Transcranial magnetic stimulation-induced ‘visual echoes’ are generated in early visual cortex

Transcranial magnetic stimulation (TMS) of the early visual areas can trigger perception of a flash of light, a so-called phosphene. Here we show that a very brief presentation of a stimulus can modulate features of a subsequent TMS-induced phosphene, to a level that participants mistake phosphenes for real stimuli, inducing ‘visual echoes’ of a previously seen stimulus. These ‘echoes’ are modulated by visual context at the moment of magnetic stimulation, showing that they are generated in early visual areas, and that the brain processes these ‘echoes’ as if they are factually presented stimuli. This shows that TMS can re-activate weak visual representations in early visual areas. Based on the pattern of contextual modulation of visual echoes, we theorize that perception of these echoes is not a passive reactivation of residual activity in early visual cortex, but an active interpretation of the combined activity of TMS-induced neural noise and cortical state.     

Motor control over the phantom limb in above-elbow amputees and its relationship with phantom limb pain

Recent evidence shows that the primary motor cortex continues to send motor commands when amputees execute phantom movements. These commands are retargeted toward the remaining stump muscles as a result of motor system reorganization. As amputation-induced reorganization in the primary motor cortex has been associated with phantom limb pain we hypothesized that the motor control of the phantom limb would differ between amputees with and without phantom limb pain. Eight above-elbow amputees with or without pain were included in the study. They were asked to produce cyclic movements with their phantom limb (hand, wrist, and elbow movements) while simultaneously reproducing the same movement with the intact limb. The time needed to complete a movement cycle and its amplitude were derived from the kinematics of the intact limb. Electromyographic (EMG) activity from different stump muscles and from the homologous muscles on the intact side was recorded. Different EMG patterns were recorded in the stump muscles depending on the movement produced, showing that different phantom movements are associated with distinct motor commands. Phantom limb pain was associated with some aspects of phantom limb motor control. The time needed to complete a full cycle of a phantom movement was systematically shorter in subjects without phantom limb pain. Also, the amount of EMG modulation recorded in a stump muscle during a phantom hand movement was positively correlated with the intensity of phantom limb pain. Since phantom hand movement–related EMG patterns in above-elbow stump muscles can be considered as a marker of motor system reorganization, this result indirectly supports the hypothesis that amputation-induced plasticity is associated with phantom limb pain severity. The discordance between the (amputated) hand motor command and the feedback from above-elbow muscles might partially explain why subjects exhibiting large EMG modulation during phantom hand movement have more phantom limb pain.     

Effects of short-term training on sensory and motor function in severed nerves of long-term human amputees

Much has been studied and written about plastic changes in the CNS of humans triggered by events such as limb amputation. However, little is known about the extent to which the original pathways retain residual function after peripheral amputation. Our earlier, acute study on long-term amputees indicated that central pathways associated with amputated peripheral nerves retain at least some sensory and motor function. The purpose of the present study was to determine if these functional connections would be strengthened or improved with experience and training over several days time. To do this, electrodes were implanted within fascicles of severed nerves of long-term human amputees to evaluate the changes in electrically evoked sensations and volitional motor neuron activity associated with attempted phantom limb movements. Nerve stimulation consistently resulted in discrete, unitary, graded sensations of touch/pressure and joint-position sense. There was no significant change in the values of stimulation parameters required to produce these sensations over time. Similarly, while the amputees were able to improve volitional control of motor neuron activity, the rate and pattern of change was similar to that seen with practice in normal individuals on motor tasks. We conclude that the central plasticity seen after amputation is most likely primarily due to unmasking, rather than replacement, of existing synaptic connections. These results also have implications for neural control of prosthetic limbs.     

Motor cortical excitability and inhibition in acquired mirror pain

‘Mirror pain’ describes when the observation of another's pain experience induces a personal experience of pain. It has been suggested that mirror pain could result from changes in neural excitability or inhibition. In this study we used transcranial magnetic stimulation (TMS) to investigate motor cortical excitability in lower-limb amputees who experience mirror pain. Using paired-pulse TMS to assess motor cortical inhibition (CI) and cortical facilitation (CF), recordings were taken from the right first dorsal interosseus in lower-limb amputees who experience mirror pain (MP+), lower-limb amputees who do not experience mirror pain (MP−), and non-amputee controls. No differences in CI or CF were observed between the MP+ and both control groups. Thus, when not paired with a pain-related stimulus, changes in motor cortical excitability do not appear to contribute to the experience of mirror pain in lower-limb amputees.     

Motor performance benefits of matched limb imitation in prosthesis users

Our previous work demonstrated that the action encoding parietofrontal network, which is crucial in planning and executing motor tasks, is less active in prosthesis users who imitate movements of intact actors (mismatched limb) versus prosthesis users (matched limb). Such activation could have behavioral consequences in prosthesis users rehabilitating with intact therapists. The goal was to identify behavioral effects of matched versus mismatched limb action imitation in naïve users of prostheses. Intact subjects donned a specially adapted prosthetic device to simulate the wrist and forearm movement that transradial amputees experience. While electrogoniometry was recorded, non-amputated prosthesis users (NAPUs) observed and imitated demonstrations of a skillful motor task performed by either an intact actor or NAPU. We hypothesized that NAPUs would elicit less motion variability when performing matched versus mismatched imitation. Matched imitation resulted in a significant decrease in shoulder motion variability compared with mismatched imitation. The matched group also developed elbow motion patterns similar to the NAPU demonstrator, while the mismatched group attempted patterns similar to the intact demonstrator. This suggests a behavioral advantage to matched imitation when adapting to a prosthetic device, as it yielded more consistent movements and facilitated development of new motor patterns. Further, these results suggest that when prosthesis users are faced with the impossible task of imitating movements of an intact hand, they perform this action with greater variability and poorer technique. This work has implications on how prosthetic device operation is conveyed to persons with amputation as their clinical interactions often involve mismatched limb imitation.     

Staying in dynamic balance on a prosthetic limb: A leg to stand on?

With the loss of a lower limb, amputees lack the active muscle empowered control of the ankle that is important for balance control. We examined single-leg stance on prosthesis vs. sound limb balancing on narrow ridges in transtibial amputees. When balancing on the prosthetic limb, the lateral displacement of the center of pressure was reduced and was compensated by an increase in counter-rotation. We show that single-leg stance on a prosthetic limb can be compared to balancing on a narrow ridge. Standing on a prosthetic limb involves the same balance mechanisms as balancing on narrow ridges of 40-mm to 20-mm width. Yet, the ability to balance on a narrow ridge with the sound limb was only a weak predictor for an amputee's ability to stand on the prosthetic limb. Balancing in single-leg stance on a prosthetic limb is not a common activity. The ability to compensate with the sound limb may therefore be functionally more important than the ability to stay in dynamic balance on the prosthetic limb.     

Automatic segmentation of magnetic resonance images of the trans-femoral residual limb

An automatic algorithm for the extraction of the skin and bone boundaries from axial magnetic resonance images of the residual limb of trans-femoral amputees is presented. The method makes use of K-means clustering and mathematical morphology. Statistical analysis of the results indicates that the computer-generated boundaries compare favourably to those drawn by human observers. The boundaries may be used in biomechanical modelling of the interaction between the residual limb and the prosthetic socket. The limb/socket interface determines the quality of prosthetic fit, therefore knowledge of this interface is important for the improvement of socket design in order to achieve patient comfort and mobility.     

Polygalasaponin G promotes neurite outgrowth of cultured neuron on myelin

Myelin contains many axonal outgrowth inhibitory components which contribute to regeneration failure after neuronal injury in the mammalian central nervous system (CNS). In an attempt to develop small molecular agents to promote axonal outgrowth, we screened a compound library purified from traditional Chinese herbs, and found a small molecular compound polygalasaponin G (PS-G), extracted from Polygala japonica, which has a potent neurotrophic activity on PC12 cells and cultured cortical neurons. We reported, to our knowledge for the first time, that PS-G could promote neurite outgrowth of neurons cultured on the myelin substrates and inhibit the activation of RhoA. Thus, our results could represent a therapeutic approach to improve axon regeneration after CNS injuries.     

Artificial neural interfaces for bionic cardiovascular treatments

An artificial nerve, in the broad sense, may be conceptualized as a physical and logical interface system that reestablishes the information traffic between the central nervous system and peripheral organs. Studies on artificial nerves targeting the autonomic nervous system are in progress to explore new treatment strategies for several cardiovascular diseases. In this article, we will review our research targeting the autonomic nervous system to treat cardiovascular diseases. First, we identified the rule for decoding native sympathetic nerve activity into a heart rate using transfer function analysis, and established a framework for a neurally regulated cardiac pacemaker. Second, we designed a bionic baroreflex system to restore the baroreflex buffering function using electrical stimulation of the celiac ganglion in a rat model of orthostatic hypotension. Third, based on the hypothesis that autonomic imbalance aggravates chronic heart failure, we implanted a neural interface into the right vagal nerve and demonstrated that intermittent vagal stimulation significantly improved the survival rate in rats with chronic heart failure following myocardial infarction. Although several practical problems need to be resolved, such as those relating to the development of electrodes feasible for long-term nerve activity recording, studies of artificial neural interfaces with the autonomic nervous system have great possibilities in the field of cardiovascular treatment. We expect further development of artificial neural interfaces as novel strategies to cope with cardiovascular diseases resistant to conventional therapeutics. Part of this article is a translation of an article in Japanese that appeared in Jinkozoki 2006;3(3):352–355     

干细胞与中枢神经系统损伤的修复

内源性神经干细胞，外源性神经干细胞以及胚胎干细胞具有分化为各种神经细胞的能力，神经细胞的再生在恢复中枢神经系统受损伤的功能时起着关键作用。将近年来神经干细胞和胚胎干细胞对中枢神经系统损伤的修复研究作一综述。     

Observing shadow motions: Resonant activity within the observer's motor system?

Several studies have demonstrated that the human motor cortex is activated by the mere observation of actions performed by others. In the present study, we explored whether the perception of ‘impoverished motion stimuli’, such as shadow animations, is sufficient to activate motor areas. To do so, transcranial magnetic stimulation (TMS) was applied over the hand area of the primary motor cortex (M1) while subjects observed shadow animations depicting finger motions. Data showed that resonant motor responses in M1 were only found when a biological effector was recognized from the observed shadow animation. Interestingly, M1 responses were similar for observing shadow or real motions. Therefore, the loss of ‘pictorial’ movement features in a shadow animation appeared to have no effect on motor resonance in M1. In summary, these findings suggest that the ‘recognition’ of biological motion from sparse visual input is both necessary and sufficient to recruit motor areas. This supports the hypothesis that the motor system is involved in recognizing the actions performed by others.     

The injured nervous system: a Darwinian perspective

Much of the permanent damage that occurs in response to nervous system damage (trauma, infection, ischemia, etc.) is mediated by endogenous secondary processes that can contribute to cell death and tissue damage (excitotoxicity, oxidative damage and inflammation). For humans to evolve mechanisms to minimize secondary pathophysiological events following CNS injuries, selection must occur for individuals who survive such insults. Two major factors limit the selection for beneficial responses to CNS insults: for many CNS disease states the principal risk factor is advanced, post-reproductive age and virtually all severe CNS traumas are fatal in the absence of modern medical intervention. An alternative hypothesis for the persistence of apparently maladaptive responses to CNS damage is that the secondary exacerbation of damage is the result of unavoidable evolutionary constraints. That is, the nervous system could not function under normal conditions if the mechanisms that caused secondary damage (e.g., excitotoxicity) in response to injury were decreased or eliminated. However, some vertebrate species normally inhabit environments (e.g., hypoxia in underground burrows) that could potentially damage their nervous systems. Yet, neuroprotective mechanisms have evolved in these animals indicating that natural selection can occur for traits that protect animals from nervous system damage. Many of the secondary processes and regeneration-inhibitory factors that exacerbate injuries likely persist because they have been adaptive over evolutionary time in the healthy nervous system. Therefore, it remains important that researchers consider the role of the processes in the healthy or developing nervous system to understand how they become dysregulated following injury.     

Cortical reorganization and phantom phenomena in congenital and traumatic upper-extremity amputees

The relationship between phantom limb phenomena and cortical reorganization was examined in five subjects with congenital absence of an upper limb and nine traumatic amputees. Neuromagnetic source imaging revealed minimal reorganization of primary somatosensory cortex in the congenital amputees (M=0.69 cm, SD 0.24) and the traumatic amputees without phantom limb pain (M=0.27 cm, SD 0.25); the amputees with phantom limb pain showed massive cortical reorganization (M=2.22 cm, SD 0.78). Phantom limb pain and nonpainful phantom limb phenomena were absent in the congenital amputees. Whereas phantom limb pain was positively related to cortical reorganization (r=0.87), nonpainful phantom phenomena were not significantly correlated with cortical reorganization (r=0.34). Sensory discrimination was normal and mislocalization (referral of stimulation-induced sensation to a phantom limb) was absent in the congenital amputees. The role of peripheral and central factors in the understanding of phantom limb pain and phantom limb phenomena is discussed in view of these findings. Received: 4 June 1997 / Accepted: 13 September 1997     

Sensory feedback prosthesis reduces phantom limb pain: proof of a principle

Background

Constrained functionality and phantom limb pain (PLP) are major concerns for forearm amputees. Neuroscientific investigations of PLP suggest that behaviorally relevant stimulation of the stump can decrease PLP. Furthermore the prosthesis user could use feedback information of the prosthesis hand for optimizing prosthesis motor control when handling soft and fragile objects. Somatosensory feedback information from a prosthetic hand may therefore help to improve prosthesis functionality and reduce phantom limb pain.

Objectives

We wanted to find out whether a two weeks training on a hand prosthesis that provides somatosensory feedback may help to improve prosthesis functionality and reduce phantom limb pain.

Methods

Eight forearm amputees with phantom limb pain were trained for two weeks to use a hand prosthesis with somatosensory feedback on grip strength.

Results

The current study demonstrates a significant increase of functionality of the prosthesis in everyday tasks. Furthermore, the study shows that usage of a prosthesis that provides somatosensory feedback on the grip strength is effective to reduce phantom limb pain.

Conclusions

A prosthesis with a feedback function appears to be a promising therapeutic tool to reduce phantom limb pain and to increase functionality in everyday tasks. Future studies should further investigate the scope of application of that principle.     

HIV Pharmacology: Barriers to the Eradication of HIV from the CNS

Abstract

Total eradication of HIV-1 is not yet achievable, in part because reservoirs of latent HIV-1 can develop within lymphoid tissue, the testes, and the central nervous system (CNS). The presence of HIV-1 in the CNS is clinically significant because of its association with the development of HIV dementia, which occurs in up to one fifth of untreated patients. This review summarizes current theory regarding HIV-1 infection within the CNS, describes physiologic and pharmacologic factors limiting CNS penetration of antiretroviral drugs used to treat HIV-1 infection, and reviews current treatment of CNS HIV-1 infection and HIV encephalopathy.     

A rare case of survival from primary amebic meningoencephalitis

Primary amebic meningoencephalitis (PAM) is a rare and fatal disease of central nervous system (CNS) caused by Naegleria fowleri, an ameba found in soils and warm waters. It enters the CNS after insufflation of infected water by attaching itself to the olfactory nerves. The infection is usually difficult to diagnose and has a poor prognosis. The present case is one such case in which CSF examination led us to the diagnosis of PAM and finally to a favorable outcome when treated with Amphoterracin B and antibiotics.     

Intent Recognition in a Powered Lower Limb Prosthesis Using Time History Information

New computerized and powered lower limb prostheses are being developed that enable amputees to perform multiple locomotion modes. However, current lower limb prosthesis controllers are not capable of transitioning these devices automatically and seamlessly between locomotion modes such as level-ground walking, stairs and slopes. The focus of this study was to evaluate different intent recognition interfaces, which if configured properly, may be capable of providing more natural transitions between locomotion modes. Intent recognition can be accomplished using a multitude of different signals from mechanical sensors on the prosthesis. Since these signals are non-stationary over any given stride, and gait is cyclical, time history information may improve locomotion mode recognition. The authors propose a dynamic Bayesian network classification strategy to incorporate prior sensor information over the gait cycle with current sensor information. Six transfemoral amputees performed locomotion circuits comprising level-ground walking and ascending/descending stairs and ramps using a powered knee and ankle prosthesis. Using time history reduced steady-state misclassifications by over half (p < 0.01), when compared to strategies that did not use time history, without reducing intent recognition performance during transitions. These results suggest that including time history information across the gait cycle can enhance locomotion mode intent recognition performance.     

Image-to-sound conversion: experience-induced plasticity in auditory cortex of blindfolded adults

The ability to adapt to environmental changes is based on the impressive capacity of the central nervous system for plasticity changes. A better understanding of the requirements of neuroplasticity will help to apprehend and predict the success of sensory prostheses. To investigate neuroplastic changes associated with (1) blindfolding and (2) the use of a mobile visual–auditory substitution system, five normally sighted adults underwent weekly measurements of neuromagnetic activity using a 122-channel whole head neuromagnetometer. The substitution device converted visual images into sound patterns. During measurements subjects listened to “geometric sounds” converted from images of geometric shapes, “natural sounds” representing photographs of everyday objects, as well as to original “environmental sounds”. To assess the role of visual deprivation, three individuals were blindfolded throughout a 3-week testing period. To assess the effect of extended exposure to “visual sounds”, three subjects—two blindfolded, one sighted—had free use of the substitution device. Neuromagnetic responses were restricted to the auditory cortex across all measurements. Activity at 100 ms after presentation of “natural sounds”, but not other auditory stimuli, showed a significant enhancement over time only in blindfolded subjects using the substitution system, indicating that the combination of visual deprivation and practice facilitated intra-modal plasticity. The fact that changes occurred only in response to “natural sounds” probably reflects the increased behavioural relevance of this category evident only for blindfolded subjects using the substitution device.