Large-fiber Sensory Neuropathy Research Articles

Sensorimotor control in the congenital absence of functional muscle spindles.

Hereditary sensory and autonomic neuropathy type III (HSAN III), also known as familial dysautonomia or Riley-Day syndrome, results from an autosomal recessive genetic mutation that causes a selective loss of specific sensory neurones, leading to greatly elevated pain and temperature thresholds, poor proprioception, marked ataxia and disturbances in blood pressure control. Stretch reflexes are absent throughout the body, which can be explained by the absence of functional muscle spindle afferents - assessed by intraneural microelectrodes inserted into peripheral nerves in the upper and lower limbs. This also explains the greatly compromised proprioception at the knee joint, as assessed by passive joint-angle matching. Moreover, there is a tight correlation between loss of proprioceptive acuity at the knee and the severity of gait impairment. Surprisingly, proprioception is normal at the elbow, suggesting that participants are relying more on sensory cues from the overlying skin; microelectrode recordings have shown that myelinated tactile afferents in the upper and lower limbs appear to be normal. Nevertheless, the lack of muscle spindles does affect sensorimotor control in the upper limb: in addition to poor performance in the finger-to-nose test, manual performance in the Purdue pegboard task is much worse than in age-matched healthy controls. Unlike those rare individuals with large-fibre sensory neuropathy, in which both muscle spindle and cutaneous afferents are absent, those with HSAN III present as a means of assessing sensorimotor control following the selective loss of muscle spindle afferents.

To Find Frequency of Large Fibre Sensory Neuropathy in Diabetes Mellitus and to Compare Hand Grip Strength in patients of DM with and without Large Fibre Sensory Neuropathy

Aim: To find frequency of large fiber sensory neuropathy in diabetes mellitus and to compare hand grip strength in patients of diabetes mellitus with and without large fiber sensory neuropathy Study setting: The study was conducted at Department of Medicine/ Diabetic Foot Care Clinic, Mayo Hospital, Lahore. Duration of study: August 25, 2020 to February 25, 2021 Study design: Cross-sectional study Methods: Total 100 patients with diabetes were enrolled. Patients had their handgrip checked. Handgrip strength of each participant was tested in morning after routine breakfast, with the help of Jammar hand dynamometer. Three readings were taken for each patient with dominant hand and average of these three was calculated for final analysis. Large fiber sensory neuropathy was assessed as per operational definition. Data were entered and analyzed by SPSS v25.0. Peripheral neuropathy was tested by Chi Square test. Data were stratified for age, gender, duration of DM and BMI. Hand grip was compared between groups by t-test. A p-value of ≤0.05 was taken as significant. Results: In this study, 100 patients presenting with diabetes mellitus were enrolled. Among these patients, 68(68.0%) were males, while 32(32.0%) were females. Age range in this study was from 18 to 60 years with mean age of 42.8±11.6 year. Frequency of large fiber sensory neuropathy was 42(42.0%) among cases presenting diabetes mellitus. Mean handgrip strength in patients with large fiber sensory neuropathy was 20.71±2.39 kg and 28.10±5.18 kg among cases without large fiber sensory neuropathy with p-value as 0.0001, which is statistically significant. Conclusion: Long-standing large fiber sensory neuropathy with type-II diabetes mellitus seems to result in a decrease in hand grip strength. This physical limitation may contribute to low productivity in people with large fiber sensory neuropathy among type-II diabetes mellitus. Keywords: Hand Grip Strength, Type-2 Diabetes Mellitus, Large Fiber Sensory Neuropathy.

Late Onset Pompe Disease with Novel Mutations and Atypical Phenotypes.

Late onset Pompe disease (LOPD) is rare and generally manifests predominantly as progressive limb girdle muscle weakness. It is linked to the pathogenic mutations in GAA gene, which leads to glycogen accumulation in various tissues. We describe the unusual clinical, biochemical, histopathological and genetic characteristics of 5 cases of LOPD. The first case had progressive anterior horn cell like disease (AHCD) that evolved later to classical limb girdle syndrome and respiratory failure, the second patient had rigid spine syndrome with gastrointestinal manifestations, the third had limb girdle weakness superimposed with episodic prolonged worsening and respiratory failure, the fourth had large fibre sensory neuropathy without primary muscle involvement and the fifth presented with classical limb girdle muscle weakness. Two homozygous missense mutations c.1461C > A (p.Phe487Leu) and c.1082C > T (p.Pro361Leu) in the GAA gene were identified in case 1 and 2 respectively. Case 3 was compound heterozygous with inframe c.1935_1940del (p.Val646_Cys647del) and an intronic splice effecting variant c.-32-13T > G. Compound heterozygous missense variants c.971C > T (p.Pro324Leu) and c.794G > A (p.Ser265Asn) were identified in case 4. Case 5 had a frameshift insertion c.1396dupG (p.Val466GlyfsTer40) and a synonymous splice affecting variant c.546G > T(p.Thr182=). We are describing for the first time from India on LOPD with unusual phenotypes identified. A high degree of clinical suspicion and diagnosing rare phenotypes of Pompe disease is imperative to consider early initiation of Enzyme Replacement Therapy (ERT).

A rare case of deafferentation reveals an essential role of proprioception in bilateral coordination

Loss of proprioception has been shown to produce deficits in intralimb coordination and in the ability to stabilize limb posture in the absence of visual feedback. However, the role of proprioceptive signals in the feedforward and feedback control of interlimb coordination remains unclear. To address this issue, we examined bimanual coordination in a deafferented participant (DP) with large-fiber sensory neuropathy, which resulted in the loss of proprioception and touch in both arms, and in age-matched control participants. The task required participants to move a single virtual bar with both hands to a rectangular target with horizontal orientation. The participants received visual feedback of the virtual bar, but not of the hand positions along the bar-axis. Although the task required symmetrical movement between the arms, there were significant differences in the trajectories of the dominant and non-dominant hands in the deafferented participant, and thus more final errors and impaired coordination compared to controls. Deafferentation was also associated with an asymmetric deficit in stabilizing the hand at the end of motion, where the dominant arm showed more drift than the non-dominant arm. While the findings with DP may reflect a unique adaptation to deafferentation, they suggest that 1) Bilateral coordination depends on proprioceptive feedback, and 2) Postural stability at the end of motion can be specified through feedforward mechanisms, in the absence of proprioceptive feedback, but this process appears to be asymmetric, with better stability in the non-dominant arm.

Anticipation and compensation for somatosensory deficits in object handling: evidence from a patient with large fiber sensory neuropathy.

The purpose of this study was to determine the contributions of feedforward and feedback processes on grip force regulation and object orientation during functional manipulation tasks. One patient with massive somatosensory loss resulting from large fiber sensory neuropathy and 10 control participants were recruited. Three experiments were conducted: 1) perturbation to static holding; 2) discrete vertical movement; and 3) functional grasp and place. The availability of visual feedback was also manipulated to assess the nature of compensatory mechanisms. Results from experiment 1 indicated that both the deafferented patient and controls used anticipatory grip force adjustments before self-induced perturbation to static holding. The patient exhibited increased grip response time, but the magnitude of grip force adjustments remained correlated with perturbation forces in the self-induced and external perturbation conditions. In experiment 2, the patient applied peak grip force substantially in advance of maximum load force. Unlike controls, the patient's ability to regulate object orientation was impaired without visual feedback. In experiment 3, the duration of unloading, transport, and release phases were longer for the patient, with increased deviation of object orientation at phase transitions. These findings show that the deafferented patient uses distinct modes of anticipatory control according to task constraints and that responses to perturbations are mediated by alternative afferent information. The loss of somatosensory feedback thus appears to impair control of object orientation, whereas variation in the temporal organization of functional tasks may reflect strategies to mitigate object instability associated with changes in movement dynamics.NEW & NOTEWORTHY This study evaluates the effects of sensory neuropathy on the scaling and timing of grip force adjustments across different object handling tasks (i.e., holding, vertical movement, grasping, and placement). In particular, these results illustrate how novel anticipatory and online control processes emerge to compensate for the loss of somatosensory feedback. In addition, we provide new evidence on the role of somatosensory feedback for regulating object orientation during functional prehensile movement.

Loss of function MPZ mutation causes milder CMT1B neuropathy.

Mutations in Myelin Protein Zero (MPZ) cause CMT1B, the second leading cause of CMT1. Many of the >200 mutations cause neuropathy through a toxic gain of function by the mutant protein such as ER retention, activation of the Unfolded Protein Response (UPR) or disruption of myelin compaction. While there is extensive literature on the loss of function consequences of MPZ in heterozygous Mpz +/- null mice, there is little known of the consequences of MPZ haploinsufficiency in humans. We identified six patients from different families with p.Tyr68Ter or p.Asp104fs heterozygous mutations of MPZ that are predicted to cause a premature termination and nonsense mediated decay of the mutant allele. Five patients were evaluated in Milan and one in Iowa City; all should be haploinsufficient for MPZ. Patients were evaluated clinically and by electrophysiology. Sensory ataxia dominated the clinical presentation with only mild weakness present in five of the six patients. Symptoms presented in adulthood in all patients and only one individual had a CMTNSv2 >5. Deep tendon reflexes were absent in all patients. Patients with likely MPZ loss of function due to mutations that cause haplodeficiency in MPZ have a mild, predominantly large fiber sensory neuropathy that serves as a human equivalent to the neuropathy observed in heterozygous Mpz null mice. Successful therapeutic approaches in treating Mpz deficient mice may be candidates for trials in these and similar patients.

Idiopathic distal sensory polyneuropathy: ACTTION diagnostic criteria.

To present standardized diagnostic criteria for idiopathic distal sensory polyneuropathy (iDSP) and its subtypes: idiopathic mixed fiber sensory neuropathy (iMFN), idiopathic small fiber sensory neuropathy (iSFN), and idiopathic large fiber sensory neuropathy (iLFN) for use in research. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities and Networks (ACTTION) public-private partnership with the Food and Drug Administration convened a meeting to develop consensus diagnostic criteria for iMFN, iSFN, and iLFN. After background presentations, a collaborative, iterative approach was used to develop expert consensus for new criteria. An iDSP diagnosis requires at least 1 small fiber (SF) or large fiber (LF) symptom, at least 1 SF or LF sign, abnormalities in sensory nerve conduction studies (NCS) or distal intraepidermal nerve fiber density (IENFD), and exclusion of known etiologies. An iMFN diagnosis requires that at least 1 of the above clinical features is SF and 1 clinical feature is LF with abnormalities in sensory NCS or IENFD. Diagnostic criteria for iSFN require at least 1 SF symptom and at least 1 SF sign with abnormal IENFD, normal sensory NCS, and the absence of LF symptoms and signs. Diagnostic criteria for iLFN require at least 1 LF symptom and at least 1 LF sign with normal IENFD, abnormal sensory NCS, and absence of SF symptoms and signs. Adoption of these standardized diagnostic criteria will advance research and clinical trials and spur development of novel therapies for iDSPs.

Brief Report: Demographic and Genetic Associations With Markers of Small and Large Fiber Sensory Neuropathy in HIV Patients Treated Without Stavudine.

Neurotoxic antiretroviral therapy (ART) such as stavudine has been now replaced with safer therapies, reducing the prevalence of neuropathy from 34% to 15% in HIV+ Indonesians. However, it is unclear whether the residual cases display damage to small or large nerve fibers and whether both are influenced by known risk factors, including alleles of CAMKK2 associated with neuropathy in HIV patients. The encoded protein influences the growth and repair of nerve fibers. HIV-positive adults on ART for >12 months without exposure to stavudine were screened for neuropathy using the AIDS Clinical Trials Group Brief Peripheral Neuropathy Screen (BPNS). Large fiber neuropathy was assessed by nerve conduction (NC) and small fiber neuropathy using stimulated skin wrinkling (SSW) applied to the fingers. CAMKK2 alleles were assessed by TaqMan OpenArray technology. Neuropathy diagnoses were more common with SSW than BPNS (49/173 vs 26/185, χ; P = 0.0009), with poor alignment between these outcomes (P = 0.60). NC and BPNS diagnosed neuropathy at similar frequencies (29/151 vs 26/185; P = 0.12) and were aligned (P < 0.0001). In bivariate analyses, all diagnoses were associated with patients' age and persistent HIV replication, with minor effects from CD4 T-cell counts and time on ART. CAMKK2 alleles associated with neuropathy diagnosed with BPNS and SSW but not NC. Multivariable analyses confirmed the importance of age and HIV replication, with distinct CAMKK2 polymorphisms affecting BPNS and SSW. Paradoxically, height was protective against skin wrinkling. Overall the data link CAMKK2 genotypes with small rather than large fiber damage. SSW may reflect pathology distinct from that identified using BPNS.

Reviewing the evidence base for the peripheral sensory examination

Many students find the peripheral sensory examination confusing. We set out to summarise the evidence base in order to provide guidance on the most useful manoeuvres. We performed a literature review starting with 5 secondary sources, supplemented by a literature search on MEDLINE. A useful approach to neuropathy is to divide these into large fibre sensory neuropathy (LFSN) in which vibration and proprioception are affected, and small fibre sensory neuropathy (SFSN) in which pain and temperature are affected. Positive sensory symptoms such as burning, electric or sunburn pain point to a SFSN; negative symptoms such as loss of sensation, numbness or deep pain point to a LFSN. If LFSN is suspected, the most reproducible and best studied physical examination is a 10 g monofilament, but vibration sense is also useful. There is much less data on the best physical examination for a SFSN. The most appropriate diagnostic test for SFSN is quantitative sensory testing, whereas for LFSN a nerve conduction study is indicated. A modest amount of evidence is available to guide peripheral sensory examination but more research is needed.

The fusimotor and reafferent origin of the sense of force and weight

Signals associated with the command the brain sends to muscles are thought to create the sensation of heaviness when we lift an object. Thus, as a muscle is weakened by fatigue or partial paralysis (neuromuscular blockade), the increase in the motor command needed to lift a weight is thought to explain the increasing subjective heaviness of the lifted object.With different fatiguing contractions we approximately halved the force output of the thumb flexor muscles, which were then used to lift an object. For two deafferented subjects the perceived heaviness of the lifted object approximately doubled, in keeping with the central-signal theory. However, for normal subjects this resulted in objects feeling the same or lighter, inconsistent with the central-signal theory but consistent with the expected effects of the conditioning contractions on the sensitivity of peripheral receptors. In separate experiments we subjected the forearm muscles to complete paralysis with a non-depolarising neuromuscular blocking agent and then allowed them to recover to approximately half-force output. This also resulted in objects feeling lighter when lifted by the semi-paralysed thumb, even though the motor command to the motoneurons must have been greater. This is readily explained by reduced lift-related reafference caused by the prolonged paralysis of muscle spindle intrafusal fibres.We conclude that peripheral signals, including a major contribution from muscle spindles, normally give rise to the sense of exerted force. In concept, however, reafference from peripheral receptors may also be considered a centrally generated signal that traverses efferent and then afferent pathways to feed perceptual centres rather than one confined entirely to the central nervous system. These results therefore challenge the distinction between central- and peripheral-based perception, and the concept that muscle spindles provide only information about limb position and movement.

Electrophysiological markers of large fibre sensory neuropathy: a study of sensory and motor conduction parameters

The frequency of sural sensory nerve action potential (SNAP) abnormalities in large fibre sensory neuropathy (LFSN) is uncertain. When sural SNAPs are normal, the sural/radial amplitude ratio (SRAR) was found to improve diagnostic yield in some studies. Motor parameters have been studied rarely, but may be helpful in this setting. The electrophysiology of 105 consecutive patients with LFSN was reviewed and compared with that of 62 controls. We determined (i) the frequency of abnormal sural SNAPs, (ii) the proportion of patients with normal sural SNAPs but reduced SRAR <0.21 and (iii) the utility of motor studies (motor nerve conduction velocity, compound muscle action potential, F-wave). Reduced age-adjusted sural SNAPs were present in 54.3% of all patients. In those with normal age-adjusted sural SNAPs, SRAR <0.21 offered a sensitivity of 52.1% and specificity of 83.9%, and prolonged lower limb F-wave latency >105% of the upper limit of normal (ULN) offered a sensitivity of 29.2% and specificity of 90%. Independently and in combination, both parameters significantly improved diagnostic yield. The combined use of SRAR <0.21 and/or lower limb F-wave delay >105% of the ULN may be useful in patients with LFSN and normal sural SNAPs.

Optimal sensorimotor transformations for balance

Here we have identified a sensorimotor transformation that is used by a mammalian nervous system to produce a multijoint motor behavior. Using a simple biomechanical model, a delayed-feedback rule based on an optimal tradeoff between postural error and neural effort explained patterns of muscle activation in response to a sudden loss of balance in cats. Following the loss of large sensory afferents, changes in these muscle-activation patterns reflected an optimal reweighting of sensory feedback gains to minimize postural instability. Specifically, a loss of center-of-mass-acceleration information, which allowed for a rapid initial rise in the muscle activity in intact animals, was absent after large-fiber sensory neuropathy. Our results demonstrate that a simple and flexible neural feedback control strategy coordinates multiple muscles over time via a small set of extrinsic, task-level variables during complex multijoint natural movements.

10.11 The relation between motor deficit and proprioceptiveloss after large-fibre sensory neuropathy

10.11 The relation between motor deficit and proprioceptiveloss after large-fibre sensory neuropathy

Characterization of neuropathies associated with elevated IgM serum levels

Background In contrast to the IgM monoclonal gammopathies the neuropathy associated with polyclonal IgM gammopathy has not been well characterized. Objective To characterize the neuropathy in patients with elevated serum IgM. Design Retrospective review. Setting Academically based neuropathy center. Patients 45 patients with elevated quantitative immunoglobulin M were identified. Main outcome measures Patients are described with regard to clinical phenotype, electrodiagnostic features of demyelination or focality, presence of IgM monoclonal gammopathy, and presence of autoantibody activity. Results Elevated IgM levels occurred in 45 (11.5%) of 391 patients. Of these, 24 (53%) had polyclonal gammopathy and 21 (47%) had an IgM monoclonal gammopathy. Anti-nerve antibodies occurred in 14/21 (67%) of patients with monoclonal gammopathy, as compared to 1/24 (4%) with polyclonal gammopathy. Clinically, most patients in all groups had a predominantly large fiber sensory neuropathy. Thirty patients underwent electrodiagnostic testing. Of these, 22/30 (73%) fulfilled at least one published criteria for CIDP, including 92% of the monoclonal gammopathy patients and 59% of the polyclonal gammopathy patients. Fifteen of the 30 patients had evidence of focality or multifocality, with 14 of these 15 showing evidence of demyelination. Conclusions Monoclonal and polyclonal IgM patients have similar distributions of neuropathy phenotypes. Neuropathy in association with elevated serum IgM, with or without monoclonal gammopathy or autoantibody activity, is more likely to be demyelinating or multifocal. Serum quantitative IgM level and immunofixation in neuropathy patients may aid in identification of an immune mediated or a demyelinating component.

Neurophysiological testing correlates with clinical examination according to fibre type involvement and severity in sensory neuropathy

Objective: To investigate a comprehensive battery of neurophysiological tests for objective evaluation of sensory neuropathies including fibre type involvement and severity, and to determine the relation between neurophysiological data and...

Target tissue production and axonal transport of neurotrophin-3 are reduced in streptozotocin-diabetic rats.

Neurotrophin-3 (NT-3) acts as a target-derived neurotrophic factor for large calibre sensory neurones and plays a role in the maintenance of the adult phenotype of proprioceptive and mechanoreceptive fibres. Large fibre sensory neuropathy is common in diabetes mellitus and the aim of this study was to determine whether endogenous NT-3-dependent neurotrophic support was sub-optimal in the streptozotocin-diabetic rat. NT-3 gene expression was analysed by Northern blotting and ELISA in hindlimb skeletal muscle and found to be decreased by up to 70% (p < 0.05) in rats with 4-6 weeks of diabetes compared to aged-matched controls. Treatment of other diabetic rats with insulin prevented development of deficits of both NT-3 protein and of its mRNA. The deficits in target tissue production of NT-3 were coincident with significant decreases in its anterograde and retrograde axonal transport in sciatic nerve at 6 weeks of diabetes. The mRNA expression in lumbar dorsal root ganglia of the specific receptor for NT-3, trkC, was also down-regulated at 12 weeks of diabetes by 50% (p < 0.05). The observed decreases in NT-3 target tissue production and related axonal transport suggest that large calibre sensory neurones expressing trkC may be receiving sub-optimal neurotrophic support in experimental diabetes.

Physiological characterization of Taxol-induced large-fiber sensory neuropathy in the rat.

The cancer chemotherapeutic agent Taxol (paclitaxel) causes a dose-related peripheral neuropathy in humans. We produced a dose-dependent large-fiber sensory neuropathy, without detrimental effects on general health, in mature rats by using two intravenous injections 3 days apart. Tests of other dosing schedules demonstrated the dependence of the severity of the neuropathy and of animal health on both the dose and the frequency of dosing. Pathologically, severe axonal degeneration and hypomyelination were observed in sections of dorsal roots, whereas ventral roots remained intact. Electrophysiologically, H-wave amplitudes in the hindlimb and amplitudes of predominantly sensory compound nerve action potentials in the tail were reduced. These effects persisted for at least 4 months after treatment. Motor amplitudes were not affected, but both motor and sensory conduction velocities decreased. The ability of rats to remain balanced on a narrow beam was impaired, indicating proprioceptive deficits. Muscle strength, measured by hindlimb and forelimb grip strength, and heat nociception, measured by tail-flick and hindlimb withdrawal tests, were not affected by Taxol. This model of Taxol-induced neuropathy in mature rats, with minimal effects on general health, parallels closely the clinical syndrome observed after Taxol treatment in humans.

Single-joint rapid arm movements in normal subjects and in patients with motor disorders.

In normal subjects the execution of single rapid one-joint movements is characterized by an electromyographic (EMG) pattern composed of three discrete bursts of activity; two bursts (first and second agonist bursts, or AG1 and AG2) are present in the agonist muscle separated by an almost complete period of electrical silence. During this pause, another burst (antagonist burst, or ANT) occurs in the antagonist muscle. If a rapid movement is executed during tonic activation of the agonist muscle, tonic activity is inhibited just prior to AG1 onset (agonist inhibition). Similarly, if the movement is performed during tonic activation of the antagonist muscle, such activity is also inhibited prior to AG1 onset (antagonist inhibition). Antagonist inhibition also starts prior to AG1 onset and lasts until ANT onset. A general descriptor of the kinematic features related to the EMG pattern described above is a symmetrical and unimodal velocity profile that is bell-shaped and shows an acceleration time roughly equal to the deceleration time. This holds true for movements performed under low accuracy constraints; as accuracy demands become stricter and stricter, the peak velocity decreases but, as long as the movement is made with one continuous trajectory, the velocity profile remains roughly symmetrical. In general terms, the function of AG1 is to provide the impulsive force to start the movement; the function of ANT is to halt the movement at the desired end-point; and the function of AG2 is to dampen out the oscillations which might occur at the end of the movement. The timing and size of the bursts vary according to the speed and amplitude of the movement. The origin of the EMG pattern is a central programme, but afferent inputs can modulate the voluntary activity. In this paper, we also review the EMG and kinematic abnormalities that are present during the execution of single-joint, rapid arm movements in patients with Parkinson's disease, Huntington's disease, Sydenham's chorea, dystonia, athetosis, cerebellar deficits, upper motor neuron syndrome, essential tremor and large-fibre sensory neuropathy. The data from these studies lead us to the following conclusions: (i) the basal ganglia have a role in scaling the size of AG1, reinforcing the voluntary command and inhibiting inappropriate EMG activity; (ii) the cerebellum has a role in timing the voluntary bursts and probably in implementing muscle force phasically; (iii) the corticospinal tract has a role in determining spatial and temporal recruitment of motor units; (iv) proprioceptive feedback is not necessary to produce the triphasic pattern but it contributes to the accuracy of both the trajectory and the end-point of rapid movements.

Evidence of a limited visuo-motor memory used in programming wrist movements.

Human subjects can pre-program movements on the basis of visual cues. Experience in a particular task leads to the storage of appropriate control parameters which are used in programming subsequent movements, via a short-term motor memory. The form, duration and usage of this memory are, however, uncertain. Repetitive wrist flexion and extension movements were measured in four subjects. Three were neurologically normal men; the fourth subject had a peripheral large-fibre sensory neuropathy, depriving him of proprioceptive information about wrist movement. Subjects made alternating 45 degrees wrist movements between two visual targets; visual feedback of wrist position was provided for the first part of each trial. After 10 s of tracking, the subjects paused for an interval of 0-24 s before resuming tracking without visual feedback of wrist position. The positional accuracy of subsequent movements was analysed with respect to pause interval. Movement accuracy was reduced by the removal of visual feedback in all four subjects: movements after the pause interval were less accurate than those before the pause. Errors also accumulated within each sequence of movements made without visual feedback. Analysis of the first movement in each trial after the pause indicated a clear relationship between movement accuracy and pause interval. In all four subjects, movement accuracy decayed with longer pause intervals. In the deafferented subject, manipulation of the visual inputs (requiring visual fixation, rather than normal pursuit of the target; or direct viewing of the hand instead of viewing a cursor on a computer screen) affected the relationship between pause interval and subsequent movement accuracy. We propose that the memory used when producing these movements is a short-lasting visuo-motor signal, lasting a few seconds, which is derived from visual knowledge of previous movements, rather than a memory of a particular motor output. This visuo-motor signal is used to scale the amplitude of subsequent wrist movements. The brevity of the visuo-motor memory and the resultant inaccuracy of this deafferented subject and of our neurologically normal subjects implies that human feedforward control of the amplitude and position of wrist movements is severely limited.

Peripheral Neuropathies: Will Growth Factors Be Effective as Therapies?

Neurotrophic factors are proteins that promote the survival and differentiation of specific neuronal popula tions. With the successful cloning and large-scale production of many different neurotrophic factors, it has become practical to consider their application in the treatment of neurological disease. Several categories of neurotrophic factors hold particular promise for the treatment of peripheral neuropathy in the near future. Preclinical studies have demonstrated the potential utility of factors like nerve growth factor for the treatment of small-fiber peripheral neuropathy and, possibly, compressive sensory neuropathies. Brain-derived neu rotrophic factor, ciliary neurotrophic factor, and insulin-like growth factor-I are likely to be applied in the treatment of motor neuropathy. Neurotrophin-3 has particular promise for the treatment of large-fiber sensory neuropathy. Although, for the most part, neurotrophic factors do not appear to have major toxicity, they represent a new class of drugs and clinical trials must proceed with caution. Clinical trials of several of these growth factors are currently underway, and others are being planned. The Neuroscientist 1:176-182, 1995