Imbalance of p75(NTR)/TrkB protein expression in Huntington's disease: implication for neuroprotective therapies.

Neuroprotective therapies based on brain-derived neurotrophic factor (BDNF) administration have been proposed for Huntington's disease (HD) treatment. However, our group has recently reported reduced levels of TrkB in HD mouse models and HD human brain suggesting that besides a decrease on BDNF levels a reduction of TrkB expression could also contribute to diminished neurotrophic support in HD. BDNF can also bind to p75 neurotrophin receptor (p75(NTR)) modulating TrkB signaling. Therefore, in this study we have analyzed the levels of p75(NTR) in several HD models, as well as in HD human brain. Our data demonstrates a p75(NTR)/TrkB imbalance in the striatum of two different HD mouse models, Hdh(Q111/111) homozygous knockin mice and R6/1 mice that was also manifested in the putamen of HD patients. The imbalance between TrkB and p75(NTR) levels in a HD cellular model did not affect BDNF-mediated TrkB activation of prosurvival pathways but induced activation of apoptotic cascades as demonstrated by increased JNK phosphorylation. Moreover, BDNF failed to protect mutant huntingtin striatal cells transfected with p75(NTR) against NMDA-mediated excitotoxicity, which was associated with decreased Akt phosphorylation. Interestingly, lack of Akt activation following BDNF and NMDA treatment correlated with increased PP1 levels. Accordingly, pharmacological inhibition of PP1 by okadaic acid (OA) prevented mutant huntingtin striatal cell death induced by NMDA and BDNF. Altogether, our findings demonstrate that the p75(NTR)/TrkB imbalance induced by mutant huntingtin in striatal cells associated with the aberrant activity of PP1 disturbs BDNF neuroprotection likely contributing to increasing striatal vulnerability in HD. On the basis of this data we hypothesize that normalization of p75(NTR) and/or TrkB expression or their signaling will improve BDNF neuroprotective therapies in HD.

Evidence-based guideline: Treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation.

OBJECTIVE: To develop a scientifically sound and clinically relevant evidence-based guideline for the treatment of painful diabetic neuropathy (PDN). METHODS: We performed a systematic review of the literature from 1960 to August 2008 and classified the studies according to the American Academy of Neurology classification of evidence scheme for a therapeutic article, and recommendations were linked to the strength of the evidence. The basic question asked was: "What is the efficacy of a given treatment (pharmacologic: anticonvulsants, antidepressants, opioids, others; and nonpharmacologic: electrical stimulation, magnetic field treatment, low-intensity laser treatment, Reiki massage, others) to reduce pain and improve physical function and quality of life (QOL) in patients with PDN?" RESULTS AND RECOMMENDATIONS: Pregabalin is established as effective and should be offered for relief of PDN (Level A). Venlafaxine, duloxetine, amitriptyline, gabapentin, valproate, opioids (morphine sulfate, tramadol, and oxycodone controlled-release), and capsaicin are probably effective and should be considered for treatment of PDN (Level B). Other treatments have less robust evidence or the evidence is negative. Effective treatments for PDN are available, but many have side effects that limit their usefulness, and few studies have sufficient information on treatment effects on function and QOL.

Median "pseudoneurapraxia" at the wrist: reassessment of palmar stimulation of the recurrent median nerve.

OBJECTIVE: To determine the occurrence and effect of incidental deep ulnar nerve (DUN) costimulation during palmar stimulation of the recurrent median nerve (RMN). DESIGN: Observational. SETTING: Electromyography laboratory. PARTICIPANTS: Seventeen asymptomatic adult volunteers (34 hands) and 4 fresh cadaver hands. MAIN OUTCOME MEASURES: Median nerve stimulation at the wrist and careful incremental surface and subcutaneous (needle) palmar stimulation were performed while recording thenar and first dorsal interosseous manus compound muscle action potentials. Thenar palm-to-wrist amplitude difference (P -- W Delta) and palm-to-wrist amplitude ratio (P/W) were compared with published values. Correlation of DUN costimulation with falsely elevated P -- W Delta and P/W values was assessed. Multiplanar magnetic resonance imaging (MRI) and subsequent dissection of 4 fresh cadaver hands was done to measure the distance between the RMN and DUN at the palmar stimulation site. RESULTS: Two groups emerged: Group I (63%), with DUN stimulation, and II (37%), with no DUN stimulation. When DUN costimulation occurred (Group I), there was a statistically significant increase in P -- W Delta (p =.002 percutaneous, p =.02 subcutaneous) and P/W (p =.004 percutaneous, p =.007 subcutaneous) when compared with previously published data. Combining all trials on all hands, 53% and 25% had P -- W Delta values and P/W values that exceeded previously published normative data, respectively. The mean distance between the DUN and RMN at the palmar stimulation site was determined by dissection (1.2cm) and MRI (1.5cm). CONCLUSIONS: Close proximity of the DUN to the RMN causes frequent and often unavoidable DUN activation during palmar stimulation of the RMN. This inadvertent stimulation may cause a false diagnosis of median neurapraxia at the wrist.

Electrophysiologic mapping and cadaveric dissection of the lateral foot: implications for tibial motor nerve conduction studies.

OBJECTIVE: To clarify, through electrophysiologic mapping and cadaveric dissection of the lateral foot, the previously published "proximal" and "distal" recording sites for tibial motor nerve conduction studies. DESIGN: Observational. SETTING: Electromyography laboratory; anatomy laboratory. PATIENTS OR OTHER PARTICIPANTS: Ten asymptomatic feet; eight cadaveric feet. MAIN OUTCOME MEASURES: (1) Amplitudes and onset latencies of compound muscle action potentials (CMAPs) recorded over a grid on the lateral foot that included the "proximal" and "distal" recording sites; (2) nerve supply and anatomic boundaries of the abductor digiti minimi pedis (ADMP) and nearby muscles, particularly as they relate to the above recording sites. RESULTS: (1) Relatively large CMAPs were recorded at and around the "proximal" and "distal" sites, with significantly shorter "proximal" latencies. (2) In all cadaveric feet, ADMP was innervated by only the inferior calcaneal nerve (ICN) and was located deep to the "proximal" site, with virtually no muscle fibers deep to the "distal" site. The flexor digiti minimi brevis (FDMB) was conspicuously located immediately deep to the "distal" site and was innervated by only the lateral plantar nerve (LPN). CONCLUSIONS: This study strongly suggests that the "proximal" site records predominantly from the ICN-innervated ADMP, whereas the "distal" site predominantly records from the LPN-innervated FDMB.

Electrodiagnostic evaluation of the foot.

Focal entrapment neuropathies in the foot, as compared to those of the hand, represent a daunting diagnostic challenge to many electromyographers. This article emphasizes an understanding of the anatomy of the foot as a fundamental key to its electrodiagnostic evaluation. The anatomic course of specific nerves will be described in terms of entrapment sites, and the clinical and electrophysiologic manifestations of each nerve entrapment will be discussed.

Abductor hallucis false motor points: electrophysiologic mapping and cadaveric dissection.

False motor points (FMPs) can occur in intrinsic foot or hand muscles, causing spuriously prolonged distal motor latencies by misrepresenting the compound muscle action potential (CMAP) onset. We investigated the motor point (MP) and possible FMPs in abductor hallucis (AH) by three methods: (1) electrophysiologic mapping of the CMAP with a grid of approximately 29 G1 sites over AH (n = 20), including commonly used MPs just anterior to (Ant-MP) and posterior to (Post-MP) the navicular tuberosity; (2) electrophysiologic mapping with direct percutaneous threshold stimulation of AH (same grid as above); and (3) cadaveric dissection (n = 4). We found AH FMPs in 19 of 20 feet (2.7 FMPs/foot) which resulted in prolongation of the CMAP onset latency by 0.5-2.3 ms. Post-MP had a significantly lower mean threshold stimulus intensity than all other grid sites, including the FMPs. The anatomic MP of AH was consistently found just inferior and posterior to the navicular tuberosity. This study demonstrates that AH FMPs: (1) can be identified in virtually all feet; (2) do not correspond to the true MP (i.e., Post-MP); and (3) are likely due to superimposed compound action potentials from nearby muscles or nerves.

Generator sources for the early and late ulnar hypothenar premotor potentials: short segment electrophysiologic studies and cadaveric dissection.

OBJECTIVE: Determine the generator sources for the ulnar hypothenar premotor potentials (PMPs). DESIGN: Observational. SETTING: EMG laboratory. SUBJECTS: Ten asymptomatic adult volunteers, three cadaver hands. MAIN OUTCOME MEASURE: Far-field versus near-field characteristics of recorded PMPs as determined by bipolar and referential recording electrode montages. A possible anatomic basis for any observed differences between ulnar PMPs and previously studied median PMPs were explored through cadaveric dissection. RESULTS: An early PMP (E-PMP) had a latency that varied with changes in the position of G1 only. A late PMP (L-PMP was seen only when G1 and G2 were on different volumes (palm vs fifth digit, or second digit vs fifth digit); its latency did not vary significantly with changes in the position of G1 and G2. CONCLUSIONS: (1) E-PMP is a near-field potential generated by the ulnar nerve passing near the G1 electrode. (2) L-PMP represents a far-field potential generated by the ulnar digital nerves as they traverse from the hand volume containing G1 to the finger volume containing G2. (3) Greater L-PMP-to-CMAP separation in the median than in the ulnar nerve was explained by cadaveric dissection, which revealed that the motor branch (responsible for the trailing CMAP) is longer in the median nerve than in the ulnar nerve relative to each nerve's corresponding digital sensory branch (responsible for the preceding L-PMP). (4) The PMP that is typically recorded with G1 at the hypothenar motor point and G2 on the fifth digit most likely represents E-PMP. (5) Any proposed diagnostic use of the ulnar PMPs must take into consideration these generator sources.

Generators of the early and late median thenar premotor potentials.

The generator sources of the median thenar premotor potentials (PMPs) have remained elusive despite debate in the literature. By studying the median nerve in the hand with a variety of bipolar and referential recording montages, we systematically examined the possible near-field and far-field sources that may determine these potentials. The results suggest that the early PMP is a near-field potential recorded by G1 and generated by the median nerve traversing the distal carpal tunnel. The late PMP represents a far-field potential generated by the median digital nerve fibers as they pass from the palm volume into the thumb volume. Characteristics of the late PMP are explained using the leading/trailing dipole (L/TD) model of far-field potential generation. The diagnostic utility of these PMPs is questionable, since they are recorded from "regions" along the nerve rather than from more clearly defined sites.

The medial calcaneal nerve: anatomy and nerve conduction technique.

We report a new technique for studying conduction in the medial calcaneal nerve (MCN). Dissection of 14 cadaver feet revealed the optimal G1 site to be one third of the way from the apex of the heel to a point midway between the navicular tuberosity and the prominence of the medial malleolus. Seventy-two feet (36 healthy volunteers) were studied using surface stimulation of the tibial nerve 10 cm proximal to the G1 surface electrode. Averaging technique was not required. Reference values (mean +/- 2 SD) were determined for MCN onset latency (2.0 +/- 0.3 ms), peak latency (2.5 +/- 0.3 ms), onset conduction velocity (61 +/- 11 m/s), peak conduction velocity (40 +/- 5 m/s), baseline-to-peak amplitude (18 +/- 6 microV), and maximum intrasubject side-to-side differences in these values (0.3 ms, 0.3 ms, 15 m/s, 5 m/s, and 17 microV, respectively). This study provides an easily performed, reproducible method for electrophysiologic evaluation of the MCN.

Development of a model of the premotor potential.

This study explored the sensory nature of the small negative premotor potential (PMP) that is often seen preceding the compound muscle action potential. We developed a model of the PMP, using the ulnar and superficial radial sensory (SRS) nerves. Standard conduction studies of the deep ulnar motor nerve recording over the first dorsal interosseous manus (FDIM) and of the SRS nerve recording over the same site were done separately, then simultaneously, on 20 normal hands. In all subjects, there was no FDIM PMP, but with simultaneous stimulation of both nerves, there was a potential in all subjects that appeared similar to their median thenar and ulnar hypothenar PMPs. Reference data for the median thenar, ulnar hypothenar, and model PMP were generated. Findings from this study are discussed and appear to support the concept of the PMP being either a sensory potential or a junctional potential.

Corneal sensory pathway in the rat: a horseradish peroxidase tracing study.

The methods of transganglionic transport of horseradish peroxidase (HRP) and horseradish peroxidase--wheat germ agglutinin (HRP-WGA) were used to determine the location within the trigeminal ganglion of the primary afferent neurons that innervate the rat central cornea, and the brainstem and spinal cord termination sites of these cells. In each of 18 animals, solutions of HRP or HRP-WGA were applied to the scarified corneal surface and allowed to infiltrate into the corneal epithelium and stroma for 15 minutes. Postmortem examination of the corneal whole mounts from the experimental animals, and of corneas and neural tissues from several control animals, showed that the HRP/HRP-WGA remained confined to the central cornea with no spread into adjacent intra- or extraorbital tissues. HRP-labeled corneal afferent somata were located in the dorsal part of the ophthalmic region of the ipsilateral trigeminal ganglion. The central fibers of the corneal afferent neurons projected very heavily to interstitial nuclei of Cajal in the spinal tract of V at the level of caudal pars interpolaris and rostral pars caudalis, lightly to the pars caudalis/C1 transition zone, and sparsely to the dorsal horn of spinal cord segments C1-C3. The trigeminal main sensory nucleus, pars oralis, the rostral three-fourths of pars interpolaris, and an extensive midregion of pars caudalis were totally devoid of reaction product. Terminal fields in caudal pars caudalis and in the spinal cord dorsal horn were concentrated largely in the outer half of lamina II, with lesser accumulations in lamina I, the deeper half of lamina II, and in lamina III. The present study demonstrates for the first time by means of an anatomical tracing procedure the brainstem termination sites of corneal afferent neurons in the rat. The patchy, discontinuous nature of the corneal afferent projection to the caudal trigeminal brainstem nuclear complex (TBNC), and the total lack of corneal projections to rostral subdivisions of the TBNC, provide an exception to the general rule of trigeminal organization in which most areas of the head and face are represented as continuous columns throughout the rostrocaudal extent of the ipsilateral TBNC.