Amphetamine enhances training-induced motor cortex plasticity

OBJECTIVES: Repetitive synchronized movements lead to short-term plastic changes in the primary motor cortex, which can be assessed by transcranial magnetic stimulation (TMS). Drugs which enhance such plastic changes could be of therapeutical interest, e.g. in patients with cerebral lesions. MATERIAL AND METHODS: We studied the effect of amphetamine on motor performance and plastic changes in the motor cortex as revealed by TMS mapping in healthy humans, who had to train a repetitive synchronized movement over 1 h. RESULTS: Cortical plastic changes observed after 1 h of training were more pronounced with amphetamine, whereas motor performance did not differ between training sessions with and without amphetamine. CONCLUSION: We conclude that amphetamine is able to enhance training-induced motor cortex plasticity. This effect could be due to its known influence on the GABAergic and glutamatergic system, but might also result from its role as an indirect catecholaminergic agonist.     

Dejerine-Sottas' neuropathy caused by the missense mutation PMP22 Ser72Leu

OBJECTIVE: To describe a patient with the Dejerine-Sottas' syndrome due to a de novo Ser72Leu amino acid substitution in the PMP22 protein and summarize the phenotype associated with this frequent mutation. CASE REPORT: The proband has a medical history of early onset, severe, and progressive demyelinating neuropathy, accompanied by mild ptosis and limitations of eye movements. Ulnar nerve motor conduction velocities were extremely reduced (2.6 and 2.2 m/s), and the sural nerve biopsy showed onion bulbs and thinly myelinated axons. Duplication of chromosome 17p11.2 was ruled out, and the Ser72Leu substitution was found upon sequencing the PMP22 gene. CONCLUSION: The Ser72Leu substitution is being confirmed as the most frequent point mutation in the PMP22 gene. This 'hot spot' should be considered in the strategy of looking for point mutations in the hereditary demyelinating neuropathies.     

Bilateral corticospinal projections arise from each motor cortex in the macaque monkey: a quantitative study

The corticospinal projection is considered to influence fine motor function through nearly exclusively contralateral projections from the cortex in primates. However, unilateral lesions to this system in various species are frequently followed by significant functional improvement, raising the possibility that bilateral projections of this pathway may exist or emerge after injury. To examine the detailed anatomy and projections of the corticospinal motor neurons in rhesus monkeys (n = 4), we injected the high-resolution anterograde tracer biotinylated dextran amine (BDA) into 126 sites centered about the right lower extremity (LE) primary motor cortex. Projection and termination patterns were quantified at lumbar levels L1, L4, and L7 and mapped by using serial-section reconstructions. Notably, a mean of 10.1 +/- 0.6% (+/- SEM) of corticospinal tract (CST) axons descended in the lateral CST ipsilateral to the cortical BDA injection, and 87.9 +/- 1.0% of total CST axons projected in the contralateral lateral CST. The ipsilateral ventral CST contained only 1.0 +/- 0% of all projecting CST axons, whereas the contralateral ventral CST contained 0.3 +/- 0.2% of all axons. In addition, a minor dorsal column CST projection was identified. Measurement of BDA-labeled terminals in the spinal cord gray matter revealed that 11.2 +/- 2.2% of CST axons terminated ipsilateral to the side of cortical injection, and the remainder terminated contralaterally. As previously reported, most CST axons terminated in spinal cord laminae V-VIII, as well as the laterodorsal motoneuronal group of lamina IX (which innervates distal extremity muscles). Notably, many CST axons crossed the spinal cord midline (mean 19.9 +/- 4.9 axons per 40-microm-thick section). Detailed single-axon reconstructions revealed that most ipsilaterally projecting lateral CST axons terminated in ipsilateral gray matter. Notably, we found that the bouton-like swellings of many ipsilateral CST axons descending in the dorsolateral tract were located within Rexed's lamina IX, in close proximity to motoneuronal somata. Thus, bilateral projections of corticospinal axons originating from a single motor cortex could contribute to bilateral control of spinal motor neurons and to the highly evolved degree of fine motor control in primates. Furthermore, bilateral CST projections from a single motor cortex could represent a potential source of plasticity after injury, as well as a target of therapeutic effort in neural regeneration strategies.     

Comparative cellular distribution of GABAA and GABAB receptors in the human basal ganglia: immunohistochemical colocalization of the alpha 1 subunit of the GABAA receptor, and the GABABR1 and GABABR2 receptor subunits

The GABA(B) receptor is a G-protein linked metabotropic receptor that is comprised of two major subunits, GABA(B)R1 and GABA(B)R2. In this study, the cellular distribution of the GABA(B)R1 and GABA(B)R2 subunits was investigated in the normal human basal ganglia using single and double immunohistochemical labeling techniques on fixed human brain tissue. The results showed that the GABA(B) receptor subunits GABA(B)R1 and GABA(B)R2 were both found on the same neurons and followed the same distribution patterns. In the striatum, these subunits were found on the five major types of interneurons based on morphology and neurochemical labeling (types 1, 2, 3, 5, 6) and showed weak labeling on the projection neurons (type 4). In the globus pallidus, intense GABA(B)R1 and GABA(B)R2 subunit labeling was found in large pallidal neurons, and in the substantia nigra, both pars compacta and pars reticulata neurons were labeled for both receptor subunits. Studies investigating the colocalization of the GABA(A) alpha(1) subunit and GABA(B) receptor subunits showed that the GABA(A) receptor alpha(1) subunit and the GABA(B)R1 subunit were found together on GABAergic striatal interneurons (type 1 parvalbumin, type 2 calretinin, and type 3 GAD neurons) and on neurons in the globus pallidus and substantia nigra pars reticulata. GABA(B)R1 and GABA(B)R2 were found on substantia nigra pars compacta neurons but the GABA(A) receptor alpha(1) subunit was absent from these neurons. The results of this study provide the morphological basis for GABAergic transmission within the human basal ganglia and provides evidence that GABA acts through both GABA(A) and GABA(B) receptors. That is, GABA acts through GABA(B) receptors, which are located on most of the cell types of the striatum, globus pallidus, and substantia nigra. GABA also acts through GABA(A) receptors containing the alpha(1) subunit on specific striatal GABAergic interneurons and on output neurons of the globus pallidus and substantia nigra pars reticulata.     

Cortical connections of the lateral mediodorsal thalamus in cynomolgus monkeys

The prefrontal cortex has been defined as that cortical territory that has "essential or sustaining" connections with the mediodorsal (MD) nucleus of the thalamus. However, recent studies in the monkey have documented projections from MD to the more caudal, agranular regions of the frontal cortex, suggesting that the connections of MD may be characterized by a breadth of distribution and diversity of functional roles too great to be useful as a unifying and defining feature for a specific cortical territory. In this study, we placed tracer injections in the lateral divisions of MD in cynomolgus monkeys (Macaca fascicularis) to assess the relative proportions of connections devoted to diverse regions of the frontal cortex (FC). Three different patterns of label were observed in the cortex, associated with different locations within lateral MD. We have designated these as the ventrolateral MD-arcuate FC circuit, having most label in areas 8 and 6; the caudoventral MD-dorsomedial FC circuit, having most label in areas 24 and presupplementary motor area (SMA); and the anterodorsal MD-anterior FC circuit, with the most label in areas 9, 46, 12, and 10. Only two of the nine cases injected in lateral MD were predominantly connected with the anterior FC. Thus, particular locales within lateral MD are connected with multiple, functionally diverse cortical regions, including several not classically recognized as "prefrontal" areas. This divergence may distinguish MD-frontocortical and reciprocal corticothalamic pathways from the largely segregated pathways arising from the other thalamic nuclei that are interconnected with the frontal cortex, such as those from the ventrolateral nuclear group.     

Mice carrying the szt1 mutation exhibit increased seizure susceptibility and altered sensitivity to compounds acting at the m-channel

Summary:  Purpose: Mutations in the genes that encode subunits of the M-type K⁺ channel ( KCNQ2 / KCNQ3 ) and nicotinic acetylcholine receptor ( CHRNA4 ) cause epilepsy in humans. The purpose of this study was to examine the effects of the Szt1 mutation, which not only deletes most of the C-terminus of mouse Kcnq2 , but also renders the Chnra4 and Arfgap-1 genes hemizygous, on seizure susceptibility and sensitivity to drugs that target the M-type K⁺ channel.
Methods: The proconvulsant effects of the M-channel blocker linopirdine (LPD) and anticonvulsant effects of the M-channel enhancer retigabine (RGB) were assessed by electroconvulsive threshold (ECT) testing in C57BL/6J- Szt1 /+ ( Szt1 ) and littermate control C57BL/6J+/+ (B6) mice. The effects of the Szt1 mutation on minimal clonic, minimal tonic hindlimb extension, and partial psychomotor seizures were evaluated by varying stimulation intensity and frequency.
Results: Szt1 mouse seizure thresholds were significantly reduced relative to B6 littermates in the minimal clonic, minimal tonic hindlimb extension, and partial psychomotor seizure models. Mice were injected with LPD and RGB and subjected to ECT testing. In the minimal clonic seizure model, Szt1 mice were significantly more sensitive to LPD than were B6 mice [median effective dose (ED₅₀) = 3.4 ± 1.1 mg/kg and 7.6 ± 1.0 mg/kg, respectively]; in the partial psychomotor seizure model, Szt1 mice were significantly less sensitive to RGB than were B6 mice (ED₅₀= 11.6 ± 1.4 mg/kg and 3.4 ± 1.3 mg/kg, respectively).
Conclusions: These results suggest that the Szt1 mutation alters baseline seizure susceptibility and pharmacosensitivity in a naturally occurring mouse model.     

Organization of rat vibrissa motor cortex and adjacent areas according to cytoarchitectonics, microstimulation, and intracellular stimulation of identified cells

The relationship between motor maps and cytoarchitectonic subdivisions in rat frontal cortex is not well understood. We use cytoarchitectonic analysis of microstimulation sites and intracellular stimulation of identified cells to develop a cell-based partitioning scheme of rat vibrissa motor cortex and adjacent areas. The results suggest that rat primary motor cortex (M1) is composed of three cytoarchitectonic areas, the agranular medial field (AGm), the agranular lateral field (AG1), and the cingulate area 1 (Cg1), each of which represents movements of different body parts. Vibrissa motor cortex corresponds entirely and for the most part exclusively to AGm. In area AG1 body/head movements can be evoked. In posterior area Cg1 periocular/eye movements and in anterior area Cg1 nose movements can be evoked. In all of these areas stimulation thresholds are very low, and together they form a complete representation of the rat's body surface. A strong myelinization and an expanded layer 5 characterize area AGm. We suggest that both the strong myelinization and the expanded layer 5 of area AGm may represent cytoarchitectonic specializations related to control of high-speed whisking behavior.     

Projections from the superior colliculus to the trigeminal system and facial nucleus in the rat

To determine the influence of the superior colliculus (SC) in orienting behaviors, we examined SC projections to the sensory trigeminal complex, the juxtatrigeminal region, and the facial motor nucleus in rats. Anterograde tracer experiments in the SC demonstrated predominantly contralateral colliculotrigeminal projections. Microinjections in the deep layers of the lateral portion showed labeled nerve fibers and terminals in the ventromedial parts of the caudal principal nucleus and of the rostral oral subnucleus and in the medial part of the interpolar subnucleus. Some terminals were also observed in the juxtatrigeminal region and in the dorsolateral part of the facial motor nucleus contralaterally, overlying the orbicularis oculi motoneuronal region. Verification by retrograde tracer injections into the trigeminal target regions showed labeled SC neurons mostly in lateral portions of layers 4-7. When the juxtatrigeminal region was involved, a remarkable increase of labeled neurons was observed, having a patch-like arrangement with a decreasing gradient from lateral to medial SC portions. Retrograde tracer injections in the dorsolateral VII nucleus showed bilateral labeled neurons mainly in the deep lateral SC portion. Retrograde BDA microinjections into the same trigeminal or juxtatrigeminal regions, followed by gold-HRP into the dorsolateral VII nucleus, demonstrated a significant number of SC neurons in deep layers 6-7 projecting to both structures by axon collaterals. These neurons are mediolaterally grouped in patches along the rostrocaudal SC extent; a subset of them are immunoreactive for glutamic acid decarboxylase (GAD). They could be involved in the coordination of facial movements. Simultaneous anterograde and retrograde tracer injections into the lateral SC portion and the VII nucleus respectively localized trigeminofacial neurons receiving collicular input in the trigeminal principal nucleus and pars oralis. Therefore the SC should play a crucial role in regulating motor programs of both eye and eyelid movements.     

Transmission of scotopic signals from the rod to rod-bipolar cell in the mammalian retina

Mammals can see at low scotopic light levels where only 1 rod in several thousand transduces a photon. The single photon signal is transmitted to the brain by the ganglion cell, which collects signals from more than 1000 rods to provide enough amplification. If the system were linear, such convergence would increase the neural noise enough to overwhelm the tiny rod signal. Recent studies provide evidence for a threshold nonlinearity in the rod to rod bipolar synapse, which removes much of the background neural noise. We argue that the height of the threshold should be 0.85 times the amplitude of the single photon signal, consistent with the saturation observed for the single photon signal. At this level, the rate of false positive events due to neural noise would be masked by the higher rate of dark thermal events. The evidence presented suggests that this synapse is optimized to transmit the single photon signal at low scotopic light levels.     

Physical workload, ergonomic problems, and incidence of low back injury: a 7.5-year prospective study of San Francisco transit operators

BACKGROUND: The etiologic role of biomechanical factors for low back injury (LBI) needs to be confirmed in prospective studies that control for psychosocial factors. METHODS: Complete baseline information on 1,233 vehicle operators was gathered during medical examinations and by questionnaire. First LBI during 7.5 years of follow-up was ascertained from insurance records. Hazard ratios and etiologic fractions were analyzed with Cox regression models stratified by injury severity and controlling for age, sex, height, weight, ethnicity, and biomechanical and psychosocial job factors. Severe LBI was defined as medically diagnosed postlaminectomy syndrome, spinal stenosis, herniated lumbar disc, sciatica, or spinal instability. RESULTS: An exponential dose-response relationship was found between weekly driving hours and incidence of first LBI. Indicators of physical workload were more strongly associated with more severe low back injuries compared to less severe injuries. Rates of severe LBI increased 39% for every 10-hr increase in weekly driving (hazard ratio 1.39, 95% confidence interval 1.15-1.68). Higher risks of severe LBI were also found among operators performing heavy physical labor on cable cars (hazard ratio 2.76, 95% confidence intervals 1.24-6.14) or reporting more ergonomic problems at baseline (HR for upper quartile 1.65 (95% confidence interval 1.08-2.50). Estimates of etiologic fractions suggest that reduction of ergonomic problems to the low level currently experienced by 25% of drivers would result in a 19% reduction of severe LBI among all drivers. A change from full- (more than 30 hr) to part-time driving (20-30 hr) could reduce the number of severe LBI by 59%, although this gain would be reduced to 28% at the company level if injuries expected among additional employees, hired to maintain full service are included. CONCLUSIONS: Duration of professional driving and ergonomic problems are independent and preventable risk factors for LBI even after adjustment for psychosocial factors.