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  • 1.
    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.

  • 2.
    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.

  • 3.
    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, 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.

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  • 4.
    Alstermark, Bror
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Hultborn, Hans
    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

  • 5.
    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.

  • 6.
    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.

  • 7.
    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.

  • 8.
    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)
  • 9.
    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.

  • 10.
    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.

  • 11.
    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.

  • 12.
    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.

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  • 13.
    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, 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.

  • 14.
    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.

  • 15.
    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.

  • 16.
    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, 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.

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  • 17.
    Athanassiadis, Tuija
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Physiology. Umeå University, Faculty of Medicine, Odontology.
    Neural circuits engaged in mastication and orofacial nociception2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    A deeper understanding of both movement control and the effects of nociceptor inputs on our motor systems is critical for proper clinical diagnosis of musculo-skeletal dysfunctions and for development of novel rehabilitation schemes. In the jaw system, masticatory movements are produced by a central pattern generator (CPG) located in the brainstem. Considerable efforts have been made in deciphering this neuronal network. The present thesis contributes towards an increasingly detailed understanding of its essential elements, and presents a hypothesis of how deep somatic pain (i.e. muscle pain) may be evoked and interferes with the masticatory CPG circuitry.

    In Paper I, the expression of c-Fos-like protein was used as a molecular marker to visualize brainstem neurons that were active during induced fictive mastication in the anesthetized and paralyzed rabbit. Our findings provide a previously lacking detailed record of the neuronal populations that form the masticatory motor pattern. Certain cells were located in brainstem areas previously suggested to be involved in the masticatory CPG. However, it was a new finding that neurons in the dorsal part of the trigeminal main sensory nucleus (NVsnpr-d) may belong to this circuitry. Paper II focused on the discovered neurons in NVsnpr in an in vitro slice preparation from young rats.  Intracellular recordings allowed us to define two cell types based on their response to depolarizing current. Microstimulation applied to the trigeminal motor nucleus, its reticular border, the parvocellular reticular formation and the nucleus reticularis pontis caudalis, elicited postsynaptic potentials in 81% of the neurons tested. Responses obtained were predominately excitatory and sensitive to gluta-matergic antagonists DNQX or/and APV. Some inhibitory and biphasic responses were also evoked. Bicuculline methiodide or strychnine blocked the IPSPs indicating that they were mediated by GABAA or glycinergic receptors. About one third of the stimulations activated both types of neurons antidromically. Neurons in NVsnpr-d seem to gather all the conditions that can theoretically account for a role in masticatory rhythm generation.

    In Paper III, the masticatory model system was used to investigate the possible role of muscle spindle primary afferents in development of persistent musculoskeletal pain. Following intramuscular acidic (pH 4.0) saline injections of rat masseter muscles, in vitro whole cell recordings were done from jaw closing muscle spindle somata located in the trigeminal mesencephalic nucleus (NVmes). Compared to control neurons, the somata of afferents exposed to acid had more hyperpolarized membrane potentials, more hyperpolarized thresholds for firing, high frequency membrane oscillations and ectopic bursting of action potentials. These changes in membrane properties lasted for up to 35 days. Within the same time frame experi-mental animals showed hypersensitivity to touch on the skin covering the injected muscle. Similar saline injections also resulted in a significant increase of activity dependent c-Fos expression in NVmes neurons compared to controls. Immuno-fluorescence and lectin binding studies indicated that small-caliber muscle afferents containing known nociceptor markers (CGRP, SP, P2X3, TRPV1 and IB4) and expressing glutamate receptors are found close to the annulo-spiral endings of the NVmes afferents. Combined, our new observations support the hypothesis that excessive release of glutamate, within muscle spindles due to ectopically evoked antidromic action potentials, could lead to development of persistent musculoskeletal pain by activation and/ or sensitization of adjacent muscle afferent nociceptors.

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  • 18.
    Athanassiadis, Tuija
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Olsson, Kurt A
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Kolta, A
    Westberg, Karl-Gunnar
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Identification of c-Fos immunoreactive brainstem neurons activated during fictive mastication in the rabbit2005In: Experimental Brain Research, ISSN 0014-4819, E-ISSN 1432-1106, Vol. 165, no 4, p. 478-489Article in journal (Refereed)
    Abstract [en]

    In the present study we used the expression of the c-Fos-like protein as a "functional marker" to map populations of brainstem neurons involved in the generation of mastication. Experiments were conducted on urethane-anesthetized and paralyzed rabbits. In five animals (experimental group), rhythmical bouts of fictive masticatory-like motoneuron activity (cumulative duration 60-130 min) were induced by electrical stimulation of the left cortical "masticatory area" and recorded from the right digastric motoneuron pool. A control group of five animals (non-masticatory) were treated in the same way as the experimental animals with regard to surgical procedures, anesthesia, paralysis, and survival time. To detect the c-Fos-like protein, the animals were perfused, and the brainstems were cryosectioned and processed immunocytochemically. In the experimental group, the number of c-Fos-like immunoreactive neurons increased significantly in several brainstem areas. In rostral and lateral areas, increments occurred bilaterally in the borderzones surrounding the trigeminal motor nucleus (Regio h); the rostrodorsomedial half of the trigeminal main sensory nucleus; subnucleus oralis-gamma of the spinal trigeminal tract; nuclei reticularis parvocellularis pars alpha and nucleus reticularis pontis caudalis (RPc) pars alpha. Further caudally-enhanced labeling occurred bilaterally in nucleus reticularis parvocellularis and nucleus reticularis gigantocellularis (Rgc) including its pars-alpha. Our results provide a detailed anatomical record of neuronal populations that are correlated with the generation of the masticatory motor behavior.

  • 19.
    Athanassiadis, Tuija
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Westberg, Karl-Gunnar
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Olsson, Kurt A
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Kolta, A
    Physiological characterization, localization and synaptic inputs of bursting and nonbursting neurons in the trigeminal principal sensory nucleus of the rat2005In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 22, no 12, p. 3099-3110Article in journal (Refereed)
    Abstract [en]

    A population of neurons in the trigeminal principal sensory nucleus (NVsnpr) fire rhythmically during fictive mastication induced in the in vivo rabbit. To elucidate whether these neurons form part of the central pattern generator (CPG) for mastication, we performed intracellular recordings in brainstem slices taken from young rats. Two cell types were defined, nonbursting (63%) and bursting (37%). In response to membrane depolarization, bursting cells, which dominated in the dorsal part of the NVsnpr, fired an initial burst followed by single spikes or recurring bursts. Non-bursting neurons, scattered throughout the nucleus, fired single action potentials. Microstimulation applied to the trigeminal motor nucleus (NVmt), the reticular border zone surrounding the NVmt, the parvocellular reticular formation or the nucleus reticularis pontis caudalis (NPontc) elicited a postsynaptic potential in 81% of the neurons tested for synaptic inputs. Responses obtained were predominately excitatory and sensitive to glutamatergic antagonists DNQX and/or APV. Some inhibitory and biphasic responses were also evoked. Bicuculline methiodide or strychnine blocked the IPSPs indicating that they were mediated by GABA(A) or glycinergic receptors. About one-third of the stimulations activated both types of neurons antidromically, mostly from the masseteric motoneuron pool of NVmt and dorsal part of NPontc. In conclusion, our new findings show that some neurons in the dorsal NVsnpr display both firing properties and axonal connections which support the hypothesis that they may participate in masticatory pattern generation. Thus, the present data provide an extended basis for further studies on the organization of the masticatory CPG network.

  • 20.
    Awad, Amar
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Functional brain imaging of sensorimotor dysfunction and restoration: investigations of discomplete spinal cord injury and deep brain stimulation for essential tremor2022Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The nervous system exists to generate adaptive behaviour by processing sensory input from the body and the environment in order to produce appropriate motor output, and vice versa. Consequently, sensorimotor dysfunction is the basis of disability in most neurological pathologies. In the current thesis, I explore two conditions with different types and degrees of sensorimotor dysfunction by means of functional magnetic resonance imaging (fMRI). In part 1, I assess residual sensory connections to the brain in clinically complete spinal cord injury (SCI) with seemingly complete loss of sensorimotor function below the injury level. In part 2, fMRI is combined with deep brain stimulation (DBS) to investigate interventional mechanisms of restoring dysfunctional sensorimotor control in essential tremor (ET).

    Part 1: SCI disrupts the communication between the brain and below-injury body parts, but rarely results in complete anatomical transection of the spinal cord. In studies I and II, we demonstrate somatosensory cortex activation due to somatosensory (tactile and nociceptive) stimulation on below-level insensate body parts in clinically complete SCI. The results from studies I and II indicate preserved somatosensory conduction across the spinal lesion in some cases of clinically complete SCI, as classified according to international standards. This subgroup is referred to as sensory discomplete SCI, which represents a distinct injury phenotype with an intermediate degree of injury severity between clinically complete and incomplete SCI.

    Part 2: ET is effectively treated with DBS in the caudal zona incerta, but the neural mechanisms underlying the treatment effect are poorly understood. By exploring DBS mechanisms with fMRI, DBS was shown to cause modulation in the activity of the sensorimotor cerebello-cerebral regions during motor tasks (study III), but did not modulate the functional connectivity during resting-state (study IV).

    fMRI is a valuable tool to investigate sensorimotor dysfunction and restoration in SCI and DBS-treated ET. There is evidence for sensory discomplete SCI in about half of the patients with clinically complete SCI. DBS modulates DBS modulation of the activity in the sensorimotor cerebello-cerebral circuit during motor tasks, but not during resting-state, is action-dependent.

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  • 21.
    Awad, Amar
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Ryggmärgsskador av ”discomplete” -typ och smärta2015In: BestPractice Nordic, Vol. 6, no 12, p. 6-9Article in journal (Other academic)
  • 22.
    Awad, Amar
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Grill, Filip
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Blomstedt, Patric
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Eriksson, Johan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Deep brain stimulation does not modulate fMRI resting- state functional connectivity in essential tremorManuscript (preprint) (Other academic)
  • 23.
    Awad, Amar
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Levi, Richard
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Rehabilitation Medicine.
    Lindgren, Lenita
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Hultling, Claes
    Department of Neurobiology, Care Sciences and Society (Neurorehabilitation), Karolinska Institute, Stockholm, Sweden.
    Westling, Göran
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Eriksson, Johan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Preserved somatosensory conduction in a patient with complete cervical spinal cord injury2015In: Journal of Rehabilitation Medicine, ISSN 1650-1977, E-ISSN 1651-2081, Vol. 47, no 5, p. 426-431Article in journal (Refereed)
    Abstract [en]

    Objective: Neurophysiological investigation has shown that patients with clinically complete spinal cord injury can have residual motor sparing ("motor discomplete"). In the current study somatosensory conduction was assessed in a patient with clinically complete spinal cord injury and a novel ethodology for assessing such preservation is described, in this case indicating "sensory discomplete" spinal cord injury. Methods: Blood oxygenation level-dependent functional magnetic resonance imaging (BOLD fMRI) was used to examine the somatosensory system in a healthy subject and in a subject with a clinically complete cervical spinal cord injury, by applying tactile stimulation above and below the level of spinal cord injury, with and without visual feedback. Results: In the participant with spinal cord injury, somatosensory stimulation below the neurological level of the lesion gave rise to BOLD signal changes in the corresponding areas of the somatosensory cortex. Visual feedback of the stimulation strongly modulated the somatosensory BOLD signal, implying that cortico-cortical rather than spino-cortical connections can drive activity in the somatosensory cortex. Critically, BOLD signal change was also evident when the visual feedback of the stimulation was removed, thus demonstrating sensory discomplete spinal cord injury. Conclusion: Given the existence of sensory discomplete spinal cord injury, preserved but hitherto undetected somatosensory conduction might contribute to the unexplained variability related to, for example, the propensity to develop decubitus ulcers and neuropathic pain among patients with clinically complete spinal cord injury.

  • 24.
    Awad, Amar
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Levi, Richard
    Department of Rehabilitation Medicine in Linköping, Department of Health, Medicine and Caring Sciences, Linköping University.
    Waller, Mikael
    Rehabilitation Medicine Clinic, Sunderby Hospital, Region Norrbotten.
    Westling, Göran
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Lindgren, Lenita
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Nursing.
    Eriksson, Johan
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Preserved somatosensory conduction in complete spinal cord injury: Discomplete SCI2020In: Clinical Neurophysiology, ISSN 1388-2457, E-ISSN 1872-8952, Vol. 131, no 5, p. 1059-1067Article in journal (Refereed)
    Abstract [en]

    Objective: Spinal cord injury (SCI) disrupts the communication between brain and body parts innervated from below-injury spinal segments, but rarely results in complete anatomical transection of the spinal cord. The aim of this study was to investigate residual somatosensory conduction in clinically complete SCI, to corroborate the concept of sensory discomplete SCI.

    Methods: We used fMRI with a somatosensory protocol in which blinded and randomized tactile and nociceptive stimulation was applied on both legs (below-injury level) and one arm (above-injury level) in eleven participants with chronic complete SCI. The experimental design accounts for possible confounding mechanical (e.g. vibration) and cortico-cortical top-down mechanisms (e.g. attention/expectation).

    Results: Somatosensory stimulation on below-level insensate body regions activated the somatotopically corresponding part of the contralateral primary somatosensory cortex in six out of eleven participants.

    Conclusions: Our results represent afferent-driven cortical activation through preserved somatosensory connections to the brain in a subgroup of participants with clinically complete SCI, i.e. sensory discomplete SCI.

    Significance: Identifying patients with residual somatosensory connections might open the door for new rehabilitative and restorative strategies as well as inform research on SCI-related conditions such as neuropathic pain and spasticity.

  • 25. Azim, Eiman
    et al.
    Alstermark, Bror
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Skilled forelimb movements and internal copy motor circuits2015In: Current Opinion in Neurobiology, ISSN 0959-4388, E-ISSN 1873-6882, Vol. 33, p. 16-24Article in journal (Refereed)
    Abstract [en]

    Mammalian skilled forelimb movements are remarkable in their precision, a feature that emerges from the continuous adjustment of motor output. Here we discuss recent progress in bridging the gap between theory and neural implementation in understanding the basis of forelimb motor refinement. One influential theory is that feedback from internal copy motor pathways enables fast prediction, through a forward model of the limb, an idea supported by behavioral studies that have explored how forelimb movements are corrected online and can adapt to changing conditions. In parallel, neural substrates of forelimb internal copy pathways are coming into clearer focus, in part through the use of genetically tractable animal models to isolate spinal and cerebellar circuits and explore their contributions to movement.

  • 26.
    Azim, Eiman
    et al.
    Howard Hughes Medical Institute, Kavli Institute for Brain Science, Mortimer B. Zuckerman Mind Brain Behavior Institute, Departments of Neuroscience and Biochemistry and Molecular Biophysics, Columbia University, New York, USA.
    Jiang, Juan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Alstermark, Bror
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Jessell, Thomas M
    Howard Hughes Medical Institute, Kavli Institute for Brain Science, Mortimer B. Zuckerman Mind Brain Behavior Institute, Departments of Neuroscience and Biochemistry and Molecular Biophysics, Columbia University, New York, USA.
    Skilled reaching relies on a V2a propriospinal internal copy circuit2014In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 508, no 7496, p. 357-363Article in journal (Refereed)
    Abstract [en]

    The precision of skilled forelimb movement has long been presumed to rely on rapid feedback corrections triggered by internally directed copies of outgoing motor commands, but the functional relevance of inferred internal copy circuits has remained unclear. One class of spinal interneurons implicated in the control of mammalian forelimb movement, cervical propriospinal neurons (PNs), has the potential to convey an internal copy of premotor signals through dual innervation of forelimb-innervating motor neurons and precerebellar neurons of the lateral reticular nucleus. Here we examine whether the PN internal copy pathway functions in the control of goal-directed reaching. In mice, PNs include a genetically accessible subpopulation of cervical V2a interneurons, and their targeted ablation perturbs reaching while leaving intact other elements of forelimb movement. Moreover, optogenetic activation of the PN internal copy branch recruits a rapid cerebellar feedback loop that modulates forelimb motor neuron activity and severely disrupts reaching kinematics. Our findings implicate V2a PNs as the focus of an internal copy pathway assigned to the rapid updating of motor output during reaching behaviour.

  • 27.
    Baugh, Lee A.
    et al.
    Queen's University Kingston, Ontario.
    Kao, Michelle
    Queen's University Kingston, Ontario.
    Johansson, Roland S.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Flanagan, J. Randall
    Queen's University Kingston, Ontario.
    Material evidence: interaction of well-learned priors and sensorimotor memory when lifting objects2012In: Journal of Neurophysiology, ISSN 0022-3077, E-ISSN 1522-1598, Vol. 108, no 5, p. 1262-1269Article in journal (Refereed)
    Abstract [en]

    Skilled object lifting requires the prediction of object weight. When lifting new objects, such prediction is based on well-learned size-weight and material-density correlations, or priors. However, if the prediction is erroneous, people quickly learn the weight of the particular object and can use this knowledge, referred to as sensorimotor memory, when lifting the object again. In the present study, we explored how sensorimotor memory, gained when lifting a given object, interacts with well-learned material-density priors when predicting the weight of a larger but otherwise similar-looking object. Different groups of participants 1st lifted 1 of 4 small objects 10 times. These included a pair of wood-filled objects and a pair of brass-filled objects where 1 of each pair was covered in a wood veneer and the other was covered in a brass veneer. All groups then lifted a larger, brass-filled object with the same covering as the small object they had lifted. For each lift, we determined the initial peak rate of change of vertical load-force rate and the load-phase duration, which provide estimates of predicted object weight. Analysis of the 10th lift of the small cube revealed no effects of surface material, indicating participants learned the appropriate forces required to lift the small cube regardless of object appearance. However, both surface material and core material of the small cube affected the 1st lift of the large block. We conclude that sensorimotor memory related to object density can contribute to weight prediction when lifting novel objects but also that long-term priors related to material properties can influence the prediction.

  • 28. Bengtsson, Fredrik
    et al.
    Brasselet, Romain
    Johansson, Roland S
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Arleo, Angelo
    Jörntell, Henrik
    Integration of sensory quanta in cuneate nucleus neurons in vivo2013In: PLOS ONE, E-ISSN 1932-6203, Vol. 8, no 2, p. e56630-Article in journal (Refereed)
    Abstract [en]

    Discriminative touch relies on afferent information carried to the central nervous system by action potentials (spikes) in ensembles of primary afferents bundled in peripheral nerves. These sensory quanta are first processed by the cuneate nucleus before the afferent information is transmitted to brain networks serving specific perceptual and sensorimotor functions. Here we report data on the integration of primary afferent synaptic inputs obtained with in vivo whole cell patch clamp recordings from the neurons of this nucleus. We find that the synaptic integration in individual cuneate neurons is dominated by 4-8 primary afferent inputs with large synaptic weights. In a simulation we show that the arrangement with a low number of primary afferent inputs can maximize transfer over the cuneate nucleus of information encoded in the spatiotemporal patterns of spikes generated when a human fingertip contact objects. Hence, the observed distributions of synaptic weights support high fidelity transfer of signals from ensembles of tactile afferents. Various anatomical estimates suggest that a cuneate neuron may receive hundreds of primary afferents rather than 4-8. Therefore, we discuss the possibility that adaptation of synaptic weight distribution, possibly involving silent synapses, may function to maximize information transfer in somatosensory pathways.

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  • 29.
    Berginström, Nils
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Nordström, Peter
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Ekman, Urban
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Karolinska Inst, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden.
    Eriksson, Johan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Andersson, Micael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Nordström, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Fatigue after traumatic brain injury is linked to altered striato-thalamic-cortical functioning2017In: Brain Injury, ISSN 0269-9052, E-ISSN 1362-301X, Vol. 31, no 6-7, p. 755-755Article in journal (Refereed)
    Abstract [en]

    Mental fatigue is a common symptom in the chronic phase of traumatic brain injury. Despite its high prevalence, no treatmentis available for this disabling symptom, and the mechanisms underlying fatigue are poorly understood. Some studies have suggested that fatigue in traumatic brain injury and other neurological disorders might reflect dysfunction within striato-thalamic-cortical loops. In the present study, we investigated whether functional magnetic resonance imaging(fMRI) can be used to detect chronic fatigue after traumatic brain injury (TBI), with emphasis on the striato-thalamic cortical-loops. We included patients who had suffered traumatic brain injury (n = 57, age range 20–64 years) and experienced mental fatigue > 1 year post injury (mean = 8.79 years, SD = 7.35), and age- and sex-matched healthycontrols (n = 27, age range 25–65 years). All participants completed self-assessment scales of fatigue and other symptoms, underwent an extensive neuropsychological test battery and performed a fatiguing 27-minute attention task (the modified Symbol Digit Modalities Test) during fMRI. Accuracy did not differ between groups, but reaction times were slower in the traumatic brain injury group (p < 0.001). Patients showed a greater increase in fatigue than controls from before to after task completion (p < 0.001). Patients showed less fMRI blood oxygen level–dependent activity in several a priori hypothesized regions (family-wise error corrected,p < 0.05), including the bilateral caudate, thalamus and anterior insula. Using the left caudate as a region of interest and testing for sensitivity and specificity, we identified 91% of patients and 81% of controls. As expected, controls showed decreased activation over time in regions of interest—the bilateral caudate and anterior thalamus (p < 0.002, uncorrected)—whereas patients showed no corresponding activity decrease. These results suggest that chronic fatigue after TBI is linked to altered striato-thalamic-cortical functioning. The high precision of fMRI for the detection of fatigue is of great clinical interest, given the lack of objective measures for the diagnosis of fatigue.

  • 30.
    Berginström, Nils
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Nordström, Peter
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Ekman, Urban
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Karolinska Inst, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden.
    Eriksson, Johan
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Andersson, Micael
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Nordström, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Using Functional Magnetic Resonance Imaging to Detect Chronic Fatigue in Patients With Previous Traumatic Brain Injury: changes linked to altered Striato-Thalamic-Cortical Functioning2018In: The journal of head trauma rehabilitation, ISSN 0885-9701, E-ISSN 1550-509X, Vol. 33, no 4, p. 266-274Article in journal (Refereed)
    Abstract [en]

    Objective: To investigate whether functional magnetic resonance imaging (fMRI) can be used to detect fatigue after traumatic brain injury (TBI).

    Setting: Neurorehabilitation clinic.

    Participants: Patients with TBI (n = 57) and self-experienced fatigue more than 1 year postinjury, and age- and gender-matched healthy controls (n = 27).

    Main Measures: Self-assessment scales of fatigue, a neuropsychological test battery, and fMRI scanning during performance of a fatiguing 27-minute attention task.

    Results: During testing within the fMRI scanner, patients showed a higher increase in self-reported fatigue than controls from before to after completing the task (P < .001).The patients also showed lower activity in several regions, including bilateral caudate, thalamus, and anterior insula (all P < .05). Furthermore, the patients failed to display decreased activation over time in regions of interest: the bilateral caudate and anterior thalamus (all P < .01). Left caudate activity correctly identified 91% of patients and 81% of controls, resulting in a positive predictive value of 91%.

    Conclusion: The results suggest that chronic fatigue after TBI is associated with altered striato-thalamic-cortical functioning. It would be of interest to study whether fMRI can be used to support the diagnosis of chronic fatigue in future studies.

  • 31.
    Berginström, Nils
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine. Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Rehabilitation Medicine.
    Nordström, Peter
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Nordström, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    White matter hyperintensities increases with traumatic brain injuryseverity: associations to neuropsychological performance and fatigueManuscript (preprint) (Other academic)
    Abstract [en]

    Objective: To examine the prevalence of white matter hyperintensities (WMHs) in patients with traumatic brain injury (TBI) as compared to healthy controls, and to investigate whether there is an association between WMH lesion burden and performance on neuropsychological tests in patients with TBI.

    Methods: A total of 59 patients with TBI and 27 age- and gender- matched healthy controls underwent thorough neuropsychological testing and magnetic resonance imaging. The quantification of WMH lesions was performed using the fully automated Lesion Segmentation Tool.

    Results: WMH lesions were more common in patients with TBI than in healthy controls (p = 0.032), and increased with higher TBI severity (p = 0.025). Linear regressions showed that WMH lesions in patients with TBI were not related to performance on any neuropsychological tests (p > 0.05 for all). However, a negative relationship between number of WMH lesions in patients with TBI and self-assessed fatigue was found (r = –0.33, p = 0.026).

    Conclusion: WMH lesions are more common in patients with TBI than in healthy controls, and WMH lesions burden increases with TBI severity. However, these lesions do not seem to explain the decreased cognitive functioning or the increased fatigue in patients with TBI.

  • 32.
    Bergström, Fredrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    The neural substrates of non-conscious working memory2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Despite our distinct impression to the contrary, we are only conscious of a fraction of all the neural activity underlying our thoughts and behavior. Most neural processes occur non-consciously, and in parallel with our conscious experience. However, it is still unclear what the limits of non-conscious processes are in terms of higher cognitive functions. Many recent studies have shown that increasingly more advanced functions can operate non-consciously, but non-conscious information is still thought to be fleeting and undetectable within 500 milliseconds. Here we used various techniques to render information non-conscious, together with functional magnetic resonance imaging (fMRI), to investigate if non-consciously presented information can be retained for several seconds, what the neural substrates of such retention are, and if it is consistent with working memory maintenance.

    Results: In Study I we used an attentional blink paradigm to render stimuli (single letters) non-conscious, and a variable delay period (5 – 15 s) prior to memory test. It was found that non-conscious memory performance was above chance after all delay durations, and showed no signs of decline over time. Univariate fMRI analysis showed that the durable retention was associated with sustained BOLD signal change in the prefrontal cortex and cerebellum during the delay period. In Study II we used continuous flash suppression (CFS) to render stimuli (faces and tools) non-conscious, and a variable delay period (5 or 15 s) prior to memory test. The durable retention of up to 15 s was replicated, and it was found that stimuli identity and spatial position was retained until prospective use. In Study III we used CFS to render tools non-conscious, and a variable delay period (5 – 15 s) prior to memory test. It was found that memory performance was not better than chance. However, by using multi-voxel pattern analysis it was nonetheless possible to detect the presence vs. absence of non-conscious stimuli in the frontal cortex,and their spatial position (left vs. right) in the occipital cortex during the delay.

    Conclusions: Overall these findings suggest that non-consciously presented information (identity and/or position) can be retained for several seconds,and is associated with BOLD signal in frontal and posterior regions. These findings are consistent with working memory maintenance of non-consciously presented information, and thereby constrain models of working memory and theories of consciousness.

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  • 33.
    Bergström, Fredrik
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Eriksson, Johan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Maintenance of non-consciously presented information engages the prefrontal cortex2014In: Frontiers in Human Neuroscience, E-ISSN 1662-5161, Vol. 8, p. 938-Article in journal (Refereed)
    Abstract [en]

    Conscious processing is generally seen as required for flexible and willful actions, as well as for tasks that require durable information maintenance. Here we present research that questions the assumption that only consciously perceived information is durable (>500 ms). Using the attentional blink (AB) phenomenon, we rendered otherwise relatively clearly perceived letters non conscious. In a first experiment we systematically manipulated the delay between stimulus presentation and response, for the purpose of estimating the durability of non-conscious perceptual representations. For items reported not seen, we found that behavioral performance was better than chance across intervals up to 15 s. In a second experiment we used fMRI to investigate the neural correlates underlying the maintenance of non conscious perceptual representations. Critically, the relatively long delay period demonstrated in experiment 1 enabled isolation of the signal change specifically related to the maintenance period, separate from stimulus presentation and response. We found sustained BOLD signal change in the right mid-lateral prefrontal cortex, orbitofrontal cortex, and crus II of the cerebellum during maintenance of non consciously perceived information. These findings are consistent with the controversial claim that working-memory mechanisms are involved in the short-term maintenance of non-conscious perceptual representations.

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  • 34.
    Bergström, Fredrik
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Faculty of Psychology and Educational Sciences, University of Coimbra, Portugal.
    Eriksson, Johan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Neural evidence for non-conscious working memory2018In: Cerebral Cortex, ISSN 1047-3211, E-ISSN 1460-2199, Vol. 28, no 9, p. 3217-3228Article in journal (Refereed)
    Abstract [en]

    Recent studies have found that non-consciously perceived information can be retained for several seconds, a feat that has been attributed to non-conscious working memory processes. However, these studies have mainly relied on subjective measures of visual experience, and the neural processes responsible for non-conscious short-term retention remains unclear. Here we used continuous flash suppression to render stimuli non-conscious in a delayed match-to-sample task together with fMRI to investigate the neural correlates of non-conscious short-term (5-15 s) retention. The participants' behavioral performance was at chance level when they reported no visual experience of the sample stimulus. Critically, multivariate pattern analyses of BOLD signal during the delay phase could classify presence versus absence of sample stimuli based on signal patterns in frontal cortex, and its spatial position based on signal patterns in occipital cortex. In addition, univariate analyses revealed increased BOLD signal change in prefrontal regions during memory recognition. Thus, our findings demonstrate short-term maintenance of information presented non-consciously, defined by chance performance behaviorally. This non-consciously retained information seems to rely on persistent neural activity in frontal and occipital cortex, and may engage further cognitive control processes during memory recognition.

  • 35.
    Bergström, Fredrik
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Eriksson, Johan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    The conjunction of non-consciously perceived object identity and spatial position can be retained during a visual short-term memory task2015In: Frontiers in Psychology, E-ISSN 1664-1078, Vol. 6, article id 1470Article in journal (Refereed)
    Abstract [en]

    Although non-consciously perceived information has previously been assumed to be short-lived (<500 ms), recent findings show that non-consciously perceived information can be maintained for at least 15s Such findings can be explained as working memory without a conscious experience of the information to be retained. However, whether or not working memory can operate on non-consciously perceived information remains controversial, and little is known about the nature of such non-conscious visual short-term memory (VSTM). Here we used continuous flash suppression to render stimuli non-conscious, to investigate the properties of non-consciously perceived representations in delayed match-to-sample (DMS) tasks. In Experiment I we used variable delays (5 or 15s) and found that performance was significantly better than chance and was unaffected by delay duration, thereby replicating previous findings. In Experiment II the DMS task required participants to combine information of spatial position and object identity on a trial-by-trial basis to successfully solve the task. We found that the conjunction of spatial position and object identity was retained, thereby verifying that non-conscious, trial-specific information can be maintained for prospective use. We conclude that our results are consistent with a working memory interpretation, but that more research is needed to verify this interpretation.

  • 36.
    Birznieks, Ingvars
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Physiology.
    Tactile Sensory Control of Dexterous Manipulation in Humans2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    During dexterous manipulation with the fingertips, forces are applied to objects' surfaces. To achieve grasp stability, these forces must be appropriate given the properties of the objects and the skin of the fingertips, and the nature of the task. It

    has been demonstrated that tactile sensors in the fingertips provide crucial information about both object properties and mechanical events critical for the control of fingertip forces, while in certain tasks vision may also contribute to predictions of required fingertip actions. This thesis focuses on two specific aspects of the sensory control of manipulation: (i) how individual fingers are controlled for grasp stability when people restrain objects subjected to unpredictable forces tangential to the grasped surfaces, and (ii) how tactile sensors in the fingertips encode direction of fingertip forces and shape of surfaces contacted by the fingertips.

    When restraining objects with two fingers, subjects adjust the fingertip forces to the local friction at each digit-object interface for grasp stability. This is accomplished primarily by partitioning the tangential force between the digits in a way that reflects the local friction whereas the normal forces at the involved digits are scaled by the average friction and the total load. The neural control mechanisms in this task rely on tactile information pertaining to both the friction at each digit-object interface and the development of tangential load. Moreover, these mechanisms controlled the force application at individual digits while at the same time integrating sensory inputs from all digits involved in the task.

    Microneurographical recordings in awake humans shows that most SA-I, SA-II and FA-I sensors in the distal phalanx are excited when forces similar to those observed during actual manipulation are applied to the fingertip. Moreover, the direction of the fingertip force influences the impulse rates in most afferents and their responses are broadly tuned to a preferred direction. The preferred direction varies among the afferents and, accordingly, ensembles of afferents can encode the direction of fingertip forces. The local curvature of the object in contact with the fingertip also influenced the impulse rates in most afferents, providing a curvature contrast signals within the afferent populations. Marked interactions were observed in the afferents' responses to object curvature and force direction. Similar findings were obtained for the onset latency in individual afferents. Accordingly, for ensembles of afferents, the order by which individual afferents initially discharge to fingertip events effectively represents parameters of fingertip stimulation. This neural code probably represents the fastest possible code for transmission of parameters of fingertip stimuli to the CNS.

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  • 37.
    Birznieks, Ingvars
    et al.
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Physiology.
    Burstedt, Magnus K
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Physiology.
    Edin, Benoni B
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Physiology.
    Johansson, Roland S
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Physiology.
    Mechanisms for force adjustments to unpredictable frictional changes at individual digits during two-fingered manipulation.1998In: Journal of Neurophysiology, ISSN 0022-3077, E-ISSN 1522-1598, Vol. 80, no 4, p. 1989-2002Article in journal (Refereed)
    Abstract [en]

    Previous studies on adaptation of fingertip forces to local friction at individual digit-object interfaces largely focused on static phases of manipulative tasks in which humans could rely on anticipatory control based on the friction in previous trials. Here we instead analyze mechanisms underlying this adaptation after unpredictable changes in local friction between consecutive trials. With the tips of the right index and middle fingers or the right and left index fingers, subjects restrained a manipulandum whose horizontal contact surfaces were located side by side. At unpredictable moments a tangential force was applied to the contact surfaces in the distal direction at 16 N/s to a plateau at 4 N. The subjects were free to use any combination of normal and tangential forces at the two fingers, but the sum of the tangential forces had to counterbalance the imposed load. The contact surface of the right index finger was fine-grained sandpaper, whereas that of the cooperating finger was changed between sandpaper and the more slippery rayon. The load increase automatically triggered normal force responses at both fingers. When a finger contacted rayon, subjects allowed slips to occur at this finger during the load force increase instead of elevating the normal force. These slips accounted for a partitioning of the load force between the digits that resulted in an adequate adjustment of the normal:tangential force ratios to the local friction at each digit. This mechanism required a fine control of the normal forces. Although the normal force at the more slippery surface had to be comparatively low to allow slippage, the normal forces applied by the nonslipping digit at the same time had to be high enough to prevent loss of the manipulandum. The frictional changes influenced the normal forces applied before the load ramp as well as the size of the triggered normal force responses similarly at both fingers, that is, with rayon at one contact surface the normal forces increased at both fingers. Thus to independently adapt fingertip forces to the local friction the normal forces were controlled at an interdigital level by using sensory information from both engaged digits. Furthermore, subjects used both short- and long-term anticipatory mechanisms in a manner consistent with the notion that the central nervous system (CNS) entertains internal models of relevant object and task properties during manipulation.

  • 38.
    Birznieks, Ingvars
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Jenmalm, Per
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Goodwin, Antony W
    University of Melbourne, Victoria.
    Johansson, Roland S
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Encoding of direction of fingertip forces by human tactile afferents2001In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 21, no 20, p. 8222-8237Article in journal (Refereed)
    Abstract [en]

    In most manipulations, we use our fingertips to apply time-varying forces to the target object in controlled directions. Here we used microneurography to assess how single tactile afferents encode the direction of fingertip forces at magnitudes, rates, and directions comparable to those arising in everyday manipulations. Using a flat stimulus surface, we applied forces to a standard site on the fingertip while recording impulse activity in 196 tactile afferents with receptive fields distributed over the entire terminal phalanx. Forces were applied in one of five directions: normal force and forces at a 20 degrees angle from the normal in the radial, distal, ulnar, or proximal directions. Nearly all afferents responded, and the responses in most slowly adapting (SA)-I, SA-II, and fast adapting (FA)-I afferents were broadly tuned to a preferred direction of force. Among afferents of each type, the preferred directions were distributed in all angular directions with reference to the stimulation site, but not uniformly. The SA-I population was biased for tangential force components in the distal direction, the SA-II population was biased in the proximal direction, and the FA-I population was biased in the proximal and radial directions. Anisotropic mechanical properties of the fingertip and the spatial relationship between the receptive field center of the afferent and the stimulus site appeared to influence the preferred direction in a manner dependent on afferent type. We conclude that tactile afferents from the whole terminal phalanx potentially contribute to the encoding of direction of fingertip forces similar to those that occur when subjects manipulate objects under natural conditions.

  • 39.
    Birznieks, Ingvars
    et al.
    Prince of Wales Medical Research Institute, Sydney, New South Wales 2031, Australia.
    Macefield, Vaughan G
    Prince of Wales Medical Research Institute, Sydney, New South Wales 2031, Australia.
    Westling, Göran
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Johansson, Roland S
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Slowly adapting mechanoreceptors in the borders of the human fingernail encode fingertip forces2009In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 29, no 29, p. 9370-9379Article in journal (Refereed)
    Abstract [en]

    There are clusters of slowly adapting (SA) mechanoreceptors in the skin folds bordering the nail. These "SA-IInail" afferents, which constitute nearly one fifth of the tactile afferents innervating the fingertip, possess the general discharge characteristics of slowly adapting type II (SA-II) tactile afferents located elsewhere in the glabrous skin of the human hand. Little is known about the signals in the SA-IInail afferents when the fingertips interact with objects. Here we show that SA-IInail afferents reliably respond to fingertip forces comparable to those arising in everyday manipulations. Using a flat stimulus surface, we applied forces to the finger pad while recording impulse activity in 17 SA-IInail afferents. Ramp-and-hold forces (amplitude 4 N, rate 10 N/s) were applied normal to the skin, and at 10, 20, or 30 degrees from the normal in eight radial directions with reference to the primary site of contact (25 force directions in total). All afferents responded to the force stimuli, and the responsiveness of all but one afferents was broadly tuned to a preferred direction of force. The preferred directions among afferents were distributed all around the angular space, suggesting that the population of SA-IInail afferents could encode force direction. We conclude that signals in the population of SA-IInail afferents terminating in the nail walls contain vectorial information about fingertip forces. The particular tactile features of contacted surfaces would less influence force-related signals in SA-IInail afferents than force-related signals present in afferents terminating in the volar skin areas that directly contact objects.

  • 40. Bitaraf, Nazanin
    et al.
    Ahmed, Ahmed
    Druzin, Michael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Ramser, Kerstin
    Development of a multifunctional microfluidic system for studies of nerve cell activity during hypoxic and anoxic conditions2009In: International Federation for Medical and Biological Engineering Proceedings; 25, 2009, p. 176-179Conference paper (Refereed)
    Abstract [en]

     

    Abstract

    —Hemoproteins usually supply cells and tissue

     with oxygen. A new hemoprotein mainly present in nerve cells called Neuroglobin was recently discovered. Enhanced expression of the protein has been shown to reduce hypoxic neural injury but the mechanism behind this function remains unknown. Methods enabling investigation of the protein in single functional neurons need to be developed. Here, we have studied how the electrical signaling capacity of a neuron was affected by hypoxic environments. Preliminary results show a trend of higher noise-level when a neuron is exposed to hypoxic compared to normoxic surroundings, which implies increased ion-channel activity. The setup used today shows shortages such as reduced control over the oxygen content due to leakage. Therefore, a gas-tight, multifunctional microfluidic system is under development which enables us to study influences of Neuroglobin concentrations on neuronal activity during hypoxia and anoxia. For electrophysiological recordings a patch-clamp micro pipette will be molded into the walls of the microfluidic system. A single biological cell is steered towards the pipette and attached there by means of optical tweezers. The Neuroglobin oxygen binding state will be studied using optical spectroscopy and the neuron environment will be manipulated by applying flows of varying oxygen content through the microfluidic system. This system will constitute a powerful tool in the investigation of the Neuroglobin mechanism of action. 

  • 41.
    Blomstedt, Yulia
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Stenmark Persson, Rasmus
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Awad, Amar
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Hariz, Gun-Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Philipson, Johanna
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Hariz, Marwan
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences. UCL Institute of Neurology, Queen Square, London, United Kingdom.
    Fytagoridis, Anders
    Department of Neurosurgery, Karolinska University Hospital, Stockholm, Sweden.
    Blomstedt, Patric
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    10 years follow-up of deep brain stimulation in the caudal zona incerta/posterior subthalamic area for essential tremor2023In: Movement Disorders Clinical Practice, E-ISSN 2330-1619, Vol. 10, no 5, p. 783-793Article in journal (Refereed)
    Abstract [en]

    Background: Long-term data on the effects of deep brain stimulation (DBS) for essential tremor (ET) is scarce, especially regarding DBS in the caudal Zona incerta (cZi) and the posterior subthalamic area (PSA). Objectives: The aim of this prospective study was to evaluate the effect of cZi/PSA DBS in ET at 10 years after surgery.

    Methods: Thirty-four patients were included. All patients received cZi/PSA DBS (5 bilateral/29 unilateral) and were evaluated at regular intervals using the essential tremor rating scale (ETRS).

    Results: One year after surgery, there was a 66.4% improvement of total ETRS and 70.7% improvement of tremor (items 1–9) compared with the preoperative baseline. Ten years after surgery, 14 patients had died and 3 were lost to follow-up. In the remaining 17 patients, a significant improvement was maintained (50.8% for total ETRS and 55.8% for tremor items). On the treated side the scores of hand function (items 11–14) had improved by 82.6% at 1 year after surgery, and by 66.1% after 10 years. Since off-stimulation scores did not differ between year 1 and 10, this 20% deterioration of on-DBS scores was interpreted as a habituation. There was no significant increase in stimulation parameters beyond the first year.

    Conclusions: This 10 year follow up study, found cZi/PSA DBS for ET to be a safe procedure with a mostly retained effect on tremor, compared to 1 year after surgery, and in the absence of increase in stimulation parameters. The modest deterioration of effect of DBS on tremor was interpreted as habituation.

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  • 42.
    Boraxbekk, Carl-Johan
    et al.
    Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR).
    Lundquist, Anders
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Nordin, Annelie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    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.
    Nilsson, Lars-Göran
    Aging Research Center, Karolinska Institutet.
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Free Recall Episodic Memory Performance Predicts Dementia 10 Years Prior to Clinical Diagnosis: Findings from the Betula Longitudinal Study2015In: Dementia and Geriatric Cognitive Disorders Extra, E-ISSN 1664-5464, Vol. 5, no 2, p. 191-202Article in journal (Refereed)
    Abstract [en]

    Background/Aims: Early dementia diagnosis is a considerable challenge. The present study examined the predictive value of cognitive performance for a future clinical diagnosis of late-onset Alzheimer's disease or vascular dementia in a random population sample. Methods: Cognitive performance was retrospectively compared between three groups of participants from the Betula longitudinal cohort. Group 1 developed dementia 11-22 years after baseline testing (n = 111) and group 2 after 1-10 years (n = 280); group 3 showed no deterioration towards dementia during the study period (n = 2,855). Multinomial logistic regression analysis was used to investigate the predictive value of tests reflecting episodic memory performance, semantic memory performance, visuospatial ability, and prospective memory performance. Results: Age-and education-corrected performance on two free recall episodic memory tests significantly predicted dementia 10 years prior to clinical diagnosis. Free recall performance also predicted dementia 11-22 years prior to diagnosis when controlling for education, but not when age was added to the model. Conclusion: The present results support the suggestion that two free recall-based tests of episodic memory function may be useful for detecting individuals at risk of developing dementia 10 years prior to clinical diagnosis.

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  • 43.
    Boraxbekk, Carl-Johan
    et al.
    Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Salami, Alireza
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Aging Research Center (ARC), Karolinska Institute, Stockholm, Sweden.
    Wåhlin, Anders
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Physical activity over a decade modifies age-related decline in perfusion, gray matter volume, and functional connectivity of the posterior default mode network: a multimodal approach2016In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 131, p. 133-141Article in journal (Refereed)
    Abstract [en]

    One step toward healthy brain aging may be to entertain a physically active lifestyle. Studies investigating physical activity effects on brain integrity have, however, mainly been based on single brain markers, and few used a multimodal imaging approach. In the present study, we used cohort data from the Betula study to examine the relationships between scores reflecting current and accumulated physical activity and brain health. More specifically, we first examined if physical activity scores modulated negative effects of age on seven resting state networks previously identified by Salami, Pudas, and Nyberg (2014). The results revealed that one of the most age-sensitive RSN was positively altered by physical activity, namely, the posterior default-mode network involving the posterior cingulate cortex (PCC). Second, within this physical activity-sensitive RSN, we further analyzed the association between physical activity and gray matter (GM) volumes, white matter integrity, and cerebral perfusion using linear regression models. Regions within the identified DMN displayed larger GM volumes and stronger perfusion in relation to both current and 10-years accumulated scores of physical activity. No associations of physical activity and white matter integrity were observed. Collectively, our findings demonstrate strengthened PCC–cortical connectivity within the DMN, larger PCC GM volume, and higher PCC perfusion as a function of physical activity. In turn, these findings may provide insights into the mechanisms of how long-term regular exercise can contribute to healthy brain aging.

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  • 44.
    Bowman, Miles C
    et al.
    Centre for Neuroscience Studies and Department of Psychology, Queen’s University, Kingston, ON K7L 3N6, Canada.
    Johansson, Roland S
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Flanagan, John Randall
    Centre for Neuroscience Studies and Department of Psychology, Queen’s University, Kingston, ON K7L 3N6, Canada.
    Eye-hand coordination in a sequential target contact task2009In: Experimental Brain Research, ISSN 0014-4819, E-ISSN 1432-1106, Vol. 195, no 2, p. 273-283Article in journal (Refereed)
    Abstract [en]

    Most object manipulation tasks involve a series of actions demarcated by mechanical contact events, and gaze is typically directed to the locations of these events as the task unfolds. Here, we examined the timing of gaze shifts relative to hand movements in a task in which participants used a handle to contact sequentially five virtual objects located in a horizontal plane. This task was performed both with and without visual feedback of the handle position. We were primarily interested in whether gaze shifts, which in our task shifted from a given object to the next about 100 ms after contact, were predictive or triggered by tactile feedback related to contact. To examine this issue, we included occasional catch contacts where forces simulating contact between the handle and object were removed. In most cases, removing force did not alter the timing of gaze shifts irrespective of whether or not vision of handle position was present. However, in about 30% of the catch contacts, gaze shifts were delayed. This percentage corresponded to the fraction of contacts with force feedback in which gaze shifted more than 130 ms after contact. We conclude that gaze shifts are predictively controlled but timed so that the hand actions around the time of contact are captured in central vision. Furthermore, a mismatch between the expected and actual tactile information related to the contact can lead to a reorganization of gaze behavior for gaze shifts executed greater than 130 ms after a contact event.

  • 45. Brasselet, R
    et al.
    Johansson, Roland
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Coenen, Olivier
    Arleo, Angelo
    Fast encoding/decoding of haptic microneurography data based on first spike latencies2009In: BMC Neuroscience, E-ISSN 1471-2202, Vol. 10, no 1, p. 349-350Article in journal (Other academic)
    Abstract [en]

    During haptic exploration tasks, forces are applied to the fingertips, which constitute the most sensitive parts of the hand and are prominently involved in object manipulation/ recognition tasks. The epidermis is innervated with thousands of sensory cells, called mechanoreceptors, that encode the mechanical indentations and deformations of the skin. These cells project directly to a dorsal column nucleus called the cuneate nucleus (CN) that constitutes the first synaptic relay to the central nervous system.

    Recent microneurography studies in humans [1] suggest that the relative timing of impulses from ensembles of mechanoreceptor afferents can convey information about important contact parameters faster than the fastest possible rate code and are fast enough to account for the use of tactile signals in natural manipulation.

    Here, we study a biologically plausible encoding/decoding process accounting for the relative spike timing of the signals propagating from peripheral nerve fibres onto second- order CN neurons. The CN is modelled as a population of 450 spiking neurons receiving as inputs the spatiotemporal responses of real mechanoreceptors obtained via microneurography recordings in humans. An information-theoretic approach is used to quantify the efficiency of the haptic discrimination process. To this extent, a novel entropy definition has been derived analytically.

    This measure proved to be a promising decoding scheme to generalize the classical Shannon's entropy for spiking neural codes, and it allowed us to compute mutual information (MI) in the presence of a large output space (i.e., 450 CN spike train responses) with a 1 ms temporal precision. Using a plasticity rule designed to maximise information transfer explicitly [2], a complete discrimination of 81 distinct stimuli occurred already within 40 ms after the first afferent spike, whereas a partial discrimination (80% of the maximum MI) was possible as rapidly as 20 ms.

    The rationale behind this study was to corroborate our working hypothesis that the CN does not constitute a mere synaptic relay, but it rather conveys an optimal contextual account (in terms of both fast and reliable information transfer) of peripheral tactile inputs to downstream structures (in particular to the thalamus and the cerebellum). Therefore, the CN may play a relevant role in the early processing of haptic information and it would constitute an important component of the haptic classification process (e.g., by facilitating fast discrimination of haptic contexts, minimising destructive interference over lifelong learning, and maximising memorycapacity).

  • 46. Brasselet, Romain
    et al.
    Johansson, Roland
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Arleo, Angelo
    Optimal context separation of spiking haptic signals by second-order somatosensory neurons2009In: Advances in neural information processing systems, Vol. 22, p. 180-188Article in journal (Refereed)
    Abstract [en]

    We study an encoding/decoding mechanism accounting for the relative spike timing of the signals propagating from peripheral nerve fibers to second-order somatosensory neurons in the cuneate nucleus (CN). The CN is modeled as a population of spiking neurons receiving as inputs the spatiotemporal responses of real mechanoreceptors obtained via microneurography recordings in humans. The efficiency of the haptic discrimination process is quantified by a novel definition of entropy that takes into full account the metrical properties of the spike train space. This measure proves to be a suitable decoding scheme for generalizing the classical Shannon entropy to spike-based neural codes. It permits an assessment of neurotransmission in the presence of a large output space (i.e. hundreds of spike trains) with 1 ms temporal precision. It is shown that the CN population code performs a complete discrimination of 81 distinct stimuli already within 35 ms of the first afferent spike, whereas a partial discrimination (80% of the maximum information transmission) is possible as rapidly as 15 ms.

    This study suggests that the CN may not constitute a mere synaptic relay along the somatosensory pathway but, rather, it may convey optimal contextual accounts (in terms of fast and reliable information

    transfer) of peripheral tactile inputs to downstream structures of the central nervous system.

  • 47.
    Brasselet, Romain
    et al.
    Université Pierre et Marie Curie, Paris.
    Johansson, Roland S
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Arleo, Angelo
    Université Pierre et Marie Curie, Paris.
    Quantifying neurotransmission reliability through metrics-based information analysis2011In: Neural Computation, ISSN 0899-7667, E-ISSN 1530-888X, Vol. 23, no 4, p. 852-881Article in journal (Refereed)
    Abstract [en]

    We set forth an information-theoretical measure to quantify neurotransmission reliability while taking into full account the metrical properties of the spike train space. This parametric information analysis relies on similarity measures induced by the metrical relations between neural responses as spikes flow in. Thus, in order to assess the entropy, the conditional entropy, and the overall information transfer, this method does not require any a priori decoding algorithm to partition the space into equivalence classes. It therefore allows the optimal parameters of a class of distances to be determined with respect to information transmission. To validate the proposed information-theoretical approach, we study precise temporal decoding of human somatosensory signals recorded using microneurography experiments. For this analysis, we employ a similarity measure based on the Victor-Purpura spike train metrics. We show that with appropriate parameters of this distance, the relative spike times of the mechanoreceptors? responses convey enough information to perform optimal discrimination?defined as maximum metrical information and zero conditional entropy?of 81 distinct stimuli within 40 ms of the first afferent spike. The proposed information-theoretical measure proves to be a suitable generalization of Shannon mutual information in order to consider the metrics of temporal codes explicitly. It allows neurotransmission reliability to be assessed in the presence of large spike train spaces (e.g., neural population codes) with high temporal precision.

  • 48.
    Burstedt, Magnus K
    et al.
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Physiology.
    Birznieks, Ingvars
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Physiology.
    Edin, Benoni B
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Physiology.
    Johansson, Roland S
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Physiology.
    Control of forces applied by individual fingers engaged in restraint of an active object.1997In: Journal of Neurophysiology, ISSN 0022-3077, E-ISSN 1522-1598, Vol. 78, no 1, p. 117-128Article in journal (Refereed)
    Abstract [en]

    We investigated the coordination of fingertip forces in subjects who used the tips of two fingers to restrain an instrumented manipulandum with horizontally oriented grip surfaces. The grip surfaces were subjected to tangential pulling forces in the distal direction in relation to the fingers. The subjects used either the right index and middle fingers (unimanual grasp) or both index fingers (bimanual grasp) to restrain the manipulandum. To change the frictional condition at the digit-object interfaces, either both grip surfaces were covered with sandpaper or one was covered with sandpaper and the other with rayon. The forces applied normally and tangentially to the grip surfaces were measured separately at each plate along with the position of the plates. Subjects could have performed the present task successfully with many different force distributions between the digits. However, they partitioned the load in a manner that reflected the frictional condition at the local digit-object interfaces. When both digits contacted sandpaper, they typically partitioned the load symmetrically, but when one digit made contact with rayon and the other with sandpaper, the digit contacting the less slippery material (sandpaper) took up a larger part of the load. The normal forces were also influenced by the frictional condition, but they reflected the average friction at the two contact sites rather than the local friction. That is, when friction was low at one of the digit-object interfaces, only the applied normal forces increased at both digits. Thus sensory information related to the local frictional condition at the respective digit-object interfaces controlled the normal force at both digits. The normal:tangential force ratio at each digit appeared to be a controlled variable. It was adjusted independently at each digit to the minimum ratio required to prevent frictional slippage, keeping an adequate safety margin against slippage. This was accomplished by the scaling of the normal forces to the average friction and by partitioning of the load according to frictional differences between the digit-object interfaces. In conclusion, by adjusting the normal:tangential force ratios to the local frictional condition, subjects avoided excessive normal forces at the individual digit-object interfaces, and by partitioning the load according the frictional difference, subjects avoided high normal forces. Thus the local frictional condition at the separate digit-object interfaces is one factor that can strongly influence the distribution of forces across digits engaged in a manipulative act.

  • 49.
    Burstedt, Magnus K
    et al.
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Physiology.
    Edin, Benoni B
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Physiology.
    Johansson, Roland S
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Physiology.
    Coordination of fingertip forces during human manipulation can emerge from independent neural networks controlling each engaged digit.1997In: Experimental Brain Research, ISSN 0014-4819, E-ISSN 1432-1106, Vol. 117, no 1, p. 67-79Article in journal (Refereed)
    Abstract [en]

    We investigated the coordination of fingertip forces in subjects who lifted an object (i) using the index finger and thumb of their right hand, (ii) using their left and right index fingers, and (iii) cooperatively with another subject using the right index finger. The forces applied normal and tangential to the two parallel grip surfaces of the test object and the vertical movement of the object were recorded. The friction between the object and the digits was varied independently at each surface between blocks of trials by changing the materials covering the grip surfaces. The object's weight and surface materials were held constant across consecutive trials. The performance was remarkably similar whether the task was shared by two subjects or carried out unimanually or bimanually by a single subject. The local friction was the main factor determining the normal:tangential force ratio employed at each digit-object interface. Irrespective of grasp configuration, the subjects adapted the force ratios to the local frictional conditions such that they maintained adequate safety margins against slips at each of the engaged digits during the various phases of the lifting task. Importantly, the observed force adjustments were not obligatory mechanical consequences of the task. In all three grasp configurations an incidental slip at one of the digits elicited a normal force increase at both engaged digits such that the normal:tangential force ratio was restored at the non-slipping digit and increased at the slipping digit. The initial development of the fingertip forces prior to object lift-off revealed that the subjects employed digit-specific anticipatory mechanisms using weight and frictional experiences in the previous trial. Because grasp stability was accomplished in a similar manner whether the task was carried out by one subject or cooperatively by two subjects, it was concluded that anticipatory adjustments of the fingertip forces can emerge from the action of anatomically independent neural networks controlling each engaged digit. In contrast, important aspects of the temporal coordination of the digits was organized by a "higher level" sensory-based control that influenced both digits. In lifts by single subjects this control was mast probably based on tactile and visual input and on communication between neural control mechanisms associated with each digit. In the two-subject grasp configuration this synchronization information was based on auditory and visual cues.

  • 50.
    Burzynska, A Z
    et al.
    Max Planck Institute for Human Development, Berlin.
    Preuschhof, C
    Max Planck Institute for Human Development, Berlin.
    Bäckman, L
    Max Planck Institute for Human Development, Berlin, Karolinska Institute.
    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.
    Li, S-C
    Max Planck Institute for Human Development, Berlin.
    Lindenberger, U
    Max Planck Institute for Human Development, Berlin, .
    Heekeren, H R
    Max Planck Institute for Human Development, Berlin, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig.
    Age-related differences in white matter microstructure: region-specific patterns of diffusivity.2010In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 49, no 3, p. 2104-2112Article in journal (Refereed)
    Abstract [en]

    We collected MRI diffusion tensor imaging data from 80 younger (20-32 years) and 63 older (60-71 years) healthy adults. Tract-based spatial statistics (TBSS) analysis revealed that white matter integrity, as indicated by decreased fractional anisotropy (FA), was disrupted in numerous structures in older compared to younger adults. These regions displayed five distinct region-specific patterns of age-related differences in other diffusivity properties: (1) increases in both radial and mean diffusivity; (2) increases in radial diffusivity; (3) no differences in parameters other than FA; (4) a decrease in axial and an increase in radial diffusivity; and (5) a decrease in axial and mean diffusivity. These patterns suggest different biological underpinnings of age-related decline in FA, such as demyelination, Wallerian degeneration, gliosis, and severe fiber loss, and may represent stages in a cascade of age-related degeneration in white matter microstructure. This first simultaneous description of age-related differences in FA, mean, axial, and radial diffusivity requires histological and functional validation as well as analyses of intermediate age groups and longitudinal samples.

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