Biomedical subjects
Publications and source records attributed to Göran Lundborg.
Functional magnetic resonance imaging (fMRI) was used to study the cortical integration of an osseointegrated prosthetic thumb that had been attached to the amputee's hand 13 years ago. We found that tactile stimuli applied to the prosthesis activated the primary somatosensory cortex on both sides.
To explore whether contralateral deafferentation by tourniquet-induced anaesthesia can improve function in a nerve-injured hand, we investigated 14 patients with median or ulnar nerve injuries at wrist level. Deafferentation of the contralateral forearm and hand resulted in significantly improved tactile discrimination, threshold for perception of touch in the injured nerve area and in the area corresponding to the intact nerve in the injured hand, and significantly increased grip strength. Improvements lasted at least 15 min. The results show that hand function after peripheral nerve injury can be temporarily enhanced by manipulation of the process of brain plasticity. Our results may have practical applications in the rehabilitation of peripheral nerve-injured patients.
To characterize the gene activity that may be required for neuronal survival and regeneration, we used the Affymetrix GeneChip Mu74A to screen 12000 genes and expressed sequence tag (EST) mRNA from L4 and L5 mouse dorsal root ganglia (DRG) 12 h and 24 h after sciatic nerve transection. At 12 h, we found 17 upregulated transcripts, and at 24 h, 49 that met our criteria of a significant 2-fold increase in expression. The alterations included a total of eight transcription factors and several genes associated with TGF-beta- and IL-6-mediated signaling. Two of the changes, amphiregulin and plasminogen activator inhibitor-1 (PAI-1), were confirmed by real-time quantitative PCR (QPCR). Addition of amphiregulin (20 ng/ml) to organ-cultured DRG stimulated axonal outgrowth while PAI-1 (20 nM) inhibited migration of Schwann cells from the ganglia.
We hypothesised that pieces of nerve that are normally trimmed away during graft repair could be a source of Schwann cells and used to create an autologous cell-containing nerve graft. To test the idea a transsection injury was made on the rat sciatic nerve. Seven days later, pieces from the proximal and distal stumps were used for immediate isolation of its non-neuronal cells. These cells, of which 80% were Schwann cells, were injected into a silicone tube bridging a 10 mm gap on the same nerve. Tubes containing cells showed superior regeneration of nerve fibres across the gap compared with tubes with no cells. This new repair technique is rapid, does not require the sacrifice of a healthy donor nerve, or the time-consuming culturing and expansion of Schwann cells. The method has the potential to replace current methods for repair of extended nerve injuries.
A new method of acute dissociation of Schwann cells was used to study the effect of addition of such cells to a tendon autograft--a recently-described graft material--on peripheral nerve regeneration in rats. Autologous Schwann cells were obtained from enzymatic dissociation of predegenerated nerves. The tendon autografts were supplied with Schwann cells through brief in vitro coincubation. Schwann cell-free tendon autografts were used as controls. Axonal outgrowth was measured immunohistochemically after four, seven, and 10 days. At seven days, outgrowth was significantly longer in the pretreated autografts. The use of acutely-dissociated Schwann cells is a new approach to tissue engineering in nerve reconstruction, and may abolish the need for time-consuming culture of Schwann cells.
The capacity of the central nervous system for plastic alterations is the base for our ability to adapt to environmental needs. The crossmodal capacity of the brain makes interaction between senses possible, and deprivation of one sense leads to compensatory changes in other senses. We have recently shown how hearing can substitute for sensation in a transplanted insensitive hand by using a sensor glove equipped with small microphones that pick up the sound of friction, which is elicited by active touch. Here we have used functional magnetic resonance imaging (fMRI) in healthy people to illustrate their capacity for cortical audiotactile interaction with activation of the somatosensory cortex induced by auditory stimuli. The phenomenon occurred only in subjects trained to substitute sensibility by hearing, and no audiotactile interaction was found in untrained subjects.
Treatment with a mirror gives an illusion of function in a missing or non-functioning hand. The method is based on the concept that the central representation of phantoms and body image can change rapidly, and has been described in the treatment of phantom pain and stroke. We show in three pilot cases new applications for the use of the mirror in rehabilitation after hand surgery.
Acute improvement of sensory functions in the contralateral hand during experimental, tourniquet-induced anaesthesia has been described. Tourniquet compression over an extended time period, however, may be painful - which may influence the result. To study the effects of deafferentation of the upper extremity with the pain factor eliminated, we investigated 100 patients with anaesthetised axillary plexus for perception of touch and tactile discrimination in the contralateral (unanaesthetised) hand. Anaesthesia induced a rapid, significant, improvement in tactile discrimination in the contralateral hand, compared with before anaesthesia, measured as two-point discrimination (p=0.0001), and perception of touch, measured with Semmes-Weinstein monofilament (p=0.0005). The improvement lasted as long as the arm was anaesthetised. Understanding the mechanisms of brain plasticity, including interhemispheric plasticity, is essential for designing appropriate strategies for upregulation and downregulation of cortical reorganisational changes to promote sensory relearning after nerve injury.
The end-to-side nerve-repair technique, i.e., when the distal end of an injured nerve is attached end-to-side to an intact nerve trunk in an attempt to attract nerve fibers by collateral sprouting, has been used clinically. The technique has, however, been questioned. The aim of the present study was to investigate end-to-side repair in the upper extremity of rats with emphasis on functional recovery, source, type, and extent of regenerating fibers. End-to-side repair was used in the upper limb, and the radial or both median/ulnar nerves were attached end-to-side to the musculocutaneous nerve. Pawprints and tetanic muscle force were used to evaluate functional recovery during a 6-month recovery period, and double retrograde labeling was used to detect the source of the regenerated nerve fibers. The pawprints showed that, in end-to-side repair of either one or two recipient nerves, there was a recovery of toe spreading to 60-72% of the preoperative value (lowest value around 47%). Electrical stimulation of the end-to-side attached radial or median/ulnar nerves 6 months after repair resulted in contraction of muscles in the forearm innervated by these nerves (median tetanic muscle force up to 70% of the contralateral side). Retrograde labeling showed that both myelinated (morphometry) sensory and motor axons were recruited to the end-to-side attached nerve and that these axons emerged from the motor and sensory neuronal pool of the brachial plexus. Double retrograde labeling indicated that collateral sprouting was one mechanism by which regeneration occurred. We also found that two recipient nerves could be supported from a single donor nerve. Our results suggest that end-to-side repair may be one alternative to reconstruct a brachial plexus injury when no proximal nerve end is available.
To study cortical reorganisation after acute hand deafferentation, we investigated 10 experimental subjects and 10 controls for function in the left hand, before, during and after tourniquet induced anaesthesia of the right hand. fMRI was performed in three experimental subjects. Right hand anaesthesia resulted in rapid significant improvement in grip strength, tactile discrimination and sensibility in the left hand. Tactile discrimination and grip strength improvements lasted at least 15 mins after anaesthesia. fMRI showed increased activation in the right primary motor cortex after anaesthesia. We conclude that tourniquet induced anaesthesia is an easy way to induce rapid and significant improvement in contralateral hand function. This finding may have a potential clinical application for evolving sensory relearning strategies after nerve repair.
BACKGROUND: The primary sensory cortex (S1) in the postcentral gyrus is comprised of four areas that each contain a body map, where the representation of the hand is located with the thumb most laterally, anteriorly and inferiorly and the little finger most medially, posteriorly and superiorly. Previous studies on somatotopy using functional MRI have either used low field strength, have included a small number of subjects or failed to attribute activations to any area within S1. In the present study we included twenty subjects, who were investigated at 3 Tesla (T). We focused specifically on Brodmann area 3b, which neurons have discrete receptive fields with a potentially more clearcut somatotopic organisation. The spatial distribution for all fingers' peak activation was determined and group as well as individual analysis was performed. RESULTS: Activation maps from 18 subjects were of adequate quality; in 17 subjects activations were present for all fingers and these data were further analysed. In the group analysis the thumb was located most laterally, anteriorly and inferiorly with the other fingers sequentially positioned more medially, posteriorly and superiorly. At the individual level this somatotopic relationship was present for the thumb and little finger, with a higher variability for the fingers in between. The Euclidian distance between the first and fifth finger was 17.2 mm, between the first and second finger 10.6 mm and between the remaining fingers on average 6.3 mm. CONCLUSION: Results from the group analysis, that is both the location of the fingers and the Euclidian distances, are well comparable to results from previous studies using a wide range of modalities. On the subject level the spatial localisation of the fingers showed a less stringent somatotopic order so that the location of a finger in a single subject cannot be predicted from the group result.
PURPOSE: Good to excellent clinical results have been shown in the initial studies on osseointegrated metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joint implants that consist of a flexible silicone spacer connected to osseointegrated titanium fixtures. A high fracture rate of the silicone spacer, however, has been reported, diminishing the value of this implant system. The purpose of this study was to evaluate the osseointegration of the titanium fixture itself in a large study group and compare patients with rheumatoid arthritis with those with osteoarthrosis as a base for further development of the implant concept. METHODS: Two hundred thirty-nine implants (27 PIP, 212 MCP) in 86 patients were retrospectively evaluated radiographically. Two hundred implants were in patients with rheumatoid arthritis. Radiographic evaluation included measuring the length and width of resorption zones around the titanium fixtures. A scoring system was used that grouped observations in 4 groups, from 0 (little or no change) to 3 (loosening). Status of the silicone spacer was also noted. RESULTS: At follow-up evaluation an average of 41 months (range, 12-103 months) after surgery, complete osseointegration was found in 450 of 478 fixtures (94%). Loosening was found in 10 proximal and 18 distal fixtures. The proximal fixtures showed loosening mainly during the first 3 years after surgery and the distal fixtures also had loosening. In the 31 MCP joint implants that were evaluated for more than 5 years, the osseointegration rate was 97%. CONCLUSIONS: Implant stem fixation with osseointegrated titanium fixtures is a valuable method that works well in rheumatoid arthritis patients. Further development will focus on a more durable constrained joint mechanism.
The morphology of the abductor pollicis brevis muscle was studied in 20 patients suffering from hand-arm vibration syndrome. The main morphological changes observed were centrally located myonuclei and fibre type grouping (found in all 20 muscle biopsies), angulated muscle fibres (found in 19 biopsies), ring fibres and regenerating fibres (found in 18 biopsies) and fibrosis (found in 17 biopsies). The observed abnormalities are believed to reflect damage to both the muscle fibres and the motor nerve. The changes were related to different vibration exposure parameters. The number of fibres demonstrating centrally located nuclei correlated significantly with the cumulative vibration exposure, while the number of angulated fibres correlated significantly with the total vibration exposure time. This indicates that the vibrating tools may cause direct damage to muscle fibres as well as nerves.
The role of c-Jun activation for survival and regeneration of sensory neurons is unclear. Here we report that c-Jun N-terminal kinase (JNK)-mediated c-Jun activation is important for axonal outgrowth of sensory neurons in rat nodose and dorsal root ganglia (DRG). Peripheral severance of the vagus or the sciatic nerve resulted in a massive and rapid, but transient increase of the activated JNK (p-JNK) in neuronal nuclei, followed by c-Jun phosphorylation and activating transcription factor-3 (ATF3) induction. JNK inhibition by the selective JNK inhibitors SP600125 and (D)-JNKI1 did not affect neuronal survival in explanted or dissociated ganglia, but dramatically reduced axonal outgrowth, c-Jun activation, and ATF3 induction. Using retrograde labeling, we demonstrated that activated c-Jun (p-c-Jun) and ATF3 were associated with regenerative neurons. Taken together, our results suggest that JNK-mediated c-Jun activation is one of the first cell body reactions in response to nerve injury and that this activation and subsequent ATF3 induction are associated with axonal outgrowth.
Hands were transplanted from brain-dead donors for the treatment of two male unilateral amputees, aged 35 years and 32 years, involved in the Italian Hand Transplantation Programme. Each had lost his right dominant hand, in a farming accident and an explosion, respectively. In one case artificial sensibility was applied postoperatively using a Sensor Glove that transformed vibrotactile stimuli induced by touch, to stereophonic vibroacoustic stimuli perceived through earphones. The principle is based on the brain's capacity for multimodal plasticity, implying that deprivation of one sense (somatosensory) can be compensated for by another sense (auditory). Functional magnetic resonance images (fMRI) taken at regular intervals showed that cortical remodelling of the transplanted hand within the sensory-motor maps occurred early in the patient who used the artificial sensibility regimen compared with the one who did not. We conclude that postoperative use of a device using hearing as a substitution for sensation in hand transplantation may have considerable potential value for speeding up cortical integration of a transplanted hand.
The cortical representation of body parts is constantly modulated in response to the afferent input, and acute deafferentation of a body part results in bilateral cortical reorganization. To study the effects on hand function of right forearm anaesthesia, we investigated ten human subjects (group 1) for perception of touch, tactile discrimination and grip strength in the right (ipsilateral) and left (contralateral) hand before, during and 24 h after forearm skin anaesthesia with a local anaesthetic cream (EMLA). Ten age-matched controls (group 2) were investigated in the same way but received placebo. In group 1 a significant improvement was seen in tactile discrimination in the ipsilateral hand compared to base line (P = 0.009) and compared to group 2 (P = 0.006). The improvement in tactile discrimination remained for at least 24 h after anaesthesia. Perception of touch, was improved during anaesthesia compared to baseline values in group 1 (P = 0.046) and remained for at least 24 h. Grip strength did not change. These findings suggest that transient selective deafferentation of an extremity results in enhanced sensory functions of the functionally preserved parts of the same extremity, presumably as a result of expansion of adjacent cortical territories. Such rapid functional changes suggest unmasking of pre-existing synaptic connections as the mechanism underlying the acute modulation of sensory functions in the hand. Our findings open new perspectives for sensory re-education and rehabilitation following injury to the peripheral and central nervous system.
The Model instrument for outcome after nerve repair has so far proved valid and reliable. It supports the authors' hypothesis that the summary of specific limitations of body function agrees with patients' opinions on the impact of the nerve injury on ADL. These features together with its flexibility make the Model instrument for outcome after nerve repair a psychometrically sound and clinically useful diagnosis-specific outcome instrument for routine evaluation after nerve repair. An optimal choice in the future when assessing the outcome after nerve repair may be a combined use of this model and a more generic outcome instrument. Such a protocol would take into account specific body functions and well being in a wider perspective.
Muscle strength in extrinsic and intrinsic hand muscle was assessed in 21 patients with hand-arm vibration syndrome. Twenty-one age-matched healthy workers served as controls. Grip and pinch strength was significantly reduced in the vibration-exposed group (18%; p = 0.006 and 18% p = 0.007, respectively) as well as strength of palmar abduction of the thumb (28%; p < 0.0001) and radial abduction of the index finger (37%; p < 0.0001) while abduction strength in the little finger was not significantly reduced (7%). We postulate that the reduced manipulative skill and impaired dexterity of the hand, which often is associated with vibration syndrome, is not only of sensorineural origin but may also be an effect of reduced intrinsic muscle strength. Reduced strength in abduction of the index finger is an important indicator of intrinsic muscular dysfunction in subjects who use hand-held vibrating tools.