on ventral mesencephalic organotypic tissue cultures.2007In: Brain Research, ISSN 0006-8993, Vol. 1133, no 1, p. 10-9Article in journal (Refereed)
    Abstract [en]

    Glial cell line-derived neurotrophic factor (GDNF) is potent for survival and promotion of nerve fibers from midbrain dopamine neurons. It is also known to exert different effects on specific subpopulations of dopamine neurons. In organotypic tissue cultures, dopamine neurons form two diverse nerve fiber growth patterns, targeting the striatum differently. The aim of this study was to investigate the effect of GDNF on the formation of dopamine nerve fibers. Organotypic tissue cultures of ventral mesencephalon of gdnf gene-deleted mice were studied. The results revealed that dopamine neurons survive in the absence of GDNF. Tyrosine hydroxylase immunoreactivity demonstrated, in gdnf knockout and wildtype cultures, nerve fiber formation with two separate morphologies occurring either in the absence or the presence of astrocytes. The outgrowth that occurred in the absence of astrocytes was unaffected by gdnf deletion, whereas nerve fibers guided by the presence of astrocytes were affected in that they reached significantly shorter distances from the gdnf gene-deleted tissue slice, compared to those measured in wildtype cultures. Treatment with GDNF reversed this effect and increased nerve fiber density independent of genotype. Furthermore, migration of astrocytes reached significantly shorter distances from the tissue slice in GDNF knockout compared to wildtype cultures. Exogenous GDNF increased astrocytic migration in gdnf gene-deleted tissue cultures, comparable to lengths observed in wildtype tissue cultures. In conclusion, cultured midbrain dopamine neurons survive in the absence of GDNF, and the addition of GDNF improved dopamine nerve fiber formation - possibly as an indirect effect of astrocytic stimulation.

  • 4.
    af Bjerkén, Sara
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Marschinke, Franziska
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Strömberg, Ingrid
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Inhibition of astrocytes promotes long-distance growing nerve fibers in ventral mesencephalic cultures2008In: International Journal of Developmental Neuroscience, ISSN 0736-5748, E-ISSN 1873-474X, Vol. 26, no 7, p. 683-691Article in journal (Refereed)
    Abstract [en]

    Tyrosine hydroxylase-positive nerve fiber formation occurs in two diverse morphological patterns in rat fetal ventral mesencephalic slice cultures; one is non-glial-associated and the other is glial-associated. The aim of this study was to characterize the non-glial-associated nerve fibers and its relation to migration of astrocytes. Organotypic slice cultures were prepared from embryonic days 12, 14, and 18 rat fetuses and maintained for 5, 7 or 14 days in vitro. Inhibition of cell proliferation using cytosine beta-D-arabinofuranoside was conducted in embryonic day 14 ventral mesencephalic cultures. The treatment impaired astrocytic migration at 7 and 14 days in vitro. The reduced migration of astrocytes exerted a negative effect on the glial-associated tyrosine hydroxylase-positive nerve fibers, reducing the outgrowth from the tissue slice. The non-glial-associated outgrowth was, however, positively affected by reduced astrocytic migration, reaching distances around 3mm in 2 weeks, and remained for longer time in culture. Co-cultures of fetal ventral mesencephalon and frontal cortex revealed the cortex as a target for the non-glial-associated tyrosine hydroxylase-positive outgrowth. The age of the fetal tissue at plating affected the astrocytes such that older tissue increased the length of astrocyte migration. Younger tissue at plating promoted the presence of non-glial-associated outgrowth and long radial-glia-like processes, while older tissue promoted migration of neurons instead of formation of nerve fiber network. In conclusion, inhibition of astrocytic proliferation promotes the persistence of long-distance growing tyrosine hydroxylase-positive nerve fibers in ventral mesencephalic slices cultures. Furthermore, the long-distance growing nerve fibers target the frontal cortex and are absent in cultures derived from older tissue.

  • 5.
    af Bjerkén, Sara
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Nevalainen, Nina
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Lundblad, Martin
    Pomerleau, Francois
    Gerhardt, Greg A.
    Strömberg, Ingrid
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    L-DOPA conversion to dopamine in the rat dopamine-depleted striatumManuscript (Other academic)
  • 6.
    Agarkova, Irina
    et al.
    ETH-Zurich Hoenggerberg.
    Schoenauer, Roman
    ETH-Zurich Hoenggerberg.
    Ehler, Elisabeth
    King×s College London,.
    Carlsson, Lena
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Carlsson, Eva
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Thornell, Lars-Eric
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Perriard, Jean-Claude
    ETH-Zurich Hoenggerberg.
    The molecular composition of the sarcomeric M-band correlates with muscle fiber type2004In: European Journal of Cell Biology, ISSN 0171-9335, Vol. 83, no 5, p. 193-204Article in journal (Refereed)
    Abstract [en]

    The M-band is the transverse structure that cross-links the thick filaments in the center and provides a perfect alignment of the A-band in the activated sarcomere. The molecular composition of the M-bands in adult mouse skeletal muscle is fiber-type dependent. All M-bands in fast fibers contain M-protein while M-bands in slow fibers contain a significant proportion of the EH-myomesin isoform, previously detected only in embryonic heart muscle. This fiber-type specificity develops during the first postnatal weeks. However, the ratio between the amounts of myosin and of myomesin, taken as sum of both isoforms, remains nearly constant in all studied muscles. Ultrastructural analysis demonstrates that some of the soleus fibers show a diffuse appearance of the M-band, resembling the situation in the embryonic heart. A model is proposed to explain the functional consequence of differential M-band composition for the physiological and morphological properties of sarcomeres in different muscle types.

  • 7.
    Ahlgren, Christina
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Waling, Kerstin
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Kadi, Fawzi
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Djupsjöbacka, Mats
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation. Centre for Musculoskeletal Research, National Institute for Working Life, Umeå , Sweden.
    Thornell, Lars-Eric
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Sundelin, Gunnevi
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation.
    Effects on physical performance and pain from three dynamic training programs for women with work-related trapezius myalgia2001In: Journal of Rehabilitation Medicine, ISSN 1650-1977, E-ISSN 1651-2081, Vol. 33, no 4, p. 162-9Article in journal (Refereed)
    Abstract [en]

    To compare training programs for women with trapezius myalgia regarding physical performance and pain, 102 women were randomized to strength, endurance, co-ordination and non-training groups. Before and after the intervention, static strength and dynamic muscular endurance in shoulder muscles were measured on a Cybex II dynamometer. Muscle activity in shoulder muscles was monitored via surface EMG. The signal amplitude ratio between the active and passive phase of repeated contractions indicated the ability to relax. Pain at present, pain in general and pain at worst were measured on visual analogue scales. After training, within group comparisons showed that the training groups rated less pain, and in the strength training group ratings of pain at worst differed from the non-training group. Using the non-training group as a reference, static strength increased in the strength and endurance training groups and muscular endurance in all training groups. The study indicates that regular exercises with strength, endurance or co-ordination training of neck/shoulder muscles might alleviate pain for women with work-related trapezius myalgia.

  • 8.
    Ahmadi, Mahboobah
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Liu, Jing-Xia
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Stål, Per
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Pedrosa-Domellöf, Fatima
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Human extraocular muscles in ALS2010In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 51, no 7, p. 3494-3501Article in journal (Refereed)
    Abstract [en]

    PURPOSE. To investigate the general morphology, fiber type content, and myosin heavy chain (MyHC) composition of extraocular muscles (EOMs) from postmortem donors with amyotrophic lateral sclerosis (ALS) and to evaluate whether EOMs are affected or truly spared in this disease. METHODS. EOM and limb muscle samples obtained at autopsy from ALS donors and EOM samples from four control donors were processed for immunohistochemistry with monoclonal antibodies against distinct MyHC isoforms and analyzed by SDS-PAGE. In addition, hematoxylin and eosin staining and nicotinamide tetrazolium reductase (NADH-TR) activity were studied. RESULTS. Wide heterogeneity was observed in the appearance of the different EOMs from each single donor and between donors, irrespective of ALS type or onset. Pathologic morphologic findings in ALS EOMs included presence of atrophic and hypertrophic fibers, either clustered in groups or scattered; increased amounts of connective tissue; and areas of fatty replacement. The population of fibers stained with anti-MyHCslow tonic was smaller than that of MyHCIpositive fibers and was mostly located in the orbital layer in most of the ALS EOM samples, whereas an identical staining pattern for both fiber populations was observed in the control specimens. MyHCembryonic was notably absent from the ALS EOMs. CONCLUSIONS. The EOMs showed signs of involvement with altered fiber type composition, contractile protein content, and cellular architecture. However, when compared to the limb muscles, the EOMs were remarkably preserved. EOMs are a useful model for the study of the pathophysiology of ALS.

  • 9.
    Alakpa, Enateri V.
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Jayawarna, Vineetha
    Burgess, Karl E. V.
    West, Christopher C.
    Peault, Bruno
    Ulijn, Rein V.
    Dalby, Matthew J.
    Improving cartilage phenotype from differentiated pericytes in tunable peptide hydrogels2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 6895Article in journal (Refereed)
    Abstract [en]

    Differentiation of stem cells to chondrocytes in vitro usually results in a heterogeneous phenotype. This is evident in the often detected over expression of type X collagen which, in hyaline cartilage structure is not characteristic of the mid-zone but of the deep-zone ossifying tissue. Methods to better match cartilage developed in vitro to characteristic in vivo features are therefore highly desirable in regenerative medicine. This study compares phenotype characteristics between pericytes, obtained from human adipose tissue, differentiated using diphenylalanine/serine (F2/S) peptide hydrogels with the more widely used chemical induced method for chondrogenesis. Significantly higher levels of type II collagen were noted when pericytes undergo chondrogenesis in the hydrogel in the absence of induction media. There is also a balanced expression of collagen relative to aggrecan production, a feature which was biased toward collagen production when cells were cultured with induction media. Lastly, metabolic profiles of each system show considerable overlap between both differentiation methods but subtle differences which potentially give rise to their resultant phenotype can be ascertained. The study highlights how material and chemical alterations in the cellular microenvironment have wide ranging effects on resultant tissue type.

  • 10.
    Alakpa, Enateri V.
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Saeed, Anwer
    Chung, Peter
    Riehle, Mathis O.
    Gadegaard, Nikolaj
    Dalby, Matthew J.
    Cusack, Maggie
    The Prismatic Topography of Pinctada maxima Shell Retains Stem Cell Multipotency and Plasticity In Vitro2018In: Advanced Biosystems, ISSN 2366-7478, Vol. 2, no 6, article id 1800012Article in journal (Refereed)
    Abstract [en]

    The shell of the bivalve mollusc Pinctada maxima is composed of the calcium carbonate polymorphs calcite and aragonite (nacre). Mother-of-pearl, or nacre, induces vertebrate cells to undergo osteogenesis and has good osteointegrative qualities in vivo. The calcite counterpart, however, is less researched in terms of the response of vertebrate cells. This study shows that isolation of calcite surface topography from the inherent chemistry allows viable long-term culture of bone marrow derived mesenchymal stem cells (MSCs). Self-renewal is evident from the increased gene expression of the self-renewal markers CD63, CD166, and CD271 indicating that cells cultured on the calcite topography maintain their stem cell phenotype. MSCs also retain their multipotency and can undergo successful differentiation into osteoblasts and adipocytes. When directed to adipogenesis, MSCs cultured on prism replicas are more amenable to differentiation than MSCs cultured on tissue culture polystyrene indicating a higher degree of plasticity in MSCs growing on calcite P. maxima prismatic topography. The study highlights the potential of the calcite topography of P. maxima as a biomimetic design for supporting expansion of MSC populations in vitro, which is of fundamental importance if it meets the demands for autologous MSCs for therapeutic use.

  • 11.
    Albiin, Nils
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Middle ear structure in relation to function: the rat in middle ear research1985Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The present study was undertaken to evaluate the rat as a model for middle ear re­search. The rat was chosen primarily because the gross structure of its middle ear shows several similarities to that of man. It was considered of great importance to make a thorough structural study of the rat middle ear and to compare the results with those reported for the human middle ear. The thesis therefore includes indepen­dent studies on various aspects of rat middle ear structure and function as well as a review of the literature. The most pertinent findings in the experimental part of this study were the following.

    The rat Eustachian tube consists of a nasopharyngeal, and a cartilaginous and bony portion. The orifice of the nasopharyngeal portion is composed of two soft tissue lips, which appear to be opened mainly by the action of the salpingopharyngeal mus­cle, but also by the levator and tensor veli palatini muscles. The cartilaginous por­tion appears to be opened solely by the tensor veli palatini muscle. The tensor tympani muscle seems to have no effect on the tube.

    A ciliated and secretory epithelium lines the inferomedial walls of the tube throughout its length. In the tympanic cavity these thelial cell types extend as two tracts - one anterior and the other inferoposterior to  the promontory - which communicate with the epitympanic/attic compartments. The remaining parts of the tube and the tympanic cavity are covered by a squamous/cuboidal, non-ciliated epithelium. The subepithelial loose connective tissue contains vessels, nerves, and connective tissue cells, among these mast cells. The mast cells are confined to areas covered by the ciliated epithelium, and in the floor of the bulla, in the pars flaccida, and along the manubrial vessels. Glands are restricted to the Eustachian tube.

    In the clearance/transport of serum-like material, from the epitympanum towards the tube, hydrostatic forces appear to be important.

    The tympanic membrane is vascularized from meatal and tympanal vessels. Meatal ves­sels branch in the pars flaccida and along the handle of the malleus, where they are localized directly beneath the outer, keratinizing, stratified, squamous epithelium. Furthermore, meatal vessels form a vascular network at the junction between the fi­brocartilaginous annulus and the tympanic sulcus. Tympanal vessels send branches to the periphery of the pars tensa, where they run immediately beneath the tympanal, simple, squamous epithelium. In the major portion of the pars tensa, no blood vessels were found.

    The rat stapedial artery is a thin-walled vessel with a wide lumen. Without branch­ing, it runs through the tympanic cavity to the extratympanal regions it supplies. In contrast to the corresponding artery in man, the rat stapedial artery persists throughout life. The artery does not seem to be affected by the fluid produced during experimentally induced otitis media with effusion.

    The middle ear structure in the rat and in man show both similarities and differ­ences. If the differences are kept in mind and considered, it would seem that the rat is indeed a suitable model for experimental middle ear research.

  • 12. Al-Bishri, Awwad
    et al.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Al-Thobaiti, Yasser
    Sunzel, Bo
    Rosenquist, Jan
    Effect of betamethasone on the degree of macrophage recruitment and nerve growth factor receptor p75 immunoreaction during recovery of the sciatic nerve after injury: an experimental study in rats.2008In: British Journal of Oral & Maxillofacial Surgery, ISSN 0266-4356, E-ISSN 1532-1940, Vol. 46, no 6, p. 455-9Article in journal (Refereed)
    Abstract [en]

    PURPOSE: This study was designed to explain our previous findings of beneficial effects of betamethasone given perioperatively on decreasing the incidence of neurosensory disturbance after sagittal split osteotomy and improving functional recovery after crush injury to rat sciatic nerves. We analysed the pattern of macrophage recruitment and expression of nerve growth factor p75. MATERIAL AND METHODS: The sciatic nerve was crushed in each of 42 animals by tying the nerve against a glass rod for 30s. Half the rats were given betamethasone and half were not. The effect of betamethasone was evaluated immunohistochemically in a double blind manner after 2, 7 and 17 days using antibodies against macrophage marker (ED1) and p75. RESULTS: We found an initial and significant decrease in the number of macrophages recruited after two days in the group treated with betamethasone compared with controls (p=0.001). By 7 days there were significantly more macrophages in the steroid group than in the control group (p=0.001). There was however, a tendency for the number of p75R to be higher in the in the steroid group but the difference was not significant. At 17 days, there were significantly fewer macrophages in the steroid group (p=0.008) than in the control. CONCLUSION: We conclude that the beneficial effect of a moderate perioperative dose of betamethasone on recovery of a nerve is reflected in the recruitment of macrophages but to only a small extent in expression of p75.

  • 13.
    Alfredson, H.
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Öhberg, L.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Is vasculo-neural ingrowth the cause of pain in chronic Achilles tendinosis?: An investigation using US and colour Doppler, immunohistochemistry, and diagnostic injections2003In: Knee Surgery, Sports Traumatology, Arthroscopy, ISSN 0942-2056, Vol. 11, no 5, p. 334-338Article in journal (Refereed)
  • 14.
    Alfredson, Hakan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). ISEH, UCLH, London, UK.
    Persistent pain in the Achilles midportion?: Consider the plantaris tendon as a possible culprit!2017In: British Journal of Sports Medicine, ISSN 0306-3674, E-ISSN 1473-0480, Vol. 51, no 10, p. 833-834Article, review/survey (Refereed)
  • 15.
    Alfredson, Håkan
    et al.
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy.
    Thorsen, Kim
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Sports Medicine.
    Fahlström, Martin
    Umeå University, Faculty of Medicine, Community Medicine and Rehabilitation, Rehabilitation Medicine. Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Sports Medicine.
    Johansson, Håkan
    Lorentzon, Ronny
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Sports Medicine.
    Glutamate NMDAR1 receptors localised to nerves in human Achilles tendons. Implications for treatment?2001In: Knee Surgery, Sports Traumatology, Arthroscopy, ISSN 0942-2056, E-ISSN 1433-7347, Vol. 9, no 2, p. 123-126Article in journal (Refereed)
    Abstract [en]

    In this investigation, we show the presence of both free glutamate (microdialysis) and glutamate NMDAR1 receptors (immunohistochemical analyses of tendon biopsies), in tendons from patients with chronic Achilles tendon pain (Achilles tendinosis) and in controls (pain-free tendons). The NMDAR1 immunoreaction was usually confined to acetylcholinesterase-positive structures, implying that the reaction is present in nerves. Glutamate is a potent pain mediator in the human central nervous system, and in animals it has been shown that peripherally administered glutamate NMDA receptor antagonists diminish the response to formalin-induced nociception. Our present finding of glutamate NMDA receptors in human Achilles tendons might have implications for pain treatment.

  • 16.
    Alfredson, Håkan
    et al.
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy.
    Thorsen, Kim
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Sports Medicine.
    Lorentzon, Ronny
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Sports Medicine.
    In vivo microdialysis and immunohistochemical analyses of tendon tissue demonstrated high amounts of free glutamate and glutamate NMDAR1 receptors, but no signs of inflammation, in Jumper's knee.2001In: Journal of Orthopaedic Research, ISSN 0736-0266, E-ISSN 1554-527X, Vol. 19, no 5, p. 881-886Article in journal (Refereed)
    Abstract [en]

    This investigation describes, to our knowledge, the first experiment where the microdialysis technique was used to study certain metabolic events in human patellar tendons in combination with immunohistochemical analyses of tendon biopsies. In five patients (four men and one woman) with a long duration (range 12-36 months) of pain symptoms from Jumper's knee (localized tenderness in the patellar tendon verified as tendon changes with ultrasonography or MRI), and in five controls (four men and one woman) with normal patellar tendons, a standard microdialysis catheter was inserted into the patellar tendon under local anestesia. The local concentrations of glutamate (excitatory neurotransmitter) and prostaglandin E2 (PGE2) were registered under resting conditions. Samplings were done every 15 min during a 2 h period. In all individuals (patients and controls) biopsies were taken for immunohistochemical analyses. The results showed that it was possible to detect and measure the concentrations of glutamate and PGE2 in the patellar tendon with the use of microdialysis technique. There were significantly higher concentrations of free glutamate, but not PGE2, in tendons with tendinosis compared to normal tendons. In the biopsies, there were no inflammatory cell infiltrates, but, for the first time, it was shown that there was immunoreaction for the glutamate receptor NMDAR1 in association with nerve structures in human patellar tendons. These findings altogether indicate that glutamate might be involved in painful Jumper's knee, and further emphasizes that there is no chemical inflammation (normal PGE2 levels) in this chronic condition.

  • 17.
    Alfredson, Håkan
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Spang, Christoph
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Bilateral Achilles tendinosis: the similar morphological appearance and the benefit of unilateral treatment has benefits for the contralateral tendon2013In: International journal of experimental pathology (Print), ISSN 0959-9673, E-ISSN 1365-2613, Vol. 94, no 4, p. A18-A18Article in journal (Other academic)
  • 18.
    Alfredson, Håkan
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Spang, Christoph
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Unilateral surgical treatment for patients with midportion Achilles tendinopathy may result in bilateral recovery2014In: British Journal of Sports Medicine, ISSN 0306-3674, E-ISSN 1473-0480, Vol. 48, no 19, p. 1421-1424Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Bilateral midportion Achilles tendinopathy/tendinosis is not unusual, and treatment of both sides is often carried out. Experiments in animals suggest of the potential involvement of central neuronal mechanisms in Achilles tendinosis. OBJECTIVES: To evaluate the outcome of surgery for Achilles tendinopathy. METHODS: This observational study included 13 patients (7 men and 6 women, mean age 53 years) with a long duration (6-120 months) of chronic painful bilateral midportion Achilles tendinopathy. The most painful side at the time for investigation was selected to be operated on first. Treatment was ultrasound-guided and Doppler-guided scraping procedure outside the ventral part of the tendon under local anaesthetic. The patients started walking on the first day after surgery. Follow-ups were conducted and the primary outcome was pain by visual analogue scale. In an additional part of the study, specimens from Achilles and plantaris tendons in three patients with bilateral Achilles tendinosis were examined. RESULTS: Short-term follow-ups showed postoperative improvement on the non-operated side as well as the operated side in 11 of 13 patients. Final follow-up after 37 (mean) months showed significant pain relief and patient satisfaction on both sides for these 11 patients. In 2 of 13 patients operation on the other, initially non-operated side, was instituted due to persisting pain. Morphologically, it was found that there were similar morphological effects, and immunohistochemical patterns of enzyme involved in signal substance production, bilaterally. CONCLUSION: Unilateral treatment with a scraping operation can have benefits contralaterally; the clinical implication is that unilateral surgery may be a logical first treatment in cases of bilateral Achilles tendinopathy.

  • 19.
    Alfredson, Håkan
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Willberg, Lotta
    Öhberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Ultrasound and doppler-guided artthroscopic shaving for the treatment of patellar tendinopathy/jumper´s knee: biological background and description of method2011In: Anterior knee pain and patellar instability / [ed] Sanchis-Alfonso, Vicente, London: Springer London, 2011, p. 367-371Chapter in book (Refereed)
    Abstract [en]

    Treatment with ultrasound and Doppler-guided arthroscopic shaving of the region with vessels and nerves outside the dorsal tendon has shown promising clinical results in patients with proximal patellar tendinopathy/Jumper´s knee. The results concerning only a limited patient material has been published in a scientific paper. Results on larger materials are under evaluation for later publication. Proper understanding of the ultrasound and Doppler findings, to enable for a precise and minimal arthroscopic shaving procedure on the dorsal side of the tendon, are cornerstones using this new type of treatment.

  • 20.
    Alrifaiy, Ahmed
    et al.
    Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF). Luleå University of Technology.
    Bitaraf, Nazanin
    Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF). Luleå University of Technology.
    Druzin, Michael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Lindahl, Olof
    Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics. Luleå University of Technology.
    Ramser, K
    Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF). Luleå University of Technology.
    Hypoxia on a chip: a novel approach for patch-clamp studies in a microfluidic system with full oxygen control2013In: World Congress on Medical Physics and Biomedical Engineering May 26-31, 2012, Beijing, China / [ed] Mian Long, Springer Berlin/Heidelberg, 2013, p. 313-316Conference paper (Refereed)
    Abstract [en]

    A new approach to perform patch-clamp experiments on living cells under controlled anoxic and normoxic conditions was developed and tested. To provide an optimal control over the oxygen content and the biochemical environment a patch-clamp recording micropipette was integrated within an oxygen tight poly-methyl methacrylate (PMMA) based microchip. The oxygen content within the microfluidic chamber surrounding patch-clamp micropipette was maintained at 0.5-1.5 % by a continuous flow of artificial extracellular solution purged with nitrogen. The nerve and glial cells acutely obtained from the male rat brain were trapped by the optical tweezers and steered towards the patch-clamp micropipette through the channels of the microchip in order to achieve a close contact between the pipette and the cellular membrane. The patch-clamp recordings revealed that optical tweezers did not affect the electrophysiological properties of the tested cells suggesting that optical trapping is a safe and non-traumatizing method to manipulate living cells in the microfluidic system. Thus, our approach of combining optical tweezers and a gas-tight microfluidic chamber may be applied in various electrophysiological investigations of single cells were optimal control of the experimental conditions and the sample in a closed environment are necessary.

  • 21.
    Alstermark, Bror
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Ekerot, Carl-Fredrik
    Department of Experimental Medical Sciences, Section for Neuroscience, Lund.
    The lateral reticular nucleus: a precerebellar centre providing the cerebellum with overview and integration of motor functions at systems level. A new hypothesis.2013In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 591, no 22, p. 5453-5458Article in journal (Refereed)
    Abstract [en]

    The lateral reticular nucleus (LRN) is a major precerebellar centre of mossy fibre information to the cerebellum from the spinal cord that is distinct from the direct spinocerebellar paths. The LRN has traditionally been considered to provide the cerebellum with segregated information from several spinal systems controlling posture, reaching, grasping, locomotion, scratching and respiration. However, results are presented that show extensive convergence on a majority of LRN neurons from spinal systems. We propose a new hypothesis suggesting that the LRN may use extensive convergence from the different input systems to provide overview and integration of linked motor components to the cerebellum. This integrated information is sent in parallel with the segregated information from the individual systems to the cerebellum that finally may compare the activity and make necessary adjustments of various motor behaviours.

  • 22.
    Alstermark, Bror
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Ekerot, Carl-Fredrik
    The lateral reticular nucleus: integration of descending and ascending systems regulating voluntary forelimb movements2015In: Frontiers in Computational Neuroscience, ISSN 1662-5188, E-ISSN 1662-5188, Vol. 9, article id 102Article in journal (Refereed)
    Abstract [en]

    Cerebellar control of movements is dependent on mossy fiber input conveying information about sensory and premotor activity in the spinal cord. While much is known about spino-cerebellar systems, which provide the cerebellum with detailed sensory information, much less is known about systems conveying motor information. Individual motoneurones do not have projections to spino-cerebellar neurons. Instead, the fastest route is from last order spinal interneurons. In order to identify the networks that convey ascending premotor information from last order interneurons, we have focused on the lateral reticular nucleus (LRN), which provides the major mossy fiber input to cerebellum from spinal interneuronal systems. Three spinal ascending systems to the LRN have been investigated: the C3-C4 propriospinal neurones (PNs), the ipsilateral forelimb tract (iFT) and the bilateral ventral flexor reflex tract (bVFRT). Voluntary forelimb movements involve reaching and grasping together with necessary postural adjustments and each of these three interneuronal systems likely contribute to specific aspects of forelimb motor control. It has been demonstrated that the command for reaching can be mediated via C3-C4 PNs, while the command for grasping is conveyed via segmental interneurons in the forelimb segments. Our results reveal convergence of ascending projections from all three interneuronal systems in the LRN, producing distinct combinations of excitation and inhibition. We have also identified a separate descending control of LRN neurons exerted via a subgroup of cortico-reticular neurones. The LRN projections to the deep cerebellar nuclei exert a direct excitatory effect on descending motor pathways via the reticulospinal, vestibulospinal, and other supraspinal tracts, and might play a key role in cerebellar motor control. Our results support the hypothesis that the LRN provides the cerebellum with highly integrated information, enabling cerebellar control of complex forelimb movements.

  • 23.
    Alstermark, Bror
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Hultborn, H
    University of Copenhagen Department of Neuroscience and Pharmacology Copenhagen N. Denmark.
    Jankowska, E
    Sahlgrenska Academy, University of Gothenburg Department of Physiology Gothenburg Sweden.
    Pettersson, L-G
    Sahlgrenska Academy, University of Gothenburg Department of Physiology Gothenburg Sweden.
    Anders Lundberg (1920-2009).2010In: Experimental Brain Research, ISSN 0014-4819, E-ISSN 1432-1106, Vol. 200, no 3-4, p. 193-195Article in journal (Other (popular science, discussion, etc.))
    Abstract [en]

    Anders Lundberg was one of the founding editorial board members for EBR when it began its life in 1976 under the editorship of John Eccles. He was also one of the most prolific contributors to the journal with a total of 49 papers, including a series of 16 on the topic of “integration in descending motor pathways controlling the forelimb in the cat”. He continued as an editor of the journal until volume 16 when he persuaded his younger colleague Hans Hultborn to take his place. Hans is one of the authors of the obituary. –John Rothwell

  • 24.
    Alstermark, Bror
    et al.
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Physiology.
    Isa, T
    Pettersson, L-G
    Sasaki, S
    The C3-C4 propriospinal system in the cat and monkey: a spinal pre-motoneuronal centre for voluntary motor control.2007In: Acta Physiol (Oxf), ISSN 1748-1708, Vol. 189, no 2, p. 123-40Article in journal (Refereed)
    Abstract [en]

    This review deals with a spinal interneuronal system, denoted the C3-C4 propriospinal system, which is unique in the sense that it so far represents the only spinal interneuronal system for which it has been possible to demonstrate a command mediating role for voluntary movements. The C3-C4 propriospinal neurones govern target reaching and can update the descending cortical command when a fast correction is required of the movement trajectory and also integrate signals generated from the forelimb to control deceleration and termination of reaching.

  • 25.
    Alstermark, Bror
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Isa, Tadashi
    Natl Inst Physiol Sci, Dept Dev Physiol, Okazaki, Aichi 4448585, Japan.
    Circuits for skilled reaching and grasping2012In: Annual Review of Neuroscience, Palo alto: ANNUAL REVIEWS, 2012, p. 559-578Chapter in book (Refereed)
    Abstract [en]

    From an evolutionary perspective, it is clear that basic motor functions such as locomotion and posture are largely controlled by neural circuitries residing in the spinal cord and brain-stem. The control of voluntary movements such as skillful reaching and grasping is generally considered to be governed by neural circuitries in the motor cortex that connect directly to motoneurons via the corticomotoneuronal (CM) pathway. The CM pathway may act together with several brain-stem systems that also act directly with motoneurons. This simple view was challenged by work in the cat, which lacks the direct CM system, showing that the motor commands for reaching and grasping could be mediated via spinal interneurons with input from the motor-cortex and brain-stem systems. It was further demonstrated that the spinal interneurons mediating the descending commands for reaching and grasping constitute separate and distinct populations from those involved in locomotion and posture. The aim of this review is to describe populations of spinal interneurons that are involved in the control of skilled reaching and grasping in the cat, monkey, and human.

  • 26.
    Alstermark, Bror
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Isa, Tadashi
    Premotoneuronal and direct corticomotoneuronal control in the cat and macaque monkey.2002In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 508, p. 281-97Article in journal (Refereed)
    Abstract [en]

    The literature on premotoneuronal and direct corticomotoneuronal (CM) control in the cat and macaque monkey is reviewed. The available experimental findings are not in accordance with a recently proposed hypothesis that direct CM connections have "replaced" the premotoneuronal pathways. Instead, we propose that premotoneuronal CM control plays an important role in motor control also in primates and that the direct CM connection has been added during phylogeny.

  • 27.
    Alstermark, Bror
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Lan, N
    Pettersson, L-G
    Building a realistic neuronal model that simulates mulit-joint arm and hand movements in 3D-space.2007In: HFSP Journal, Vol. 1, no 4, p. 209-214Article in journal (Refereed)
  • 28.
    Alstermark, Bror
    et al.
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Physiology.
    Ogawa, Jun
    In vivo recordings of bulbospinal excitation in adult mouse forelimb motoneurons.2004In: Journal of Neurophysiology, ISSN 0022-3077, Vol. 92, no 3, p. 1958-62Article in journal (Refereed)
    Abstract [en]

    Here we report on pyramidal and reticulospinal excitation in forelimb motoneurons in the adult mouse using intracellular recordings in vivo. The results have been obtained in BALB/C mice, which were anesthetized with midazolam fentanyl/fluanison. In contrast to the rat, only weak and infrequent pyramidal excitation could be evoked with a minimal trisynaptic linkage. Disynaptic reticulospinal excitation could always be evoked, as well as monosynaptic excitation from the medial longitudinal fasciculus. The results suggest that the reticulospinal pathway in the mouse is important in voluntary motor control of the forelimbs and that the role of the corticospinal tract might be different in mouse compared with rat. Our study provides an opening for studying the effect of genetic manipulation on specified descending systems in the mouse in vivo.

  • 29.
    Alstermark, Bror
    et al.
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Physiology.
    Ogawa, Jun
    Isa, T
    Lack of monosynaptic corticomotoneuronal EPSPs in rats: disynaptic EPSPs mediated via reticulospinal neurons and polysynaptic EPSPs via segmental interneurons.2004In: Journal of Neurophysiology, ISSN 0022-3077, Vol. 91, no 4, p. 1832-9Article in journal (Refereed)
    Abstract [en]

    In the rat, some findings have been taken to suggest the existence of monosynaptic corticomotoneuronal (CM) connections. Because this connection is believed to be largely responsible for the ability to make independent digit movements in primates and man, it has been inferred that the monosynaptic CM connection in the rat is likewise important for skilled prehension. Comparison of intra- and extracellular recordings from forelimb motoneurons in anesthetized rats, revealed no monosynaptic CM excitatory postsynaptic potentials (EPSPs). The fastest descending excitation in forelimb motoneurons was disynaptically mediated via a corticoreticulospinal pathway and slowly conducted excitation via corticospinal fibers and segmental interneurons. The findings stress the importance of di- and trisynaptic excitatory corticofugal pathways to forelimb motoneurons in the control of skillful digit movements.

  • 30.
    Alstermark, Bror
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Pettersson, L G
    University of Gothenburg.
    Nishimura, Y
    National Institute for Physiological Sciences, Okazaki.
    Yoshino-Saito, K
    National Institute for Physiological Sciences, Okazaki.
    Tsuboi, F
    National Institute for Physiological Sciences, Okazaki.
    Takahashi, M
    National Institute for Physiological Sciences, Okazaki.
    Isa, T
    National Institute for Physiological Sciences, Okazaki.
    Motor command for precision grip in the macaque monkey can be mediated by spinal interneurons2011In: Journal of Neurophysiology, ISSN 0022-3077, E-ISSN 1522-1598, Vol. 106, no 1, p. 122-126Article in journal (Refereed)
    Abstract [en]

    In motor control, the general view is still that spinal interneurons mainly contribute to reflexes and automatic movements. The question raised here is whether spinal interneurons can mediate the cortical command for independent finger movements, like a precision grip between the thumb and index finger in the macaque monkey, or if this function depends exclusively on a direct corticomotoneuronal pathway. This study is a followup of a previous report (Sasaki et al. J Neurophysiol 92: 3142-3147, 2004) in which we trained macaque monkeys to pick a small piece of sweet potato from a cylinder by a precision grip between the index finger and thumb. We have now isolated one spinal interneuronal system, the C3-C4 propriospinal interneurons with projection to hand and arm motoneurons. In the previous study, the lateral corticospinal tract (CST) was interrupted in C4/C5 (input intact to the C3-C4 propriospinal interneurons), and in this study, the CST was interrupted in C2 (input abolished). The precision grip could be performed within the first 15 days after a CST lesion in C4/C5 but not in C2. We conclude that C3-C4 propriospinal interneurons also can carry the command for precision grip.

  • 31.
    Alstermark, Bror
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Pettersson, Lars-Gunnar
    Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg Gothenburg, Sweden..
    Endogenous plasticity in neuro-rehabilitation following partial spinal cord lesions2014In: Frontiers in Neuroscience, ISSN 1662-4548, E-ISSN 1662-453X, Vol. 8, p. 59-Article in journal (Refereed)
    Abstract [en]

    Currently, much interest in neuro-rehabilitation is focused on mechanisms related to axonal outgrowth and formation of new circuits although still little is known about the functionality in motor behavior. This is a highly exciting avenue of research and most important to consider when dealing with large lesions. Here, we address endogenous mechanisms with the potential of modifying the function of already existing spinal circuits via associative plasticity. We forward a hypothesis based on experimental findings suggesting that potentiation of synaptic transmission in un-injured pathways can be monitored and adjusted by a Cerebellar loop involving the Reticulospinal, Rubrospinal and Corticospinal tracts and spinal interneurons with projection to motoneurons. This mechanism could be of relevance when lesions are less extensive and the integrity of the neural circuits remains in part. Endogenous plasticity in the spinal cord could be of clinical importance if stimulated in an adequate manner, e.g., by using optimal training protocols.

  • 32.
    Alstermark, Bror
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Pettersson, Lars-Gunnar
    Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg , Gothenburg.
    Skilled reaching and grasping in the rat: lacking effect of corticospinal lesion2014In: Frontiers in Neurology, ISSN 1664-2295, E-ISSN 1664-2295, Vol. 5, article id 103Article in journal (Refereed)
    Abstract [en]

    The corticospinal system is a major motor pathway in the control of skilled voluntary movements such as reaching and grasping. It has developed considerably phylogenetically to reach a peak in humans. Because rodents possess advanced forelimb movements that can be used for reaching and grasping food, it is commonly considered that the corticospinal tract (CST) is of major importance for this control also in rodents. A close homology to primate reaching and grasping has been described but with obvious limitations as to independent digit movements, which are lacking in rodents. Nevertheless, it was believed that there are, as in the primate, direct cortico-motoneuronal connections. Later, it was shown that there are no such connections. The fastest excitatory pathway is disynaptic, mediated via cortico-reticulospinal neurons and in the spinal cord the excitation is mainly polysynaptically mediated via segmental interneurons. Earlier behavioral studies have aimed at investigating the role of the CST by using pyramidotomy in the brainstem. However, in addition to interrupting the CST, a pyramidal transection abolishes the input to reticulospinal neurons. It is therefore not possible to conclude if the deficits after pyramidotomy result from interruption of the CST or the input to reticulospinal neurons or both. We have re-investigated the role of the CST by examining the effect of a CST lesion in the C1-C2 spinal segments on the success rate of reaching and grasping. This lesion spares the cortico-reticulospinal pathway. In contrast to investigations using pyramidal transections, the present study did not demonstrate marked deficits in reaching and grasping. We propose that the difference in results can be explained by the intact cortical input to reticulospinal neurons in our study and thus implicate an important role of this pathway in the control of reaching and grasping in the rat.

  • 33.
    Andersson, Gustav
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Influences of paratendinous innervation and non-neuronal substance P in tendinopathy: studies on human tendon tissue and an experimental model of Achilles tendinopathy2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Pain of the musculoskeletal system is one of the most common reasons for people seeking medical attention, and is also one of the major factors that prevent patients from working. Chronic tendon pain, tendinopathy, affects millions of workers world-wide, and the Achilles tendon is an important structure often afflicted by this condition. The pathogenesis of tendinopathy is poorly understood, but it is thought to be of multifactoral aetiology. It is known that tendon pain is often accompanied not only by impaired function but also by structural tissue changes, like vascular proliferation, irregular collagen organisation, and hypercellularity, whereby the condition is called tendinosis. In light of the poor knowledge of tendinosis pathophysiology and recent findings of a non-neuronal signalling system in tendon tissue, the contributory role of neuropeptides such as substance P (SP) has gained increased interest. SP, known for afferent pain signalling in the nervous system, also has multiple efferent functions and has been described to be expressed by non-neuronal cells. As pain is the most prominent symptom of tendinopathy, the focus of the studies in this thesis was the innervation patterns of the tissue ventral to the Achilles tendon (i.e. the tissue targeted in many contemporary treatment methods) as well as the distribution of SP and its preferred receptor, the neurokinin-1 receptor (NK-1R), in the tendon tissue itself. It was hereby hypothesised that the source of SP affecting the Achilles tendon might be the main cells of the tendon tissue (the tenocytes) as well as paratendinous nerves, and that SP might be involved in tendinosis- development. The studies were conducted, via morphological staining methods including immunohistochemistry and in situ hybridisation, on tendon biopsies from patients suffering from Achilles tendinosis and on those from healthy volunteers. The hypothesis of the thesis was furthermore tested using an experimental animal model (rabbit) of Achilles tendinopathy, which was first validated. The model was based on a previously established overuse protocol of repetitive exercise. In the human biopsies of the tissue ventral to the Achilles tendon, there was a marked occurrence of sympathetic innervation, but also sensory, SP-containing, nerve fibres. NK-1R was expressed on blood vessels and nerve fascicles of the paratendinous tissue, but also on the tenocytes of the tendon tissue proper itself, and notably more so in patients suffering from tendinosis. Furthermore, the human tenocytes displayed not only NK-1R mRNA but also mRNA for SP. The animal model was shown to produce objectively verified tendinosis-like changes, such as hypercellularity and increased vascularity, in the rabbit Achilles tendons, after a minimum of three weeks of the exercise protocol. The contralateral leg of the animals in the model was found to be an unreliable control, as bilateral changes occured. The model furthermore demonstrated that exogenously administered SP triggers an inflammatory response in the paratendinous tissue and accelerates the intratendinous tendinosis-like changes such that they now occur after only one week of the protocol. Injections of saline as a control showed similar results as SP concerning hypercellularity, but did not lead to vascular changes or pronounced paratendinous inflammation. In summary, this thesis concludes that interactions between the peripheral sympathetic and sensory nervous systems may occur in Achilles tendinosis at the level of the ventral paratendinous tissue, a region thought to be of great importance in chronic tendon pain since many successful treatments are directed toward it. Furthermore, the distribution of NK-1R:s in the Achilles tendon described in these studies gives a basis for SP, whether produced by nerves mainly outside the tendon or by tenocytes within the tendon, to affect blood vessels, nerve structures, and/or tendon cells, especially in tendinosis patients. In light of this and of previously known SP-effects, such as stimulation of angiogenesis, pain signalling, and cell proliferation, the proposed involvement of SP in tendinosis development seems likely. Indeed, the animal model of Achilles tendon overuse confirms that SP does induce vascular proliferation and hypercellularity in tendon tissue, thus strengthening theories of SP playing a role in tendinosis pathology.

  • 34.
    Andersson, Gustav
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Backman, Ludvig J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Christensen, Jens
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Nerve distributions in insertional Achilles tendinopathy - a comparison of bone, bursae and tendon2017In: Histology and Histopathology, ISSN 0213-3911, E-ISSN 1699-5848, Vol. 32, no 3, p. 263-270Article in journal (Refereed)
    Abstract [en]

    Background/Aim. In a condition of pain in the Achilles tendon insertion there are multiple structures involved, such as the Achilles tendon itself, the retrocalcaneal bursa and a bony protrusion at the calcaneal tuberosity called Haglund's deformity. The innervation patterns of these structures are scarcely described, and the subcutaneous calcaneal bursa is traditionally not considered to be involved in the pathology. This study aimed at describing the innervation patterns of the four structures described above to provide a better understanding of possible origins of pain at the Achilles tendon insertion.

    Methods. Biopsies were taken from 10 patients with insertional Achilles tendinopathy, which had pathological changes in the subcutaneous and retrocalcaneal bursae, a Haglund deformity and Achilles tendon tendinopathy as verified by ultrasound. The biopsies were stained using immunohistochemistry in order to delineate the innervation patterns in the structures involved in insertional Achilles tendinopathy.

    Results. Immunohistochemical examinations found that the subcutaneous bursa scored the highest using a semi-quantitative evaluation of the degree of innervation when compared to the retrocalcaneal bursa, the Achilles tendon, and the calcaneal bone.

    Conclusions. These findings suggest that the subcutaneous bursa, which is traditionally not included in surgical treatment, may be a clinically important factor in insertional Achilles tendinopathy.

  • 35.
    Andersson, Gustav
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Backman, Ludvig
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Scott, Alexander
    Department of Physical Therapy, University of British Columbia, Vancouver, British Columbia, Canada; Centre for Hip Health and Mobility, Vancouver Coastal Health and Research Institute, Vancouver, British Columbia, Canada.
    Lorentzon, Ronny
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Substance P accelerates hypercellularity and angiogenesis in tendon tissue and enhances paratendinitis in response to Achilles tendon overuse in a tendinopathy model2011In: British Journal of Sports Medicine, ISSN 0306-3674, E-ISSN 1473-0480, Vol. 45, no 13, p. 1017-1022Article in journal (Refereed)
    Abstract [en]

    Background Tenocytes produce substance P (SP) and its receptor (neurokinin-1 receptor (NK-1R) is expressed throughout the tendon tissue, expecially in patients with tendinopathy and tissue changes (tendinosis) including hypercellularity and vascular proliferation. Considering the known effects of SP, one might ask whether SP contributes to these canges.

    Objectives To test whether development of tendinosislike changes (hypercellularity and angiogenesis) is accelerated during a 1-week course of ecercise with local administration of SP in an establish Achilles tendinopathy model.

    Methods Rabbits were subjected to a protocol of Achilles tendon overuse for 1 week, in conjunction with SP injections in the paratenon. Exercised control animals received NaCl injections or no injections, and unexercised, uninjected controls were also used. Tenocyte number and vascular density, as well as paratendinous inflammation, were evaluated. Immunohistochemistry and in sity hybridisation to detect NK-1R were conducted.

    Results There was a significant increase in tenocyte number in the SP-injected and NaCl-injected groups compared with both unexercised and exercised, uninjected controls. Tendon blood vessels increased in number in the SP-injected group compared with unexercised controls, a finding not seen in NaCl-injected controls or in uninjected, exercised animals. Paratendinous inflammation was more pronounced in the SP-injected group than in the NaCl controls. NK-1R was detected in blood vessel walls, nerves, inflammatory cells and tenocytes.

    Conclusions SP accelerated the development of tendinosis-like changes in the rabbit. Achilles tendon, which supports theories of a potential role of SP in tendinosis development; a fact of clinical interest since SP effects can be effectively blocked. The angiogenic response to SP injections seems related to parateninitis.

  • 36.
    Andersson, Gustav
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Backman, Ludvig
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Scott, Alexander
    Department of Physical Therapy, University of British Columbia, Vancouver, BC, Canada.
    Lorentzon, Ronny
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Substance P induces tendinosis-like changes in a rabbit model of Achilles tendon overuseManuscript (preprint) (Other academic)
    Abstract [en]

    BACKGROUND: In previous studies we found evidence favouring that human Achilles tendon cells (tenocytes) are capable of producing the neuropeptide substance P (SP). Furthermore, the preferred receptor for SP (the neurokinin-1 receptor, NK-1 R) was widely expressed throughout the tendon, especially in patients suffering from chronic tendon pain (tendinopathy) with tissue changes (tendinosis) including hypercellularity and vascular proliferation. Considering known effects of SP, one might ask whether SP contributes to tendon cell proliferation and neovascularisation in tendinosis. We have an established animal (rabbit) model of Achilles tendinopathy based on overuse in the form of repetitive exercise. Recent studies with this model have shown that tendinosis-like changes are present after 3 weeks of exercise, but not after only 1 week. The current study aimed to test whether the development of tendinosis-like changes would be accelerated during a 1 week course of exercise with repetitive local administration of SP.

    MATERIAL AND METHODS: Four groups of animals (5-6 New Zealand white rabbits per group) were used. Three groups were subjected to the previously established protocol of Achilles tendon overuse for 1 week. One of these groups was given repetitive SP injections in the paratendinous tissue of the Achilles tendon, whereas one group (‘NaCl controls’) was given an equivalent schedule of saline injections. Two additional control groups existed: One in which the animals were neither subjected to the overuse protocol nor to any injections (‘untrained controls’), and one in which the animals trained for 1 week but were not given any injections (‘1 week controls’). Tenocyte number, vascular density, and the possible occurrence of paratendinous inflammation were evaluated. Immunohistochemistry and in situ hybridisation to detect NK-1 R were also conducted.

    RESULTS: There was a significant increase in tenocyte number in the SP-injected group compared to both untrained controls and 1 week controls. However, the same phenomenon was noticed for NaCl controls, i.e. tenocyte number was significantly increased in response to NaCl injections compared to untrained controls. There was an increase in the number of tendon blood vessels in the SP-injected group as compared to untrained controls, and this increase in vascularity was not seen for the NaCl controls or the 1 week controls. Paratendinous inflammation, as evidenced by invasion of inflammatory cells in the paratenon, was clearly more pronounced in the SP-injected group than in the NaCl controls. NK-1 R was detected in blood vessel walls, on nerves, on inflammatory cells, and on tenocytes.

    DISCUSSION AND CONCLUSIONS: The observations suggest that SP induces tenocyte proliferation and angiogenesis in the rabbit Achilles tendon, thus supporting a potential role of this neuropeptide in the processes that occur in tendinosis. The study corroborates findings on the human Achilles tendon in that NK-1 R was expressed on tenocytes and tendon blood vessel walls, thereby providing a potential anatomic basis for the observed effects of SP on the development of tendinosis. The hypercellularity observed in response to NaCl injections might be due increased tissue pressure or to stimulation of endogenous SPproduction, a phenomenon not unheard of. The angiogenic effect of SP injections, on the other hand, appeared to be more specifically related to an induction of inflammation in the paratendon.

  • 37.
    Andersson, Gustav
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Arteries in the area targeted with successful sclerosing injections for Achilles tendinosis are under distinct neural control2006Conference paper (Refereed)
    Abstract [en]

    It has been scientifically demonstrated that there are blood vessels with pathologically high blood flow inside and outside the ventral part of the Achilles tendon in chronic painful tendinosis, but not in pain-free normal Achilles tendons. Injections of local anaesthesia on the outside of the ventral part of the tendon have been found to temporarily abolish the tendon pain, and this has been an inspiration in the development of a new approach in the treatment of tendinosis: Based on ultrasound- (US) and colour Doppler- (CD) guidance, the sclerosing substance polidocanol, for many years used in treatment of varicose veins, was injected targeting the area of high-flow blood vessels just outside the ventral part of the Achilles tendon. The treatment has in pilot studies and a randomized controlled clinical study been shown to cure the pain in about 70-80 % of the patients. Also, follow up examinations, using US and CD, have shown a possible remodeling potential of the tendon. There is some previous information available on the innervation patterns of the human Achilles tendon itself. However, the innervation patterns of the area just outside the ventral part of the tendon, i.e. the area that is targeted by the sclerosing injections (target area), are unknown. This includes a lack of information concerning the nerve-related characteristics of the blood vessels in the area. In this study, therefore, tissue specimens from this target area, obtained during surgical treatment of patients with chronic painful mid-portion Achilles tendinosis, were examined. Histological and immunohistochemical examinations were performed. In the tissue of the target area, in which loose connective tissue and fat cells were frequent constituents, there was a presence of arteries and nerve fascicles. The arteries were of varying dimensions, some being very large. The nerve fascicles were distinguished in sections processed for the pan-neural marker protein gene-product 9.5 (PGP 9.5).  Some of the arteries were supplied by an extensive perivascular innervation, as seen via PGP 9.5 staining. As seen via processing for the rate limiting enzyme in catecholamine synthesis, tyrosine hydroxylase (TH), sympathetic innervation was found to be a constituent of this innervation. There was furthermore a marked occurrence of immunoreactions for the α1-adrenoreceptor in arterial walls. Also, there was a presence of immunoreactions for the substance P (SP)-preferred receptor, the neurokinin-1 (NK-1) receptor in arterial walls. This receptor was particularly detected in the endothelial parts. The study shows that the arteries in the target area are accompanied by nerve fascicles and that there is a presence of a perivascular innervation, as well as a presence of adrenergic and NK-1 receptors in arterial walls, in this region. Thus, arteries in this area are under distinct neural control. The nerve-related characteristics of the area targeted in the successful polidicanol injection treatment for Achilles tendinosis are here for the first time shown.

  • 38.
    Andersson, Gustav
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Nerve-related characteristics of ventral paratendinous tissue in chronic Achilles tendinosis2007In: Knee Surgery, Sports Traumatology, Arthroscopy, ISSN 0942-2056, E-ISSN 1433-7347, Vol. 15, no 10, p. 1272-1279Article in journal (Refereed)
    Abstract [en]

    Ultrasound and Doppler examination has shown high blood flow-neovascularisation inside and outside the ventral Achilles tendon in chronic painful tendinosis, but not in pain-free normal Achilles tendons. In patients with Achilles tendinosis, injections with the sclerosing substance polidocanol, targeting the areas with increased blood flow, have been demonstrated to give pain relief. A drawback when interpreting these findings is the fact that the pattern of nerve supply in the target area, i.e. the ventral area of the tendon, is so far unknown. In this study, therefore, tissue specimens from this area, obtained during surgical treatment of patients with chronic painful midportion Achilles tendinosis, were examined. In the examined area, containing loose connective tissue, the general finding was a presence of large and small arteries and nerve fascicles. The nerve fascicles were distinguished in sections processed for the pan-neural marker protein gene-product 9.5. The nerve fascicles contain sensory nerve fibers, as shown via staining for the sensory markers substance P (SP) and calcitonin gene-related peptide, and sympathetic nerve fibers as seen via processing for tyrosine hydroxylase. In addition, there were immunoreactions for the SP-preferred receptor, the neurokinin-1 receptor, in blood vessel walls and nerve fascicles. Some of the blood vessels were supplied by an extensive peri-vascular innervation, sympathetic nerve fibers being a distinct component of this innervation. There was also a marked occurrence of immunoreactions for the alpha1-adrenoreceptor in arterial walls as well as in the nerve fascicles. Altogether, these findings suggest that the area investigated is under marked influence by the nervous system, including sympathetic and sensory components. Thus, sympathetic/sensory influences may be involved in the pain mechanisms from this area. In conclusion, the nerve-related characteristics of the area targeted by the polidicanol injection treatment for Achilles tendinosis, are shown here for the first time.

  • 39.
    Andersson, Gustav
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Presence of substance P and the neurokinin-1 receptor in tenocytes of the human Achilles tendon2008In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 150, no 1-3, p. 81-87Article in journal (Refereed)
    Abstract [en]

    Nerve signal substances, such as the tachykinin substance P (SP), may be involved in the changes that occur in response to tendinopathy (tendinosis). It is previously known that the level of SP innervation within tendon tissue is limited, but results of experimental studies have suggested that SP may have stimulatory, angiogenetic and healing effects in injured tendons. Therefore, it would be of interest to know if there is a local SP-supply in tendon tissue. In the present study, the patterns of expression of SP and its preferred receptor, the neurokinin-1 receptor (NK-1 R), in normal and tendinosis human Achilles tendons were analyzed by use of both immunohistochemistry and in situ hybridization. We found that there was expression of SP mRNA in tenocytes, and that tenocytes showed expression of NK-1 R at protein as well as mRNA levels. The observations concerning both SP and NK-1 R were most evident for tenocytes in tendinosis tendons. Our findings suggest that SP is produced in tendinosis tendons, and furthermore that SP has marked effects on the tenocytes via the NK-1 R. It cannot be excluded that the SP effects are of importance concerning the processes of reorganization and healing that occur for tendon tissue in tendinosis. In conclusion, it appears as if SPergic autocrine/paracrine effects occur in tendon tissue during the processes of tendinosis, hitherto unknown effects for human tendons.

  • 40.
    Andersson, Gustav
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Scott, Alexander
    University of British Columbia, Vancouver, Vancouver Coastal Health and Research Institute.
    Gaida, James Edmund
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Stjernfeldt, Johanna Elgestad
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Lorentzon, Ronny
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Backman, Clas
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Tenocyte hypercellularity and vascular proliferation in a rabbit model of tendinopathy: contralateral effects suggest the involvement of central neuronal mechanisms2011In: British Journal of Sports Medicine, ISSN 0306-3674, E-ISSN 1473-0480, Vol. 45, no 5, p. 399-406Article in journal (Refereed)
    Abstract [en]

    Objective To determine whether there are objective findings of tendinosis in a rabbit tendinopathy model on exercised and contralateral (non-exercised) Achilles tendons. Design Four groups of six New Zealand white rabbits per group were used. The animals of one (control) group were not subjected to exercise/stimulation. Interventions Animals were subjected to a protocol of electrical stimulation and passive flexion-extension of the right triceps surae muscle every second day for 1, 3 or 6 weeks. Main Outcome Measures Tenocyte number and vascular density were calculated. Morphological evaluations were also performed as well as in-situ hybridisation for vascular endothelial growth factor (VEGF) messenger RNA. Results There was a significant increase in the tenocyte number after 3 and 6 weeks of exercise, but not after 1 week, in comparison with the control group. This was seen in the Achilles tendons of both legs in experimental animals, including the unexercised limb. The pattern of vascularity showed an increase in the number of tendon blood vessels in rabbits that had exercised for 3 weeks or more, compared with those who had exercised for 1 week or not at all. VEGF-mRNA was detected in the investigated tissue, with the reactions being more clearly detected in the tendon tissue with tendinosis-like changes (6-week rabbits) than in the normal tendon tissue (control rabbits). Conclusions There were bilateral tendinosis-like changes in the Achilles tendons of rabbits in the current model after 3 weeks of training, suggesting that central neuronal mechanisms may be involved and that the contralateral side is not appropriate as a control.

  • 41.
    Andersson, Gustav
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Orädd, Greger
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Comparative Biology (UCCB).
    Sultan, Fahad
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Novikov, Lev N.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    In vivo Diffusion Tensor Imaging, Diffusion Kurtosis Imaging, and Tractography of a Sciatic Nerve Injury Model in Rat at 9.4T2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 12911Article in journal (Refereed)
    Abstract [en]

    Peripheral nerve injuries result in severe loss of sensory and motor functions in the afflicted limb. There is a lack of standardised models to non-invasively study degeneration, regeneration, and normalisation of neuronal microstructure in peripheral nerves. This study aimed to develop a non-invasive evaluation of peripheral nerve injuries, using diffusion tensor imaging (DTI), diffusion kurtosis imaging (DKI), and tractography on a rat model of sciatic nerve injury. 10 female Sprague Dawley rats were exposed to sciatic nerve neurotmesis and studied using a 9.4 T magnet, by performing DTI and DKI of the sciatic nerve before and 4 weeks after injury. The distal nerve stump showed a decrease in fractional anisotropy (FA), mean kurtosis (MK), axonal water fraction (AWF), and radial and axonal kurtosis (RK, AK) after injury. The proximal stump showed a significant decrease in axial diffusivity (AD) and increase of MK and AK as compared with the uninjured nerve. Both mean diffusivity (MD) and radial diffusivity (RD) increased in the distal stump after injury. Tractography visualised the sciatic nerve and the site of injury, as well as local variations of the diffusion parameters following injury. In summary, the described method detects changes both proximal and distal to the nerve injury.

  • 42.
    Andersson, Linus
    et al.
    Umeå University, Faculty of Social Sciences, Department of Psychology. Department of Occupational and Public Health Sciences, University of Gävle, Sweden.
    Claeson, Anna-Sara
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Nordin, Steven
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Short-term olfactory sensitization involves brain networks relevant for pain, and indicates chemical intolerance2017In: International journal of hygiene and environmental health (Print), ISSN 1438-4639, E-ISSN 1618-131X, Vol. 220, no 2, p. 503-509Article in journal (Refereed)
    Abstract [en]

    Chemical intolerance is a medically unexplained affliction that implies deleterious reactions to non-toxic everyday chemical exposure. Sensitization (i.e. increased reactivity to repeated, invariant stimulation) to odorous stimulation is an important component in theoretical explanations of chemical intolerance, but empirical evidence is scarce. We hypothesized that (1) individuals who sensitize to repeated olfactory stimulation, compared with those who habituate, would express a lower blood oxygenated level dependent (BOLD) response in key inhibitory areas such as the rACC, and higher signal in pain/saliency detection regions, as well as primary and/or secondary olfactory projection areas; and (2) olfactory sensitization, compared with habituation, would be associated with greater self-reported chemical intolerance. More-over, we assessed whether olfactory sensitization was paralleled by comparable trigeminal processing - in terms of perceptual ratings and BOLD responses. We grouped women from a previous functional magnetic imaging study based on intensity ratings of repeated amyl acetate exposure over time. Fourteen women sensitized to the exposure, 15 habituated, and 20 were considered "intermediate" (i.e. neither sensitizers nor habituaters). Olfactory sensitizers, compared with habituaters, displayed a BOLD-pattern in line with the hypothesis, and reported greater problems with odours in everyday life. They also expressed greater reactions to CO2 in terms of both perceived intensity and BOLD signal. The similarities with pain are discussed.

  • 43.
    Andersson, Linus
    et al.
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Claesson, Anna-Sara
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Stenberg, Berndt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Nordin, Steven
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Brain responses to olfactory and trigeminal exposure in idiopathic environmental illness (IEI) attributed to smells: An fMRI study2014In: Journal of Psychosomatic Research, ISSN 0022-3999, E-ISSN 1879-1360, Vol. 77, no 5, p. 401-408Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Idiopathic environmental intolerance (IEI) to smells is a prevalent medically unexplained illness. Sufferers attribute severe symptoms to low doses of non-toxic chemicals. Despite the label, IEI is not characterized by acute chemical senses. Theoretical models suggest that sensitized responses in the limbic system of the brain constitute an important mechanism behind the symptoms. The aim was to investigate whether and how brain reactions to low-levels of olfactory and trigeminal stimuli differ in individuals with and without IEI. METHODS: Brain responses to intranasally delivered isoamyl acetate and carbon dioxide were assessed in 25 women with IEI and 26 non-ill controls using functional magnetic resonance imaging. RESULTS: The IEI group had higher blood-oxygenated-level-dependent (BOLD) signal than controls in the thalamus and a number of, mainly, parietal areas, and lower BOLD signal in the superior frontal gyrus. The IEI group did not rate the exposures as more intense than the control group did, and there were no BOLD signal differences between groups in the piriform cortex or olfactory regions of the orbitofrontal cortex. CONCLUSIONS: The IEI reactions were not characterized by hyper-responsiveness in sensory areas. The results can be interpreted as a limbic hyperreactivity and speculatively as an inability to inhibit salient extemal stimuli.

  • 44.
    Andersson, Mikael
    et al.
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Histology and Cell Biology.
    Terasmaa, Anton
    Fuxe, Kjell
    Strömberg, Ingrid
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Histology and Cell Biology.
    Subchronic haloperidol increases CB(1) receptor binding and G protein coupling in discrete regions of the basal ganglia.2005In: Journal of Neuroscience Research, ISSN 0360-4012, Vol. 82, no 2, p. 264-72Article in journal (Refereed)
    Abstract [en]

    The present study was designed to test whether chronic neuroleptic treatment, which is known to alter both expression and density of dopamine D(2) receptors in striatal regions, has effects upon function and binding level of the cannabinoid CB(1) receptor in the basal ganglia by using receptor autoradiography. As predicted, subchronic haloperidol treatment resulted in increased binding of (3)H-raclopride and quinpirole-induced guanosine 5'-O-(gamma-[(35)S]thio)triphosphate ([(35)S]GTPgammaS) in the striatum when compared to that measured in control animals. This increased D(2) receptor binding and function after 3 days washout was normalized after a 2-week washout period. Effect of haloperidol treatment was studied for CB(1) receptor binding and CP55,940-stimulated [(35)S]GTPgammaS in the striatum, globus pallidus, and substantia nigra. (3)[H]CP55,940 binding levels were found in rank order from highest to lowest in substantia nigra > globus pallidus > striatum. Furthermore, subchronic haloperidol treatment resulted in elevated binding levels of (3)[H]CP55,940 in the striatum and the substantia nigra and CB(1) receptor-stimulated [(35)S]GTPgammaS bindings in the substantia nigra after 3 days washout. These increased binding levels were normalized at 1-4 weeks after termination of haloperidol treatment. Haloperidol treatment had no significant effect on CB(1) receptor or [(35)S]GTPgammaS binding levels in globus pallidus. The results help to elucidate the underlying biochemical mechanism of CB(1) receptor supersensitivity after haloperidol treatment.

  • 45.
    Anens, Elisabeth
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy.
    Kristensen, Bo
    Häger-Ross, Charlotte
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Reactive grip force control in persons with cerebellar stroke: effects on ipsilateral and contralateral hand2010In: Experimental Brain Research, ISSN 0014-4819, E-ISSN 1432-1106, Vol. 203, no 1, p. 21-30Article in journal (Refereed)
    Abstract [en]

    This study investigates the cerebellar contribution to reactive grip control by examining differences between (22-48 years) subjects with focal cerebellar lesion due to ischaemic stroke (CL) and healthy subjects (HS). The subjects used a pinch grip to grasp and restrain an instrumented handle from moving when it was subject to unpredictable load forces of different rates (2, 4, 8, 32 N/s) or amplitudes (1, 2, 4 N). The hand ipsilateral to the lesion of the cerebellar subjects showed delayed and more variable response latencies, e.g., 278 +/- 162 ms for loads delivered at 2 N/s, compared to HS 180 +/- 53 ms (P = 0.005). The CL also used a higher pre-load grip force with the ipsilateral hand, 1.6 +/- 0.8 N, than the HS, 1.3 +/- 0.6 N (P = 0.017). In addition, the contralateral hand in subjects with unilateral cerebellar stroke showed a delayed onset of the grip response compared to HS. Cerebellar lesions thus impair the reactive grip control both in the ipsilateral and contralateral hand.

  • 46.
    Arasu, Uma Thanigai
    et al.
    Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
    Kärnä, Riikka
    Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
    Härkönen, Kai
    Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
    Oikari, Sanna
    Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
    Koistinen, Arto
    SIB Labs, University of Eastern Finland, Kuopio, Finland.
    Kröger, Heikki
    Department of Orthopaedics and Traumatology, Kuopio University Hospital, Kuopio, Finland; Bone and Cartilage Research Unit, Surgery, Institute of Clinical Medicine, University of Eastern, Finland.
    Qu, Chengjuan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Lammi, Mikko
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). School of Public Health, Health Science Center of Xi'an Jiaotong University, Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, Xi'an, PR China.
    Rilla, Kirsi
    Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
    Human mesenchymal stem cells secrete hyaluronan-coated extracellular vesicles2017In: Matrix Biology, ISSN 0945-053X, E-ISSN 1569-1802, Vol. 64, p. 54-68Article in journal (Refereed)
    Abstract [en]

    Extracellular vesicles (EVs) secreted by stem cells are potential factors mediating tissue regeneration. They travel from bone marrow stem cells into damaged tissues, suggesting that they can repair tissue injuries without directly replacing parenchymal cells. We have discovered that hyaluronan (HA) synthesis is associated with the shedding of HA-coated EVs. The aim of this study was to test whether bone marrow-derived hMSCs secrete HA-coated EVs. The EVs secreted by MSCs were isolated by differential centrifugation and characterized by nanoparticle tracking analysis. Their morphology and budding mechanisms were inspected by confocal microscopy and correlative light and electron microscopy. Hyaluronan synthesis of hMSCs was induced by lipopolysaccharide and inhibited by RNA interference and 4-methylumbelliferone. It was found that the MSCs have extremely long apical and lateral HA-coated filopodia, typical for cells with an active HA secretion. Additionally, they secreted HA-coated EVs carrying mRNAs for CD44 and all HAS isoforms. The results show that stem cells have a strong intrinsic potential for HA synthesis and EV secretion, and the amount of HA carried on EVs reflects the HA content of the original cells. These results show that the secretion of HA-coated EVs by hMSCs is a general process, that may contribute to many of the mechanisms of HA-mediated tissue regeneration. Additionally, an HA coat on EVs may regulate their interactions with target cells and participate in extracellular matrix remodeling.

  • 47.
    Armstrong, Irene T
    et al.
    Centre for Neuroscience Studies, Queen's University, Kingston, ON, Canada.
    Judson, Melissa
    Department of Psychology, Queen's University, Kingston, ON, Canada.
    Munoz, Douglas P
    Centre for Neuroscience Studies, Queen's University, Kingston, ON, Canada, Department of Psychology, Queen's University, Kingston, ON, Canada, Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada.
    Johansson, Roland S
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Flanagan, J Randall
    Centre for Neuroscience Studies, Queen's University, Kingston, ON, Canada, Department of Psychology, Queen's University, Kingston, ON, Canada, Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada.
    Waiting for a hand: saccadic reaction time increases in proportion to hand reaction time when reaching under a visuomotor reversal2013In: Frontiers in Human Neuroscience, ISSN 1662-5161, E-ISSN 1662-5161, Vol. 7, p. 319-Article in journal (Refereed)
    Abstract [en]

    Although eye movement onset typically precedes hand movement onset when reaching to targets presented in peripheral vision, arm motor commands appear to be issued at around the same time, and possibly in advance, of eye motor commands. A fundamental question, therefore, is whether eye movement initiation is linked or yoked to hand movement. We addressed this issue by having participants reach to targets after adapting to a visuomotor reversal (or 180° rotation) between the position of the unseen hand and the position of a cursor controlled by the hand. We asked whether this reversal, which we expected to increase hand reaction time (HRT), would also increase saccadic reaction time (SRT). As predicted, when moving the cursor to targets under the reversal, HRT increased in all participants. SRT also increased in all but one participant, even though the task for the eyes-shifting gaze to the target-was unaltered by the reversal of hand position feedback. Moreover, the effects of the reversal on SRT and HRT were positively correlated across participants; those who exhibited the greatest increases in HRT also showed the greatest increases in SRT. These results indicate that the mechanisms underlying the initiation of eye and hand movements are linked. In particular, the results suggest that the initiation of an eye movement to a manual target depends, at least in part, on the specification of hand movement.

  • 48. Armstrong, Stephanie J
    et al.