Central Reorganization Research Articles

Three cases of referred sensation in traumatic nerve injury of the hand; Implications for understanding central nervous system reorganization

The aim of this observational study was to explore whether patients with traumatic peripheral nerve injury of the hand perceive referred sensations; sensations that are perceived to emanate from other areas of the body than the part being stimulated. Referred sensations have been reported following amputation, somatosensory deafferentation, local anaesthesia, stroke, brachial plexus avulsion injury, spinal cord injury and complex regional pain syndrome type 1. Ten patients with ulnar or median nerve injuries underwent sensory testing of the face, upper body and legs, involving light touch with a cotton swab. Patients were asked to describe the location of the stimulated site, the sensations emanating from it and any other sensations experienced. Three patients with referred sensations were identified and followed over a period of time. Clear and reproducible referred sensations were found in 3 out of 10 patients examined. Referred sensations were found in traumatic nerve injury, providing evidence of reorganization of the central nervous system after peripheral injury.

Die okuläre Neuromyotonie – klinisches Bild und Gedanken zur Pathogenese

Ocular neuromyotonia (ONM) is a rare neurogenic disorder of ocular motility. The affected patients complain of recurrent transient diplopia secondary to a sudden, painless deviation of one eye. This deviation occurs in the direction of action of an extraocular muscle, which is being stimulated at high frequency. ONM is usually seen after radiation therapy, but may also be caused by compression of the affected cranial nerve. The pathophysiology of ONM is incompletely understood, potential mechanisms include 1) ephaptic transmission along the affected nerve, 2) disturbances of potassium channels in the neuronal cell membrane, and 3) central neural re-organisation. The diagnosis of ONM is made based on clinical findings and can be supported by electrophysiological characteristics. Neuroimaging with attention to the affected cranial nerve should be obtained in order to exclude a compressive cause. Therapy of ONM with carbamazepine is usually effective.

Knee Osteoarthritis Pain May Be Neuropathic

Knee Osteoarthritis Pain May Be Neuropathic

China's Accession to the WTO Government Procurement Agreement--Challenges and The Way Forward

Government procurement, whilst important for international trade,1 has been largely excluded from the reach of multilateral regulation under the World Trade Organization (WTO).2 In the absence of multilateral rule, China's trade partners have made considerable efforts, before and after China's WTO accession, to persuade China to become party of the plurilateral WTO Agreement on Government Procurement (GPA). After 5 years of intensive discussion, on 28 December 2007, China finally submitted a formal application to become party to the GPA.3 This included an offer of GPA coverage (the so-called ‘Appendix I offer’) and signaled the initiation of China's GPA accession process.4 However, China's initial offer has been regarded as ‘very limited’ and ‘deeply disappointing’ by China's trade partners.5 It is safe to argue that China's GPA accession poses significant challenges for negotiators due to a number of factors. Firstly, the GPA itself, even after its recent revision, is not fully equipped to deal with acceding countries with a large state sector6 and existing GPA Parties have made little progress in extending the coverage commitments following the revision. Secondly, so far as the position of China is concerned, Chinese government structure is complicated and the problem has been aggravated by a new round of central government reorganization completed after the application and the division between the Chinese government and state enterprises is difficult to ascertain, especially with regard to investment, which make coverage negotiations problematic. Furthermore, the legal and institutional frameworks underlying current Chinese public procurement regime remain fragmented and incoherent whilst it is also evident that China has in recent years intensified the use of government procurement as a policy instrument to promote national industrial and environmental policies. These add to the lack of political supports for speeding up the GPA accession and complicate the negotiation and adaptation of domestic legislation. Finally, the structural link between administrative tribunals/judiciary and the local government gives rise to the concern of local protectionism and put the effectiveness of a GPA-compliant supplier review system in question.

The Corticospinal System and Transcranial Magnetic Stimulation in Stroke

During the last decades, transcranial magnetic stimulation (TMS) has been used as a noninvasive method to investigate motor cortical reorganization and neuroplasticity in humans after stroke. An increasing number of studies in the field of motor control have used TMS to gain an understanding of the different aspects of stroke cortical physiology and motor recovery. This review addresses the effects of corticospinal tract (CST) lesions in humans and nonhuman primates on the functional organization of the motor system. We review information on the physiological mechanisms by which the CST contributes to normal motor control and to central nervous system reorganization following stroke when the CST is injured as measured using TMS. Insight into these physiological mechanisms has led to the development of scientifically sound interventional proposals in the field of neurorehabilitation.

Multimodal Analgesia for Chronic Pain: Rationale and Future Directions

Chronic pain is a multifaceted disease requiring multimodal treatment. Clinicians routinely employ various combinations of pharmacologic, interventional, cognitive-behavioral, rehabilitative, and other nonmedical therapies despite the paucity of robust evidence in support of such an approach. Therapies are selected consistent with the biopsychosocial model of chronic pain, reflecting the subjective nature of the pain complaint, and the myriad stressors that shape it. Elucidating mechanisms that govern normal sensation in the periphery has provided insights into the biochemical, molecular, and neuroanatomic correlates of chronic pain, an understanding of which is leading increasingly to mechanism-specific multidrug therapies. Peripheral and central neuroplastic reorganization underlying the disease of chronic pain is influenced by patient-specific emotions, cognition, and memories, further impairing function and idiosyncratically defining the illness of chronic pain. Clinical perceptions of these and related subjective elements associated with the suffering of chronic pain drive psychosocial treatments, including, among other options, relaxation therapies, coping skills development, and cognitive-behavioral therapy. Treatment selection is thus guided by comprehensive assessment of the phenomenology and inferred pathophysiology of the pain syndrome; patient goals, preferences, and expectations; behavioral, cognitive, and physical function; and level of risk. Experiential, practice-based evidence may be necessary for improving patient care, but it is insufficient; certainly, well-designed studies are needed to support therapeutic decision making. This review will discuss the biochemical basis of pain, factors that govern its severity and chronicity, and foundational elements for current and emerging multimodal treatment strategies.

Cortical development, plasticity and re-organization in children with cochlear implants

A basic tenet of developmental neurobiology is that certain areas of the cortex will re-organize, if appropriate stimulation is withheld for long periods. Stimulation must be delivered to a sensory system within a narrow window of time (a sensitive period) if that system is to develop normally. In this article, we will describe age cut-offs for a sensitive period for central auditory development in children who receive cochlear implants. We will review de-coupling and re-organization of cortical areas, which are presumed to underlie the end of the sensitive period in congenitally deaf humans and cats. Finally, we present two clinical cases which demonstrate the use of the P1 cortical auditory evoked potential as a biomarker for central auditory system development and re-organization in congenitally deaf children fitted with cochlear implants. Learning outcomes: Readers of this article should be able to (i) describe the importance of the sensitive period as it relates to development of central auditory pathways in children with cochlear implants; (ii) discuss the hypothesis of de-coupling of primary from higher-order auditory cortex as it relates to the end of the sensitive period; (iii) discuss cross-modal re-organization which may occur after long periods of auditory deprivation; and (iv) understand the use of the P1 response as a biomarker for development of central auditory pathways.

A peripheral tremor associated with intractable pain after traffic accident: case report

There are debates about whether peripherally induced movement disorders exist. We report a case of upper limb tremor induced by peripheral nerve injury. A 20-year-old male patient presented with pain and tremor of the left upper extremity, 2 days after a car accident. Magnetic resonance images of the brain and cervical spine were normal. His past medical history was unremarkable and there were no family members with symptoms of movement disorders. He suffered from an aggravating tremor for about 10 minutes, four to six times a day. We treated the patient with medication, epidural infusion, cervical nerve root block and trigger point injection of the trapezius muscle. The pain subsided 50% and the incidence of tremor attacks was reduced to once or twice a day. The role of peripheral trauma in the genesis of movement disorders has not been generally accepted. It is unclear whether peripheral trauma can induce dystonia and other movement disorders. It has been proposed that peripheral trauma can alter sensory input and induce cortical and subcortical reorganization that generates a movement disorder. Some studies provide evidence for central reorganization following peripheral injury.

A Critical Perspective on the Central Governmental Reorganization of the Social Service Delivery System for People with Disabilities

A Critical Perspective on the Central Governmental Reorganization of the Social Service Delivery System for People with Disabilities

Glial vascular endothelial growth factor overexpression in rat brainstem under tolerable hypoxia: Evidence for a central chemosensitivity

The ventilatory response to hypoxia is mediated by peripheral inputs arising from the arterial chemoreceptors. In their absence, hypoxic adaptation can be achieved, possibly as a result of central cellular reorganization. To study this reorganization, we used chemodenervated rats to investigate the expression and localization of vascular endothelial growth factor (VEGF) in the brainstem. VEGF is a target gene of hypoxia-inducible factor (HIF) that is responsible for the morphofunctional remodeling induced by hypoxia. Intact and chemodenervated rats were subjected to normoxia or hypoxia for 6 hr (10% O(2) in N(2)). VEGF protein was quantified in micropunches of brainstem tissue. Only chemodenervated animals showed an increased VEGF expression in response to hypoxia, whereas, in normoxia, VEGF expression was not modified by chemodenervation. The same hypoxic condition was repeated for 8 days before immunocytochemical staining with anti-VEGF; antiglial fibrillary acidic protein (GFAP), a marker of astrocytes; and anti-rat endothelial cell antigen-1 (anti-RECA-1) that recognizes endothelial cells. Confocal analysis showed a cellular colocalization of GFAP and VEGF, indicating that VEGF was overexpressed predominantly in astrocytes. Increased RECA-1 immunolabeling indicated an enhanced angiogenesis in chemodenervated rats subjected to hypoxia. These results indicate that glial cells and the vascular network contribute to the brainstem remodeling. The peripheral chemodenervation reveals a central O(2) chemosensitivity involving a cascade of gene expression triggered by hypoxia, which in intact animals may act synergically with peripheral chemosensory inputs.

Upper limb corticomotor projections and physiological changes that occur with botulinum toxin‐A therapy in children with hemiplegic cerebral palsy

To investigate the corticomotor projection to the upper limb in children with hemiplegic cerebral palsy (CP) and the changes that occur with botulinum toxin (BTX)-A. The study design is a pilot prospective randomized trial. Twenty-two children with hemiplegic CP aged 7 years to 13 years 11 months were recruited. Treatment group (12) received one series of BTX-A injections into the upper limb. Control group (10) did not receive upper limb BTX-A. All participants except one treatment group participant also received lower limb BTX-A. Transcranial magnetic stimulation (TMS) was performed at baseline, and 1, 3 and 6 months post-injection. Outcome measures were: change in position of affected and unaffected side first dorsal interosseous optimal site of stimulation (OPTx). A shift in affected and unaffected side OPTx was observed for both treatment and control groups, and there was no statistically significant difference between groups at 1, 3 or 6 months. Poor tolerance of TMS cortical stimuli >80% was observed. Corticomotor projections associated with the upper limb in children with hemiplegic CP show significant variability over a 6-month period. This variability may reflect central motor reorganization because of systemic BTX-A effect or developmental changes. Upper limb BTX-A therapy is associated with reorganization of both affected and unaffected projections. Poor tolerance of the TMS procedure, in conjunction with higher cortical thresholds, may limit the usefulness of TMS as an investigatory tool in young children with movement disorders.

Long-term experience of neuromodulation in TACs

Improvement in the biomedical and biotechnological research fields have allowed refinement of the neuromodulation approach in the treatment of a subgroup of medical disorders otherwise refractory to pharmacological treatment, such as chronic primary headaches. Chronic pain conditions imply central sensitisations and functional reorganisation that cannot be quickly or easily reversed. It appears evident that conventional treatment can sometimes be unsuccessful or only partially successful, and that relapse is common. Cluster headache (CH) is the most frequent trigeminal autonomic cephalalgia (TAC) and the most representative of this spectrum of disorders characterised by the association of headache and loco-regional signs and symptoms of facial parasympathetic activation. The striking features of circadian rhythmicity of attacks and circannual periodicity of cluster period, together with the neuroendocrine abnormalities, are suggestive of a neurochronobiological disorder with a central-diencephalic pathogenetic involvement, confirmed by direct evidence in functional neuroimaging studies of ipsilateral posterior hypothalamic activation during cluster attack. In 2000 these findings prompted a functional neurosurgery approach, with the first case of deep brain hypothalamic stimulation (DBS) in a severely disabled chronic CH patient. Since then, 18 implants in our centre and many others in different countries have been performed. Although the outcomes are encouraging, the invasive nature of the technique and the occurrence of rare but major adverse events have suggested a safer peripheral approach with occipital nerve stimulation (ONS).

Exaggerated auditory startle responses in patients with spinal cord injury

Central nervous system reorganization following spinal cord injury (SCI) may cause functional changes in the motor tracts in patients in whom increased auditory startle responses (ASRs) have been previously reported. We hypothesized that if increased ASRs in patients with incomplete SCI were due to compensatory mechanisms, these changes would be related to severity and/or localization of the lesion. We examined ASR characteristics in 29 SCI patients and 14 age-matched healthy volunteers. Fourteen patients had incomplete and 15 complete SCI; 10 patients had cervical and 19 thoracolumbar SCI. Five auditory stimuli were applied binaurally to subjects in a sitting position, with a 5-min interstimulus interval. Surface electromyographic recordings were obtained from orbicularis oculi (OOc), sternocleidomastoid (SCM), biceps brachii (BB), and tibialis anterior (TA) muscles. ASR probability was significantly higher and area-under-the-curve was significantly larger in SCM and BB in patients than in controls. ASR latency was significantly shorter in SCM and BB in patients with cervical than in those with thoracolumbar SCI (p < 0.02), but there were no statistically significant differences between complete and incomplete SCI (p > 0.1). Time span since onset correlated significantly with ASR area in OOc, SCM and BB (p < 0.05). The capability of the adult central nervous system to reorganize its circuits over time for improved functionality following injury is probably the key to understanding the increased ASRs in patients with SCI. The exaggeration of the startle reflex is potentially important since it may be useful for augmenting voluntary movement in the clinical rehabilitation of patients with SCI.

A Case Report of Painless Moving Toes Syndrome

This is the first report of a case of painless moving toes syndrome with radiculopathy. The patient presented with bilateral painless moving toes and unilateral subclinical sacral (S1) radiculopathy. Bilateral movements with the unilateral lesion, and fluctuation with postural changes and distant muscle contraction suggest that the underlying pathomechanism was a central reorganization in the spinal level.

Age-Related Hearing Loss in C57BL/6J Mice has both Frequency-Specific and Non-Frequency-Specific Components that Produce a Hyperacusis-Like Exaggeration of the Acoustic Startle Reflex

Auditory brainstem-evoked response (ABR) thresholds were obtained in a longitudinal study of C57BL/6J mice between 10 and 53 weeks old, with repeated testing every 2 weeks. On alternate weeks, acoustic startle reflex (ASR) amplitudes were measured, elicited by tone pips with stimulus frequencies of 3, 6, 12, and 24 kHz, and intensities from subthreshold up to 110 dB sound pressure level. The increase in ABR thresholds for 3 and 6 kHz test stimuli followed a linear time course with increasing age from 10 to 53 weeks, with a slope of about 0.7 dB/week, and for 48 kHz a second linear time course, but beginning at 10 weeks with a slope of about 2.3 dB/week. ABR thresholds for 12, 24, and 32 kHz increased after one linear segment with a 0.7 dB slope, then after a variable delay related to the test frequency, shifted to a second segment having slopes of 3-5 dB/week. Hearing loss initially reduced the ASR for all eliciting stimuli, but at about 6 months of age, the response elicited by intense 3 and 6 kHz stimuli began to increase to reach values about three times above normal, and previously subthreshold stimuli came to elicit vigorous responses seen at first only for the intense stimuli. This hyperacusis-like effect appeared in all mice but was especially pronounced in mice with more serious hearing loss. These ABR data, together with a review of histopathological data in the C57BL/6 literature, suggest that the non-frequency-specific slow time course of hearing loss results from pathology in the lateral wall of the cochlea, whereas the stimulus-specific hearing loss with a rapid time course results from hair cell loss. Delayed exaggeration of the ASR with hearing loss reveals a deficit in centrifugal inhibitory control over the afferent reflex pathways after central neural reorganization, suggesting that this mouse may provide a useful model of age-related tinnitus and associated hyperacusis.

Study of Cutaneous Reflex Compensation During Locomotion After Nerve Section in the Cat

In the cat, section of all cutaneous nerves of the hindfeet except the tibial (Tib) nerve supplying the plantar surface results in a long-lasting decrease in the intensity of Tib stimulation needed for a threshold response in flexor muscles and an increase in the amplitude of the phase-dependent responses recorded in various muscles during locomotion. Stimulating through chronically implanted nerve cuffs ensured a stable stimulation over time. The increase in reflex amplitude was well above the small increase in the amplitude of the locomotor bursts themselves that results from the denervation. Short latency responses (P1) were seen in flexor muscles, especially at the knee (semitendinosus) and ankle (tibialis anterior and extensor digitorum longus), with stimuli applied in the swing phase and also to a lesser degree in the later part of the cycle. Longer latency responses (P2) were increased in hip, knee, and ankle flexors, as well as in a contralateral extensor (vastus lateralis) when applied in late stance. Responses evoked from stimulating the proximal end of sectioned nerves were not larger than before neurectomy. This suggests that the increased responsiveness to Tib stimulation is not simply caused by an increase in motoneuron excitability, because this would have resulted in a nonspecific increase of responses to stimulation of any nerve. It is concluded that the adult locomotor system is capable of central reorganization to enhance specific remaining cutaneous reflex pathways after a partial cutaneous denervation of the paw.

Deep brain stimulation for the treatment of various chronic pain syndromes

Electrical intracerebral stimulation (also referred to as deep brain stimulation [DBS]) is a tool for the treatment of chronic pain states that do not respond to less invasive or conservative treatment options. Careful patient selection, accurate target localization, and identification with intraoperative neurophysiological techniques and blinded test evaluation are the key requirements for success and good long-term results. The authors present their experience with DBS for the treatment of various chronic pain syndromes. In this study 56 patients with different forms of neuropathic and mixed nociceptive/neuropathic pain syndromes were treated with DBS according to a rigorous protocol. The postoperative follow-up duration ranged from 1 to 8 years, with a mean of 3.5 years. Electrodes were implanted in the somatosensory thalamus and the periventricular gray region. Before implantation of the stimulation device, a double-blinded evaluation was carefully performed to test the effect of each electrode on its own as well as combined stimulation with different parameter settings. The best long-term results were attained in patients with chronic low-back and leg pain, for example, in so-called failed-back surgery syndrome. Patients with neuropathic pain of peripheral origin (such as complex regional pain syndrome Type II) also responded well to DBS. Disappointing results were documented in patients with central pain syndromes, such as pain due to spinal cord injury and poststroke pain. Possible reasons for the therapeutic failures are discussed; these include central reorganization and neuroplastic changes of the pain-transmitting pathways and pain modulation centers after brain and spinal cord lesions. The authors found that, in carefully selected patients with chronic pain syndromes, DBS can be helpful and can add to the quality of life.

Altered cortical integration of dual somatosensory input following the cessation of a 20 min period of repetitive muscle activity

The adult human central nervous system (CNS) retains its ability to reorganize itself in response to altered afferent input. Intracortical inhibition is thought to play an important role in central motor reorganization. However, the mechanisms responsible for altered cortical sensory maps remain more elusive. The aim of the current study was to investigate changes in the intrinsic inhibitory interactions within the somatosensory system subsequent to a period of repetitive contractions. To achieve this, the dual peripheral nerve stimulation somatosensory evoked potential (SEP) ratio technique was utilized in 14 subjects. SEPs were recorded following median and ulnar nerve stimulation at the wrist (1 ms square wave pulse, 2.47 Hz, 1x motor threshold). SEP ratios were calculated for the N9, N11, N13, P14-18, N20-P25 and P22-N30 peak complexes from SEP amplitudes obtained from simultaneous median and ulnar (MU) stimulation divided by the arithmetic sum of SEPs obtained from individual stimulation of the median (M) and ulnar (U) nerves. There was a significant increase in the MU/M + U ratio for both cortical SEP components following the 20 min repetitive contraction task, i.e. the N20-P25 complex, and the P22-N30 SEP complex. These cortical ratio changes appear to be due to a reduced ability to suppress the dual input, as there was also a significant increase in the amplitude of the MU recordings for the same two cortical SEP peaks (N20-P25 and P22-N30) following the typing task. No changes were observed following a control intervention. The N20 (S1) changes may reflect the mechanism responsible for altering the boundaries of cortical sensory maps, changing the way the CNS perceives and processes information from adjacent body parts. The N30 changes may be related to the intracortical inhibitory changes shown previously with both single and paired pulse TMS. These findings may have implications for understanding the role of the cortex in the initiation of overuse injuries.

Normal and abnormal fMRI activation patterns in the visual cortex after recovery from optic neuritis

Recovery to normal or near normal visual acuity after an optic neuritis episode is common, despite frequent persistence of conduction abnormalities, evident in prolonged visual evoked potential (VEP) latencies. Improvement of visual function is commonly attributed to peripheral nerve recovery. However, central reorganization processes may also be involved. To assess this, we compared the patterns of fMRI activation, elicited by stimulation of the affected and the normal eye, along the visual cortical hierarchy. Activation was assessed in 8 subjects, which recovered clinically from an episode of optic neuritis but still had prolonged VEP latencies. In all patients, reduced fMRI activation was seen in V1 during stimulation of the affected eye, compared to the normal eye. The fMRI signal difference decreased in magnitude with progression along the visual hierarchy, and in some regions within the lateral occipital complex even showed the opposite preference (for the affected eye). These results may indicate a built-in robustness of the object-related areas to disruption of the visual input. Alternatively, it could reflect an adaptive functional reorganization of the cortical response to an abnormal input.

The functional anatomy of cerebral reorganisation after focal brain injury

Stroke is a major cause of disability in all age groups. Although the value of specific rehabilitative therapies is now acknowledged, the mechanisms of impairment and recovery are not well understood. There is growing interest in the role that central nervous system reorganisation might play in the recovery process, and in particular whether this reorganisation can be manipulated to provide clinical benefits for patients. The careful use of non-invasive techniques such as functional magnetic resonance imaging and transcranial magnetic stimulation allows the study of the working human brain, and studies in humans suggest that functionally relevant adaptive changes occur in cerebral networks following stroke. An understanding of how these changes influence the recovery process will facilitate the development of novel therapeutic techniques that are based on neurobiological principles and will allow the delivery of specific therapies to appropriately targeted patients suffering from stroke.