Cerebellar plasticity: modification of Purkinje cell structure by differential rearing in monkeys.

Dendritic branching in Purkinje and granule cells and the diameters of Purkinje cell somas were compared in several cerebellar areas of monkeys reared in isolation, with social experience, or in a large colony. In the colony-reared monkeys, spiny branchlets of Purkinje cells were more extensive in the paraflocculus and the nodulus than they were in the other two groups. Granule cell dendritic branching in the paraflocculus and nodulus did not differ across groups. In addition, Purkinje cell somas were larger in the uvula and the nodulus of the colony animals than in the other groups. These data indicate that the social and physical environment during development influences the morphology of cerebellar Purkinje cells.

Decreased thickness of primary motor cortex in primary lateral sclerosis.

BACKGROUND AND PURPOSE: Primary lateral sclerosis (PLS) is a rare form of motor neuron disease characterized by upper motor neuron dysfunction. Because pathologic examination has revealed a loss of neurons in the motor cortex of patients with PLS, we sought to confirm and extend this finding by using MR imaging to measure cortical thickness. METHODS: Seven patients with PLS and 7 age-matched neurologically normal control subjects were examined with heavily T1-weighted short-tau inversion recovery (STIR) MR imaging performed at 3T. Cortical thickness in the anterior and posterior banks of both the central and precentral sulci were measured. RESULTS: Primary motor cortex (M1) was significantly thinner in patients with PLS than M1 in healthy control subjects, measuring 2.32 +/- 0.21 mm compared with 2.79 +/- 0.18 mm (P = .0008). Cortical thickness did not differ between the 2 groups for primary sensory cortex or for the anterior or posterior banks of the precentral sulcus. Therefore, loss of gray matter was specific to motor cortex. Although this difference was modest, cortical thickness discriminated between the 2 groups; only 1 PLS case was within the range of normal measurements. CONCLUSION: Decreased thickness of M1 on the anterior bank of the precentral sulcus in patients with PLS, demonstrable by MR imaging, indicates a selective loss of upper motor neurons in this disease. Measurements of cortical thickness by MR imaging may provide a useful biomarker for diagnosis and study of upper motor neuron diseases.

A randomized phase II trial of thalidomide, an angiogenesis inhibitor, in patients with androgen-independent prostate cancer.

PURPOSE: Thalidomide is a potent teratogen that causes dysmelia in humans. Recently, in vitro data suggested that it inhibits angiogenesis. Prostate cancer is dependent on the recruitment of new blood vessels to grow and metastasize. Based on those data, we initiated a Phase II trial of thalidomide in patients with metastatic androgen-independent prostate cancer. EXPERIMENTAL DESIGN: This was an open-label, randomized Phase II study. Thalidomide was administered either at a dose of 200 mg/day (low-dose arm) or at an initial dose of 200 mg/day that escalated to 1200 mg/day (high-dose arm). RESULTS: A total of 63 patients were enrolled onto the study (50 patients on the low-dose arm and 13 patients on the high-dose arm). Serum prostate-specific antigen (PSA) decline of > or = 50% was noted in 18% of patients on the low-dose arm and in none of the patients on the high-dose arm. Four patients were maintained for > 150 days. The most prevalent complications were constipation, fatigue, neurocortical, and neurosensory. CONCLUSION: Thalidomide, an antiangiogenesis agent, has some activity in patients with metastatic prostate cancer who have failed multiple therapies. A total of 27% of all patients had a decline in PSA of > or = 40%, often associated with an improvement of clinical symptoms. Because our preclinical studies had shown that thalidomide increases PSA secretion, we believe that the magnitude of PSA decline seen in our trial justifies further study.

Somatodendritic morphology of on- and off-cells in the rostral ventromedial medulla.

The rostral ventromedial medulla (RVM) contains two classes of physiologically defined neurons, on-cells and off-cells, that are implicated in nociceptive modulation. In a continuing effort to detail the neural circuitry that underlies the activity of these two distinct neuronal types, the somatodendritic morphology of on- and off-cells was studied in the cat, rat, and ferret. In lightly anesthetized animals, on-cells increased and off-cells decreased their discharge rate during a withdrawal reflex evoked by noxious stimuli. Following their physiological characterization by using intracellular recording, on- and off-cells were injected with either horseradish peroxidase or biocytin and their somatodendritic arborizations were examined. Labeled on- and off-cells included fusiform and stellate cells of all sizes as well as large multipolar neurons. Although the somatic shape of both on- and off-cells in RVM was heterogeneous, off-cells tended to be fusiform neurons whose long axis was oriented mediolaterally. The dendritic domains of both on- and off-cells extended bilaterally past the lateral edge of the trapezoid body or pyramid and ventrally to, and sometimes including, the trapezoid body or pyramid. In contrast to their extensive mediolateral spread, the dendritic domains of both cell types were limited to the ventral half of the reticular formation and were compressed along the rostrocaudal axis. The dendritic arbor of individual on- and off-cells extended well beyond the cytoarchitectonic boundaries of any single nuclear region, within the domain delineated as the RVM. The spatial domains of the dendritic arbors of on- and off-cells are further evidence that the on- and off-cells throughout the RVM constitute an integrated unit in the modulation of nociceptive transmission.

Physiological studies of spinal inhibitory pathways in patients with hereditary hyperekplexia.

Because hereditary hyperekplexia results from a defect in the glycine receptor, we studied in five patients several spinal inhibitory pathways that are thought to use either glycine or gamma-aminobutyric acid as a neurotransmitter. Three patients had a mutation in the alpha1 subunit of the glycine receptor, whereas two sisters with the same clinical syndrome did not have this mutation. Compared with normal subjects, reciprocal inhibition between flexor and extensor muscles of the forearm was diminished during the first period of inhibition and preserved during the second period of inhibition in all three patients tested. Facilitation after the early period of inhibition was prominent. Recurrent inhibition of the soleus H reflex was normal in four patients, as was inhibition of the H reflex produced by Achilles' tendon vibration. There was no significant difference in nonreciprocal (Ib) inhibition between patients and normal individuals, The findings suggest that disynaptic reciprocal inhibition in humans is mediated through glycinergic interneurons, but that recurrent inhibition may have a contribution from nonglycinergic mechanisms.

Peripheral neuropathy in children with HIV infection.

Peripheral neuropathy is infrequently reported in children with HIV infection, but may be underrecognized. To provide a better understanding of the patterns of peripheral neuropathy in these children, we surveyed the charts of 50 children with HIV infection referred to the EMG laboratory at the National Institutes of Health for evaluation of suspected peripheral neuropathy. Twelve children had an abnormal nerve conduction study. The findings suggested a distal sensory or sensorimotor axonal neuropathy in seven children, median nerve compression at the carpal tunnel in three, a demyelinating neuropathy in one child, and a lumbosacral polyradiculopathy in one adolescent. Distal symmetric polyneuropathy occurred mostly in older-aged children.

Blink reflex recovery in facial weakness: an electrophysiologic study of adaptive changes.

OBJECTIVE: To study the electrophysiologic effects of unilateral facial weakness on the excitability of the neuronal circuitry underlying blink reflex, and to localize the site of changes in blink reflex excitability that occur after facial weakness. BACKGROUND: Eyelid kinematic studies suggest that adaptive modification of the blink reflex occurs after facial weakness. Such adaptations generally optimize eye closure. A report of blepharospasm following Bell's palsy suggests that dysfunctional adaptive changes can also occur. METHODS: Blink reflex recovery was evaluated with paired stimulation of the supraorbital nerve at different interstimulus intervals. Comparisons were made between normal control subjects and patients with Bell's palsy who either recovered facial strength or who had persistent weakness. RESULTS: Blink reflex recovery was enhanced in patients with residual weakness but not in patients who recovered facial strength. Facial muscles on weak and unaffected sides showed enhancement. In patients with residual weakness, earlier blink reflex recovery occurred when stimulating the supraorbital nerve on the weak side. Sensory thresholds were symmetric. CONCLUSION: Enhancement of blink reflex recovery is dependent on ongoing facial weakness. Faster recovery when stimulating the supraorbital nerve on the paretic side suggests that sensitization may be lateralized, and suggests a role for abnormal afferent input in maintaining sensitization. Interneurons in the blink reflex pathway are the best candidates for the locus of this plasticity.

Physiologic studies of spinal inhibitory circuits in patients with stiff-person syndrome.

OBJECTIVE: To test inhibitory spinal circuits in patients with stiff-person syndrome (SPS). BACKGROUND: Patients with SPS have fluctuating muscle stiffness and spasms, and most have antibodies against GABAergic neurons. We predicted they would also have abnormalities of spinal GABAergic circuits. DESIGN/METHODS: Physiologic methods using H-reflexes were used to test reciprocal inhibition in the forearm and thigh, vibration-induced inhibition of flexor carpi radialis and soleus H-reflexes, recurrent inhibition, and nonreciprocal (1b) inhibition of soleus H-reflexes. RESULTS: Vibration-induced inhibition of H-reflexes was diminished in eight of nine patients tested, but the presynaptic period of reciprocal inhibition was normal in most patients. Both circuits are presumed to involve presynaptic inhibition and GABAergic interneurons. Presumed glycinergic circuits, including the first period of reciprocal inhibition and nonreciprocal (1b) inhibition, showed occasional abnormalities. Recurrent inhibition was normal in all five patients tested. CONCLUSION: Differences between the two presumptive GABAergic circuits may indicate that not all populations of GABAergic neurons are uniformly affected in SPS. The involvement of presumptive glycinergic circuits in some patients could point to impairment of nonGABAergic neurons, unrecognized involvement of GABAergic neurons in these inhibitory circuits, or, more likely, alterations of supraspinal systems that exert descending control over spinal circuits.

Distortions induced in neuronal quantification by camera lucida analysis: comparisons using a semi-automated data acquisition system.

Quantitative analysis of dendritic structure is widely used in assessing neural relationships in Golgi-stained tissue. Quantitative techniques are tedious and time-consuming. A computer-microscope system is described which speeds data acquisition and analysis. Three neuronal samples are analyzed both by this computerized system and by camera lucida techniques. We demonstrate that the computerized techniques result in far fewer errors in data transcription and analysis than the camera lucida procedure. In addition, we show that the amount of distortion in camera lucida drawings caused by collapsing 3 dimensions into 2 varies both with cell class and cell dendrite type. This prevents the use of any simple statistical procedures for deriving 3-dimensional information from 2-dimensional data.

Evidence that inhibition of a nociceptive flexion reflex by stimulation in the rostroventromedial medulla in rats occurs at a premotoneuronal level.

The amplitude of the hamstring monosynaptic reflex was measured before and during stimulation of the rostroventromedial medulla (RVM) in the lightly anaesthetized rat. The RVM was stimulated at currents sufficient to completely inhibit a paw withdrawal reflex evoked by noxious heat. At these currents, RVM stimulation produced no significant change in monosynaptic reflex amplitude, evidence that inhibition occurs at a premotoneuronal level.

Transplantation of fetal postmitotic neurons to rat cortex: survival, early pathway choices and long-term projections of outgrowing axons.

A system for studying growth and development of transplanted subpopulations of postmitotic cerebral cortical neurons is described. The cytotoxic drug methylazoxymethanol (MAM) was given to pregnant rats on the fourteenth day of gestation to destroy precursor cells of layers II-IV of the fetal cerebral cortex. Layer V and VI precursor cells which had completed their final division before MAM treatment and were unaffected by it, were labeled by a prior injection of [3H]thymidine. This strategy provides a donor cerebral cortex containing mainly neurons destined to form layers V and VI of the adult cerebral cortex; these cells are postmitotic. Pieces of donor cerebral cortex were transplanted to the cerebral hemispheres of normal newborn hosts at one day, two days, or 6 days after MAM treatment; survival was assessed 1-12 weeks after transplantation by autoradiography of histological sections. Radiolabeled graft cells survived in 89% of recipients and many of these grew axons into the host, as indicated by retrograde labeling with horseradish peroxidase. Significant numbers of graft cells could also be stained immunocytochemically for glutamic acid decarboxylase or for the peptides, somatostatin, vasoactive intestinal polypeptide or cholecystokinin. A second group of experiments examined the routes of early axon outgrowth from normal and postmitotic fetal grafts. When the donor cortex had been incubated in a mixture of [3H]proline and [3H]leucine for 20 min prior to transplantation, the earliest axons growing out of the graft into normal newborn hosts could be assessed by autoradiography of axoplasmic transport after survivals in the host of 7 days. Normal and postmitotic grafts taken at E15 or E20 were capable of outgrowth, though the axons of E20 postmitotic cells did not grow far. The location of the transplant was the major determinant of where graft cells' axons grew and growth was mainly into existing axonal pathways of the host. In a third group of experiments, long term axonal projections from normal and postmitotic fetal transplants to 4 regions of the host brain--thalamus, contralateral cortex, striatum, and hippocampus--were examined with retrograde tracers 2-4 months after transplantation. Projections from grafts to the 4 host sites were highly dependent on the presence of nearby host axons connecting with those sites. Neurons in all types of graft projected to one or other of the 4 sites, but generally in small numbers. Higher proportions of cells in grafts from E15 MAM-treated donors projected to the host thalamus.(ABSTRACT TRUNCATED AT 400 WORDS)

The morphology and phased outgrowth of callosal axons in the fetal rat.

The growth of axons of the corpus callosum was studied in fetal and early postnatal rats by means of anterograde and retrograde transport of horseradish peroxidase (HRP) applied to the developing cerebral cortex in the frontal and presumptive sensory motor regions. In the sensorimotor regions, the first axons to reach the midline at E18 arise from two separated groups of cells situated medially near the superior sagittal sinus and laterally just above the rhinal sulcus. Each group forms a stratum just beneath the cortical plate. Axons from cells in intervening regions arrive at the midline approximately one day later. By the first postnatal day (P0), a second stratum of callosally projecting cells can be identified superficial to the first. Callosal axons grow out from this stratum in the same sequence as those from the deeper stratum, axons from medial and lateral regions preceding those from intervening regions. [3H]thymidine labeling of animals later injected with HRP, indicates that callosal cells in the deep stratum enter their final mitosis at E15 and those in the superficial stratum at E16. Growing callosal axons have identifiable growth cones and filopodia at their tips but, as far as they could be traced, the axons do not branch. They grow orthogonal to radial glial processes of the cerebral hemisphere and diverge early from simultaneously outgrowing corticofugal axons directed to subcortical sites, as though following separate cues. Callosal axons advancing from one side grow directly into the path taken by those advancing from the other side.

"Pseudo-conduction block" in a patient with vasculitic neuropathy.

A 63-year-old man presented with progressive asymmetric weakness and numbness in his hands of 2 weeks duration. Nerve conduction studies showed low amplitude motor evoked potentials of both median nerves. The right ulnar, left tibial and peroneal nerves had normal potentials on distal stimulation with markedly decreased amplitudes proximally, suggestive of "conduction block". Three weeks later, amplitudes were decreased throughout. The patient was diagnosed with vasculitis. The acute ischemic injury presumably resulted in axonal damage between the distal and proximal stimulation sites, with subsequent Wallerian degeneration.

Neuromuscular junction toxicity with tandutinib induces a myasthenic-like syndrome.

BACKGROUND: Tandutinib (MLN 518, Millennium Pharmaceuticals, Cambridge, MA) is an orally active multitargeted tyrosine kinase inhibitor that is currently under evaluation for the treatment of glioblastoma and has been used in the treatment of leukemia. In prior clinical and animal studies, a dose-dependent muscular weakness has been observed with this drug, though the etiology of the weakness has not been defined. METHODS: Standard neurophysiologic techniques, including repetitive nerve stimulation, needle EMG, and single-fiber EMG, were used to evaluate patients who developed weakness while being treated with tandutinib and bevacizumab (Avastin, Genentech, South San Francisco, CA) for glioblastoma (NCT00667394). RESULTS: Six patients were observed to develop a reversible weakness that correlated with the administration of the tandutinib. The onset of weakness after starting tandutinib occurred within 3 to 112 days and in less than 15 days in 3 patients. Electrophysiologic studies showed that all patients developed abnormal repetitive nerve stimulation studies. Four patients had short duration motor unit potentials. Two of these patients also had abnormal single-fiber EMG, as did a third patient who did not have standard needle EMG. The clinical and electrophysiologic abnormalities improved with the termination or reduction in the dose of tandutinib. CONCLUSION: These observations suggest that tandutinib is toxic to the neuromuscular junction, possibly by reversibly binding to a molecule on the postsynaptic acetylcholine receptor complex. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that tandutinib 500 mg twice daily induces reversible muscle weakness and electrophysiologic changes consistent with neuromuscular junction dysfunction.

Excitation of lumbar motoneurons by the medial longitudinal fasciculus in the in vitro brain stem spinal cord preparation of the neonatal rat.

1. The excitation of lumbar motoneurons by reticulospinal axons traveling in the medial longitudinal fasciculus (MLF) was investigated in the newborn rat using intracellular recordings from lumbar motoneurons in an in vitro preparation of the brain stem and spinal cord. The tracer DiI (1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine) was introduced into the MLF of 6-day-old littermate rats that had been fixed with paraformaldehyde to evaluate the anatomic extent of this developing pathway. 2. Fibers labeled from the MLF by DiI were present in the cervical ventral and lateral white matter and a smaller number of labeled fibers extended to the lumbar enlargement. Patches of sparse terminal labeling were seen in the lumbar ventral gray. 3. In the in vitro preparation of the brain stem and spinal cord, MLF stimulation excited motoneurons through long-latency pathways in most motoneurons and through both short-(< 40 ms) and long-latency connections in 16 of 40 motoneurons studied. Short- and longer-latency components of the excitatory response were evaluated using mephenesin to reduce activity in polysynaptic pathways. 4. Paired-pulse stimulation of the MLF revealed a modest temporal facilitation of the short-latency excitatory postsynaptic potential (EPSP) at short interstimulus intervals (20-200 ms). Trains of stimulation at longer interstimulus intervals (1-30 s) resulted in a depression of EPSP amplitude. The time course of the synaptic depression was compared with that found in EPSPs resulting from paired-pulse stimulation of the dorsal root and found to be comparable. 5. The short-latency MLF EPSP was reversibly blocked by 6-cyano-7-nitroquinoxaline (CNQX), an antagonist of non-N-methyl-D-aspartate glutamate receptors, with a small CNQX-resistant component. Longer-latency components of the MLF EPSP were also blocked by CNQX, and some late components of the PSP were sensitive to strychnine. MLF activation of multiple polysynaptic pathways in the spinal cord is discussed.

H-reflexes of different sizes exhibit differential sensitivity to low frequency depression.

The amplitude of the H-reflex declines when activated repetitively. The magnitude of decline is greater when the amplitude of the H-reflex is small. To explore whether pre- or postsynaptic factors contribute to the differences observed in H-reflexes of different sizes, changes in the amplitude of H-reflexes of different sizes were measured during a train of stimulation in 10 normal subjects. Amplitudes of different sizes were obtained using differing stimulus intensities or during superimposed contraction, two manipulations which differently affect the number of active afferents and the excitation of the motoneuron pool. Small amplitude H-reflexes depressed to a lower plateau than larger H-reflexes and superimposed contraction did not alleviate the depression during each train. Nearly all the decline in larger amplitude H-reflexes occurred in a component that was in common with smaller amplitude H-reflexes. This suggests that the depressibility of the earliest activated units is greater than later activated units in H-reflexes and that the magnitude of decline is affected by prior activity as well as size.